The prognosis for children with high-risk neuroblastoma is often poor and survivors can suffer from severe side effects. Predictive preclinical models and novel therapeutic strategies for high-risk disease are therefore a clinical imperative. However, conventional cancer cell line-derived xenografts can deviate substantially from patient tumors in terms of their molecular and phenotypic features. Patient-derived xenografts (PDXs) recapitulate many biologically and clinically relevant features of human cancers. Importantly, PDXs can closely parallel clinical features and outcome and serve as excellent models for biomarker and preclinical drug development. Here, we review progress in and applications of neuroblastoma PDX models. Neuroblastoma orthotopic PDXs share the molecular characteristics, neuroblastoma markers, invasive properties and tumor stroma of aggressive patient tumors and retain spontaneous metastatic capacity to distant organs including bone marrow. The recent identification of genomic changes in relapsed neuroblastomas opens up opportunities to target treatment-resistant tumors in well-characterized neuroblastoma PDXs. We highlight and discuss the features and various sources of neuroblastoma PDXs, methodological considerations when establishing neuroblastoma PDXs, in vitro 3D models, current limitations of PDX models and their application to preclinical drug testing. One of the main reasons for the high attrition rate in oncology drug development is a lack of preclinical models that recapitulate the genotype and phenotype of the patient’s disease. Xenografts based on conventional cancer cell lines have been used for decades and while this model system can provide valuable data, cultured cell lines that have adapted to the in vitro microenvironment often differ from the original tumor found in patients. Specifically, the addition of fetal calf serum to the culture medium can lead to cellular differentiation and significant genetic aberrations  are generated from the subcutaneous or orthotopic implantation of intact patient tumor fragments directly into immunodeficient mice or rats, thereby avoiding in vitro adaptation. The concept of PDXs has been around for decades but interest in PDXs has recently increased due to greater insights into the limitations of classical xenografts and the development of personalized cancer medicines based on genomic profiling. Thus, PDXs have been established and characterized for various malignant tumor types including breast cancer, malignant melanoma, colorectal cancer, pancreatic adenocarcinoma, non-small cell lung cancer and more   implemented the Pediatric Preclinical Testing Program (PPTP), which generated hundreds of pediatric subcutaneous tumor xenografts including neuroblastomas. Importantly, many of these xenografts were established at relapse following multi-modal chemotherapy. Several anti-cancer agents have been tested in the PPTP using in vivo and in vitro models and the effects of some of these agents are consistent with their known clinical activity , neuroblastoma protein markers , cellular differentiation status and proliferative index of their corresponding patient tumors. In contrast to many conventional cell-derived xenografts, PDOXs invade the surrounding tissues. Importantly, PDOXs spontaneously metastasize to the liver, lungs and bone marrow  through implantation of either fresh or viably cryopreserved naïve and relapsed high-risk neuroblastoma tumor fragments , the Targeting Of Resistance in PEDiatric Oncology program , the IMI2 ITCC-P4 program (http://cordis.europa.eu/project/rcn/210764_en.html) and the recently established NCI-funded Pediatric Preclinical Testing Consortium  are other programs that aim to establish and characterize pediatric PDXs. In addition, The EuroPDX consortium, although mainly focused on adult cancers, has started to include pediatric PDXs (http://www.europdx.eu/).The Childhood Solid Tumor Network (CSTN) at St Jude Children’s Research Hospital has established and characterized a number of pediatric cancer PDXs including neuroblastoma PDOXs. These PDOXs have undergone comprehensive molecular characterization including genomic and epigenomic analyses as well as drug sensitivity testing using short-term cultured cells , or tumor stroma, is critical for cancer progression, metastasis and treatment resistance  tumor cells in serum-free medium requires more experience, patience and time compared to classical serum-cultured cell lines. However, in light of the aberrant changes seen in serum-cultured cells and the preservation of molecular features in cells cultured in 3D in serum-free medium, we believe that this is well worth the effort. Furthermore, 3D-cultured human tumor cells provide a means to implement the important principles of the 3Rs  to minimize animal experimentation.Despite the promise of PDX models, they also have their limitations: (1) an abnormal immune system in the host mice, (2) the murine tumor microenvironment and (3) tumor heterogeneity. First, athymic nude mice lack functional T cells, NOD-scid mice lack functional T and B cells, while the NOD-scid-gamma (NSG) strain lack functional T, B and NK cells. The immunosuppressed status of these mice precludes immunotherapy testing until methods have been established to reconstitute the human immune system in the animals. It is conceivable that other therapeutic strategies also affect immune cells, a parameter not included in xenograft studies. Attempts are being made to reconstitute the human immune system in mice by injection of human hematopoietic stem cells  contain various subclones with different genotypes resulting in intratumoral heterogeneity , MAPPYACTS , SMPaeds, iTHER and INFORM , the IMI2 ITCC-P4 program (http://cordis.europa.eu/project/rcn/210764_en.html) and the EU funded Targeting Of Resistance in PEDiatric Oncology program . Genomics analyses of relapsed neuroblastomas indicate that such treatments could include inhibition of ALK and the RAS-MAPK pathway, YAP inhibition and/or pathways involved in EMT  are stored in ice-cold medium and cryopreserved through stepwise cooling in cryopreservation medium. These cryopreserved and viable samples can be stored and/or shipped on dry ice to another laboratory for implantation. We have previously shown that it is feasible to establish PDOXs from cryopreserved high-risk neuroblastoma samples (Braekeveldt et al. Clearly, establishing additional neuroblastoma PDXs from relapsed or post-mortem tumors would be very useful for testing therapies against treatment-resistant disease. Collection and injection of circulating tumor cells can also add value to the PDX model system (Girotti et al. Non-dissociated tumor fragments are commonly utilized to establish and serially propagate PDXs. As discussed above, cell culturing can lead to molecular and phenotypic deviations from the original patient tumor (Baysan et al. There is a possibility of contamination of tumor cells. First, patient tumor cell cultures can easily be contaminated with EBV-infected B lymphoblasts from the same patient tumor sample. Unfortunately, proliferative EBV lymphoblasts can, after prolonged culturing or in vivo growth, completely overgrow the tumor cells (Bondarenko et al. The site of implantation/injection will affect the features of established tumors. In experiments comparing subcutaneous injection of neuroblastoma cells versus orthotopic injection into the adrenal gland, orthotopic tumors retained a more relevant biological phenotype and spontaneous metastases to distant organs (Khanna et al. Not all patient tumor samples engraft in mice. The tumor engraftment rate using orthotopic implantations is around 50% (Braekeveldt et al. A final issue relates to the choice of mouse strain. Traditionally, patient samples have been implanted into athymic nude mice or scid mice to establish patient xenografts. We and others utilized severely immunodeficient NSG mice lacking T, B and NK cells, based on the assumption that these mice are more permissive to tumor engraftment due to their immunosuppressed status. Indeed, injection of patient-derived malignant melanoma cells results in much higher engraftment in NSG mice compared to NOD-scid mice (Quintana et al. There are a number of methodological issues regarding the establishment and use of PDXs as preclinical neuroblastoma models. Here, we discuss eight important issues that researchers using or intending to use these models might wish to consider.Subcutaneous and orthotopic neuroblastoma PDXs have been established at various institutions internationally and these PDXs retain the molecular and phenotypic features of patient tumors. Furthermore, neuroblastoma PDOXs retain robust spontaneous metastatic capacity and are therefore excellent models for targeting neuroblastoma metastasis. PDXs from various tumor types can predict clinical outcome, making them extremely good models for biomarker and preclinical drug development. Neuroblastoma PDXs might thus play an important role for personalized and precision medicine strategies against treatment-resistant disease, especially given our recent understanding of the genomic changes associated with relapsed neuroblastomas. However, establishing and characterizing additional PDXs from high-risk and relapsed tumors is crucial to cover the different biological subsets of high-risk neuroblastoma. Furthermore, initiation of a global clinical academic collaboration to include and share all existing neuroblastoma PDXs would increase the utility of these promising models. Despite their limitations, neuroblastoma PDXs hold promise to improve the treatment of children with high-risk metastatic neuroblastoma.


A 32-year-old female with a history of cholecystectomy three years prior, presented to the emergency department with epigastric pain. Liver function tests (LFTs) were abnormal , however ultrasound (US) imaging was negative for gallbladder pathology and the patient was discharged home with normal vital signs and instructed to follow up in two days if symptoms persisted. At her follow up visit, her LFTs worsened  and the patient underwent a magnetic resonance cholangiopancreatography (MRCP) which showed a dilated common bile duct (CBD) with filling defect suspicious of stone . The patApproximately 5% of patients who have undergone cholecystectomy continue to have symptoms of abdominal pain, vomiting, dyspepsia, loose stool, and are thought to suffer from postcholecystectomy syndrome (PCS).1CBD stones are a serious complication after cholecystectomy, therefore the diagnosis of PCS must always be considered in patients status post cholecystectomy with upper abdominal pain.What do we already know about this clinical entity?Magnetic resonance cholangiopancreatography (MRCP) identifies retained stones in patients with prior gallbladder surgery, however MRCP is not a tool readily available to emergency physicians.What is the major impact of the image(s)?Given the wealth of information provided, perhaps MRCP imaging can be incorporated as part of a routine postcholecystectomy syndrome (PCS) workup and help to limit unnecessary hospital admissions.How might this improve emergency medicine practice?MRCP imaging can help to improve diagnostic capabilities for patients suffering from PCS presenting to the emergency department.


