Recent efforts to narrow the spread in equilibrium climate sensitivity (ECS) across global climate models have focused on identifying observationally based constraints, which are rooted in empirical correlations between ECS and biases in the models' present-day climate. This study reexamines one such constraint identified from CMIP3 models: the linkage between ECS and net top-of-the-atmosphere radiation biases in the Southern Hemisphere (SH). As previously documented, the intermodel spread in the ECS of CMIP3 models is linked to present-day cloud and net radiation biases over the midlatitude Southern Ocean, where higher cloud fraction in the present-day climate is associated with larger values of ECS. However, in this study, no physical explanation is found to support this relationship. Furthermore, it is shown here that this relationship disappears in CMIP5 models and is unique to a subset of CMIP models characterized by unrealistically bright present-day clouds in the SH subtropics. In view of this evidence, Southern Ocean cloud and net radiation biases appear inappropriate for providing observationally based constraints on ECS. Instead of the Southern Ocean, this study points to the stratocumulus-to-cumulus transition regions of the SH subtropical oceans as key to explaining the intermodel spread in the ECS of both CMIP3 and CMIP5 models. In these regions, ECS is linked to present-day cloud and net radiation biases with a plausible physical mechanism: models with brighter subtropical clouds in the present-day climate show greater ECS because 1) subtropical clouds dissipate with increasing CO2 concentrations in many models and 2) the dissipation of brighter clouds contributes to greater solar warming of the surface.

Atomic scale features of polyvinylidene fluoride molecules (PVDF) were observed with aberration corrected transmission electron microscopy. Thin, self-supporting PVDF nanofibers were used to create images that show conformations and relative locations of atoms in segments of polymer molecules, particularly segments near the surface of the nanofiber. Rows of CF2 atomic groups, at 0.25 nm intervals, which marked the paths of segments of the PVDF molecules, were seen. The fact that an electron microscope image of a segment of a PVDF molecule depended upon the particular azimuthal direction, along which the segment was viewed, enabled observation of twist around the molecular axis. The 0.2 nm side-by-side distance between the two fluorine atoms attached to the same carbon atom was clearly resolved. Morphological and chemical changes produced by energetic electrons, ranging from no change to fiber scission, over many orders of magnitude of electrons per unit area, promise quantitative new insights into radiation chemistry. Relative movements of segments of molecules were observed. Promising synergism between high resolution electron microscopy and molecular dynamic modeling was demonstrated. This paper is at the threshold of growing usefulness of electron microscopy to the science and engineering of polymer and other molecules.

Background

Human Cub and Sushi Multiple Domains 1 (CSMD1) is a novel candidate tumor-suppressor gene that codes for multiple domains, including complement regulatory and adhesion proteins, and has recently been shown to have alterations in multiple cancers. We investigated CSMD1 in esophageal squamous cell carcinoma (ESCC) by performing an integrated analysis on somatic copy number alterations (CNAs), including copy-number gain or loss, allelic imbalance (AI), loss of heterozygosity (LOH), and the expressions of mRNA and its target miRNAs on specimens from the same patients with ESCC.

Results

(i) Two-thirds of ESCC patients had all three types of alterations studied-somatic DNA alterations in 70%, and abnormal expressions of CSMD1 RNA in 69% and in target miRNAs in 66%; patterns among these alterations were complex. (ii) In total, 97% of 888 CSMD1 SNPs studied showed somatic DNA alterations, with most located near exons 4-11, 24-25, 39-40, 55-56, and 69-70. (iii) In total, 68% of SNPs with a CNA were correlated with expression of CSMD1. (iv) A total of 33 correlations between non-coding SNPs and expression of CSMD1 target miRs were found.

Conclusions

Our results indicate that the CSMD1 gene may play a role in ESCC through complex patterns of DNA alterations and RNA and miRNA expressions. Alterations in some somatic SNPs in non-coding regions of CSMD1 appear to influence expression of this gene and its target miRNAs.

