Phase 4 Multinational Multicenter Retrospective and Prospective Real-World Study of Nivolumab in Recurrent and Metastatic Squamous Cell Carcinoma of the Head and Neck.

This study examined the real-world use of nivolumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). This was a multinational retrospective study (VOLUME) assessing treatment effectiveness and safety outcomes and a prospective study (VOLUME-PRO) assessing HRQoL and patient-reported symptoms. There were 447 and 51 patients in VOLUME and VOLUME-PRO, respectively. Across both studies, the median age was 64.0 years, 80.9% were male, and 52.6% were former smokers. Clinical outcomes of interest included real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). The median rwOS was 9.2 months. Among patients with at least one assessment, 21.7% reported their best response as 'partial response', with 3.9% reporting 'complete response'. The median duration of response (DoR) and median rwPFS were 11.0 months and 3.9 months, respectively. At baseline, VOLUME-PRO patients reported difficulties relating to fatigue, physical and sexual functioning, dyspnea, nausea, sticky saliva, dry mouth, pain/discomfort, mobility, and financial difficulties. There were improvements in social functioning and financial difficulties throughout the study; however, no other clinically meaningful changes were noted. No new safety concerns were identified. This real-world, multinational, multicenter, retrospective and prospective study supports the effectiveness and safety of nivolumab for R/M SCCHN patients.

Self-Esteem Mediates the Effects of Loneliness on Problematic Alcohol Use.

Loneliness has been associated with problematic alcohol use, but it is not known whether self-perceptions mediate this relationship. In this study, the general population in China (N = 1123) and Germany (N = 1018) was surveyed to assess whether self-esteem and self-efficacy mediate the effect of loneliness on problematic alcohol use in two culturally distinct environments. Multiple regression analysis demonstrated that higher AUDIT scores were negatively associated with self-esteem (b = -0.08, p < .001). Self-esteem mediated the effect of loneliness on AUDIT score (indirect effect: 0.06, CI: 0.03 - 0.10, p < .001), while self-efficacy did not (indirect effect: 0.02, CI: -0.003 - 0.05, p = .10). These findings suggest that self-esteem explains the relationship between loneliness and problematic alcohol use. As self-esteem may be more modifiable than external social factors, these results have positive practical implications for alcohol use disorder treatment strategies.

Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes.

BACKGROUND: Amongst risk alleles associated with late-onset Alzheimer's disease (AD), those that converged on the regulation of microglia activity have emerged as central to disease progression. Yet, how canonical amyloid-ß (Aß) and tau pathologies regulate microglia subtypes during the progression of AD remains poorly understood. METHODS: We use single-cell RNA-sequencing to profile microglia subtypes from mice exhibiting both Aß and tau pathologies across disease progression. We identify novel microglia subtypes that are induced in response to both Aß and tau pathologies in a disease-stage-specific manner. To validate the observation in AD mouse models, we also generated a snRNA-Seq dataset from the human superior frontal gyrus (SFG) and entorhinal cortex (ERC) at different Braak stages. RESULTS: We show that during early-stage disease, interferon signaling induces a subtype of microglia termed Early-stage AD-Associated Microglia (EADAM) in response to both Aß and tau pathologies. During late-stage disease, a second microglia subtype termed Late-stage AD-Associated Microglia (LADAM) is detected. While similar microglia subtypes are observed in other models of neurodegenerative disease, the magnitude and composition of gene signatures found in EADAM and LADAM are distinct, suggesting the necessity of both Aß and tau pathologies to elicit their emergence. Importantly, the pattern of EADAM- and LADAM-associated gene expression is observed in microglia from AD brains, during the early (Braak II)- or late (Braak VI/V)- stage of the disease, respectively. Furthermore, we show that several Siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of Siglec-10, the human orthologue of Siglecg, is progressively elevated in an AD-stage-dependent manner but not shown in non-AD tauopathy. CONCLUSIONS: Using scRNA-Seq in mouse models bearing amyloid-ß and/or tau pathologies, we identify novel microglia subtypes induced by the combination of Aß and tau pathologies in a disease stage-specific manner. Our findings suggest that both Aß and tau pathologies are required for the disease stage-specific induction of EADAM and LADAM. In addition, we revealed Siglecs as biomarkers of AD progression and potential therapeutic targets.

