Image-guided tumor ablation provides curative treatment in properly selected patients or appropriate therapeutic options whenever surgical techniques are precluded. Tumor response assessment post ablation is important in determining treatment success and future therapy. Accurate interpretation of post-ablation imaging findings is crucial for therapeutic and follow-up strategies. Computed Tomography (CT) and Ultrasound (US) play important roles in patients’ follow-up post liver thermal ablation therapies. Contrast-enhanced ultrasound (CEUS) can provide valuable information on the ablation effects faster and at a lower cost than computed tomography or magnetic resonance imaging. However, a disadvantage is that the technique cannot examine total liver parenchyma for disease progression as CT and Magnetic Resonance (MR) imaging can. Follow-up strategies for assessment of tumor response includes contrast enhanced multiphasic  imaging with Computed Tomography at three, six, and 12 months post ablation session and annually ever since in order to prove sustained effectiveness of the ablation or detect progression. Hepatocellular carcinoma is the fifth most common cancer type, accounting for 7% of all cancers and the third most common cause of cancer-related death ,2. Imagii.e., treatment success), for follow-up and as a proof for need or not of additional therapy. Ideally, imaging post ablation should be performed by a reproducible and repeatable, cost-effective method that carries no risk to the patient and which can detect residual viable tumor tissue or confirm complete tumor necrosis. Since tumor marker levels can be normal even in cases of partial necrosis, the evaluation of ablation’s effect is based mainly upon imaging studies [Imaging in ablation practice apart from acting as a guiding mode is also used for evaluation of the ablation zone , Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and 1.1) or by functional  criteria ,6,7. MagBy definition, the term curative ablation describes an ablation zone, which covers the whole tumor along with a clear margin  all around the tumor ,9,10. Inetc.) but to preliminarily evaluate therapeutic outcomes as well. Ablation outcome is evaluated within six weeks post treatment in order for post ablative inflammatory changes to subside. This first post-ablation scan serves as the new baseline scan for future evaluation. Subsequently, follow-up strategy for assessment of tumor response includes contrast enhanced multiphasic  imaging with Computed Tomography at three, six, and 12 months post ablation session and annually ever since in order to prove sustained effectiveness of the ablation or detect progression.Immediately post ablation session, a CT scan seems mandatory . MultiphEvaluation of the ablation outcome is important for determining treatment success and future therapy. WHO criteria and RECIST included the initial guidelines for tumor response assessment ,12. BothNowadays, mRECIST criteria are used for tumor response assessment requiring image acquisition protocols with contrast medium, as well as optimization and consistency in the same protocol throughout follow-up examinations ,14. AsseStandard ultrasound structural changes such as hyperechogenicity post treatment are not reliable for the evaluation of ablation’s outcome since residual viable tumor and coagulation necrosis areas are not adequately demonstrated . ContrasMore recent advancements in technology allow demonstration of ablated areas and residual lesions in three dimensions (CE 3D US), this technique is extremely useful for detailed outcome evaluation and seems to be governed by good concordance with the results of contrast enhanced CT in three dimensions . HoweverDynamic Contrast enhanced multi-detector CT scans  are widely used for the evaluation of tumor response in the post-ablation follow-up. Total necrosis and successful ablation of a hepatic lesion appears in CT as a homogeneous non-enhancing attenuation extending all over the ablated volume . A hypoaAbnormal findings of imaging after percutaneous ablation of hepatocellular carcinoma apart from residual or recurrent disease include biliary or vascular complications, infection and any other non-target injury . Biliaryversus 89%) for residual disease detection when compared to Magnetic Resonance Imaging [Computed Tomography scans are governed by lower sensitivity (44%  Imaging . Keeping Imaging . In thes Imaging . In addi Imaging . In thes Imaging ,27. HoweSpecific response criteria based upon certain imaging findings are necessary in order to evaluate the outcome of ablation in hepatocellular carcinoma. Outcome evaluation is crucial not only for valuing a specific ablation technique but also for predicting a patient’s prognosis. In order to successfully evaluate the outcome, post ablation prerequisites include understanding of various response systems, thorough imaging in predefined time points, and occasionally multimodality imaging. Ultrasounds with contrast agents and CTs are widely available and can be considered key players among equals for the evaluation of therapeutic outcomes.


A 26-year-old woman presented with symptomatic recurrent desmoid tumor to her anterior abdominal wall. The patient underwent radical resection of the desmoid tumor. She was left with only 30% of her anterior abdominal wall intact, creating a large defect requiring composite reconstruction.What is a desmoid tumor?What are treatment options for desmoid tumor?What are surgical options for composite abdominal wall reconstruction?What specific considerations should be made when deciding a particular reconstructive surgery?Desmoid tumors are derived from the proliferation of spindle-shaped mesenchymal fibroblast-like cells. Desmoid tumors often present as an aggressive fibroproliferative process, with a variable clinical course. Metastatic disease and dedifferentiation into high-grade malignancy are not typical features.,Treatment options for desmoid tumors include surgical excision, radiotherapy, systemic medical treatment, or combinations of these.1This is a case of a 26-year-old woman who had presented with symptomatic recurrence of desmoid tumor to her anterior abdominal wall . The pat,Composite full-thickness abdominal wall defects continue to be a challenge to the reconstructive surgeon, and special considerations should be made when deciding a reconstructive surgery. The surgeon is required to address the structural, functional, and aesthetic features when considering surgical options. Pedicled ALT flaps are an option for abdominal wall reconstruction. However, the surgeon needs to consider that the pedicled variant is restricted by the pedicle length and therefore is more suitable for reconstruction of the lower abdominal quadrants.4


Carassius gibelio has been revealed to possess multiple modes of unisexual gynogenesis and sexual reproduction, but the cytological and developmental mechanisms have remained unknown. In this study, normal meiosis completion was firstly confirmed by spindle co-localization of β-tubulin and Spindlin. Moreover, three types of various nuclear events and development behaviors were revealed by DAPI staining and BrdU-incorporated immunofluorescence detection during the first mitosis in the fertilized eggs by three kinds of different sperms. They include normal sexual reproduction in response to sperm from the same clone male, typical unisexual gynogenesis in response to sperm from the male of another species Cyprinus carpio, and an unusual hybrid-similar development mode in response to sperm from another different clone male. Based on these findings, we have discussed cytological and developmental mechanisms on multiple reproduction modes in the polyploid fish, and highlighted evolutionary significance of meiosis completion and evolutionary consequences of reproduction mode diversity in polyploid vertebrates.Unisexual polyploid vertebrates are commonly known to reproduce by gynogenesis, parthenogenesis, or hybridogenesis. One clone of polyploid  Ambystoma salamander has been estimated to be up to 5 million years89891011Sexual reproduction is universal in animals even though a twofold cost relative to unisexual or asexual reproduction is often attributed to the production of males and genome dilution1256Poecilia formosa, was found in 1932681015Carassius gibelio was discovered to possess abundant genetic diversity and multiple modes of unisexual gynogenesis and sexual reproduction8Carassius gibelio, commonly known as Prussian carp, silver crucian carp or gibel carp, also named as a subspecies Carassius auratus gibelio of Carassius auratus818in situ hybridization (FISH), individual chromosome painting, and evolutionary history analysis of two divergent Dmrt1 genes22232526272881981735Ambystoma salamandersPoeciliopsis fishAspidoscelis lizardsMisgurnus loachesPoecilia formosa and the triploid hybridsCarassius gibelio, a similar cytological mechanism of ameiosis was previously hypothesized to explain the mother’s ploidy level maintenance in Russia, China and Japan194345464748Since the first unisexual fish, the Amazon molly Carassius gibelio, we collected different stage maturing oocytes and mature eggs from the artificial induction spawning females. Firstly, the cryo-sections of previous stage oocytes were stained by PI red fluorescence and DAPI blue fluorescence to recognize and trace meiotic chromosome dynamics and germinal vesicle breakdown (GVBD) process. As shown in To investigate whether normal meiosis was completed in clone D of Subsequently, the β-tubulin-specific mouse antibody was used to localize meiotic spindle on the cryo-sections of late stage oocytes and mature eggs by showing red immunofluorescence with Rhodamine-conjugated goat anti-mouse antibody, and the DAPI-stained blue chromosomes were simultaneously employed to present dynamic course of homologous chromosome separation and the first polar body extrusion. As shown in To confirm normal meiosis completion, we isolated GVs from full grown oocytes of clone D and prepared the DAPI-stained meiotic chromosome spread to determine numbers of meiotic chromosomes in each GV. As shown in To further confirm the above observation about meiosis completion, we used Spindlin-specific and β-tubulin-specific antibodies to co-localize meiotic spindles because previous study had demonstrated that Spindlin co-localized with β-tubulin on the meiotic spindlesCyprinus carpio , some early nuclear events, including sperm nucleus swelling and second polar-body extrusion before 10 min Pelophylax esculentus)Squalius alburnoides complex that are composed of diploid hybrid, triploid and tetraploid formsMisgurnus loach complex with diploids, triploids and tetraploids, some clonal diploid lineages were also found to reproduce by gynogenesis, and such clonal diploid loach hybrids were able to generate the unreduced diploid eggs through a premeiotic endoreplication mechanismCarassius gibelio, all of the above polyploid lineages are allopolyploids, which imply that a similar evolutionary way might have occurred in these polyploid animals. However, in contrast with the above other polyploid lineages, the reduced eggs generated from normal meiosis in the clone D are able to perform both of sexual reproduction and unisexual gynogenesis, and the various development initiation only depends the entered sperm. As reported previously by us823Carassius gibelio might originate from the already diploidized tetraploid, and diploidization should have continually proceeded. As an ongoing or nearly diploidized polyploid, clone D has evolved into normal meiosis. It is the meiosis completion that further develops and maintains the multiple reproduction modes, including sexual reproduction and unisexual reproduction. A recent finding from genome duplicated plant (Arabidopsis arenosa) has revealed that adapting meiosis is a necessary step on the way to becoming a successful polyploidActually, normal meiosis and sexual reproduction were also observed in green toads  used in this study were maintained and obtained from Guanqiao Experimental Station, Institute of Hydrobiology, Chinese Academy of Sciences. During the reproduction season, the selected brood fish of clone D were artificially induced into spawning by intraperitoneal injections with a mixture of acetone-dried carp pituitary, HCG, and LRH-A. Different stage oocytes were collected by a self-made egg-taker every 2 h from the injection until the moment of mature spawning. The ovulated eggs were inseminated by three kinds of different sperms from the same clone (clone D) males or different clone (clone F) males or from another species red common carp as described previouslyClone D and clone F in polyploid Oocytes or mature eggs were collected and freshly fixed for 6–8 h by MSB  at room temperature. After the oocytes or eggs were sectioned at 10 μm in thickness with frozen microtomy (Leica), they were incubated with primary antibody (anti-β-tubulin antibody) and secondary antibody (Rhodamine-conjugated goat anti-mouse antibody). Finally, propidium iodide (PI) or DAPI were employed for nuclei staining. The slides were imaged on Laser scanning confocal microscope (Zeiss LSM710) or Leica fluorescence microscope. All details were described previously45The collected oocytes from mature females were placed in PBS, and the germinal vesicles (GVs) were isolated using fine forceps according to a previous report in lizardsBrdU (5-bromo-2-deoxy-uridine) incorporation assay was performed as described previouslyHow to cite this article: Zhang, J. et al. Meiosis completion and various sperm responses lead to unisexual and sexual reproduction modes in one clone of polyploid Carassius gibelio. Sci. Rep. 5, 10898; doi: 10.1038/srep10898 (2015).


