Whether the effects of cannabis use on brain function persist or recover following abstinence remains unclear. Therefore, using meta-analytic techniques, we examined whether functional alterations measured using fMRI persist in cannabis users abstinent for over 25 days (or 600 h) as evidence suggests that the effects on cognitive performance no longer persist beyond this period. Systematic literature search identified 20 studies, of which, 12 examined current cannabis users (CCU) (361 CCU versus 394 non-cannabis using controls (NU)) and 3 examined abstinent cannabis users (ACU) in 5 separate comparisons (98 ACU versus 106 NU). Studies in ACU were carried out in adolescents and suggest significantly greater activation in components of the central executive and default mode networks in adolescent ACU compared to NU. While this evidence is to be interpreted with caution because studies were carried out in overlapping samples, they indicate a pressing need for independent confirmation whether certain neurofunctional alterations in adolescent cannabis users may persist even after cannabis and its metabolites are likely to have left their bodies. Following abstinence, cognitive performance has been found to improve in cannabis users (CU)  to the lHowever, whether the effects of recreational cannabis use on brain function persist not only beyond the acute intoxication stage typically lasting 2–3 h when use are of pWe have recently examined the residual effects of recreational cannabis use on brain function in adult and adolescent cannabis users by meta-analytically combining the data from 20 published studies employing functional MRI techniques . While s22.1A systematic search was competed on the 13/12/2017 following the Cochrane Handbook  and the •A published peer-reviewed manuscript reported in English•A data-based publication•Comparison of cannabis users to a non-cannabis using control group (NU) using fMRI•Reported whole-brain imaging analysis results and not just region-of-interest analysis results•Used a cognitive or emotional activation task with no cannabis-related stimuliInclusion criteria were:Manuscripts were separated into three categories, based on the type of cannabis-using groups reported. Those that reported at least one comparison with current cannabis users (CCU) or with abstinent cannabis users (ACU) were included while those that did not report either of the previous comparisons were excluded (flow-chart in 2.2d mapping (SDM)(www.sdmproject.com/utilities /?show = statistics). In case of studies where no inferential statistical values were reported, a ‘p’ or ‘n’ was used to indicate a positive or negative peak, respectively. As per protocol for SDM meta-analysis  was conding (SDM) and are analysis  a study-analysis .Information regarding the brain template used to report cluster coordinates  or Talairach) was included in each study-specific file text file created as above. Any study that reported no significantly different activation peaks was also included. Each contrast completed between CU (CCU or ACU) and controls was extracted and treated as a separate studies, for example if a study reported the results of separate encoding and recall conditions in a memory task, these were treated as two separate studies, following established protocol . Each st2.3Meta-analysis was carried out using seed based-d-mapping , using tThree initial meta-analyses were completed comparing CCU to NU; comparing ACU to NU and, comparing activation in CCU to ACU. Two further meta-analyses were completed, as the ACU group contained only adolescent participants, comparing adolescent CCU compared to adolescent NU and comparing adolescent CCU to the adolescent ACU. Results have been thresholded to ensure voxel threshold = p < 0.005, peak height threshold: peak SDM-Z < 1, and a cluster-size threshold of clusters ≥ 10 voxels. The co-ordinates of cluster peaks were reported using MNI coordinates.2.4Heterogeneity Q statistic was assessed in terms of a chi-squared distribution after conversion to standard z values and reported. Between–study heterogeneity was assessed by comparison of heterogeneity maps. Funnel plots were created for each cluster peak and Egger’s test performed in order to asses publication bias .2.5Quality assessment of each study was completed using criteria previously used for fMRI studies , which w33.1Twenty studies were identified as meeting study inclusion criteria as detailed earlier. Of those, twelve manuscripts met inclusion criteria as reporting CCU, with 22 separate comparisons, comparing 361 CCU to 394 NU . Three mSummary of quality assessment of studies included in the present meta-analyses are reported in All studies qualifying for the ACU group, were carried out in adolescent users. Further meta-analysis comparing ACU and CCU, using only adolescent studies was completed. Data from three manuscripts reporting on current adolescent users, with four separate comparisons, with 69 CCU and 70 NU were used for comparison with the abstinent adolescent user group described above. Results for all meta-analyses are reported in 3.2Meta-analysis of CCU revealed that CCU had increased activation when compared to NU in the medial frontal gyrus bilaterally and right insula, extending ipsilaterally to the inferior frontal gyrus. A decrease in activation was found in CCU compared to NU in the left cuneus, extending ipsilaterally to the superior, middle, and inferior occipital gyri; and in the right precentral gyrus, .3.3Meta-analysis of adolescent ACU compared to NU revealed that ACU had increased activation in the right inferior frontal gyrus; right precuneus, extending ipsilaterally to the superior parietal gyrus; and the right middle occipital gyrus, extending ipsilaterally to the superior occipital gyrus and cuneus; the middle frontal gyrus extending to the superior frontal gyrus bilaterally and the inferior parietal gyri bilaterally, extending to the superior parietal gyrus bilaterally and the right angular gyrus. There were no areas where brain activation was significantly decreased in ACU compared to NU .3.4Meta-analysis comparing CCU including both adult and adolescent studies to adolescent ACU, revealed no areas where brain activation was significantly increased in CCU compared to ACU, However, ACU had increased activation in the right precuneus, extending ipsilaterally to postcentral and superior parietal gyrI; the left lingual gyrus, extending ipsilaterally to superior and middle occipital gyri; the left middle frontal gyrus extending ipsilaterally to superior frontal gyrus; and the inferior parietal lobule bilaterally extending to superior parietal gyrus bilaterally and to the right angular gyrus, .3.5Meta-analysis of adolescent CCU revealed that adolescent CCU had increased activation when compared to NU in the right middle frontal gyrus extending ipsilaterally to the inferior frontal gyrus ; and the middle occipital gyrus on the right side. There were no areas where brain activation was significantly decreased in adolescent CCU compared to .3.6Meta-analysis of adolescent CCU compared to adolescent ACU, revealed that there were no areas where brain activation was significantly different between adolescent CCU and adolescent ACU NU .3.7Funnel plots were created and examined for each cluster from each meta-analysis. Egger’s tests were used with no cluster reaching significance, indicating no publication bias see . SDM-Z s4The key comparisons of interest in the present set of analyses relate to the brain activation differences between ACU and NU and that between ACU and CCU. Although the ACU versus NU comparison was limited to only studies in adolescent cannabis users (as no studies in adult users met our stringent inclusion criteria for ACU), we found significantly greater activation in the dorsolateral and ventrolateral prefrontal and posterior parietal cortices, which are part of the central executive network and are known to be involved in higher order cognitive processes such as attentional control, executive function and working memory . These fCollectively, results of the present meta-analysis clearly suggest that at least in adolescent cannabis users, brain functional alterations persist even after periods of abstinence equivalent to around 25 days, by when cannabis metabolites are no longer detectable in urine. One cannot be certain on the basis of present analyses whether similar functional alterations also persist in adult regular cannabis users after comparable periods of abstinence. However, functional alterations in similar brain areas as reported here have also been observed in adult occasional cannabis users compared to non-users after prolonged abstinence , b. AdolWhat might underlie these functional differences between abstinent adolescent cannabis users and non-users? Evidence from two independent studies suggest downregulation of cannabinoid receptor 1 density in regular cannabis users , which rNotwithstanding limitations highlighted above, results from the present meta-analyses suggest that certain neurofunctional alterations in components of the central executive and default mode networks in adolescent cannabis users may persist even after cannabis and its metabolites are likely to have left their bodies. However, given the overlap in the samples that support the key conclusions reported here, there is an urgent need for independent studies investigating whether brain function in abstinent cannabis users differ significantly from non-users following a sustained period of monitored abstinence, both in adolescents as well as in adults. Furthermore, whether these persistent brain functional alterations underlie short-term or longer-term risks of mental, social and behavioural disturbances , 2018, pThe views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. All authors have approved the final version of the paper.None.


