C13orf31 (FAMIN) is a central regulator of immunometabolic function.

Single-nucleotide variations in C13orf31 (LACC1) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.

DNA synthesis is required for reprogramming mediated by stem cell fusion.

Embryonic stem cells (ESCs) can instruct the conversion of differentiated cells toward pluripotency following cell-to-cell fusion by a mechanism that is rapid but poorly understood. Here, we used centrifugal elutriation to enrich for mouse ESCs at sequential stages of the cell cycle and showed that ESCs in S/G2 phases have an enhanced capacity to dominantly reprogram lymphocytes and fibroblasts in heterokaryon and hybrid assays. Reprogramming success was associated with an ability to induce precocious nucleotide incorporation within the somatic partner nuclei in heterokaryons. BrdU pulse-labeling experiments revealed that virtually all successfully reprogrammed somatic nuclei, identified on the basis of Oct4 re-expression, had undergone DNA synthesis within 24 hr of fusion with ESCs. This was essential for successful reprogramming because drugs that inhibited DNA polymerase activity effectively blocked pluripotent conversion. These data indicate that nucleotide incorporation is an early and critical event in the epigenetic reprogramming of somatic cells in experimental ESC-heterokaryons.

Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision.

BACKGROUND: Hereditary adenomatous polyposis syndromes, including familial adenomatous polyposis and other rare adenomatous polyposis syndromes, increase the lifetime risk of colorectal and other cancers. METHODS: A team of 38 experts convened to update the 2008 European recommendations for the clinical management of patients with adenomatous polyposis syndromes. Additionally, other rare monogenic adenomatous polyposis syndromes were reviewed and added. Eighty-nine clinically relevant questions were answered after a systematic review of the existing literature with grading of the evidence according to Grading of Recommendations, Assessment, Development, and Evaluation methodology. Two levels of consensus were identified: consensus threshold (≥67% of voting guideline committee members voting either 'Strongly agree' or 'Agree' during the Delphi rounds) and high threshold (consensus ≥ 80%). RESULTS: One hundred and forty statements reached a high level of consensus concerning the management of hereditary adenomatous polyposis syndromes. CONCLUSION: These updated guidelines provide current, comprehensive, and evidence-based practical recommendations for the management of surveillance and treatment of familial adenomatous polyposis patients, encompassing additionally MUTYH-associated polyposis, gastric adenocarcinoma and proximal polyposis of the stomach and other recently identified polyposis syndromes based on pathogenic variants in other genes than APC or MUTYH. Due to the rarity of these diseases, patients should be managed at specialized centres.

Outcome of patients with perihilar cholangiocarcinoma and previous biliary instrumentation: an observational study.

BACKGROUND: To assess the outcome of previously untreated patients with perihilar cholangiocarcinoma who present to a cancer referral center with or without pre-existing trans-papillary biliary drainage. METHODS: Consecutive patients with a diagnosis of perihilar cholangiocarcinoma presenting between January 1, 2013, and December 31, 2017, were identified from a prospective surgical database and by a query of the institutional database. Of 237 patients identified, 106 met inclusion criteria and were reviewed. Clinical information was obtained from the Electronic Medical Record and imaging studies were reviewed in the Picture Archiving and Communication System. RESULTS: 73 of 106 patients (69%) presenting with a new diagnosis of perihilar cholangiocarcinoma underwent trans-papillary biliary drainage (65 endoscopic and 8 percutaneous) prior to presentation at our institution. 8 of the 73 patients with trans-papillary biliary drainage (11%) presented with and 5 developed cholangitis; all 13 (18%) required subsequent intervention; none of the patients without trans-papillary biliary drainage presented with or required drainage for cholangitis (p = 0.008). Requiring drainage for cholangitis was more likely to delay treatment (p = 0.012) and portended a poorer median overall survival (13.6 months, 95%CI [4.08, not reached)] vs. 20.6 months, 95%CI [18.34, 37.51] p = 0.043). CONCLUSION: Trans-papillary biliary drainage for perihilar cholangiocarcinoma carries a risk of cholangitis and should be avoided when possible. Clinical and imaging findings of perihilar cholangiocarcinoma should prompt evaluation at a cancer referral center before any intervention. This would mitigate development of cholangitis necessitating additional drainage procedures, delaying treatment and potentially compromising survival.