Hylocichla mustelina). We tracked individual birds between multiple breeding sites in North America and nonbreeding sites in Central America. First, we compared body condition of nonbreeding birds migrating to the same general region of the breeding range with spring migration performance  obtained from light-level geolocators. Second, we assessed the Normalized Difference Vegetation Index (NDVI) as a proxy for nonbreeding habitat quality, and predicted that birds from wetter habitat or in wetter years (higher NDVI) would show improved migration performance relative to birds from drier sites. We found no evidence of individual-level carry-over effects of nonbreeding season body condition on spring migration performance. Lower NDVI of nonbreeding habitat resulted in delayed spring migration departure, but this effect disappeared by arrival at breeding sites. Birds occupying drier nonbreeding sites migrated faster and for fewer days, compensating for their relatively late departure. We also documented a broader pattern in NDVI and migration timing and distance, in that birds that occupied the wettest areas in the southern part of the nonbreeding range departed significantly later and migrated farther. Our results suggest that individual carry-over effects of nonbreeding habitat quality may be compensated for by a faster and shorter migration strategy. At a broad scale, consistently later spring timing and longer migration distances were associated with the wettest areas  of the Wood Thrush non-breeding range. This supports the theory that high-quality habitats offset the costs of farther migration, resulting in a leap-frog migration pattern.For migratory animals, conditions during the nonbreeding period may carry-over to influence spring migration performance. Animals in low-quality habitats are predicted to be in poorer condition, show later migration timing, and travel at slower speeds. This can result in subsequent negative effects on fitness. We tested the hypothesis that nonbreeding season body condition and habitat quality carry-over to affect spring migration performance of a long-distance migratory songbird, the Wood Thrush ( It has been demonstrated theoretically  and withOne limitation of studies of nonbreeding site carry-over effects is that tracking small birds from start-to-finish on spring migration was not possible until the recent miniaturization of tracking devices . PreviouHylocichla mustelina Gmelin, JF, 1789) over their entire spring migration to their breeding sites. Wood Thrushes are a rapidly declining forest songbird that breeds in eastern North America , to, to25], 2 = 0.32, F3,48 = 8.9, P <0.001). This relationship was even stronger at the crossing of the Gulf of Mexico and at arrival to breeding sites . March NDVI was not a predictor of spring migration duration or speed, either within population , another small Neotropical migratory songbird, a decline in body condition of 8% over the nonbreeding season resulted in a 6-day delay in spring migration departure [Mniotilta varia) at a migration stopover found a more complex relationship between body condition and migration performance; birds arriving first (i.e. better migration performance) were in poorer condition than those arriving later, but birds arriving during the mid-migration period were in the best body condition [en route for any differences in departure condition. It is also possible that Wood Thrushes from Belize, which migrate relatively short distances  to breed in south-eastern U. S. may not require high levels of fat or muscle required for longer-distance migrations. Regardless, carry-over effects of nonbreeding body condition on individual migration performance were not apparent.Broad variation in body condition of nonbreeding birds in Belize did not correlate with their individual migration performance, in contrast to our predictions that poor body condition would cause negative carry-over effects on migration performance. In American Redstarts , suggests that birds may be able to compensate for delays caused by poor-quality habitat. In fact, the birds occupying relatively dry sites left later, but they also spent less time on migration and travelled more quickly, indicating that they can compensate for a later start. Further studies of start-to-finish migration strategies could elucidate whether an early-but-longer migration has greater fitness benefits than the late-start, faster migration strategy.We also found a significant relationship between NDVI and migration performance when comparing birds from Belize and Costa Rica. These two study sites were consistently different in terms of habitat moisture  and in migration strategy . This broad-scale relationship likely contributes to the range-wide parallel, leap-frog migration system documented in this species , 35, wheThe mechanisms driving the evolution of leap-frog migration, a pattern that is widespread within and among species, are still not well understood . In the Setophaga petechia) did not detect any carry-over effects of nonbreeding habitat on arrival date or reproductive success [Setophaga magnolia) captured during spring migration [Several studies have shown that birds in the same breeding population that arrive from more wet nonbreeding habitats  produce more young , 3, 18,  success ,. Carry-igration . Recent igration . All of Overall our results show that carry-over effects of nonbreeding body condition are absent in our study population, and that nonbreeding habitat moisture has some effects on migration strategy  but does not affect breeding arrival date. Our data also suggest that the species-level parallel, leap-frog migration pattern in Wood Thrushes could be driven by a range-wide gradient in nonbreeding habitat quality combined with differences in breeding site phenology. This pattern results in populations occupying nonbreeding habitat further southeast in more productive habitat migrating further and later than populations occupying drier habitat to the north. This hypothesis could be further explored in other species that show a gradient in nonbreeding habitat quality over a broad geographical area that would produce migration distance differences.S1 FileResults of mixed effects linear models of the effect of March NDVI on individual migration performance for Wood Thrushes from the same breeding site (PA = Pennsylvania) and population-level migration performance at two nonbreeding sites  (Table B). Migratory origins and destinations of birds breeding in Pennsylvania and from nonbreeding sites in Belize and Costa Rica . Histogram of arrival dates to the Tropics (first date south of 24.5°N) for Wood Thrushes that eventually occupied nonbreeding sites in Belize and Costa Rica .(DOCX)Click here for additional data file.


