The clinical utility of a glaucoma polygenic risk score in four population-based European-ancestry cohorts.

OBJECTIVE: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DESIGN: Secondary analysis of four prospective population-based studies. PARTICIPANTS: We included four European-ancestry cohorts: the United States (US) based Nurses' Health Study (NHS), NHS2, and the Health Professionals Follow-up Study, and the Rotterdam Study (RS) in the Netherlands. The US cohorts included female nurses and male health professionals aged 55+ years. The RS included residents aged 45 years or older living in Rotterdam, the Netherlands. METHODS: PRS weights were estimated by applying the Lassosum method on imputed genotype and phenotype data from the UK-Biobank. This resulted in 144,020 variants, single nucleotide polymorphism (SNPs) and indels, with non-zero betas that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C-statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. MAIN OUTCOME MEASURES: The relative risk for POAG and Harrell's C-statistic (the equivalent of an area-under-the-curve for longitudinal models). RESULTS: Among 1,046 cases and 38,809‬ controls, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08, 5.18) in the US cohorts, and 4.89 (2.93, 8.17) in the Rotterdam Study, compared with participants with median genetic risk (3rd quintile). In restricted cubic spline analyses, the relation between continuous PRS and POAG risk increased exponentially in the US and Rotterdam cohorts (Pspline<0.05). Combining age, sex, intraocular pressure >25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (0.73, 0.75). Adding the PRS to this model improved the concordance to 0.82 (0.80, 0.84). In a meta-analysis of all cohorts, cases in the highest tertile had a larger cup-disc ratio at diagnosis, by 0.11 (0.07, 0.15), and a 2.07-fold increased risk of requiring glaucoma surgery (1.19, 3.60). CONCLUSIONS: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.

Comparing barriers to early stage diagnosis of hepatocellular carcinoma between safety net hospitals and academic medical centers: An analysis from the United States Safety-Net Collaborative.

BACKGROUND AND OBJECTIVES: Early detection of hepatocellular carcinoma (HCC) is associated with improved survival. However, a greater proportion of patients treated at safety net hospitals (SNHs) present with late-stage disease compared to those at academic medical centers (AMCs). This study aims to identify barriers to diagnosis of HCC, highlighting differences between SNHs and AMCs. METHODS: The US Safety Net Collaborative-HCC database was queried. Patients were stratified by facility of diagnosis (SNH or AMC). Patient demographics and HCC screening rates were examined. The primary outcome was stage at diagnosis (AJCC I/II-"early"; AJCC III/IV-"late"). RESULTS: 1290 patients were included; 50.2% diagnosed at SNHs and 49.8% at AMCs. At SNHs, 44.4% of patients were diagnosed late, compared to 27.6% at AMCs. On multivariable regression, Black race was associated with late diagnosis in both facilities (SNH: odds ratio 1.96, p = 0.03; AMC: 2.27, <0.01). Screening was associated with decreased odds of late diagnosis (SNH: 0.46, p = 0.04; AMC: 0.37, p < 0.01). CONCLUSIONS: Black race was associated with late diagnosis of HCC, while screening was associated with early diagnosis across institutional types. These results suggest socially constructed racial bias in screening and diagnosis of HCC. Screening efforts targeting SNH patients and Black patients at all facilities are essential to reduce disparities.

Maternal Placental Growth Factor (PlGF) levels, sonographic placental parameters, and outcomes of IVF pregnancies with and without embryo trophectoderm biopsy.

