Differences in mutations across tumour sizes in clear-cell renal cell carcinoma.

OBJECTIVE: To assess the distribution of key mutations across tumour sizes in clear-cell renal cell carcinoma (ccRCC), and secondarily to examine the prognostic impact of aggressive mutations in smaller ccRCCs. PATIENT AND METHODS: The distribution of mutations (VHL, PBRM1, SETD2, BAP1 and CDKN2A loss) across tumour sizes was assessed in 1039 ccRCCs treated with nephrectomy in cohorts obtained from the Tracking Cancer Evolution (TRACERx), The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) projects. Logistic regression was used to model the presence of each mutation against size. In our secondary analysis, we assessed a subset of ccRCCs ≤7 cm for associations of key aggressive mutations (SETD2, BAP1, and CDKN2A loss) with metastasis, invasive disease and overall survival, while controlling for size. A subset of localised tumours ≤7 cm was also used to assess associations with recurrence after nephrectomy. RESULTS: On logistic regression, each 1-cm increase in tumour size was associated with aggressive mutations, SETD2, BAP1, and CDKN2A loss, at odds ratios (ORs) of 1.09, 1.10 and 1.19 (P < 0.001), whereas no significant association was observed between tumour size and PBRM1 (OR 1.02; P = 0.23). VHL was mildly negatively associated with a 1-cm increase in size (OR 0.95; P = 0.01). Among tumours ≤7 cm, SETD2 and CDKN2A loss were associated with metastatic disease at ORs of 3.86 and 3.84 (P < 0.05) while controlling for tumour size. CDKN2A loss was associated with worse overall survival, with a hazard ratio (HR) of 2.19 (P = 0.03). Among localised tumours ≤7 cm, SETD2 was associated with worse recurrence-free survival (HR 2.00; P = 0.03). CONCLUSION: Large and small ccRCCs are genomically different. Aggressive mutations, namely, SETD2, BAP1, and CDKN2A loss, are rarely observed in small ccRCCs and are observed more frequently in larger tumours. However, when present in tumours ≤7 cm, SETD2 mutations and CDKN2A loss were still independently associated with invasive disease, metastasis, worse survival, and recurrence after resection, after controlling for size.

Neural Correlates of Visual Feature Binding.

We perceive visual objects as unified although different brain areas process different features. An attentional mechanism has been proposed to be involved with feature binding, as evidenced by observations of binding errors (i.e., illusory conjunctions) when attention is diverted. However, the neural underpinnings of this feature binding are not well understood. We examined the neural mechanisms of feature binding by recording EEG during an attentionally demanding discrimination task. Unlike prestimulus alpha oscillatory activity and early ERPs (i.e., the N1 and P1 components), the N1pc, reflecting stimulus-evoked spatial attention, was reduced for errors relative to correct responses and illusory conjunctions. However, the later SPCN, reflecting visual short-term memory, was reduced for illusory conjunctions and errors compared with correct responses. Furthermore, binding errors were associated with distinct posterior lateralized activity during this 200- to 300-msec window. These results implicate a temporal binding window that integrates visual features after stimulus-evoked attention but before encoding into visual short-term memory.

Incidence of Central Nervous System Relapse in Primary Mediastinal Large B-Cell Lymphoma: Implications for Central Nervous System Prophylaxis.

BACKGROUND: Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of aggressive B-cell non-Hodgkin lymphoma. PMBCL shares some clinical and biologic features with nodular sclerosis classic Hodgkin lymphoma (cHL). Central nervous system (CNS) relapse is exceedingly rare in cHL. Therefore, it may be expected that CNS relapse in PMBCL is also uncommon. Herein, we examined the incidence of CNS relapse in patients with PMBCL treated with standard chemoimmunotherapy. PATIENTS AND METHODS: This retrospective single center analysis included 154 patients with newly diagnosed PMBCL seen at Mayo Clinic. The CNS relapse rate was calculated using a competing risk model, with death considered as a competing risk. RESULTS: With a median follow-up of 39 months, 3 patients experienced CNS relapse, all associated with systemic relapse. The cumulative incidence of CNS relapse for the entire cohort was 1.43% (95% CI, 0.3%-4.6%) at 1 year and 2.21% (95% CI, 0.6%-5.8%) at both 2 and 5 years. For those who did not receive CNS prophylaxis (n = 131), the incidence was 0.85% (95% CI, 0.1%-4.2%) at 1 year and 1.80% (95% CI, 0.3%-5.8%) at both 2 and 5 years. All 3 patients who experienced CNS relapse had R-CHOP as frontline therapy; 2 patients did not receive any CNS prophylaxis, while 1 patient received intrathecal CNS prophylaxis. CONCLUSION: The risk of CNS relapse in PMBCL appears to be very low after treatment with standard chemoimmunotherapy, suggesting routine CNS prophylaxis is not necessary.

