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Abstract Background Diabetes mellitus (DM) is identified as a negative prognostic indicator in hepatocellular carcinoma (HCC), though the basis for this is unknown. Methods This is a retrospective analysis of a prospectively collected database of 191 HCC patients treated at the University of Rochester Medical Center (URMC) with orthotopic liver transplantation between 1998–2008. Clinical characteristics were compared between patients with and without DM prior to liver transplantation and logistic regression analyses were conducted to assess the effect of DM on clinical outcomes including vascular invasion. Results Eighty-four of 191 (44%) transplanted patients had DM at time of transplantation. An association of DM with invasive disease was found among transplanted HCC patients where histologically confirmed macrovascular invasion was found in 20.2% (17/84) of diabetics compared to 9.3% of non-diabetics (10/107) (p=0.032). This difference also remained significant when adjusting for tumor size, number of nodules, age, obesity and etiologic risk factors in multivariate logistic regression analysis (OR=3.2, p=0.025). Conclusions DM is associated with macrovascular invasion among a cohort of transplanted HCC patients.

Objective: This study examined relationships between home smoking/vaping bans and caregiver restrictions on child access to tobacco in the home among rural, Black/African American caregivers who smoke., Methods: Data were from the baseline survey of a randomized trial conducted in 2020-2022 among caregivers who smoke cigarettes and/or little cigars/cigarillos (N = 188). Logistic regressions examined associations between independent variables (tobacco product-specific and comprehensive home smoking/vaping bans) and dependent variables (caregiver keeps tobacco in the home; among caregivers with tobacco at home, caregiver restricts child tobacco access at home) . Models were adjusted for caregiver tobacco use, income, and additional covariates based on stepwise selection., Results: Compared to caregivers with no bans, caregivers with full bans on cigar smoking and vaping were less likely to keep cigars and e-cigarettes at home, respectively. Caregivers with full bans across all tobacco products and no/partial bans across some products were less likely than those with lesser bans to keep e-cigarettes and "other tobacco products" (hookah, pipe, smokeless tobacco, IQOS) at home. Among caregivers with cigarettes at home, those with partial cigarette smoking bans were more likely than those with no bans to restrict child cigarette access at home. Among caregivers with e-cigarettes at home, those with no/partial bans on some products were less likely than those with lesser bans to restrict child e-cigarette access at home., Conclusions: Interventions addressing intergenerational tobacco use among socially-disadvantaged groups may benefit by supporting the implementation of home smoking/vaping bans and caregiver restrictions on child access to tobacco in the home., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

This article describes Arkansas Community Engagement Alliance Against COVID-19 Disparities (CEAL) Coalition initiatives and changes in measures of organizational capacity and sustainability via two waves of surveys. The Arkansas CEAL Coalition used several initiatives to address racial/ethnic COVID-19 disparities by building the capacity of community-based organizations and businesses to increase COVID-19 protective behaviors among their clients. Our study can inform future strategies that use a community-engaged coalition structure to reduce disparities among communities that suffer disproportionately from COVID-19. ( Am J Public Health . ( Am J Public Health . 2024;114(S1):S59-S64. https://doi.org/10.2105/AJPH.2023.307470).