PURPOSE: In vitro fertilization (IVF) is associated with abnormal trophoblast invasion and resultant decreased levels of circulating placental biomarkers such as placental growth factor (PlGF). Our objective was to evaluate maternal serum levels of second/third trimester PlGF, sonographic placental parameters, and clinical outcomes among IVF frozen embryo transfer (FET) pregnancies with and without embryo trophectoderm biopsy. METHODS: This was a retrospective study of pregnant patients who conceived using a single frozen embryo transfer (FET) and gave birth between 30 January 2018 and 31 May 2021. We compared PlGF levels, sonographic placental parameters, and clinical outcomes between FET with biopsy and FET without biopsy groups. RESULTS: The median PlGF level was 614.5 pg/mL (IQR 406-1020) for FET pregnancies with biopsy, and 717.0 pg/mL (IQR 552-1215) for FET pregnancies without biopsy. The adjusted mean difference was 190.9 pg/mL lower in the FET biopsy group (95% CI, -410.6, 28.8; p = 0.088). There were no statistically significant differences in placental parameters or clinical pregnancy outcomes. CONCLUSION: This exploratory study demonstrated a possible trend toward lower maternal serum PlGF in the pregnancies conceived with FET using a biopsied embryo. Further investigation is warranted into the potential placental health effects of trophectoderm biopsy.

A Cross Sectional Survey of Factors Related to Cannabis Use as a Sleep Aid Among Canadian Cancer Survivors.

OBJECTIVES: Poor sleep is a common side effect of cancer. Cannabis is increasingly used to manage cancer treatment-related symptoms, including sleep. This study investigated factors related to cannabis use for sleep among Canadian cancer survivors. METHOD: Adult Canadian cancer survivors (N = 940) were recruited via the Angus Reid Institute and completed an online, cross-sectional survey. Univariate and multiple binomial logistic regression models identified factors associated with cannabis use for sleep. RESULTS: Of the participants (Mage = 64.5 yrs; Women = 51.1%; White = 92.9%), 25.1% (n = 236) currently use cannabis for sleep. Participants were at greater odds of using cannabis for sleep if they identified as a gender other than man or woman (AOR = 11.132), were diagnosed with multiple medical conditions (2:AOR = 1.988; 3+:AOR = 1.902), two psychological conditions (AOR = 2.171), multiple sleep disorders (AOR = 2.338), insomnia (AOR = 1.942), bone (AOR = 6.535), gastrointestinal (AOR = 4.307), genitourinary (AOR = 2.586), hematological (AOR = 4.739), or an unlisted cancer (AOR = 3.470), received hormone therapy only (AOR = 3.054), drink heavily (AOR = 2.748), or had mild insomnia (AOR = 1.828). Older participants (AOR=.972) and those with sleep apnea were less likely to use cannabis for sleep (AOR=.560). CONCLUSION: Given its prevalence, research is needed to understand how factors associated with cannabis use as a sleep aid among Canadian cancer survivors may influence its use and effectiveness and whether these factors are barriers to accessing evidence-based treatments.

Cancer-associated DNA Hypermethylation of Polycomb Targets Requires DNMT3A Dual Recognition of Histone H2AK119 Ubiquitination and the Nucleosome Acidic Patch.

During tumor development, promoter CpG islands (CGIs) that are normally silenced by Polycomb repressive complexes (PRCs) become DNA hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) catalyze CpG methylation at PRC-regulated regions remains unclear. Here we report a cryo-EM structure of the DNMT3A long isoform (DNMT3A1) N-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine 119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 N-terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Furthermore, aberrant redistribution of DNMT3A1 to Polycomb target genes inhibits their transcriptional activation during cell differentiation and recapitulates the cancer-associated DNA hypermethylation signature. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for countering promoter CGI DNA hypermethylation, a major molecular hallmark of cancer.

Efficacy and Safety of Cell-based Immunotherapy in The Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma - A Systematic Review and Meta-analysis.

BACKGROUND: Recurrent/Metastatic Nasopharyngeal Carcinoma (RM-NPC) remains difficult to treat and contributes to considerable mortality. The first-line treatment for RM-NPC is Gemcitabine and Cisplatin and second-line treatment options differ. The endemic variant of NPC is associated with Epstein-Barr Virus (EBV). Therefore, Cell-based Immunotherapy (CBI) targeting EBV-specific RM-NPC may be effective. METHODS: We systematically searched PubMed, Embase and the Cochrane Library for randomised or observational studies investigating the efficacy and safety of CBI in the treatment of RM-NPC. We performed all meta-analyses using the random-effects model. Studies were further stratified by endemicity, nature of disease and drug type to investigate for potential between-study heterogeneity and additional pre-specified tests were employed to assess for publication bias. RESULTS: We screened 1,671 studies and included 13 studies with 403 participants in the systematic review, of which nine studies were eligible for meta-analysis. The use of CBI monotherapy as second or subsequent line treatment for EBV-positive RM-NPC revealed an ORR of 10 % (95 %CI = 3 %-29 %), median PFS of 2.37 months (95 %CI = 1.23-3.51) and median OS of 10.16 months (95 %CI = 0.67-19.65). For EBV-specific Cytotoxic T-Lymphocyte monotherapy, the pooled PD rate was 54 % (95 %CI = 9 %-93 %), SD rate was 22 % (95 %CI = 2 %-75 %) and incidence rate of any grade adverse events was 45 %. For Dendritic Cell monotherapy, a PD rate of 80 % (95 % CI = 29 %-98 %), SD rate of 11 % (95 % CI = 0 %-82 %) and incidence rate of any grade adverse events of 29 % was achieved. CONCLUSION: CBI monotherapy demonstrates some activity in pre-treated RM-NPC. More trials are needed to better understand how to integrate CBI into RM-NPC care.

Improving care in lung cancer surgery: a review of quality measures and evolving standards.

PURPOSE OF REVIEW: Lung cancer is the leading cause of cancer-related death in the United States. Pulmonary resection, in addition to perioperative systemic therapies, is a cornerstone of treatment for operable patients with early-stage and locoregional disease. In recent years, increased emphasis has been placed on surgical quality metrics: specific and evidence-based structural, process, and outcome measures that aim to decrease variation in lung cancer care and improve long term outcomes. These metrics can be divided into potential areas of intervention or improvement in the preoperative, intraoperative, and postoperative phases of care and form the basis of guidelines issued by organizations including the National Cancer Center Network (NCCN) and Society of Thoracic Surgeons (STS). This review focuses on established quality metrics associated with lung cancer surgery with an emphasis on the most recent research and guidelines. RECENT FINDINGS: Over the past 18 months, quality metrics across the peri-operative care period were explored, including optimal invasive mediastinal staging preoperatively, the extent of intraoperative lymphadenectomy, surgical approaches related to minimally invasive resection, and enhanced recovery pathways that facilitate early discharge following pulmonary resection. SUMMARY: Quality metrics in lung cancer surgery is an exciting and important area of research. Adherence to quality metrics has been shown to improve overall survival and guidelines supporting their use allows targeted quality improvement efforts at a local level to facilitate more consistent, less variable oncologic outcomes across centers.

Early change in fatigue, insomnia, and cognitive impairment and symptom severity 3 years post-treatment in breast cancer survivors.

PURPOSE: Breast cancer is the most common form of cancer among Canadian women. Survivorship challenges include fatigue, sleep disturbance, and cognitive impairment. This study examined (1) symptom trajectory from diagnosis to 3 years; (2) whether symptom change in the first 4 months was associated with prolonged difficulties after 3 years; and (3) which factors were associated with deterioration in symptoms during the first 4 months. METHODS: This prospective observational cohort study examined 53 women (Mage = 58.6, 96.2% White, 67.9% stage I) with newly diagnosed breast cancer over 3 years. Women completed assessments before starting treatment, 4 months, and 3 years after diagnosis. Three-way repeated-measures ANOVAs evaluated symptom trajectories. A repeated-measures mediation analysis was performed to determine if change from pre-treatment to 4 months accounted for change from pre-treatment to 3 years. A series of between-subjects ANOVAs were used to determine what variables significantly differed by deterioration status. RESULTS: Perceived cognitive impairment and fatigue increased linearly from diagnosis to 3 years. Change in fatigue in the first 4 months fully accounted for its change over 3 years. Insomnia severity and sleep quality deteriorated from diagnosis to 4 months, but returned to pre-treatment levels at 3 years. Those whose fatigue and cognitive ability deteriorated during the first 4 months were younger. CONCLUSION: Efforts to identify those who are at risk of experiencing fatigue, sleep disturbance, and cognitive impairment; monitor patients early after receiving a diagnosis; and provide targeted interventions may prevent long-term deterioration and improve well-being.

