Synthetic Aperture Radar has shown its large potential for retrieving soil moisture maps at regional scales. However, since the backscattered signal is determined by several surface characteristics, the retrieval of soil moisture is an ill-posed problem when using single configuration imagery. Unless accurate surface roughness parameter values are available, retrieving soil moisture from radar backscatter usually provides inaccurate estimates. The characterization of soil roughness is not fully understood, and a large range of roughness parameter values can be obtained for the same surface when different measurement methodologies are used. In this paper, a literature review is made that summarizes the problems encountered when parameterizing soil roughness as well as the reported impact of the errors made on the retrieved soil moisture. A number of suggestions were made for resolving issues in roughness parameterization and studying the impact of these roughness problems on the soil moisture retrieval accuracy and scale. When the algorithm was applied to the entire test site, only a small percentage of pixels resulted in a normal solution. A similar problem was reported by Ji et al. [et al. [et al. [a priori knowledge of roughness parameters. They used a SIR-C/X-SAR scene and calibrated the model for two agricultural fields where soil moisture data were available. Results were compared to moisture estimates obtained from a hydrological model, yielding better results for L-band data than for C-band. The results obtained were strongly influenced by the vegetated cover of the fields. Fung and Chen [Applying Oh's model to SIR-C measurements over the Little Washita River watershed, Wang et al.  found thi et al. , and wasi et al.  obtained [et al.  found th [et al.  found a  [et al.  reported [et al.  carried and Chen  reportedet al. [ks < 2.5 and incidence angles larger than 30°.The Dubois model relates the HH or VV polarization to the soil's dielectric constant, surface roughness, incidence angle and radar frequency. Basically, for a given radar configuration and soil roughness, this model linearly relates the dielectric constant of a soil to the backscattering coefficient, expressed in dB. Dubois et al.  restrictet al. [et al. [s < 0.6 cm), an overestimation for surfaces with an RMS height larger than 1.6 cm, and a correct simulation for surfaces with an intermediate roughness. For soil moisture contents smaller than 30%, Baghdadi and Zribi [et al. [Ji et al.  applied  [et al.  applied  [et al.  generallnd Zribi  observed [et al.  applied et al. [et al. [et al. [Leconte et al.  applied  [et al. , many st [et al.  develope2.3.A number of theoretically rigorous and approximate solutions for electromagnetic scattering from rough surfaces, described as stochastic random processes, have been developed over the past decades . SeThe most popular approximate scattering models are the Small Perturbation Model , Kirchhoσ0 of a bare soil, given the radar properties , surface characteristics (dielectric constant and surface roughness) and local incidence angle. The theoretical derivation of the IEM starts from the Stratton-Chu integral which describes the scattered electric field sE observed at the sensor in terms of the tangential electric and magnetic fields at the soil surface. Because the Stratton-Chu integral is complex some approximations as described in Fung [et al. [The Integral Equation Model encompasses the Kirchhoff and small perturbation models in the high and low frequency regions respectively ,28,40,97 in Fung  have to  [et al. , the val [et al. .In order to invert the IEM to dielectric constants , sevks < 3 [For bare soil studies, the IEM has become the most widely used scattering model . The valks < 3 , howeverks < 3  found thMv > 30%) and large incidence angles (θ> 44°).The IEM has been validated successfully at fine scales in a laboratory setting ,111-113.et al. [et al. [i.e. an underestimation of the HH backscattering coefficient) by Baghdadi and Zribi [et al. [et al. [Rakotoarivony et al.  and Zrib [et al.  observednd Zribi . Mattia  [et al.  showed t [et al.  found tha posteriori verified [s and l, but introduced a new set of parameters that were related to multi-scale surface properties. One result obtained with this novel roughness description was that the backscattering from very smooth agricultural soils could be predicted better [According to Zribi and Dechambre  the diffverified  and secoverified  reformuld better .et al. [et al. [et al. [et al. [Other improvements of the IEM have been reported: Boisvert et al.  and Weimet al.  adapted et al.  included [et al.  introduc [et al.  introduc [et al. ; and Che [et al.  improved [et al. , which i [et al. .3.et al. [et al. [Soil roughness can be considered as a stochastic varying height of the soil surface towards a reference surface . This reet al.  show a b [et al.  reporteds and l, where the latter is usually regarded as a fitting parameter [s, l and ACF that characterize single-scale roughness.Generally, the characterization of surface roughness is obtained from the analysis of height variations observed along transects , from wharameter ,128. As 3.1.N points with surface height iz, the RMS height, s, is calculated as [For discrete one-dimensional surface roughness profiles consisting of lated as :(1)s=1Net al. [In order to obtain a consistent RMS height measurement, Bryant et al.  concludeet al. ,103,129.et al. [et al. [The relationship between RMS height and environmental variables such as tillage and soil texture has been extensively studied in the past ,130,131.et al.  derived  [et al.  investig3.2.l, describes the horizontal distance over which the surface profile is autocorrelated with a value larger than 1/e (≅ 0.368) [The correlation length, ≅ 0.368) ,133. Alt≅ 0.368) ,65,134. ≅ 0.368)  and depe≅ 0.368) ,103,129,Various values for an optimum profile length have been suggested for measuring correlation length, varying from a couple of meters  to more et al. [et al. [et al. [Baghdadi et al.  mentione [et al.  measured [et al. , who fou [et al. .3.3.ξ = jΔx, and Δx the spatial resolution of the profile, is given by:The normalized autocorrelation function, for lags  density ,21,51.In order to fully characterize the ACF of a surface, a discretization interval, used to sample the profile, should be at least as small as one tenth of the correlation length ,135, as In backscatter models, often two types of ACFs are used , i.e. thand the Gaussian function is defined as:l the correlation length. Depending on which ACF is chosen, IEM produces strongly different results as demonstrated by s and l.with et al. [Compared to the Gaussian ACF, the exponential one is characterized by smaller correlations at small lags. This causes that exponential ACFs to better describe the micro-roughness in the profile than Gaussian ACFs . Howeveret al.  introducet al. ,135,137;et al. ,138. In et al. . For a set al. .et al. [et al. [Following Zhixiong et al. , the aut [et al.  in a sen4.et al. [Although the characterization of soil roughness seems a fairly straightforward methodology, the parameterization faces many problems. One major problem is that roughness parameters often show little or no spatial dependency. In other words, surface height measurements and derived roughness parameters taken at one position often do not, or only poorly, represent their surrounding area which makes them physically meaningless. For example, this was observed by Lehrsch at al.  who carret al.  recognizet al. . This unet al. .In the following sections, a review on the different sources of errors will be given, and when available from literature, the influence of these errors on soil moisture retrieval will be discussed.4.1.Several methods have been suggested for estimating the roughness parameters. These can be subdivided in two groups : contactThe meshboard technique involves inserting a gridded board in the soil and making a picture after which it is digitized. The main advantages of a meshboard are its low cost and the fact that it is easy to make. A major disadvantage of the instrument is that it is quite difficult to insert the meshboard sufficiently deep into a rough soil  without disturbing the roughness, especially, when the soil is compacted. Meshboard measurements are typically affected by parallax errors which are caused by the fact that the picture of the intersection of the soil and the meshboard cannot be taken at ground level, but generally is taken at a height of about 90 cm . FurtherThe pin profiler is constructed out of a number of vertically movable pins which are lowered onto the ground surface . The posNoncontact instruments include laser techniques e.g. ,153,154),154153,1A laser profiler makes use of a laser beam measuring the distance between a horizontally positioned rail, on which the carriage with the laser beam moves, and the soil surface. The main advantage of this instrument is that it allows for an accurate measurement of the roughness profile having a sufficient horizontal resolution. Yet, these instruments are also characterized by different disadvantages including the interference of light from other sources ,154, theet al. [et al. [2) of 0.6. For meshboards, a significant error was found in the roughness measurements (compared to laser profiler measurements), which, according to Mattia et al. [Unfortunately, a thorough investigation comparing measurement techniques and accuracy assessment has not been performed yet . In a stet al.  found thet al. . This fi [et al. , where aa et al. , is mostet al. [In order to fully comprehend the effect of roughness characterization from different measurement techniques on soil moisture retrieval from SAR, an in-depth study is required that compares the different techniques over the same sites for different roughness situations. Some preliminary results, based on a study that only focused on the RMS height measurements from pin profiler and laser scanning, have been presented by Bryant et al. . They co4.2.et al. [The soil roughness parameters describe the statistical variation of the stochastic varying surface height towards a reference surface. Generally, only the first order component from the measured profile is removed. This assumes that the reference surface is a plane, which is not necessarily horizontal, and accounts for the fact that the measurement device may have been slightly tilted with respect to the reference surface. This assumption is only valid when short profiles are measured , but foret al. , the topet al. .et al. [et al. [In order to parameterize these single-scale roughness deviations, one should filter out the curved reference surface. Different methodologies can be applied such as detrending using piecewise linear regressions, applying a highpass filter, applying a moving average filter, and detrending using a higher order polynomial . Generalet al.  found th [et al.  did not et al. [Bryant et al.  demonstr4.3.Bryant et al  stated t4.3.1.et al. [The horizontal resolution is defined by the instrument that is used. For laser profilers, the horizontal distance between two measurements generally ranges between 1 mm  and 5 mmet al.  state thet al. .et al. [In order to prevent major errors in the estimations of roughness parameters, Oh and Hong  suggesteet al.  advised 4.3.2.Although the vertical resolution is an instrument property introducing errors in the measured profile, little attention has been given to the effect of this accuracy on the determination of roughness parameters or the impact on the soil moisture retrieval. Values with respect to the vertical accuracy of different instruments are rarely published. Jester and Klik  mentione4.3.3.Both the non-electronic pin profiler and the meshboard technique require a digitization. With pin profilers, the position of the upper part of the pins is photographed and digitized, whereas, the soil surface is immediately digitized when using a meshboard. Archer and Wadge  have shoet al. [s,l) of . If 12 different people digitized the same profile, similar average roughness values were obtained, i.e.  = , and a coefficient of variation of 4.52% and 4.51% for respectively RMS height and correlation length was found. Although these examples are statistically not representative, one could conclude that errors introduced in the digitization process are very small, and therefore, although not assessed, the impact on soil moisture retrieval is expected to be small.Since the digitization of pins is much less subjective then making a difference between soil and plate when using meshboard pictures, D'Haese et al.  digitize4.4.et al. [et al. [It is well known that the values of the roughness parameters depend on the profile length used ,129,163.et al.  found th [et al.  obtainedet al. [Smooth profiles required a minimum length of 10 m to get an estimation of the RMS height that was comparable to what was obtained when 25-m profiles were analyzed, whereas for rough profiles, 5-m profiles seem sufficient. Zhixiong et al.  reportedet al.  deduced et al. [In order to get accurate estimations of the correlation length, much longer profiles are necessary. Furthermore, the increase rate for the correlation length with increasing profile lengths is larger than for the RMS height . For shoet al.  found siet al. , profiles2) is proportional to the profile length. Baghdadi et al. [η and γ two calibration constants and γ corresponds to the asymptotical RMS-value (obtained for profile lengths L → ∞). Callens et al. [s and L following:a and b are parameters obtained through a least squares fitting. They furthermore suggested a similar relationship for describing the dependency of the correlation length on L. They used both relationships to estimate the asymptotical value of both roughness parameters from 4-m profiles, such that infeasible long profile lengths (extending 25 m in some cases) are no longer required.Sayles and Thomas  suggestei et al.  discovers et al.  further Despite the different studies devoted to this scaling behavior of the roughness parameters, an assessment of the errors made on the soil moisture retrieval when applying roughness values obtained from different profile lengths has not been reported yet. Such a study would be extremely useful in order to determine the profile lengths needed such that roughness parameters can be estimated at a scale that is relevant for the scattering process.4.5.et al. [et al. [Baghdadi et al.  mentione [et al.  reportedOgilvy  demonstret al. [The effect of averaging soil roughness parameters from a different number of profiles on the soil moisture retrieval was assessed by Bryant et al. . They di4.6.et al. [Álvarez-Mozos et al.  studied et al. .4.7.et al. [Different studies e.g. ,166,167),167166,1et al.  mentioneet al. [et al. [During three months, Callens et al.  measured [et al.  found noet al. [s decreased whereas an increase in correlation length was observed with time. Even if these temporal changes in roughness were not strongly significant if the in-field spatial variability was taken into account, their influence on the backscattering coefficient can be important because both effects (s reductions and 1 increments) contribute to a more specular-like behavior of soils. Therefore, backscattering values increase at low incidence angles and decrease at large incidence angles as the surface smoothens. When studying the impact on soil moisture retrieval, Álvarez-Mozos et al. [Álvarez-Mozos et al.  also invs et al.  demonstr5.5.1./f power spectrum (i.e S(f) ∝ 1ν/f where ν = (7 − 2D) and D is the surface fractal dimension). For these random processes, traditional roughness parameters, namely the profile height rms (s) and profile correlation length (l) are not intrinsic properties of the surface, but depend on the measured profile length [1/f surfaces always possess more important high frequency components than single-scale Gaussian correlated surfaces. On the contrary, they may possess larger or smaller high frequency components than single-scale exponentially correlated surfaces, depending on ν  scales rather than at a single fundamental scale. For instance, over large scales land surface roughness depends on climatic conditions . Wherease length . This pre length ,178,179)found in ,181).Based on the aforementioned description, different researchers have tried to describe soil surfaces using band-limited fractals e.g. ,182-184)-184182-15.2.et al. [Since the correlation lengths assessed from field measurements are generally inaccurate, Baghdadi et al.  proposeda and β are calibration constants depending on incidence angle and polarization. This relation was parameterized by fitting the IEM results to radar measurements until a good agreement was obtained. Their results revealed that the calibrated correlation length was strongly related to the RMS height, but that these relations were dependent on the radar configuration. Baghdadi et al. [where i et al.  found thFor surfaces characterized by a Gaussian autocorrelation function, they found that a linear relationship better fitted the IEM results:et al. [α and β were dependent on the polarization and incidence angle of the SAR observations used, and α and β values for C-band data were recommended.In a later study, Baghdadi et al.  found thet al. [in situ measurements of surface soil moisture and accounted for the very complex relation between s and l found in heterogeneous landscapes.Although generally better retrieval results are obtained when using these calibration approaches, this technique does not allow to extrapolate the obtained models, unless the sites on which it is applied are similar to the one used for its development. Rahman et al.  used the5.3.z can be obtained by stereo-image matching or by using  laser scanners. Jester and Klik [et al. [In the past, soil surface height measurements were almost exclusively taken along one-dimensional profiles. Thus it was not possible to carry out an analysis of the two-dimensional soil surface height field, which may possibly lead to different roughness characterizations then compared to the one-dimensional case. Two-dimensional height maps and Klik  found th [et al. .et al. [The terrestrial measurements may be complemented by airborne laser scanner measurements, which have become the main data source for high quality digital terrain models . Even thet al. ,189 showet al. , which i5.4.et al. [Another approach to overcome roughness parameterization effects in the soil moisture retrieval consists of combining two or more SAR images of different incidence angle with the IEM to separate the effects of soil moisture and roughness for several tillage types ,191-193.et al.  reportedσ0) generated by the IEM model with two different incidence angles, keeping all other parameters constant, was proportional to roughness only, expressed as a ratio of s2/l termed the Z-index. Rahman et al. [s and l separately from the Z-index using the IEM with a SAR image acquired with dry soil conditions. The resulting maps of distributed roughness can be used to parameterize IEM for producing surface soil moisture maps without the need for ancillary data [Zribi and Dechambre  found thn et al.  showed tary data . The app5.5.et al. [et al. [An alternative way to address the roughness problem is to make use of polarimetric parameters such as, for example, the entropy, the α angle and the anisotropy . This shet al.  found th [et al.  discover5.6.et al. [Satalino et al.  suggest et al. . This pret al. ,130.et al. [et al. [et al. [Knowledge on the tillage state of a field, however, does not allow for accurate roughness parameterization. On the contrary, there exists a range of roughness values possible for the specific tillage state, and this vague information should be used in the retrieval process in order to determine a range of possible soil moisture values and/or a most likely soil moisture value. Satalino et al.  trained  [et al.  applied  [et al. -198 to p [et al.  developeet al. [et al. [The results of Satalino et al.  and Verh [et al.  show tha6.From an extensive literature study, it is clear that roughness parameterization is an important yet problematic issue in SAR-based soil moisture retrieval. Basically, the way roughness needs to be described and measured for the modeling of backscattering is not fully understood, and generally, the problem is simplified through assumptions of single-scale, isotropic roughness.In most backscatter models, two roughness parameters are required, i.e. the RMS height and the correlation length, and in theoretical models such as the Integral Equation Model (IEM), the shape of the autocorrelation function (ACF) also needs to be known. For natural surfaces, an exponentially decaying function appears to be a reasonable approximation of the ACF, but given the high sensitivity of theoretical models to the selected ACF, even small deviations can cause differences in the calculated backscatter on the order of several decibels. Yet, the largest problems for the parameterization of the roughness are encountered with respect to the correlation length. This parameter is characterized by a very high variability, causing average values of generally a small number of roughness measurements to be characterized by a high uncertainty. Since the RMS height values are less variable between roughness profiles, its parameterization is less problematic.The profile length used in the field for characterizing roughness highly determines the roughness parameters. Longer profiles result in higher values and a smaller variability for both RMS height and correlation length. Since different parameters may thus result for the same roughness, the profile length used will have an important impact on the retrieval of soil moisture, given the high sensitivity of the backscattered signal to roughness. Therefore, several authors argue that long profiles should be used for an accurate estimation of the roughness parameters. Also, it may be important to collect height measurements in two dimensions. However, it has never been shown at what scale or dimension surface roughness needs to be measured in order to be relevant for an accurate description of the scattering phenomenon. Further research on this issue is thus very important such that adequate roughness parameters can be determined in the field in order to support backscatter modeling or soil moisture retrieval. If not, techniques which try to circumvent the in-field measurement of roughness  will have to be developed in order to make further progress in SAR soil moisture retrieval, like those discussed in Section 5.in situ measurements is not an option. New techniques that allow for moisture retrieval need to be further explored that circumvent roughness characterization  or that allow for roughness characterization based on remote sensing . Alternatively, ranges of  roughness values can be assigned to different tillage practices which can then be used as a priori information as input to soil moisture retrieval algorithms.If SAR is to be used on an operational scale for soil moisture mapping, then soil roughness parameterization through The advent of new high resolution sensors observing in X- and L-band , and C-band sensors yielding polarimetric data (RADARSAT-2) should allow for a better characterization of surface parameters. It is expected that a combined use of data from these different platforms, can lead to retrieving soil roughness information at a spatial scale relevant to the observed scattering. These roughness values can then be used for operational soil moisture retrieval from SAR imagery.Several studies have been devoted to improving the roughness characterization, to assessing errors and to estimating scaling behavior of the roughness parameters. However, there is still no comprehensive assessment of the impact of these roughness problems on the soil moisture retrieval. Nevertheless, an improved insight in the roughness parameterization and its impact on soil moisture retrieval is a prerequisite for making further advances in electromagnetic backscatter modeling and soil moisture retrieval. It is important that the obtained soil moisture products are accompanied by an accuracy measure, as such information is of major importance in order to properly assimilate these spatial soil maps into land surface models . Howeve