Oncolytic viral immunotherapies are agents which can directly kill tumor cells and activate an immune response. Oncolytic viruses (OVs) range from native/unmodified viruses to genetically modified, attenuated viruses with the capacity to preferentially replicate in and kill tumors, leaving normal tissue unharmed. Talimogene laherparepvec (T-VEC) is the only OV approved for patient use in the United States; however, during the last 20 years, there have been a substantial number of clinical trials using OV immunotherapies across a broad range of cancers. Like T-VEC, many OV immunotherapies in clinical development are based on the herpes simplex virus type 1 (HSV-1), with genetic modifications for tumor selectivity, safety, and immunogenicity. Despite these modifications, HSV-1 OV immunotherapies are often treated with the same biosafety guidelines as the wild-type virus, potentially leading to reduced patient access and logistical hurdles for treatment centers, including community treatment centers and small group or private practices, and healthcare workers. Despite the lack of real-world evidence documenting possible transmission to close contacts, and in the setting of shedding and biodistribution analyses for T-VEC demonstrating limited infectivity and low risk of spread to healthcare workers, barriers to treatment with OV immunotherapies remain. With comprehensive information and educational programs, our hope is that updated biosafety guidance on OV immunotherapies will reduce logistical hurdles to ensure that patients have access to these innovative and potentially life-saving medicines across treatment settings. This work reviews a comprehensive collection of data in conjunction with the opinions of the authors based on their clinical experience to provide the suggested framework and key considerations for implementing biosafety protocols for OV immunotherapies, namely T-VEC, the only approved agent to date., Competing Interests: ER: Replimune: consultant. NZ: Replimune, Inv; SunPharma, Inv/consultant; Biofrontera: Inv, consultant; Castle Biosciences: Inv and speaker program; Dermasensor: Inv; Regeneron: Inv and speaker program (all outside submitted work). MO: Delcath: consultant/advisory board; Ideaya: consultant/advisory board; Immunocore: consultant/advisory board, speaker; Trisalus: scientific advisory board., (Copyright © 2023 Robilotti, Zeitouni and Orloff.)