User-Centered Design and Usability of a Culturally Adapted Virtual Survivorship Care App for Chinese Canadian Prostate Cancer Survivors: Qualitative Descriptive Study.

BACKGROUND: Cultural adaptations of digital health innovations are a growing field. However, digital health innovations can increase health inequities. While completing exploratory work for the cultural adaptation of the Ned Clinic virtual survivorship app, we identified structural considerations that provided a space to design digitally connected and collective care. OBJECTIVE: This study used a community-based participatory research and user-centered design process to develop a cultural adaptation of the Ned Clinic app while designing to intervene in structural inequities. METHODS: The design process included primary data collection and qualitative analysis to explore and distill design principles, an iterative design phase with a multidisciplinary team, and a final evaluation phase with participants throughout the design process as a form of member checking and validation. RESULTS: Participants indicated that they found the final adapted prototype to be acceptable, appropriate, and feasible for their use. The changes made to adapt the prototype were not specifically culturally Chinese. Instead, we identified ways to strengthen connections between the survivor and their providers; improve accessibility to resources; and honor participants' desires for relationality, accountability, and care. CONCLUSIONS: We grounded the use of user-centered design to develop a prototype design that supports the acts of caring through digital technology by identifying and designing to resist structures that create health inequities in the lives of this community of survivors. By designing for collective justice, we can provide accessible, feasible, and relational care with digital health through the application of Indigenous and Black feminist ways of being and knowing.

Honoring the Care Experiences of Chinese Canadian Survivors of Prostate Cancer to Cultivate Cultural Safety and Relationality in Digital Health: Exploratory-Descriptive Qualitative Study.

BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed nonskin cancer for Canadian men and has one of the highest 5-year survival rates, straining systems to provide care. Virtual care can be one way to relieve this strain, but survivors' care needs and technology use are influenced by intersecting social and cultural structures. Cultural adaptation has been posited as an effective method to tailor existing interventions to better serve racialized communities, including Chinese men. However, cultural adaptations may inadvertently draw attention away from addressing structural inequities. OBJECTIVE: This study used qualitative methods to (1) explore the perceptions and experiences of Chinese Canadian PCa survivors with follow-up and virtual care, and (2) identify implications for the cultural adaptation of a PCa follow-up care app, the Ned (no evidence of disease) Clinic. METHODS: An axiology of relational accountability and a relational paradigm underpinned our phenomenologically informed exploratory-descriptive qualitative study design. A community-based participatory approach was used, informed by cultural safety and user-centered design principles, to invite Chinese Canadian PCa survivors and their caregivers to share their stories. Data were inductively analyzed to explore their unmet needs, common experiences, and levels of digital literacy. RESULTS: Unmet needs and technology preferences were similar to broader trends within the wider community of PCa survivors. However, participants indicated that they felt uncomfortable, unable to, or ignored when expressing their needs. Responses spoke to a sense of isolation and reflected a reliance on culturally informed coping mechanisms, such as "eating bitterness," and familial assistance to overcome systemic barriers and gaps in care. Moreover, virtual care was viewed as "better than nothing;" it did not change a perceived lack of focus on improving quality of life or care continuity in survivorship care. Systemic changes were identified as likely to be more effective in improving care delivery and well-being rather than the cultural adaptation of Ned for Chinese Canadians. Participants' desires for care reflected accessibility issues that were not culturally specific to Chinese Canadians. CONCLUSIONS: Chinese Canadian survivors are seeking to strengthen their connections in a health care system that provides privacy and accessibility, protects relationality, and promotes transparency, accountability, and responsibility. Designing "trickle-up" adaptations that address structural inequities and emphasize accessibility, relationality, and privacy may be more effective and efficient at improving care than creating cultural adaptations of interventions.