Background. Paranasal and nasal cavity malignancies are rare tumors that frequently present at advanced stages. Tumor extension and anatomic complexity pose a challenge for their treatment. Due to their peculiar physical and biological properties particle radiation therapy, i.e. protons and ions can have a role in their management. We performed a systematic literature review to gather clinical evidence about their use to treat sinonasal malignancies. Materials and Methods. We searched the browsers PubMed and Medline as well as specific journals and conference proceedings. Inclusion criteria were: at least 10 patients, English language, reporting outcome and/or toxicity data. Results. We found six studies with data on clinical outcome. Carbon and helium ions were each used in one study, protons in four. Toxicity was specifically described in five studies. One reported acute toxicity of carbon ions, one dealt with brain toxicity from both carbon ions and protons. Three papers reported on visual toxicity: one from carbon ions, one from protons and one from both. Specific data were extracted and compared with the most pertinent literature. Conclusion. Particle radiation therapy is in its early phase of development. Promising results achieved so far must be confirmed in further studies. Paranasal sinus and nasal cavity malignancies are rare with an incidence rate estimated to range from 0.3 to 3.5 per 100.000 per annum . They acSinonasal malignancies present frequently at advanced stages due to late symptom onset. This, combined with the complex regional anatomy and the presence of several organs at risk (OARs) such as brain and optic structures, poses a challenge for their best management. The mainstay of treatment is surgery : traditi Radiation therapy has been employed either as adjuvant treatment for high-risk cases or as definitive therapy for unresectable disease. No clear evidence exists for a routine use of chemotherapy, which is administered generally in a case-by-case scenario , 18. DesParticle radiation therapy, that is, protons and heavy ions, is a relatively new type of radiation therapy that could enhance the therapeutic ratio for sinonasal malignancies. Protons and heavy ions share the same characteristic dose distribution, the so-called Bragg Peak, that is the release of almost all their energy in a few millimeters at the end of their path see . This pend(1 + d/α/β), [n), the single dose (d), and the α/β ratio that is a radiobiological parameter that characterizes the response of every tissue to radiations.An altered fractionation regimen is any radiotherapy schedule that differs from the standard delivery of 1.8–2.0 Gy, 5 days a week for an overall treatment time of about 6-7 weeks. They can be classified as hyperfractionated, accelerated, or hypofractionated with possible combinations as well. They all try to increase the therapeutic index that is, the ratio of the probability of tumor control to the probability of normal tissue toxicity. Published papers in the head and neck field have proved their effectiveness in comparison to standard fractionation , 34. Par d/α/β), , allows Since particle radiation therapy is not very widespread and basically still under development, data of its use to treat sinonasal malignancies are scant.In this paper we performed a systematic review of the literature to gather all the clinical experience so far accumulated on this issue focusing on outcome and side effects.The Population-Interventions-Comparators-Outcomes (PICO)  frameworEligibility criteria were as follows: studies published in the English language, reporting outcome and/or toxicity data on definitive treatment with particle radiation treatment of nasal and paranasal sinus malignancies. Studies were accepted if photon radiation therapy was combined with particle radiation and if radiation therapy was used either in definitive, adjuvant, or neoadjuvant setting. Any use of chemotherapy was allowed. Studies had to include at least 10 patients and to report data on tumor control and/or on toxicity. Studies including multiple head and neck sites were considered and included if it was possible to extract specific information on sinonasal malignancies. In case of publications with overlapping data, the study with the largest number and wider data was chosen. Review articles, case reports, and planning studies were not considered.Data extracted from publications meeting the eligibility criteria were first author, year of publication, institution, number of patients, gender, median age, pathology, stage, type of surgery received if any, type of chemotherapy received if any, and followup. Regarding radiation treatment, the following data were extracted: possible combination with photon, type of particle used, RBE employed, total dose, dose per fraction, number of fractions and number of fractions a week of the particle used, total dose, dose per fraction, number of fraction and number of fractions a week of photons; combined total dose was reported as well. For studies reporting results on tumor control the following data were recorded: local, regional and distant control, overall survival, type, scale and grade of toxicity, time to toxicity, and risk factors individuated. For studies dealing particularly with toxicity apart from the available data as above, the diagnostic criteria used were reported as well as the maximum dose to affected organs and side effect risk factors. Any toxicity scale used was also reported.The initial literature research identified 2012 studies including duplicates see . 1985 weAll the studies reporting data on outcome have been published in peer-reviewed journals apart from the one from Malayapa  that hasThe first publication included in the paper, by Castro et al. , dates bMizoe et al.  publisheα/β=3)( > 130 Gy (RBE) was associated with late toxicity as well as with high fraction size.Tokuuye et al.  from theData from Massachusetts General Hospital, Harvard Cyclotron Laboratory, Francis Burr Proton Center, USA, are available in the paper of Resto et al.  From 199Zenda et al.  from theThe University Of Florida Proton Therapy (UFPT) Institute's experience is reported in the paper of Malyapa et al.  since JaA total of five studies dealing specifically with toxicity after particle radiation therapy were found. Jensen et al.  from themax > 110 Gy (RBE) (α/β = 3) were observed as possible risk factors. Diabetes was statistically significant at multivariate analysis too. Demizu et al. , from thmax of the optic nerve >57 Gy (RBE), and D10-50. At multivariate analysis, D20 > 60 Gy (RBE) was still significant. In the paper of Hasegawa et al. , from thWeber et al.  describeα/β value of 3.6. Radiation-induced brain changes (RIBCs) were evaluated by MRI findings on T2-weighted or postcontrast images and graded according to the LENT-SOMA scale. Related symptoms were scored according to CTCAE versus 3.0 scale. After a median interval of 31 (range: 6–49) and 27.5 (range: 19–36) months, respectively, three patients, treated by protons, and two by carbon ions developed radiation-induced brain changes. Radiologic toxicity grades for the three protons-treated patients were G1, G2, and G3 and for the two carbon ions-treated patients were G3 and G2. For protons-treated patients, clinical grading was G1 for one and G2 for two, meanwhile it was G3 and G1 for the two carbon ions-treated patients. G3 clinical toxicity consisted of epilepsy requiring steroids and anticonvulsants. From the analysis of the whole group, carbon ions were statistically more frequently associated with RIBCs than protons (P = 0.02). Minimal median dose to RIBCs sites for the three proton patients was 117.1 Gy (RBE)3 (range: 59.4–117.1 Gy (RBE)) and 27.5 Gy (RBE)3 (range: 102.4–110.6 Gy (RBE)3) for the two receiving carbon ions. Most of the RIBCs were induced by doses ≥80 Gy (RBE)3, occurring within two years from radiation in comparison to those induced by lower doses that developed after two years. Lobe volumes receiving more than 83, 90, and 100 Gy (RBE)3 were significantly associated with RIBCs. The experience of The Hyogo Ion Beam Medical Center about radiation-induced brain injury after proton or carbon ions is reported in the paper of Miyawaki et al. . Twenty-We were able to find 11 studies reporting outcome and/or toxicity results relative to the use of particle radiation therapy for the treatment of paranasal sinus and nasal cavity malignancies. There are some common limitations for these studies that must be emphasized. All but one study  were reHeavy particle radiotherapy is in its early phase of development, and it is mainly employed for unresectable or high-risk cases. This type of radiation therapy combined with photons or not is feasible and well tolerated by patients either as definitive or as adjuvant treatment. The delivery of the prescribed dose was possible in all studies, and all patients could complete their treatment. Altered fractionation schemes were safely employed to increase the therapeutic ratio , 44, 48,P = 0.32). Castro et al. [P = 0.03, P = 0.02). Local control rates compare positively with those from Institutions that used photon radiation therapy . Local co et al.  reportedo et al.  had one-o et al.  at the mo et al. , 9 out oo et al.  must be o et al.  local coIn general, for particle radiation therapy studies, rates of distant metastasis free-survival and overall survival are not substantially different from other studies. Obviously, this means that an efficient systemic therapy capable of dealing with metastasis is needed for particle therapy too. Regional control is reported in the papers of Resto et al.  and ZendAcute toxicity seems to be mild, well tolerated, and does not interfere with treatment delivery as pointed out in the specific paper by Jensen et al. . Late toAmong the possible risk factors, all the studies of particle radiation therapy found important the maximum dose delivered. This confirms both the concept that many optic structures are serial organs and the results from previous studies. Parsons et al.  observedA volume factor for the irradiated OAR has been individuated as risk factor in the study of Hasegawa et al. . The dosDry-eye syndrome is a serious side effect associated with head and neck radiotherapy . In thisOther risk factors found by the specific studies were diabetes mellitus that has already been associated with toxicity by other authors , 61 and 3 and volumes of cerebral lobe receiving more than 83, 90, and 100 Gy (RBE)3. Maximum dose and volume receiving a given dose are recognized risk factors for brain toxicity. From the review of published data, Lawrence et al. [α/β=  3). Schlampp et al. [3 of the temporal lobe. Carbon ions were found by Miyawaki et al. [Brain late side effects have always been among the most dreaded consequences of radiation therapy. Significant neurologic alterations have been described in association with photon and particle radiotherapy for paranasal and nasal cavity malignancies , 62. Thee et al.  could cos et al.  about 36p et al.  observedi et al.  to be sii et al.  about 10i et al.  in theirParticle radiation therapy is a promising tool for the treatment of paranasal and nasal cavity malignancies. Considering that it is in its early phases of development, it has shown to be feasible and well tolerated. Results regarding local control are encouraging and late toxicity is acceptable. Further research is needed to establish its exact role and its best combination with surgery and chemotherapy.


