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Background: Protein-energy malnutrition is associated with poor surgical outcomes in liver transplant patients, but its impact on healthcare use has not been precisely characterized. We sought to quantify the burden of protein-energy malnutrition in hospitalized patients undergoing liver transplantation., Methods: Current Procedural Terminology codes were used to identify United States hospitalizations between 2011 and 2018 for liver transplantation using the Nationwide Inpatient Sample. Patients <18 years old were excluded. Protein-energy malnutrition was identified by International Classification of Diseases Ninth and Tenth Revision codes. Multivariable regression was used to determine associations between protein-energy malnutrition and hospital outcomes, including hospital length of stay and hospital charges/costs., Results: Of 9856 hospitalizations, 2835 (29%) had protein-energy malnutrition. Patients with protein-energy malnutrition had greater comorbidity burden and in-hospital acuity (eg, dialysis, sepsis, vasopressors, or mechanical ventilation). The adjusted median difference of protein-energy malnutrition vs no protein-energy malnutrition for length of stay was 6.4 days (95% CI, 5.6-7.1; P < 0.001), for hospital charges was $108,063 (95% CI, $93,172-$122,953; P < 0.001), and for hospital costs was $23,636 (95% CI, $20,390-$26,882; P < 0.001)., Conclusion: Among patients undergoing liver transplantation, protein-energy malnutrition was associated with increased length of stay and hospital charges/costs. The additional cost of protein-energy malnutrition to liver transplantation programs was $23,636 per protein-energy malnutrition hospitalization. Our data justify the development of and investment in personnel and programs dedicated to reversing-or even preventing-protein-energy malnutrition in patients awaiting liver transplantation., (© 2024 American Society for Parenteral and Enteral Nutrition.)

Goals and Background: Patients with cirrhosis undergoing liver transplant evaluation have high rates of pain and mental health comorbidities; both may significantly impair health-related quality of life (HRQL). We investigated the association between pain, anxiety/depression, and HRQL in this population., Study: In 62 patients with cirrhosis undergoing liver transplant evaluation, we performed 4 validated assessments to characterize: pain (Brief Pain Inventory-Short Form, BPI-SF), anxiety (Generalized Anxiety Disorder-7), depression (Patient Health Questionnaire-8), and liver-specific HRQL (Chronic Liver Disease Questionnaire). The presence of pain was determined using the BPI-SF screening question. Linear regression was used to identify demographic or clinical factors predictive of pain severity (PS) and interference (PI) and to evaluate the association between pain, anxiety/depression, and HRQL., Results: Seventy-one percent of patients reported pain, 26% had clinical depression, and 24% had moderate-severe anxiety. Neither liver disease severity, nor its complications were associated with pain (PS or PI), but anxiety and depression were predictors of pain on bivariate analysis. Only depression remained a significant predictor of PS (b=0.28, P<0.05) and PI (b=0.30, P<0.05) in multivariable models. HRQL was inversely associated with PS, PI, depression, and anxiety, but only anxiety (b=-0.14, P=0.003) remained associated with HRQL in the adjusted model., Conclusions: Pain is present in over 70% of patients with cirrhosis undergoing liver transplant evaluation. Anxiety and depression were highly correlated with pain and appeared to be key drivers in predicting poor HRQL. Evaluating and managing mental health comorbidities should be explored as a strategy to improve HRQL in patients with cirrhosis and pain., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Cancer risk is modulated by hereditary and somatic mutations, exposures, age, sex, and gender. The mechanisms by which sex and gender work alone and in combination with other cancer risk factors remain underexplored. In general, cancers that occur in both the male and female sexes occur more commonly in XY compared with XX individuals, regardless of genetic ancestry, geographic location, and age. Moreover, XY individuals are less frequently cured of their cancers, highlighting the need for a greater understanding of sex and gender effects in oncology. This will be necessary for optimal laboratory and clinical cancer investigations. To that end, we review the epigenetics of sexual differentiation and its effect on cancer hallmark pathways throughout life. Specifically, we will touch on how sex differences in metabolism, immunity, pluripotency, and tumor suppressor functions are patterned through the epigenetic effects of imprinting, sex chromosome complement, X inactivation, genes escaping X inactivation, sex hormones, and life history.

