VAMP7 modulates ciliary biogenesis in kidney cells

Epithelial cells elaborate specialized domains that have distinct protein and lipid compositions, including the apical and basolateral surfaces and primary cilia. Maintaining the identity of these domains is required for proper cell function, and requires the efficient and selective SNARE-mediated fusion of vesicles containing newly synthesized and recycling proteins with the proper target membrane. Multiple pathways exist to deliver newly synthesized proteins to the apical surface of kidney cells, and the post-Golgi SNAREs, or VAMPs, involved in these distinct pathways have not been identified. VAMP7 has been implicated in apical protein delivery in other cell types, and we hypothesized that this SNARE would have differential effects on the trafficking of apical proteins known to take distinct routes to the apical surface in kidney cells. VAMP7 expressed in polarized Madin Darby canine kidney cells colocalized primarily with LAMP2-positive compartments, and siRNA-mediated knockdown modulated lysosome size, consistent with the known function of VAMP7 in lysosomal delivery. Surprisingly, VAMP7 knockdown had no effect on apical delivery of numerous cargoes tested, but did decrease the length and frequency of primary cilia. Additionally, VAMP7 knockdown disrupted cystogenesis in cells grown in a three-dimensional basement membrane matrix. The effects of VAMP7 depletion on ciliogenesis and cystogenesis are not directly linked to the disruption of lysosomal function, as cilia lengths and cyst morphology were unaffected in an MDCK lysosomal storage disorder model. Together, our data suggest that VAMP7 plays an essential role in ciliogenesis and lumen formation. To our knowledge, this is the first study implicating an R-SNARE in ciliogenesis and cystogenesis. © 2014 Szalinski et al

The binding of Varp to VAMP7 traps VAMP7 in a closed, fusogenically inactive conformation.

SNAREs provide energy and specificity to membrane fusion events. Fusogenic trans-SNARE complexes are assembled from glutamine-contributing SNAREs (Q-SNAREs) embedded in one membrane and an arginine-contributing SNARE (R-SNARE) embedded in the other. Regulation of membrane fusion events is crucial for intracellular trafficking. We identify the endosomal protein Varp as an R-SNARE-binding regulator of SNARE complex formation. Varp colocalizes with and binds to VAMP7, an R-SNARE that is involved in both endocytic and secretory pathways. We present the structure of the second ankyrin repeat domain of mammalian Varp in complex with the cytosolic portion of VAMP7. The VAMP7-SNARE motif is trapped between Varp and the VAMP7 longin domain, and hence Varp kinetically inhibits the ability of VAMP7 to form SNARE complexes. This inhibition will be increased when Varp can also bind to other proteins present on the same membrane as VAMP7, such as Rab32-GTP

Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

BACKGROUND: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. METHODS: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. FINDINGS: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. INTERPRETATION: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. FUNDING: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe

The global, regional, and national burden of oesophageal cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Background Oesophageal cancer is a common and often fatal cancer that has two main histological subtypes: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Updated statistics on the incidence and mortality of oesophageal cancer, and on the disability-adjusted life-years (DALYs) caused by the disease, can assist policy makers in allocating resources for prevention, treatment, and care of oesophageal cancer. We report the latest estimates of these statistics for 195 countries and territories between 1990 and 2017, by age, sex, and Socio-demographic Index (SDI), using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD). Methods We used data from vital registration systems, vital registration-samples, verbal autopsy records, and cancer registries, combined with relevant modelling, to estimate the mortality, incidence, and burden of oesophageal cancer from 1990 to 2017. Mortality-to-incidence ratios (MIRs) were estimated and fed into a Cause of Death Ensemble model (CODEm) including risk factors. MIRs were used for mortality and non-fatal modelling. Estimates of DALYs attributable to the main risk factors of oesophageal cancer available in GBD were also calculated. The proportion of oesophageal squamous cell carcinoma to all oesophageal cancers was extracted by use of publicly available data, and its variation was examined against SDI, the Healthcare Access and Quality (HAQ) Index, and available risk factors in GBD that are specific for oesophageal squamous cell carcinoma (eg, unimproved water source and indoor air pollution) and for oesophageal adenocarcinoma (gastro-oesophageal reflux disease). Findings There were 473 000 (95% uncertainty interval [95% UI] 459 000–485 000) new cases of oesophageal cancer and 436 000 (425 000–448 000) deaths due to oesophageal cancer in 2017. Age-standardised incidence was 5·9 (5·7–6·1) per 100 000 population and age-standardised mortality was 5·5 (5·3–5·6) per 100 000. Oesophageal cancer caused 9·78 million (9·53–10·03) DALYs, with an age-standardised rate of 120 (117–123) per 100 000 population. Between 1990 and 2017, age-standardised incidence decreased by 22·0% (18·6–25·2), mortality decreased by 29·0% (25·8–32·0), and DALYs decreased by 33·4% (30·4–36·1) globally. However, as a result of population growth and ageing, the total number of new cases increased by 52·3% (45·9–58·9), from 310 000 (300 000–322 000) to 473 000 (459 000–485 000); the number of deaths increased by 40·0% (34·1–46·3), from 311 000 (301 000–323 000) to 436 000 (425 000–448 000); and total DALYs increased by 27·4% (22·1–33·1), from 7·68 million (7·42–7·97) to 9·78 million (9·53–10·03). At the national level, China had the highest number of incident cases (235 000 [223 000–246 000]), deaths (213 000 [203 000–223 000]), and DALYs (4·46 million [4·25–4·69]) in 2017. The highest national-level age-standardised incidence rates in 2017 were observed in Malawi (23·0 [19·4–26·5] per 100 000 population) and Mongolia (18·5 [16·4–20·8] per 100 000). In 2017, age-standardised incidence was 2·7 times higher, mortality 2·9 times higher, and DALYs 3·0 times higher in males than in females. In 2017, a substantial proportion of oesophageal cancer DALYs were attributable to known risk factors: tobacco smoking (39·0% [35·5–42·2]), alcohol consumption (33·8% [27·3–39·9]), high BMI (19·5% [6·3–36·0]), a diet low in fruits (19·1% [4·2–34·6]), and use of chewing tobacco (7·5% [5·2–9·6]). Countries with a low SDI and HAQ Index and high levels of indoor air pollution had a higher proportion of oesophageal squamous cell carcinoma to all oesophageal cancer cases than did countries with a high SDI and HAQ Index and with low levels of indoor air pollution. Interpretation Despite reductions in age-standardised incidence and mortality rates, oesophageal cancer remains a major cause of cancer mortality and burden across the world. Oesophageal cancer is a highly fatal disease, requiring increased primary prevention efforts and, possibly, screening in some high-risk areas. Substantial variation exists in age-standardised incidence rates across regions and countries, for reasons that are unclear. Funding Bill & Melinda Gates Foundation