Vasculogenic mimicry (VM), a new pattern of tumor microcirculation, is important for the growth and progression of tumors. Epithelial-mesenchymal transition (EMT) is pivotal in malignant tumor progression and VM formation. With increasing knowledge of cancer stem cell (CSC) phenotypes and functions, increasing evidence suggests that CSCs are involved in VM formation. Recent studies have indicated that EMT is relevant to the acquisition and maintenance of stem cell-like characteristics. Thus, in this review we discuss the correlation between CSCs, EMT and VM formation. This process is characterized by the loss of epithelial traits and the acquisition of mesenchymal phenotypes –23. ActiNormal tissues and tumors contain a small subset of cells, known as stem cells, with the capacity for self-renewal and the multipotency to differentiate into diverse committed lineages ,27. Tumo+/CD38− subpopulation of leukemic cells . From a retrospective study of 109 patients with IBC, the patient prognosis and metastasis trends showed a significant correlation with aldehyde dehydrogenase 1 (ALDH1) expression, a specific marker of CSCs. Both in vitro and xenograft assays showed that invasion and metastasis in IBC are mediated by a cellular component that exhibits ALDH activity − cadherin+ melanoma cells, which have the ability to form VM , loss of cell polarity and intercellular adhesion molecules (for instance E-cadherin and occludin), which is concomitant with upregulation of mesenchymal markers  and acquisition of fibroblast-like morphology with cytoskeleton reorganization ,22,71. Tet al demonstret al–76, Sluget al, Twist (et al, SOX4 (7et al and ZEB et al, and sevet al–83. Snaiet al,79,84. Tet al. Twist1 et al. In a sp al(et al demonstr al(et al identifi al(et al,89. Furt al(et al.et al(et al(in vitro, while the well-differentiated cell line HepG2 did not form VM. These findings indicated that EMT is involved in VM formation.Recently, evidence has shown that EMT is involved in the process of VM formation. In VM-positive colorectal carcinoma samples, Liu et al found thet al. Furtheret al. Lirdpra al(et al have repet al(Researchers have been engaged in discovering the origin of CSCs for a number of years. It is widely accepted that tumor formation is due to the multistep mutation of genomes. Considering the longer lifespan of stem cells, normal stem cells suffer from the accumulation of mutations over time. Thus, it is hypothesized that CSCs derive from normal stem cells with genetic mutations, and this has been demonstrated by independent investigators ,94. In aet al classifiet al(et al(et al(+ T cells acquired certain characteristics of breast CSCs, including potent tumorigenicity, resistance to conventional treatment, and the ability to form spheroids. Fang et al(+/CD24− cells. Breast cancer cells exposed to TGF-β and TNF-α lead to the generation of breast cancer cells with stem-like characteristics by induction of EMT (et al(et al(in vivo tumorigenicity in nude mice and stem cell marker expression. Chen et al(+ cells exhibit a high level of expression of Snail, and knockdown of Snail significantly decreased the expression of ALDH1. These data suggest that epithelial cells within tumors are able to convert into CSCs via EMT (et al(An increasing body of evidence shows that EMT is associated with the acquisition of CSC properties. In 2008, Mani et al reportedet al,97. More al(et al also ind al(et al found thang et al demonstrn of EMT . In addiMT (et al identifiMT (et al. In HNSC al(et al found thhen et al revealed via EMT . MoreoveMT (et al demonstret al(et al demonstrated that Snail promotes the induction of Flk1+ endothelial cells in an early subset of differentiating mouse embryonic stem cells, depending on fibroblast growth factor signaling as well as the repression of the miR-200 family (et al(VM allows tumor cells to express the endothelial phenotype and play a similar functional role to endothelial cells in forming blood vessel-like structures. In fact, both epithelial and mesenchymal markers have been observed in tumor cells engaged in VM formation ,106,107.et al found th0 family . Hypoxia0 family ,110–112.ly (et al found thly (et al,115. Thu3 depending on the diffusion of oxygen and nutrients (et al(It is clear that tumors are able to grow to a size of ~1–2 mmutrients . In ordeutrients . Keunen ts (et al found thet al(In reality, the coexistence of angiogenesis and VM is common within aggressive tumors. Angiogenesis inhibitors have little or even no effect on VM ,19 and Vet al reportedFor quite some time, the survival rate of patients with aggressive tumors has remained at a low level, despite the administration of surgery, chemotherapy and radiotherapy. The existence of CSCs was thought to be an underlying cause. Although CSCs comprise only a small proportion of tumor cell populations, CSCs have high resistance to multiple chemotherapeutics and ionizing radiation. Remaining CSCs are able to induce recurrence following treatment with chemotherapy and radiotherapy. Furthermore, it has been demonstrated that CSCs are implicated in VM formation. In this context, CSCs have been considered as a promising treatment target in cancer patients with VM. It has been observed that tumors undergoing the process of EMT acquire resistance to chemotherapy . EMT is


We have applied the mathematical model of compartmentalized energy transfer for analysis of experimental data on the dependence of oxygen consumption rate on heart workload in isolated working heart reported by Williamson et al. The analysis of these data show that even at the maximal workloads and respiration rates, equal to 174 μmol O2 per min per g dry weight, phosphocreatine flux, and not ATP, carries about 80–85% percent of energy needed out of mitochondria into the cytosol. We analyze also the reasons of failures of several computer models published in the literature to correctly describe the experimental data.In this review we analyze the recent important and remarkable advancements in studies of compartmentation of adenine nucleotides in muscle cells due to their binding to macromolecular complexes and cellular structures, which results in non-equilibrium steady state of the creatine kinase reaction. We discuss the problems of measuring the energy fluxes between different cellular compartments and their simulation by using different computer models. Energy flux determinations by  This value matches the maximum total activity of CK in the direction of MgATP synthesis, 62.4 ± 4.5 mM/s, measured in perfused rat hearts . The conet al. [et al.  and showModel also reproduces the observed PCr levels at different workloads .et al. described above [ed above –8.et al. for 2- dimensional analysis of metabolites’ diffusion within ICEUs [The A-S model was upgraded further by Vendelin in ICEUs . The newin ICEUs . Both moin ICEUs , explainin ICEUs ,103. Nowin ICEUs  proportim of 31.7 s−1, in contrast to that value in [−1. What are the declared reasons for these simplifications? An early observations of Erickson-Viitanen et al. 1982 [in vivo? Using isolated mitochondria, it was shown that by simple addition of creatine to a mitochondrial suspension, in the presence of respiratory substrates without added nucleotide, these mitochondria produce and release PCr into the supernatant that is formed by intra-mitochondrially cycling ATP and ADP via creatine-stimulated respiration . The results of probability model calculations are essentially in line with recent direct experimental measurements by Timokhina et al. [in vitro and in vivo.Further, experimental studies with application of Metabolic Control Analysis showed very high control strength within the MI structure at high level of ATP in the permeabilized cardiomyocytes ,77. Thisa et al. . Basing a et al.  on nullimito. With taken general model parameters, the experimental tmito values of about 4 seconds were fitted by membrane permeability parameter PSm = 13.3 s−1, while with PSm = 0.1 s−1 from [mito was about 15 s  models [Very high permeability of MOM to ADP was inferred by van Beek ,103 froms−1 from  the tmit31.7 s−1 . In the ) models ) should −1*kg wm−1) to medium (0.678 mmol ATP*s−1*kg wm−1) workload. Steady-state parameters for these workloads are indicated in Table 3 in [mito can be approximated even at imposed severe diffusion restrictions for ADP on MOM. The parent relation of our models [et al. [et al. in order to understand how is it possible to use similar models to attain principally different results. Data of such modeling, performed with our model [mito value at very high, about 90%, fraction of PCr diffusion out the rat heart mitochondria. Myoplasmic PCr/Cr ratios during the diastole are high, 2.6–1.8. In the System A on the second line in ble 3 in  for glucr models ,89 to a  [et al. ,103 allomito value is high, 8.7 s, out the experimental estimations. In similar conditions van Beek estimated tmito as high as 15 s  and adenine nucleotides. Last line in mito and PCr/Cr ratios, not affecting the low fraction of energy export by PCr. The question arises, how justified are the changes in model parameters made in van Beek’s group? Authors ascribe these changes to peculiarities of rabbit heart muscle [High tbout 4 s . This rebout 4 s —15 ± 8%.t muscle . Availab3 contents are slightly lower in rabbit heart mitochondria  than in protein  ), but tectively ). Takingectively ), we havectively . As relaectively ,103, the [et al. : in rabb [et al. . This es [et al. . Based o [et al. ,103 by tet al., the stability of total CK unidirectional flux is lost at extremely high energy demand levels leading to a drop of total CK unidirectional flux and to a bypass of CK shuttle by direct ATP transfer from the mitochondria to the myofibrils [A recent manuscript published in the