Autism spectrum disorder (ASD) is characterized by deficits in social functioning and language and communication, with restricted interests or stereotyped behaviors. Anatomical differences have been found in the parietal cortex in children with ASD, but parietal subregions and associations between Sylvian fissure (SF) and parietal anatomy have not been explored. In this study, SF length and anterior and posterior parietal volumes were measured on MRI in 30 right-handed boys with ASD and 30 right-handed typically developing boys (7–14 years), matched on age and non-verbal IQ. There was leftward SF and anterior parietal asymmetry, and rightward posterior parietal asymmetry, across groups. There were associations between SF and parietal asymmetries, with slight group differences. Typical SF asymmetry was associated with typical anterior and posterior parietal asymmetry, in both groups. In the atypical SF asymmetry group, controls had atypical parietal asymmetry, whereas in ASD there were more equal numbers of individuals with typical as atypical anterior parietal asymmetry. We did not find significant anatomical-behavioral associations. Our findings of more individuals in the ASD group having a dissociation between cortical asymmetries warrants further investigation of these subgroups and emphasizes the importance of investigating anatomical relationships in addition to group differences in individual regions.


Sunitinib, a multityrosine kinase inhibitor, is currently the standard first-line therapy in metastatic renal cell carcinoma (mRCC) and is also used in treating patients with pancreatic neuroendocrine and imatinib-resistant gastrointestinal stromal tumors (GIST). Nevertheless, most patients eventually relapse secondary to intrinsic or acquired sunitinib resistance. Autophagy has been reported to contribute to both chemo-sensitivity and -resistance. However, over the last few years, controversial regulatory effects of sunitinib on autophagy have been reported. Since gaining insights into the underlying molecular insights and clinical implications is indispensible for achieving optimum therapeutic response, this minireview article sheds light on the role of a network of prosurvival signaling pathways recently identified as key mediators of sunitinib resistance with established and emerging functions as autophagy regulators. Furthermore, we underscore putative prognostic biomarkers of sunitinib responsiveness that could guide clinicians toward patient stratification and more individualized therapy. Importantly, innovative therapeutic strategies/approaches to overcome sunitinib resistance both evaluated in preclinical studies and perspective clinical trials are discussed which could ultimately be translated to better clinical outcome. Following the initial breakthrough success of imatinib, the first FDA-approved tyrosine kinase inhibitor(TKI), TKIs were deemed to revolutionize cancer therapy. Nevertheless, emergence of imatinib-resistance prompted development of novel structurally distinct TKIs  is a central player  has been linked to tumorigenesis  and Mcl-1 protein levels could serve as markers that predict sunitinib response. Additionally, elevated IncARSR levels in pre-treatment RCC patients significantly correlated with poor sunitinib response. In contrast, low IncARSR levels conferred improved progression-free survival and favorable prognosis following sunitinib therapy  Ideally, though not easily achievable in clinical practice, tailoring sunitinib dose per each patient based on their response should select patients that need escalation of sunitinib dose to reach cytotoxic effects at tolerable doses. Rovithi et al. showed that an alternating schedule of high sunitinib efficiently impaired tumor growth (ii) Alternatively, pharmacological targeting of Mcl-1 and mTOR presents a promising strategy in combating/reversing sunitinib resistance. It is worth mentioning that FDA has already approved sequential treatment of sunitinib-resistant mRCC patients with everolimus, mTOR inhibitor. In addition, a phase I clinical trial aiming at determining the highest tolerable dose of “sunitinib and temsirolimus (mTOR inhibitor)” combination that could be administered to mRCC patients has lately been completed. There are also parallel clinical trials testing the efficacy of sorafenib in treating sunitinib-resistant mRCC and GIST patients. Yet, the clinical outcome of combining sunitinib and Mcl-1 and/or mTOR inhibitor in sunitinib-resistant patients remains to be investigated. Consistent with the emerging role of MET and AXL signaling in mediating sunitinib resistance, combining a small molecule inhibitior of both MET and AXL, BMS777607, with sunitinib both suppressed the growth of sunitinib-resistant RCC xenografts and prevented the emergence of sunitinib resistance  and lysosomal dysfunction (owing to sunitinib sequestration and hence inactivation). Both events acted as pro-survival adaptive responses that compromised the anticancer activity of sunitinib. Conversely, cytotoxic sunitinib levels destabilized Mcl-1, inhibited mTORC1 and activated autophagy. Hence, this may mechanistically resolve the previously described discrepancy in terms of “ON/OFF” autophagy regulation by sunitinib. Gaining deeper mechanistic insights into sunitinib resistance would provide better prognostic biomarkers that could guide clinicians toward patient stratification and more individualized therapy. Importantly, this would offer more innovative therapeutic strategies/approaches to overcome sunitinib resistance which could ultimately be translated to a better clinical outcome.AKA conceived and wrote the manuscript. ABA, SS, SM, and ME revised the manuscript. SM and ME reviewed the outline and content of the manuscript. All authors have read and approved the submitted manuscript for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Reinforcement learning involves flexible adaptation towards a changing environment and is driven by dopaminergic reward prediction error  – expectation (Q)) signaling in the midbrain and projecting regions, such as the ventral striatum . Schizophrenia patients show heightened dopamine levels in the striatum  as well as deficits in reinforcement learning  which may be mediated by disrupted prediction error signaling . Using model-based fMRI, the present study aims to assess these neural signals during a reversal learning paradigm in unmedicated schizophrenia patients and healthy individuals.In the current study, 19 schizophrenia patients and 23 age- and gender-matched healthy controls completed a reversal learning paradigm  during fMRI scanning where subjects had to choose between two neutral stimuli to maximize their reward. A Rescorla Wagner learning model  was fitted against the individual choice data using a softmax function. Individual RPE trajectories from the fitted Rescorla Wager learning model were correlated with the BOLD response during feedback onset. Parameter estimates of ventral striaral RPE trajectories were correlated with psychopathology scores from the PANSS .In the reversal learning task, schizophrenia patients chose the correct stimulus less often compared to healthy individuals . Across all participants, the RPE trajectories correlated with BOLD response in the bilateral ventral striatum . Schizophrenia patients displayed decreased RPE coding in the right ventral striatum compared to healthy individuals . In patients, extracted parameter estimates from the right ventral striatum correlated negatively with the PANSS total symptoms score .We found that unmedicated schizophrenia patients performed worse in the reversal learning task and displayed decreased striatal prediction error signaling. This neural deficit was increased in patients with overall higher symptom severity. While RPE coding seems to be intact in patients receiving antipsychotic medication , our findings are in line with previous studies in unmedicated schizophrenia patients . Therefore, deficient neural coding of this core reinforcement learning mechanism may reflect a characteristic of the disorder of schizophrenia and does not result from antipsychotic medication.