It is generally believed that enhanced permeability and retention (EPR) plays a key role in nanocarriers' accumulation in preclinical tumor models and is a clinically relevant phenomenon in certain cancer types. However, use of EPR effect as an across-the-board explanation for nanoparticle tumor access is likely over-simplified, particularly in the stroma rich solid tumors such as PDAC. Recently, ample evidences including our own data showed that it is possible to use transcytosis as a major mechanism for PDAC drug delivery. In this mini-review, we summarize the key studies that discuss how transcytosis can be employed to enhance EPR effect in PDAC, and potentially, other cancer malignancies. We also mentioned other vasculature engineering approaches that work beyond the classic EPR effect.Numerous nano drug delivery systems have been developed for preclinical cancer research in the past 15 years with the hope for a fundamental change in oncology. The robust nanotherapeutic research has yielded early-stage clinical products as exemplified by the FDA-approved nano formulations (Abraxane Most nanocarriers currently being tested in clinical trials rely on passive delivery, which conceptually depends on the enhanced permeability and retention (EPR) effectth leading cause of cancer death. According to the American Cancer Society's estimation, there were 56,770 new PDAC cases and 45,750 patient death cases in the US in 2019PDAC is the 4in situ observation with ultrastructural resolution to answer the question about if the enlarged tumor fenestration is the solo factor that determines nanoparticle tumor access. Alternatively stated, does nanoparticle extravasation primarily rely on “leakiness”  that assists nanoparticle tumor homing effectiveness   , which achieved efficient delivery of the drug to the PDAC and other tumor sites by taking the advantage of caveolae-mediated transcytosis mechanismvia transcytosis. This allows the particle entry into perivascular tumor areas, followed by the binding to uPAR-expressing PDAC tumor cells and tumor-associated stromal cellset al., designed a γ-glutamyl transpeptidase-responsive camptothecin-polymer conjugate. The idea was to use γ-glutamyl transpeptidase that was overexpressed on the endothelial cell membrane to cleave the γ-glutamyl moieties, leading to the positive primary amines on the particle surfaceIn addition, it was also demonstrated that albumin can mediate a transcytosis process in endothelial cells by targeting the 60-kDa glycoprotein (gp60) receptor, which binds to caveolin-1 by forming transcytotic vesicleset al. demonstrated that Tf-coated PLGA-NPs entered massively within brain-developed F98 glioma tumorset al. also developed zoledronic acid loaded nanoparticles with Tf-conjugation for transcytosis mediated BBB access and efficacy improvement in an orthotopic glioblastoma modelet al. found a type of PLGA-PEG mesoscale nanoparticles (~400 nm) selectively target to kidney via transcytosis mechanism across depend predominantly on size and surface functionalization (non-opsonizing surface) but is independent of moderate surface chargeset al. design a series of linear and branched histidine-lysine (HK) peptide carriers as nonviral vectors for gene and siRNA delivery, this type of HK polyplexes can target neuropilin-1 receptor on endothelial cells and tumor cells which mediated the transcytosis through the tumor endothelium and lead high tumor distribution and efficient transfection in MDA-MB-435 breast cancer modelTranscytosis is a type of transcellular transport across the interior of a cell which extensively studied initially for macromolecules delivery through the blood-brain barrier (BBB)vs tumor have generated promising preclinical outcomeWhile the use of transcytosis to improve drug delivery is still not fully understood yet, ample evidences strongly suggested that physicochemical characteristics of nanocarriers may determine the effectiveness of transcytosis at tumor site. This includes the early-stage observations on particle chemical composition, size, shape, charge, surface modification, which may alter the rate and abundance of transcytosisst wave to open the stromal vascular gate, thereby allowing rapid tumor entry by 2nd wave drug carriers. This is in the line with nano-enabled engineered approach, which uses a multistage/multistep combination treatment to provide an impact on PDAC stroma, such as augmented blood vessel permeability, inhibition of drug inactivating enzymes and/or target specific biological factorsAnother example to broaden the EPR concept is increased stromal vascular access by reducing pericyte coverage in PDACFrom the translational nanomedicine aspect, there is a clear agenda to predict and quantify the EPR effect in cancer patients. This notion holds true to explore new mechanism(s) such as transcytosis to facilitate nanocarriers' tumor access, especially in non-leaky tumor types. It is noteworthy to dissect the complexity of each cancer indication as well as the differences among each individual with the same cancer indication. In fact, MRI imaging (using fluorescently labeled iron oxide nanoparticles) followed by quantitative intravital fluorescence visualization can identify “responder” for nanomedicine therapyIn summary, it is not surprising that major efforts are underway to study drug delivery using nano-enable approach for PDAC treatment. It becomes clear that transcytosis (perhaps with other unknown mechanisms) may coexist with the so-called EPR effect, which may not be a dominate factor in the case of PDAC. Further investigations are still required to fully understand this emerging approach, which may allow nanoparticle tumor targeting with major augment with respect to homing abundance, efficiency and time kinetics.


The prevalence of food allergy has been steadily rising worldwide with the highest incidence noted among younger children, and increasingly recognized as a growing public concern. The first known ingestion of foods often causes allergic reaction, suggesting that sensitization of offspring with food allergens may occur during pregnancy and/or through breastfeeding. This creates a milieu that shapes the neonatal immune responses to these allergens. However, the effects of maternal allergen exposure and maternal sensitization with allergens on development of allergies in offspring remain controversial. This review discusses recent advances from human data in our understanding of how maternal factors, namely, food allergens, allergen-specific immunoglobulins, cytokines, genetics, and environmental factors transferred during pregnancy or breastfeeding influence offspring allergies and how such effects may be applicable to food allergy. Based on information obtained from mouse models of asthma and food allergy, the review also dissects the mechanisms by which maternal factors, including the impact of immune complexes, transforming growth factor-β, vitamin A, and regulatory T-cell responses, contribute to the induction of neonatal tolerance vs. development of allergic responses to maternally transferred allergens. The rise in the prevalence of allergic diseases such as asthma, pollinosis, and food allergy has continued worldwide for more than 50 years and has become a global public health concern, especially in young children. Sensitization rate to one or several allergens among school children are approaching 40 to 50% worldwide . ConsistFood allergy currently affects 5–8% of the United States population . The prein utero and via breast milk, together with genetic and environmental factors that could further facilitate the neonatal immune responses to allergens.The first known ingestion of foods often causes allergic reactions , suggestin utero as major food allergens could appear in amniotic fluid in an intact form  recommended that atopic mothers should avoid consumption of peanut and peanut products during pregnancy and breastfeeding to prevent peanut allergy in offspring. Following this recommendation, however, the prevalence of peanut allergy in school-age children increased and even resulted in the highest prevalence of peanut allergy in 4- to 5-year-old children  , 0.56] . The preR, 0.31) . HoweverR, 0.31) . AnotherPlacental transfer of maternal Igs is known to provide a protective passive immunity to the fetus against infection . The selOver the last decade, the importance of commensal bacteria in the host immune responses has been increasingly recognized, particularly bacteria colonizing the gastrointestinal tract. The composition of intestinal microbiota in newborn infants is dependent on many factors, such as type of maternal deliveries. Cesarean delivery has been associated with the incidence of atopy and allergic diseases in children, including atopic dermatitis, rhinitis, asthma, and eosinophilic esophagitis –46. Throin utero and continues after birth D) in cord blood have been inversely associated with the risk of asthma and wheeze during childhood (p = 0.02) by maternal vitamin D supplementation  and omega 3 (n-3) polyunsaturated fatty acids (PUFAs), commonly found in many nuts, seeds, and vegetable oils, during pregnancy shows different capacities to alter the incidence of atopic sensitization and allergy in children . ArachidN = 640). Among the infants who were initially negative for skin-prick test (N = 530), the prevalence of peanut allergy at 60 months of age was considerably lower in the consumption group (1.9%) than those in the avoidance group (13.7%). Among the infants who were initially positive for skin-prick test (N = 98), the prevalence of peanut allergy was 10.6% and 35.3% in the consumption group and in the avoidance group, respectively (p = 0.004). Interestingly, levels of peanut-specific IgG4 were increased in the consumption group whereas levels of peanut-specific IgE were increased in the avoidance group. The study concluded that early introduction of peanut reduced the development of peanut allergy in high-risk children and that early peanut introduction does not prevent other allergies , sensitization to other food allergens  and aeroallergens, or reported allergic reactions to tree nuts and sesame (p = 0.32). However, in families that closely adhered to the challenging protocol, the prevalence of any food allergy was considerably lower in the EIG than in the SIG , as was the incidence of peanut allergy  and egg allergy . There was no significant effect with respect to the prevalence of allergy to milk, sesame, fish, or wheat. These studies suggest that the early introduction of all 6 allergic foods, although not easily achieved, may have beneficial effects in preventing food-allergen sensitization in high-risk children.The recent clinical report by American Association of Pediatrics (AAP) proposes that no conclusions can be drawn regarding the effects of breastfeeding on preventing or delaying the development of food allergies in offspring , howeverd sesame . A follod sesame . The stup = 0.003) . These results suggest that a combination, but not alone, of maternal peanut consumption while breastfeeding and direct introduction of peanut in the first year of life provides a significant protection from peanut sensitization. Although the readout was peanut sensitization and not challenge-proven peanut allergy, this study raises an important point that the combination of maternal and offspring factors together during breastfeeding period plays a critical role in the prevention of food allergy in offspring.In addition to early direct food introduction to children, maternal consumption of potentially allergic foods during breastfeeding has been suggested to prevent food sensitization in offspring. A Canadian cohort study with 342 infants analyzed the association of maternal peanut consumption while breastfeeding, timing of direct peanut introduction to infants, and a combination of both, with peanut sensitization at 7 years of age . BreastfMaternal food allergen