Purpose: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM)., Methods and Materials: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry., Results: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors., Conclusions: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: We aimed to characterize pain and analgesic use in a large contemporary cohort of patients with cirrhosis and to associate pain with unplanned health care utilization and clinical outcomes in this population., Methods: We included all patients with cirrhosis seen in UCSF hepatology clinics from 2013 to 2020. Pain severity and location were determined using documented pain scores at the initial visit; "significant pain" was defined as moderate or severe using established cutoffs. Demographic, clinical, and medication data were abstracted from electronic medical records. Associations between significant pain and our primary outcome of 1-year unplanned health care utilization (ie, emergency department visit or hospitalization) and our secondary outcomes of mortality and liver transplantation were explored in multivariable models., Results: Among 5333 patients with cirrhosis, 32% had a nonzero pain score at their initial visit and 25% had significant (ie moderate/severe) pain. Sixty percent of patients with significant pain used ≥1 analgesic; 34% used opioids. Patients with cirrhosis with significant pain had similar Model for End-Stage Liver Disease-Sodium scores (14 vs. 13), but higher rates of decompensation (65% vs. 55%). The most common pain location was the abdomen (44%). Patients with abdominal pain, compared to pain in other locations, were more likely to have decompensation (72% vs. 56%). Significant pain was independently associated with unplanned health care utilization (adjusted odds ratio: 1.3, 95% CI: 1.1-1.5) and mortality (adjusted hazard ratio: 1.4, 95% CI: 1.2-1.6)., Conclusions: Pain among patients with cirrhosis is often not well-controlled despite analgesic use, and significant pain is associated with unplanned health care utilization and mortality in this population. Effectively identifying and treating pain are essential in reducing costs and improving quality of life and outcomes among patients with cirrhosis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Opioid use is extremely prevalent among patients with cirrhosis and those who received liver transplant (LT), despite concerns regarding opioid-related risks in this population. While there are many theoretical risks of opioids in patients with hepatic dysfunction, there is limited evidence on the effect of opioid use on clinical outcomes in cirrhosis and patients before and after LT specifically. As a result, there is significant center-level variability in opioid-related practices and policies. The existing data-largely based on retrospective observational studies-do suggest that opioids are associated with increased health resource utilization pre-LT and post-LT and that they may precipitate HE in patients with cirrhosis and increase the risk of graft loss and death after LT. The strongest predictor of opioid use after LT is opioid use before transplant; thus, a focus on safe opioid use in the pretransplant and peritransplant periods is essential for minimizing opioid-related harms. We describe 3 strategies to guide LT providers including (1) improved characterization of pain, mental health symptoms, and opioid and polysubstance use; (2) minimization of opioid prescriptions for those at highest risk of adverse events; and (3) safe prescribing strategies for those who do use opioids and for the management of opioid use disorder. Ultimately, our goal is to improve the quality of life and transplant outcomes among patients with cirrhosis and those who received LT, particularly those living with concurrent pain, mental health, and substance use disorders., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: The significant sex and gender differences that exist in cancer mechanisms, incidence, and survival, have yet to impact clinical practice. One barrier to translation is that cancer phenotypes cannot be segregated into distinct male versus female categories. Instead, within this convenient but contrived dichotomy, male and female cancer phenotypes are highly overlapping and vary between female- and male- skewed extremes. Thus, sex and gender-specific treatments are unrealistic, and our translational goal should be adaptation of treatment to the variable effects of sex and gender on targetable pathways., Methods: To overcome this obstacle, we profiled the similarities in 8370 transcriptomes of 26 different adult and 4 different pediatric cancer types. We calculated the posterior probabilities of predicting patient sex and gender based on the observed sexes of similar samples in this map of transcriptome similarity., Results: Transcriptomic index (TI) values were derived from posterior probabilities and allowed us to identify poles with local enrichments for male or female transcriptomes. TI supported deconvolution of transcriptomes into measures of patient-specific activity in sex and gender-biased, targetable pathways. It identified sex and gender-skewed extremes in mechanistic phenotypes like cell cycle signaling and immunity, and precisely positioned each patient's whole transcriptome on an axis of continuously varying sex and gender phenotypes., Conclusions: Cancer type, patient sex and gender, and TI value provides a novel and patient- specific mechanistic identifier that can be used for realistic sex and gender-adaptations of precision cancer treatment planning., (© 2024. The Author(s).)