Navigating the management complexity in long-term asymptomatic immunodeficiency.

Background: Common variable immunodeficiency disorder (CVID) is a condition associated with recurrent infections and non-infectious outcomes, including lung disease like bronchiectasis and granulomatous and lymphocytic interstitial lung diseases (GLILD), autoimmune disease, enteropathy, and lymphoma. Treatment involves initiation of replacement immunoglobulin (Ig), which is a lifelong commitment. Prior to Ig replacement, life expectancy for patients with CVID was less than 15 years. With replacement Ig, it has improved to over 50 years. In most cases, patients present to a clinician with a history of recurrent infections, and treatment is indicated. However, in patients with asymptomatic disease, the best timing to start treatment can be difficult to determine. Case: We present a case of an otherwise healthy male who had an incidental diagnosis of CVID. Results: Workup revealed hypogammaglobulinemia for over 30 year. Discussion: Though successful in reducing infections, Ig replacement can come with many side effects, as well as a heavy medical burden to the patient and the healthcare system. It is also a big life adjustment, and can greatly affect a patient's quality of life. In the military, a diagnosis of an immunodeficiency, and the need for monthly intravenous immunoglobulin (IVIG) can be detrimental to deployment readiness, and a patient's military career. Risks and benefits need to be weighed prior to initiating Ig therapy.

Novel pharmacological developments in the management of paediatric inflammatory bowel disease: Time for guideline update - A narrative review.

AIM: The incidence of paediatric inflammatory bowel disease (IBD) continues to increase in both adults and children across the globe, with more than one third of the patients not responding to anti-tumour necrosis factor biologics and immune modulators. This narrative review provides an overview of novel pharmacological developments in the management of paediatric IBD, including new biological therapies. METHODS: A PubMed Medline search was performed to include randomised controlled trials, retrospective and prospective observational studies, and relevant case reports of children with IBD published between 2018 and January 2023. Guidelines and protocols from relevant paediatric and adult gastroenterology societies, such as the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organisation, were also included. Non-pharmacological treatments including therapeutic diets and faecal microbiota transplantation were outside the scope of this work. RESULTS: Early real-world evidence suggests that newer biologics and small molecules, such as anti-integrins, interleukin-12 and/or interleukin-23 inhibitors, Janus kinase and signal transducer and activator of transcription proteins inhibitors, are safe and effective in adult patients with IBD, with promising growing evidence for paediatric IBD. CONCLUSION: While many developments have been achieved with novel pharmacological treatments to manage IBD, ongoing research is required to confirm their effectiveness and safety in the paediatric age. Extending the licence of novel treatments to children will be crucial to tackle the increasing loss of response to conventional treatments. International guidelines will require timely updating to incorporate novel treatments within the existing protocols.

A cross-sectional survey of the prevalence and patterns of using cannabis as a sleep aid in Canadian cancer survivors.

PURPOSE: Poor sleep is one of the most common side effects of cancer. It can persist for years beyond treatment and negatively impact quality of life and health. Cannabis is increasingly used to manage cancer treatment-related symptoms, including sleep. This study investigated the use and perceived effects of cannabis as a sleep aid in Canadian cancer survivors. METHODS: Adult Canadian cancer survivors (N = 1464) were recruited via the Angus Reid Institute and completed an online, cross-sectional survey including the Insomnia Severity Index and questions about cannabis use for sleep. Standard descriptive statistics, such as means, standard deviations, and ranges were produced for measured variables to assess the ways cancer survivors use cannabis for sleep. Frequencies were tabulated for categorical and ordinal variables. RESULTS: On average, participants (Mage = 61.1 years; Women = 50%: Men = 48%) received their cancer diagnosis 12.5 years prior. Of participants, 23.5% (n = 344) currently use cannabis as a sleep aid, with reported benefits including relaxation, reduced time to fall asleep, fewer nocturnal awakenings and improved sleep quality. Two thirds (68.3%, n = 235) only began using cannabis for sleep after their cancer diagnosis. Over a third of participants (36.3%, n = 125) use cannabis as a sleep aid every day. Among the 344, the most common other reasons for using cannabis were pain (31.4%, n = 108), recreational use (24.4%, n = 84), and anxiety (12.5%, n = 43). CONCLUSIONS: Given the prevalence and potential impact, research is needed to examine the actual efficacy of cannabis as a sleep aid. IMPLICATIONS FOR CANCER SURVIVORS: It is important that cancer survivors have information on methods to help their sleep to avoid impairments to quality of life and health.