consumption results in an appearance of allergen in breast milk, though not always. Ara h 2 and Ara h 6 are detectable in breast milk . Ara h 6p = 0.01). Fecal sIgA concentration in breastfed infants was significantly higher in those in formula-fed infants (p <0.05). The association of breastfeeding with the increased levels of fecal sIgA in infants may suggest potential protective effects in early life.Maternal cow's milk avoidance was associated with lower levels of milk allergen-specific IgA and IgG4 antibodies and the development of cow's milk allergy in infants . High coA systematic review suggests a positive association between concentration of TGF-β1 or TGF-β2 in breast milk and a reduction in IgE titer and atopic inflammation in infancy and early childhood . In contp = 0.02). Within breastfed children, there was no significant association between the incidence of food allergy and direct breastfeeding vs. bottle-feeding (p = 0.27). Collectively, these studies indicate the association of prolonged breastfeeding with reduced risk of allergic sensitization and food allergy. Regarding feeding modes, a prospective birth cohort study in Canada with 3,296 children examined the effects of infant feeding modes on childhood asthma  sensitization with OVA/alum and i.p. OVA injection (+ T cells from offspring of OVA-fed DO11.10 dams (transgenic mice bearing OVA-specific T-cell receptor) proceeded into S phase 72-h after in vitro stimulation with OVA. In contrast, the majority of CD4+ T cells from offspring of unexposed DO11.10 dams were arrested in G0/G1 phase, suggesting that offspring T-cells are primed in utero by oral administration of dams with allergen. It is noteworthy that OVA was undetectable in amniotic fluid, placental serum, or breast milk from OVA-fed dams during pregnancy. In contrast, when dams were orally administered during the first week of breastfeeding, OVA was detectable in milk from OVA-fed dams in proportion to the dam's intake dose. Levels of maternal allergen-specific Igs were not examined in this study. These results suggest that oral exposure of dams to low-dose allergen during pregnancy may result in T-cell priming to allergen in utero, although whether maternal Igs are involved in this setting is not clear. Intranasal exposure of WT dams with OVA before conception resulted in the induction of tolerance in offspring toward allergic airway inflammation as well as allergen-specific Th2 responses following i.p. sensitization with OVA and alum and intranasal OVA challenge (+ regulatory T cells (Treg) in utero, suggesting a role of allergen-IgG-IC in the induction of neonatal tolerance during pregnancy. More recent study demonstrated that anti-IgE antibody treatment of pregnant dams prevents allergen-specific IgE production in offspring following allergen sensitization  dams with OVA during pregnancy has been shown to decrease allergen sensitization in offspring . Oral adnjection . Oral adhallenge . Interestization .i.p. injected with IFN-γ during pregnancy, then offspring were fostered after birth and nursed by normal dams untreated with IFN-γ (IFN/Nor). Conversely, offspring of naïve dams were fostered and nursed by dams treated with IFN-γ (Nor/IFN) or untreated normal dams (Nor/Nor). Following OVA inhalation, both IFN/Nor and Nor/IFN offspring showed reduced numbers of eosinophils in bronchoalveolar lavage fluid, but only IFN/Nor offspring showed almost normal lung histology. IFN/Nor offspring also showed amelioration of passive cutaneous anaphylaxis. These results suggest that maternal IFN-γ induces stronger protective effects when prenatally transferred in utero than when postnatally transferred via breast milk against allergic airway inflammation in offspring.Effects of maternal IFN-γ on development of offspring asthma were investigated in dams treated with IFN-γ . Dams wei.p. sensitization and intranasal challenge with OVA. Offspring of OVA-fed dams nursed by naïve dams were also protected, suggesting the role of in utero IgG transfer in decreasing the disease severity in offspring. Offspring of FcRn-deficient dams, unable to transport IgG through placenta, nursed by OVA-fed WT dams showed protective effects against OVA-induced asthma-like symptoms, indicating the contribution of IgG transfer also via breast milk to protection of offspring. Anti-IFN-γ treatment of offspring during sensitization and challenge with allergen abolished the protection. This study suggests that this maternal IgG-mediated suppression of allergic airway inflammation is dependent on offspring IFN-γ, indicating the synergistic effects of maternal-offspring factors in shaping neonatal responses to allergic diseases. How OVA administration to dams through usually tolerizing oral route results in generation of allergen-specific IgG was not clear in this study.The importance of IFN-γ in the protection of offspring against allergic inflammation was proposed in another study that demonstrated that transfer of maternal IgG to the offspring induced offspring tolerance against asthma-like phenotype . OffspriAcinetobacter lwoffii F78 during prenatal period resulted in prevention of experimental asthma in their offspring, which was dependent on maternal TLR signaling  and challenge with OVA aerosol compared with offspring of dams with Th2-biased immunity or naïve dams. Offspring of dams with Th1-biased immunity to bovine serum albumin did not show protection against development of OVA-specific IgE or OVA-induced airway inflammation, suggesting that the suppression of allergic airway inflammation in offspring from Th1-biased dams is antigen-specific. Although offspring of Th2-biased dams failed to show protection against OVA-induced airway inflammation, these offspring showed a trend toward lower levels of OVA-specific IgE as compared to offspring of naive dams , factors , and dose of those factors in the interplay of pathogenic vs. regulatory responses in allergic diseases in offspring will be needed to understand this complex relationship.Collectively, these observations indicate that maternal environment and maternal factors directly or indirectly affect offspring immune system during pregnancy likely contribute to the induction of tolerance. Potential preventive effects of  allergy , suggestin utero period, maternal factors such as allergen, Igs, IC, and TGF-β in breast milk induce allergen-specific tolerance against allergic sensitization and inflammation. Maternal immune cells are present in breast milk and are transferred into offspring tissues  of peanut extract to offspring with breast milk from sensitized or naïve dams during post-weaning period failed to enhance the induction of tolerance compared to those orally administered peanut extract alone in offspring. The authors suggest that dose of dietary allergens contained in breast milk may not be adequate to induce oral tolerance in their system. These results support the recent recommendations of no restrictions in diet for pregnant and breastfeeding mothers. Human milk containing peanut allergens induced partial protection in young mice following peanut sensitization  preconceptionally exposed to peanut exhibited variable levels of maternal Igs in sera and breast milk, though, maternal preconceptional peanut exposure or also during pregnancy and breastfeeding showed no influence on offspring peanut allergy induced by oral immunization with peanut and cholera toxin (CT) and oral plus hallenge . The efftization , supporttization . OffspriIl4 mRNA expression, and numbers of mucosal mast cells in proximal colon compared to those in offspring from unsensitized and unchallenged (naïve) dams. Offspring from dams unsensitized and challenged with OVA exhibited a partial but a significant reduction in food allergic responses compared to those from naïve dams. Offspring from OVA-sensitized dams without oral OVA challenge showed comparable food allergic responses to offspring of naïve dams, indicating that there is no increase in food allergy susceptibility of offspring by in utero factors from allergen-sensitized dams in this system. OVA-specific IgG was detectable in breast milk and serum of offspring from OVA-sensitized dams regardless of oral OVA challenge. OVA-specific IgA was detectable in breast milk only from OVA-sensitized and challenged dams. These results suggest that allergen-specific IgG and oral allergen exposure during breastfeeding resulting in production of allergen-specific IgA were required to induce an effective protection toward food allergy in offspring. These results suggest that even allergen-sensitized dams could have preventive effects on offspring allergies through breastfeeding. A recent study also demonstrated that allergen-sensitized dams protect offspring against food allergy through breast milk , and OVA-specific IgE antibodies compared to naïve offspring nursed by naïve dams. The duration of oral tolerance elicited by breast milk toward food allergy was assessed in offspring of unsensitized dams nursed by dams preconceptionally immunized i.p. with OVA/alum then fed OVA during lactation. Breastfeeding by OVA-dams decreased the frequencies of allergic diarrhea in response to multiple oral OVA challenges in 6-week-old, but not in 13-week-old, offspring. TGF-β supplementation after weaning till 12-week prolonged protection toward diarrhea and enhanced gut barrier in 13-week-old mice nursed by OVA-dams. Lactation by allergen-sensitized dams together with offspring TGF-β supplementation may maintain long-lasting prevention of allergic diarrhea , black , and Hispanic  singleton for joint effects of maternal race/ethnicity and asthma on the odds of obstetrical/neonatal complications indicated that maternal asthma status did not confer additional risks for asthma or complications  to black women and their infants, while maternal asthma status increased risk for both asthma and many complications to white and Hispanic (p = 0.037)  . Materna= 0.037) . The effWhile these studies have been useful and will continue to identify novel genes for food allergy and other allergies, future approaches to investigate the mechanisms by which such genetic factors play a role in maternal influences over food allergy in offspring will improve our understanding of the disease mechanisms and produce potential opportunities for prevention and treatment of the disease.N = 103)  showed a lower prevalence of atopy at 12 months compared to those in control group (N = 185) with unrestricted diets, occurring from reduced food-associated atopic dermatitis, urticaria, and/or gastrointestinal disease by 12 months (p = 0.007) and any positive food skin test by 24 months (p = 0.019) in the prophylactic-treated group. However, the suppression of prevalence of food allergy and milk sensitization was significant only before 2 years of age and none of the prevalence in food allergy, atopic dermatitis, allergic rhinitis, asthma, any atopic disease, and serum IgE levels were differed at 7 years of age  showed that schoolchildren who consumed linoleic acid-rich margarine exhibited a higher risk of hay fever as compared to schoolchildren who did not consume margarine  have been equivocal . Eicosanargarine . Similarargarine . Since nargarine . Maternaargarine . Beneficp = 0.026). The study suggests that the reduction in Treg cells in offspring by maternal exposure to phthalate may facilitate the development of atopic dermatitis in early childhood.Maternal health condition including control of maternal allergies and maternal exposure to certain chemicals are important factor to influence neonatal health condition. Maternal severe asthma without using inhalant corticosteroid treatment related to reduced birth weights of female children . HoweverMaternal adverse life events such as separation or divorce, marital problems, problems with the children, pregnancy problems, involuntary job loss experience, involuntary job loss of partner, money problems, a residential move, death