Late preterm birth confers increased risk of developmental delay, academic difficulties and social deficits. The late third trimester may represent a critical period of development of neural networks including the default mode network (DMN), which is essential to normal cognition. Our objective is to identify functional and structural connectivity differences in the posteromedial cortex related to late preterm birth.Thirty-eight preadolescents  and 19 at term) without access to advanced neonatal care were recruited from a low socioeconomic status community in Brazil. Participants underwent neurocognitive testing, 3-dimensional T1-weighted imaging, diffusion-weighted imaging and resting state functional MRI (RS-fMRI). Seed-based probabilistic diffusion tractography and RS-fMRI analyses were performed using unilateral seeds within the posterior DMN  and lateral parietal DMN .Late preterm children demonstrated increased functional connectivity within the posterior default mode networks and increased anti-correlation with the central-executive network when seeded from the posteromedial cortex (PMC). Key differences were demonstrated between PMC components with increased anti-correlation with the salience network seen only with posterior cingulate cortex seeding but not with precuneus seeding. Probabilistic tractography showed increased streamlines within the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus within late preterm children while decreased intrahemispheric streamlines were also observed. No significant differences in neurocognitive testing were demonstrated between groups.Late preterm preadolescence is associated with altered functional connectivity from the PMC and lateral parietal cortex to known distributed functional cortical networks despite no significant executive neurocognitive differences. Selective increased structural connectivity was observed in the setting of decreased posterior interhemispheric connections. Future work is needed to determine if these findings represent a compensatory adaptation employing alternate neural circuitry or could reflect subtle pathology resulting in emotional processing deficits not seen with neurocognitive testing. Advances in perinatal care over the past few decades have increased the number of surviving preterm neonates. The effects of increased risk for medical conditions, learning disabilities, and psychological problems among early preterm infants lasting into adulthood have a visible impact on developed societies , 2. PretThis study aims to ascertain possible functional connectivity and anatomical connectivity alterations in children born at late preterm that could relate to neurocognitive differences.The default mode network (DMN) is a group of neuroanatomical structures acting in synchrony at-rest as indicated by resting state functional MRI (RS-fMRI) that are thought to integrate associative information and play a role in self-referential (introspective) thought activities , 14. ThePreterm birth-related effects demonstrate a posterior predilection with greater grey matter reductions in the parieto-occipital cortices and white matter injury predominantly affecting the posterior limb of the internal capsule and posterior portions of the corpus callosum –26. AnimAs part of a longitudinal international collaborative investigation of the genetic and environmental influences of prematurity on long-term neurocognitive functioning and health outcomes, 19 preadolescent pairs of twins (38 participants aged 9–13 years) were recruited from Minas Gerais, a developing region in Northeastern Brazil. The preadolescent twin pairs were recruited through an existing twin registry by newspaper advertisements. The registry is comprised of twins who had participated in prior studies investigating genetic influences on oral health , 29. SamResearch protocols were approved by local Institutional Review Boards in the United States  and Montes Claros, Brazil . Written informed consent was obtained from study participants’ parents or legal guardians.Neurocognitive measures employed in this study included the Rey-Osterrieth Complex Figure Test (CFT), the Trail-Making Test , and selected non-verbal subtests from the NEPSY-II, including Memory for Designs (Immediate and Delayed), Affect Recognition, 3D Block Construction, Geometric Puzzles and Route Finding. Neurocognitive test administration was carried out in Portuguese by a Brazilian neuropsychologist after all test instructions had been translated into Portuguese. Moreover, an experienced, American neuropsychologist (JLW) was present for much of the neurocognitive test administration to ensure consistency and adherence to testing protocols. The neurocognitive tests were scored in accordance with published procedures  and US n2, one scan acquired without diffusion weighting (b = 0 s/mm2) and 32 scans acquired with diffusion gradient direction according to the Philips Achieva 32-direction sequence.Diffusion scans were acquired at 1.5 T with the following parameters: Spin-Echo EPI, TR = 6000 ms, TE = 90 ms, slice thickness = 2 mm, matrix = 112 X 112, FOV = 22.4 cm X 22.4 cm, SENSE factor = 2, b value = 1000 s/mmhttp://brainsuite.usc.edu) including the SVReg atlas [http://fsl.fmrib.ox.ac.uk/fsl/fsl-4.1.9/fdt/fdt_probtrackx.html). This process is depicted graphically in 3).Between-group probabilistic tractography analysis was carried out in a similar manner as a previously published method . Diffusieg atlas –34. SeedResting-state BOLD was acquired on a Philips 1.5T Achieva scanner. Scan parameters were: TR = 3000 ms, TE = 50 ms, FOV = 21.1 cm X 21.1 cm, imaging matrix = 80 X 80, slice thickness = 4 mm, 30 slices acquired covering the whole brain, SENSE factor = 2, 100 volumes acquired for a total scan time of 5 minutes per run. Two scan runs were acquired: one with the child asked to keep his eyes open, and one with eyes closed. There was a brief time gap (approximately 15 seconds) between runs to allow the examiner to provide instructions to study participants to close their eyes.3).The data processing procedure closely followed that of Power et al. , shown tWe report results from a community-based cohort of low-to-moderate socioeconomic status preadolescent (ages 9–13) twin pairs born late preterm or at full term. This study is part of an international collaborative longitudinal research program to investigate genetic and environmental influences on prematurity, long-term neurocognitive functioning and general health outcomes. The preadolescents in this study were recruited from a city in Northeast Brazil . This region not only has a high incidence of natural multiple gestation pregnancies but also a high rate of late preterm birth coupled with limited healthcare resources . As a reThe neuropsychological test battery performed by all participants included the Rey-Osterrieth Complex Figure Test (CFT), the Trail Making Test (children’s version), and selected subtests of the NEPSY-II assessing visuospatial, visuo-perceptual, and memory functions: Affect Recognition, Memory for Designs, Block Construction, Geometric Puzzles, and Route Finding. No significant difference in cognitive performance was seen between preterm and term preadolescents after controlling for age  = 0.735, p > 0.5). A nominally significant difference in the direction of the preterm preadolescents outperforming the term preadolescents was detected only on Block Construction  = 4.131, p = 0.049), not surviving correction for multiple comparisons.Late preterm individuals during preadolescent childhood demonstrate increased functional connectivity when seeding from the PMC as shown in As shown in Strength of increased functional connectivity within the posterior DMN was greater for the right hemispheric seeds compared to left-sided seeding as displayed in Hyperconnectivity of the DMN in late preterm children was also demonstrated when seeding from the lateral parietal cortex  as shown in Increased streamlines were demonstrated within the right inferior longitudinal  fasciculus (ILF) and overlapping inferior fronto-occipital fasciculus (IFOF) as shown In seeding the right and left posteromedial cortex as depicted in Seeding from the right lateral parietal cortex as shown in Late preterm birth is increasingly recognized as an important influence in brain development with documented impairments in learning and neuropsychological performance . In our late premature birth (32–36 weeks) may affect the development of the DMN and how such possible alterations can affect brain organization.During the late third trimester, what mainly shapes brain development is the organization and reorganization of connections between existing neurons, as neurogenesis is considered largely complete . At the Recent progress has been made in understanding the early formation of resting state networks during late gestation. Some research posits a rich-club network of highly clustered cortical hubs within the infant brain develops by 30 weeks' gestation . The latDespite lacking significant cognitive differences between preadolescent children born late preterm versus at term in this study, there remains valuable information regarding possible anatomical and functional connectivity explanations for increased risk of developmental delay and cognitive disability with prematurity. Because of an increased risk of autism with preterm birth, preterm birth could share changes in brain connectivity with autism , 58. In Increased excitatory activity or, as suggested in our study, excess functional hyperconnectivity within posterior DMN structures may relate to disruption of normal synaptic pruning that is expected to occur postnatal development, but may be altered in a variety of conditions such as autism and obsessive-compulsive disorder , 67. In While the clinical significance of hyperconnectivity observed in this study is not definitively associated with cognitive dysfunction, the context of these findings combined with that of others in autism and prenatal injury strongly suggests that a developmental deficit in pruning of local connections may be responsible for neurocognitive deficits seen in late prematurity. This lack of pruning may occur with greater preponderance in the posterior regions as indicated by predominant hyperconnectivity within the posterior default mode network and established posterior cortical vulnerability.Probabilistic tractography differences were less pronounced in comparison to the previously described functional connectivity findings as expected in this group of late preterms without significant cognitive deficits. Nevertheless, in this study, we observe selectively increased streamlines in our probabilistic tractography analysis of later preterm versus term infants within the region of the right inferior occipito-frontal fasciculus (IFOF) and right inferior longitudinal  fasciculus (ILF). In addition, the left PMC showed increased streamlines within right parietal white matter. These increases occurred in the setting of decreased streamlines within the splenium of the corpus callosum from the left PMC and right lateral parietal cortex, thereby implying deceased interhemispheric connections.Previously, others  have notOn the other hand, earlier voxel-based morphometry studies of earlier preterms show decreased white matter volume in the longitudinal fasciculi both during infancy and early adolescence , 76. In We propose that the finding of increased right IFOF/ILF streamlines suggests compensatory increased anatomical connectivity within the right hemisphere. The conventional pathway for semantic language processing follows the inferior fronto-occipital fasciculus (IFOF) with the inferior longitudinal fasciculus (ILF) constituting an indirect pathway . Prior wAnother possible explanation for selective increased streamlines within the IFOF and ILF in late preterm infants may represent aberrant white matter development that affects brain function not assessed by conventional neuropsychological tests. Prior work in William’s syndrome has shown similar increased FA within the IFOF that is thought related to increased myelination . While tThis study included individuals who were born at late preterm versus term gestational age and examined brain development during the preadolescent period. One important aspect of this study population is the lack of early perinatal intervention in a preterm population from a poor, developing region , 29. Whipost hoc, there was a slight but statistically significant increase in the number of included scans in the eyes-open condition for the preterm group, although not for the eyes-closed condition. Accordingly, there was a slight but significant difference in the framewise displacement (FD) parameter between groups in the eyes-open condition  though not for the eyes-closed condition . As part of the functional connectivity data processing, WM and CSF values were not included as regressors in the analysis as they were not shown to significantly change the results. These minor technical limitations are not expected to significantly affect the results of this study due to the rigorous frame inclusion criteria, however future studies may benefit from these additional data analysis strategies.In analyzing this data Serial data examining patterns of development would strengthen our understanding developmental phenomena related to late preterm birth by looking at dynamic changes over time within the individual rather than at one point in time. Despite promising results from an increasing body of literature, both methods are indirect indicators of functional and anatomical connectivity, respectively. Moreover, conventional DTI is limited by its inability to distinguish tracts within axon-rich crossing-fiber regions, a limitation that may be overcome with future work employing diffusion spectrum imaging.One other key aspect of this study was the use of participant-specific anatomic parcellation to accurately identify the function of the anatomic PMC structures. Function-based parcellation may yield differing results that could add further detail to our study. In addition, the use of other methods such as graph theory or independent components analysis could be helpful to validate our findings. Moreover, future work comparing our findings with those of earlier preterm infants in a different setting would enrich our understanding of the magnitude of brain development alterations related to prematurity within the posterior DMN and other critical neuroanatomical regions.Our findings support appreciable abnormalities in brain development in infants born late preterm even in the absence of detectable differences in neuropsychological performance. Thus, the late prenatal period represents a key timeframe for the formation of mature resting state networks and disruption of these neural connections may incite increased local functional connectivity within the posterior DMN, greater anti-correlation with salience and executive networks and lead to the strengthening of additional axonal pathways within the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus that serve as compensatory alterations or pathologic sequelae that could affect emotional processing and social function not adequately assessed on routine neuropsychological testing.