Resveratrol for the Management of Human Health: How Far Have We Come? A Systematic Review of Resveratrol Clinical Trials to Highlight Gaps and Opportunities.

Resveratrol has long been proposed as being beneficial to human health across multiple morbidities, yet there is currently no conclusive clinical evidence to advocate its recommendation in any healthcare setting. A large cohort with high-quality clinical data and clearly defined biomarkers or endpoints are required to draw meaningful conclusions. This systematic review compiles every clinical trial conducted using a defined dose of resveratrol in a purified form across multiple morbidities to highlight the current 'state-of-play' and knowledge gaps, informing future trial designs to facilitate the realisation of resveratrol's potential benefits to human health. Over the last 20 years, there have been almost 200 studies evaluating resveratrol across at least 24 indications, including cancer, menopause symptoms, diabetes, metabolic syndrome, and cardiovascular disease. There are currently no consensus treatment regimens for any given condition or endpoint, beyond the fact that resveratrol is generally well-tolerated at a dose of up to 1 g/day. Additionally, resveratrol consistently reduces inflammatory markers and improves aspects of a dysregulated metabolism. In conclusion, over the last 20 years, the increasing weight of clinical evidence suggests resveratrol can benefit human health, but more large, high-quality clinical trials are required to transition this intriguing compound from health food shops to the clinic.

Inequalities in cancer mortality trends in people with type 2 diabetes: 20 year population-based study in England.

AIMS/HYPOTHESIS: The aim of this study was to describe the long-term trends in cancer mortality rates in people with type 2 diabetes based on subgroups defined by sociodemographic characteristics and risk factors. METHODS: We defined a cohort of individuals aged ≥35 years who had newly diagnosed type 2 diabetes in the Clinical Practice Research Datalink between 1 January 1998 and 30 November 2018. We assessed trends in all-cause, all-cancer and cancer-specific mortality rates by age, gender, ethnicity, socioeconomic status, obesity and smoking status. We used Poisson regression to calculate age- and calendar year-specific mortality rates and Joinpoint regression to assess trends for each outcome. We estimated standardised mortality ratios comparing mortality rates in people with type 2 diabetes with those in the general population. RESULTS: Among 137,804 individuals, during a median follow-up of 8.4 years, all-cause mortality rates decreased at all ages between 1998 and 2018; cancer mortality rates also decreased for 55- and 65-year-olds but increased for 75- and 85-year-olds, with average annual percentage changes (AAPCs) of -1.4% (95% CI -1.5, -1.3), -0.2% (-0.3, -0.1), 1.2% (0.8, 1.6) and 1.6% (1.5, 1.7), respectively. Higher AAPCs were observed in women than men (1.5% vs 0.5%), in the least deprived than the most deprived (1.5% vs 1.0%) and in people with morbid obesity than those with normal body weight (5.8% vs 0.7%), although all these stratified subgroups showed upward trends in cancer mortality rates. Increasing cancer mortality rates were also observed in people of White ethnicity and former/current smokers, but downward trends were observed in other ethnic groups and non-smokers. These results have led to persistent inequalities by gender and deprivation but widening disparities by smoking status. Constant upward trends in mortality rates were also observed for pancreatic, liver and lung cancer at all ages, colorectal cancer at most ages, breast cancer at younger ages, and prostate and endometrial cancer at older ages. Compared with the general population, people with type 2 diabetes had a more than 1.5-fold increased risk of colorectal, pancreatic, liver and endometrial cancer mortality during the whole study period. CONCLUSIONS/INTERPRETATION: In contrast to the declines in all-cause mortality rates at all ages, the cancer burden has increased in older people with type 2 diabetes, especially for colorectal, pancreatic, liver and endometrial cancer. Tailored cancer prevention and early detection strategies are needed to address persistent inequalities in the older population, the most deprived and smokers.