of a close relative, and death of a close friend during pregnancy are suggested to link an increased risk for atopic disorders in offspring .In addition to genetic predispositions linked to allergies, these studies clearly suggest a critical involvement of maternal health and environmental factors in the development and manifestation of allergy in offspring. Optimal management of maternal health might be essential in determining the allergic predisposition and clinical symptoms in offspring.p = 0.001), IL-10 (p = 0.04), and β-lactoglobulin-specific IgA (p = 0.005) were lower in breast milk from mothers of infants with cow's milk allergy than in breast milk from mothers of infants without cow's milk allergy  in 4-day-old newborn mice before induction of airway inflammation by suboptimal sensitization protocol resulted in the increased susceptibility to allergic airway inflammation in normal offspring. In contrast, depletion of CD25high T cell resulted in a substantial reduction in asthma symptoms in offspring of allergic dams. Anti-glucocorticoid-induced tumor necrosis factor receptor-family related receptor (GITR) antibody (clone DTA-1) treatment before induction of airway inflammation with suboptimal sensitization protocol significantly attenuated the susceptibilities to allergic airway inflammation in offspring of both naïve and asthmatic dams. Contrary, anti-GITR antibody treatment after induction of airway inflammation enhanced the development of asthma-like allergic inflammation in normal offspring, but induced only a slight deterioration of allergic airway inflammation in the offspring of asthmatic dams. The authors suggest that the increased asthma susceptibility in offspring of asthmatic dams can be prevented by modulating maternal Th2 responses as well as neonatal regulatory responses with anti-CD25 (pre-sensitization in asthma-prone offspring) or -GITR antibodies . As OVA-dams were not exposed to OVA during lactation, these data may indicate that lack of allergen transfer through milk together with maternal sensitization is critical for maternal transmission of asthma risk to offspring  male mice that exhibit an impaired skin barrier due to homozygous mutations of filaggrin (Flg) and mattrin (Tmem79ma) genes (Flgft/ft/Tmem79ma/ma). Resulting Flgft/+/Tmem79ma/+ offspring showed an increase in food allergen sensitization, serum mMCP1, and anaphylaxis to food allergen sensitization through tape stripped skin with peanut extract and Alternaria alternate extract followed by food allergen challenge compared to those born from unsensitized WT dams  to determine the induction of tolerance vs. allergy outcome in offspring through Th1, Th2, and Treg cell responses.lack maternal allergen exposure during pregnancy and breastfeeding. Other studies suggest maternal transmission of tolerance to offspring against asthma through breast milk allergen and IC. Although the investigations using experimental food allergy within this area are still developing, those studies consistently suggest that maternal sensitization and exposure with allergen induce tolerance in offspring, especially via breast milk. These results from experimental asthma and food allergy models may seem inconsistent at first glance, yet they are consistent in that maternal allergen sensitization plus allergen exposure during pregnancy and breastfeeding, which are likely tolerogenic periods, are critical in the induction of tolerance vs. allergies in offspring (Current human data are not sufficient to draw firm conclusions regarding the role of breastfeeding in preventing or delaying the development of food allergies in offspring , howeverffspring . Those sDevelopment of a feasible and optimal instruction for maternal and offspring consumption of potentially allergenic food and nutrient during pregnancy and breastfeeding are urgently needed. Thorough analysis of human amniotic fluid and breast milk component based on challenge-proven food allergies in offspring in combination with genetic analysis may help with development of such instruction. Consideration of dose, frequencies, and period of food consumption during pregnancy and breastfeeding together with nutrient or immunological supplementation of breast milk may help with the novel strategies for prevention and treatment of food allergy in offspring.The precise mechanisms by which maternal factors, such as allergen exposure during breastfeeding, exert a lasting effect on determining the susceptibility of offspring toward allergy need further investigations. Findings in mouse studies need to be carefully interpreted due to the differences between mice and humans. However, the powers of animal models are being able to investigate specific questions that are impossible or unethical to address in human subjects. To date, epidemiological studies have been performed at population levels and not at personal levels. Combined future research of translational and clinical science will help us with understandings of the role of maternal factors on offspring food allergy and will lead to effective preventive care of the disease.TF, SL, YN, and MO wrote the paper. TF and MO arranged and revised the manuscript. SK and MO conceived and supervised the paper. TF, SL, and MO have agreed to be accountable for all aspects of the manuscript and in securing that questions related to the accuracy of any part of the manuscript. MO has given a final approval of the version of the manuscript to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


KIT or PDGFRA mutations, which lead to the susceptibility of these tumors to small-molecule tyrosine kinase inhibitors such as imatinib and sunitinib. However, previous studies have shown that patients with a PDGFRA D842V mutation in GISTs have a very low rate of response to imatinib treatment. Therefore, novel tyrosine kinase inhibitors (TKIs) are currently being evaluated in clinical trials to treat GISTs harboring a PDGFRA D842V mutation. Anaplastic lymphoma kinase (ALK) overexpression was not expected to be present in the GIST, and it has been used as a biomarker to distinguish GISTs from other types of mesenchymal tumors.Gastrointestinal stromal tumors (GISTs) are the most common type of adult mesenchymal neoplasms. The events that drive GIST oncogenesis are primarily PDGFRA D842V mutation. We unexpectedly found that the GIST in this patient exhibited simultaneous ALK expression.Here, we report a 37-year-old male patient who presented with a large mass in the right upper abdomen and was subsequently diagnosed with a GIST harboring a This is the first case reported of a GIST with ALK expression. This rare phenomenon suggests that the diagnosis of a GIST cannot be excluded absolutely if a tumor exhibits ALK expression. In addition, ALK may be a potential therapeutic target for patients with imatinib-resistant stromal tumors. KIT), while 5 to 10% harbor activating mutations of platelet-derived growth factor receptor alpha (PDGFRA); both are members of the type III tyrosine kinase receptor family [A gastrointestinal stromal tumor (GIST) is a type of mesenchymal tumor that arises throughout the gastrointestinal tract . Up to 8r family , 3.KIT exon 11 mutations are most sensitive to imatinib, whereas GISTs harboring a mutation in PDGFRA exon 18 (p.D842V) are considered imatinib-resistant [PDGFRA D842V suggests that the mutant protein binds imatinib with a lower affinity than the wild-type structure [PDGFRA D842V do not possess any actionable recurrent molecular events of therapeutic significance. Therefore, it is necessary to explore new therapeutic targets for patients with drug-resistant GIST harboring PDGFRA D842V.The use of KIT/PDGFRA tyrosine kinase inhibitors (TKIs) has transformed the therapeutic pattern of localized and advanced GIST. In general, tumors with n 18 p.D82V are coesistant . Molecultructure , 7. To oALK rearrangements [PDGFRA D842V. Previously, it was reported that ALK was not found in GISTs, and ALK staining was applied as a way to distinguish GIST from IMT [Anaplastic lymphoma kinase (ALK), belonging to the insulin receptor superfamily, is a transmembrane receptor tyrosine kinase. Overexpression of ALK, which is associated with oncogenesis, can be caused by gene fusion, mutations and amplification. The rearrangements of the ALK gene have been implicated in the pathogenicity of a number of neoplasms that include anaplastic large cell lymphoma (ALCL), a subset of pulmonary adenocarcinoma, inflammatory myofibroblastic tumor (IMT), and epithelioid fibrous histiocytoma (EFH); the rearrangements result in fusion proteins that constitutively activate the ALK tyrosine kinase domain –10. In pngements . Severalngements , 13. Howfrom IMT . In the A 37-year-old male patient presenting with abdominal distention for more than 10 days without abdominal pain, diarrhea, nausea or vomiting was admitted to our hospital. Computed tomography (CT) showed a large irregular mass located in the right upper abdominal cavity  PCR  was common (9/11 by antibody clone number D5F3), but none of their cases with positive IHC staining of ALK showed evidence of ALK rearrangement or copy number gain by FISH [PDGFRA might be implicated in the resistance of ALK-positive non-small cell lung cancer to targeted therapies [Here, we present a case of a giant tumor that occurred in the greater omentum. Pathological examination revealed that the tumor mainly consisted of round or oval epithelioid cells. Based on the location of the lesion and the morphology of the tumor cells, the diagnosis of epithelioid GIST was first taken into consideration; epithelioid GIST is the most common category of mesenchymal tumors of the gastrointestinal tract. Second, we excluded the diagnosis of leiomyoma and mesothelioma based on the results of immunohistochemical staining (IHC). IHC results showed that the two specific markers for GIST, CD117 and DOG1, were positive, while SMA and other indicators were negative, all of which supported the diagnosis of epithelioid GIST. Sanger sequencing results demonstrated that the lesion harbored a PDGFRA mutation in exon 18 (p.D842V). This further confirmed the diagnosis of GIST. There was a lack of inflammatory cell infiltration around tumor cells, which was useful in ruling out inflammatory myofibroblastic tumors with epithelial morphology. ALK overexpression is detected in 50–60% of IMT cases . Therefoherapies . Anotherherapies . The corALK-translocated IMT [ALK-rearranged tumors on ALK-mediated signaling and suggest a therapeutic option for genetically identified patients with the aggressive form of this soft-tissue tumor. In addition, Noah A. Cohen found that imatinib increased the expression of activated MET in imatinib-sensitive human GIST cell lines and in a genetically engineered mouse model of GIST. Moreover, the combination of crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Finally, cabozantinib, a dual MET and KIT small-molecule inhibitor, was remarkably more effective than imatinib when used in multiple preclinical models of imatinib-sensitive and imatinib-resistant GISTs [PDGFRA mutations, including mutations resulting in the substitution alteration at Asp842, had a lower risk of recurrence than patients with KIT mutations [ALK may play an important role in the early recurrence of GIST harboring PDGFRA mutations.ALK inhibitors have shown remarkable effects against ALK-driven tumors. Several studies have shown that crizotinib exhibits impressive therapeutic effects in patients with ated IMT , 21. Thent GISTs . Althougnt GISTs , 23. Togutations . In thisIn summary, we reported the first case of GIST with ALK expression, which may present as a potential source of diagnostic confusion, as it could be mistaken for IMT. The mechanism underlying ALK expression is still unknown, with ALK rearrangement or amplification being excluded. Further studies are warranted to elucidate the mechanism and significance of ALK expression in these tumors.