Journal of Biological Chemistry by Vendelin, Hoerter, Mateo, Soboll, Gillet and Mazet entitled: “Modulation of energy transfer pathways between mitochondria and myofibrils by changes in performance of perfused heart”  is also ofibrils . For treofibrils .in vivo kinetic studies and metabolic flux determination is the isotope tracer method, as described above. Another technique of labeling the phosphoryl groups in ATP and PCr in heart cells is 31P NMR saturation or inversion transfer, already applied in many laboratories [et al. [et al. [These results and their interpretation, made in the work referred to above, are not consistent with a large body of existing data, including Vendelin’s own results published before in many articles ,102,104.ratories ,47–50. Tratories  and Kupr [et al. . In sevein vivo, tubulin binding to voltage-dependent anion channel in mitochondrial outer membrane specifically decreases its permeability for ATP, but not for creatine and phosphocreatine and coupled reactions in Mitochondrial Interactosome, consisting of tubulin, VDAC, MtCK and ATP Synthasome result in effective phosphocreatine (PCr) synthesis with PCr/O2 ratio close to 6 [18O2 measurements described above. There is, however, also a certain proportion of MM-CK in the cytoplasm that is in a quasi equilibrium state, which does not depend on the workload, if PCr and ATP contents do not change, as it is seen in heart in the state of metabolic stability [31P-NMR saturation or inversion transfer techniques would still show the total CK activity that is present. If the cells are intact, this activity would not change, and CK flux measured by 31P NMR therefore should not change either and never decrease. Vendelin et al. [The CK pathway is now described in great detail –28. In hose to 6 . This letability . Even ifn et al.  now are n et al. ? For the2+ concentration together with isoprenaline, a method which is known to induce severe damage in cardiac cells [2+ concentration induced by catecholamines is known to induce mitochondrial permeability transition pore (PTP) opening, mitochondrial swelling, MtCK detachment, sarcolemmal rupture and CK release. It is also known that uncoupling of MtCK from the mitochondrial adenosine nucleotide translocase (ANT), which results in a loss of creatine-stimulated respiration, ultimately leads to significantly increased production of highly reactive ROS or RNS species [et al.: total content of ATP decreased from 7.78 to 4.7 mM in the presence of high Ca and isoprenaline. The dramatic 40% decrease of ATP and 200% increase of Pi .et al. is equal to 75 μmol O2 per min per g dry weight, less than half of the maximal respiration rate 168 μmol O2 per min per g dry weight obtained in experiments with working heart model when workload change is induced by changing ventricular filling on the basis of Frank-Starling mechanism [Note that with this drastic means of catecholamine-induced increase in workload in the presence of 4.0 mM Ca leading to degradation of 40% of ATP, manifold increase of Pi content and loss of CK flux, respiration rate achieved in the work by Vendelin echanism ,99.Most surprisingly, the authors themselves were aware of the importance of the stability of the metabolites’ levels in the studies of energy fluxes: in their previous work  they wriThe other main question is: how adequate are the “mathematical models” used. et al. [In conclusion, both correct modeling by taking into account all existing experimental data, as well as qualified experiments avoiding artifacts such as induced in the work by Vendelin et al. , are nee31P saturation transfer spectroscopy to study the kinetics of the creatine kinase in muscle cells by saturating γ-ATP phosphate and recording the transfer of magnetization to PCr, Nabuurs et al. discovered the binding of ATP and ADP to macromolecular complexes in the cells, explaining the mechanisms of ATP compartmentation and non-equilibrium state of the creatine kinase reaction in the cells [18O transfer method that in the heart, the phosphocreatine fluxes from mitochondria into cytoplasm transport about 80% of energy needed for contraction and ion transport, and about 20% of energy is transported into cytoplasm via adenylate kinase and glycolytic phosphotransfer pathways [There is an excellent agreement between recently published data from many laboratories, which give now the possibility of quantitative description of the energy fluxes between mitochondria and cytoplasm in muscle cells. By using the pathways –9. Very pathways ,89. The pathways  and by cpathways .


Thus, in addition to decreasing the frequency of occurrence and growth of tumours, fucoxanthin has a cytotoxic effect on cancer cells. Some studies show that this effect is selective, i.e., fucoxanthin has the capability to target cancer cells only, leaving normal physiological cells unaffected/less affected. Hence, fucoxanthin and its metabolites show great promise as chemotherapeutic agents in cancer. Fucoxanthin is a marine carotenoid exhibiting several health benefits. The anti-cancer effect of fucoxanthin and its deacetylated metabolite, fucoxanthinol, is well documented. In view of its potent anti-carcinogenic activity, the need to understand the underlying mechanisms has gained prominence. Towards achieving this goal, several researchers have carried out studies in various cell lines and  With the establishment of the anti-carcinogenic property of fucoxanthin, it was important to understand the mechanism by which it exerted its effect in cells. With this goal in mind, several researchers have been trying to elucidate the molecules and pathways that can be modulated and regulated by fucoxanthin. Mechanistic studies by various researchers have shown that fucoxanthin can affect many cellular processes, and so far have failed to establish a single primary mechanism of action. The objective of this review is to summarize the effect of fucoxanthin in cancer and the underlying mechanisms that have been elucidated in reported studies. The various mechanisms discussed further in this review are shown in Fucoxanthin is a marine carotenoid found in numerous classes of microalgae  and brown macroalgae (phaeophytes) ,2. The cet al.  have revN-ethyl-N′-nitro-N-nitrosoguanidine (ENNG)-induced mouse duodenal carcinogenesis. In addition to the decrease in the percentage of tumor bearing mice, the mean number of tumors per mouse was also significantly lower in fucoxanthin fed mice. A decrease in the percentage of tumor-bearing mice as well as a decrease in the number of tumors induced per mouse by ENNG in the fucoxanthin group was also observed by Okuzumi and co-workers [et al. [et al. [in vivo study by Ishikawa et al. [Nishino  has repo-workers ,11. Admi-workers . Das et  [et al.  and Kim  [et al.  have obsa et al.  revealeda et al. .et al. [2O2 resistant cell lines, they have concluded that reactive oxygen species (ROS) is not the mainstream pathway for apoptosis caused. Contradictory to this, Kim et al. [2O2 and O2− as a result of treatment with fucoxanthin along with accumulation of cells containing sub G1 DNA content (indicating cell cycle arrest in G1 stage). On co-treatment with a commercial antioxidant (NAC), the number of apoptotic bodies and DNA fragmentation of cells was decreased, attributing the apoptotic effect of fucoxanthin to ROS generated. Thus, they have concluded that cytotoxic effect of fucoxanthin is by ROS generation that triggers apoptosis in HL-60 cells, which is contrary to the results of Kotake-Nara et al. [et al. [Several reports on the potent antioxidant property of fucoxanthin and its metabolites are available ,18,19,20et al.  have hypet al. , they ham et al.  have obsa et al. . Shimoda [et al.  have rep [et al.  have repin vivo has been explored by many researchers [et al. [et al. [The effect of fucoxanthin on cell viability in cancer cells such as GOTO, HL-60, Caco-2, HepG-2, Neuro2a, DU145, PEL, PC-3, HeLa, H1299, HT-29, DLD-1 cells, and earchers ,32,33,34 [et al.  comparedet al. [et al. [et al. [et al. [et al. [Yamamoto et al.  have con [et al.  have rep [et al.  have rep [et al.  on 11 ca [et al.  have repUndaria pinnatifida (Wakame), for one week [et al. [Thus, fucoxanthin was found to have a significant effect on cell viability and anti-proliferative effect and in several studies the potency was different for different cell types/lines. In addition, in several studies, the normal cells were unaffected/less affected than cancer cells indicating differential effect of fucoxanthin and focused targeting of cancer cells ,36,37,38one week . In anot [et al.  have rep0/G1 stage by fucoxanthin has been observed in many studies involving different cell lines [et al. [2/M phase. Muthuirullappan and Francis [et al. [0-G1 phase with a significant decrease in cells in the S phase, indicating a block in the progression of the cells to S phase from the G0-G1 phase, resulting in inhibition of proliferation of the cells has been reported in GOTO cell line [1 stage and this was accompanied by alteration in the expression of more than 50 genes in HEPG2 cells [et al. [et al. [1 peak along with concentration of cells in G0/G1 phase and their decrease in the S and G2/M phases. In addition, pRb, cyclin D1, cyclin D2, and CDK4 levels were decreased along with increased p15INK4B, p27KIP1 levels. Murakami et al. [in vitro.The arrest of the cell cycle in the Gll lines ,44,45,46 [et al.  have obs Francis  have att [et al.  have repell line . FucoxanG2 cells . In addi [et al.  have fou [et al.  have obsi et al.  have repet al. [0/G1 phase at lower concentrations of fucoxanthin (25 µM), followed by apoptosis at high concentrations (>50 µM) with increased cells in sub G1 phase (index of apoptotic DNA fragmentation) and fragmentation of nuclei. Low and high