Clinical trials in cancer screening, prevention and early diagnosis (SPED): a systematic mapping review.

BACKGROUND: Global annual cancer incidence is forecast to rise to 27.5 M by 2040, a 62% increase from 2018. For most cancers, prevention and early detection are the most effective ways of reducing mortality. This study maps trials in cancer screening, prevention, and early diagnosis (SPED) to identify areas of unmet need and highlight research priorities. METHODS: A systematic mapping review was conducted to evaluate all clinical trials focused on cancer SPED, irrespective of tumour type. The National Cancer Research Institute (NCRI) portfolio, EMBASE, PubMed and Medline were searched for relevant papers published between 01/01/2007 and 01/04/2020. References were exported into Covidence software and double-screened. Data were extracted and mapped according to tumour site, geographical location, and intervention type. RESULTS: One hundred seventeen thousand seven hundred one abstracts were screened, 5157 full texts reviewed, and 2888 studies included. 1184 (52%) trials focussed on screening, 554 (24%) prevention, 442 (20%) early diagnosis, and 85 (4%) a combination. Colorectal, breast, and cervical cancer comprised 61% of all studies compared with 6.4% in lung and 1.8% in liver cancer. The latter two are responsible for 26.3% of global cancer deaths compared with 19.3% for the former three. Number of studies varied markedly according to geographical location; 88% were based in North America, Europe, or Asia. CONCLUSIONS: This study shows clear disparities in the volume of research conducted across different tumour types and according to geographical location. These findings will help drive future research effort so that resources can be directed towards major challenges in cancer SPED.

Automated prediction of extubation success in extremely preterm infants: the APEX multicenter study.

BACKGROUND: Extremely preterm infants are frequently subjected to mechanical ventilation. Current prediction tools of extubation success lacks accuracy. METHODS: Multicenter study including infants with birth weight ≤1250 g undergoing their first extubation attempt. Clinical data and cardiorespiratory signals were acquired before extubation. Primary outcome was prediction of extubation success. Automated analysis of cardiorespiratory signals, development of clinical and cardiorespiratory features, and a 2-stage Clinical Decision-Balanced Random Forest classifier were used. A leave-one-out cross-validation was done. Performance was analyzed by ROC curves and determined by balanced accuracy. An exploratory analysis was performed for extubations before 7 days of age. RESULTS: A total of 241 infants were included and 44 failed (18%) extubation. The classifier had a balanced accuracy of 73% (sensitivity 70% [95% CI: 63%, 76%], specificity 75% [95% CI: 62%, 88%]). As an additional clinical-decision tool, the classifier would have led to an increase in extubation success from 82% to 93% but misclassified 60 infants who would have been successfully extubated. In infants extubated before 7 days of age, the classifier identified 16/18 failures (specificity 89%) and 73/105 infants with success (sensitivity 70%). CONCLUSIONS: Machine learning algorithms may improve a balanced prediction of extubation outcomes, but further refinement and validation is required. IMPACT: A machine learning-derived predictive model combining clinical data with automated analyses of individual cardiorespiratory signals may improve the prediction of successful extubation and identify infants at higher risk of failure with a good balanced accuracy. Such multidisciplinary approach including medicine, biomedical engineering and computer science is a step forward as current tools investigated to predict extubation outcomes lack sufficient balanced accuracy to justify their use in future trials or clinical practice. Thus, this individualized assessment can optimize patient selection for future trials of extubation readiness by decreasing exposure of low-risk infants to interventions and maximize the benefits of those at high risk.

Parents' perspective on recovery at home following adenotonsillectomy: a prospective single-centre qualitative analysis.