Background: Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority of whom progressed on prior checkpoint inhibitors., Methods: In this open-label, multicenter, phase 1b, dose-escalation trial, HLA-A*02:01-positive patients with mCM received weekly intravenous tebentafusp with increasing monthly doses of durvalumab and/or tremelimumab starting day 15 of each cycle. The primary objective was to identify the maximum tolerated dose (MTD) or recommended phase 2 dose for each combination. Efficacy analyses were performed in all tebentafusp with durvalumab±tremelimumab treated patients with a sensitivity analysis in those who progressed on prior anti-PD(L)1 therapy., Results: 85 patients were assigned to receive tebentafusp in combination with durvalumab (n=43), tremelimumab (n=13), or durvalumab and tremelimumab (n=29). Patients were heavily pretreated with a median of 3 prior lines of therapy, including 76 (89%) who received prior anti-PD(L)1. Maximum target doses of tebentafusp (68 mcg) alone or in combination with durvalumab (20 mg/kg) and tremelimumab (1 mg/kg) were tolerated; MTD was not formally identified for any arm. Adverse event profile was consistent with each individual therapy and there were no new safety signals nor treatment-related deaths. In the efficacy subset (n=72), the response rate was 14%, tumor shrinkage rate was 41% and 1-year OS rate was 76% (95% CI: 70% to 81%). The 1-year OS for triplet combination (79%; 95% CI: 71% to 86%) was similar to tebentafusp plus durvalumab (74%; 95% CI: 67% to 80%)., Conclusion: At maximum target doses, the safety of tebentafusp with checkpoint inhibitors was consistent with safety of each individual therapy. Tebentafusp with durvalumab demonstrated promising efficacy in heavily pretreated patients with mCM, including those who progressed on prior anti-PD(L)1., Trial Registration Number: NCT02535078., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma., Methods: Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1)., Results: The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD 30); and being on the speaker’s bureau for Bristol-Myers Squibb, Regeneron, and Castle Biosciences. ST reports honoraria, consulting or advisory role, research funding, speaker’s bureau, and travel, accommodations, expenses with Bristol-Myers Squibb, Merck, Pfizer, Ipsen, Amgen, Genentech, and Foundation One. MW reports receiving honoraria from Novartis, Pfizer, and Roche; consulting or advisory role with Bristol-Myers Squibb, Novartis, Pfizer, Cellex GmbH, Eli Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, GEMoaB, Roche, MSD, AstraZeneca, Amgen, and Immatics; research funding from Roche; and travel, accommodations, and expenses from Pfizer, Bristol-Myers Squibb, AstraZeneca, Roche, Amgen, and GEMoaB. MC reports speaker’s bureau participation with Sirtex Medical. ED-M reports receiving honoraria from Castle Biosciences; consulting or advisory role and speaker’s bureau with Regeneron; and research funding from Clinigen. GQP reports honoraria from IBSA; consulting or advisory role with Acella, Amneal, and Terns; and patents, royalties, or other intellectual property with Virginia Commonwealth University. JMK reports consulting role with Amgen, Ankyra Therapeutics, Applied Clinical Intelligence, Axio Research, Becker Pharmaceutical Consulting, Bristol-Myers Squibb, Cancer Network, Checkmate Pharmaceuticals, DermTech, Fenix Group International, Harbour BioMed, Immunocore, Iovance Biotherapeutics, IQVIA, Istari Oncology, Merck, Natera, Novartis, Oncocyte, OncoSec, Pfizer, Replimune, Scopus BioPharma, SR One Capital Management LP, Takeda Development Center Americas, and Takeda Pharmaceutical Company; and research trial support to institution from Amgen, Bristol-Myers Squibb, Checkmate Pharmaceuticals, Harbour BioMed, ImmVira, Immunocore, Iovance Biotherapeutics, Novartis, Takeda, and Verastem. JCH reports honorarias for talks from Almirall, Amgen, Bristol-Myers Squibb, GSK, JSD Pharma, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma; advisory boards for GSK, MSD, Pierre Fabre, Sun Pharma (personal), and Bristol-Myers Squibb, Immunocore, Nektar, Novartis, and Philogen (institution); research funding from Bristol-Myers Squibb, Sun Pharma, and Sanofi; and travel, accommodations, and expenses from Sun Pharma. MO reports consulting or advisory role with TriSalus, Immunocore, Ideaya, and Delcath, and her husband is an employee of GSK. JL reports receiving honoraria from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, and Bristol-Myers Squibb; consulting or advisory role with iOnctura, Apple Tree, Merck, Bristol-Myers Squibb, Eisai, Debiopharm, and Incyte; research funding from Bristol-Myers Squibb, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar, Covance, Immunocore, Pharmacyclics, and Aveo; and travel, accommodations, and expenses from Pierre Fabre, Roche, and GSK. JW reports stock or other ownership with Biond, Instil Bio, OncoV4, and Evaxion; honoraria and consulting or advisory role with Bristol-Myers Squibb, GSK, Pfizer, Sellas, Biond, OncoC4, ImCheck, Genentech, AstraZeneca, Regeneron, Instil Bio, Iovance Biotherapeutics, Evaxion, and Ultimovacs; research funding from Bristol-Myers Squibb, Moderna, Merck, Incyte, and Genentech; patents, royalties, or other intellectual property with Moffitt Cancer Center and Biodesix. AJSF reports consulting or advisory role with Immunocore and GSK; speaker’s bureau participation with Bristol-Myers Squibb, Ipsen, and Eisai; and travel, accommodations, and expenses from ESMO. NIK reports stock and other ownership interest with Bellicum Pharmaceuticals, Amarin Corporation, and Asensus Surgical; consulting or advisory role with Bristol-Myers Squibb, AstraZeneca, Regeneron, Array BioPharma, Immunocore, Merck, Incyte, Jounce Therapeutics, Iovance Biotherapeutics, NCCN/Pfizer, Genzyme, Novartis, Nektar, Castle Biosciences, and InstilBio; research funding from Bristol-Myers Squibb, Merck, Novartis, GSK, HUYA Bioscience International, Amgen, Regeneron, Celgene, and Replimune; and other relationships with Nektar, Regeneron, Bristol-Myers Squibb/Celgene, and Replimune. TM reports consulting or advisory role with Merck, Bristol-Myers Squibb, Iovance Biotherapeutics, Moderna, Nektar, Regeneron, Exicure, Checkmate Pharmaceuticals, BioAtla, Xencor, Replimune, Day One Biopharmaceuticals, Pfizer, and Taiga. MEE reports consultant or advisory role with Iovance Biotherapeutics and receiving research funding from SkylineDx. FGF, MJ, PH, GS, WS, and XW are employees of Iovance Biotherapeutics and hold stock and/or stock options. Further, FGF is in a leadership position at Iovance Biotherapeutics; owns stocks from Adverum Biotechnologies, Roche, Bristol-Myers Squibb, and Johnson & Johnson; and holds patents, royalties, or other intellectual property rights with Bristol-Myers Squibb. PH additionally reports receiving honoraria from Janssen, Amgen, Karyopharm, Bristol-Myers Squibb, and Sanofi; has been paid for a consultant or advisory role by Janssen, Amgen, Karyopharm, Bristol-Myers Squibb, and Allogen; and received travel, accommodations, and expenses from Johnson & Johnson, Bristol-Myers Squibb, and Sanofi. AS reports honoraria and consulting or advisory role with Iovance Biotherapeutics, Guidepoint, Defined Health, Huron Consulting Group, KeyQuest Health, Istari, Gerson Lehrman Group, Physicians’ Educational Resource, Medscape and MedStar Health; and holds patents, royalties, or other intellectual property rights with Moffitt Cancer Center, Iovance Biotherapeutics, and Provectus., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Metastatic uveal melanoma (mUM) is an advanced ocular malignancy characterized by a hepatotropic pattern of spread. As the incidence of brain metastases (BM) in mUM patients has been thought to be low, routine CNS surveillance has not been recommended. Notably, no formal assessment of BM incidence in mUM has to date been published to support this clinical practice. We aimed to determine the true rate of BM in mUM and to clarify the clinical and genomic risk factors associated with BM patients through a collaborative multicenter, retrospective research effort. Data collected from 1,845 mUM patients in databases across four NCI-designated comprehensive cancer centers from 2006-2021 were retrospectively analyzed to identify patients with BM. Brain imaging in most cases were performed due to onset of neurological symptoms and not for routine surveillance. An analysis of demographics, therapies, gene expression profile, tumor next generation sequencing (NGS) data, time to metastasis (brain or other), and survival in the BM cohort was completed. 116/1,845 (6.3%) mUM patients were identified with BM. The median age at time of UM diagnosis was 54 years old (range: 18-77). The median time to any metastasis was 4.2 years (range: 0-30.8). The most common initial metastatic site was the liver (75.9%). 15/116 (12.9%) BM patients presented with BM at the time of initial metastatic diagnosis. Median survival after a diagnosis of BM was 7.6 months (range: 0.4-73.9). The median number of organs involved at time of BM diagnosis was 3 (range: 1-9). DecisionDX-UM profiling was completed on 13 patients: 10-Class 2, 2-Class 1B, and 1-Class 1A. NGS and cytogenetic data were available for 34 and 21 patients, respectively. BM was identified in 6.3% of mUM cases and was associated with high disease burden and a median survival of under 8 months once diagnosed. Since most patients in this cohort were symptomatic, the incidence of asymptomatic BM remains unknown. These data suggest the use of routine brain imaging in all mUM patients at risk for developing BM for early detection., Competing Interests: Author MO is a consultant for Immunocore, Ideaya, and Delcath and is on the scientific advisory board for Trisalus. Author RC serves as a consultant and/or advisory board member for AstraZeneca, Aura Biosciences, Iconic Therapeutics, Janssen, Merck, Novartis, Rgenix, and Thomson Reuter. The remaining 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 © 2022 Wei, Uriel, Porcu, Manos, Mercurio, Caplan, Hulse, Seedor, Holovatska, Francis, Khan, McDonnell, Bogomolny, Sato, Marr, Haq, Orloff, Shoushtari and Carvajal.)