Cognitive dysfunction following radiotherapy (RT) is one of the most common complications associated with RT delivered to the brain, but the precise mechanisms behind this dysfunction are not well understood, and to date, there are no preventative measures or effective treatments. To improve patient outcomes, a better understanding of the effects of radiation on the brain's functional systems is required. Functional magnetic resonance imaging (fMRI) has shown promise in this regard, however, compared to neural activity, hemodynamic measures of brain function are slow and indirect. Understanding how RT acutely and chronically affects functional brain organization requires more direct examination of temporally evolving neural dynamics as they relate to cerebral hemodynamics for bridging with human studies. In order to adequately study the underlying mechanisms of RT-induced cognitive dysfunction, the development of clinically mimetic RT protocols in animal models is needed. To address these challenges, we developed a fractionated whole-brain RT protocol (3Gy/day for 10 days) and applied longitudinal wide field optical imaging (WFOI) of neural and hemodynamic brain activity at 1, 2, and 3 months post RT. At each time point, mice were subject to repeated behavioral testing across a variety of sensorimotor and cognitive domains. Disruptions in cortical neuronal and hemodynamic activity observed 1 month post RT were significantly worsened by 3 months. While broad changes were observed in functional brain organization post RT, brain regions most impacted by RT occurred within those overlapping with the mouse default mode network and other association areas similar to prior reports in human subjects. Further, significant cognitive deficits were observed following tests of novel object investigation and responses to auditory and contextual cues after fear conditioning. Our results fill a much-needed gap in understanding the effects of whole-brain RT on systems level brain organization and how RT affects neuronal versus hemodynamic signaling in the cortex. Having established a clinically-relevant injury model, future studies can examine therapeutic interventions designed to reduce neuroinflammation-based injury following RT. Given the overlap of sequelae that occur following RT with and without chemotherapy, these tools can also be easily incorporated to examine chemotherapy-related cognitive impairment., (© 2023. The Author(s).)

Background: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with MGMT-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O 6 -Methylguanine-DNA Methyltransferase (MGMT) activity in murine and human models of GBM., Methods and Results: In vitro recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genes Bmal1 and Per2, as well as in the DNA repair enzyme, MGMT. Independent measures of MGMT transcript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription. We found that in vivo morning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O 6 -Benzylguanine abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression., Conclusion: We conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity and that scoring MGMT methylation status requires controlling for time of day of biopsy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Survivors of pediatric brain tumors experience significant cognitive deficits from their diagnosis and treatment. The exact mechanisms of cognitive injury are poorly understood, and validated predictors of long-term cognitive outcome are lacking. Resting state functional magnetic resonance imaging allows for the study of the spontaneous fluctuations in bulk neural activity, providing insight into brain organization and function. Here, we evaluated cognitive performance and functional network architecture in pediatric brain tumor patients. Forty-nine patients (7-18 years old) with a primary brain tumor diagnosis underwent resting state imaging during regularly scheduled clinical visits. All patients were tested with a battery of cognitive assessments. Extant data from 139 typically developing children were used as controls. We found that obtaining high-quality imaging data during routine clinical scanning was feasible. Functional network organization was significantly altered in patients, with the largest disruptions observed in patients who received propofol sedation. Awake patients demonstrated significant decreases in association network segregation compared to controls. Interestingly, there was no difference in the segregation of sensorimotor networks. With a median follow-up of 3.1 years, patients demonstrated cognitive deficits in multiple domains of executive function. Finally, there was a weak correlation between decreased default mode network segregation and poor picture vocabulary score. Future work with longer follow-up, longitudinal analyses, and a larger cohort will provide further insight into this potential predictor., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Imaging is central to the clinical surveillance of brain tumors yet it provides limited insight into a tumor's underlying biology. Machine learning and other mathematical modeling approaches can leverage paired magnetic resonance images and image-localized tissue samples to predict almost any characteristic of a tumor. Image-based modeling takes advantage of the spatial resolution of routine clinical scans and can be applied to measure biological differences within a tumor, changes over time, as well as the variance between patients. This approach is non-invasive and circumvents the intrinsic challenges of inter- and intratumoral heterogeneity that have historically hindered the complete assessment of tumor biology and treatment responsiveness. It can also reveal tumor characteristics that may guide both surgical and medical decision-making in real-time. Here we describe a general framework for the acquisition of image-localized biopsies and the construction of spatiotemporal radiomics models, as well as case examples of how this approach may be used to address clinically relevant questions., Competing Interests: 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., (Copyright © 2023 Bond, Curtin, Ranjbar, Afshari, Hu, Rubin and Swanson.)