Harmonization techniques make different gene expression profiles and their sets compatible and ready for comparisons. Here we present a new bioinformatic tool termed Shambhala for harmonization of multiple human gene expression datasets obtained using different experimental methods and platforms of microarray hybridization and RNA sequencing.Unlike previously published methods enabling good quality data harmonization for only two datasets, Shambhala allows conversion of multiple datasets into the universal form suitable for further comparisons. Shambhala harmonization is based on the calibration of gene expression profiles using the auxiliary standardization dataset. Each profile is transformed to make it similar to the output of microarray hybridization platform Affymetrix Human Gene. This platform was chosen because it has the biggest number of human gene expression profiles deposited in public databases. We evaluated Shambhala ability to retain biologically important features after harmonization. The same four biological samples taken in multiple replicates were profiled independently using three and four different experimental platforms, respectively, then Shambhala-harmonized and investigated by hierarchical clustering.Our results showed that unlike other frequently used methods: quantile normalization and DESeq/DESeq2 normalization, Shambhala harmonization was the only method supporting sample-specific and platform-independent biologically meaningful clustering for the data obtained from multiple experimental platforms.The online version of this article (10.1186/s12859-019-2641-8) contains supplementary material, which is available to authorized users. Public repositories of gene expression data cover a rich spectrum of normal and pathological conditions, including all known human diseases and developmental features –4. The mThis non-comparability of gene expression data hampers further levels of data analysis for the different datasets, e.g. finding differentially expressed genes and assessing activation of molecular pathways , 12.To solve this problem, the data must be either normalized  or harmonized (when different platforms were used) . For theThe normalization methods include quantile normalization (QN) , frozen However, to our knowledge all previously published harmonization methods have a substantial limitation that they are capable of performing harmonization for only two expression datasets . Thus, oShambhala that may be considered a more universal tool compared to the existing approaches. Unlike previous harmonizers, Shambhala is independent on (i) number of harmonized datasets and/or experimental platforms, and (ii) number of samples in every dataset. The Shambhala harmonization protocol includes several specific features such as the auxiliary calibration dataset that helps to initially transform the data, and the reference definitive dataset that defines the universal shape of the output harmonized gene expression profile. Next, we investigated the performance of Shambhala to harmonize the gene expression data from multiple experimental platforms obtained from the Microarray Quality Control (MAQC) [Here, we present a new method for cross-platform data harmonization termed l (MAQC)  and Sequl (MAQC) . Our datreference definitive dataset (Q). The process of profile transformation involves multiple iteration steps, when the dataset P, which contains profiles under harmonization, is altered, whereas the dataset Q remains unchanged. Consequently, the output of such transform has gene expression profiles like those obtained using the same experimental platform, as for the dataset Q.We developed Shambhala method for cross-platform comparisons of multiple datasets. In its present form, the method was tailored for the comparison of human gene expression data, and its application for other organism data requires further specific data search. Let us look at the problem of cross-platform harmonization in more detail. Imagine an arbitrary set of experimental platforms that has produced a set gene expression profiles. Our goal is to make them all comparable. To do so, we may make them similar to a pre-defined reference. This reference may be taken from a set of profiles that has been obtained at a widely used experimental platform; we can term this set the Q-shape, we should equalize it using another pre-defined dataset called auxiliary calibration dataset (P0). In other words, it means that each individual gene expression profile under harmonization, say i, is transformed into the Q-shape not within the original dataset of unharmonized profiles from certain experimental platform, but rather being taken alone, and then merged with P0. Namely, we quantile-normalize [i with the dataset P0, which produces the dataset P for further transformation. This dataset P is then transformed into the shape of the dataset Q, thus producing the dataset P1. From this dataset P1, only the transformed single profile i is taken for further analysis. This procedure is then applied to all other gene expression profiles which need to be harmonized  to increase stability of the results, Shambhala uses spherical (cosine-based) [P and Q datasets.Some features of this pipeline, which are used for transformation of dataset N method  that shoN method . Such fee-based) , 29 rathP0 and Q, the latter acting as the reference for gene expression profiles after harmonization, and the former serving for preliminary calibration of expression level ranges. As the dataset Q for this application, we used the mRNA expression profiles taken from the Genotype Tissue Expression (GTEx) project [Q dataset because it is frequently considered the golden standard for microarray hybridization of human tissues [Q-set obtained using the Illumina HiSeq 2000 platform.Importantly, the Shambhala pipeline depends on two datasets,  project , namely  tissues , 32, whiP0) for Shambhala implementation, we found that our previous experimental dataset including 39 human gene expression profiles obtained using CustomArray microchip platform  showed the best performance in clustering tests compared to more than twenty other datasets of the comparable size (data not shown). Interestingly, our attempts to use the GTEx dataset for both P0 and Q, have failed to produce good sample clustering.When selecting the optimal auxiliary calibration dataset , Affymetrix Human Genome U133 Plus 2.0 Array (GPL570) and Illumina Sentrix Human-6 Expression Beadchip (GPL2507). In the SEQC project, the microarray expression profiles for the same biosamples were compared with the RNA sequencing data obtained using Illumina HiSeq 2000 platform (GPL11154), see Table To assess quality of data harmonization, we tested whether hierarchical clustering of the harmonized genes expression profiles will be biologically meaningful or rather dependent on the experimental platforms used. For the clustering, Euclidean distance was used as a metric of proximity. An ideal method for data harmonization would allow grouping of output expression profiles according to the type of biosamples (A to D), but not according to a platform used. Similar types of biosamples  were expected to show more tight clustering. In contrast, the platform-based clustering independent on the biological similarities of biosamples could be considered bad result.Quantile normalization, QN .estimateSizeFactors module. To make the microarray data formally suitable for DESeq/DESeq2 normalization, we took an integer part of all microarray-measured expression level values for each gene and each sample. The intensity values for microarray-measured signal were taken as they were deposited in GEO repository, i.e. after device-dependent primary background correction or equilibration but before any cross-platform transformation or harmonization. Although the DESeq/DESeq2 method was designed for normalization of NGS data and assumes that the count data follow a negative binomial distribution, there were several examples when DESeq/DESeq2 was formally applied to rounded microarray data, both in model investigations based on microarray profiles [Differential expression analysis for sequence count data, DESeq /DESeq2  using thprofiles  and for profiles , 36. MorShambhala harmonization with two different GTEx definitive datasets (obtained using either microarray Affymetrix or NGS Illumina HiSeq 2000 platforms). Shambhala method was compared with other above normalization techniques  because they are popular tools used for merging data from multiple datasets. The standard harmonization methods such as XPN  are not To test Shambhala, we took data from three experimental platforms for MAQC dataset and from four platforms for SEQC. All gene expression profiles were harmonized using three alternative methods:We tested Shambhala, QN and DESeq/DESeq2 methods for their abilities to simultaneously harmonize data from three experimental microarray platforms  from the MAQC project.Q-set and QN/DESeq2 normalization  project , Table 1The results obtained Fig.  suggest Q-dataset .Although attempts to develop universal cross-platform transcriptome harmonization technique are known for more than a decade, the acceptable performance was shown before only for harmonization of up to two expression datasets , 21. In In this study, we tried two sets of expression profiles (obtained using microarray Affymetrix and Illumina HiSeq 2000 platforms) from the GTEx project  as the rP0-dataset) were to provide the best merging of biologically relevant profiles after harmonization. During the training stage, we selected the P0-dataset, which could ensure the good-quality harmonization of the MAQC dataset, namely for the profiles obtained using the Affymetrix and Agilent microarray platforms. Importantly, we did not observe good clustering quality when trying the same GTEx dataset as both P0 and Q, so we had to select another dataset (originated from the CustomArray platfrom) as P0.The criteria for selecting the auxiliary calibration dataset Additional file 2:Q) and auxiliary calibration (P0) datasets for the Shambhala method. (XLSX 42198 kb)Definitive Additional file 4:Harmonized SEQC gene expression profiles. (XLSX 219245 kb)Additional file 5:A detailed view of hierarchical clustering for gene expression levels for MAQC project data after application different harmonization methods. (PPTX 857 kb)Additional file 6:A detailed view of hierarchical clustering for gene expression levels for SEQC project data after application different harmonization methods. (PPTX 647 kb)