Lipidomics of infant mesenchymal stem cells associate with the maternal milieu and child adiposity.

Our objective was to interrogate infant mesenchymal stem cell (MSC) lipid metabolism and gestational exposures that may contribute to child obesity risk. MSCs were cultured from term infants of mothers with obesity (n=16) or normal-weight (n=15). In MSCs undergoing myogenesis in vitro, we used lipidomics to distinguish phenotypes by unbiased cluster analysis and lipid challenge (24h excess fatty acid, 24hFA). We measured MSC AMP-activated protein kinase (AMPK) activity and fatty acid oxidation (FAO), and a composite index of maternal glucose, insulin, triglycerides, free fatty acids, tumor necrosis factor-α, high density lipoprotein- and total- cholesterol in fasting blood from mid- and late-gestation (~17, ~27wks). We measured child adiposity at birth (n=29), 4-6m (n=29), and 4-6y (n=13). Three MSC clusters were distinguished by triacylglycerol (TAG) stores, with greatest TAGs in Cluster-2. All Clusters increased acylcarnitines and TAGs with 24hFA, though Cluster-2 was more pronounced and corresponded to AMPK activation and FAO. Maternal metabolic markers predicted MSC Clusters and child adiposity at 4-6y (both highest in Cluster-3). Our data supports that MSC phenotypes are predicted by comprehensive maternal metabolic milieu exposures, independent of maternal BMI, and suggest utility as an at-birth predictor for child adiposity, though validation with larger longitudinal samples is warranted.

Xanthogranulomatous Pyelonephritis: A pooled quantitative analysis of published cases.

Xanthogranulomatous Pyelonephritis (XGP) is a serious and rare inflammatory disease of unknown etiology. This systematic review analyzes XGP cases. We performed a literature search for "Pyelonephritis, Xanthogranulomatous." The primary composite outcome was recovery with post-surgery complications, partial recovery, death, or chronic kidney disease. The secondary outcome was any presentation or treatment complication. Predictor variables consisted of demographics, history, symptoms, and diagnosis/management. Among the 251 patients, the mean age was 36.1 years, and 57.4% were female. The most common symptom and finding were fever (55.0%) and renal stones (53.8%), respectively. There were 15.5% with the composite outcome. There were 51.0% with any presentation or treatment complication. Multivariate logistic regression analysis for the composite outcome showed that kidney of both/horseshoe (OR:3.86, 95% CI:1.01, 14.73, p = 0.048), dialysis required (OR:8.64, 95% CI:2.27, 32.94, p = 0.002), and operative treatment of nephrostomy or nephrostomy followed by nephrectomy (OR:4.57, 95% CI:1.58, 13.17, p = 0.01) were each significantly associated with increased odds. Fever (OR:3.04, 95% CI:1.63, 5.67, p <0.001) and renal stones (OR:2.55, 95% CI:1.35, 4.81, p = 0.004) were each significantly associated with increased odds for any presentation/treatment complication. In conclusion, XGP patients with involvement of both or horseshoe kidneys, dialysis requirements, or treatment of nephrostomy or nephrostomy followed by nephrectomy may require aggressive treatment to mitigate poor patient outcomes.

Patterns of blunt and cigar use in the United States, 2015-2019.

