We investigated whether microRNA expression profiles can predict clinical outcome of NSCLC patients. Using real-time RT-PCR, we obtained microRNA expressions in 112 NSCLC patients, which were divided ...into the training and testing sets. Using Cox regression and risk-score analysis, we identified a five-microRNA signature for the prediction of treatment outcome of NSCLC in the training set. This microRNA signature was validated by the testing set and an independent cohort. Patients with high-risk scores in their microRNA signatures had poor overall and disease-free survivals compared to the low-risk-score patients. This microRNA signature is an independent predictor of the cancer relapse and survival of NSCLC patients.
Huntington's disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) ...is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.
Since December 2019, an epidemic caused by novel coronavirus (2019-nCoV) infection has occurred unexpectedly in China. As of 8 pm, 31 January 2020, more than 20 pediatric cases have been reported in ...China. Of these cases, ten patients were identified in Zhejiang Province, with an age of onset ranging from 112 days to 17 years. Following the latest
National recommendations for diagnosis and treatment of pneumonia caused by 2019-nCoV
(the 4th edition) and current status of clinical practice in Zhejiang Province, recommendations for the diagnosis and treatment of respiratory infection caused by 2019-nCoV for children were drafted by the National Clinical Research Center for Child Health, the National Children’s Regional Medical Center, Children’s Hospital, Zhejiang University School of Medicine to further standardize the protocol for diagnosis and treatment of respiratory infection in children caused by 2019-nCoV.
The osteogenic differentiation of mesenchymal stem cells (MSCs) is governed by multiple mechanisms. Growing evidence indicates that ubiquitin‐dependent protein degradation is critical for the ...differentiation of MSCs and bone formation; however, the function of ubiquitin‐specific proteases, the largest subfamily of deubiquitylases, remains unclear. Here, we identify USP34 as a previously unknown regulator of osteogenesis. The expression of USP34 in human MSCs increases after osteogenic induction while depletion of USP34 inhibits osteogenic differentiation. Conditional knockout of Usp34 from MSCs or pre‐osteoblasts leads to low bone mass in mice. Deletion of Usp34 also blunts BMP2‐induced responses and impairs bone regeneration. Mechanically, we demonstrate that USP34 stabilizes both Smad1 and RUNX2 and that depletion of Smurf1 restores the osteogenic potential of Usp34‐deficient MSCs in vitro. Taken together, our data indicate that USP34 is required for osteogenic differentiation and bone formation.
Synopsis
Combining in vitro and in vivo approaches, this study identifies ubiquitin‐specific protease USP34 as a new regulator of osteogenesis. USP34 activates BMP2 signaling by deubiquitinating and stabilizing Smad1 and RUNX2, thereby promoting osteogenic differentiation.
Depletion of USP34 impairs osteogenic differentiation in vivo and in vitro.
Usp34‐depleted mice have low bone mass.
USP34 is required to activate BMP2 signaling during bone formation.
USP34 stabilizes Smad1 and RUNX2 by deubiquitination.
USP34 counteracts ubiquitin ligase Smurf1, which targets Smad1 and RUNX2.
Combining in vitro and in vivo approaches, this study identifies USP34 as a new regulator of osteogenesis via targeted stabilization of Smad1 and RUNX2, illustrating a role for protein deubiquitination in bone formation.
Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct ...disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.
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•First deep proteogenomic landscape of non-smoking lung adenocarcinoma in East Asia•Identified age, sex-related endogenous, and environmental carcinogen mutagenic processes•Proteome-informed classification distinguished clinical features within early stages•Protein networks identified tumorigenesis hallmarks, biomarkers, and druggable targets
Deep proteogenomic landscape of early stage lung adenocarcinoma in a cohort of mostly non-smokers reveals unique drivers and biomarkers, as well as gender-associated mutagenesis.
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs (typically consisting of 18–25 nucleotides) that negatively control expression of target genes at the post-transcriptional level. Owing to the ...biological significance of miRNAs, miRTarBase was developed to provide comprehensive information on experimentally validated miRNA–target interactions (MTIs). To date, the database has accumulated >13,404 validated MTIs from 11,021 articles from manual curations. In this update, a text-mining system was incorporated to enhance the recognition of MTI-related articles by adopting a scoring system. In addition, a variety of biological databases were integrated to provide information on the regulatory network of miRNAs and its expression in blood. Not only targets of miRNAs but also regulators of miRNAs are provided to users for investigating the up- and downstream regulations of miRNAs. Moreover, the number of MTIs with high-throughput experimental evidence increased remarkably (validated by CLIP-seq technology). In conclusion, these improvements promote the miRTarBase as one of the most comprehensively annotated and experimentally validated miRNA–target interaction databases. The updated version of miRTarBase is now available at http://miRTarBase.cuhk.edu.cn/.