How to Effectively Leverage Twitter as a Medical Student.

Twitter provides students with a centralized platform to learn about numerous opportunities within radiology. The platform can be immensely beneficial to students by providing opportunities to learn, network, connect with mentors, and find events while also preparing applicants for The Match. Having a prominent Twitter presence can pay dividends in the long term throughout one's training. We aim to provide a guide for medical students on how to create a Twitter account and best utilize the platform.

Evaluating the Public Climate School-A School-Based Programme to Promote Climate Awareness and Action in Students: Protocol of a Cluster-Controlled Pilot Study.

Introduction: School-based programmes may promote knowledge and skills required to address climate change and better health and well-being in adolescents, yet evidence of their effectiveness is limited. In preparation for evaluating the Public Climate School, a school-based intervention to promote climate awareness and action in adolescents, we conduct a pilot study intended to assess procedures for participant recruitment, retention, and data collection, data quality issues and to provide preliminary parameter estimates to guide sample size calculations. Methods and analysis: This unblinded, cluster-controlled pilot study targets students in twelve classes from grades seven to thirteen in German public schools. Seven and five classes were allocated to the intervention and waitlist control arms, respectively. The intervention consisted of (1) live lessons on YouTube, (2) climate-related challenges of the day, (3) workshops and (4) peer exchange sessions. Waitlist control classes participated three weeks later. Measures included the proportion of students completing baseline and follow-up surveys, a comparison of baseline characteristics between students in the retained subsample and those lost to follow-up, proportions of students completing online and paper-pencil-based surveys and problems during data collection based on information reported by teachers. Data quality was assessed as proportions of missing data, associations between missingness and sociodemographic measures using logistic regression models and basic psychometric properties of scales including ceiling effects and internal consistency. Intentions to reduce one's ecological footprint, the primary outcome, and all secondary outcomes for effect estimation were assessed one week pre- and post-intervention from November to December 2021 using items adapted from internationally used instruments and will be investigated using generalised linear mixed models and intention-to-treat analyses. Conclusions: The pilot study will lay the methodological groundwork for a large-scale cluster-randomised effectiveness and process evaluation of the Public Climate School. If proven effective and rolled out more broadly, the Public Climate School has the potential to contribute meaningfully to national climate mitigation and adaptation efforts by reaching a substantial share of adolescents in public schools, including those traditionally less involved in climate action.

Cancer risk among firefighters and police in the Ontario workforce.

OBJECTIVE: Firefighters and police often work in high-stress, complex environments with known and suspected carcinogenic exposures. We aimed to characterise cancer incidence among firefighters and police. METHODS: The Occupational Disease Surveillance System (ODSS) was used to identify workers employed as firefighters or police in Ontario. A cohort of workers were identified using lost-time workers' compensation claims data and followed for cancer in the Ontario Cancer Registry (1983-2020). Cox proportional hazard models were used to estimate HRs and 95% CIs for primary site-specific cancer diagnoses adjusted for age at start of follow-up, birth year and sex. RESULTS: A total of 13 642 firefighters and 22 595 police were identified in the cohort. Compared with all other workers in the ODSS, firefighters and police had increased risk of prostate cancer (firefighters: HR=1.43, 95% CI 1.31 to 1.57; police: HR=1.47, 95% CI 1.35 to 1.59), colon cancer (firefighters: HR=1.39, 95% CI 1.19 to 1.63; police: HR=1.39, 95% CI 1.21 to 1.60) and skin melanoma (firefighters: HR=2.38, 95% CI 1.99 to 2.84; police: HR=2.27, 95% CI 1.96 to 2.62). Firefighters also had increased risk of cancer of the pancreas, testis and kidney, as well as non-Hodgkin's lymphoma and leukaemia. Police had increased risk of thyroid, bladder and female breast cancer. When compared directly with the police, firefighters had an elevated risk of mesothelioma and testicular cancer. CONCLUSIONS: Firefighters and police demonstrated some similar as well as some unique cancer risks. Findings from this larger worker population may have important implications for workplace and policy-level changes to improve preventative measures and reduce potential exposures to known carcinogenic hazards.