Drosophila embryo showed that the key PCM component Cnn specifically incorporates near centrioles, suggesting that centrioles play an ongoing role in PCM assembly Caenorhabditis elegans embryo. We find that recruitment of the scaffold component SPD-5 occurs throughout the PCM. Incorporation of additional PCM subunits is therefore not limited to specific nucleation sites near centrioles, which has profound implications for the organization of the PCM lattice and the role of centrioles in centrosome assembly.Centrosomes are important regulators of microtubule organization in animal cells. Within the centrosome, microtubule nucleation and anchorage are mediated by proteins in the pericentriolar material (PCM) that accumulates around centrioles. The spatial organization of the PCM and the contribution of centrioles to its recruitment remain poorly understood. Previous work in the  C. elegans SPD-5 Unlike centrioles, the PCM displays no apparent higher-order organization when examined by electron microscopy, although proteins occupy distinct domains based on high-resolution light microscopy To monitor SPD-5 behavior, we generated a GFP fusion under endogenous regulatory sequences by transposon-mediated insertion at a defined chromosomal locus (MosSCI). This transgene was rendered RNAi-resistant by resequencing, enabling specific depletion of the endogenous protein . ImportaDrosophila embryos have shown that Cnn specifically incorporates near centrioles C. elegans embryo, around 60 times that in Drosophila embryos or vertebrate cultured cells Elegant experiments performed in C. elegans. Rather, the PCM expands isotropically by incorporation of additional SPD-5 throughout its volume. Similar results are now reported for Cnn in Drosophila somatic cells (see accompanying manuscript by Conduit and Raff). Unlike crystals in solution or typical polymers, the PCM lattice must be able to stretch to accommodate additional subunits. This sponge-like behavior hints at an internal flexibility that would seem at odds with the ability of centrosomes to resist external pulling forces. Cytoplasmic SPD-5 is known to exist in monomeric form in vitro properties of SPD-5 and other scaffolding proteins give rise to this unique and dynamic structure.Thus, there is no privileged role for centrioles in scaffold assembly in


Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim of the current review is to summarize the origin and characteristics of CAFs, and to describe the role of CAFs in tumor progression and metastasis. Furthermore, we focus on the presence of CAFs in hypoxic conditions in relation to multiple myeloma disease. It is now well-accepted that growth and progression of a multitude of malignancies depends on interactions of the tumor cells with their local tumor microenvironment. Distinct cell types of this microenvironment including endothelial cells, immune cells and fibroblasts contribute to tumorigenesis by secretion of cytokines and/or direct cell-cell contact . A partiNormal fibroblasts maintain tissue homeostasis, regulate inflammation and epithelial differentiation, and play a crucial role in the wound healing process. They exert distinct functions including the secretion of extracellular matrix (ECM) components and ECM-degrading enzymes like matrix metalloproteinases. During wound healing, they recruit endothelial precursor cells and promote angiogenesis. In addition, they also promote epithelial cell growth and induce epithelial-mesenchymal transition to bridge wounds. Under the influence of transforming growth factor beta (TGF-β), normal fibroblasts become myofibroblasts which are responsible for wound contraction. In contrast to normal fibroblasts and myofibroblasts, CAFs are continuously activated and are not able to revert into a normal phenotype or undergo apoptosis. They are defined as activated fibroblasts which are present in the stroma surrounding the tumor ,6.Fibroblasts form a heterogeneous cellular component of connective tissues. Tissue damage induces their activation and increased collagen, cytokine and growth factor secretion, which regulate the wound healing processes. CAFs are a subpopulation of fibroblasts found in the tumor microenvironment . DespiteIt has been described that CAFs originate from at least four different cellular components. Normal fibroblasts or fibroblast precursors are the most obvious cell type, which can differentiate into CAFs upon stimulation with paracrine signals. TGF-β has been recognized as the most potent inducer of transformation of fibroblasts to CAFs . RecentlIt is widely assumed that CAFs may also develop from mesenchymal stem cells (MSCs). Both cell types show more similarities than differences including the expression of cell surface markers  and cytoskeleton proteins like vimentin and αSma. Although the relationship between both cell types has not established, fibroblasts are considered as more differentiated cells with a more restricted differentiation potential. Importantly, CAFs showed a higher proliferation rate and increased production of cytokines, chemokines and growth factors  when compared to MSCs . Spaeth CAFs isolated from different types of human carcinomas including breast, lung, prostate and ovarian actively take part in tumor development and growth. Under influence of tumor cells CAFs show morphological differences and increased secretory and metabolic activities compared to normal fibroblasts . As GabbIn vitro experiments furthermore showed that co-culturing of the MDA-MB-231 breast cancer cell line with human CAFs isolated from mammary tissue resulted in an increased proliferation rate with a great proportion of tumor cells in S phase compared to tumor cells co-cultured with normal fibroblasts [A recent report by Peng and colleagues reveals a list of up-regulated genes in CAFs isolated from primary breast infiltrating ductal carcinomas of grade II compared to the normal fibroblasts. It is shown that CAFs over-express genes involved in cell proliferation  and growth factors . roblasts . CAFs moroblasts ,33.In different tumor contexts soluble factors secreted by CAFs act in a paracrine and/or autocrine manner to sustain tumor cell proliferation and maintain the activated CAF phenotype ,35. NotwUp till now TGF-β is considered as one of the major mediators of CAFs activation. TGF-β, a pleiotropic cytokine secreted by different cell types, including epithelial cells and fibroblasts, is stored as a reservoir in the ECM . TGF-β1 Several studies on breast, pancreatic, prostatic and ovarian cancers report that treatment of normal fibroblasts with tumor cell conditioned media triggers phenotypic modifications such as expression of activation markers and increased CAFs secretory properties. Solid tumor cells can secrete growth factors, such as endothelin-1, thrombin, PDGF, FGF-2 and CXCL12, that can stimulate directly or indirectly the myofibroblastic differentiation ,44. PDGFBesides effects mediated by growth factors, CAFs activation processes depend on many other stimuli that modify the homeostatic microenvironment. Tumor cells’ aberrant proliferation disrupts normal ECM composition, causing the delivery of these diffusible soluble factors as well as mechanical stress. Solid tumors are mostly characterized by matrix stiffness modifications that are involved in the CAFs activation and function. Fibroblasts perceive mechanical signals from the ECM through integrin receptors that physically link the ECM to the cytoskeleton acting as force transducers. In fibroblastic cells it is reported that RhoA, a small guanosine 5'-triphosphatase, is an important link in integrin-dependent mechanotransduction . RhoGAP All these data confirm that factors secreted by tumor cells and changes in matrix composition and organization synergistically collaborate in stimulating fibroblast activation, as shown in et al. [in vivo. Furthermore, Lotti and colleagues [in vivo tumor growth. Besides the influence of tumor cells on CAFs activation, it is important to realize that cytotoxic therapy can also induce fibroblast activation. Ravani et al.  showed tlleagues  demonstrCAFs involvement in tumor progression has been demonstrated independently in several laboratories using murine xenograft models. Co-injection of CAFs with tumor cells resulted in enhanced tumor formation. In contrast, co-injection of normal fibroblasts with tumor cells was not able to give the same results in terms of tumor take, growth rate and tumor load ,50. For In vitro co-culture and migration experiments using several human mesothelioma cell lines  and human embryonic lung fibroblast cell lines showed that mesothelioma cells secreted FGF-2 and PDGF-AA. These growth factors attract and activate fibroblasts in the tumor region increasing their cell growth and HGF secretion [In vitro experiments showed that conditioned media of gastric cancer cell lines induced IL-6 secretion by fibroblasts through IL-1 involvement. In turn, IL-6 acts in a paracrine manner increasing tumor gastric cell line proliferation through STAT3 signaling [CAFs and tumor cells create a cytokine network, working directly on both cell types which results in increased tumor progression. In malignant pleural mesothelioma, Li and colleagues  assessedecretion . In gastignaling .de novo induction of vasculogenesis [Moreover, experimental data from the most widespread solid carcinomas demonstrated that CAFs directly modulate tumor growth by secreting factors with oncogenic and mitogenic functions that are able to increase tumor cell proliferation