A reference map of the human binary protein interactome.

Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype-phenotype relationships1,2. Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. The integration of HuRI with genome3, transcriptome4 and proteome5 data enables cellular function to be studied within most physiological or pathological cellular contexts. We demonstrate the utility of HuRI in identifying the specific subcellular roles of protein-protein interactions. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms that might underlie tissue-specific phenotypes of Mendelian diseases. HuRI is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes.

Longitudinal health utility and symptom-toxicity trajectories in patients with head and neck cancers.

BACKGROUND: This study examined long-term health utility and symptom-toxicity trajectories among patients with head and neck cancer (HNC). METHODS: For patients diagnosed with HNC (2014-2019), Health Utility Index 3 (HUI-3), Edmonton Symptom Assessment Scale (ESAS), and MD Anderson Symptom Inventory (MDASI) surveys (including both the core and head and neck cancer modules) were prospectively collected at multiple time points (at the baseline, after surgery, during radiotherapy, and 3, 6, 12, and 24 months after treatment). Locally estimated scatterplot smoothing plots were generated to describe HUI-3, ESAS, and MDASI trajectories over time by clinicodemographic factors, treatment modality, and tumor subsite. Contributions of clinical factors were assessed with univariable and multivariable analyses. RESULTS: In 800 patients, the treatment modality and the tumor subsite produced unique HUI-3, ESAS, and MDASI trajectories. Patients treated with surgery alone experienced rapid improvements in HUI-3, ESAS, and MDASI scores postoperatively. Among patients treated with chemoradiotherapy, patients with nasopharyngeal carcinoma had greater declines in HUI-3 during treatment in comparison with patients with oropharyngeal carcinoma, but they had similar ESAS/MDASI scores. Among patients treated with radiotherapy, patients with laryngeal carcinoma had better HUI-3/ESAS/MDASI scores than those with oropharyngeal carcinoma during treatment, but they slowly converged after treatment. Female sex, an age > 75 years, a household income < $40,000, a Charlson comorbidity score > 1, an Eastern Cooperative Oncology Group performance status > 0 (at the baseline), and current smoking were independently associated with worse HUI-3 trajectories. HUI-3 had mild to moderate correlations (ρ = 0.2-0.5) with individual symptom-toxicity trajectories. CONCLUSIONS: Long-term HUI-3 trajectories are associated with tumor subsite, clinicodemographic, and treatment factors, and this may be partly explained by relationships with symptoms/toxicities. Separate evaluations by subsite and treatment should occur in health utility and symptom-toxicity studies of HNC. LAY SUMMARY: This study indicates that the long-term health utility and symptoms/toxicities of patients with the most common head and neck cancers (ie, squamous cell carcinomas and nasopharyngeal carcinomas) differ over time with a variety of factors, including the tumor anatomic site, treatment volume, clinicodemographic characteristics (eg, age, human papillomavirus status, tumor stage, gender, smoking status, alcohol status, education, and comorbidities), and treatment modalities. Generalizations across all head and neck cancers should be strongly discouraged. Future studies should evaluate health utility, symptoms and toxicities, and patient need assessments separately for each anatomic site and treatment modality.

Circulating miR-26a and miR-21 as biomarkers for glioblastoma multiform.

Glioblastoma multiform is the most common and lethal primary central nervous system tumor. Circulating microRNAs (miRNAs), present in cell-free bodily fluids, have been gaining importance as cancer biomarkers. The primary aim of this study was to assess whether circulating miRNA-128, -21, and -26a in glioblastoma patients can be used as diagnostic biomarkers. Venous blood samples were collected from 11 noncancerous volunteers and 15 glioblastoma patients pre- and post operation. Also, tissue tumor samples were obtained intra-operationally to assay consistency of miRNA levels in serum and tissue samples. Serum and tissue levels of miRNAs were determined by quantitative reverse transcription PCR. miR-21 and miR-26a were both significantly upregulated in pre- and postoperation serum samples of glioblastoma patients compared with the serum samples of noncancerous controls. We found that all three miR-128, -21, and -26a expression levels were reduced in postoperative serum samples compared with pre-operative serum samples, though this decrease was only significant for miR-26a. The serum miR-26a and miR-21 upregulation in glioblastoma patients compared to noncancerous controls and their downregulation in postoperative serum from glioblastoma patients suggest that these miRNAs could be used as serum-derived miRNA biomarkers for glioblastoma.

Association of post-treatment longitudinal symptom severity clusters with subsequent survival in oropharyngeal cancer.

BACKGROUND: Patients with cancer often experience multiple symptoms concurrently. We identified patient clusters based on longitudinal symptom severity trajectories in oropharyngeal cancer (OPC) and evaluated the potential clinical utility of this approach. METHODS: A retrospective OPC patient cluster analysis using 6 months of symptom severity data from radiotherapy initiation. The clinico-demographic characteristics and overall survival of patients were compared between clusters. RESULTS: We identified four clusters of patients differing in longitudinal symptom severity. Cluster A (n = 168) included patients with the mildest longitudinal symptoms, cluster B (n = 59) and cluster C (n = 63) were intermediate, and cluster D (n = 30) included patients with the worst symptoms. The clusters differed in their HPV status, ECOG performance status, smoking history, drinking history, treatment modality, and 5-year survival. These clusters separated symptom severity trajectories more distinctly than individual clinico-demographic characteristics. CONCLUSIONS: Early symptom severity trajectory clustering revealed distinct patient clusters that were prognostic of overall survival.