Poor health disparities among racialized students in a Canadian university.

OBJECTIVE: The short report aims to examine differences in self-rated general health across racialized post-secondary students at a university in Ontario, Canada. METHODS: Binary logistic regression analysis was used to examine poor health as an outcome among racialized students as whole, as well as across Asian, South Asian, Afro-Caribbean and Middle Eastern student groups in comparison to white Caucasian post-secondary students. RESULTS: After adjusting for several covariates, racialized students as a whole had 2.43 times the odds of reporting poor general health compared to white Caucasian students. Asian (OR = 2.77; CI = 1.84-4.18; p < 0.05) and South Asian (OR = 2.52; CI = 1.56-4.08; p < 0.05) students were significantly more likely to report poor health compared to white Caucasian students. CONCLUSION: The findings call for further attention to the health needs of racialized post-secondary students living in Canada and creating campuses where diverse student populations feel safe and systemically included.

Expansion of myeloid-derived suppressor cells contributes to metabolic osteoarthritis through subchondral bone remodeling.

BACKGROUND: Osteoarthritis (OA) subsequent to acute joint injury accounts for a significant proportion of all arthropathies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells classically known for potent immune-suppressive activity; however, MDSCs can also differentiate into osteoclasts. In addition, this population is known to be expanded during metabolic disease. The objective of this study was to determine the role of MDSCs in the context of OA pathophysiology. METHODS: In this study, we examined the differentiation and functional capacity of MDSCs to become osteoclasts in vitro and in vivo using mouse models of OA and in MDSC quantitation in humans with OA pathology relative to obesity status. RESULTS: We observed that MDSCs are expanded in mice and humans during obesity. MDSCs were expanded in peripheral blood of OA subjects relative to body mass index and in mice fed a high-fat diet (HFD) compared to mice fed a low-fat diet (LFD). In mice, monocytic MDSC (M-MDSC) was expanded in diet-induced obesity (DIO) with a further expansion after destabilization of the medial meniscus (DMM) surgery to induce post-traumatic OA (PTOA) (compared to sham-operated controls). M-MDSCs from DIO mice had a greater capacity to form osteoclasts in culture with increased subchondral bone osteoclast number. In humans, we observed an expansion of M-MDSCs in peripheral blood and synovial fluid of obese subjects compared to lean subjects with OA. CONCLUSION: These data suggest that MDSCs are reprogrammed in metabolic disease, with the potential to contribute towards OA progression and severity.

Systemic Therapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma- A Systematic Review and Meta-Analysis.

BACKGROUND: The most effective regimen is unclear for patients with recurrent or metastatic head and neck squamous cell carcinomas (R/M HNSCC). We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating only systemic therapy for R/M HNSCC. METHODS: This systematic review followed PRISMA and the Cochrane Collaboration Handbook for Systematic Reviews of Interventions. Endpoints included overall survival (OS), progression-free survival (PFS) and overall response rates (ORR). RESULTS: 55 RCTs from 1990-November 2019 qualified for review (n=12132). Only PD-1/PDL-1 inhibitors increased OS in R/M HNSCC platinum-resistant disease against their control (HR = 0·79, 95%CI 0·70-0.90, p<0·001), especially for PD-L1 ≥ 1% expressing tumours (HR = 0·72, 95%CI 0·60-0·86, p<0·001). PFS was prolonged for anti-EGFR agents against methotrexate when used in a second line setting (HR = 0·74, 95 %CI 0·62-0·87, p=0·001), and when cetuximab (HR = 0·60, 95%CI 0·49-0·72, p<0·0001) and panitumumab (HR = 0·76, 95%CI 0·65-0·89, p=0·001) were introduced to platinum-based regimens for first-line treatment. CONCLUSIONS: PD-1/PD-L1 inhibitors may represent the future of R/M HNSCC treatment. However, EGFR inhibitors may still play improve clinical outcomes.