and to protect them from apoptosis. CAFs can also act indirectly by secreting chemotactic factors to recruit other stromal cell types into the tumor compartment and also by secreting pro-angiogenic factors resulting in increased angiogenesis. In fact, CAFs release a great number of pro-angiogenic factors including VEGF, CXCL12, FGF, IL-8/CXCL8 and PDGF-C in the ECM to recruit other stromal cell types such as endothelial cells and their precursors in order to stimulate tumor angiogenesis and vasculogenesis . For exaogenesis . In pancogenesis .et al. [Several reports also demonstrated the importance of the microenvironment in inducing the cancer stem cell (CSC) phenotype. CSC are a small subpopulation of cells that play a crucial role in tumor initiation, progression an refractoriness. Vermeulen et al.  showed tet al. . It is well known that CAFs actively participate to the creation of a niche where cancer cells can proliferate and also sustain their dissemination by setting up the most advantageous “soil” conditions where the “seeds” can grow better. in vitro and in vivo invasion of tumor cells as a consequence of their increased ability to degrade matrix proteins [Cancer metastasis is a multistep process correlated to the invasive and migratory behavior of tumor cells that escape from the site of origin, enter in the blood circulation and colonize distant organs. This complex series of events can be regulated intrinsically by the tumor cells and also extrinsically by the surrounding stroma. CAFs could also be considered as modulators of local tumor cell invasion and regulators of the tumor cell spread to distant secondary metastatic sites. It is demonstrated that CAFs involvement in tumor cell metastasis could not only be dependent on the release of soluble factors but also on their physical involvement ,59. Receproteins . Duda and colleagues  demonstrin vivo experiments demonstrated the role of S100A4 expressed by stromal fibroblasts to stimulate metastasis formation. The authors reported that after co-injection of mouse mammary CSML100 tumor cells with S100A4 (+/+) fibroblasts mice developed metastatic tumors in the lung. In contrast, mice lacking S100A4 expression showed inhibition of the metastatic formation [in vivo experiment using an orthotopic colon cancer model whereby HCT116 colorectal cancer cells were co-injected respectively with fibroblasts isolated from wild type mice or from STC1−/− mice. Tumors that developed from HCT116 cells and STC1−/− MEF co-injection were smaller compared to tumors in tcontrol group and interestingly the treated experimental group showed decreased small metastatic lesions [In the last decades, many scientific reports described that the role of CAFs in the invasion process is also related to the secretion of soluble factors that trigger cancer cell migration. One of the most important chemotactic factors released by CAFs is HGF. It binds the cMET receptor on the tumor cells, thereby stimulating tumor invasiveness and growth. Among the several factors with chemotactic properties secreted by CAFs Karnoub and colleagues reported that in breast cancer CCL5 is involved in metastasis formation . In addiormation . Pena an lesions . All theversus tumor suppressive cells is shifted. CAFs induce immunosuppression by an increase in Th2 cells, Th17 cells and regulatory T-cells. Importantly, fibroblasts not only recruit myeloid cells into tumors via cytokine and chemokine production, but also by modifying the ECM [A recent review by Raz and colleagues described the role of fibroblasts on immune cell recruitment in cancer. Briefly, cytokines and chemokines secreted by CAFs recruit leukocytes, monocytes/macrophages and mast cells to the tumor, thereby contributing to the cancer-related inflammation . CCL2 se the ECM ,67,68. K the ECM .et al. [Activated fibroblasts not only promote tumor growth but play a major role in therapy resistance. Müerköster et al.  demonstret al. . Anotheret al. . Furtheret al. . in vitro without stromal support, indicating the direct dependence of MM cells on the associated stroma [Multiple Myeloma (MM) is an incurable hematological malignancy characterized by the abnormal growth of malignant monoclonal plasma cells in the bone marrow. Clinical features of this disease include anemia, bone pain, renal failure, frequent occurrence of infections and hypercalcaemia. The supportive role of the bone marrow microenvironment in MM development has been widely accepted. The cellular compartment includes fibroblasts/bone marrow stromal cells (BMSC), endothelial cells, osteoclasts, osteoblasts and immune cells, while the non-cellular compartment is composed of a liquid milieu containing growth factors, chemokines and cytokines. MM cells home to the bone marrow and adhere to ECM and BMSC. This interaction activates distinct signaling cascades and confers tumor cells resistance. BMSC also release pro-angiogenic factors contributing to the BM neovascularization, an important feature in MM progression. The imbalance between osteoblasts and osteoclasts results in bone resportion ,74. Impod stroma .in vitro experiments showed that CAFs sustain MM cell proliferation and render them more resistant to apoptosis; in vivo experiments demonstrated that co-injection of MM cells with CAFs favors tumor take and growth. We also demonstrated that the CAFs-MM cell interaction involves CXCL12/CXCR4 pathway and several integrins confirming the importance of contact between tumor and stromal cells. CAFs were also found to sustain MM disease indirectly by stimulating the angiogenic process by recruitment of endothelial cells in the tumor [Until now, only very little data exist about the role of CAFs in hematological malignancies. Among the different cell types that create the bone marrow niche little is known about the role of CAFs in the pathophysiology of MM. Recently, we were the first to describe phenotypic features and functional involvement of CAFs in MM development. CAFs were defined as stromal cells expressing different levels of FSP1, αSma and FAP proteins. Interestingly, a direct correlation was demonstrated between the aggressiveness and progression of disease and the proportion of CAFs in the bone marrow of patients . The reshe tumor .Proteomic profiling by Slany’s group identified different proteins in fibroblast-like cells of non-neoplastic control patients, MGUS patients and MM patients. Proteins involved in ECM remodeling  were progressively upregulated in MGUS and MM, indicating an important role of fibroblasts in MM progression .− cells has been identified within the CD38+ MM cell population. CD138− cells were less sensitive to treatment  compared to CD138+ cells and could possibly contribute to the high incidence of relapse of MM patients. Co-culture experiments of MM cells with stromal cell lines or primary MSC cultures increased the number of the CD138− cell fraction, implying the involvement of the bone marrow microenvironment in relapsed MM patients [et al. showed bortezomib was able to downregulate CD49d and CD44 expression factors that mediate the adhesion of human Hodgkin lymphoma cells to fibroblasts, indicating effects of myeloma treatment on CAFs [In MM, a small subpopulation of CD138patients ,79. Alth on CAFs . Togethe2) supply and the O2 consumption in cells or tissues. Decreased O2 levels are observed in several pathological conditions including cancer. Hypoxia not only increases gene amplification and genomic instability in the cancer cells, but also induces expression of pro-angiogenic factors , and ABC transporters, and promotes the invasive capacity of the tumor cells [In vivo treatment of 5T33MM mice with TH-302 induced apoptosis of MM cells in the bone marrow microenvironment and decreased paraprotein secretion [in vivo and strongly decreased angiogenesis and the development of osteolytic bone lesions [Hypoxia results from an imbalance between the oxygen , a marker highly expressed in terminally differentiated stromal cells, was described as an important driver of HIF-1α expression and was associated with an activated CAF phenotype. Briefly, a crosstalk between HIF-1α and Cav-1 induces autophagy/mitophagy in the tumor stroma, and consequently provides cancer cells with essential amino acids and nucleotides to drive tumor growth and metastasis. Cancer cells themselves are protected against apoptosis due to the upregulation of the autophagy inhibitor TIGAR . FurtherA recent publication by Kim and colleagues investigated different fibroblast-specific conditional knockout mice using a FSP-cre strain. In contrast to previous data, they observed that ablation of HIF-1α in stromal fibroblasts was able to increase tumor growth and perfusion . AlthougCAFs are a heterogeneous subpopulation of fibroblasts, extensively studies in solid carcinomas. They become activated by distinct features including growth factors, mechanical stress and hypoxic conditions, which characterizes the growing tumors. Furthermore, CAFs influences tumor cell proliferation through physical interaction, cytokine secretion and interactions with other cell types including endothelial cells and immune cells. Although the role of CAFs in hematological malignancies is unclear, recent data indicate that CAFs are important mediators of tumor progression in MM. MM is a plasma cell cancer characterized by a hypoxic bone marrow niche, which may favor the fibroblast activation. It is evident that the contribution of CAFs to tumor progression and metastasis cannot be neglected and needs to be further clarified.