PURPOSE: In North America, pediatric adenotonsillectomy (TA) is conducted as an ambulatory procedure, thus shifting the burden of postoperative care to parents. The purpose of this study was to describe this parental experience. METHODS: We conducted a prospective single-centre qualitative study, recruiting the families of children (n = 317) undergoing elective TA in 2018. Parents were invited to submit written comments to two open-ended questions. We coded the comments from 144 parents in a grounded theory analysis and report representative exemplars. Themes and subthemes for the problems encountered, and strategies employed by parents, were developed. We then coded and classified factors that helped/hindered parents and developed models of the experience. RESULTS: Some parents felt ill-prepared for the severity and duration of pain. Specific findings included a lack of strategies to manage pain at night, refusals, and night terrors. Parents identified the use of pain scales, pain diaries, and liaison with the research team as helpful supports at home. Inconsistent messaging was a barrier. The odynophagia associated with elixirs of acetaminophen and ibuprofen was a barrier to achieving analgesia. CONCLUSIONS: The findings from this qualitative analysis provide insight into the challenges faced by parents when caring for their children at home following TA; these challenges included difficulties managing physical needs and pain. The analysis suggests that educational content should be standardized and include the use of pain scales and diaries, and both pharmacologic and nonpharmacologic strategies. Development of support at home, including a practicable liaison with health care providers, seems to be warranted. STUDY REGISTRATION: ClinicalTrials.gov (NCT03378830); registered 20 December 2017.

RéSUMé: OBJECTIF: En Amérique du Nord, l'adéno-amygdalectomie pédiatrique est réalisée en intervention ambulatoire, transférant ainsi le fardeau des soins postopératoires aux parents. Le but de cette étude était de décrire cette expérience parentale. MéTHODE: Nous avons réalisé une étude qualitative prospective monocentrique, recrutant les familles d'enfants (n = 317) subissant une adéno-amygdalectomie non urgente en 2018. Les parents ont été invités à soumettre des commentaires écrits sur deux questions ouvertes. Nous avons codé les commentaires de 144 parents dans une analyse théorique ancrée et rapporté des exemples représentatifs. Des thèmes et sous-thèmes pour les problèmes rencontrés, ainsi que des stratégies employées par les parents, ont été développés. Nous avons ensuite codé et classé les facteurs qui aidaient / gênaient les parents et développé des modèles de l'expérience. RéSULTATS: Certains parents se sentaient mal préparés à la gravité et à la durée de la douleur. Les résultats spécifiques comprenaient un manque de stratégies pour gérer la douleur la nuit, les refus et les terreurs nocturnes. Les parents ont indiqué que l'utilisation d'échelles de douleur, de journaux de douleur et de liaison avec l'équipe de recherche étaient des soutiens utiles à la maison. Le manque d'uniformité des messages a constitué un obstacle. L'odynophagie associée aux élixirs d'acétaminophène et d'ibuprofène était un obstacle à l'analgésie. CONCLUSION: Les résultats de cette analyse qualitative donnent un aperçu des défis auxquels font face les parents lorsqu'ils et elles s'occupent de leurs enfants à la maison après une adéno-amygdalectomie; ces défis comprenaient des difficultés à gérer les besoins physiques et la douleur. L'analyse suggère que le contenu éducatif devrait être normalisé et inclure l'utilisation d'échelles et de journaux de douleur, ainsi que de stratégies pharmacologiques et non pharmacologiques. L'élaboration d'un soutien à domicile, y compris d'une communication fonctionnelle avec les prestataires de soins de santé, semble justifiée. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT03378830); enregistrée le 20 décembre 2017.

Recurrence of Hepatocellular Carcinoma After Complete Radiologic Response to Trans-Arterial Embolization: A Retrospective Study on Patterns, Treatments, and Prognoses.