Goals: We sought to determine whether race/ethnicity is associated with hospitalization outcomes among patients admitted with acute cholangitis., Background: Few studies have evaluated the association between race and outcomes in patients with acute cholangitis., Study: We analyzed United States hospitalizations from 2009 to 2018 using the Nationwide Inpatient Sample (NIS). We included patients 18 years old or above admitted with an ICD9/10 diagnosis of cholangitis. Race/ethnicity was categorized as White, Black, Hispanic, or Other. We used multivariable regression to determine the association between race/ethnicity and in-hospital outcomes of interest, including endoscopic retrograde cholangiopancreatography (ERCP), early ERCP (<48 h from admission), length of stay (LOS), and in-hospital mortality., Results: Of 116,889 hospitalizations for acute cholangitis, 70% identified as White, 10% identified as Black, 11% identified as Hispanic, and 9% identified as Other. The proportion of non-White patients increased over time. On multivariate analysis controlling for clinical and sociodemographic variables, compared with White patients, Black patients had higher in-hospital mortality (adjusted odds ratio: 1.4, 95% confidence interval: 1.2-1.6, P <0.001). Black patients were also less likely to undergo ERCP, more likely to undergo delayed ERCP, and had longer LOS ( P <0.001 for all)., Conclusions: In this contemporary cohort of hospitalized patients with cholangitis, Black race was independently associated with fewer and delayed ERCP procedures, longer LOS, and higher mortality rates. Future studies with more granular social determinants of health data should further explore the underlying reasons for these disparities to develop interventions aimed at reducing racial disparities in outcomes among patients with acute cholangitis., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Pediatric brain tumor patients often experience significant cognitive sequelae. Resting-state functional MRI (rsfMRI) provides a measure of brain network organization, and we hypothesize that pediatric brain tumor patients treated with proton therapy will demonstrate abnormal brain network architecture related to cognitive outcome and radiation dosimetry., Participants and Methods: Pediatric brain tumor patients treated with proton therapy were enrolled on a prospective study of cognitive assessment using the NIH Toolbox Cognitive Domain. rsfMRI was obtained in participants able to complete unsedated MRI. Brain system segregation (BSS), a measure of brain network architecture, was calculated for the whole brain, the high-level cognition association systems, and the sensory-motor systems., Results: Twenty-six participants were enrolled in the study for cognitive assessment, and 18 completed rsfMRI. There were baseline cognitive deficits in attention and inhibition and processing speed prior to radiation with worsening performance over time in multiple domains. Average BSS across the whole brain was significantly decreased in participants compared with healthy controls (1.089 and 1.101, respectively; P  = 0.001). Average segregation of association systems was significantly lower in participants than in controls ( P  < 0.001) while there was no difference in the sensory motor networks ( P  = 0.70). Right hippocampus dose was associated with worse attention and inhibition ( P  < 0.05) and decreased segregation in the dorsal attention network ( P  < 0.05)., Conclusion: Higher mean dose to the right hippocampus correlated with worse dorsal attention network segregation and worse attention and inhibition cognitive performance. Patients demonstrated alterations in brain network organization of association systems measured with rsfMRI; however, somatosensory system segregation was no different from healthy children. Further work with preradiation rsfMRI is needed to assess the effects of surgery and presence of a tumor on brain network architecture., Competing Interests: Conflicts of Interest: Stephanie Perkins is a paid member of the advisory committee for Mevion Medical Systems, LLC. The authors have no additional conflicts of interest to disclose., (©Copyright 2023 The Author(s).)

