SummaryBackgroundData on carcinogenicity of human papillomavirus (HPV) types in the anus are needed to inform anal cancer prevention through vaccination and screening. This is particularly the case for people infected with HIV, who are at an increased risk of anal cancer.MethodsWe did a systematic review of studies published from January, 1986, to July, 2017, in MEDLINE, Embase, and the Cochrane Library on anal HPV infection, without any language restrictions. Eligible studies reported type-specific HPV prevalence by strata of cytopathological or histopathological anal diagnosis, sex, and HIV status. Data requests were made to authors when necessary. We did a meta-analysis of type-specific HPV prevalence across the full spectrum of anal diagnoses, from normal cytology to anal cancer. We assessed the main outcome of type-specific HPV prevalence ratios [PR], calculated across strata of anal diagnoses, gender, or HIV status, by use of generalised linear models.Findings95 studies were identified from the search, published between 1992–2017, from which 18 646 individuals fulfilled the criteria for inclusion in the analyses: 8534 people with normal cytology, 5730 with low-grade lesions, 2024 with high-grade lesions, and 2358 with anal cancer. HPV prevalence varied in normal cytology from 42% in HIV-negative women to 76% in HIV-positive men and, for each diagnosis, was higher in individuals who were HIV positive than those who were HIV negative. HPV16 positivity increased with diagnosis severity, being the only HPV type accounting for more HPV infection in anal cancer than normal cytology, both in individuals who were HIV negative (PR 5·0, 95% CI 3·8–6·6, p<0·0001) and those who were HIV positive (2·3, 1·9–2·7, p<0·0001). HPV16 positivity increased even between high-grade lesions and anal cancer, whereas other high-risk HPV types accounted for high proportions of low-grade or high-grade lesions but their prevalence decreased in anal cancer. However, HPV16 was less frequent in HIV-positive than HIV-negative anal cancer, both in men (PR 0·8, 95% CI 0·7–0·9, p<0·0001) and women (0·8, 0·6–1·0, p=0·063), and in HIV-positive versus HIV-negative high-grade lesions in women (0·6, 0·5–0·9, p=0·0077). Type-specific attribution of the non-HPV16 fraction of HIV-positive anal cancer is hindered by a high prevalence of multiple HPV infections.InterpretationHPV16 is by far the most carcinogenic HPV type in the anus, with enrichment of HPV16 even from high-grade lesions to anal cancer, both in individuals who are HIV negative and those who are HIV positive. Nevertheless, the fraction of anal cancer attributable to HPV16 is smaller in the HIV-positive population.FundingInternational Agency for Research on Cancer.

In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called mitophagy. The ERmitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/ calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells.

Background Understanding disparities in the burden of cancer attributable to different risk factors is crucial to inform and improve cancer prevention and control. In this report, we estimate the site-specific population-attributable fractions (PAFs) for 23 potentially modifiable risk factors across all provinces in China. MethodsIn this comparative risk assessment study, we used 2014 cancer mortality data for adults from 978 countylevel surveillance points in 31 provinces of mainland China. Risk-factor prevalence estimates were obtained from representative surveys. We used summary relative risks obtained from several recent large-scale pooled analyses or high-quality meta-analyses of studies in China. We calculated PAFs using multiple formulae incorporating exposure prevalence and relative risk data stratified by age, sex and province and then combined to create summary PAFs by sex, cancer site, and risk factors. Findings About 1 036 004 cancer deaths (45•2% of all cancer deaths [95% CI 44•0-46•4]) in China in 2014 in adults aged 20 years or older were attributable to 23 evaluated risk factors. The PAF was higher in men (51•2% [95% CI 50•0-52•4]) than in women (34•9% [33•6-36•2]), with the leading risk factors being active smoking in men and low fruit intake in women. By province, the PAF in both sexes combined ranged from 35•2% in Shanghai to 52•9% in Heilongjiang, while the PAF varied from 40•9% in Shanghai to 56•4% in Guangdong among men and from 26•9% in Shanghai to 48•0% in Heilongjiang among women. The highest PAF among men was smoking in all 31 provinces, whereas among women it varied among low fruit intake (14 provinces), hepatitis B virus infection (seven provinces), smoking (six provinces), excess bodyweight (three provinces), and human papilloma virus infection (one province).Interpretation The PAFs of cancers attributable to potentially modifiable risk factors vary substantially across provinces in China. Regional adoption of effective primary cancer prevention strategies has a vast potential to reduce the burden of cancer and disparities in China. Smoking, poor diet, and infection warrant particular policy attention as they contributed a large proportion to the total cancer burden.

Edited by Noboru MizushimaKeywords: Mitophagy UNC-51 like kinase Adenosine 5 0 -monophosphate (AMP)-activated protein kinase Hypoxia Autophagy Mitochondria a b s t r a c t UNC-51 like kinase (ULK1) translocates to dysfunctional mitochondria and is involved in mitophagy, but the mechanisms responsible for ULK1 activation and translocation remain unclear. Here, we found that hypoxia induces phosphorylation of ULK1 at Serine-555 by Adenosine 5 0 -monophosphate (AMP)-activated protein kinase (AMPK). Unlike wild-type ULK1, an ULK1 (S555A) mutant cannot translocate to mitochondria in response to hypoxia. Inhibition or knockdown of AMPK prevents ULK1 translocation and inhibits mitophagy. Finally, the phospho-mimic ULK1 (S555D) mutant, but not ULK1 (S555A), rescues mitophagy in AMPK-knockdown cells. Thus, we conclude that AMPK-dependent phosphorylation of ULK1 is critical for translocation of ULK1 to mitochondria and for mitophagy in response to hypoxic stress.

Sexual preference and HIV infection are independent and similarly strong determinants of male anal HPV16 infection, confirming HIV-positive MSM as priorities for anal cancer prevention.