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed higher prostate cancer incidence in men supplemented with high-dose α-tocopherol. We, therefore, examined whether presupplementation plasma α-tocopherol or γ-tocopherol was associated with overall or high-grade prostate cancer. A stratified case-cohort sample that included 1,746 incident prostate cancer cases diagnosed through June 2009 and a subcohort of 3,211 men was derived from the SELECT trial of 35,533 men. Plasma was collected at entry from 2001 to 2004, and median follow-up was 5.5 years (range, 0-7.9 years). Incidence of prostate cancer as a function of plasma α-tocopherol, γ-tocopherol, and supplementation with α-tocopherol or selenomethionine was estimated by the hazard ratio (HR). Plasma γ-tocopherol was not associated with prostate cancer. Men with higher α-tocopherol concentrations seemed to have risk similar to that of men with lower concentrations [overall HR for fifth (Q5) vs. first quintile (Q1), 1.21; 95 % confidence interval (CI), 0.88-1.66; P-trend = 0.24; in the trial placebo arm, Q5 HR, 0.85; 95% CI, 0.44-1.62; P-trend = 0.66]. We found a strong positive plasma α-tocopherol association among men receiving the trial selenomethionine supplement [Q5 HR, 2.04; 95% CI, 1.29-3.22; P-trend = 0.005]. A positive plasma α-tocopherol-prostate cancer association also seemed limited to high-grade disease (Gleason grade, 7-10; overall Q5 HR, 1.59; 95% CI, 1.13-2.24; P-trend = 0.001; among men receiving selenomethionine, Q5 HR, 2.12; 95% CI, 1.32-3.40; P-trend = 0.0002). Our findings indicate that higher plasma α-tocopherol concentrations may interact with selenomethionine supplements to increase high-grade prostate cancer risk, suggesting a biologic interaction between α-tocopherol and selenium itself or selenomethionine.

Helicobacter pylori (Hp) is the primary cause of gastric cancer but we know little of its relative abundance and other microbes in the stomach, especially at the time of gastric cancer diagnosis. Here we characterized the taxonomic and derived functional profiles of gastric microbiota in two different sets of gastric cancer patients, and compared them with microbial profiles in other body sites. Paired non-malignant and tumor tissues were sampled from 160 gastric cancer patients with 80 from China and 80 from Mexico. The 16S rRNA gene V3-V4 region was sequenced using MiSeq platform for taxonomic profiles. PICRUSt was used to predict functional profiles. Human Microbiome Project was used for comparison. We showed that Hp is the most abundant member of gastric microbiota in both Chinese and Mexican samples (51 and 24%, respectively), followed by oral-associated bacteria. Taxonomic (phylum-level) profiles of stomach microbiota resembled oral microbiota, especially when the Helicobacter reads were removed. The functional profiles of stomach microbiota, however, were distinct from those found in other body sites and had higher inter-subject dissimilarity. Gastric microbiota composition did not differ by Hp colonization status or stomach anatomic sites, but did differ between paired non-malignant and tumor tissues in either Chinese or Mexican samples. Our study showed that Hp is the dominant member of the non-malignant gastric tissue microbiota in many gastric cancer patients. Our results provide insights on the gastric microbiota composition and function in gastric cancer patients, which may have important clinical implications.

BACKGROUND: Gastric cancer (GC), a molecularly heterogeneous disease, is the third leading cause of cancer death worldwide. The majority of GC cases worldwide occur in East Asia, predominantly China. Mutational Signature Framework offers an elegant approach to identify mutational processes present in tumors. METHODS: To identify mutational signature patterns, we conducted whole exome sequencing (WES) analysis in Chinese patients with GC. Mutect2 and MutsigCV were used to identify significantly mutated genes in 175 Chinese GC cases using paired tumor-normal tissues. We investigated mutational signatures using Catalogue of Somatic Mutations in Cancer (COSMIC) Version 2 (V2) and Version 3 (V3). RESULTS: We identified 104 mutated genes with P < 0.01. Seven genes (OR6B1, B2M, ELF3, RHOA, RPL22, TP53, ARIDIA) had q < 0.0001, including six previously associated with GC. Mutational signatures (COSMIC-V3) observed include 14 single base substitutions (SBS), one doublet base substitution (DBS) Signature A, and one InDel (ID2). The most frequent SBS signatures (SBS05, SBS01, SBS15, SBS20, SBS40) were also observed in 254 White GC cases from The Cancer Genome Atlas (TCGA) Project. However, SBS01 and SBS20 showed significant differences between Whites vs. All Asians (19.3% vs. 11.3% for SBS 1 (P = 0.012) and 11.4% vs. 5.9% for SBS20 (P = 0.025), respectively). Using COSMIC V2, signatures 6, 15, and 1 were the most frequent in Chinese GC cases. Further, most Chinese GC cases carried multiple signatures. CONCLUSIONS: This effort represents the most detailed mutational signatures analysis of GC cases from China to date. Results hold promise for new insights in understanding risk and prognosis factors in GC.

Context

Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer.

Objective

To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men.

Design, setting, and participants

A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer.

Interventions

Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years.

Main outcome measures

Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer.

Results

As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group.

Conclusion

Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.

Trial registration

clinicaltrials.gov identifier: NCT00006392.

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One possible link between poor oral health and ESCC involves the alteration of the microbiome. We performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed similar ESCC-associated bacterial communities in these cancers. Because these genera are traditionally considered members of the oral microbiota, we next explored whether there was a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes were significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of some ESCC patients.

Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer.