Citations

AbstractWe aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical‐grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis‐associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47–2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30–2.75, p = 0.004), while absence was associated with shorter OS in low‐grade serous carcinomas (HR: 2.95, 95% CI 1.61–5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype‐specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.

Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin (HN) is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. The present study aimed to test the hypothesis that chronic supplementation of exogenous HN in middle-aged mice could prevent and reverse cardiac fibrosis and apoptosis in the aging heart. Female C57BL/6N mice at 18 mo of age received 14-mo intraperitoneal injections of vehicle (old group; n = 6) or HN analog (HNG; 4 mg/kg 2 times/wk, old + HNG group, n = 8) and were euthanized at 32 mo of age. C57BL/6N female mice (young group, n = 5) at 5 mo of age were used as young controls. HNG treatment significantly increased the ratio of cardiomyocytes to fibroblasts in aging hearts, as shown by the percentage of each cell type in randomly chosen fields after immunofluorescence staining. Furthermore, the increased collagen deposition in aged hearts was significantly reduced after HNG treatment, as indicated by picrosirius red staining. HNG treatment also reduced in aging mice cardiac fibroblast proliferation (5′-bromo-2-deoxyuridine staining) and attenuated transforming growth factor-β1, fibroblast growth factor-2, and matrix metalloproteinase-2 expression (immunohistochemistry or real-time PCR). Myocardial apoptosis was inhibited in HNG-treated aged mice (TUNEL staining). To decipher the pathway involved in the attenuation of the myocardial fibrosis by HNG, Western blot analysis was done and showed that HNG upregulated the Akt/glycogen synthase kinase -3β pathway in aged mice. Exogenous HNG treatment attenuated myocardial fibrosis and apoptosis in aged mice. The results of the present study suggest a role for the mitochondria-derived peptide HN in the cardioprotection associated with aging. NEW & NOTEWORTHY Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. Here, we demonstrate, for the first time, that exogenous humanin treatment attenuated myocardial fibrosis and apoptosis in aging mice. We also detected upregulated Akt/glycogen synthase kinase-3β pathway in humanin analog-treated mice, which might be the mechanism involved in the cardioprotective effect of humanin analog in aging mice.

SummaryBackgroundCurrent management of refractory benign oesophageal strictures with endoscopic dilations and stenting leads to resolution of dysphagia in only 30% of patients. Oesophageal self‐dilation may be an alternative.AimTo evaluate the efficacy and safety of oesophageal self‐dilation at a tertiary referral centre.MethodsWe conducted a retrospective review of patients with refractory benign oesophageal strictures who participated in oesophageal self‐dilation at Mayo Clinic (Rochester, MN, USA) between 2003 and 2017. Clinical data including stricture characteristics, Dakkak and Bennett Dysphagia Score, number and dates of endoscopies, and complications were collected. A two‐tailed paired Student's t test was used to compare the measures of efficacy, with differences considered significant at a 5% probability level.ResultsWe identified 52 patients with refractory strictures treated with self‐dilation. The median number of endoscopic interventions was reduced from 9.5 (range 5‐30) to 0 (range 0‐3) within 12 months before and after self‐dilation, respectively (P < 0.0001). A median intervention‐free interval of 417 days (IQR 256‐756 days) was observed. The mean dysphagia score at baseline was 2.5 (95% CI 2.2‐2.8) and 0.33 (95% CI 0.11‐0.53) after self‐dilation. 23 of 27 (85%) patients who received enteral nutrition prior to self‐dilation had their feeding tubes removed.ConclusionsOesophageal self‐dilation is an effective way of maintaining oesophageal patency in refractory benign oesophageal strictures, with safety comparable to current standard of care. Prospective studies are needed to further validate the role of self‐dilation in treatment of refractory benign oesophageal strictures.

AbstractEpidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10−3), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10−3) and concordance in effect direction (P = 2.0 × 10−3) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10−5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10−8, OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by levels of histologic grade and proliferation. We pooled risk factor and pathology data on 5,905 HR+ breast cancer cases and 26,281 controls from 11 epidemiological studies. Proliferation was determined by centralized automated measures of KI67 in tissue microarrays. Odds ratios (OR), 95% confidence intervals (CI) and p‐values for case–case and case–control comparisons for risk factors in relation to levels of grade and quartiles (Q1–Q4) of KI67 were estimated using polytomous logistic regression models. Case–case comparisons showed associations between nulliparity and high KI67 [OR (95% CI) for Q4 vs. Q1 = 1.54 (1.22, 1.95)]; obesity and high grade [grade 3 vs. 1 = 1.68 (1.31, 2.16)] and current use of combined hormone therapy (HT) and low grade [grade 3 vs. 1 = 0.27 (0.16, 0.44)] tumors. In case–control comparisons, nulliparity was associated with elevated risk of tumors with high but not low levels of proliferation [1.43 (1.14, 1.81) for KI67 Q4 vs. 0.83 (0.60, 1.14) for KI67 Q1]; obesity among women ≥50 years with high but not low grade tumors [1.55 (1.17, 2.06) for grade 3 vs. 0.88 (0.66, 1.16) for grade 1] and HT with low but not high grade tumors [3.07 (2.22, 4.23) for grade 1 vs. 0.85 (0.55, 1.30) for grade 3]. Menarcheal age and family history were similarly associated with HR+ tumors of different grade or KI67 levels. These findings provide insights into the etiologic heterogeneity of HR+ tumors.

Differences in the molecular structure or organ distribution of receptors can limit the usefulness of a given species for drug studies. In this work, we have studied cholecystokinin (CCK) receptors in cynomolgus monkey, an animal model useful for preclinical testing. The type A CCK receptor cDNA was cloned and predicted to encode a 428 amino acid peptide that was 98% identical to the human receptor. Only 2 of the 10 residues that were distinct from the human receptor were not present in other cloned CCK receptor species. A Chinese hamster ovary cell line that stably expressed this receptor was developed. The cynomolgus receptor expressed in this environment was functionally indistinguishable from the human receptor, binding CCK with high affinity [inhibition constant ( KI) = 1.8 ± 0.5 nM] and exhibiting a potent intracellular calcium signaling response to this hormone (EC50= 6.6 ± 2.1 pM). Like the human type A CCK receptor, this receptor was expressed prominently in monkey gallbladder and stomach and was expressed in low levels in brain and pancreas. The type B CCK receptor cDNA was cloned from stomach and brain (450 residue receptor that is 96% identical to the human receptor), where it was highly expressed yet was undetectable in gallbladder or pancreas. This work confirms the relevance of the cynomolgus species for preclinical testing of drugs acting on the type A CCK receptor.

Background. The strength of associations between total testosterone (TT) and metabolic parameters may vary in different nature of population structure; however, no study has ever given this information in Chinese population, especially those without metabolic syndrome (MS). We aimed to analyze the association magnitudes between TT and multiple metabolic parameters in general Chinese men. Methods. 4309 men were recruited from SPECT-China study in 2014-2015, which was performed in 22 sites in East China. TT, weight status, and various metabolic parameters were measured. Linear and logistic regressions were used to analyze the associations. Results. Men in lower TT quartiles had worse metabolic parameters including body mass index, triglycerides, HbA1c, and HOMA-IR (all P for trend < 0.001). Body mass index (B −0.32, 95%CI −0.35 to −0.29) and obesity (OR 0.40, 95%CI 0.35–0.45) had the largest association magnitude per one SD increment in TT, while blood pressure and hypertension (OR 0.90, 95%CI 0.84–0.98) had the smallest. These associations also persisted in individuals without metabolic syndrome. Conclusions. Obesity indices had closer relationships with TT than most other metabolic measures with blood pressure the least close. These associations remained robust after adjustment for adiposity and in subjects without metabolic syndrome.