Goals/background: Pain is common among cirrhosis patients, particularly those hospitalized with acute illness. Managing pain in this population is challenging due to concern for adverse events and lack of guidelines for analgesic use. We sought to characterize analgesic use among inpatients with cirrhosis compared with matched noncirrhosis controls, as well as hospital-level variation in prescribing patterns., Methods: We utilized the Vizient Clinical Database, which includes clinical and billing data from hospitalizations at >500 US academic medical centers. We identified cirrhosis patients hospitalized in 2017-2018, and a matched cohort of noncirrhosis patients. Types of analgesic given-acetaminophen (APAP), nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and adjuvants (eg, gabapentinoids, antidepressants) were defined from inpatient prescription records. Conditional logistic regression was used to associate cirrhosis diagnosis with analgesic use., Results: Of 116,363 cirrhosis inpatients, 83% received at least 1 dose of an analgesic and 58% had regular inpatient analgesic use, rates that were clinically similar to noncirrhosis controls. Cirrhosis inpatients were half as likely to receive APAP (26% vs. 42%, P <0.01) or NSAIDs (3% vs. 7%, P <0.01), but were more likely to receive opioids (59% vs. 54%, P <0.01), particularly decompensated patients (60%). There was notable variation in analgesic prescribing patterns between hospitals, especially among cirrhosis patients., Conclusions: Analgesic use was common among inpatients, with similar rates among patients with and without cirrhosis. Cirrhosis patients-particularly decompensated patients-were less likely to receive APAP and NSAIDs and more likely to receive opioid analgesics. Because of lack of evidence-based guidance for management of cirrhosis patients with pain, providers may avoid nonopioid analgesics due to perceived risks and consequently may overutilize opioids in this high-risk population., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Researchers are exploring sex differences in experimental models of both development and disease-but are we doing enough? In this collection of Voices, we celebrate researchers who are asking this question and starting to offer mechanistic clues on sexually dimorphic differences seen in interorgan communication, metabolic disease, neurological disorders, and more., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue., Methods: Using positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity., Findings: We found that male glioblastoma surgical specimens are enriched for amino acid metabolites, including glutamine. Fluoroglutamine PET imaging analyses showed that gliomas in affected male individuals exhibit significantly higher glutamine uptake. These sex differences were well modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and tricarboxylic acid (TCA) cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase (PC)-mediated TCA cycle replenishment, and knockdown of PC sensitized females to GLS1 inhibition., Conclusion: Our results show that clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism may improve treatments through further laboratory and clinical research., Funding: This work was supported by NIH grants, Joshua's Great Things, the Siteman Investment Program, and the Barnard Research Fund., Competing Interests: Declarations of interests G.J.P. is a scientific advisor for Cambridge Isotope Laboratories. The Patti laboratory has a collaboration agreement with Agilent Technologies and Thermo Fisher Scientific., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Lung cancer is the leading cause of cancer-related death. Intriguingly, males with non-small cell lung cancer (NSCLC) have a higher mortality rate than females. Here, we investigated the role of serine metabolism as a predictive marker for sensitivity to the antifolate pemetrexed in male and female NSCLC cell lines. Using [ 13 C 6 ] glucose tracing in NSCLC cell lines, we found that a subset of male cells generated significantly more serine from glucose than female cells. Higher serine biosynthesis was further correlated with increased sensitivity to pemetrexed in male cells only. Concordant sex differences in metabolic gene expression were evident in NSCLC and pan-cancer transcriptome datasets, suggesting a potential mechanism with wide-reaching applicability. These data were further validated by integrating antifolate drug cytotoxicity and metabolic pathway transcriptome data from pan-cancer cell lines. Together, these findings highlight the importance of considering sex differences in cancer metabolism to improve treatment for all patients., Competing Interests: S.D. serves on the advisory board of Genentech., (© 2022 The Authors.)