Following a stroke, the resulting lesion creates contralateral motor impairment and an interhemispheric imbalance involving hyperexcitability of the contralesional hemisphere. Neuronal reorganization may occur on both the ipsilesional and contralesional hemispheres during recovery to regain motor functionality and therefore bilateral activation for the hemiparetic side is often observed. Although ipsilesional hemispheric reorganization is traditionally thought to be most important for successful recovery, definitive conclusions into the role and importance of the contralesional motor cortex remain under debate. Through examining recent research in functional neuroimaging investigating motor cortex changes post-stroke, as well as brain-computer interface (BCI) and transcranial magnetic stimulation (TMS) therapies, this review attempts to clarify the contributions of each hemisphere toward recovery. Several functional magnetic resonance imaging studies suggest that continuation of contralesional hemisphere hyperexcitability correlates with lesser recovery, however a subset of well-recovered patients demonstrate contralesional motor activity and show decreased functional capability when the contralesional hemisphere is inhibited. BCI therapy may beneficially activate either the contralesional or ipsilesional hemisphere, depending on the study design, for chronic stroke patients who are otherwise at a functional plateau. Repetitive TMS used to excite the ipsilesional motor cortex or inhibit the contralesional hemisphere has shown promise in enhancing stroke patients' recovery. Stroke remains a leading cause of long-term disability  , Action Research Arm Test (ARAT), and Stroke Impact Scale (SIS) ], saw significant motor gains associated with increased ipsilesional M1 recruitment with their experimental group as compared to control (Ramos-Murguialday et al., Reasons for the differences found in the BCI studies probably relate to the BCI/BMI designs and the patient exclusion criteria. For instance, Young and Song recruited patients with a greater range of severity of motor impairments than Ramos (Ramos-Murguialday et al., Overall, multiple BCI studies have found improved motor function for the severely impaired stroke patient correlated with contralesional M1 recruitment (Song et al., TMS therapy can inhibit or excite targeted brain regions, and applications of this technique may encourage stroke rehabilitation Hallett,  without Another method to regain interhemispheric balance and improve recovery is to excite the ipsilesional side with TMS (Talelli et al., A few studies have compared inhibiting the contralesional hemisphere to exciting the ipsilesional side through rTMS although the results remain inconclusive. Khedr et al.  comparedMajor factors influencing unilateral recovery post-stroke appear to include chronicity, as well as lesion size and location. Increases in unilateral ipsilesional M1 activation for movement on the affected side appears to positively correlate with chronicity, especially for well-recovered patients (Ward et al., BCI training demonstrates potential in assisting with motor recovery for stroke sufferers who have reached a functional plateau following traditional rehabilitation. Evidence suggests that this therapy, even for chronic stroke sufferers, may induce neuromodulatory changes that enhance motor function. Both BCI designs that demonstrate development of the contralesional M1, as well as designs that increase ipsilesional M1 activity, appear to enhance motor recovery. It is currently unclear if either type of BCI design is superior to the other for all, or certain subsets of, patients.Meanwhile, TMS is an effective and safe tool for research into this field and offers promising potential to be utilized for rehabilitation. TMS studies confirm that increased contralesional M1 activity as compared to the ipsilesional M1 is associated with lesser clinical outcome. Some TMS research suggests that for some well-recovered stroke patients contralesional corticomotor excitability does not decrease, but rather only the ipsilesional corticomotor excitability increases with recovery (Stinear et al., Both inhibition of the contralesional side and excitation of the ipsilesional side appear effective for motor recovery post-stroke. A few studies suggest that contralesional inhibition may be slightly more effective than ipsilesional M1 excitation although this is not seen throughout the literature. Initial degree of motor impairment and chronicity (Rose et al., Current evidence favors ipsilesional M1 excitation and development to be the most important for stroke recovery over contralesional hemispheric recruitment. However, the contralesional side does appear to play a significant role for at least a subset of stroke patients and some research suggests that certain BCI paradigms targeting the contralesional hemisphere may be beneficial for motor recovery. It is important to note the numerous confounding variables that require more research to completely understand their effects including lesion location and size, and chronicity.KD wrote the manuscript, VN and VP reviewed and edited it, and provided key guidance.VP has a pending US patent on the closed-loop neurofeedback used for BCI-facilitated intervention, application number 12/715090. The patent was filed jointly by VP and J. Williams. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Prehistoric human activities have contributed to the dispersal of many culturally important plants. The study of these traditional interactions can alter the way we perceive the natural distribution and dynamics of species and communities. Comprehensive research on native crops combining evolutionary and anthropological data is revealing how ancient human populations influenced their distribution. Although traditional diets also included a suite of non-cultivated plants that in some cases necessitated the development of culturally important technical advances such as the treatment of toxic seed, empirical evidence for their deliberate dispersal by prehistoric peoples remains limited. Here we integrate historic and biocultural research involving Aboriginal people, with chloroplast and nuclear genomic data to demonstrate Aboriginal-mediated dispersal of a non-cultivated rainforest tree.Castanospermum australe (Fabaceae), a non-cultivated culturally important riparian tree that produces toxic but highly nutritious water-dispersed seed. We validated cultural evidence of recent human-mediated dispersal by revealing genomic homogeneity across extensively dissected habitat, multiple catchments and uneven topography in the southern range of this species. We excluded the potential contribution of other dispersal mechanisms based on the absence of suitable vectors and current distributional patterns at higher elevations and away from water courses, and by analyzing a comparative sample from northern Australia.We assembled new anthropological evidence of use and deliberate dispersal of Innovative studies integrating evolutionary and anthropological data will continue to reveal the unexpected impact that prehistoric people have had on current vegetation patterns. A better understanding of how traditional practices shaped species’ distribution and assembly will directly inform cultural heritage management strategies, challenge “natural” species distribution assumptions, and provide innovative baseline data for pro-active biodiversity management. Studies of prehistoric human influences on the Australian vegetation have primarily centered around broad-scale change associated with the practice and cessation of Aboriginal burning , 2] and and2] anLivistona mariae in central Australia ..C. austrCastanospermum australe (black bean) is distributed along coastal eastern Australia, from Cape York to subtropical northern New South Wales . ). Castanredation . These credation , as wellredation .Our sampling strategy within the context of local Aboriginal dispersal focused on sites representing the species’ southern distributional margin in northern New South Wales  and was not intended to exhaustively represent all populations to explore continent-wide connectivity, or broader biogeographic questions. Sampling was undertaken under a Scientific Licence (#100569), Section 132c of the National Parks and Wildlife Services Act 1974 issued by the New South Wales Office of Environment and Heritage (sampling did not involve endangered or protected species). The objective was to ensure sufficient geographic representation across the main NNSW catchment areas in order to investigate genomic homogeneity vs. genomic heterogeneity hypotheses. Highly homogeneous maternally-inherited plastid genomes across the study area, would suggest rapid and recent dispersal from a small founder event, while plastid heterogeneity would suggest lengthier local persistence and / or multiple founder events. The focus on NNSW was influenced by the current paucity of local disperser fauna and absence of megafauna , and by Casuarius casuarius johsonii). This northern area also has an extended archaeological record of the use of C. australe’s seeds  de de26] de the AWT , 21], [, [C. aus the AWT  includinRecent mitochondrial DNA studies revealed that Aboriginal people have inhabited Australia in consistent geographic arrangements for up to 50,000 years . ContinuC. australe in NNSW  seeds as he journeyed inland from the east coast to the western Ranges . Common inheritance from the MRCA results in Bandjalangic vocabulary being inherited with only few sound changes [C. australe is uniformly bugam. This is in contrast with the rest of the distribution of C. australe where the terms exhibit little homology, even within members of the same low-level clade such as the Djirbalic languages from the AWT  is likely to be close to 1,500 years old , catchments and regions. Analyses of sequence data across 96 individual trees from 12 distinct sites yielded 987 cpDNA SNPs  and 29 nrDNA SNPs . None of these 12 sites yielded within-site cpDNA variability, suggesting that all eight individuals sampled within each population originated from a single maternal lineage. The nrDNA sequences produced between four and 12 heterozygotic variants across 5,813bp, confirming a pattern of low within-population diversity  and 5,813bp of nuclear ribosomal DNA (nrDNA) were analysed and compared among iversity .C. australe [C. australe is unlikely to favor rapid water-mediated inland expansion  and topographically complex area , and a single founder lineage would have rapidly expanded to its current distribution as habitat became increasingly available. Environmental niche models representing the availability of climatic conditions suitable to C. australe during the LGM suggest that available habitat is likely to have increased in the current interglacial period, and that environmental suitability in the south remains marginal compared to the north  cannot be excluded. However oceanic currents, tidal processes, extreme weather events or river capture cannot explain the location of multiple sites inland and well above current and historical sea level . SecondaC. australe is therefore at odds with its large, toxic and reward-free seeds. Even within the AWT, where the highest diversity of frugivorous animals persists , the high genetic divergence measured between neighbouring catchments  in collaboration with Aboriginal knowledge custodians.The new, combined evidence presented supports the deliberate dispersal of Cosgrove  suggesteEvidence of prehistoric Australian Aboriginal people dispersing plant propagules for their direct need and benefit also significantly challenges assumptions of “natural” plant distributions, requiring reassessment of distributional interpretations that omit the possible impact of prehistoric human intervention . CurrentC. australe, future studies can explore broader biogeographic questions including possible dispersal routes along eastern Australia and across the Pacific Islands. A scenario of long-distance dispersal by ancestors from the north was independently put forward by Aboriginal knowledge custodian Uncle Ron Heron Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S4 Appendix(DOCX)Click here for additional data file.S5 Appendix(DOCX)Click here for additional data file.S6 Appendix(MP4)Click here for additional data file.


The whole-genome sequences of eight fungal strains that were selected for exposure to microgravity at the International Space Station are presented here. These baseline sequences will help to understand the observed production of novel bioactive compounds. In a screening project of natural products, fungal strains isolated from environments associated with the Chernobyl nuclear power plant (ChNPP) accident  have beeAspergillus niger, an industrially important filamentous fungus, contains a sequence resembling the fumonisin gene cluster, which suggests that the fungus has the genetic potential to produce carcinogenic fumonisins   . Data frThis whole-genome shotgun project has been deposited in DDBJ/ENA/GenBank under the accession numbers given in