Purpose: To understand conditional prognostic value of the Cancer Genome Atlas (TCGA) for uveal melanoma metastasis based on event-free survival at 1, 2, 3, 4, and 5 years., Methods: A retrospective study of eyes with uveal melanoma categorized according to TCGA and studied for nonconditional and conditional risks for metastasis at 5 and 10 years., Results: Of 1001 eyes with uveal melanoma, the nonconditional (standard, at presentation) 5-year/10-year metastatic rate was 18%/25%. The conditional 5-year/10-year metastatic rate (for those without metastasis at 2 years) revealed 10%/18% and the conditional 10-year metastatic rate (for those without metastasis at 5 years) revealed 9%. The TCGA categories included Group A ( n = 486, 49%), B ( n = 141, 14%), C ( n = 260, 26%), and D ( n = 114, 11%). The non-conditional 5-year/10-year metastatic rate revealed Group A (4%/6%), Group B (12%/20%), Group C (23%/49%), and Group D (60%/68%). The conditional 5-year/10-year metastatic rate (for those without metastasis at 2 years) revealed Group A (2%/5%), Group B (8%/18%), Group C (21%/40%), and Group D (38%/50%). The conditional 10-year metastatic rate (for those without metastasis at 5 years) revealed Group A (2%), Group B (10%), Group C (33%), and Group D (20%). The peak incidence of metastasis for Groups A and B occurred during years 5-6, C during years 4-6, and D during years 1-2., Conclusion: Survival outcomes for uveal melanoma as non-conditional (at presentation) and conditional (event-free survival during follow-up) reveal reduction in metastatic rate over time. For those with 5-year metastasis-free survival, the 10-year conditional risk for metastasis was 9%., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Saudi Journal of Ophthalmology.)