To evaluate the performances of six different bone substitute materials used as graft in maxillary sinus augmentation by means of histological and histomorphometric analysis of bone biopsies retrieved from human subjects after a 6-month healing period.β-TCP 30/70), or bioapatite-collagen (BC). After 6 months, bone core biopsies were retrieved and 13 implants were placed. Bone samples were processed for histological and histomorphometric analysis. CT scans were taken before and after surgery. After 4 months of healing, patients were restored with a provisional fixed acrylic resin prosthesis, as well as after further 2-4 months with a definitive cemented zirconia or porcelain-fused-to-metal crowns. Six consecutive patients , healthy, nonsmokers, and with good oral hygiene, presenting edentulous posterior maxilla with a residual bone crest measuring ≤ 4 mm in vertical height and 3 to 5 mm in horizontal thickness at radiographic examination, were selected to receive sinus augmentation and delayed implant placement. Under randomized conditions, sinus augmentation procedures were carried out using mineralized solvent-dehydrated bone allograft (MCBA), freeze-dried mineralized bone allograft (FDBA), anorganic bovine bone (ABB), equine-derived bone (EB), synthetic micro-macroporous biphasic calcium-phosphate block consisting of 70% beta-tricalcium phosphate and 30% hydroxyapatite :  The lack of adequate bone height and thickness negatively affects implant-supported rehabilitation in the edentulous posterior maxilla. Therefore, bone-grafting procedures are needed to increase the available bone volume and to provide structural and mechanical support for the placement of dental implants.Among graft materials, autologous bone is considered the gold standard due to its osteogenic, osteoinductive, and osteoconductive properties –3. HowevTo overcome these disadvantages, a large number of biomaterials have been used alone or in combination with autografts in augmentation procedures –19. AmonThe two-stage sinus lift augmentation with delayed implant insertion was considered a good clinical model to evaluate the performance of graft materials, because bone formation occurs within an enclosed space and with a minimal interference from external factors. In addition, this procedure is highly predictable and allows collecting bone biopsy specimens during implant insertion avoiding any additional discomfort for the patients , 20.The aim of the present study was to evaluate the performances of six different bone substitute materials used as graft in maxillary sinus augmentation, by means of histological and histomorphometric analysis of bone biopsies retrieved from human subjects after a healing period of 6 months.Six patients  who were healthy, nonsmokers, and with good oral hygiene were recruited in this study among those referred to Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, for implant-supported rehabilitation in the posterior atrophic maxilla . InclusiAll the clinical procedures were performed in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines. The protocol of the study was approved by the Ethical Committee of the Sapienza University of Rome (n. 3447).The preoperative antibiotic and analgesic therapy with Amoxicillin 875 mg + Clavulanic acid 125 mg  and Ketoprofene 200 mg  was given orally 1 hour prior to surgery. Immediately prior to surgery, patients rinsed with a chlorhexidine digluconate solution 0.2%  for 2 min, to be continued for 2 weeks postoperatively.Surgery was performed under sterile conditions and local anesthesia . A lateral window technique was used for sinus floor elevation. A slightly palatal crestal incision and two vertical releasing incisions were made mesial and distal on the buccal mucosa according to the sinus anatomy to elevate a mucoperiosteal flap . On the After 6 months clinical and radiographic examinations were performed and each patient was reappointed for biopsy and implant placement in the same location. Under local anesthesia, a full thickness flap was raised and a bone biopsy was performed using a 3.5 mm trephine bur under sterile saline solution irrigation, guided by the radiographic/surgical template in the selected implant site. A total of six bone samples were retrieved from the occlusal aspect of the alveolar crest, one from each augmented site and at least two implants , were placed according to the manufacturer's indications Figures .To identify crestal bone during histologic and histomorphometric procedures, the harvested specimens were marked with toluidine blue stain on the occlusal side.After 4 months of healing, patients were provisionally restored with a fixed acrylic resin prosthesis and after 2 to 4 months of function, the definitive prosthetic rehabilitation was applied with cemented zirconia or porcelain-fused-to-metal crowns.β-TCP 30/70, BioCer Entwicklungs GmbH, Bayreuth, Germany); and bioapatite-collagen .Under randomized conditions, each sinus augmentation procedure was carried out using one of the following six commercial bone substitute materials: mineralized solvent-dehydrated bone allograft ; freeze-dried mineralized bone allograft ; anorganic bovine bone ; equine-derived bone , Italy); synthetic micro-macroporous biphasic calcium-phosphate block consisting of 70% beta-tricalcium phosphate and 30% hydroxyapatite , which preserves the bone architecture maintaining its biomechanical properties and minimizing antigenicity and infective potential , 9, 22.FDBA is freeze-dried mineralized bone allograft processed using lyophilization; it maintains both the organic and the inorganic component , and when used as a graft material, the mineral content is broken down by osteoclasts, becoming osteoinductive proteins available to induce new bone formation. However, to release osteoinductive proteins from the FDBA organic matrix, a prolonged osteoclast mediated demineralization is needed .μm in the form of granules. Its native crystal-line structure is chemically and physically highly similar to human bone and its porous nature promotes the initial biologic processes of cell adhesion and proliferation [ABB is a xenogenic material formed by deproteinized sterilized bovine cancellous bone with 75% porosity and a crystal size of about 10 feration . This maferation –26.EB is an equine-derived bone tissue deantigenated by a proteolytic low temperature process that preserves type 1 bone collagen and makes it anorganic although it conserves unaltered its mineral structure of hydroxyapatite saving the resorption potential , 27–29.β-TCP 30/70 is a new bioceramic with reticular structure, which seems to have a better resorption and an increased bone formation due to the levels of released calcium and phosphorous ions able to stimulate new bone formation [HA-ormation , 30–33. BC is hydroxyapatite associated with type I bovine collagen plus glucosamine. Different studies showed its efficacy as human bone substitute material in the sinus augmentation procedure , 35. Theμ m, and ground down to about 30 μm with a specially designed grinding machine Precise 1 Automated System . Three slides were obtained from each specimen. These slides were stained with acid fuchsin and toluidine blue and examined with transmitted light Leitz Laborlux microscope .The bone cores were retrieved and were immediately stored in 10% buffered formalin and processed to obtain thin ground sections. The specimens were processed using the Precise 1 Automated System  . The speHistomorphometry of the percentages of newly formed bone, residual grafted material, and marrow spaces was carried out using a light microscope  connected to a high-resolution video camera  and interfaced with a monitor and PC . This optical system was associated with a digitizing pad  and a histometry software package with image capturing capabilities .The healing process after sinus augmentation procedures was uneventful. No postoperative complications were present. In no case there was perforation of the sinus membrane. No clinical sign of sinus pathology was observed. Six months after sinus augmentation, the radiographic evaluation of all patients showed the presence of dense bone in the maxillary sinuses where the biomaterials were inserted .Primary stability of the implants was achieved in all cases independently of the use of bone substitute material . All 13 implants placed during the biopsy retrievement had no complications and were osseointegrated at the end of prosthetic rehabilitation. No failures and no dropouts occurred.Mineralized solvent-dehydrated bone (MCBA). At low magnification, trabecular bone with large marrow spaces and biomaterial particles was observed . The bioFreeze-dried mineralized bone allograft (FDBA). At low power magnification, newly formed bone with marrow spaces and particles of residual biomaterial was present. In a marginal portion of the sample, preexisting bone with small remodeling areas could be observed . At highAnorganic bovine bone (ABB). At low power magnification, the specimen appeared to be formed by two separate fragments, each presenting several residual biomaterial particles . At highEquine-derived bone (EB). At low magnification, trabecular bone with large marrow spaces and biomaterial particles was observed . The parβ-TCP 30/70). In the examined sample, newly formed trabecular bone and preexisting bone with marrow spaces and residual biomaterial could be observed . In the examined sample, trabecular bone with marrow spaces and residual biomaterial was observed . SpecifiThe histomorphometric results of bone biopsies are summarized in Sinus augmentation is a well-documented technique for creating adequate bone volume to successfully place dental implants in resorbed maxillary posterior regions . HoweverWithin the limits of the present investigation, whose results referred to a limited number of patients, the histological and histomorphometric analysis of the regenerated tissues might provide useful information regarding the nature and amount of newly formed bone of the six tested biomaterials.At histologic examination all biomaterials were in close contact with newly formed bone and showed the same pattern of bone formation surrounding the graft granules and producing a bridge-like network between the grafted particles.From the present histologic investigation, the MCBA sample showed the highest biocompatibility, because no signs of acute inflammation were present, which was furthermore affirmed by the ability to form and maintain new bone bridging the greatest part of the biomaterial particles, as reported by other previous studies , 22, 38.Histomorphometry of FDBA sample showed that newly formed bone represented 32.1%, the highest value among the compared biomaterials. This data was similar to results of Kolerman et al. , who repABB was used as grafting material in a great number of studies, taking advantage of its well- known osteoconductive properties . Some auCompared to ABB, EB showed a greater amount of newly formed bone (22.8%) and lower residual graft material (30.1%), in accordance with the results of a randomized clinical trial, which evaluated samples harvested 6 months after sinus augmentation with both of these materials . This hiThe presence, observed in our sample, of new bone surrounding the biomaterial particles, of many large vessels and in some fields of osteoblasts apposing bone directly on the particle surface is comparable to other studies , 47. Theβ-TCP 30/70 blocks used in the present investigation had a reticular structure, manufactured by a rapid prototyping (RP) technique offering a precise control of the porosity and external shape of a Ha-TCP ratio ceramic bone substitute [The HA-bstitute  so as toβ-TCP 30/70, whose degradation can be tailored by varying its chemical composition together with the incorporation of pores, seems to be a good strategy to overcome the low degradation rate of CaP ceramics, which represents a limitation of these materials [Indeed, the use of HA-aterials .On 3D reconstruction and quantitative analysis, the HA/TCP scaffolds exhibited good performances in terms of both bone regeneration and vascularization, independently of the specific scaffold morphology  . HoweverThe histological and histomorphometric aspects of BC sample were similar to those of the other materials tested and confirm the osteoconductive property of this biomaterial as shown in previous studies , 35. MorWithin the limitations of the present investigation, all the six biomaterials tested in two-stage maxillary sinus augmentation model showed good biocompatibility and osteoconductive properties and could be used successfully in sinus augmentation procedure. Although, the FDBA seemed to have the best histomorphometric result in terms of newly formed bone and residual graft material. Nevertheless, longer term histological studies will be needed to understand better resorption times and modalities , 54.