The objective of this analysis was to identify topographic and bioclimatic factors that predict occurrence of forest and grassland patches within tropical montane forest-grassland mosaics. We further investigated whether interactions between topography and bioclimate are important in determining vegetation pattern, and assessed the role of spatial scale in determining the relative importance of specific topographic features. Finally, we assessed the role of elevation in determining the relative importance of diverse explanatory factors. The study area consists of the central and southern regions of the Western Ghats of Southern India, a global biodiversity hotspot. Random forests were used to assess prediction accuracy and predictor importance. Conditional inference classification trees were used to interpret predictor effects and examine potential interactions between predictors. GLMs were used to confirm predictor importance and assess the strength of interaction terms. Overall, topographic and bioclimatic predictors classified vegetation pattern with approximately 70% accuracy. Prediction accuracy was higher for grassland than forest, and for mosaics at higher elevations. Elevation was the most important predictor, with mosaics above 2000m dominated largely by grassland. Relative topographic position measured at a local scale (within a 300m neighbourhood) was another important predictor of vegetation pattern. In high elevation mosaics, northness and concave land surface curvature were important predictors of forest occurrence. Important bioclimatic predictors were: dry quarter precipitation, annual temperature range and the interaction between the two. The results indicate complex interactions between topography and bioclimate and among topographic variables. Elevation and topography have a strong influence on vegetation pattern in these mosaics. There were marked regional differences in the roles of various topographic and bioclimatic predictors across the range of study mosaics, indicating that the same pattern of grass and forest seems to be generated by different sets of mechanisms across the region, depending on spatial scale and elevation. Montane forest-grassland mosaics in the tropics form hotspots within hotspots of global biodiversity ,2 supporAs in other forest-grassland mosaics ,9, thereTopographic heterogeneity has complex effects on microclimate , impactiElevation and topography affect the incidence, frequency and spread of disturbance processes such as fire –24. TopoAlthough many studies have examined the effects of climate on forest-grassland mosaics, there is no quantitative study on the effect of topography on vegetation pattern across the full range of bioclimatic conditions in which these mosaics are found. A better understanding of the importance of various topographic features, how they interact with bioclimate and the spatial measurement scale at which they influence vegetation pattern could provide insights into mechanistic processes maintaining grasses and trees in tropical montane forest-grassland mosaics. Such an analysis could also help inform the management and conservation of these biologically important mosaics, especially in the face of climate change and other anthropogenic factors.The main objectives of this analysis were to answer the following questions: i) to what extent can topography and bioclimate predict the pattern of occurrence of grass and forest patches within forest-grassland mosaics of the Western Ghats? ii) how does the relative importance of topography and bioclimate vary at different elevations? iii) what are the important interactions between topography and bioclimate for vegetation patterns? iv) what are the relevant measurement scales for topographic predictors that affect vegetation pattern within mosaics?The study area encompasses montane forest-grassland mosaics of the Western Ghats between 8°22’-13°31’ latitude and 74°50’-77°30’ longitude . These hshola’. The boundary between forest and grassland is abrupt. Sholas have been classified as wet montane temperate forests [The mosaics consist of undulating grasslands interspersed with patches of stunted evergreen forests, locally known as ‘ forests , and as  forests . Trees a forests . Dominan forests ,12. The  forests ,29.sholas merge into continuous forest were necessarily subjective. These were drawn conservatively to restrict the study area to forests that occur within a matrix of grassland. Areas within and around Periyar Tiger Reserve were excluded because some of these grasslands appear qualitatively different from the grasslands in other mosaics (pers. obs.). All the mosaics depicted in Mosaics were identified using high-resolution satellite imagery in Google Earth . PolygonA systematic sample of point locations covering the study area was created in ArcGIS v.10.0 , with a A total of 1960 points of the original 2020 points were imported into ArcGIS 10.0 for analysis. A subset of points located in extreme topographic positions was used to confirm that spatial registration of imagery matched that of the DEM.Selection of putative predictors of occurrence of forest and grassland within the mosaic was based on available published literature on the determinants of these patterns in such mosaics globally ,15,22–24The ASTER Global Digital Elevation Model (GDEM) v.2 tiles   for the TPI was calculated at local, intermediate and landscape scales , definedAs the dataset comprised several highly correlated predictors likely to have complex interactions, a classification tree (CT) approach  was usedCTs based on conditional inference  were conA single CT built using all predictors and a random subset of the data was found to be quite unstable, with small changes in the training data yielding a different tree. Hence random forests  was usedr > 0.7) predictors that were of lower importance. Random forests was then re-run with this smaller set of predictors and the cross-validated “out-of-bag” prediction accuracy reassessed as described above. Finally, to enhance our understanding of the effects and interactions between predictors, a conditional inference CT was built using the full dataset and the selected subset of predictors.In order to maximize the size of the training dataset, a random subsample of two-thirds of the data was used in building the random forest and the remaining third “out-of-bag” data was used to assess its prediction error. The random forest algorithm was run 20 times with each run consisting of a 1000 conditional inference CTs . For anyGeneralised linear modelling  was usedTo avoid the effects of collinearity and limit the number of predictors, and the number of models considered, we further eliminated predictors based on i) collinearity and ii) very low predictor importance (near 0) as demonstrated by the random forest analysis. Thus, the initial random forest analysis did feed into the GLMs, but not to the extent that it would seriously affect our final inference, since only obviously unimportant predictors were eliminated. Model-averaged estimates of each standardized beta coefficient were obtained as a weighted (using Akaike weights) average across all models containing that predictor. We also obtained unconditional standard errors (SE), which includes model selection uncertainty . The 95%We note that neither the CT nor GLM approaches as used by us represent confirmatory analyses  to test As the factors affecting vegetation pattern are likely to differ at low-medium versus high elevations (e.g. frost occurs only above a certain elevation), we assessed the change in the relative importance of topographic and bioclimatic predictors with elevation by repeating the above analyses for a subset of the data representing forest-grassland mosaics in the Nilgiris and Eravikulam plateaus above 1500m elevation . These hn = 1000, forest n = 960) cover a wide range of topographic and bioclimatic conditions  indicated that elevation was the most important predictor, followed by local-scale TPI (tpi3.10). Predictors with the lowest importance values were TCI (30m pixel), curvature (30m pixel), sine aspect, slope and Beers aspect . TherefoBased on collinearity and the results of the permutation variable importance, the following subset of 11 predictors was chosen: elevation, local-scale TPI (tpi3.10), dry quarter precipitation, curvature (90m pixel), landscape-scale TPI (tpi10.67), annual temperature range, TCI (90m pixel), annual precipitation, distance to coast, cosine aspect and ruggedness. A marginal improvement in mean prediction accuracy for the full dataset was achieved over ten random forest runs for the “out-of-bag” data with this subset of predictors .n = 783; 43% forest, 57% grass), the full set of predictors had an overall mean prediction accuracy of 72.1% , with many forest points being assigned to grass by the random forest algorithm. Elevation was the most important predictor, followed by maximum temperature of the warmest month (r ≥ 0.95)), gained importance over local-scale TPI. Landscape-scale TPI was more important than local-scale TPI at high elevations (r = -0.67). Annual precipitation and dry quarter precipitation were less important at higher elevations , annual temperature range, local-scale TPI (tpi3.10), dry quarter precipitation, curvature (90m pixel), cosine aspect, annual precipitation, distance to coast, TCI (90m pixel) and ruggedness. A higher overall mean prediction accuracy of 73.1%  was achieved with this subset of predictors and the “out-of-bag” data.The conditional inference CT for the full dataset, using the subset of 11 predictors, indicated that local-scale TPI (tpi3.10) and elevation were important splitting variables followed by dry quarter precipitation and cosine aspect . The iniSites between 1144–2038m elevation, with flat or elevated topographic positions and dry quarter precipitation ≤ 30mm,were predominantly grassland , node 19There seemed to be complex interactions among topographic variables as well as between elevation and annual temperature range Figs  and 4. FThe CT built from the subset of 12 predictors for Nilgiris-Eravikulam, showed that between 1500–2555m, elevation was the most important splitting variable, followed by local-scale TPI at lower elevations and local curvature (curve90) at higher elevations . Points n = 1960) using 11 predictors and interactions between some of the predictors, indicated that the two best models had the following predictors for occurrence of forest: elevation, dry quarter precipitation, local-scale TPI, annual temperature range, interaction between annual temperature range and dry quarter precipitation, curvature (90m pixel) and cosine aspect. Predictors with highest summed Akaike weights were: elevation, dry quarter precipitation, local-scale TPI, annual temperature range, an interaction between annual temperature range and dry quarter precipitation, curvature (90m pixel) and cosine aspect .Important bioclimatic predictors not highly correlated with elevation were dry quarter precipitation and annual temperature range . Both shn = 783) indicated that the best model based on AIC had the following predictors: elevation, annual temperature range, curvature (90m pixel), cosine aspect, distance to coast, and an interaction between cosine aspect and distance to coast. These predictors also had the highest summed Akaike weights  was the most relevant for prediction of forest and grassland patches , Table 2Topography and bioclimate were able to predict the occurrence of grass and forest within forest-grasslands mosaics of the Western Ghats with approximately 70% accuracy. Prediction accuracies were higher for grass compared to forest and for mosaics at higher elevations (1500–2000m). Topography alone was able to predict forest and grassland pattern well, however inclusion of bioclimatic predictors that captured latitudinal gradients in climate improved predictive accuracy.The misclassification of high elevation forest points may be due to the fact that the predictors measured at the given scales were unable to correctly classify many of the smaller sized (< 2 ha) forest patches that occur in these mosaics. The inclusion of microclimatic data  could imOverall, the instability found in the CT analysis indicates regional differences in predictor effects and interactions between topography and bioclimate across the range of these mosaics. Hence the same pattern of grassland and forest seems to be generated by different sets of mechanisms across the Western Ghats.Sankaran et al.  demonstrshola patches in the Western Nilgiris shows high turnover between 1900-2000m (A. Das unpublished data), with an increasing component of upper montane taxa and frost-resistant species above 2000m [Temperature is the major limiting factor for tree growth at treelines . While tve 2000m . Ohsawa ve 2000m  posits tve 2000m  report tThe climate signal implied by this altitudinal shift in the occurrence of forest lends support to the role of frost in restricting forest above 2000m . It is usholas expand into grassland through succession beginning with establishment of frost-resistant woody species in grasslands, and subsequently creating suitable conditions for establishment of lower montane species. An analogous process of forest expansion occurs in subtropical forest-grassland mosaics of Southeastern Brazil, where fire has a major influence on vegetation pattern [Mohandass and Davidar  found ev pattern .In mosaics below 2000m, dry season precipitation is an important predictor of forest occurrence. There is some evidence that its influence is mediated by both topographic position and elevation . This coFinally, the importance of the interaction between dry quarter precipitation and annual temperature range on the presence of forest implies that forests at mid-elevation (approx. 1000–2000m) areas of the central Western Ghats such as the Nilgiris plateau and the Siruveni hills could be more strongly influenced by these bioclimatic factors than elsewhere .pers. obs.). The greater importance of local curvature in high elevation mosaics could reflect the influence of concave depressions along hill slopes [As expected, topographic position is an important predictor of vegetation pattern in these mosaics—certainly as a main effect, possibly also in interaction with elevation. Sites with lower topographic position were associated with forest. This could indicate an effect of soil moisture, especially in mid-lower elevation mosaics. Local depressions and valleys are likely to be wetter and therefore less vulnerable to fire . Howeverl slopes  that prol slopes ,62.It is interesting that local topographic position and surface curvature were more important predictors of vegetation pattern than topographic convergence, as previous studies have found topographic convergence to be an important predictor of forest occurrence ,63.Aspect, specifically northness, is an important predictor of forest in high elevation mosaics, which has been attributed to differences in radiation exposure . Bunyan Fletcher et al.  show thaA major limitation of this study is that it does not consider resource and disturbance gradients such as soil characteristics, fire and grazing, that have been found to be critical in shaping vegetation pattern in other forest-grassland systems ,24,61. MThere is an urgent need for accurate, high resolution spatio-temporal datasets on disturbance, particularly fire, across the study area. We found that global satellite-derived burned area products largely underestimated fire frequency in several mosaics, precluding their use in this analysis.shola restoration efforts by State Forest Departments in mosaics above 2000m, should be focused on north-western to north-eastern aspects. Given past conversion of large areas of grassland into exotic tree plantations, recent global trends of forest expansion into grasslands [shola does not take place at the expense of existing grasslands [The results indicate that ongoing asslands  and palaasslands , it is iasslands .As mosaics differ widely in the extent and manner in which topography and bioclimate influence vegetation pattern , managemThe importance of local topography indicates that microclimate  regulateS1 FigStacked barplots showing the regional identity and vegetation community type of data points falling in each of the terminal nodes of the classification tree in (PDF)Click here for additional data file.