Patients with intractable temporal lobe epilepsy (TLE) undergo surgical resection of the anterior temporal lobe. Preoperative assessment of TLE patients involves a multidisciplinary assessment and may involve the use of invasive electroencephalogram (EEG) recording for lateralization of seizure focus in ambiguous cases. Understanding the white matter fibre tracts affected in TLE may assist in preoperative lateralization and planning. We studied pre- and postoperative white matter fibre tract changes in six patients with TLE who underwent surgical resection. Our results indicate that changes in the corpus callosum are highly specific, with the ability to lateralize the epileptogenic side in 100% of our patients (six of six). Contralateral changes were found in all patients with variable involvement of white matter tracts. Postoperatively, most patients (five of six) exhibited further changes to the tracts on the ipsilateral side, with three patients showing contralateral abnormalities. We provide a detailed assessment of pre- and postoperative white matter fibre tracts in patients with TLE and confirm that abnormalities in the ipsilateral corpus callosum may aid in preoperative lateralization and obviate the need for invasive EEG monitoring. Approximately 20% of patients with temporal lobe epilepsy (TLE) are refractory, exhibiting no response to anti-epileptic drugs . A subseThis study was approved by our Human Resources Ethics Committee via Institutional Review Board. The study included six patients with a history of epilepsy resistant to anti-seizure medication . Clinicopathological data are summarized in Table We performed whole-brain tractography using the BrightMatter™ System  neurosurgical planning system, which performs automated processing of T1-weighted anatomical images and diffusion-weighted images to perform skull-stripping, co-registration, diffusion tensor fitting, and whole brain tractography. Specific bundles were assessed through 1) modulating the tract filtering slide bars, 2) displaying tracts in specific orthogonal planes, and 3) filtering tracts according to the intersection with a surgical trajectory.Qualitative assessment was performed by the study author (FS) assessing reconstructed tracts on superimposed three-dimensional (3D) T1-weighted images and the methodology was verified by a neuroradiologist (MS). The anatomic course of each fibre was verified in axial, coronal, and sagittal planes. The healthy side was compared to the contralateral epileptogenic side. The preoperative and postoperative images and tracts were also evaluated for differences. In the postoperative patients, thinning was documented if there was additional thinning compared to the preoperative images only. Tract thinning between hemispheres was assessed by first isolating the tract using appropriate coronal or axial slices, then sweeping the tract reduction (thresholding) sliders across their extents, while assessing whether any asymmetries exist. Assessment parameters included macroscopic white matter tract dislocation or thinning. The abnormalities were documented in the ipsilateral and contralateral sides in the preoperative and postoperative images and compared.All patients underwent surgical resection following planning by a multidisciplinary team of epilepsy neurologists and neurosurgeons. Mesial temporal resection included the amygdala and anterior part of the hippocampus. Postoperative pathology was concordant with preoperative MRI findings in four patients with mesial temporal sclerosis (MTS). Two patients demonstrated non-specific gliosis.The white matter tracts evaluated for this study are the corpus callosum (CC), fornix (F), cingulum (C), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), arcuate fasciculus (AF), uncinate fasciculus (UF), inferior fronto-orbital fasciculus (IFOF), optic radiations (OR), corona radiata (CR), and corticospinal tracts (CST). Abnormalities in preoperative studies included thinning of white matter tracts on the side ipsilateral to the epileptogenic side (six patients), the contralateral side (six patients), or bilateral abnormalities (six patients) were appreciated in some tracts as specified below. The details are recorded in Table All six patients exhibited thinning and disruption of the corpus callosum in the ipsilateral side with no documented abnormalities in the contralateral side Figure . AdditioNew or further thinning and disruption of ipsilateral white matter tracts were present in four patients. Table Recent DTI studies have demonstrated abnormalities within several white matter tracts in patients with TLE . The curWe evaluated six patients with TLE who underwent resection of the mesial temporal lobe for drug-resistant epilepsy. Fiber tract thinning and asymmetry was found in both the ipsilateral and contralateral sides to the seizure focus. Assessment of pre- and post-surgical white matter fiber bundles by MR imaging tractography revealed abnormalities in all 11 tracts studied. Pre-surgically, all patients demonstrated asymmetry in the white matter tracts within their ipsilateral corpus callosum, with most patients (five of six) exhibiting ipsilateral changes in the fornix, cingulum, uncinate process, and the CSTs. The strong association of ipsilateral thinning of the corpus callosum fibers, mainly along with the described abnormalities, may provide further lateralizing information and aid in the determination of the epileptogenic side. Tractography may serve as an additional tool in the preoperative assessment of patients in whom the epileptogenic focus is indeterminate and may obviate the need for invasive EEG recording, including subdural and depth electrodes.Our findings are in keeping with previous studies that showed abnormalities in the cingulum, fornix, and corpus callosum to provide distinctive diffusion indices in patients with TLE with the ability to distinguish the pathological side . Nazem-ZPostoperative assessment of the white matter fiber tract showed the progression of preoperative abnormalities or new fiber tract abnormalities, most prominently in the OR and CR, as expected. These fibers course through the temporal lobe and surgical resection impacts the anatomy and function. Ipsilateral abnormalities in postoperative patients can be directly attributed to resection of the surgical lesion. The abnormalities were not, however, limited to the ipsilateral temporal lobe, concordant with previous findings of widespread changes in TLE patients who undergo resection . DegradaInvestigators have found more widespread contralateral and bilateral abnormalities in patients with left TLE, with more ipsilateral abnormalities in patients with right TLE . We founThe corpus callosum is a major interhemispheric tract that is essential in cognitive functions, and previous DTI studies have reported a high specificity for asymmetrical interruption of ipsilateral corpus callosum for lateralization of epilepsy. In our series, only one patient demonstrated changes to the contralateral corpus callosum postoperatively. The connections that exist between the corpus callosum and the temporal lobe may contribute to these postoperative abnormalities. Fiber tracts that originate from hippocampal formation and amygdala, which are involved in epileptogenesis and connections to other ipsilateral and contralateral anatomical structures, play an essential role in spreading neuronal activity during seizures and are altered in patients with TLE. Recently, reorganization of language tracts in the contralateral non-dominant hemisphere following resection of the anterior temporal lobe has been demonstrated , in keepThis small case series suggests the potential for the specificity of corpus callosum thinning in the ipsilateral side to the epileptogenic focus in patients with TLE for lateralization. All patients exhibited ipsilateral thinning and disruption of the corpus callosum preoperatively compared to the contralateral side. Therefore, preoperative whole brain tractography may be considered as an additional tool to complement EEG and clinical assessment in cases with an ambiguous seizure side, potentially obviating the need for invasive EEG recordings. We also demonstrated bilateral changes in pre- and postoperative patients, in keeping with the diffuse connectivity network involved in temporal lobe epileptogenesis and propagation. Further studies are underway to include inter-rater reliability assessment and correlation with quantitative evaluation.


The electrocardiogram (ECG) is an essential investigation in the evaluation of chest pain in the emergency room (ER). Correct interpretation of the ECG findings, determines the diagnosis and management strategy. This ECG spot diagnosis will improve the skills of the residents and physicians working in ER. A 46-year-old man, who was earlier in sinus rhythm, presented with anginal type of chest pain of three hours duration. The electrocardiogram recorded in emergency room (ER) is shown in The electrocardiogram shows ST segment elevation in inferior leads suggesting inferior wall myocardial infarction. The underlying rhythm is atrial fibrillation. The irregularly, irregular R-R interval coupled with the continuously varying morphology of the fibrillatory waves establishes the diagnosis of atrial fibrillation. Though the rhythm appears like atrial flutter, this is unlikely due to the above mentioned reasons. Atrial flutter is characterized by undulating sawtooth like monomorphic flutter waves and the R-R interval is regularly, irregular due to fixed heart block. The varying atrioventricular block results in long-short cycle sequences that are followed by QRS complexes with increased width 130 msec) (indicated by * in 30 msec (Atrial fibrillation complicating inferior wall myocardial infarction with intermittent ventricular premature beats.As the fast, irregular ventricular response aggravates myocardial ischemia, reverting to sinus rhythm is mandatory. Since it is a new onset atrial fibrillation, electrical cardioversion can be done safely. The patient also requires reperfusion of the infarct related coronary artery at the earliest. He underwent successful fibrinolysis and electrical cardioversion to sinus rhythm. Post cardioversion he was started on oral beta-blocker therapy. The further in hospital course was uneventful and he continued to be in sinus rhythm at 4 months of follow-up.Atrial fibrillation complicating acute myocardial infarction is associated with increased morbidity and mortality. The proposed mechanism of atrial fibrillation in acute myocardial infarction includes congestive heart failure, ischemia and infarction of the conduction system, atrial infarction or ischemia, and vagal reflexes or increased sympathetic activity . ElectriIn conclusion, electrocardiographic recognition of atrial arrhythmias is important to risk stratify acute coronary syndrome patients. Identification and prompt treatment of atrial arrhythmias improve outcomes.


Arabidopsis, treating shoots with uniconazole can result in enhanced primary root elongation and bolting delay. Uniconazole spraying has become an important cultivation technique in controlling the flowering and improving the fruit-setting of litchi. However, the mechanism by which uniconazole regulates the complicated developmental processes in litchi remains unclear. This study aimed to determine which signal pathways and genes drive the responses of litchi inflorescences to uniconazole treatment. We monitored the transcriptional activity in inflorescences after uniconazole treatment by Illumina sequencing technology. The global expression profiles of uniconazole-treated litchi inflorescences were compared with those of the control, and 4051 differentially expressed genes were isolated. KEGG pathway enrichment analysis indicated that the plant hormone signal transduction pathway served key functions in the flower developmental stage under uniconazole treatment. Basing on the transcriptional analysis of genes involved in flower development, we hypothesized that uniconazole treatment increases the ratio of female flowers by activating the transcription of pistil-related genes. This phenomenon increases opportunities for pollination and fertilization, thereby enhancing the fruit-bearing rate. In addition, uniconazole treatment regulates the expression of unigenes involved in numerous transcription factor families, especially the bHLH and WRKY families. These findings suggest that the uniconazole-induced morphological changes in litchi inflorescences are related to the control of hormone signaling, the regulation of flowering genes, and the expression levels of various transcription factors. This study provides comprehensive inflorescence transcriptome data to elucidate the molecular mechanisms underlying the response of litchi flowers to uniconazole treatment and enumerates possible candidate genes that can be used to guide future research in controlling litchi flowering.In  Litchi is an important tropical fruit widely cultivated in more than 20 countries in tropical and subtropical regions worldwide , 2. In CArabidopsis, treating shoots with uniconazole can result in enhanced primary root elongation and bolting delay , and flowering time  ] .LUG, which is a critical regulator of gynoecium marginal tissue development [AGAMOUS expression in the first two whorls of the Arabidopsis flower [LUG genes were highly induced by uniconazole treatment  controlling the development of flower have been cloned in Arabidopsis thaliana. SPT and ALC may be relevant to pistil development [AMS and DYT1 are closely related to the morphogenesis of anthers [The bHLH family includes genes regulating diverse processes of flower development. Four bHLH transcription factors Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S1 File(DOC)Click here for additional data file.S2 File(DOCX)Click here for additional data file.


We have described a myocardial infarct scar identified by a standard dual source CT coronary angiography (CTCA). We were able to detect the scar during the routine coronary assessment without contrast late enhancement and without additional radiation exposure. It is therefore feasible to assess chronic scar using a standard CTCA technique. CT coronary angiography (CTCA) has become a robust and accurate imaging modality for the non-invasive assessment of coronary vessels. It is now being widely used, particularly in the low to intermediate cardiovascular risk group for the diagnosis and assessment of coronary disease severity .It has been postulated that the data obtained from multi-detector CT (MDCT) during CTCA can also be used to quantify myocardial scar and viability but only by using delayed myocardial contrast enhancement, which involves a second, albeit low radiation dose , 3.Late gadolinium-enhanced cardiac magnetic resonance imaging (CMRI) is considered the gold standard for detection of myocardial scar and viability, and few pilot studies have reported favorable results when comparing CTCA with MRI , 3.Delayed enhancement studies usually offer more accurate information about the infarct size but at the cost of additional radiation exposure and more contrast. Cury et al demonstrated that patients with recent myocardial infarction (MI)  could be detected using a standard MDCT dataset based on the presence of a perfusion defect (hypo-attenuation) with a sensitivity and specificity of 94% and 97% [We report the case of a 63-year-old gentleman presenting with chest pain who had previously undergone multi-vessel PCI in 2005. He underwent a CTCA  in March 2013 for the evaluation of his coronary arteries as well assessment of his stents, which revealed an antero-apical, antero-lateral and infero-lateral myocardial scar and wall motion abnormalities in the same territories . The ste99mTc-sestamibi) was performed. SPECT slices and polar displays, illustrated on In view of proximal LAD lesion patient was referred for myocardial perfusion scan to assess ischemic burden. Stress (treadmill exercise + regadenoson) radionuclide myocardial perfusion imaging single photon emission CT (MPI SPECT) study with the 2 days protocol  studies. Also it may be of prognostic importance in patients with previous silent infarction and in patients presenting with atypical chest pain in whom infarct size could influence the future management. However, we need to develop a technique to improve the accuracy of scar detection on the standard CTCA dataset without the need for further contrast and radiation exposure.