Memristive devices have elicited intense research in the past decade thanks to their inherent low voltage operation, multi-bit storage and cost-effective manufacturability. Nonetheless, several outstanding performance and manufacturability challenges have prevented the widespread industry adoption of redox-based memristive matrices. Here, we discuss these challenges in terms of key metrics and propose a roadmap towards realizing competitive memristive-based neuromorphic processing systems. Heterogeneous hardware that combines traditional digital circuitry with two-terminal analog memory devices, promises to handle the Zettabyte storage and processing requirements of modern applications such as the Internet of Things (IoT) and Artificial Intelligence (AI). Several emerging device concepts, based on electrochemical metallization, phase change, and redox phenomena have been intensely explored. This work led to some successful commercial products, like Adesto’s Moneta electrochemical metallization memory for low-energy applications and Intel-Micron’s phase change memory Optane for storage class memory. Despite this fact, the most highly sought application nowadays, namely non-volatile neuromorphic processors, has yet to become industrially feasible.1. To emulate the complexity and ultra-low power consumption of biological neural networks, neuromorphic hardware platforms have to deliver an ultra-high density (>1 Tb/cm2) and energy efficient (<10 fJ/operation) solution. If we want to implement large neural networks with billions of synaptic devices, resistive switches are particularly suited thanks to three disruptive attributes: low-voltage multi-bit programmability, an inherent non-volatility of their resistance state, and a scalable two-terminal structure appropriate for matrix integration.We believe that redox memristive memory will be the technology to fuel the AI era in the upcoming decades by enabling competitive implementations of neuromorphic processors. These switches can facilitate the energy and space efficiency required for emulating synaptic weights—the programmable connections that equip a neuromorphic system with its learning and memory capabilities. The synaptic weights can be implemented with commercially available technologies, but they typically require tens of devices for emulating a single synapse, which renders large-scale systems impractical. For comparison, redox memristive cells can outshine by 2–3 orders of magnitude in density and lower energy consumption of the implementations featuring more mature technologies2. Redox resistive devices are bipolar so a desired state can be accessed either during set or reset, which decreases the latency to program the matrix. Redox memristors typically report the lowest energy consumption/switching among emerging analog memory solutions, ~10fJ3. Moreover, the switching time has been shown to be as low as 85 ps4 for nitride materials.The physics of resistive switching is on our side from an energy-consumption perspective, since in theory the state of the device can change through the movement of just a few ions under a very low voltage. Once the voltage is removed, the ions halt in place and the state is retained without any further use of energy. The fine synaptic programmability is a key element for neuromorphic algorithms and redox resistive devices have achieved the best analog capacity to date (>100 discernible states per single cell)An ideal neuromorphic platform would take advantage of these properties in an integrated fashion. Such a system would have hundreds of layers of resistive switching matrices integrated over traditional digital circuitry to achieve high performance at a low manufacturing cost.This bold dream has fueled intense research in the field. Significant progress has been made, but in all honesty, at a slower pace than anticipated. No miracle material stack that leads to the perfect device properties has been discovered yet. Several performance and manufacturability challenges prevent industry adoption. Yet we are optimistic that our community will overcome these challenges and develop a resistive switching technology of unparalleled performance for the next generation of neuromorphic hardware.While neuromorphic computation is considered to be resilient to hardware defects, memristor variability is costly. If each device performs slightly different and its characteristics vary in time, programming to a desired state becomes a personalized endeavor. This approach is not feasible for training large matrices with billions of devices, as it consumes time, energy, and chip real-estate for supporting circuitry.5  and the energy consumption and affecting the write/read margin Fig. . Sneak p8 Fig. . These i8 Fig. .29  which has already shown <10 nm half pitch lines. However, the industry can benefit from its technological potential only when the issues of variability and latency are solved, so that should be the short-term focus in our opinion Fig. .Fig. 2RoTackling them requires a data-driven approach to accelerate the understanding and gaining control over the physics of switching, the materials and the manufacturing process. The necessity of having low access resistance and selector devices introduces extra complexity, requiring designs with higher number of manufacturing steps and state-of-the-art cleanroom equipment. The characterization of large matrices is resource intensive as well, involving custom data acquisition set-ups. The solution is the integration of memristor matrices with the digital read/write circuitry which requires foundry material compatibility and sustained academia-industrial partnerships. Appropriate performance benchmarking amongst distinct materials, standardized device/matrix sizes and methods of testing are also needed to ensure reproducible results across different labs. A repository of these large datasets would strengthen the research capabilities of the community, enabling accurate device modeling and system-level simulations.In the coming years, memristive neuromorphic hardware will likely flourish in select embedded applications based on medium-sized matrices suitable for cost-effective training off-site and pre-deployment. Complex systems would take longer to reach commercial maturity since they require larger memristive matrices with lower density of imperfections appropriate for fast on-site continuous learning. Ultimately though, the balance between system-level performance vs. manufacturing cost will be what drives widespread adoption.


Late-onset sepsis is frequently seen in preterm infants and is associated with poor neurodevelopmental outcome. White matter damage is proposed as substrate of poor outcome, with contributing factors as regional hypoxia and effects of cytokines on oligodendrocytes. We investigated the relation between cerebral oxygenation during (suspected) late-onset sepsis and neurodevelopmental outcome. Prospective cohort study, including preterm infants  with (suspected) late-onset sepsis underwent NIRS registration during the first 72 hours of suspected late-onset sepsis. At two years corrected age neurodevelopment was scored using the Bayley Scales of Infant Development-II. Thirty-two infants were included. Twenty-seven infants were identified with proven late-onset sepsis and five infants had clinical sepsis without positive blood culture. In this study, late-onset sepsis was predominantly caused by coagulase negative staphylococci (CoNS) (72%). All NIRS values were within normal limits. No association was found between NIRS and impaired neurodevelopmental outcome (n = 4) at corrected age two years: composite cognitive score 105 (80–115), composite motor score 103 (82–118) (median and range). In this pilot study, late-onset sepsis , was not associated with aberrant NIRS values, nor with impaired neurodevelopmental outcome. Further research might establish our findings and elucidate effects of other micro-organisms on cerebral perfusion. Preterm and very low birth weight infants are at risk of acquiring nosocomial sepsis due to their immature immune system. ApproxiThe long-term effects of sepsis in preterm newborns are well established. Sepsis is associated with adverse long term neurodevelopment, with mental or psychomotor developmental delay. HoweverThe adverse long term effects of sepsis are linked to the development of white matter injury. , 6, and To evaluate effects of nosocomial infection on the brain in preterm infants, cerebral imaging by cerebral ultrasounds or MRI can be performed. However, cerebral ultrasound will only show already established gross brain damage. Other modalities of brain monitoring might provide an additional value, e.g. by detecting changes in cerebral perfusion, which may prelude cerebral damage.et al. showed an association between lower regional cerebral oxygen saturation in the first 72 hours of life and lower neurodevelopmental outcome scores[Several studies have determined reference values of regional cerebral oxygen saturation in preterm infants –12. Alsome scores. In anotme scores.et al. studied multisite fractional tissue oxygen extraction during an episode of clinical sepsis on short term outcome[Van der Laan m outcome. The effAim of this study was to investigate the feasibility to study if late-onset sepsis effects the cerebral oxygenation during the first 72 hours after onset and its relation with psychomotor outcome at corrected age of two years.We performed a prospective, observational cohort study: the INFANT study. Data of preterm infants < 32 weeks gestational age and/or < 1500 grams admitted to the level III Neonatal Intensive Care Unit (NICU) of the VU Medical Center between August 2012 and December 2014 and suspected of late-onset sepsis were prospectively collected. Preterm infants with syndromal or chromosomal abnormalities and congenital metabolic disorders were excluded. Informed parental consent was obtained and approval was given by the medical ethical committee of the VU University Medical Center (protocol number 2008/77).Late-onset sepsis was suspected when one of the following clinical symptoms occurred: hypothermia  or hyperthermia , hypotension, tachycardia, apnea, feeding problems, irritability and/or apathy. Late-onset sepsis was defined as a positive blood culture after 72 hours of life, 17. WheClinical data were collected from patients’ medical charts. Neonatal variables included gestational age at birth, birth weight, gender, intraventricular hemorrhage according to Volpe and whit2) and replaced every three hours to prevent skin lesions. Change of position of the sensor might alter the rScO2 value measured, however Hyttel-Sorensen et al. state out of range values on average will tend to normalize[2-rScO2)/ SaO2. Analyses were performed in time frames of eight-hour duration. Artifacts in registrations were assessed. If a value of zero was registered, this value was eliminated from the data set except for severely respiratory or circulatory compromised patients, which could correspond with a value of zero. All other values were maintained.During the first 72 hours of suspicion of late-onset sepsis, cerebral oxygenation was registered by INVOS 5100C near infrared spectrometer  in combination with the small adult sensor Somasensors with emitter-detector distance of 3 and 4 cm (Covidien/ Medtronic) with data storage every 34 seconds. The sensor was placed left or right frontoparietal on the patients head providing regional cerebral oxygenation , consisting of a mental developmental index, psychomotor developmental index and a behavioral rating scale . The outStatistical analysis was performed with SPSS using version 22 . For multivariate analysis we used the non-parametric Kruskal Wallis test and if appropriate the Mann-Whitney U test. Due to the non-normality of the data these non-parametric tests were chosen. Mixed models were used as appropriate for longitudinal data analysis. A probability P value < 0.05 was considered statistically significant. To obtain a difference of 15 points (one standard deviation) on the rating scale of BSID-II with a type I error of 5% and a power of 18% 32 patients were needed for this study.Staphylococcus aureus (n = 3) and Escherichia coli (n = 1) counted for the other proven late-onset sepsis episodes.During the study period, 32 infants  were included. Patient characteristics are shown in Cognitive and motor development was assessed at corrected age of two years. One patient of 32 patients died during NICU admittance. Twenty-eight of 31 patients who survived were tested (90%). Three patients were lost to follow-up due to them moving abroad (1), cancellation of the test due to personal circumstances (1) and one patient turned out to have a severe structural cerebral disorder (double cortex) for which this patient was excluded for follow up analysis. Results of the median cognitive and motor development were within normal range . Though Brain ultrasound abnormalities occurred in four patients. rScO2 and FTOE in the first 72 hours of late-onset sepsis were not associated with echo densities on cerebral ultrasound in any localization in the cerebrum, nor with good outcome  nor with poor outcome .et al[During the first 72 hours of late-onset sepsis we did not detected changes in cerebral tissue oxygenation and consumption as measured by NIRS in our study cohort of preterm infants in comparison to the reference values the first days after birth as presented by Alderliesten et al as best et al. Due to et al.In this cohort CoNS were highly represented, 72% of all proven infections, which is in line with previously published results. CoNS inThe association of white matter injury and decreased values of rScO2 has been described in infants with congenital heart disease. It is aet al. reported that CoNS infections were associated with a cognitive delay at 36 months corrected age[In contrast to most findings, Alshaikh ected age. HoweverIn our cohort we also explored the relation between rScO2 and cFTOE and a good  or a poor outcome . We were not able to show any relation between NIRS values in the first 72 hours during late onset infection and neurodevelopmental outcome at two years. However, as CoNS infections are the most frequent etiology of late-onset sepsis, it would be interesting to explore the effects of micro-organisms other than CoNS in a larger cohort than this study provides.We do acknowledge limitations of our study. This is a single center study in a relatively small group of preterm infants. It would be interesting to study a larger cohort and compare the cerebral oxygenation values and long term follow up to a control group and evaluate other factors influencing cerebral oxygenation and the effects on long term outcome. Also, if a larger cohort is available the changes in cerebral oxygenation can be studied in more detail and confounding effects, of interventions in respiratory and circulatory support for instance, could be addressed more appropriately.Furthermore, the high incidence of coagulase-negative staphylococci limited the number of patients with late-onset sepsis caused by other bacteria. Therefore, it is difficult to assess if cerebral tissue oxygenation is influenced differently during late-onset sepsis caused by different micro-organisms like gram-negative bacteria. And if so, if there is any difference in disturbance of cerebral tissue oxygenation in the relatively mild course of CoNS versus gram negative bacteria. This pilot study could not address differences of effects on long term outcome between groups of patients with CoNS and gram negative micro-organisms, although different effects could be expected due to the more clinical instability during gram negative septicemia.NIRS monitoring registers the mixed oxygen saturation from superficial tissue e.g. the cerebral cortex and part of the white matter. Also, it is not certain whether white matter and deep grey matter were equally well represented in the registered values of cerebral oxygenation . TherefoWith this study we explored possibilities for future research in terms of combining cerebral oxygenation and cerebral ultrasound in the first days of infection in relation to causing micro-organisms. It would be very interesting to model these findings with other changes during infection, for example the changes in inflammatory mediators. In future studies these limitations have to be addressed with a larger study population to be able to identify the possible effects of these imaginable contributing factors.In conclusion, in this pilot study we did not detect any changes in cerebral oxygenation during the first 72 hours of late-onset sepsis. In this small cohort we did not detect an effect of late-onset sepsis on neurodevelopmental outcome at two years corrected age. However, this might be the result of a relatively mild course of late-onset sepsis by CoNS. Further research could elucidate the effect of other causal micro-organisms.