The Epigenomics of Pituitary Adenoma.

Background: The vast majority of pituitary tumors are benign and behave accordingly; however, a fraction are invasive and are more aggressive, with a very small fraction being frankly malignant. The cellular pathways that drive transformation in pituitary neoplasms are poorly characterized, and current classification methods are not reliable correlates of clinical behavior. Novel techniques in epigenetics, the study of alterations in gene expression without changes to the genetic code, provide a new dimension to characterize tumors, and may hold implications for prognostication and management. Methods: We conducted a review of primary epigenetic studies of pituitary tumors with a focus on histone modification, DNA methylation, and transcript modification. Results: High levels of methylation have been identified in invasive and large pituitary tumors. DNA methyltransferase overexpression has been detected in pituitary tumors, especially in macroadenomas. Methylation differences at CpG sites in promoter regions may distinguish several types of tumors from normal pituitary tissue. Histone modifications have been linked to increased p53 expression and longer progression-free survival in pituitary tumors; sirtuins are expressed at higher values in GH-expressing compared to nonfunctional adenomas and correlate inversely with size in somatotrophs. Upregulation in citrullinating enzymes may be an early pathogenic marker of prolactinomas. Numerous genes involved with cell growth and signaling show altered methylation status for pituitary tumors, including cell cycle regulators, components of signal transduction pathways, apoptotic regulators, and pituitary developmental signals. Conclusions: The limited clinical predictive capacity of the current pituitary tumor classification system suggests that tumor subclasses likely remain to be discovered. Ongoing epigenetic studies could provide a basis for adding methylation and/or acetylation screening to standard pituitary tumor workups. Identifying robust correlations between tumor epigenetics and corresponding histological, radiographic, and clinical course information could ultimately inform clinical decision-making.

Equally Interchangeable? How Sex and Gender Affect Transplantation.

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for recognition of these inequities and the development of policies that have the potential to ensure that girls and women have equitable access to transplantation.

Cell cycle arrest in replicative senescence is not an immediate consequence of telomere dysfunction.

In replicative senescence, cells with critically-short telomeres activate a DNA-damage response leading to cell-cycle arrest, while those without telomere dysfunction would be expected to cycle normally. However, population growth declines more gradually than such a simple binary switch between cycling and non-cycling states would predict. We show here that late-passage cultures of human fibroblasts are not a simple mixture of cycling and non-cycling cells. Rather, although some cells had short cycle times comparable to those of younger cells, others continued to divide but with greatly extended cycle times, indicating a more-gradual approach to permanent arrest. Remarkably, in late passage cells, the majority showed prominent DNA-damage foci positive for 53BP1, yet many continued to divide. Evidently, the DNA-damage-response elicited by critically-short telomeres is not initially strong enough for complete cell-cycle arrest. A similar continuation of the cell cycle in the face of an active DNA-damage response was also seen in cells treated with a low dose of doxorubicin sufficient to produce multiple 53BP1 foci in all nuclei. Cell cycle checkpoint engagement in response to DNA damage is thus weaker than generally supposed, explaining why an accumulation of dysfunctional telomeres is needed before marked cell cycle elongation or permanent arrest is achieved.

Mixing old and young: enhancing rejuvenation and accelerating aging.

Donor age and recipient age are factors that influence transplantation outcomes. Aside from age-associated differences in intrinsic graft function and alloimmune responses, the ability of young and old cells to exert either rejuvenating or aging effects extrinsically may also apply to the transplantation of hematopoietic stem cells or solid organ transplants. While the potential for rejuvenation mediated by the transfer of youthful cells is currently being explored for therapeutic applications, aspects that relate to accelerating aging are no less clinically significant. Those effects may be particularly relevant in transplantation with an age discrepancy between donor and recipient. Here, we review recent advances in understanding the mechanisms by which young and old cells modify their environments to promote rejuvenation- or aging-associated phenotypes. We discuss their relevance to clinical transplantation and highlight potential opportunities for therapeutic intervention.