American Indians experience high rates of cardiovascular diseases (CVD). Environmental tobacco smoke (ETS) has been linked to CVD, possibly due to pro-inflammatory and oxidative stress pathways. We examined the relationship between self-reported exposure to ETS and fatal and nonfatal CVD incidence using Cox proportional hazards models among 1843 non-smoking American Indians participating in the Strong Heart Study. We also evaluated potential modifying effects of several dietary nutrients high in anti-inflammatory and anti-oxidant properties with ETS exposure on fatal and nonfatal CVD by creating interaction terms between ETS exposure and the dietary variable. Participants exposed to ETS had a higher hazard  for developing CVD compared to persons not exposed. Interaction analyses suggested stronger effects of ETS on CVD incidence among those consuming diets lower in vitamin E as compared to those consuming higher amounts, particularly on the additive scale. Additional research is recommended to clarify whether public health prevention strategies should simultaneously target reductions in ETS exposures and improvements in diets that may exceed the expected benefits of targeting these risk factors separately. Exposure to environmental tobacco smoke (ETS) is one of the most important and common sources of indoor air pollution worldwide . ETS incIn general, American Indian populations experience higher rates of cardiovascular disease (CVD) and CVD-related risk factors as compared to the U.S. population as a whole . Eichner2.5 (particulate matter less than 2.5 microns in diameter), one of the constituents of ETS, has been implicated in CVD development , a sensitive and specific marker of ETS exposure with a half-life of about 3 weeks, and cotinine, the primary metabolite of nicotine are recommended. Furthermore, evaluation of subclinical cardiovascular disease endpoints  could provide more detailed insight into mechanistic pathways. Finally, assessment of diet via a food-frequency questionnaire may allow for more accurate information on long-term nutrient intake patterns.These results are limited by the use of self-reported exposure to ETS, making it impossible to distinguish between secondhand and thirdhand smoke, as well as the use of a single 24-h recall to assess diet. ETS exposure may be confounded by socio economic factors that can also be related to CVD incidence rates. To determine ETS exposure more reliably, more accurate long-term measures such as NNAL [4-, as well as the widening ethnic/racial disparities in rates of both ETS exposure and CVD-related health outcomes, there is tremendous public health relevance in understanding how long-term exposure to ETS increases risk of developing CVD and whether or not certain subgroups of the population are more susceptible. Modifying factors, such as diets, may be important targets in future interventions to complement anti-smoking campaigns.The present analysis confirms the previously observed detrimental influence of ETS exposure on cardiovascular health. The Strong Heart Study population allows for the examination of a unique population with high smoking rates but typically low doses. Our results suggest that further research  may be warranted to investigate whether consumption of diets high in certain nutrients may reduce these damaging effects. Further research is needed to clarify whether public health prevention strategies should simultaneously target both reductions in ETS exposures and improvements in diets to exceed the expected benefits of targeting these risk factors separately.


We investigated the evolution of the neurological and neuropsychological characteristics in a right-handed woman who was 53-years-old at the onset and who showed personality changes and behavioral disorders accompanied by progressive dysarthria. She had hypernasality and a slow rate of speech with distorted consonants and vowels, which progressed as motor disturbances affecting her speech apparatus increased; finally, she became mute two years post onset. Her dysarthria due to bilateral voluntary facio-velo-linguo-pharyngeal paralysis accompanied with automatic-voluntary dissociation fit the description of anterior opercular syndrome. She showed personality changes and behavioral abnormalities from the initial stage of the disease, as is generally observed in frontotemporal degeneration (FTD), and her magnetic resonance image showed progressive atrophy in the frontotemporal lobes; thus, she was clinically diagnosed with FTLD. This patient’s symptoms suggest that FTLD, including bilateral anterior operculum degeneration, causes progressive pseudobulbar paretic dysarthria accompanied by clinical symptoms of FTD, which raises the possibility of a new clinical subtype in the FTLD spectrum.


Diabetic kidney disease is the leading cause of end-stage renal failure worldwide, however current treatments remain suboptimal. Recently various plants have shown beneficial effects not only on kidney function in diabetes mellitus, but also on kidney toxicities induced by some drugs or toxins. The active substances recognized in these plants include polysaccharides, flavonoids, xanthones and peptides.Panax quinquefolium, Vitis vinifera and glycosides from Stelechocarpus cauliflorus have also been shown to protect renal damage  have been completely observed by the authors.None declared.


Bone marrow (BM) aspiration showed erythrocyte phagocytosis by macrophages (18F-fluorodeoxyglucose positron emission tomography (FDG-PET) performed for the staging showed splenic and multiple abdominal lymph node lesions and diffuse accumulation within the bones such as the vertebrae and pelvis , peripheral blood cytopaenia  has become a standard tool for the initial staging and reassessment of Hodgkin lymphoma, which is generally characterised by contiguous lymph node involvement.Haemophagocytic lymphohistiocytosis, which is the uncontrolled activation of lymphocytes and macrophages caused by various diseases including malignant lymphoma, can induce diffuse hypermetabolism in the bone marrow reflecting a systemic cytokine storm.Recognition of false-positive findings on FDG-PET is necessary for the evaluation of bone marrow involvement in order to accurately determine the stage of Hodgkin lymphoma, which requires bone marrow examination.Patients with HLH with FDG-PET images indicating multiple lymphadenopathy and/or patchy multiple bone lesions may appear to be LA-HLH with BM involvement (BMI).


Transcranial electrical stimulation (tES) uses low intensity current to alter neuronal activity in superficial cortical regions, and has gained popularity as a tool for modulating several aspects of perception and cognition. This mini-review article provides an overview of tES and its potential for modulating spatial processes underlying successful navigation, including spatial attention, spatial perception, mental rotation and visualization. Also considered are recent advances in empirical research and computational modeling elucidating several stable cortical-subcortical networks with dynamic involvement in spatial processing and navigation. Leveraging these advances may prove valuable for using tES, particularly transcranial direct and alternating current stimulation (tDCS/tACS), to indirectly target subcortical brain regions by altering neuronal activity in distant yet functionally connected cortical areas. We propose future research directions to leverage these advances in human neuroscience. Decades of empirical research have demonstrated involvement of diverse lateral and medial brain regions in spatial processing and navigation, including parietal, prefrontal and medial temporal areas  using parietal object representations  and a range of areas including retrosplenial cortex (RSC) and PCC, and secondarily to the hippocampus and parahippocampus , Figure Behavioral outcomes related to parieto-medial temporal pathway might be dissociated with outcomes of targeting the parieto-prefrontal pathway. Specifically, targeting lateral and ventral intraparietal areas might be expected to impact visuospatial spatial working memory performance, whereas targeting the cIPL may not. These types of dissociations between stimulation locations, stimulation conditions , and behavioral outcomes can help elucidate behavioral influences of each pathway, and reveal methods for altering spatial performance. Furthermore, as research reveals the oscillatory dynamics of the parieto-medial temporal pathway, frequency-specific tACS might also prove valuable for modulating network resonance and behavioral outcomes (Ali et al., People differ dramatically in spatial abilities (Hegarty and Waller, TTB conceived the review and prepared the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cannabis use has repeatedly been associated with psychotic symptoms, with persistent risks beyond the direct effects of exogenous cannabinoids. However, it remains unknown whether cannabis use during pregnancy is a causal risk factor for psychotic symptoms in the offspring, or whether this relationship is explained by shared etiological factors, such as genetic and environmental vulnerabilities. More innovative study designs are needed to address this question. Here, we examined the adverse effects of cannabis exposure during pregnancy on psychotic symptoms in pre-adolescent offspring. Such a method would help causal inference as comparisons can be made between the observed associations of maternal versus paternal cannabis use during pregnancy and the risk of psychotic symptoms in the offspring. If the association between cannabis use and psychotic symptoms is causal, early intra-uterine exposure to cannabis could potentially affect neurodevelopment and, hence, contribute to the pathogenesis of psychotic phenomena in children who have not yet used cannabis themselves.This study used data from the Generation R Study, a prospective population-based birth cohort from Rotterdam, the Netherlands. Participants were included if data on maternal cannabis use during pregnancy of offspring psychotic-like symptoms at age ten years were available (N = 3692). To determine cannabis exposure, we used prospective maternal self-reports during pregnancy and cannabis metabolite levels from urine. Paternal cannabis use during pregnancy was obtained through maternal report. At age ten years, children were queried regarding psychotic symptoms. Ordinal logistic regression was conducted to investigate whether maternal and paternal cannabis use were associated with offspring psychotic symptoms. In a secondary analysis, a distinction was made between maternal cannabis use exclusively before versus continued maternal cannabis use during pregnancy. All models were adjusted for covariates that were previously associated with cannabis use in this cohort.Maternal cannabis use was associated with an increased risk for psychotic symptoms in their offspring . Estimates were comparable for cannabis use exclusively before pregnancy versus continued cannabis during pregnancy . Paternal cannabis use was significantly associated with offspring psychotic symptoms .Using data from a large population-based birth cohort, we demonstrated that maternal and paternal cannabis use were each associated with offspring psychotic symptoms at age ten years, well before the risk period of adolescent cannabis use initiation. Notably, estimates were similar for maternal cannabis use exclusively before pregnancy versus continued cannabis use during pregnancy. Moreover, estimates were comparable for maternal versus paternal cannabis use during pregnancy. This suggests that common etiologies, rather than solely causal intra-uterine mechanisms, underlie the association between parental cannabis use and offspring psychotic symptoms, shedding potential new light on the debated causal path from cannabis use to psychosis. Our findings indicate that diagnostic screening and preventative measures need to be adapted for young people at risk for severe mental illness, and that these programs need to offer a family-focused approach.