BACKGROUND: There is limited information about the long-term outcomes and patterns of progression in patients who have unresectable, liver-confined hepatocellular carcinoma (HCC) with complete response (CR) to transarterial embolization and do not undergo resection or transplantation (LT). METHODS: A retrospective review analyzed participants in a randomized trial comparing hepatic artery embolization (HAE) and drug-eluting bead transarterial chemoembolization (DEB-TACE) with doxorubicin who had CR according to modified response evaluation criteria in solid tumors (mRECIST). The overall survival (OS), incidence and patterns of progression, and factors associated with progression were assessed. RESULTS: Of the 101 patients in the trial, 37 with CR were included in this study. This cohort had 17 patients treated with HAE (46 %), and 20 patients managed with DEB-TACE (54 %). The median age was 67 years (range, 42-82 years). Most of the cohort were male (86.5 %) and Caucasian (78 %). The median pre-treatment Model for End-Stage Liver Disease (MELD) score was 10, and 70 % of the cohort had Barcelona Clinic Liver Cancer (BCLC) stage B or C. The median follow-up period was 49 months (95 % confidence interval [CI], 9-108 months), and the median OS was 25 months (95 % CI, 18.9-30.9 months). The 3- and 5-year survival rates were respectively 31 % (95 % CI, 16.7-45.9 %) and 18 % (95 % CI, 6.8-32.1 %). The 1- and 2-year cumulative incidences of progression were respectively 76 % (95 % CI, 57.7-86.8 %) and 92 % (95 % CI, 74.5-97.6 %). The most common first site of progression was the previously treated hepatic site or local site (32 %, 12/37). The 3-year cumulative incidence of progression was 65 % (95 % CI, 46.4-78.4 %) for the local site. CONCLUSION: Patients with advanced-stage HCC and CR to embolization do not have durable responses and experience inevitable disease progression. Most patients with progression have liver-confined disease and should be evaluated for additional consolidative treatments.

Ex vivo explant model of adenoma and colorectal cancer to explore mechanisms of action and patient response to cancer prevention therapies.

Colorectal cancer (CRC) is the second leading cause of cancer death in the UK. Novel therapeutic prevention strategies to inhibit the development and progression of CRC would be invaluable. Potential contenders include low toxicity agents such as dietary-derived agents or repurposed drugs. However, in vitro and in vivo models used in drug development often do not take into account the heterogeneity of tumours or the tumour microenvironment. This limits translation to a clinical setting. Our objectives were to develop an ex vivo method utilizing CRC and adenoma patient-derived explants (PDEs) which facilitates screening of drugs, assessment of toxicity, and efficacy. Our aims were to use a multiplexed immunofluorescence approach to demonstrate the viability of colorectal tissue PDEs, and the ability to assess immune cell composition and interactions. Using clinically achievable concentrations of curcumin, we show a correlation between curcumin-induced tumour and stromal apoptosis (P < .001) in adenomas and cancers; higher stromal content is associated with poorer outcomes. B cell (CD20+ve) and T cell (CD3+ve) density of immune cells within tumour regions in control samples correlated with curcumin-induced tumour apoptosis (P < .001 and P < .05, respectively), suggesting curcumin-induced apoptosis is potentially predicted by baseline measures of immune cells. A decrease in distance between T cells (CD3+ve) and cytokeratin+ve cells was observed, indicating movement of T cells (CD3+ve) towards the tumour margin (P < .001); this change is consistent with an immune environment associated with improved outcomes. Concurrently, an increase in distance between T cells (CD3+ve) and B cells (CD20+ve) was detected following curcumin treatment (P < .001), which may result in a less immunosuppressive tumour milieu. The colorectal tissue PDE model offers significant potential for simultaneously assessing multiple biomarkers in response to drug exposure allowing a greater understanding of mechanisms of action and efficacy in relevant target tissues, that maintain both their structural integrity and immune cell compartments.

Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.

Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and represents an attractive potential target for the development of new antibiotics. Here, we describe the application of a structure-guided fragment-based drug discovery approach to the design of a new class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library screening, followed by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecules with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and M. tuberculosis as well as against intracellular M. abscessus and M. leprae, indicating their potential as the basis for a novel class of broad-spectrum mycobacterial drugs.

Validation of the parent's postoperative pain measure with an age-appropriate reference pain scale for children 2-12 years old during a 14-day recovery after tonsillectomy: A prospective cohort study.