The Impact of Sex on Alloimmunity.

Transplantation outcomes are known to be affected by multiple factors, including donor and recipient sex. Aside from the physiological characteristics of male and female donor allografts, accumulating evidence suggests that additional features underlie sex-specific immune responses that affect graft survival. We discuss here aspects of innate and adaptive alloimmunity that are specific to males and females in the context of underlying genetic and hormonal factors. These differences likely contribute to the observed disparities in graft survival. Understanding these features in more detail may lead to improved strategies for optimizing the results of organ transplantation.

Induction chemotherapy for squamous cell carcinomas of the oral cavity: A cumulative meta-analysis.

UNLABELLED: Induction chemotherapy (ICT) is a controversial treatment for head and neck squamous cell carcinomas (HNSCC). Despite numerous randomized controlled trials (RCTs), a majority do not have enough statistical power alone to conclude ICT's treatment value among oral squamous carcinoma patients (OSCC) since many addressed HNSCC as one entity instead of by specific subtypes. By performing a systematic review and cumulative meta-analysis, we aim to determine the benefits of ICT in OSCC therapy. A literature search identified for RCTs comparing OSCC patients who received ICT against those without. Log-hazard ratio, and relative risk were used for comparison. Heterogeneity was determined using the I(2) statistic package. The primary endpoint was overall survival (OS), followed by disease-free survival (DFS), locoregional recurrence (LRR) and distant metastasis (DM) as secondary endpoints. RESULTS: 27 randomized trials were included for analysis (n=2872 patients). The shortest median follow-up was 15months whereas the longest was 11.5years. ICT does not improve OS (HR=0.947, 95% CI 0.85-1.05, p=0.318), DFS (RR=1.05, 95% CI 0.92-1.21, p=0.462) and DM (RR=0.626, CI 95% 0.361-1.086, p=0.096) compared to locoregional treatment alone. However, there was a significant improvement to LRR (RR=0.778, 95% CI 0.622-0.972, p=0.027). There is no evidence ICT improves survival outcomes for OSCC patients. However, ICT reduces locoregional recurrence of OSCC, which may need further verification.

The neuritic plaque facilitates pathological conversion of tau in an Alzheimer's disease mouse model.

A central question in Alzheimer's Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding ß-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aß-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau.

Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD).

Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.

Super-enhancers in the control of cell identity and disease.

Super-enhancers are large clusters of transcriptional enhancers that drive expression of genes that define cell identity. Improved understanding of the roles that super-enhancers play in biology would be afforded by knowing the constellation of factors that constitute these domains and by identifying super-enhancers across the spectrum of human cell types. We describe here the population of transcription factors, cofactors, chromatin regulators, and transcription apparatus occupying super-enhancers in embryonic stem cells and evidence that super-enhancers are highly transcribed. We produce a catalog of super-enhancers in a broad range of human cell types and find that super-enhancers associate with genes that control and define the biology of these cells. Interestingly, disease-associated variation is especially enriched in the super-enhancers of disease-relevant cell types. Furthermore, we find that cancer cells generate super-enhancers at oncogenes and other genes important in tumor pathogenesis. Thus, super-enhancers play key roles in human cell identity in health and in disease.

Selective inhibition of tumor oncogenes by disruption of super-enhancers.

Chromatin regulators have become attractive targets for cancer therapy, but it is unclear why inhibition of these ubiquitous regulators should have gene-specific effects in tumor cells. Here, we investigate how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition of the MYC oncogene in multiple myeloma (MM). BRD4 and Mediator were found to co-occupy thousands of enhancers associated with active genes. They also co-occupied a small set of exceptionally large super-enhancers associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impacted genes with super-enhancers, including MYC. Super-enhancers were found at key oncogenic drivers in many other tumor cells. These observations have implications for the discovery of cancer therapeutics directed at components of super-enhancers in diverse tumor types.