Hastingshartmann2015

The novel coronavirus (CoV) severe acute respiratory syndrome (SARS)-CoV-2 outbreak began at the end of 2019 in Wuhan, China, and has spread to over 200 countries. In this multicenter retrospective study, we identified 2190 adult patients admitted for laboratory-confirmed COVID-19 in three participating centers. Multivariate logistic regression was conducted in patients with comorbid hypertension to examine the potential association between clinical outcomes, disease severity, and clinical characteristics with the use of ACEI, ARB, calcium-channel blockers (CCB), beta-blockers (BB), and thiazide diuretics. The clinical outcome, dyspnea, and fatigue were significantly improved in patients, especially elderly patients who were older than 65 years, who took ARB drugs prior to hospitalization compared to patients who took no drugs. The reduction of disease severity of elderly COVID-19 patients was associated with CCB and ACEI users. Clinical indices, including CRP, lymphocyte count, procalcitonin D dimer, and hemoglobin, were significantly improved in elderly ARB users. In addition, the clinical outcomes were statistically significantly improved in patients who took antihypertension drugs ARB, BB, and CCB after statistical adjustment by all ages, gender, baseline of blood pressures, and coexisting medical conditions. Our data indicate that hypertension drugs ARB, ACEI, CCB, and BB might be beneficial for COVID-19 patients.Most cancers evolve to disable the p53 pathway, a key tumour suppressor mechanism that prevents transformation and malignant cell growth. However, only ~50% exhibit inactivating mutations of p53, while in the rest its activity is suppressed by changes in the proteins that modulate the pathway. Therefore, restoring p53 activity in cells in which it is still wild type is a highly attractive therapeutic strategy that could be effective in many different cancer types. To this end, drugs can be used to stabilise p53 levels by modulating its regulatory pathways. However, despite the emergence of promising strategies, drug development has stalled in clinical trials. The need for alternative approaches has shifted the spotlight to the 14-3-3 family of proteins, which strongly influence p53 stability and transcriptional activity through direct and indirect interactions. Here, we present the first detailed review of how 14-3-3 proteins regulate p53, with special emphasis on the mechanisms involved in their binding to different members of the pathway. This information will be important to design new compounds that can reactivate p53 in cancer cells by influencing protein-protein interactions. The intricate relationship between the 14-3-3 isoforms and the p53 pathway suggests that many potential drug targets for p53 reactivation could be identified and exploited to design novel antineoplastic therapies with a wide range of applications.The human zinc finger (C2H2-type) protein ZNF750 is a transcription factor regulated by p63 that plays a critical role in epithelial tissues homoeostasis, as well as being involved in the pathogenesis of cancer. Indeed, missense mutations, truncation and genomic deletion have been found in oesophageal squamous cell carcinoma. In keeping, we showed that ZNF750 negatively regulates cell migration and invasion in breast cancer cells; in particular, ZNF750 binds and recruits KDM1A and HDAC1 on the LAMB3 and CTNNAL1 promoters. This interaction, in turn, represses the transcription of LAMB3 and CTNNAL1 genes, which are involved in cell migration and invasion. Given that ZNF750 is emerging as a crucial transcription factor that acts as tumour suppressor gene, here, we show that ZNF750 represses the expression of the small GTPase, Ras-related C3 botulinum toxin substrate 1 (RAC1) in breast cancer cell lines, by directly binding its promoter region. In keeping with ZNF750 controlling RAC1 expression, we found an inverse correlation between ZNF750 and RAC1 in human breast cancer datasets. More importantly, we found a significant upregulation of RAC1 in human breast cancer datasets and we identified a direct correlation between RAC1 expression and the survival rate of breast cancer patient. Overall, our findings provide a novel molecular mechanism by which ZNF750 acts as tumour suppressor gene. Hence, we report a potential clinical relevance of ZNF750/RAC1 axis in breast cancer.Longitudinal characterization of SARS-CoV-2 PCR testing from COVID-19 patient's nasopharynx and its juxtaposition with blood-based IgG-seroconversion diagnostic assays is critical to understanding SARS-CoV-2 infection durations. Here, we retrospectively analyze 851 SARS-CoV-2-positive patients with at least two positive PCR tests and find that 99 of these patients remain SARS-CoV-2-positive after 4 weeks from their initial diagnosis date. For the 851-patient cohort, the mean lower bound of viral RNA shedding was 17.3 days (SD 7.8), and the mean upper bound of viral RNA shedding from 668 patients transitioning to confirmed PCR-negative status was 22.7 days (SD 11.8). Among 104 patients with an IgG test result, 90 patients were seropositive to date, with mean upper bound of time to seropositivity from initial diagnosis being 37.8 days (95% CI 34.3-41.3). Our findings from juxtaposing IgG and PCR tests thus reveal that some SARS-CoV-2-positive patients are non-hospitalized and seropositive, yet actively shed viral RNA (14 of 90 patients). This study emphasizes the need for monitoring viral loads and neutralizing antibody titers in long-term non-hospitalized shedders as a means of characterizing the SARS-CoV-2 infection lifecycle.Diverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) still remains limited. To assess the plasticity and phenotypes of immune cells within HBV/HCV-related HCC microenvironment at single-cell level, we performed single-cell RNA sequencing on 41,698 immune cells from seven pairs of HBV/HCV-related HCC tumors and non-tumor liver tissues. We combined bio-informatic analyses, flow cytometry, and multiplex immunohistochemistry to assess the heterogeneity of different immune cell subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune cell subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by diverse immune cell subsets that can transit among different states and mutually interact. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8+ T cells highly expressing XCL1 that correlated with better patient survival rates. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes, and evolution trajectory of effector CD8+ T cells from early-stage to advanced HCC were also identified. Our study provides insight into the immune microenvironment in HBV/HCV-related HCC and highlights novel macrophage and T-cell subsets that could be further exploited in future immunotherapy.Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is inherited in an autosomal dominant manner and is characterized by a combination of developmental abnormalities and a predisposition to tumor formation. Hedgehog receptor Patched 1 (PTCH1) has been identified as the mutated gene in NBCCS. We identified the PTCH1_c.3298_3299insAAG_p.1099_1100insE mutation in the transmembrane region, which comprises a sterol transporter whose abnormal function is reportedly related to pathogenicity.The development of the sequencing technologies allowed the generation of huge amounts of molecular data from a single cancer specimen, allowing the clinical oncology to enter the era of the precision medicine. This massive amount of data is highlighting new details on cancer pathogenesis but still relies on tissue biopsies, which are unable to capture the dynamic nature of cancer through its evolution. This assumption led to the exploration of non-tissue sources of tumoral material opening the field of liquid biopsies. Blood, together with body fluids such as urines, or stool, from cancer patients, are analyzed applying the techniques used for the generation of omics data. With blood, this approach would allow to take into account tumor heterogeneity (since the circulating components such as CTCs, ctDNA, or ECVs derive from each cancer clone) in a time dependent manner, resulting in a somehow "real-time" understanding of cancer evolution. Liquid biopsies are beginning nowdays to be applied in many cancer contexts and are at the basis of many clinical trials in oncology.In mammalian early embryos, the transition from maternal to embryonic control of gene expression requires timely degradation of a subset of maternal mRNAs (MRD). Recently, zygotic genome activation (ZGA)-dependent MRD has been characterized in mouse 2-cell embryo. However, in early embryos, the dynamics of MRD is still poorly understood, and the maternal factor-mediated MRD before and along with ZGA has not been investigated. Argonaute 2 (Ago2) is highly expressed in mouse oocyte and early embryos. In this study, we showed that Ago2-dependent degradation involving RNA interference (RNAi) and RNA activation (RNAa) pathways contributes to the decay of over half of the maternal mRNAs in mouse early embryos. Histone Acetyltransf inhibitor We demonstrated that AGO2 guided by endogenous small interfering RNAs (endosiRNAs), generated from double-stranded RNAs (dsRNAs) formed by maternal mRNAs with their complementary long noncoding RNAs (CMR-lncRNAs), could target maternal mRNAs and cooperate with P-bodies to promote MRD. In addition, we also showed that AGO2 may interact with small activating RNAs (saRNAs) to activate Yap1 and Tead4, triggering ZGA-dependent MRD. Thus, Ago2-dependent degradation is required for timely elimination of subgroups of maternal mRNAs and facilitates the transition between developmental states.Definitive hematopoiesis generates hematopoietic stem/progenitor cells (HSPCs) that give rise to all mature blood and immune cells, but remains poorly defined in human. Here, we resolve human hematopoietic populations at the earliest hematopoiesis stage by single-cell RNA-seq. We characterize the distinct molecular profiling between early primitive and definitive hematopoiesis in both human embryonic stem cell (hESC) differentiation and early embryonic development. We identify CD44 to specifically discriminate definitive hematopoiesis and generate definitive HSPCs from hESCs. The multipotency of hESCs-derived HSPCs for various blood and immune cells is validated by single-cell clonal assay. Strikingly, these hESCs-derived HSPCs give rise to blood and lymphoid lineages in vivo. Lastly, we characterize gene-expression dynamics in definitive and primitive hematopoiesis and reveal an unreported role of ROCK-inhibition in enhancing human definitive hematopoiesis. Our study provides a prospect for understanding human early hematopoiesis and a firm basis for generating blood and immune cells for clinical purposes.