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1-4 . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5-8 . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4 . Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES + KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in wildtype and transformed murine astrocytes, as well as patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned during early development by gonadal sex. These data provide a rationale for the further study of sex differences in radiation response and how senescence might be enhanced for radiation sensitization. The determination that p21 and gonadal sex are required for sex differences in radiation response will serve as a foundation for these future mechanistic studies., (© 2022. The Author(s).)

Background and Aims: Kidney dysfunction is associated with increased mortality among patients with cirrhosis. We investigated whether kidney dysfunction types [e.g., acute kidney injury (AKI), chronic kidney disease (CKD), and AKI on CKD] were differentially associated with inpatient mortality., Methods: We utilized the nationwide inpatient sample, a nationally representative database, from 2007 to 2014. We included all hospitalizations with previously validated codes for cirrhosis or associated decompensated cirrhosis diagnoses. We defined kidney dysfunction types also from previously validated codes, and we grouped hospitalizations into the following diagnoses: normal, AKI, CKD, and AKI on CKD. Our primary outcome was inpatient mortality., Results: There were 1,293,779 hospitalizations with cirrhosis sampled in this study. Of these hospitalizations, 849,193 (66%) had normal kidney function, 176,418 (14%) had AKI, 157,600 (12%) had CKD, and 110,568 (9%) had AKI on CKD. We found that the proportion of hospitalizations with AKI, CKD, and AKI on CKD increased significantly throughout the study period (p < 0.001, test for trend for all). Kidney dysfunction type was differentially associated with inpatient mortality, even after adjustment: as compared to those with CKD, normal kidney function: OR 0.75 [95 CI 0.73-0.78], AKI: OR 2.40 [95 CI 2.32-2.48], and AKI on CKD: OR 1.66 [95 CI 1.60-1.72]., Discussion: Using a nationally representative cohort of all hospitalizations with cirrhosis, our study highlights that the burden of kidney dysfunction, especially AKI, among hospitalizations with cirrhosis is rising, and the inclusion of kidney dysfunction type may be an opportunity to improve prognostication., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Neurodevelopmental disorders increase brain tumor risk, suggesting that normal brain development may have protective properties. Mutations in epigenetic regulators are common in pediatric brain tumors, highlighting a potentially central role for disrupted epigenetic regulation of normal brain development in tumorigenesis. For example, lysine 27 to methionine mutation (H3K27M) in the H3F3A gene occurs frequently in Diffuse Intrinsic Pontine Gliomas (DIPGs), the most aggressive pediatric glioma. As H3K27M mutation is necessary but insufficient to cause DIPGs, it is accompanied by additional mutations in tumors. However, how H3K27M alone increases vulnerability to DIPG tumorigenesis remains unclear., Results: Here, we used human embryonic stem cell models with this mutation, in the absence of other DIPG contributory mutations, to investigate how H3K27M alters cellular proliferation and differentiation. We found that H3K27M increased stem cell proliferation and stem cell properties. It interfered with differentiation, promoting anomalous mesodermal and ectodermal gene expression during both multi-lineage and germ layer-specific cell specification, and blocking normal differentiation into neuroectoderm. H3K27M mutant clones exhibited transcriptomic diversity relative to the more homogeneous wildtype population, suggesting reduced fidelity of gene regulation, with aberrant expression of genes involved in stem cell regulation, differentiation, and tumorigenesis. These phenomena were associated with global loss of H3K27me3 and concordant loss of DNA methylation at specific genes in H3K27M-expressing cells., Conclusions: Together, these data suggest that H3K27M mutation disrupts normal differentiation, maintaining a partially differentiated state with elevated clonogenicity during early development. This disrupted response to early developmental cues could promote tissue properties that enable acquisition of additional mutations that cooperate with H3K27M mutation in genesis of DMG/DIPG. Therefore, this work demonstrates for the first time that H3K27M mutation confers vulnerability to gliomagenesis through persistent clonogenicity and aberrant differentiation and defines associated alterations of histone and DNA methylation., (© 2022. The Author(s).)