concentrations of fucoxanthin up regulated the protein and mRNA levels of p21WAF1/Cip1 followed by increased levels of pRb (retinoblastoma protein), while high levels up regulated p27Kip1 as well (cdk inhibitory proteins) leading to the conclusion that fucoxanthin-induced G0/G1 cell arrest is mediated by the up regulation of p21WAF1/Cip1. They have speculated that the apoptosis observed at higher concentration may be due to partial conversion of fucoxanthin to its metabolites such as fucoxanthinol. From their results they have concluded that p21WAF1/Cip1 is important for the cell cycle arrest while p27Kip1 regulation may be a means for pro-apoptotic effect of fucoxanthin. Reduction in the phosphorylation of pRb protein, which is a regulator of cell cycle progression and down-regulation of other cell cycle regulatory proteins like cyclin D2, CDK4, CDK6, and c-Myc was reported by Yamomoto et al. [et al. [Kip1 p21Waf/Cip1, p57, and p16 were unchanged over this period indicating that inhibition of cyclin D/cdk4 activity by fucoxanthin was brought about by suppressing the levels of proteolysis and transcription of cyclin D. An increase in proteosomal activity was observed after 12 h of fucoxanthin treatment. Thus, they have suggested that fucoxanthin induced cell cycle arrest by suppression of cyclin D by proteosomal degradation and transcriptional repression. They have speculated that the decreased cyclin D expression may be due to change in the GADD45A expression.Das et al.  have obso et al. . A decre [et al. . Fucoxanet al. [Apoptosis of cancer cells is a promising method to control and treat cancer. In this regard, the apoptotic effect of fucoxanthin is of interest and has been studied by several researchers. Hosokawa et al.  have repet al. . DNA fraet al. . Howeveret al. [et al. [The results obtained by Konishi et al.  show the [et al.  have repExpression of v-FLIP and v-cyclin was inhibited and may be responsible for growth inhibition and apoptosis observed with fucoxanthin treatment . The autet al. [Metastasis is the stage of cancer at which tumor cells acquire the advantageous characteristics that allows them to escape from the primary tumor and migrate to surrounding and distant organs and tissues. Metastasis involves the interaction of the tumor cells with numerous factors and cell components including matrix metalloproteinases (MMPs). MMPs are thought to assist tumor cells in metastasis and their enhanced levels have been associated with extra-cellular matrix degradation and cancer cell invasion . Chung eet al.  have stuL, A1, Bcl-w, and Boo, while the pro-apoptotic members include Bax and Bak, Bok, Bcl-xs, Bim, Bad, Bid, Bik, Bmf, Puma, Noxa, and Hrk [et al. [et al. [L and XIAP by fucoxanthin was observed by Yamamoto et al. [et al. [et al. [et al. [L, Kotake-Nara et al. [L was unaltered, unlike other apoptosis-inducing agents that modulate the ratios of the pro- and anti-apoptotic proteins, fucoxanthin may operate through a different pathway.The family of Bcl-2 proteins has anti-apoptotic and pro-apoptotic members. Anti-apoptotic Bcl-2 family proteins include Bcl-2, Bcl-x and Hrk ,55. Seve and Hrk ,27,50. N [et al.  observed [et al.  studied o et al.  and Kim  [et al. , while I [et al.  reported [et al.  observeda et al.  on the oet al. [et al. [et al. [The caspases are cysteine proteases that control apoptosis. The extrinsic pathway involves the tumor necrosis factor and activates the caspases 8 and 10 while the intrinsic pathway involves the mitochondria and release of cytochrome c from damaged mitochondria, activating Caspase-9, which is an initiator and in turn can cleave and activate the effector Caspases such as Caspases-3, -6, and -7. These two Caspase pathways, intrinsic and extrinsic, can result in apoptosis. The intrinsic pathway involving the mitochondria and caspases-3, -6, -7, and -9 are controlled by the Bcl-2 protein family . The actet al. , Ganesan [et al. , Zhang e [et al.  have obs [et al. . Fucoxan [et al. . Express [et al. . Fucoxan [et al. . The res [et al. .2 terminal kinases, also called as stress-activated protein kinases (SAPK); (3) p38 enzymes including p38α, p38β, p38γ, p38δ, and the recently identified; (4) ERK5. ERK1 and ERK2 regulate cell processes like mitosis, meiosis, post mitotic functions, and are responsible for proliferation, cell division, differentiation, development and survival. STAT  proteins such as Stat3 are substrates that are phosphorylated by ERK and are activators of transcription. The JNK/SAPKs are activated by conditions such as oxidative stress and result in programmed cell death or apoptosis, growth and cell cycle arrest as well as inflammation and tumorigenesis and cell survival under certain conditions. C-Jun is a component of the AP-1 complex that is an important regulator of gene function and is activated by environmental stress, radiation and growth factors. The p38 MAPKs control the expression of several cytokines and are involved in the immune response mechanism in addition to cell motility, apoptosis, chromatin remodeling, and osmoregulation [The MAPK family or the mitogen activated protein kinase includes four well characterized sub-groups: (1) ERK1 and ERK2 that are extracellular signal kinases; (2) JNK1, JNK2, and JNK3 with the c-Jun NHgulation ,59. Gaddgulation ,61. et al. [et al. [Fucoxanthin was found to attenuate cisplatin induced phosphorylation of ERK, p38, and P13K/AKT (phosphatidylinositol 3 kinase family) in the studies carried out by Liu et al. . Their e [et al.  have obsN-terminal kinases (SAPK/JNK)) and its association with the GADD45 activation for cell growth arrest in LNCap cells (prostate cancer). GADD45A may be implicated in the G1 arrest observed in the study. While the GADD45A gene was enhanced, GADD45B gene expression was unaffected after fucoxanthin treatment. With respect to the MAPK family, SAPK/JNK was increased, phosphorylation of ERK 1/2 was reduced and phosphorylation of p38 was unaffected. While it is suggested that MAPKs including SAPK/JNK induce GADD45A in a p53 dependent or independent manner, the author has suggested a p53 independent mechanism in the present study. In addition, inhibition of the SAPK/JNK pathway reduced GADD45A induction while inhibition of ERK 1/2 and p38 pathways stimulated GADD45A induction. The author has suggested that each MAPK plays a different role in GADD45A induction and G1 arrest by fucoxanthin based on the negative regulation of p38 MAPK resulting in increased GADD45A expression along with other observations in prostate cancer cells. Contrasting results obtained for ERK 1/2 MAPK in LNCap cells and in DU145 cells earlier indicate that GADD45A may not be the only factor responsible for the G1 cell arrest observed in that study. Thus the growth inhibitory effect exhibited by fucoxanthin may in part be due to a GADD45A-dependent pathway and the enhanced GADD45A expression and G1 arrest are positive regulated by SAPK/JNK in prostate cancer cells.In a separate study, Satomi and Nishino  found thet al. [et al. [Yu et al.  have obs [et al.  reportedThe nuclear factor kappa B (NF-κB) is a family of closely related transcription factors that are held in the cytoplasm in the inactive form by their interaction with the inhibitor of κB (IκB). IκBs include IκBα, IκBβ, IκBε, and BCL-3. The phosphorylation of IκB results in activation of NFκB and its translocation to the nucleus, followed by induction of target genes and the resulting effects. NF-κB may be activated by many cytokines, growth factors and their receptors, tyrosine kinases, tumor necrosis factor receptor families, other signaling pathways, such as Ras/MAPK and PI3K/Akt. NF-κB promotes resistance to apoptosis and may also exhibit pro-apoptotic properties. NF-κB inhibits p53-induced apoptosis by up-regulating anti-apoptotic genes, and decreasing p53 levels. As NF-kB is associated with several tumor/cancer related processes, such as its activation by pro-inflammatory cytokines and its ability to induce cell proliferation and anti-apoptotic gene expression, as well as induction of angiogenesis, it is often considered as a hallmark of cancer ,63. et al. [Cisplatin has the potential to bind to the DNA molecules, forming platinum-DNA adducts which interfere with transcription and replication of the DNA, resulting in cell death ,65. Seveet al.  have alset al. . Differeet al. .et al. [Due to their wide range of substrate selectivity CYP3A enzymes play a major role in metabolism and are of special relevance in the metabolism of clinically used drugs . The cytet al.  have exaet al.  have obset al. [Gap junctional intracellular communication (GJIC) is a mechanism for intercellular cell communication and operates at sites of cell adhesion where plasma membranes of cells can be connected by buried paired channels. Thus, GJIC regulates the communication between cells of tissues of an organ, allowing for direct communication between the cytoplasm of cells without transit through the extracellular space, making it possible for the cells to achieve a common and integrated target/metabolic activity . Gap junet al.  have attet al.  have alset al. [et al. [et al. [et al. [N-Myc oncogene, known to be over expressed in neuroblastoma, was reduced by fucoxanthin treatment in GOTO neuroblastoma cell line and this effect was found to be reversible when fucoxanthin was removed from the media . Surviviet al.  studied  [et al. . Yamamot [et al.  and Ishi [et al.  also obset al. [Sugawara et al.  have repFucoxanthin influences a multitude of molecular and cellular processes. It exerts strong effects on cancer cells and shows synergistic activity in combination with established cytotoxic drugs. This raises the possibility that it could become an interesting anti-cancer compound in various types of cancer.