The role of attention in creative cognition remains controversial. Neuroimaging studies havereported activation of brain regions linked to both cognitive control and spontaneous imaginativeprocesses, raising questions about how these regions interact to support creative thought. Usingfunctional magnetic resonance imaging (fMRI), we explored this question by examining dynamicinteractions between brain regions during a divergent thinking task. Multivariate pattern analysisrevealed a distributed network associated with divergent thinking, including several core hubs ofthe default (posterior cingulate) and executive  networks. Theresting-state network affiliation of these regions was confirmed using data from an independentsample of participants. Graph theory analysis assessed global efficiency of the divergent thinkingnetwork, and network efficiency was found to increase as a function of individual differences indivergent thinking ability. Moreover, temporal connectivity analysis revealed increased couplingbetween default and salience network regions  at the beginning of the task,followed by increased coupling between default and executive network regions at later stages. Suchdynamic coupling suggests that divergent thinking involves cooperation between brain networks linkedto cognitive control and spontaneous thought, which may reflect focused internal attention and thetop-down control of spontaneous cognition during creative idea production. Neuroscience has made substantial progress in demystifying how the brain generates novel anduseful ideas. Despite progress in the field, however, several fundamental questions remain. Onecentral question concerns the role of attention—whether creative thought involves more orless cognitive control. Past research provides seemingly contradictory evidence, reportingactivation of brain regions associated with both cognitive control  and spontaneous imaginative processes . Moreover, these regionscorrespond to the core hubs of large-scale networks that typically act in oppositionResearch in cognitive neuroscience has increasingly focused on examining large-scale functionalnetworks257814151617Recent theorizing on the role of the DMN in creativity has received support from neuroimagingstudies linking individual default regions to performance on creative thinking tasks. For example,the precuneus—a core hub of the DMN2021222425282930Although the DMN and spontaneous thought appear to be important for creativity, past researchalso points to a role of brain regions associated with cognitive control. Supporting evidence comesfrom neuroimaging studies reporting activation within the lateral prefrontal cortex, a core hub ofthe executive control network ECN; 3, 33). The ECN is engaged during cognitive tasks that requireexternally-directed attention, such as working memory. The ECNThe controversy surrounding the role of attention in creativity is also evident in behavioralresearch on the cognitive basis of creative thought. Although early theories emphasized unconsciousand associative processes in creativity e.g., , a growi4042454647A growing body of research suggests that creative cognition recruits brain regions associatedboth cognitive control and spontaneous imaginative processes. Such work commonly implicates regionswithin large-scale networks, including the ECN and the DMN. Despite their apparent cooperation,evidence from resting-state and task-based research suggests that the DMN and ECN tend to act inopposition—activation of one network typically corresponds to suppression of the otherextended evaluationof internal information173749505153545658We believe these findings may be an artifact of the measurement methods employed in cognitiveneuroscience, most of which use paradigms that require focused external attention. Indeed, whenattention is externally directed, such as viewing a visual stimulus, the dorsal attention networkand executive networks are coupled, and both networks are anticorrelated with activity of thedefault mode network. Emerging evidence, however, suggests that the executive and default networksactually cooperate whenever it is necessary to perform a task that requires To further understand the dynamic interplay between executive and default networks, we examinedthe time-course of brain network connectivity during performance on a creative thinking task.Participants completed an alternate-uses divergent thinking task and a control task duringfunctional magnetic resonance imaging (fMRI). Multivariate pattern analysis was used to assesswhole-brain connectivity associated with divergent thinking. Seed-based and temporal connectivityanalyses explored further connections between regions identified in the whole-brain analysis. Thepresent study thus sought to identify a whole-brain network associated with divergent thinking andto explore other potential connections between regions identified in the whole-brain analysis.The original sample consisted of 28 young adults from the University of North Carolina atGreensboro (UNCG). Participants received course credit or cash payment for their involvement in thestudy. Three participants were excluded for excessive head movement (>3 mm), resulting ina final sample of 25 . All participants wereright-handed with normal or corrected-to-normal vision and no reported history of CNS-affectingdrugs or neurological disease. All participants provided written informed consent. The study wasperformed in accordance with the guidelines and regulations of UNCG’s Institutional ReviewBoard, who approved the study methods.Participants completed two tasks in the scanner: an alternate uses divergent thinking task and anobject characteristics task. The alternate uses task required participants to generate creative usesfor everyday objects ; the object characteristics task, our control task, requiredparticipants to generate typical properties of everyday objects. These two tasks provide an optimalcontrast for isolating brain activity related to the creative manipulation of objects duringdivergent thinking while controlling for activity related to the mental visualization of objectssee also61. Partiyes, 2 = no; 3 s). The purpose of the responseperiod was to ensure compliance and maintain active engagement with the task; all trials wereincluded in the subsequent analysis. A total of 46 trials were administered in an event-relateddesign. For each participant, experimental stimuli were randomly assigned to either condition. Participants were encouraged to continue to generateideas until the end of the idea generation period.The task paradigm consisted of a jittered fixation cross (4-6 s), a cue indicating the upcomingcondition , an idea generationperiod presenting an object in text , and a responseperiod requiring a button press to indicate whether an idea was successfully generated using a 16-channel headcoil. BOLD-sensitive T2*-weighted functional images were acquired using a single shot gradient-echoEPI pulse sequence  andcorrected online for head motion. The first two volumes were discarded to allow for T1 equilibrationeffects.3, normalized to the MNI templatebrain , and smoothed with an 8 mm3 isotropicGaussian kernel.Visual stimuli were presented using e-Prime and viewed through a mirror attached to the headcoil. Following functional imaging, a high resolution T1 scan was acquired for anatomicnormalization. Imaging data were slice-time corrected and realigned using the Statistical ParametricMapping (SPM) 8 package . Functional volumes werecoregistered and resliced to a voxel size of 2mmhttp://www.nitrc.org/projects/conn; 63) inMATLAB. For each participant, CONN implemented CompCor, a method for identifying principalcomponents associated with segmented white matter (WM) and cerebrospinal fluid . Past research suggests thatsubtle differences in ROI placement within a given brain region can affect the correspondingresting-state networksWe conducted resting-state functional connectivity analysis with select ROIs using an independentsample of age-matched participants (p< .05 FDR corrected). Due to the temporal lag in the BOLD signal, the first time window was notanalyzed, resulting in five temporal windows for analysis .We then conducted a series of seed-to-voxel and ROI-to-ROI analyses with the task-based data toassess pairwise correlations between the ROIs. For the seed-based analyses, we explored connectivitybetween select ROIs and all other voxels in the brain. For the ROI-to-ROI analysis, we exploreddynamic changes in functional connectivity between ROIs across the task duration. The two taskconditions (divergent thinking and object characteristics) were divided into six 2 sintervals, corresponding to the repetition time (TR) of 2 s and total task durations of12 s. We then computed task contrasts for each of the 2 s task intervals . Inter-rater reliability for the three raters’ scores was good. The global efficiency and divergent thinking composite scores werestandardized by z-score transformation. Finally, we computed the correlation between global networkefficiency and composite creativity scores. We hypothesized that network efficiency would bepositively correlated with individual differences in divergent thinking ability.p < .001 uncorrected.Seed-to-voxel analyses are reported at a cluster-level threshold ofp < .05 familywise error (FWE) corrected; ROI-to-ROI analyses are reportedwhen significant at a threshold of p < .05 false discovery rate (FDR)correctedFor all second-level analyses, T-tests on Fisher’s Z-transformed correlations were usedto test for differences in functional connectivity between tasks. Results are reported whensignificant at a voxelwise threshold of level of The MVPA task contrast  revealed adistributed network of voxel clusters associated with divergent thinking see . The netn = 42). In line with previous resting-state research, we expected that thePCC and precuneus seeds would show positive correlation with other default network regions  and negative correlation with executive network regions ; likewise, we expectedthat the DLPFC seed would show positive correlation with other executive network regions andnegative correlation with default regions.We then explored resting-state functional connectivity with select regions of the DMN (leftprecuneus and right PCC) and ECN (right DLPFC) associated with divergent thinking in the MVPA. Thisanalysis was conducted using data from an independent sample of participants. Results revealed increased functionalconnectivity between the precuneus and seven voxel clusters during divergent thinking, includingregions within the executive network  and salience network , as well as the left MTG and left pre-motor cortex . The first seed-to-voxel analysisassessed connectivity between the precuneus seed and all other voxels, left PCC, and right precuneus see ; we alsoWe then assessed dynamic changes in functional connectivity across the duration of the task. Allregions from the whole-brain MVPA were specified as ROIs , the RDLPFC did not show any significant connectivity differences with the targetROIs. However, during the third time window, the DLPFC showed increased connectivity with regionswithin the DMN, including the right PCC and right IPL, in addition to left RLPFC, left temporalpole, and right PMC see . The DLPr = .44, p = .02)—asdivergent thinking ability increased, the divergent thinking network