Uveal melanoma is the most common primary ocular malignancy in adults, characterized by gene mutations in G protein subunit alpha q ( GNAQ ) and G protein subunit alpha 11 ( GNA11 ). Although they are considered to be driver mutations, their role in MUM remains elusive. We investigated key somatic mutations of MUM and their impact on patients' survival after development of systemic metastasis (Met-to-Death). Metastatic lesions from 87 MUM patients were analyzed by next generation sequencing (NGS). GNA11 (41/87) and GNAQ (39/87) mutations were most predominantly seen in MUM. Most GNA11 mutations were Q209L (36/41), whereas GNAQ mutations comprised Q209L (14/39) and Q209P (21/39). Epigenetic pathway mutations BAP1 (42/66), SF3B1 (11/66), FBXW7 (2/87), PBRM1 (1/66), and SETD2 (1/66) were found. No specimen had the EIF1AX mutation. Interestingly, Met-to-Death was longer in patients with GNAQ Q209P compared to GNAQ/GNA11 Q209L mutations, suggesting the difference in mutation type in GNAQ/GNA11 might determine the prognosis of MUM. Structural alterations of the GNAQ/GNA11 protein and their impact on survival of MUM patients should be further investigated.

Despite successful treatment of primary uveal melanoma, up to 50% of patients will develop systemic metastasis. Metastatic disease portends a poor outcome, and no adjuvant or metastatic therapy has been FDA approved. The genetic landscape of uveal melanoma is unique, providing prognostic and potentially therapeutic insight. In this review, we discuss our current understanding of the molecular and cytogenetic mutations in uveal melanoma, and the importance of obtaining such information. Most of our knowledge is based on primary uveal melanoma and a better understanding of the mutational landscape in metastatic uveal melanoma is needed. Clinical trials targeting certain mutations such as GNAQ / GNA11 , BAP1 , and SF3B1 are ongoing and promising. We also discuss the role of liquid biopsies in uveal melanoma in this review.

Background: Studies have considered the validity of self-reported hypertension relative to hypertension detected by examination; no study has explored trends in the difference between these two measures. Our objective was to calculate these differences overtime within subpopulations of the USA., Methods: We included non-Hispanic white, non-Hispanic black and Hispanic adults who participated in the National Health and Nutrition Examination Surveys from 1999 to 2016, in the analysis (N = 44 333). We subtracted self-reported hypertension from hypertension detected by examination to calculate blood pressure difference (BPD). We fit weighted linear regression models that included important covariates along with all combination of two- and three-way interactions to predict the BPD. We used the fitted lines of the models to depict the patterns of differences in the different subpopulations., Results: Age ≥ 45 years, lack of annual clinical visit, body mass index (BMI) < 25 and time were important factors associated with increased BPD., Conclusions: People who are ≥ 45 years, have normal BMI, or do not have annual medical visits are more likely to have a bigger BPD. We can use the calculated BPD, to adjust estimates of the prevalence of self-reported hypertension., (© The Author(s) 2019. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Uveal melanoma (UM) is a rare subtype of melanoma that generally has a poor prognosis once it has metastasized. Clinical trials evaluating immune checkpoint inhibitors (ICIs) in UM have demonstrated response rates lower than those seen in cutaneous melanoma. Despite lower efficacy demonstrated in initial ICI studies, there are a number of ongoing clinical trials investigating novel immunotherapy approaches in UM., Summary: This review aims to summarize important ongoing clinical trials investigating immunotherapeutic approaches in UM and previous trials that have evaluated a number of immunologic interventions. A thorough clinical trial investigation was conducted through clinicaltrials.gov using the disease search terms "uveal melanoma" and "ocular melanoma," excluding non-immunotherapy-related trials. Here, we report on ICI, vaccine, adoptive T cells, and combination immunotherapy trials in UM., Key Messages: There is an increasing effort in the search for new, effective therapies for this difficult-to-treat disease, with immunotherapeutic approaches being of particular interest. Increasing knowledge of UM biology and development of new biomarkers will direct future drug development and trial design., Competing Interests: The funding for this manuscript was initiated by Immunocore Ltd. However, the content represents the views and opinions of the author, Dr. Orloff, with editorial review by Immunocore Ltd. for accuracy. The author has received research support from consulting and speaker fees from Bristol-Myers Squibb. She has received consulting fees, research funding to institution, and contributed to an education campaign www.thinkuvealmelanoma.com, sponsored by Immunocore Ltd., (Copyright © 2021 by S. Karger AG, Basel.)

Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways., Competing Interests: The authors have declared that no competing interests exist.

Uveal melanoma (UM) is the most common primary eye malignancy in adults and up to 50% of patients subsequently develop systemic metastasis. Metastatic uveal melanoma (MUM) is highly resistant to immunotherapy. One of the mechanisms for resistance would be the immune-suppressive tumor microenvironment. Here, we have investigated the role of tryptophan 2,3-dioxygenase (TDO) in UM. Both TDO and indoleamine 2,3-dioxygenase (IDO) catalyze tryptophan and produce kynurenine, which could cause inhibition of T cell immune responses. We first studied the expression of TDO on tumor tissue specimens obtained from UM hepatic metastasis. High expression of TDO protein was confirmed in all hepatic metastasis. TDO was positive in both normal hepatocytes and the tumor cells with relatively higher expression in tumor cells. On the other hand, IDO protein remained undetectable in all of the MUM specimens. UM cell lines established from metastasis also expressed TDO protein and increasing kynurenine levels were detected in the supernatant of MUM cell culture. In TCGA database, higher TDO2 expression in primary UM significantly correlated to BAP1 mutation and monosomy 3. These results indicate that TDO might be one of the key mechanisms for resistance to immunotherapy in UM., Competing Interests: The authors declare no conflict of interest.

Neoadjuvant radiation is standard of care for locally advanced rectal cancer. Response to radiation is highly variable and directly linked with survival. However, there currently are no validated biomarkers or molecular targets to predict or improve radiation response, which would help develop personalized treatment and ideally targeted therapies. Here, we identified a novel biomarker, coenzyme A synthase (COASY), whose mRNA expression was consistently elevated in radioresistant human rectal cancers. This observation was validated in independent patient cohorts and further confirmed in colorectal cancer cell lines. Importantly, genetic overexpression and knockdown yielded radioresistant and sensitive phenotypes, respectively, in vitro and in vivo . COASY-knockdown xenografts were more vulnerable to radiation, showing delayed tumor growth, decreased proliferation, and increased apoptosis. Mechanistically, COASY protein directly interacted with the PI3K regulatory subunit PI3K-P85α, which increased AKT and mTOR phosphorylation, enhancing cell survival. Furthermore, shRNA COASY knockdown disrupted downstream PI3K pathway activation and also hindered DNA double-strand break repair, which both led to improved radiosensitivity. Collectively, this work reveals for the first time the biological relevance of COASY as a predictive rectal cancer biomarker for radiation response and offers mechanistic evidence to support COASY as a potential therapeutic target. SIGNIFICANCE: COASY is a novel radiotherapy response modulator in rectal cancer that regulates PI3K activation and DNA repair. Furthermore, COASY levels directly correlate with radiation response and serve as a predictive biomarker., (©2019 American Association for Cancer Research.)