Background: Leptomeningeal disease and hydrocephalus are present in up to 30% of patients with diffuse intrinsic pontine glioma (DIPG), however there are no animal models of cerebrospinal fluid (CSF) dissemination. As the tumor-CSF-ependymal microenvironment may play an important role in tumor pathogenesis, we identified characteristics of the Nestin-tumor virus A (Nestin-Tva) genetically engineered mouse model that make it ideal to study the interaction of tumor cells with the CSF and its associated pathways with implications for the development of treatment approaches to address CSF dissemination in DIPG., Methods: A Nestin-Tva model of DIPG utilizing the 3 most common DIPG genetic alterations (H3.3K27M, PDGF-B, and p53) was used for this study. All mice underwent MR imaging and a subset underwent histopathologic analysis with H&E and immunostaining., Results: Tumor dissemination within the CSF pathways (ventricles, leptomeninges) from the subependyma was present in 76% (25/33) of mice, with invasion of the choroid plexus, disruption of the ciliated ependyma and regional subependymal fluid accumulation. Ventricular enlargement consistent with hydrocephalus was present in 94% (31/33). Ventricle volume correlated with region-specific transependymal CSF flow (periventricular T2 signal), localized anterior to the lateral ventricles., Conclusions: This is the first study to report CSF pathway tumor dissemination associated with subependymal tumor in an animal model of DIPG and is representative of CSF dissemination seen clinically. Understanding the CSF-tumor-ependymal microenvironment has significant implications for treatment of DIPG through targeting mechanisms of tumor spread within the CSF pathways., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Sex differences in cellular and systems biology have been evolutionarily selected to optimize reproductive success in all species with little (sperm) and big (ova) gamete producers. They are evident from the time of fertilization and accrue throughout development through genetic, epigenetic, and circulating sex hormone-dependent mechanisms. Among other effects, they significantly impact on chromatin organization, metabolism, cell cycle regulation, immunity, longevity, and cancer risk and survival. Sex differences in cancer should be expected and accounted for in basic, translational, and clinical oncology research., (Copyright © 2022 The Author. Published by Elsevier Inc. All rights reserved.)

Goal: Characterize prevalence of osmotic demyelination syndrome (ODS) in hospitalized patients with cirrhosis., Background: ODS is a serious complication of rapid serum sodium correction. Patients with cirrhosis experience labile sodium levels related to portal hypertension and diuretic use, often with rapid correction-intentional or unintentional-during hospitalizations., Study: We used validated International Classification of Diseases, Ninth Revision (ICD-9) codes to identify inpatients 18 years and older with cirrhosis from the 2009-2013 National Inpatient Sample, excluding those with liver transplantation during hospitalization. The primary outcome was ODS (ICD-9 341.8). Baveno IV defined decompensated cirrhosis (stages 3 and 4); Charlson Comorbidity Index identified severe comorbid illness (score >3). Logistic regression modeled factors associated with ODS., Results: Of 547,544 adult inpatients with cirrhosis, 94 (0.02%) had ODS. Inpatients with versus without ODS were younger (54 vs. 57 y, P=0.0001), and more likely to have alcohol-related cirrhosis (58% vs. 33%, P<0.0001). ODS did not associate with decompensated cirrhosis (33% vs. 37%, P=0.43), specific complications (ascites 33% vs. 33%, P=0.97; hepatic encephalopathy 24% vs. 17%, P=0.06), or severe comorbid illness (12% vs. 16%, P=0.24). In both univariable and multivariable analysis, age [adjusted odds ratio (ORadj): 0.97, 95% confidence interval (CI): 0.95-0.99], female gender (ORadj: 1.53, 95% CI: 1.01-2.30), Hispanic race (ORadj: 0.41, 95% CI: 0.19-0.89), alcohol-related cirrhosis (ORadj: 2.65, 95% CI: 1.71-4.09), and congestive heart failure (ORadj: 0.37, 95% CI: 0.15-0.95) significantly associated with ODS., Conclusion: In hospitalized patients with cirrhosis, ODS is extremely rare, and associated with alcohol-related cirrhosis, younger age, and female gender. ODS is not associated with liver disease severity, specific complications including ascites, or comorbid disease., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)