Mild cognitive impairment is considered as the first clinical manifestation ofAlzheimer's disease (AD), when the individual exhibits below performance onstandardized neuropsychological tests. However, some subjects before having alower performance on cognitive assessments already have a subjective memorycomplaint.  A review about subjective cognitive decline, the association with AD biomarkersand risk of conversion to dementia.  We performed a comprehensive non-systematic review on PubMed. The keywords usedin the search were terms related to subjective cognitive decline.  Subjective cognitive decline is characterized by self-experience of deteriorationin cognitive performance not detected objectively through formalneuropsychological testing. However, various terms and definitions have been usedin the literature and the lack of a widely accepted concept hampers comparison ofstudies. Epidemiological data have shown that individuals with subjectivecognitive decline are at increased risk of progression to AD dementia. Inaddition, there is evidence that this group has a higher prevalence of positivebiomarkers for amyloidosis and neurodegeneration. However, Alzheimer's disease isnot the only cause of subjective cognitive decline and various other conditionscan be associated with subjective memory complaints, such as psychiatric disordersor normal aging. The features suggestive of a neurodegenerative disorder are:onset of decline within the last five years, age at onset above 60 years,associated concerns about decline and confirmation by an informant.  These findings support the idea that subjective cognitive complaints may be anearly clinical marker that precedes mild cognitive impairment due to Alzheimer'sdisease.  From the development of biomarkers that allow the detection ofb-amyloid peptide, tau protein and neuronal injury, it is known that the AD pathologyprecedes the onset of dementia by many years.,,The working group of the National Institute on Aging-Alzheimer's Association (NIA-AA)has produced new recommendations for the diagnosis of dementia due to Alzheimer'sdisease and proposed the concept of AD stages based on the model of the "amyloidcascade".,,,,This subtle cognitive decline is characterized by a self-experience of deterioration incognitive performance not detected objectively through formal neuropsychologicaltesting.We performed a comprehensive literature non-systematic review on PubMed for referencespublished between January 1990 and July 2016. The keywords used in the search were termsand words related to subjective cognitive decline: "subjective memory complaint","self-reported memory complaint", "subjective cognitive impairment", "subjectivecognitive concerns" , "Alzheimer's disease", "Alzheimer's biomarker". The search wasrestricted to articles written in English, Spanish and Portuguese language.-,,Subjective cognitive decline: what is it and what is the risk? Various terms anddefinitions have been used in the literature, such as "subjective memory complaint","self-reported memory complaint", "subjective cognitive impairment" and "subjectivecognitive concerns".-Several epidemiological studies have shown an increased risk of progression to ADdementia among individuals with subjective cognitive decline.Reisberg et al. followed 213 individuals for about seven years and found that 54.2% ofthe group with subjective cognitive impairment declined to mild cognitive impairment ordementia, compared to 14.9% among normal controls (hazard ratio 4.5).,,Some authors question whether the complaint of the individual would itself be sufficientto increase the risk of progression to dementia. This questioning arises from twoobservations: memory complaints are very prevalent in the elderly (and therefore can benonspecific) and a high prevalence of lack of insight among patients with dementiaexists. Consequently, some studies analyzed whether confirmation of cognitive decline byan informant increases the specificity and risk for progression to dementia.,However, akin to individuals with mild cognitive impairment, many with subjectivecomplaints may remain stable or even show improvement in cognition. Alzheimer's diseaseis not the only cause of subjective cognitive decline and various other conditions canbe associated with subjective memory complaints, such as normal aging, personalitytraits, psychiatric disorders and use of psychiatric drugs.,Subjective cognitive decline: how can it be identified? Although several studies haveevaluated subjective cognitive decline and its risk of progression to dementia, there isno standard on how the evaluation should be carried out. Ideally, the assessment ofsubjective cognitive decline in any study must provide balance and not be too sensitive or very specific (and therefore too restrictive).Several questionnaires and scales have been developed and applied in clinical andepidemiological studies. The most frequent self-reported measures include: QuestionnaireAgeCoDe Study,,,,As previously mentioned, not all subjective memory complaint is due to pre-clinicalAlzheimer's disease. Of other causes, mental disorders are among the most oftenassociated and therefore the evaluation of patients with subjective memory complaintmust include a neuropsychiatric inventory. However, even excluding patients who meetcriteria for a major psychiatric disorder, symptoms of depression and anxiety or morbidpersonality traits are fairly frequently observed in epidemiological studies.-Although subjective cognitive decline is defined as a complaint without detectableimpairment by standardized neuropsychological tests, a new generation of episodic memorytests has shown utility for the diagnosis of Alzheimer's preclinical disease with a goodcorrelation with subjective complaint.-Subjective cognitive decline studies in the Brazilian population. Although anincreasingly discussed topic in Cognitive Neurology, there are few studies involving theBrazilian population.In a community-based study, seventy-one healthy older adults were asked if they hadmemory complaints, filled out the Memory Complaint Questionnaire (MAC-Q) and underwent aformal test of episodic memory . Spontaneouscomplaints were associated with poor performance on the RAVLT, but not on theMAC-Q.,On the other hand, some studies have shown no correlation between worse performance oncognitive tests and the presence of subjective decline.in vivo of pathologic findings (using biomarkers) withclinical manifestations of Alzheimer's disease.,,,,-,--Alzheimer's disease biomarkers in subjective cognitive decline. In recent years, severalstudies  have been investigating thecorrelation ,Perrotin et al. compared two groups of normal elderly, one with positive PiB PET-CT andanother with negative PiB PET-CT, for subjective cognition and performance on aneuropsychological evaluation.-,Evidence also points to a correlation between subjective cognitive decline and corticalatrophy on structural MRI, especially in commonly vulnerable regions for Alzheimerdisease.-Similarly to imaging methods, studies of b-amyloid peptide, total tau and phosphorylatedtau proteins in cerebrospinal fluid (CSF) are widely used in investigations ofsubjective cognitive decline.,In addition to the biomarkers, AD has many other risk factors, but none is betterestablished than the e4 allele of apolipoprotein E (APOE). There is ample evidence thatindividuals with subjective cognitive decline have a greater frequency of expression ofthe allele, especially among those with positive biomarkers.Several studies have shown that individuals with subjective cognitive decline are atincreased risk of progression to AD dementia. According to epidemiological data, thefeatures which increase the likelihood of conversion are: onset of decline within thelast five years, age at onset above 60 years, associated concerns about decline andconfirmation by an informant. In addition, there is evidence that this group has ahigher prevalence of positive biomarkers for amyloidosis and neurodegeneration.Consequently, these findings support the idea that subjective cognitive complaints maybe an early clinical marker of pathology and help further understanding on the naturalhistory of Alzheimer's disease from pre-dementia stages. However, due to lack ofconsensus on how to define and assess subjective cognitive decline, it is still unclearwhich characteristics of subjective cognitive decline suggest the preclinical ADstage.


Meta-analysis suggest that processing speed deficit is the largest single cognitive impairment in schizophrenia. Processing speed predicts functional outcome and indicates a vulnerability marker for schizophrenia. Several authors have proposed that abnormalities in white matter is related to reduced processing speed in schizophrenia. The purpose of this research was to investigate the relationship between processing speed and structural properties of white matter pathways in schizophrenia and healthy controls.The data using this study were from the SchizConnect. Participants included 64 patients with schizophrenia and 71 healthy controls. Diffusion tensor imaging(DTI) method was used to measure fractional anisotropy along white matter tracts. Group differences in white matter integrity-inferred from fractional anisotropy (FA), processing speed, verbal memory were examined. Mediation analysis were applied to inspect the relationship between FA and cognitive performance.Participants with schizophrenia had significantly reduced processing speed, verbal memory deficits, and whole-brain fractional anisotropy deficit. There were significant group differences in white matter integrity of the left thalamus occipital, right extreme capsule, and right thalamus occipital. FA in left thalamus occipital and right extreme capsule mediated group differences in processing speed, but not other cognitive domains.Study findings indicate that mediation effect of processing speed is regional tract-specific. These finding suggest that the structural integrity of white matter tracts associated with left thalamus occipital, right extreme capsule is closely related to reduced processing speed in schizophrenia, but not verbal memory and verbal learning.


Recently, Patrick Micke and colleagues from Uppsala University have contributed an outstanding publication on the limitations to predict prognosis in non-small cell lung cancer . For thThe authors discuss several possible reasons for the negative result, one of them that global gene expression profiles may have performed better. However, despite the availability of several non-small cell lung cancer cohorts with genome-wide data an improvement over clinicopathological parameters including performance status has not yet been demonstrated. A possible reason not discussed by the authors is that tumor tissue used for biomarker or genome-wide expression analysis was taken by surgery soon after diagnosis, while metastasis occurs usually years later. Eventually, biomarker expression undergoes changes during this period and the surgically obtained tumor tissue may no longer be sufficiently representative of the tumor that finally progresses and leads to death.Currently, numerous studies are performed in several tumor entities aimed to predict prognosis (Selinski et al., 2017; Hellwig


Most retroperitoneal tumors such as renal cell carcinoma have been associated with tumor thrombus extending into the renal vein, inferior vena cava (IVC), and heart. The retroperitoneal metastatic potential of testicular tumors is well known. We report here the first instance of a cardiac murmur prompting diagnosis of metastatic testicular neoplasia in an 18-year-old patient. Chemotherapy was delayed and after successful surgical resection of the ventricular mass, the patient recovered uneventfully. This case underscores the need to pursue abnormal cardiac exams in newly diagnosed testicular cancer patients.