Using breath analysis as a screening tool to detect gastric cancer: a systematic review.

Breath analysis has emerged as an experimental method of non-invasive screening of gastric cancer and identification of individuals suitable for confirmatory, diagnostic upper gastrointestinal endoscopy. We aimed to evaluate the accuracy and applicability of breath analysis for gastric cancer detection in adults.We searched MEDLINE, EMBASE, BIOSIS, CENTRAL, and Compendex up to 27 September 2020 for original studies analysing exhaled breath to detect gastric cancer in patients. Summary sensitivity and specificity analyses were obtained using a hierarchical bivariate method. Non-quantitative results were descriptively summarized. Risk of bias was assessed using the QUADAS-2 tool. This study protocol was pre-registered in PROSPERO (CRD42020139422).Twenty-four studies were included. Within these, breath analysis technologies most commonly used were mass spectrometry (MS)-based methods; other methods included volatile organic compound sensors and silicon nanowire field effect transistors. Fourteen studies (totaln= 3028) involving all technologies reported quantitative results, with sensitivities ranging from 67%-100% and specificities from 71%-98%. The summary sensitivity across six studies utilizing MS-based breath analysis methods was 82.4% (95% CI: 78%-86%); summary specificity was 91.3% (95% CI: 83%-96%). Based on these values, we estimated that screening with MS-based breath tests could lower the number needed to screen (NNS) by more than eight-fold in the 15 countries with the highest prevalence of gastric cancer.Breath analysis is a promising method for gastric cancer detection with good diagnostic performance and potential to decrease the NNS for endoscopy-based gastric cancer detection. However, due to the heterogeneity of breath analysis technologies, rigorous studies with standardized, reproducible methods are needed to evaluate the clinical applicability of these technologies.

miR-1266-5p and miR-185-5p Promote Cell Apoptosis in Human Prostate Cancer Cell Lines

Objective: Small non-coding RNA molecules are dysregulated in prostate cancer (PCa). In our previous study, downregulation of miR-1266 and miR-185 was demonstrated in PCa tissues and cell lines. The aim of the present study was to investigate whether miR-1266 and miR-185 are involved in the regulation of B-cell lymphoma (BCL) 2 and BCL2L1, respectively, and whether transfection of PCa cell lines with miR-1266 and miR-185 mimics can alter tumorigenic phenotypes. Methods: In order to investigate the regulation of BCL2 and BCL2L1 mRNA levels by miR-1266 and miR-185, respectively, a luciferase reporter assay was used. Real-time PCR was also used to analyze changes in the levels of BCL2 and BCL2L1 mRNAs in PCa cell lines following transfection with synthetic miR-1266 and miR-185. Cell apoptosis was determined by Annexin V protein expression analysis via flow cytometry. In addition to the MTT assay, a cell proliferation assay was performed. Result: A luciferase assay confirmed that the BCL2 and BCL2L1 genes may be targeted by miR-1266 and miR-185, respectively, through binding to their 3'UTR regions. Transfection of PC3 and DU145 cells with miR-1266 and miR-185 induced apoptosis and reduced proliferation, which also revealed an inverse correlation with BCL2 and BCL2L1 gene expression in the treated cells. Conclusion: Our data suggests that miR-1266 and miR-185 may be novel candidates for further research in PCa treatment through the anti-apoptotic pathway.

Interactomic analysis of REST/NRSF and implications of its functional links with the transcription suppressor TRIM28 during neuronal differentiation.

RE-1 silencing transcription factor (REST) is a transcriptional repressor that regulates gene expression by binding to repressor element 1. However, despite its critical function in physiology, little is known about its interaction proteins. Here we identified 204 REST-interacting proteins using affinity purification and mass spectrometry. The interactome included proteins associated with mRNA processing/splicing, chromatin organization, and transcription. The interactions of these REST-interacting proteins, which included TRIM28, were confirmed by co-immunoprecipitation and immunocytochemistry, respectively. Gene Ontology (GO) analysis revealed that neuronal differentiation-related GO terms were enriched among target genes that were co-regulated by REST and TRIM28, while the level of CTNND2 was increased by the knockdown of REST and TRIM28. Consistently, the level of CTNND2 increased while those of REST and TRIM28 decreased during neuronal differentiation in the primary neurons, suggesting that CTNND2 expression may be co-regulated by both. Furthermore, neurite outgrowth was increased by depletion of REST or TRIM28, implying that reduction of both REST and TRIM28 could promote neuronal differentiation via induction of CTNND2 expression. In conclusion, our study of REST reveals novel interacting proteins which could be a valuable resource for investigating unidentified functions of REST and also suggested functional links between REST and TRIM28 during neuronal development.