BACKGROUND: Adenotonsillectomy is associated with severe postoperative pain. The parent's postoperative pain measure (PPPM), a 15-item instrument to measure a child's pain at home, has been validated with a seven-point faces scale in children 7-12 years and with the parents' global report of pain in children 2-6 years. AIMS: Our primary objective was to validate the PPPM with a recommended age-appropriate pain scale in children 2-12 years after adenotonsillectomy. Our secondary objective was to reduce the PPPM components and validate this reduced PPPM. METHODS: We recruited 319 children out of the 563 adenotonsillectomies performed between December 19, 2017, and December 18, 2018. Parents recorded administration of analgesics and their child's pain scores twice daily for 14 days: PPPM for all children and either the face, legs, arms, crying, consolability (FLACC) pain scale for children 2-3 years or the faces pain scale-revised (FPS-R) for children 4-12 years. In addition, parents recorded analgesics. RESULTS: Among the 354 eligible children, 9% of parents declined. 252 (79%) families submitted pain diaries. The median age was 2.9 [2.5-3.3] years for FLACC (n = 114) and 5.6 [4.5-7.2] years for FPS-R (n = 138). Across the 14-day recovery period, Cronbach's alpha for PPPM was 0.77 to 0.87. Generalized linear mixed models evaluated the association between PPPM and reference pain scales after adjustment for potential confounders. Time of day and postoperative days were included as predictors in the models. PPPM was strongly associated with FLACC and FPS-R (beta coefficient = 0.4; p < 0.0001). The association decreased over time, and the reduction was more significant for FPS-R than FLACC (beta coefficient = -0.13 vs. -0.04, respectively; p < 0.0001). There was a positive association between PPPM and the use of analgesics. A reduction analysis eliminated items from the original PPPM: four for FLACC and five for FPS-R, suggesting age-related differences. The reduced PPPM instruments achieved similar associations with their respective reference pain scales (beta coefficient = 0.5; p < 0.0001). CONCLUSIONS: This study extends previous work by validating the PPPM in children as young as 2 years with a recommended age-appropriate pain scale over 14-day convalescence after adenotonsillectomy. The reduced PPPM instruments differed in the two age groups. Future studies might explore these age-appropriate reduced PPPM instruments to assess pain at home following adenotonsillectomy.

Facial Asymmetry in Children With Unilateral Congenital Ptosis.

PURPOSE: To analyze facial asymmetry in children with unilateral congenital ptosis. METHODS: This is a retrospective review of pediatric patients undergoing ptosis repair between January 1, 2017, and December 31, 2020. Charts were reviewed to ensure a diagnosis of idiopathic unilateral congenital ptosis. Sex, age, laterality, margin to reflex distance 1, levator function, and surgical intervention were collected.Clear preoperative photos without head turn were included. Using the ImageJ software ( nih.gov ), landmarks of the periorbital region, midface, and lower face were marked, and measurements between these landmarks were taken.Two-tailed Student t tests were used to compare measurements between the ptotic and non-ptotic sides. Relationships between different measurements on the same side of the face were analyzed using paired-variable regressions. RESULTS: Forty-four patients with unilateral congenital ptosis were included. The surgical management consisted of Mullerectomy in 9 of 44 (20%), levator resection in 15 of 44 (34%), and frontalis suspension in 20 of 44 (46%) patients. The side of the face with blepharoptosis was found to more often have smaller margin to reflex distance 1 ( p < 0.001), smaller margin to reflex distance 2 ( p < 0.005), smaller horizontal palpebral fissure ( p < 0.05), shorter midface height ( p < 0.001), and a more inferiorly displaced lateral canthus (canthal angle, p < 0.001) relative to the non-ptotic side of the face. The mean head tilt of patients with right sided ptosis (1.37° right tilt) was statistically significantly different from those with left sided ptosis (0.85° left tilt; p = 0.04). CONCLUSIONS: In children with unilateral congenital ptosis, the ptotic side of the face was found to be the nondominant side of the face. Patients were also found to have ipsilateral head tilt.

Inequalities in cancer screening, prevention and service engagement between UK ethnic minority groups.

More people in the UK are living with cancer than ever before. With an increasingly ethnically diverse population, greater emphasis must be placed on understanding factors influencing cancer outcomes. This review seeks to explore UK-specific variations in engagement with cancer services in minority ethnic groups and describe successful interventions. The authors wish to highlight that, despite improvement to engagement and education strategies, inequalities still persist and work to improve cancer outcomes across our communities still needs to be prioritised. There are many reasons why cancer healthcare inequities exist for minority communities, reported on a spectrum ranging from cultural beliefs and awareness, through to racism. Strategies that successfully enhanced engagement included language support; culturally-sensitive reminders; community-based health workers and targeted outreach. Focusing on the diverse city of Leicester the authors describe how healthcare providers, researchers and community champions have worked collectively, delivering targeted community-based strategies to improve awareness and access to cancer services.

Phase I, first-in-human trial of programmed cell death receptor-1 (PD-1) inhibitor, JTX-4014, in adult patients with advanced, refractory, solid tumors.

BACKGROUND: Inhibition of programmed cell death receptor protein-1 (PD-1) has proven to be a highly effective strategy for immunotherapy of cancer. Approvals of both PD-1 and PD-L1 inhibitors [PD-(L)1i] in multiple tumor types are evidence of the durable benefits they provide to patients with cancer. In this first-in-human trial, we assessed the safety and tolerability of JTX-4014, a fully human antibody targeting PD-1. METHODS: JTX-4014 was administered to 18 patients with multiple solid tumor types who had not previously received a PD-(L)1i. The primary objectives were to evaluate the safety and tolerability of JTX-4014 and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included evaluation of the pharmacokinetics (PK) of JTX-4014, anti-drug antibodies (ADA) against JTX-4014, and clinical activity. RESULTS: JTX-4014 was well tolerated and no new safety signals were identified as compared with other PD-1is. The MTD was not reached and the RP2D was selected, based on PK modelling and supportive safety data, to be 500 mg every 3 weeks or 1000 mg every 6 weeks. Clinical activity, based on RECIST v1.1 criteria, demonstrated an overall response rate of 16.7% (n = 3) with one complete and two partial responses and a disease control rate of 44.4% (n = 8). The responses occurred at different doses in patients with PD-L1 positive tumors and in tumor types that are not typically PD-1i responsive. CONCLUSIONS: Further development of JTX-4014 is warranted as a monotherapy or in combination with other innovative cancer therapies. TRIAL REGISTRATION NUMBER: NCT03790488, December 31 2018.

Risk of cancer incidence and mortality associated with diabetes: A systematic review with trend analysis of 203 cohorts.

AIM: Whether the relative risk of cancer incidence and mortality associated with diabetes has changed over time is unknown. DATA SYNTHESIS: On August 12th, 2020, we electronically searched for observational studies reporting on the association between diabetes and cancer. We estimated temporal trends in the relative risk of cancer incidence or mortality associated with diabetes and calculated the ratio of relative risk (RRR) comparing different periods. As many as 193 eligible articles, reporting data on 203 cohorts (56,852,381 participants; 3,735,564 incident cancer cases; 185,404 cancer deaths) and covering the period 1951-2013, were included. The relative risk of all-site cancer incidence increased between 1980 and 2000 [RRR 1990 vs.1980: (1.24; 95% CI: 1.16, 1.34); 2000 vs.1990: (1.23; 1.15, 1.31)] and stabilised thereafter at a relative risk of 1.2; the relative risk of all-site cancer mortality was constant at about 1.2 from 1980 to 2010. Both magnitudes and trends in relative risk varied across cancer sites: the relative risk of colorectal, female breast, and endometrial cancer incidence and pancreatic cancer mortality was constant during the observed years; it increased for bladder, stomach, kidney, and pancreatic cancer incidence until 2000; and decreased for liver while increased for prostate, colon and gallbladder cancer incidence after 2000. CONCLUSIONS: Alongside the increasing prevalence of diabetes, the temporal patterns of the relative risk of cancer associated with diabetes may have contributed to the current burden of cancer in people with diabetes.