Phonologically similar items  are more difficult to remember than dissimilar items , likely because of mutual interference of the items in the phonological store. Low-frequency transcranial magnetic stimulation (TMS), guided by functional magnetic resonance imaging (fMRI) was used to disrupt this phonological confusion by stimulation of the left inferior parietal (LIP) lobule. Subjects received TMS or placebo stimulation while remembering sets of phonologically similar or dissimilar pseudo-words. Consistent with behavioral performance of patients with neurological damage, memory for phonologically similar, but not dissimilar, items was enhanced following TMS relative to placebo stimulation. Stimulation of a control region of the brain did not produce any changes in memory performance. These results provide new insights into how the brain processes verbal information by establishing the necessity of the inferior parietal region for optimal phonological storage. A mechanism is proposed for how TMS reduces phonological confusion and leads to facilitation of phonological memory.


The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migratory capacity, which is available for metastatic cancer targeting. Prodrug activating enzyme or anticancer cytokine expressing stem cells successfully inhibited the proliferation of cancer cells. Preclinical models have clearly demonstrated anticancer activity of these two platforms against a number of different cancer types and metastatic cancer. Several systems using therapeutic stem cells or oncolytic virus have entered clinical trials, and promising results have led to late stage clinical development. Consequently, metastatic cancer therapies using stem cells and oncolytic viruses are extremely promising. The following review will focus on the metastatic cancer targeting mechanism of therapeutic stem cells and oncolytic viruses, and potential challenges ahead for advancing the field. Cancer metastasis, which is a multiple process in which malignant cells spread from the primary site to colonize distant organs, is one of the greatest challenges in cancer treatment. Although metastasis is responsible for more than 90% of cancer associated mortality, it is difficult to diagnose and treat . For manConventional strategies of cancer therapy, including surgical resection, chemotherapy, radiotherapy and immunotherapy, have made significant contributions to cancer treatment. However, many people suffer from side-effects such as insufficient anti-cancer effects that involve drug resistance and systemic adverse reactions due to off target effects . For exaA mechanistic understanding of the metastatic process is important to development of anti-metastatic therapies that could reduce patient mortality. The metastatic process is initially derived from gene mutations that correlate with proliferative ability. Cells in normal tissues only divide when they receive growth stimulatory signals from other cells and stop dividing when they receive growth inhibitory signals; however, gene mutations providing the ability to be split ignore these signaling factors . AdditioIn this review, we will discuss recent strategies for the treatment of metastatic cancer based on stem cells and oncolytic viruses. Many stem cells have intrinsic tumor tropic properties that originate from chemokine interactions with cancer cells. Using this property, we can make a specific delivery system of anticancer molecules. Stem cells can migrate towards tumor microenvironments and eliminate tumors, enabling site specific delivery. Furthermore, stem cells can be modified to stably express various anticancer agents including cytokines and prodrug activating enzymes for induction of cancer apoptosis and removal of specific tumors. In addition, oncolytic viruses are a therapeutically useful system that can be used to selectively infect and damage tumor tissues without off target effects on normal tissues. Each virus has a specific cellular tropism that determines which tissues are preferentially infected. Viruses then increase in the tumors and destroy them, after which they infects another tumor cell. Viral oncotherapy can also be modified to increase tumor selectivity and enhance oncolytic activity. For example, some viruses have been modified to express capsid proteins that bind with specific cancer types and conditionally express the genes involved with the activation of host immune system. These two strategies will be able to complement the drawbacks of conventional cancer therapy.via stem cell engineering. Other signaling pathways have been found, including urokinase type plasminogen activator (uPA) - uPA receptor (uPAR) and vascular endothelial growth factor receptor 2 (VEGFR2) [Stem cells can trace cancer cells and tumor regions, which makes them very useful for tracing metastatic cancer and carrying anti-metastatic molecules. Various chemokine-chemokine receptor interactions are important to recognition of tumor cells and tumor tropism of stem cells. Stromal cell derived factor 1 alpha (SDF-1α) and its receptor, CSC chemokine receptor 4 (CXCR4), have been identified as key molecules responsible for the tropism of stem cells in many cancers . Accordi(VEGFR2) , 18. Thevia activation of JNK/activation protein-1 and stimulated the secretion of both tumor necrosis factor alpha and interferon gamma, which ultimately activated the caspase 3/7 pathway [Stem cells have intrinsic antitumor effects that occur through various factors secreted by stem cells and physical interactions of stem cells with tumor cells , 20. How pathway , 26. Neu pathway . In addi pathway . Using c pathway . Interfe pathway , 31. Sec pathway  as shownvia the bystander effect. Cytosine deaminase (CD) and 5-fluorocytosine (5-FC) are well-known suicide gene systems. E. coli cytosine deaminase can convert a prodrug, 5-FC, into its active drug, 5-FU. The metabolite of 5-FU (fluorodeoxyuridine monophosphate) binds to the nucleotide binding site of the thymidylate synthase and dNTP in tumor cells becomes imbalanced, which can cause DNA damage and cell apoptosis [Stem cell mediated suicide gene therapy is another strategy for killing tumor cells. Stem cells are engineered to express an enzyme that converts a non-toxic prodrug into a cytotoxic drug that can efficiently kill tumor cells poptosis . In addipoptosis . The CD-poptosis , 36. In poptosis . Furtherpoptosis  , which is one of the fusogenic membrane glycoproteins (FMGs) in neural stem cells, is a notable strategy for targeting tumor microenvironments . VSV-G eCancer treatments using stem cells have made improvements in regards to specific targeting of tumors, but a few obstacles must still be overcome prior to clinical application. The main concern is tumorigenicity of the stem cell and cell fate after systemic administration. To prevent therapeutic stem cells from forming tumors or aberrantly differentiating in the host, the tumorigenicity or differentiation potential should be tested in preclinical models. In addition, immortalized stem cells with therapeutic gene inserts may solve the difficulty of mass culture of stem cells and enable their stability in tumors. Therefore, it is important to develop a new strategy for mass culture of stem cells to ensure the ability of a suicide gene to perfectly eliminate stem cells after therapy. Therapeutic modifications could adversely affect the safety of stem cells. Therapeutic stem cells or secreted proteins interrupt host tolerance to self-antigens, which provokes additional complications in the patient and immune responses that might impair therapy. Improvement of stem cell specificity through detailed investigations of tumor tropism could relieve possible side effects.The idea of oncolytic virotherapy originates from clinical reports of cancer regression caused by viral infection and is currently being developed by genetically modifying viruses for the selective infection and destruction of cancer cells .The specificity of oncolytic viruses for tumors is very important to clinical trials. Many viruses have a natural specific tissue tropism for cell surface proteins that are overexpressed by cancer cells. This characteristic is very useful for metastatic cancer tracing. For example, measles virus recognizes the surface receptor CD46 (complement regulatory protein) for cell infection. CD46 is a cofactor for inactivation of complement components that is often overexpressed in cancer cells . Herpes in vitro by at least ten-fold. These data suggest an improved safety of Ad 5/3 in the setting of malignant glioma [Oncolytic viruses can be engineered to directly bind to unique surface molecules of cancer cells. This modification could assign additional specificity for metastasized tumor cells by improving infection of tumor tissues and decreasing infection of healthy tissues. This specificity can be achieved by modifying or combination protein of virus that require for cancer cell recognition. For example, glioma cells overexpress CD16 and CD80/86, which bind with adenovirus serotype 3 , 48. Bast glioma . The adet glioma . Other et glioma .Another strategy is a tumor specific transcriptional targeting using tumor specific promoters and microRNA target sequences. This strategy can restrict virus replication in off-target tissues. For example, adenovirus replication is correlated with their ability to promote cell cycle entry into the G1 phase through the viral immediate early protein E1A. Therefore, tumor specificity is achieved by placing the E1A gene under transcriptional regulation of a tumor specific promoter , CXCR4 iAfter oncolytic virus infection, cancer cells are destroyed by lysis. However, various strategies have been studied to achieve the maximum therapeutic efficacy for tumor cells. The therapeutic efficacy of oncolytic viruses can be enhanced using strategies that enable immunostimulatory factors to induce innate and adaptive immune responses against tumors. One successful strategy is the expression of granulocyte macrophage colony stimulating factor (GM-CSF), which stimulates stem cells to produce granulocytes and monocytes and stimulates adaptive immunity against tumor associated antigens . T-VEC iTransfer of metastatic suppressor genes or targeting metastasis related molecules is an effective strategy of targeting metastatic cancer. One of the tumor suppressor proteins, KAI1, plays a key role in downregulation of epidermal growth factor receptor (EGFR) signaling, which is associated with increased receptor desensitization and endocytosis . An adenSeveral studies have also explored the possibility of combining oncolytic viruses with stem cells to improve delivery . The theThe development of oncolytic viruses as therapeutic agents for metastatic cancer requires careful attention to establish appropriate clinical trial designs, as well as dosing regimens to minimize possible side effects. The most important technical challenge to overcome is the need to enhance tumor selectivity to decrease off target effects after systemic delivery of the oncolytic virus. The other major obstacle to successful application of viral therapy is neutralization of the virus by the host antibody. Many species of viruses are used in oncolytic virotherapy, and most people have already been exposed to the virus through previous vaccination or infection. Therefore, circulating antibodies can inhibit the oncolytic virus before it reaches the tumor site. Immune suppression agents and the aforementioned stem cell transport strategy is currently being investigated to solve this problem.Metastasis of cancer is one of the main factors leading to patient death. The unique properties of metastatic cancer, including their small size, high multiplicity and spread to multiple organs make it difficult to treat. Although conventional cancer treatment strategies have shown a lot of progress, they have been limited in metastatic cancer by recurrence of cancer, induction of drug resistance and systemic side effects after treatment. Accordingly, new strategies are needed to treat metastatic cancer.Stem cell based and oncolytic virus strategies have many potential benefits. Stem cell based therapies are emerging as promising strategies to treat metastatic cancer. Multiple types of stem cells have been shown to exhibit natural tropism towards tumors. In addition, when engineered to express therapeutic agents including prodrug activation enzymes, cytokines and oncolytic viruses, these vehicles can deliver treatments to target sites of metastasized tumor lesions and effectively kill the cancer cell. Many metastatic cancer models have shown therapeutic stem cells to be safe and effective. In addition, clinical trials using promising therapeutic stem cells are under investigation and summarized in Table via oncolytic virus particle modification, serotype changes and use of tumor specific activated promoters. Application of improved oncolytic viral constructs that can be delivered systemically or intratumorally will lead to effective treatments for metastatic cancer patients. Table Oncolytic virotherapy has rapidly advanced in a relatively short period through virological studies. In the early stage, oncolytic viruses destroyed tumors by their oncolysis ability alone; however, transduction of therapeutic transgenes and combination with other anti-tumor agents has enhanced the potency of the oncolytic virus platform. In addition, tumor selectivity has progressed Despite these advances, additional research is needed to develop safer strategies and a lot of validation is required before preclinical models can be applied to humans. By understanding of metastatic processes and biological mechanisms that specifically drive each step of metastasis, we can develop more advanced therapeutic stem cells and strategies of oncolytic virotherapy, which are highly promising approaches to the treatment of metastatic cancer.


Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment option for both malignant and some benign hematological diseases. During the last decade, many of the newer high-dose regimens in different intensity have been developed specifically for patients with hematologic malignancies and solid tumors. Today there are three main approaches used prior to allogeneic transplantation: Myeloablative (MA), Reduced Intensity Conditioning (RIC) and Non-MA (NMA) regimens. MA regimens cause irreversible cytopenia and there is a requirement for stem cell support. Patients who receive NMA regimen have minimal cytopenia and this type of regimen can be given without stem cell support. RIC regimens do not fit the criteria of MA and NMA: the cytopenia is reversible and the stem cell support is necessary. NMA/RIC for Allo-HSCT has opened a new era for treating elderly patients and those with comorbidities. The RIC conditioning was used for 40% of all Allo-HSCT and this trend continue to increase. In this paper, we will review these regimens in the setting of especially allogeneic HSCT and our aim is to describe the history, features and impact of these conditioning regimens on specific diseases. Treatment regimen used for hematopoietic stem cell transplantation (HSCT) must accomplish two goals depending on the patient’s disease and the source of stem cells. Since the majority of allogeneic transplantations are performed for the treatment of malignant disease, the regimen must provide tumor cytoreduction and ideally disease eradication ,5,6,7,8.Several studies showing high doses of total body irridation (TBI) causes death from marrow failure and intravenous infusion of marrow or spleen cells after TBI prevents death in mice attracted many researchers to investigate human transplantations in mid-1950s (19). Early trials of human marrow grafting had been unsuccessful since patients failed to engraft or developed fatal graft-versus-host disease (GVHD) . In lateConventional ablative allo-HSCT depends on the tolerated doses of systemic chemo-radiotherapy in order to eradicate malignant tumor burden. This resulted with high regimen-related toxicities in elderly and patients with comorbidities. In considering that, most hematological diseases occur at ages from 65 to 70 , investiThe MA/NMA/RIC conditioning regimens currently in use summarized in It is well known that a complete donor T-cell chimerism is correlated with a low risk of relapse or progression. MA regimens leads to state of full chimerism rather earlier than RIC regimens. Mixed chimerism is detected initially after transplant in most RIC conditioning regimens and in fact graft rejection is more common in RIC Allo-HSCT patients compared to conventional regimens . MyeloabIn AML, several retrospective comparisons of RIC and MA conditioning regimens are difficult to evaluate due to different patient populations. Patients who received RIC regimens had more high risk features and comorbidities than those received MA conditioning but the survival rates were found to be similar between RIC and MA conditioning . SeveralIncreased NRM in elderly patients with comorbidities may worsen the outcome of MA allo-HSCT in acute lymphoblastic leukemia (ALL). Marks et al.  had not Recently, the results of phase III multi-center randomized study of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901 have been released. This study compared outcomes on the basis of conditioning intensity in patients with Myelodysplastic syndrome (MDS) and AML. The study concluded that RIC results in higher relapse rates and lower TRM compared to MAC with a statistically significant advantage in RFS for patients receiving MAC. It has to be noted that inclusion of heterogeneous regimens in both RIC and MAC arms and lack of longer follow-up establishes the main weaknesses of the BMT CTN 0901 study .There are some controversies regarding the impact of conditioning intensity on disease control in MDS. Warlick et al. (55) reported improved disease control with MA regimens. High risk MDS patients (n=43) were treated with MA and T cell depleted alloHSCT resulted in EFS at 1 and 3 years as 47% and 34%, respectively. The overall toxicity was detected to be similar compared to multiple recorded series using RIC regimens. Martino et al.  reportedMyeloproliferative neoplasms (MPNs) include a group of clonal and chronic hematologic disorders with similar features. Classical MPNs are chronic myeloid leukemia (CML), idiopathic/primary myelofibrosis (MF), polycythemia vera (PV), essential thrombocytopenia (ET), systemic mastocytosis, chronic neutrophilic leukemia and chronic eosinophilic leukemia . Today, In newly diagnosed severe acquired idiopatic aplastic anemia patients younger than 30-40 years, allo-HSCT is the first line treatment of choice . The staIn patients with Hodgkin’s lymphoma (HL), allo-HSCT is generally performed in relapsed disease after autologous HSCT or refractory disease status but MAC followed by allo-HSCT with conventional preparative regimens had been associated with high toxicity rates and TRM in this group of patients. In the era of reduced intensity regimens, EBMT Lymhoma Working Party reported a lower NRM and improved OS with RIC allo-HSCT in patients with relapsed or refractory HL . In a reSeveral studies have evaluated the efficacy HSCT following RIC or NMA conditioning as a treatment option in relapse or refractory non-HL (NHL) after failure of autologous HSCT. The PFS rate at 3-year was 82% in 18 refractory mantle cell lymphoma (MCL) patients treated with NMA conditioning containing fludarabine, cyclophosphamide and rituximab . Maris eCLL has an indolent and prolonged clinical course and mostly patients are in older age group. Sorror et al.  reportedBased on the growing knowledge on the immune system and T cell biology, allogeneic HSCT also represents a promising approach in some solid tumors. Several EMBT phase I and II studies which were conducted by Solid Tumors Working Party documented the presence of a graft-versus solid tumor effect in patients with various solid tumors such as renal, ovarian, colon and soft tissue sarcomas [27-78]. Aglietta et al.  reportedIn conclusion, allogeneic stem cell transplantation is a curative approach in many diseases. The advantages of RIC regimens are lower toxicity profiles and lower NRM rates. RIC or NMA allo-HSCT can be a feasible option in geriatric patients and patients with comorbidities. Future studies are needed for a clear-cut understanding of the mechanisms of GVL and GVT effects of donor T cells and its subsets in order to optimize the efficacy of such treatment modalities as RIC or MAC in allo-HSCT .


Memory deficits are a hallmark of psychotic disorders such as schizophrenia. However, whether neural dysfunction underlying these deficits is present prior to onset of illness and potentially predicts conversion to psychosis are unclear. This study aimed to investigate: 1) baseline brain functional alterations during memory processing in subjects at clinical high risk (CHR); 2) whether alterations are more severe in converters compared with non-converters and are thus predictive of psychosis; and 3) associations of these alterations with task performance, baseline symptoms and memory ability.A sample of 155 individuals at CHR  and 137 subjects who did not convert ) and 108 healthy controls  were drawn from the second phase of the North American Prodrome Longitudinal Study (NAPLS-2) consortium. All participants underwent functional magnetic resonance imaging (fMRI) with a paired-associate memory paradigm, which consisted of one run for encoding and another run for retrieval. During encoding, participants were presented a series of semantically unrelated word pairs and were asked to remember the presented word pair. During retrieval, a pair of words was presented on the screen on each trial and subjects were asked to indicate whether the given word pair had been presented during the encoding session. Active baseline conditions were included in the task for both encoding and retrieval runs.Data processing was performed for each run, following the standard procedures using the Statistical Parametric Mapping software (SPM12). At individual level, preprocessed images were entered into a general linear model (GLM), generating individual contrast maps (task vs baseline). These contrast maps were further used for a group-level GLM analysis, modeling group, sex, age and site as regressors. Significance was determined using family-wise error (FWE) correction across all voxels in the brain.The observed activation alterations were further tested for potential associations with task performance, clinical symptoms and/or general memory ability. Task performance was measured using the percentage of correct responses and the mean reaction time during retrieval. Clinical symptoms were evaluated by the summed scores of each domain  in the Scale of Prodromal Symptoms (SOPS). Memory ability was quantified by the Brief Visuospatial Memory Test- Revised (BVMT-R) and the Hopkins Verbal Learning Test- Revised (HVLT-R) total recall scores.No significant group differences in activation were found during encoding. However, during retrieval, a significant group effect was observed in five brain regions: left dorsolateral prefrontal cortex , left ventrolateral prefrontal cortex , left inferior parietal lobule , left superior temporal gyrus , and right middle temporal gyrus . This effect was indicative of greater activation in converters than non-converters and controls and was particularly manifest in unmedicated subjects (P < 0.001). Baseline hyperactivation was correlated with retrieval reaction time during scan in converters , and with baseline positive, negative and disorganization symptoms  and memory scores  in the whole sample.These findings suggest that hyperactivation during memory retrieval may mark processes associated with conversion to psychosis; such measures have potential as biomarkers for psychosis prediction.