showed greater efficiency  and executive (DLPFC) networks,among other regions. Resting-state functional connectivity analysis confirmed the underlying networkaffiliations of these regions, using data from an independent sample of participants. Seed-basedanalyses found increased connectivity between the DLPFC, PCC, and precuneus, and temporal analysesrevealed dynamic coupling between these regions at different stages of the divergent thinking task.The results extend past research by revealing functional connections between regions commonlyassociated with creative cognition. Moreover, functional connectivity between hubs of large-scalenetworks points to a greater cooperation between networks associated with cognitive control andspontaneous thought processes.The whole-brain MVPA revealed a distributed network associated with divergent thinking see . This neSeed-based and ROI-to-ROI analyses were conducted to explore further connections between specificdefault and executive regions identified in the whole-brain analysis. We found increasedconnectivity between the right DLPFC seed and regions of the default network, including the rightIPL and the precuneus, as well as connectivity between the PCC seed and the DLPFC. These resultsextended the whole-brain analysis by showing direct connections between default and executivenetwork regions during the task. Such findings provide support for the notion that creative thoughtinvolves cooperation between spontaneous and controlled processes171842We also found increased connectivity between default regions (PCC and precuneus) and regions ofthe salience network . The salience network is involved inreallocating attentional resources to salient environmental events2Further support for this notion comes from results of the ROI-to-ROI temporal connectivityanalyses. Here, we examined changes in connectivity between default and executive network ROIsacross the duration of the task. We found that the PCC was more strongly connected to saliencenetwork regions  at the beginning of the task, followed by strongerconnections with executive network regions . Early coupling of the PCC with thesalience network may provide an intermediate mechanism that facilitates later coupling with theexecutive network. Moreover, we found differential coupling between the right DLPFC seed and defaultnetwork regions . Interestingly, the DLPFC only showed connectivity withdefault regions during the second half of the task , pointing to a potential roleexecutive processes at later stages of divergent thinking. Taken together, such dynamic coupling mayreflect cooperation between brain networks associated with cognitive control and spontaneousthought, consistent with recent theorizing on the role of attention in creative cognition141617The present results raise the question of how such typically opposing networks cooperate in thebrain. A large body of resting-state and task-based research has reported an antagonisticrelationship between the DMN and ECN. During working memory performance, for example, the ECN showsincreased activation while the DMN deactivatesLike other types of self-generated thought , creative thinking may requirefocused internal attention cf. , 71. But42The present study extends recent research on resting-state functional connectivity and divergentthinking abilityThe present study explored dynamic interactions between brain regions during performance on acreative thinking task. We found increased functional connectivity between regions of the defaultand executive networks, pointing to cooperation between large-scale networks underlying creativeidea production. One notable limitation of the study was our inability to capture participantresponses in the scanner, which would have shed light on task compliance and further permittedparametric analyses of brain activity related to the creative quality of responses. Yet the highcorrelation between individual differences in divergent thinking ability, assessed outside thescanner, and global efficiency of the divergent thinking network suggests that participants wereindeed engaged in divergent thinking during the task, and that the integrity of the network wassensitive to the creative ability of participants.The study was also limited to the use of a single assessment  to indicate a rather broadly defined construct (creativity). Future research shouldexamine functional connections among brain regions during other creative thinking tasks and inrelation to creative performance in specific domains, such as musical improvisationHow to cite this article: Beaty, R. E. et al. Default and Executive NetworkCoupling Supports Creative Idea Production. Sci. Rep. 5, 10964; doi: 10.1038/srep10964(2015).


Vitreous hemorrhages are important clinical manifestations of proliferative diabetic retinopathy. Non-cleared vitreous hemorrhages could lead to hemosiderosis bulbi and glaucoma. Here, we describe the case of a type 2 diabetic patient presenting anterior segment and vitreous hemorrhages that resolved three days after treatment with a single intravitreal injection of dobesilate.  Vitreous hemorrhages are an important clinical manifestation of proliferative diabetic retinopathy. A vitreous hemorrhage may spontaneously get re-absorbed over time in some cases. However, sometimes it requires a pars plana vitrectomy to remove the hemorrhage because otherwise it may lead to retinal tears, retinal detachment, hemosiderosis bulbi and glaucoma, causing a further reduction in vision , 2. HereA 68-year-old Caucasian male with type 2 diabetes presented with one-month history of intense vision loss in his right eye. The patient did not seem had suffered any recent traumatic eye accident in the affected eye. The ophthalmic microscopic examination showed a pseudophakic right eye with both non-recent and recent hemorrhages in the anterior segment Fig. . A fundoAfter approval by the Institutional Review Board, the patient signed an informed consent form, which included a comprehensive description of the off-label use of dobesilate and the proposed procedure. The patient received an intravitreal solution of dobesilate (150 μl) under sterile conditions in his right eye according to the international guidelines for intravitreal injections . ProphylA vitreous hemorrhage is a common disease that accompanies a wide variety of ophthalmological pathologies. The most common causes include proliferative diabetic retinopathy, vitreous detachment with or without retinal breaks, and trauma. Less common causes include vascular occlusive disease, retinal arterial aneurysms, hemoglobinopathies, neovascular age-related macular degeneration, and intraocular tumors. Hemorrhage into the vitreous gel results in rapid clot formation and is followed by a slow clearance of approximately 1 % per day . The comDobesilate has been used for many years for the treatment of diabetic retinopathy. Its mechanism of action has not been established, but several possibilities have been proposed, including anti-inflammatory effects and inhibition of vascular endothelial growth factor (VEGF) , 5. AlthThe data shown in this report seems support that direct application of dobesilate  could serve as a promising new clinical application to temper the most important pathological effects of vitreous hemorrhages in proliferative diabetic retinopathy.An intravitreal injection of dobesilate for the treatment of vitreous hemorrhages related to proliferative diabetic retinopathy is associated with prompt morphologic and visual improvement and may offer benefits over the natural course of the disease.Written informed consent for publication of the clinical details and images was obtained from the patient.


Constitutively activated prosurvival pathways render cancer cells addicted to their effects. Consequently they turn out to be the Achilles' heels whose inhibition can be exploited in anticancer therapy. Primary effusion lymphomas (PELs) are very aggressive non-Hodgkin's B cell lymphomas, whose pathogenesis is strictly linked to Kaposi's sarcoma herpesvirus (KSHV) infection. Here we summarized previous studies from our and other laboratories exploring the cytotoxic effect of drugs inhibiting the main prosurvival pathways activated in PEL cells. Moreover, the immunogenicity of cell death, in terms of dendritic cell (DC) activation and their potential side effect on DCs, is discussed. Primary effusion lymphomas (PELs) are very aggressive non-Hodgkin's B cell lymphomas with poor prognosis that frequently arise in immune-compromised patients . PELs orPEL cell survival relays on the constitutive activation of several pathways and also on the hyperexpression of several heat shock proteins (HSPs), a characteristic that is common among the cancer cells.By engagement of their specific cellular receptors, cytokines such as IL-6 and IL-10 and VEGF activate the JAK2/STAT3 transduction pathway that promotes the transcription of genes encoding for proteins involved in PEL resistance to apoptosis and contributes to tumor survival –13. ConsIt is known that, in addition to STAT3, cytokines like IL-6 and IL-10, VEGF, and Oncostatin M  are ableκB and PI3K/AKT/m-TOR, has been reported [Mitogen activated protein kinases (MAPKs) including ERKs, JNKs, and p38 kinases control a vast array of physiological processes . They careported . In a rereported . A prosureported . In addireported .κB, constitutively activated in PEL cells due also to the effect mediated by KSHV-encoded viral FLICE-inhibitory protein (v-FLIP) expression [κB inhibition with Bay11-7082 exerts a strong reduction of PEL cell survival [κB inhibition [An essential role in PEL cell survival is known to be played by NF-pression , 34. It survival . Moreovehibition , even ifhibition . We havehibition , 37. Morhibition .A further effect mediated by the activation of pathways such as Ras/MAPK and JAK/STAT3 is the increase of heat shock protein (HSP) expression , 39. HSPPEL cells harbour KSHV, which persists in a latent state in the majority of the cells. Upon appropriate stimuli, latent infection can be switched into lytic productive infection that generally leads to cell lysis and spread of the viral particles. The possibility to kill tumor cells by inducing viral replication can be explored in the therapy against tumors latently infected with DNA viruses, especially because during viral replication tumor cells become sensitive to the effects induced by the antiviral drugs. For the above reasons, strategies that allow the manipulation of viral life cycle, reducing or promoting viral production, are potentially explorable in PELs. One of the strategies that allow manipulating the viral life cycle is the modulation of the cellular autophagy which has been shown to have a strong impact on KSHV replication .κB with Bortezomib  polymerase (PARP) cleavage. PARP cleavage generally represents a final event of an apoptotic cell death and is mainly mediated by caspase activation . We founIn conclusion, the use of drugs that target constitutively activated pathways in PEL cells could represent a valid alternative in translational therapies, especially considering the ability of most of them to induce an immunogenic cell death. In addition, their use is very promising because they have a low side effect towards the immune cells, and DCs in particular, rendering their use safer than conventional chemotherapies.