Breast cancer surgical decision-making. Experiences of Non-Caucasian women globally. A qualitative systematic review.

OBJECTIVES: To perform a qualitative systematic review exploring the influencing factors within the surgical decision-making (SDM) processes following a breast cancer diagnosis in non-caucasian women globally. STUDY DESIGN: Qualitative systemic review following PRISMA guidelines. METHODS: A comprehensive search strategy was applied to four databases. 5243 papers were screened using a composed inclusion and exclusion criteria resulting in 10 total papers to be included. These papers underwent JBI quality assessment and ConQual assessment to ensure strength in validation, reliability, and quality. RESULTS: Six main overarching themes relating to SDM were determined: fear, information, patient-doctor relationship, wellbeing, external influences, and culture. All ethnicities experienced fear in one way. Misinformation was widely experienced in concordance with either a lack of education (Iranian and Ghanian women) or language barriers (immigrant populations). Trust was overarching in all patient-doctor relationships, some being overshadowed by an authoritative dynamic in Ghanian and Iranian women. Well-being, both psychological and body image was noted in all but the Ghanian and Iranian women. Every ethnicity experienced external influences involving either others, time or cost. Lastly, cultural expectations and beliefs of the doctor was present in all native or immigrant Asian communities. CONCLUSIONS: The study identified several factors which were common between ethnicities, notably multifactorial fear, well-being factors, opinions and trust of others, and timing. Conversely, information availability and the nature of patient-doctor relationships varied widely between ethnicities. The study has identified some realistic and achievable focus areas for practice improvement, but also notes the challenges of changing long-established cultural norms.

A reduction in hospital length of stay reduces costs for colorectal surgery: an economic evaluation of the National Surgical Quality Improvement Program in Singapore.

PURPOSE: In 2017, the National Surgical Quality Improvement Program (NSQIP) was introduced in the Department of Colorectal Surgery at Singapore General Hospital as a pilot quality improvement initiative. This study aimed to examine the cost-effectiveness of NSQIP by evaluating its effects on surgical outcomes, length of stay (LOS), and costs. METHODS: We retrospectively reviewed patients undergoing colorectal surgery (2017-2020). Patients were divided into two cohorts: pre-NSQIP (2017-2018) and post-NSQIP (2019-2020). Outcomes evaluated were 30-day postoperative complications, LOS, and costs. Total cost-savings from NSQIP intervention's impact on LOS were estimated using a decision model with a one-way sensitivity analysis. Multivariate logistic regression was performed to identify factors for prolonged LOS. RESULTS: 1905 patients underwent colorectal surgery, with 996 in the pre-NSQIP cohort and 909 in the post-NSQIP cohort. A significant reduction in overall postoperative complications of 4.7% was observed in the post-NSQIP cohort (36.5% vs. 31.8%, p = 0.029). Patients in the post-NSQIP cohort had a shorter median LOS (8.0 vs. 6.0 days, p < 0.001). The implementation of NSQIP resulted in an 8.5% decrease in prolonged LOS > 6 days (p < 0.001), saving S$0.31 million on LOS. Total costs per case were reduced by 20.8% following NSQIP (S$39,539.05 vs. S$31,311.93, p < 0.001). CONCLUSION: Implementing NSQIP has significantly reduced overall postoperative complications, LOS, and costs and achieved cost savings following colorectal surgery.