Inguinal lymph node metastasis from rectum is uncommon but well-known occurrence, whereas that from colon adenocarcinoma is extremely rare. Inguinal lymph node metastasis from colon adenocarcinoma has only been reported in previous cases involving primary tumor invasion of the abdominal wall, or in those involving colon cancer metastasis to external iliac lymph nodes. We describe a case of inguinal lymph node metastasis from colon cancer without primary tumor invasion to the abdominal wall.A 42-year-old female, who had undergone twice cesarean sections before, underwent open sigmoidectomy for sigmoid colon adenocarcinoma and received 12 cycles of FOLFOX regimen as adjuvant chemotherapy. Two years after sigmoidectomy, a follow-up CT scan revealed enlarged inguinal lymph nodes as well as growth of enhanced mass lesions on the abdominal wall at site of the cesarean section scar. Biopsy of both lesions revealed well-differentiated adenocarcinoma, and immunohistochemistry demonstrated positive expression of CDX2, substantiating its gastrointestinal origin. We therefore performed dissection of left inguinal lymph nodes and mass lesion of the abdominal wall. The patient died 51 months after lymph node dissection.This is the first reported case of inguinal lymph node metastasis from colon cancer without invasion of the primary tumor to the abdominal wall or without involvement of the external iliac lymph nodes, suggesting that the pathway of inguinal metastasis originated from the abdominal wall metastasis. When inguinal lymph node metastasis from colon cancer is suspected, if an R0 resection was possible, inguinal lymph node dissection may be a potentially effective treatment.The online version of this article (10.1186/s12885-019-5386-x) contains supplementary material, which is available to authorized users. Inguinal lymph node metastasis from lower rectum is uncommon but well-known occurrence , whereasA literature search of reports published in English identified only five cases of colon adenocarcinoma with inguinal lymph node metastasis –7. In foA 42-year-old woman who had undergone twice cesarean sections presented with hematochezia and was evaluated by CT scan in August 2011. A CT only detected an enhanced abdominal wall mass near the abdominal scar, which was thought to be desmoid at the time


Cerebral amyloidomas are rare cerebral mass lesions often associated with significant morbidity. Cerebral amyloid accumulation can be the result of a number of disease states and it is crucial for proper patient care to identify the pathogenic process leading to amyloidoma formation. Low grade clonal B-cell processes are one cause of cerebral amyloidomas. We report a case of an 87-year-old woman who presented with a lymphoplasmacytic lymphoma associated cerebral amyloidoma complicated by cerebral hemorrhage, discuss the proper workup of this disease entity, and present a review of the literature on this topic. Cerebral amyloidomas are uncommon cerebral mass lesions that prior to biopsy are often thought to be glial neoplasms, high grade lymphomas, or immune mediated processes. Following identification of a brain mass as amyloidoma, the etiology of the massive central nervous system (CNS) amyloid deposition must still be determined. Causes of CNS amyloidomas include clonal CNS B-cells, cerebral amyloid angiopathy (CAA), and inherited amyloidopathies. We report a case of an 87-year-old with a biopsy diagnosed cerebral amyloidoma, discuss the appropriate workup to identify the underlying disease cause and present a literature review of cases of B-cell associated CNS amyloidomas, and raise the possibility that patients with cerebral amyloidomas may be at risk for cerebral hemorrhages.A previously well 87-year-old Caucasian woman living in a senior assisted care center presented to the neurology clinic with complaints of six months of slowly progressing left sided weakness. Initial difficulty in ambulating and using the stairs progressed to being wheelchair bound. Neurologic exam revealed diffuse 3/5 left sided weakness, left leg drift, and left facial droop. Brain magnetic resonance imaging (MRI) revealed a large confluent white matter T2-hyperintensity in the right frontal lobe with multifocal nodular enhancement of the left cerebral hemisphere . Foci ofAll sample analysis described below were performed on material obtained by brain biopsy as part of clinical care. All samples were obtained with appropriate consent.A biopsy of the mass was performed and revealed extensive parenchymal lakes and vascular and perivascular deposition of amorphous, amyloid like material . Congo-rλ-type and not β amyloid or an amyloid associated with a hereditary amyloidosis. Further analysis of the perivascular lymphoid populations was undertaken. Histologically, the monotonous populations of perivascular lymphoid cells demonstrated a lymphoplasmacytic appearance  resulting from a primary CNS lymphoplasmacytic lymphoma. Lymphomas confined to the brain, primary central nervous system lymphomas (PCNSL), are rare and account for only 2-3% of all brain tumors and <1% of all non-Hodgkin's lymphoma (NHL). A recent epidemiological review of the data from 10 Surveillance, Epidemiology, and End Results (SEER) cancer registries in the United States between 1992 and 2011 estimated that 90% of PCNLs are B-cell lymphomas, of which the vast majority (75%) are aggressive diffuse large B-cell lymphomas. Primary brain involvement by less aggressive small mature B-cell lymphomas is even more rare. Close to 40% of PCNSL are associated with immunosuppression, in the form of either human immunodeficiency virus (HIV) infection or drug induced immunosuppression. No immunodeficiency was identified in the patient in this case. Over the last few decades the incidence of primary central nervous system (CNS) lymphomas has however shown a significant increase in immunocompetent patients [The amyloidoma in this case was caused by a CNS low grade lymphoplasmacytic lymphoma. Low grade small B-cell lymphomas can have overlapping morphological and immunophenotypic features and varying degrees of plasmacytic differentiation that make their diagnosis challenging. Typically, LPL involves the bone marrow but may also involve other sites such as spleen and lymph nodes. The majority of LPL produce IgM monoclonal paraprotein, which is also known as Waldenström macroglobulinemia and may cause systemic hyperviscosity related symptoms. Rarely, systemic LPL may involve the central nervous system, a condition known as Bing Neel syndrome. In our case, no systemic LPL was identified. Recently, Xu et al. reported the presence of MYD88 L265P) mutations in approximately 90% IgM paraprotein producing LPLs [P mutatioβ-amyloid accumulation in Alzheimer's disease and cerebral amyloid angiopathy. However, primary CNS involvement by AL subtype are less common. It is important to note that CNS involvement by systemic amyloidosis seldom occurs due to the extremely ineffective passage of systemic amyloid across the blood brain barrier [Monoclonal immunoglobulin deposition in the brain, like elsewhere in the body, can either be in the form of light chain deposition disease (LCDD) or amyloidosis. In LCDD, the light chain deposits are characterized by less structural organization and do not stain positive on Congo-red stain. In amyloidosis on the other hand, the light chains form compact beta pleated sheet predominant structures that stain positive for Congo-red and show a characteristic apple-green birefringence on polarization . Amyloid barrier .β et al. demonstrated clonality in cases of CNS AL amyloidomas with background nonspecific inflammatory infiltrates by chromogenic in situ hybridization (CISH) for kappa and lambda light chains and IgH rearrangement studies [To gain further insight into the occurrence of low grade B-cell lymphomas and their association with the formation of CNS amyloidomas, we performed a literature search of the PubMed database for primary CNS small low grade B-cell lymphoma. Our search identified 12 cases of primary CNS lymphoplasmacytic lymphoma –10, one  studies . AL amyl studies .There is no clear treatment modality of choice for AL amyloidomas with low grade lymphomas of the CNS, and the cases reported have been treated with surgery, radiation, and chemotherapy either in isolation or in combination. Irrespective of treatment method, these low grade lymphomas tend to behave in an indolent manner. One patient  relapsedIn conclusion, workup of a cerebral amyloidoma should include studies to characterize the nature of the amyloid and if indicated to identify a clonal/neoplastic B-cell population. If a B-cell neoplasm is identified, treatment of the underlying B-cell tumor is indicated. Increased surveillance for hemorrhagic vascular infarcts is warranted given the association of vascular amyloid deposition and a risk of cerebral hemorrhage.