Deep learning for digital pathology is hindered by the extremely high spatial resolution of whole-slide images (WSIs). Most studies have employed patch-based methods, which often require detailed ...annotation of image patches. This typically involves laborious free-hand contouring on WSIs. To alleviate the burden of such contouring and obtain benefits from scaling up training with numerous WSIs, we develop a method for training neural networks on entire WSIs using only slide-level diagnoses. Our method leverages the unified memory mechanism to overcome the memory constraint of compute accelerators. Experiments conducted on a data set of 9662 lung cancer WSIs reveal that the proposed method achieves areas under the receiver operating characteristic curve of 0.9594 and 0.9414 for adenocarcinoma and squamous cell carcinoma classification on the testing set, respectively. Furthermore, the method demonstrates higher classification performance than multiple-instance learning as well as strong localization results for small lesions through class activation mapping.
Cell membranes are an intricate yet fragile interface that requires substrate support for stabilization. Upon cell death, disassembly of the cytoskeletal network deprives plasma membranes of ...mechanical support and leads to membrane rupture and disintegration. By assembling a network of synthetic hydrogel polymers inside the intracellular compartment using photo-activated crosslinking chemistry, we show that the fluid cell membrane can be preserved, resulting in intracellularly gelated cells with robust stability. Upon assessing several types of adherent and suspension cells over a range of hydrogel crosslinking densities, we validate retention of surface properties, membrane lipid fluidity, lipid order, and protein mobility on the gelated cells. Preservation of cell surface functions is further demonstrated with gelated antigen presenting cells, which engage with antigen-specific T lymphocytes and effectively promote cell expansion ex vivo and in vivo. The intracellular hydrogelation technique presents a versatile cell fixation approach adaptable for biomembrane studies and biomedical device construction.
Abstract
Background
Owing to the heterogeneity of microbiota among individuals and populations, only
Fusobacterium nucleatum
and
Bacteroides fragilis
have been reported to be enriched in colorectal ...cancer (CRC) in multiple studies. Thus, the discovery of additional bacteria contributing to CRC development in various populations can be expected. We aimed to identify bacteria associated with the progression of colorectal adenoma to carcinoma and determine the contribution of these bacteria to malignant transformation in patients of Han Chinese origin.
Methods
Microbiota composition was determined through 16S rRNA V3–V4 amplicon sequencing of autologous adenocarcinomas, adenomatous polyps, and non-neoplastic colon tissue samples (referred to as “tri-part samples”) in patients with CRC. Enriched taxa in adenocarcinoma tissues were identified through pairwise comparison. The abundance of candidate bacteria was quantified through genomic quantitative polymerase chain reaction (qPCR) in tissue samples from 116 patients. Associations of candidate bacteria with clinicopathological features and genomic and genetic alterations were evaluated through odds ratio tests. Additionally, the effects of candidate bacteria on CRC cell proliferation, migration, and invasion were evaluated through the co-culture of CRC cells with bacterial cells or with conditioned media from bacteria.
Results
Prevotella intermedia
was overrepresented in adenocarcinomas compared with paired adenomatous polyps. Furthermore, co-abundance of
P. intermedia
and
F. nucleatum
was observed in tumor tissues. More notably, the coexistence of these two bacteria in adenocarcinomas was associated with lymph node involvement and distant metastasis. These two bacteria also exerted additive effects on the enhancement of the migration and invasion abilities of CRC cells. Finally, conditioned media from
P. intermedia
promoted the migration and invasion of CRC cells.
Conclusion
This report is the first to demonstrate that
P. intermedia
is enriched in colorectal adenocarcinoma tissues and enhances the migration and invasion abilities of CRC cells. Moreover,
P. intermedia
and
F. nucleatum
exert additive effects on the malignant transformation of colorectal adenomas into carcinomas. These findings can be used to identify patients at a high risk of malignant transformation of colorectal adenomas or metastasis of CRC, and they can accordingly be provided optimal clinical management.
Background
Women and their health care providers need a reliable answer to this important question: If a woman chooses to participate in regular mammography screening, then how much will this choice ...improve her chances of avoiding a death from breast cancer compared with women who choose not to participate?
Methods
To answer this question, we used comprehensive registries for population, screening history, breast cancer incidence, and disease‐specific death data in a defined population in Dalarna County, Sweden. The annual incidence of breast cancer was calculated along with the annual incidence of breast cancers that were fatal within 10 and within 11 to 20 years of diagnosis among women aged 40 to 69 years who either did or did not participate in mammography screening during a 39‐year period (1977‐2015). For an additional comparison, corresponding data are presented from 19 years of the prescreening period (1958‐1976). All patients received stage‐specific therapy according to the latest national guidelines, irrespective of the mode of detection.
Results
The benefit for women who chose to participate in an organized breast cancer screening program was a 60% lower risk of dying from breast cancer within 10 years after diagnosis (relative risk, 0.40; 95% confidence interval, 0.34‐0.48) and a 47% lower risk of dying from breast cancer within 20 years after diagnosis (relative risk, 0.53; 95% confidence interval, 0.44‐0.63) compared with the corresponding risks for nonparticipants.
Conclusions
Although all patients with breast cancer stand to benefit from advances in breast cancer therapy, the current results demonstrate that women who have participated in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than do those who have not participated.
After 20 years of follow‐up, women who participate in mammography screening have a 47% lower risk of dying from breast cancer. Although all patients with breast cancer potentially can benefit from advances in breast cancer therapy, women who participate in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than those who do not participate.
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