INTRODUCTION: The use of cigars for blunts (i.e., cannabis rolled in cigar paper) is well-documented; prevalence of cigar and blunt use and associated characteristics are less studied. METHODS: Pooled data from the 2015-2019 National Survey on Drug Use and Health (NSDUH) were analyzed in 2023. Respondents aged 12+ who reported past 30-day cigar use were categorized into three mutually exclusive use categories: (1) exclusively cigars, (2) exclusively blunts, and (3) both cigars and blunts. We examined associations between cigar-blunt use categories and sociodemographic characteristics. RESULTS: Among respondents aged 12+ who reported past 30-day cigar use, 48.6% (95% CI=47.6-49.6) reported exclusive cigar use; 44.3% (95% CI=43.3-45.3) reported exclusive blunt use; and 7.2% (95% CI=6.8-7.6) reported cigars and blunts. The prevalence differed by age, with exclusive blunt use most prevalent among youth (72.5% [95% CI=70.7-74.3]) and young adults (62.4% [95% CI=61.4-63.5]), and exclusive cigar use most prevalent among adults 26+ (61.2% [95% CI=59.8-62.5]). Exclusive blunt users smoked more days in the past month (17.5; 95% CI=16.8-18.2), compared to 13.8 days (95% CI=13.2-14.4) for cigar and blunt users, and 7.7 days (95% CI=7.5-8.0) for exclusive cigar users. There were significant differences in sociodemographic characteristics, with female (41.6%; 95% CI=40.3-42.9) and Hispanic (18.2%; 95% CI=17.3-19.2) participants more likely to report exclusive blunt use. CONCLUSIONS: Exclusive blunt use was the most prevalent pattern of past-30-day cigar use among youth and young adults. Those who use cigars as blunts smoked more cigars per month, suggesting this may be an important group for education and policy efforts. IMPLICATIONS: Studies that aggregate cigars and blunts into one group may limit potentially meaningful subgroup risk profiles. Additionally, when assessing cigar use, particularly among youth and young adults, it is important to consider blunt use to avoid missing youth who exclusively use cigars for blunts and may not consider blunts as cigar products. Accurate measurement may better inform tobacco and cannabis regulatory actions. Finally, given the high prevalence of blunt use among youth and young adults identified in the present study, additional education efforts may be warranted for this population to reduce long-term risks.

Does No Mean No? Situational and Dispositional Factors Influence Emerging Adult Men's Intentions to Use Assault Tactics in Response to Women's Sexual Refusal During Hookups.

Hookups can result in sexual assault when men do not listen to requests from women to stop. It is thus important to identify factors that influence men's decisions to override direct refusals in these situations. Presently, we administered first-person vignettes depicting a prototypical hookup wherein the woman refuses the man's attempt to escalate intimacy. Using a national sample of emerging adult men (N = 420), we found that they on average did not completely rule out coercive or forcible tactics, but those elevated on rape myth acceptance, hypermasculinity, and psychopathy were uniquely at risk of assault when controlling for several other traits known to correlate with rape. Participants also reported being likelier to use coercive sexual practices when refusals occurred at higher levels of sexual intimacy already attained. Notably, diagnostic analyses revealed that a subset of men had a disproportionate influence on the regression estimates, and that these men were not only elevated across a range of assault-relevant traits, but also endorsed higher likelihoods of using coercion and force in the face of female sexual refusal. Although removal of these cases did not substantively alter the results, exploratory analyses revealed that these individuals responded differently to situational factors in ways that suggested sexual opportunism. Theoretical and practical implications of these findings are discussed.

Central mechanisms of emesis: A role for GDF15.

BACKGROUND: Nausea and emesis are ubiquitously reported medical conditions and often present as treatment side effects along with polymorbidities contributing to detrimental life-threatening outcomes, such as poor nutrition, lower quality of life, and unfavorable patient prognosis. Growth differentiation factor 15 (GDF15) is a stress response cytokine secreted by a wide variety of cell types in response to a broad range of stressors. Circulating GDF15 levels are elevated in a range of medical conditions characterized by cachexia and malaise. In recent years, GDF15 has gained scientific and translational prominence with the discovery that its receptor, GDNF family receptor α-like (GFRAL), is expressed exclusively in the hindbrain. GFRAL activation may results in profound anorexia and body weight loss, effects which have attracted interest for the pharmacological treatment of obesity. PURPOSE: This review highlights compelling emerging evidence indicating that GDF15 causes anorexia through the induction of nausea, emesis, and food aversions, which encourage a perspective on GDF15 system function in physiology and behavior beyond homeostatic energy regulation contexts. This highlights the potential role of GDF15 in the central mediation of nausea and emesis following a variety of physiological, and pathophysiological conditions such as chemotherapy-induced emesis, hyperemesis gravidarum, and cyclic vomiting syndrome.

How peer status and ability track shape behavioral disengagement over the transition from primary to secondary school.

The transition from primary to secondary school is often associated with an increase in behavioral disengagement, which undermines students' academic development. Prior studies examined the average development of behavioral disengagement across school transitions. This study examined how students' peer status in primary school and ability track in secondary school relate to trajectories of behavioral disengagement. We followed n = 1564 students who transitioned to secondary school across three time points: February/March, and May/June in students' final year of primary school and January/February, roughly 6 months after students transited to secondary school. Latent Growth Curve Analyses showed that on average, behavioral disengagement increased, but this increase mostly occurred before transitioning to secondary school. Peer status and track related to students' initial levels of behavioral disengagement, but not to their development in behavioral disengagement over the transition. Specifically, students who were viewed as more popular by peers, and students who ended up in the lowest track showed more behavioral disengagement in primary school, whereas students who were more accepted by peers were less disengaged in primary school.

Flavonols improve tomato pollen thermotolerance during germination and tube elongation by maintaining ROS homeostasis.

Elevated temperatures impair pollen performance and reproductive success, resulting in lower crop yields. The tomato (Solanum lycopersicum) anthocyanin reduced (are) mutant harbors a mutation in FLAVANONE 3-HYDROXYLASE (F3H), resulting in impaired flavonol antioxidant biosynthesis. The are mutant has reduced pollen performance and seed set relative to the VF36 parental line, phenotypes that are accentuated at elevated temperatures. Transformation of are with the wild-type F3H gene, or chemical complementation with flavonols, prevented temperature-dependent reactive oxygen species (ROS) accumulation in pollen and restored the reduced viability, germination, and tube elongation of are to VF36 levels. Overexpression of F3H in VF36 prevented temperature-driven ROS increases and impaired pollen performance, revealing that flavonol biosynthesis promotes thermotolerance. Although stigmas of are had reduced flavonol and elevated ROS levels, the growth of are pollen tubes was similarly impaired in both are and VF36 pistils. RNA-seq was performed at optimal and stress temperatures in are, VF36, and the F3H overexpression line at multiple timepoints across pollen tube elongation. The number of differentially expressed genes increased over time under elevated temperatures in all genotypes, with the greatest number in are. These findings suggest potential agricultural interventions to combat the negative effects of heat-induced ROS in pollen that lead to reproductive failure.

Linoleoyl-lysophosphatidylcholine suppresses immune-related adverse events due to immune checkpoint blockade.

Immune related adverse events (irAEs) after immune checkpoint blockade (ICB) therapy occur in a significant proportion of cancer patients. To date, the circulating mediators of ICB-irAEs remain poorly understood. Using non-targeted mass spectrometry, here we identify the circulating bio-active lipid linoleoyl-lysophosphatidylcholine (LPC 18:2) as a modulator of ICB-irAEs. In three independent human studies of ICB treatment for solid tumor, loss of circulating LPC 18:2 preceded the development of severe irAEs across multiple organ systems. In both healthy humans and severe ICB-irAE patients, low LPC 18:2 was found to correlate with high blood neutrophilia. Reduced LPC 18:2 biosynthesis was confirmed in preclinical ICB-irAE models, and LPC 18:2 supplementation in vivo suppressed neutrophilia and tissue inflammation without impacting ICB anti-tumor response. Results indicate that circulating LPC 18:2 suppresses human ICB-irAEs, and LPC 18:2 supplementation may improve ICB outcomes by preventing severe inflammation while maintaining anti-tumor immunity.

Peripheral nerve injury results in a biased loss of sensory neuron subpopulations.

ABSTRACT: There is a rich literature describing the loss of dorsal root ganglion (DRG) neurons following peripheral axotomy, but the vulnerability of discrete subpopulations has not yet been characterised. Furthermore, the extent or even presence of neuron loss following injury has recently been challenged. In this study, we have used a range of transgenic recombinase driver mouse lines to genetically label molecularly defined subpopulations of DRG neurons and track their survival following traumatic nerve injury. We find that spared nerve injury leads to a marked loss of cells containing DRG volume and a concomitant loss of small-diameter DRG neurons. Neuron loss occurs unequally across subpopulations and is particularly prevalent in nonpeptidergic nociceptors, marked by expression of Mrgprd. We show that this subpopulation is almost entirely lost following spared nerve injury and severely depleted (by roughly 50%) following sciatic nerve crush. Finally, we used an in vitro model of DRG neuron survival to demonstrate that nonpeptidergic nociceptor loss is likely dependent on the absence of neurotrophic support. Together, these results profile the extent to which DRG neuron subpopulations can survive axotomy, with implications for our understanding of nerve injury-induced plasticity and pain.

Decoding the decline: unveiling drivers of sarcopenia.

There remains a critical need to define molecular pathways underlying sarcopenia to identify putative therapeutic targets. Research in the mechanisms of aging and sarcopenia relies heavily on preclinical rodent models. In this issue of the JCI, Kerr et al. implemented a clinically-relevant sarcopenia classification system of aged C57BL/6J mice, capturing sarcopenia prevalence across both sexes. The authors performed detailed physiological, molecular, and energetic analyses and demonstrated that mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in male mice. Sarcopenia was less prevalent in female mice with fewer alterations compared with the male-affected processes. The findings highlight factors beyond age as necessary for classifying the sarcopenic phenotype in rodent models, reveal sexual dimorphism across the trajectory of age-related declines in muscle mass and function in a commonly used rodent model, and provide insight into sex-dependent molecular alterations associated with sarcopenia progression.

Spinal Arachnoid Web.

Case Presentation: We describe a case of a 57-year-old male with multiple medical comorbidities who presented to the emergency department with a two-week history of upper back pain with associated numbness. Physical exam demonstrated sensory loss in a bilateral third and fourth thoracic dermatome distribution. The diagnosis of spinal arachnoid web was made based on neurological exam and imaging findings. Discussion: Spinal arachnoid web is a rare diagnosis, but consideration is important, as early recognition and surgical intervention can resolve symptoms and prevent worsening neurological sequelae.

Enantioselective Nickel-Catalyzed α-Spirocyclization of Lactones.

Herein we report a strategy for the enantioselective synthesis of spirocycles containing all-carbon quaternary centers via nickel-catalyzed intramolecular addition of lactone enolates to aryl nitriles. The established lactone α-spirocyclization efficiently and enantioselectively forges 5-, 6-, and 7-membered rings, performing best in the synthesis of 7-membered rings (up to 90% ee). This discovery represents an expansion of the synthetic toolkit for enantioselective spirocyclization, providing access to chiral, pharmaceutically relevant spirocyclic products.

ScreenDMT reveals DiHOMEs are replicably inversely associated with BMI and stimulate adipocyte calcium influx.

Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME are both replicably inversely associated with BMI and mechanistically activate calcium influx in mouse brown and white adipocytes in vitro, which implicates this signaling pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.

Leveraging and learning from the long COVID experience: Translating telerehabilitation into practice.

BACKGROUND: Telerehabilitation, or the delivery of rehabilitation services through telehealth platforms, has existed since the late 1990 s. Telerehabilitation was characterized by unprecedented, exponential growth at the beginning of the novel coronavirus-2019 (COVID-19) pandemic. Medical systems sought to reduce the likelihood of disease transmission by using telerehabilitation to limit physical proximity during routine care. This dramatic change in how medical care was delivered forced many professions to adapt processes and practices. Following the change, debates sparked regarding the best path to move forward for the betterment of patients, clinicians, systems, and society. Long COVID has emerged as a complex chronic health condition arising from COVID-19. The unique needs and dynamic disease process of Long COVID has incentivized medical systems to create equitable ways for patients to safely access interdisciplinary care. OBJECTIVES: The purpose of this commentary is to describe what medical systems must consider when deploying high-quality telerehabilitation to deliver rehabilitation through asynchronous (e.g., text, portal) and synchronous modalities (e.g., phone or video). We highlight lessons learned to help guide decision-makers on key actions to support their patients and clinicians. METHODS: Not applicable. RESULTS: Not applicable. CONCLUSIONS: Key action steps from our lessons learned may be used to address complex chronic health conditions such as Long COVID and prepare for future challenges that may disrupt medical systems.

Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function.

A key challenge in aging research is extending lifespan in tandem with slowing down functional decline so that life with good health (healthspan) can be extended. Here, we show that monthly clearance, starting from 20 months, of a small number of cells that highly express p21Cip1 (p21high) improves cardiac and metabolic function and extends both median and maximum lifespans in mice. Importantly, by assessing the health and physical function of these mice monthly until death, we show that clearance of p21high cells improves physical function at all remaining stages of life, suggesting healthspan extension. Mechanistically, p21high cells encompass several cell types with a relatively conserved proinflammatory signature. Clearance of p21high cells reduces inflammation and alleviates age-related transcriptomic signatures of various tissues. These findings demonstrate the feasibility of healthspan extension in mice and indicate p21high cells as a therapeutic target for healthy aging.

Psilocybin Facilitates Fear Extinction: Importance of Dose, Context, and Serotonin Receptors.

A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, although these changes were sensitive to dose. Analysis of sex differences showed that females may respond to a narrower range of doses than males. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Cotreatment with a 5-HT2A receptor antagonist blocked psilocybin's effects for extinction, extinction retention, and fear renewal, whereas 5-HT1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.