A commentary onMen and women show distinct brain activations during imagery of sexual and emotional infidelityby Takahashi, H., Matsuura, M., Yahata, N., Koeda, M., Suhara, T., and Okubo, Y. (2006). Neuroimage 32, 1299–1307.Among complex social emotions, there is a very important emotion called “romantic jealousy.” “Romantic jealousy is defined as a complex of thoughts, feelings, and actions which follow threats to self-esteem and/or threats to the existence or quality of the relationship, when those threats are generated by the perception of a real or potential attraction between one's partner and a (perhaps imaginary) rival” White, , p. 24. attention” or “attentional networks”; and “attention and evaluative bias” to explain their results, which is the main focus of this paper.Takahashi et al.  discusseTakahashi et al.  used funThe full brain volumes were imaged using 40 transaxial contiguous with a slice thickness of 3 mm. To assess the specific condition effect, they used the contrasts of sexual infidelity minus neutral (SI-N) and emotional infidelity minus neutral (EI-N). Correlation coefficients between the degree of activation and rating of jealousy for emotional infidelity were also calculated.They did not find gender differences in ratings, but they did find neural differences. Common brain areas such as the frontal regions  and the cingulate cortex were activated in both groups for the emotional infidelity condition. However, men demonstrated greater activation in the amygdala and hypothalamus than women. In contrast, women demonstrated greater activation in the posterior superior temporal sulcus (pSTS) (angular gyrus). A positive linear correlation was also observed between self-rating of jealousy for emotional infidelity and the degree of activation in insula for men and in pSTS for women. Takahashi et al.  explaineattention and evaluative bias” toward the processing of negative information, which might contribute gender differences in the processing of emotional information. It has been reported that females showed remarkable attention and evaluative bias even for the processing of moderately negative information, whereas males showed neither biases for these information  and the cingulate cortex, both of which areas are involved in attentional networks. Pessoa et al. (Apart from gender differences, Takahashi et al.  did not a et al.  suggestea et al.  suggestea et al. . This nea et al. , despiteattention and evaluative biases,” and “attentional network” mechanisms underlying emotional processing in males and females. These interpretations have implications to understanding the complete picture of gender differences observed in neural processing of emotion information. Future work should be done toward investigating the functional differences between males and females for different emotion processing.Together with explanations reported in the Takahashi et al.  study, i


This review has been done after careful research of articles published in indian journal of psychiatry with the search words of manic depressive psychosis and bipolar mood disorder. Many articles in the following areas are included: 1) Etiology: genetic studies: 2) Etiology – neuro psychological impairment: 3) Adult bipolar disorder 4) Epidemological 5) Clinical picture – phenomenology: 6) Course of bipolar mood disorder: 7) Juvenile onset bipolar affective disorder 8) Secondary mania: 9) Clinical variables and mood disorders: 10) Disability: 11) Comorbidity: 12) Treatment: biological 13) Recent evidence: 14) Pharmacological evidence in special population. Though there seems to be significant contribution, there are still lot of areas which need careful intervention. The findings in various studies from the indian point of view are reviewed. In 1896, Kraeplin reported ‘manic-depressive psychoses’ as a circumscribed disease entity. Ever since, manic depressive psychosis, or the current term used nosologically as ‘bipolar’ mood disorder, has been studied in the Indian perspective. Though it seems like there is no orderliness in the research pursuit of understanding this disorder in the Indian context, one gets an impression that all aspects like nosology, clinical syndromes, course, pharmacological and in special populations as well, were attempted to be looked at from the Indian context. This review is an attempted peep into Indian context research.A review of the studies on bipolar mood disorders (Manic Depressive Psychosis) over the last many decades, published in Indian Journal of Psychiatry, conveys the feeling that over the years, though many aspects have been studied, there is no consistency in reports across the country. Reviewing research would find case reports to studies and reviews. Representative studies have come from across the country and in a way present the diversity of various centers; it doesn’t seem to come from one center alone. We attempt to collect all the studies published in this area by going through as many old issues of Indian Journal of Psychiatry as were available.vis a vis normal groups in various measures. The significance found was - Patients with manic depressive psychosis and with positive family h/o had differed as a group with negative family h/o, making the authors to conclude that genetic factors do play a role in manic depressive psychosis.Dermatoglyphics as a diagnostic tool studied 100 normal, 60 manic depressive psychosis subjects, 30 unipolar subjects, 30 bipolar subjects at Chandigarh.[Among 25 patients with 1.4 years of optimum serum level of 0.6 M.EQ/L, precise and absence of positive h/o of psychiatric illness in first degree relatives of family members was seen. The patients were divided into two groups based on chart reviews in responders and non responders. Responders significantly had positive family h/o affective illness. Though this study had only a small sample, for the first time in Indian literature, it commented on the genetic aspects of pharmacological response.et al. 2000 at Central Institute of Psychiatry (CIP), Ranchi;[Genomic imprinting in bipolar affective disorder was studied by R. Kumar , Ranchi; in the fM Taj and Padmavathi R have asset al.[Chopra HD et al. have attChatterjee and Kulhara have repIn this study, the behavior affect, speech, delusions and hallucinations was done using PSE Items and the periodic assessments helped to show the resolution time of each symptoms preponderance of male subjects was noted. Mean duration of current episode was shorter in males compared to females.Symptomatologically, Indian patients differed significantly as having distractibility as symptoms and more of embarrassing behavior. Hostile irritability is the dominant affect, 62.5% had one or more delusions. In this sample, which is more than many studies reported by other international studies notably Taylor and Abrams (1973) Carlson and Goodwin (1973) in terms of recovery by four weeks, delusions and hallucinations disappear.Authors comment that where some symptoms resolving quickly, where some resolve quickly, others much slowly. Only 15% remained hospitalized for 90 days, and majority got discharged early; authors conclude that in India Mania patients resolve early with treatment. This is one study which systematically studied the clinical symptomatology in the Indian context, at PGIMER Chandigarh.et al.[et al. 1998).R Kumar et al. have carThere were three factors which had significant variance-factor number one had motor activity, pressured speech, racing thoughts, increased sexuality, increased contact as the clinical symptoms and, in essence, picks up psychomotor acceleration as the main factor and has largest variance in the patient sample. The second factor picked up thought disorder and psychosis with grandiosity, lack of insight and paranoid factors. The third factor, which has about 13.8% variance, represented mood with large percent having irritability (82%), euphoria (51%), aggression (70%), anxiety (59%) as phenomenology, the study has a good sample size, good methodology representing Indian population.et al.[et al. and using survival plot of resolution. The authors attempted to see gender differences in resolution of manic symptoms, in sample of 40 . The attempt included to see the differences both in severity and symptomatology across the genders. There were significant difference at Index rating on certain items in females-viz. increased sexuality and aggression.R Kumar et al. have stuet al. In contret al. the methet al.[Srinivasan et al. have attet al. studied et al. This data is from the Primary Health Centre, Sakalwara, adapted at NIMHANS, 27 patients of 34 patients evaluated had not received any treatment at all, though there were many episodes 15% of patient has had rapid cycling, episodes of manic accounted for 72% of episodes. None of the variables examined could predict the total number of episodes. However, patients receiving psycho pharmacological agents are likely to develop rapid cycling. A mania predominant course was observed in this study cohort.A naturalistic course of bipolar disorder in rural India was repoThere are very few studies in this area, published in Indian journal of Psychiatry, except for case reports.et al.[Narasimha Rao IV L et al. have foret al. has repoTricyclic anti depressant-induced mania was presented in a case report of four mono polar depressed patients who developed mania after tricyclic anti depressant therapy. This stuet al.[There are many case reports of mania occurring due to other medical conditions or due to drugs were reported-Chronic mania due to polio encephalomyelitis, Tertiaryet al. have triYadav R and Pinto C report aet al.[et al.[Mania in HIV infection was reported by Venugopal D et al. where thl.[et al. discussel.[et al. seen foll.[et al. Turners l.[et al.Mania starting during hypno therapy into manet al.[Gurmeet Singh et al. have attet al.[Singhal A K et al. have invet al.[Tapas K A et al. have attet al.[H Taroor et al. attempteet al.[et al.[A few case reports of comorbid, other psychiatric illnesses in bipolar mood disorders were reported in Indian literature. Dysmorphophobia as a comorbid disorder occurring in both depressive episodes and manic episodes in a case of bipolar mood disorder was described by Sengupta et al. The diffl.[et al. have disThere has been a large volume of research reported in the treatment aspects. There have been models to explain the treatment approaches and various clinical trials to show early evidence for various drugs both from experience and experimental.Interestingly, the first report on treatment of manic depressive psychosis treated with long term electro convulsive therapy was by Bhaskaran, who descet al.[Lithium kinetics was studied by Pradhan N et al. They havet al.[et al.[N Desai et al. Gangadhal.[et al. have, inl.[et al. in a firI. P. Khalkho and Khess C. R. J have attThe role of quetiapine monotherapy was presented in a case report by Khazaal Y arguing et al.[Solanki R K et al. have, inet al.[M Trivedi et al. have, inPradeep R J has highIn an interesting case report, V Agarwal and Tripathi report oR Balon has in het al.[Khandelwal S K et al. have repMohandas E and Rajmohan V have in There has been a lot of research on bipolar mood disorders. Significantly, not many studies have been reported on biological, neuro imaging and genetic studies and long term course of bipolar disorders. There is also less replication of significant aspects of the bipolar mood disorder. Most studies have a small number as sample, the later studies methodologically improved. Multi centric studies done across the study with sound methodology and in various above areas of different areas will have to be done to generate the Indian data. Likewise, pharmacologically, the often repeated subjective to experience of optional dose of various medications will also have to be studied.Transcultural differences have to be highlighted by attempting to do research in these areas. More naturalistic studies done across rural and urban background will help us to understand the course of bipolar in Indian context. The specific factors of psycho social and compliance issues in drug and therapy in the Indian context need to be studied.