Severe Immune-Mediated Colitis Induced by Checkpoint Inhibitors in an Adolescent With Lynch Syndrome.

Lynch syndrome is a hereditary colorectal cancer caused by mutations in DNA mismatch repair genes. Immune checkpoint therapies have shown promise in treating Lynch syndrome-associated cancers but can lead to immune-related adverse events, such as colitis. In this report, we present a severe case of immune-mediated colitis (IMC) induced by checkpoint inhibitors in a young patient with Lynch syndrome. This 20-year-old male with Lynch syndrome and a history of glioblastoma underwent dual checkpoint therapy, after initial treatment with systemic steroids. Despite this, his condition worsened, resulting in complications, such as toxic megacolon and small bowel obstruction. He was subjected to various treatments, including infliximab and vedolizumab, but ultimately required total abdominal colectomy with J-pouch creation. This case highlights the challenges of managing severe IMC in patients with Lynch syndrome. The patient's suboptimal response to standard treatments and the development of complications emphasizes the need for a better understanding and alternative therapeutic options for IMC. This case also calls into question whether a subset of patients with IMC should be "treated to target," even though the current standard of care for IMC is guided by symptom response, and if so, further research is necessary to identify potential therapeutic targets. Further research is also required to understand the mechanisms of IMC and develop effective treatment strategies tailored to patients with Lynch syndrome and immune-related adverse events.

Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1.

SUV420H1 di- and tri-methylates histone H4 lysine 20 (H4K20me2/H4K20me3) and plays crucial roles in DNA replication, repair, and heterochromatin formation. It is dysregulated in several cancers. Many of these processes were linked to its catalytic activity. However, deletion and inhibition of SUV420H1 have shown distinct phenotypes, suggesting that the enzyme likely has uncharacterized non-catalytic activities. Our cryoelectron microscopy (cryo-EM), biochemical, biophysical, and cellular analyses reveal how SUV420H1 recognizes its nucleosome substrates, and how histone variant H2A.Z stimulates its catalytic activity. SUV420H1 binding to nucleosomes causes a dramatic detachment of nucleosomal DNA from the histone octamer, which is a non-catalytic activity. We hypothesize that this regulates the accessibility of large macromolecular complexes to chromatin. We show that SUV420H1 can promote chromatin condensation, another non-catalytic activity that we speculate is needed for its heterochromatin functions. Together, our studies uncover and characterize the catalytic and non-catalytic mechanisms of SUV420H1, a key histone methyltransferase that plays an essential role in genomic stability.

Structural basis of histone H2A lysine 119 deubiquitination by Polycomb repressive deubiquitinase BAP1/ASXL1.

Histone H2A lysine 119 (H2AK119Ub) is monoubiquitinated by Polycomb repressive complex 1 and deubiquitinated by Polycomb repressive deubiquitinase complex (PR-DUB). PR-DUB cleaves H2AK119Ub to restrict focal H2AK119Ub at Polycomb target sites and to protect active genes from aberrant silencing. The PR-DUB subunits (BAP1 and ASXL1) are among the most frequently mutated epigenetic factors in human cancers. How PR-DUB establishes specificity for H2AK119Ub over other nucleosomal ubiquitination sites and how disease-associated mutations of the enzyme affect activity are unclear. Here, we determine a cryo-EM structure of human BAP1 and the ASXL1 DEUBAD in complex with a H2AK119Ub nucleosome. Our structural, biochemical, and cellular data reveal the molecular interactions of BAP1 and ASXL1 with histones and DNA that are critical for restructuring the nucleosome and thus establishing specificity for H2AK119Ub. These results further provide a molecular explanation for how >50 mutations in BAP1 and ASXL1 found in cancer can dysregulate H2AK119Ub deubiquitination, providing insight into understanding cancer etiology.