Different roles for Tet1 and Tet2 proteins in reprogramming-mediated erasure of imprints induced by EGC fusion.

Genomic imprinting directs the allele-specific marking and expression of loci according to their parental origin. Differential DNA methylation at imprinted control regions (ICRs) is established in gametes and, although largely preserved through development, can be experimentally reset by fusing somatic cells with embryonic germ cell (EGC) lines. Here, we show that the Ten-Eleven Translocation proteins Tet1 and Tet2 participate in the efficient erasure of imprints in this model system. The fusion of B cells with EGCs initiates pluripotent reprogramming, in which rapid re-expression of Oct4 is accompanied by an accumulation of 5-hydroxymethylcytosine (5hmC) at several ICRs. Tet2 was required for the efficient reprogramming capacity of EGCs, whereas Tet1 was necessary to induce 5-methylcytosine oxidation specifically at ICRs. These data show that the Tet1 and Tet2 proteins have discrete roles in cell-fusion-mediated pluripotent reprogramming and imprint erasure in somatic cells.

Metabolism, excretion, and pharmacokinetics of [14C]mirogabalin, a novel α2δ ligand, in healthy volunteers following oral administration.

The metabolism, excretion, and pharmacokinetics of mirogabalin were investigated following a single oral administration of [14C]mirogabalin at 30 mg/5.55 MBq to six healthy male subjects.The mean recovery values of radioactivity in urine and faeces were 96.85 and 1.21%, respectively. The main component of radioactivity in the plasma, urine, and faeces was mirogabalin. A204-4455 (lactam form), mirogabalin N-glucuronide, and glucuronide of oxidized A204-4455 were detected as minor components in the specimens. Renal clearance of mirogabalin was higher than the glomerular filtration rate of the human kidneys, indicating renal secretion is involved in the clearance.In vitro studies revealed that UDP-glucuronosyltransferase produced two metabolites: A204-4455, formed via mirogabalin acylglucuronide, and a ring-opened form of mirogabalin N-glucuronide.Mirogabalin was absorbed almost completely, and was eliminated via urine. A part of the orally administered dose of mirogabalin was metabolized through glucuronidation at the amine and carboxylic acid moiety, which represents the primary metabolic pathway.

A Presurgical Study of Curcumin Combined with Anthocyanin Supplements in Patients with Colorectal Adenomatous Polyps.

Adenomatous polyps are precancerous lesions associated with a higher risk of colorectal cancer (CRC). Curcumin and anthocyanins have shown promising CRC-preventive activity in preclinical and epidemiological studies. The objective of this window-of-opportunity, proof-of principle trial was to evaluate the effect of curcumin combined with anthocyanin supplements on tissue biomarkers of colorectal adenomatous polyps. Eligible patients received either anthocyanin and curcumin supplementation or related matching placebo for 4-6 weeks before polyp removal. Adenomatous polyps and adjacent tissue biopsies were collected at baseline and after supplementation for immunohistochemical assessment of ß-catenin, NF-kappa B (NF-κB), Ki-67, P53, and dysplasia. No differences were observed in baseline biomarker expression between normal and dysplastic tissues. The combination of anthocyanins and curcumin resulted in a significant borderline reduction of NF-κB immunohistochemistry (IHC) expression in adenoma tissue (geometric mean ratio (GMR): 0.72; 95% confidence interval (CI): 0.51-1.00; p-value: 0.05) and a trend to a reduction of Ki-67 (GMR: 0.73; 95% CI: 0.50-1.08; p-value: 0.11). No significant modulation of biomarkers in normal adjacent mucosa was observed. We concluded that the combined supplementation of anthocyanins and curcumin seems to lead to a potentially favorable modulation of tissue biomarkers of inflammation and proliferation in colon adenomas.