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Mood stabilizers have revolutionized the treatment of bipolar affective disorders. We review data originating from India in the form of efficacy, effectiveness, usefulness, safety and tolerability of mood stabilizers. Data is mainly available for the usefulness and side-effects of lithium. A few studies in recent times have evaluated the usefulness of carbamazepine, valproate, atypical antipsychotics and verapamil. Occasional studies have compared two mood stabilizers. Data for long term efficacy and safety is conspicuously lacking. Psychopharmacology has revolutionized the understanding and treatment of major mental disorders. With the help of psychopharmacological agents, not only is the neurobiology of various psychiatric disorders being understood, but effective treatments have improved relapse rates, symptom free period, significantly improved the quality of life of patients and have reduced the burden experienced by patients and their families.Prior to lithium, typical antipsychotics and electroconvulsive therapy was used for management of bipolar disorders. However, over the years many drugs have been evaluated as mood stabilizers and have been shown to be efficacious, although the definition of a mood stabilizer is not yet settled.Psychopharmacological research in India regarding mood stabilizers has lagged behind the data from the West. However, there has been a shift of research from mere case series to attempts at multicentric double blind controlled trials. In this review, we would review data on mood stabilizers originating from India on various mood stabilizers. The review shall focus on the research published in Indian Journal of Psychiatry and studies reported in PubMed indexed journals.Amongst various mood stabilizers now available in India, lithium has been the most researched of all. There are a few studies on other mood stabilizers such as carbamazepine and sodium valproate.After its introduction in India in the late 1960s, lithium aroused a lot of research interest in the 1970s and 80s, with most of the research revolving around open trials to see its usefulness in various disorders (mainly mood disorders) and its side-effect.et al.[564et al.[The mood stabilizing property of lithium has led Indian researchers to see its effects in affective disorders. In their earliest work on role of lithium on mood disorders, Dube et al. in an unet al.–8 Most oet al.568 Studiet al.56 and goodet al.56 and preset al.565 Patientet al.5649 Studieet al.564 whereas et al.564 In an ef564et al. found th564et al.With regard to early onset bipolar disorder a retrospective chart review found that lithium was the most commonly used mood stabilizer, followed by valproate. However, during the follow-up period of three to 56 months it was seen that 28% of subjects relapsed despite being on apparently adequate doses of lithium.et al.[With regard to organic mania, a recent case report by Loganathan et al. reportedet al. (1980)[+, K+, Li+ to extra cellular concentration of these ions in a group of 22 patients of bipolar affective disorder who were divided into responders and non-responders. No significant difference between two groups was found as regards to these values.Sampath l. (1980) determinl. (1980) examinedIn a double blind placebo controlled cross over trial between lithium and chlorpromazine lasting for four weeks, Dube and Sethi reportedStudies have also showed that lithium is useful in management of aggression in patients of various diagnostic categories who were non-responsive to antipsychotics, electroconvulsive therapy, antiepileptics and sedatives. Authors recommended use of lithium in dose of 500- 750 mg/day (Serum lithium 0.75-1.2 mEq/L) in patients with unspecified aggression. Lithium et al.[et al.[et al.[et al.[et al.[Attempts have been made to estimate saliva levels and see their correlation with serum lithium levels with conflicting results. Prakash et al. investiget al. lithium l.[et al. comparedl.[et al. observedl.[et al. who basel.[et al. found thl.[et al. In a casl.[et al. reportedResearch on side-effects of lithium has been focused on general side-effects and specific side-effects on various systems.et al.[et al.[Venkoba Rao et al. examinedl.[et al. reportedet al.[One study compared the cognitive function of 34 bipolar patients on lithium (serum lithium between 0.6-1.2 mEq/L) with 30 matched controls. There was no difference on cognitive testing as measured by Bhatia Battery test, PGI memory scale and Bender Gestalt test. However, on self assessment of cognitive functions, patients experienced feeling of subjective cognitive impairment.[et al. performeet al.[et al.[Residual neurological side-effects after lithium toxicity in the form of dysarthria, nystagmus and generalized cerebellar damage have been reported.–40 Andraet al. also repl.[et al. reportedl.[et al. reported+ excretion, normal glomerular filtration rate (GFR) and renal tubular acidification. It has also been shown that serum lithium levels correlate positively with daily urine volume and negatively with urine specific gravity. Studies have also shown that there is no relationship between total amount of lithium consumed or duration of treatment with renal impairments.[44Five controlled studies have examined renal side-effects of lithium in humans.44–47 In airments.4446 A rerments.44 Another rments.44 In one srments.44 Despite et al.[4, free thyroid index or TSH. Srivastava et al.[3 levels and decreased T4 levels in 13% of subjects with bipolar disorder. The authors noted that high dose and high serum lithium levels increase the possibility of reduction of thyroid function status. In a case report Jayesh[Despite well-documented adverse effects of lithium on thyroid functions and good quality research from West, there has been little enthusiasm to study thyroid functions in Indian subjects. In an uncontrolled study which included 40 patients with bipolar disorder on prophylactic lithium with serum lithium of 0.83 (SD 0.20 mEq/L), Kuruvilla et al. assessedva et al. comparedrt Jayesh reportedet al.[P < 0.05) with lithium treatment ranging from 61 to 240 months as compared to the corresponding values in the control group.In a study from PGIMER, Chandigarh, Deodhar et al. comparedet al.[et al.[Venkoba Rao and Hariharsubramaniam examinedet al. reportedl.[et al. reportedet al.[+2, Ca+2 levels in 17 patients of affective disorder, on lithium and followed them prospectively and observed increase of total serum Mg+2, which was more so in patients who relapsed and the authors pointed at deficiency of Mg+2 at cellular level as a probable cause of episodes.Srinivasan et al. assessedParvathi Devi and Rao labeled et al.[In a case report Grover and Gupta reportedet al. with theIn a case report, abrupt withdrawal of lithium in a patient with recurrent depressive disorder led to development of hypomania.et al.[et al.[In contrast to lithium there has been little research on use of carbamazepine in psychiatric disorders from India. In a controlled trial, Sethi et al. recruitel.[et al. reportedet al.[et al.[Based on the kindling hypothesis, Das et al. divided et al. reportedl.[et al. reportedA case series suggested that carbamazepine (600 mg/day) can lead to worsening of psychotic symptoms in toxic range.Among the three mood stabilizers, valproate has been used most recently for treatment of mood disorders. Some of the recent studies have compared the efficacy/effectiveness of valproate with other mood stabilizers.–74 A few75et al.[Chadda et al. evaluateet al.In a recent case series, Pradeep presenteet al.[P < 0.01). The mean YMRS score of 37.2 at baseline reduced to 14.5 at the end of the trial in the risperidone group and this was significantly better than the placebo group. Extrapyramidal side-effects were reported by 35% of subjects in the risperidone group (compared to 6% in the placebo group) and these were the most frequently reported adverse events in the risperidone group. Another side-effect which was reported by more than 10% of subjects was insomnia; however there was no difference between the two groups on the incidence of the same.In a three-week randomized, double-blind trial, Khanna et al. includedFew studies have compared the efficacy/effectiveness of various mood stabilizers in affective disorders. In a randomized controlled trial of four weeks duration, Prakash and Bharath comparedet al.[P = 0.123).In the primary efficacy analysis, valproate group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the carbamazepine group. In the CBZ group, significantly more patients required rescue medication during the week 2 and the requirement was quantitatively more as compared to the valproic acid group. In a recet al. comparedP <; 0.01). In a 1 week parallel group randomized comparative prospective study trial, Solanki et al.[A significantly greater number of patients in divalproex group experienced one or more adverse drug events as compared to patients in the oxcarbazepine group , Khess et al. comparedet al.[et al.[In an open label six-month prospective randomized controlled trial, Gangadhar et al. comparedl.[et al. are alsol.[et al.Various case reports have suggested that use of multiple medications in subjects with affective disorders can lead to side-effects like Steven Johnson syndrome.–85 Case Most of the literature on mood stabilizers pertains to lithium. Studies have found it to be useful in Indian patients for management of bipolar disorders. In recent times, studies have also compared valproate with lithium and have reported it to be as effective as lithium and more effective than risperidone in management of acute mania. Valproate has also been reported to be better than carbamazepine but equally efficacious to oxcarbazepine in management of acute mania. One double blind randomized controlled trial has also demonstrated risperidone to be better than placebo in the management of acute mania. Studies have also shown that addition of carbamazepine to lithium may be useful in management of acute mania.However, major limitations of the research have been small sample size and lack of multicentric studies. There are no studies which have evaluated the efficacy or effectiveness of various mood stabilizers in the management of bipolar depression. There is dearth of data with regard to usefulness of various medications for prophylaxis. There is an urgent need to conduct multicentric studies.


Cancers, papers highlighting cellular mechanisms of metastasis formation, genetic and epigenetic aspects associated with organ and tumor specific metastasis formation, as well as papers outlining experimental and clinical therapeutic concepts for anti-metastatic treatment are included.The development of secondary distant organ and lymph node metastasis has an extraordinary impact on the prognosis of patients with solid cancer. In most cases the advent of metastatic growth represents the turning point from a local, potentially curable, disease to a systemic non-curable situation. As a highly regulated process, metastasis formation follows a distinct, non-random pattern characteristic for each tumor entity. Metastasis formation and strategies to prevent this lethal event in the progression of cancer is of fundamental interest for cancer science and patient care. In this special issue of et al. [Damsky et al.  suggest et al.  and anatet al.  for deteet al.  provideset al. [et al. [Tumor microenvironment is of immense importance not only for primary cancers but also for secondary sites . In theiet al.  provide et al.  focus on [et al.  in theirUnderstanding the mechanisms of distant metastasis formation has begun to become translated into clinically relevant therapeutic consequences. Chi and Komaki  comprehe