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Tumor-derived protein tissue inhibitor of metalloproteinases-1 (TIMP1) correlates with poor prognosis in many cancers, including highly lethal pancreatic ductal adenocarcinoma (PDAC). The noncanonical signaling activity of TIMP1 is emerging as one basis for its contribution to cancer progression. However, TIMP1-triggered progression-related biological processes are largely unknown. see more Formation of neutrophil extracellular traps (NET) in the tumor microenvironment is known to drive progression of PDAC, but factors or molecular mechanisms initiating NET formation in PDAC remain elusive. In this study, gene-set enrichment analysis of a human PDAC proteome dataset revealed that TIMP1 protein expression most prominently correlates with neutrophil activation in patient-derived tumor tissues. TIMP1 directly triggered formation of NETs in primary human neutrophils, which was dependent on the interaction of TIMP1 with its receptor CD63 and subsequent ERK signaling. In genetically engineered PDAC-bearing mice, TIMP1 significantly contributed to NET formation in tumors, and abrogation of TIMP1 or NETs prolonged survival. In patient-derived PDAC tumors, NETs predominantly colocalized with areas of elevated TIMP1 expression. Furthermore, TIMP1 plasma levels correlated with DNA-bound myeloperoxidase, a NET marker, in the blood of patients with PDAC. A combination of plasma levels of TIMP1 and NETs with the clinically established marker CA19-9 allowed improved identification of prognostically distinct PDAC patient subgroups. These observations may have a broader impact, because elevated systemic levels of TIMP1 are associated with the progression of a wide range of neutrophil-involved inflammatory diseases. SIGNIFICANCE These findings highlight the prognostic relevance of TIMP1 and neutrophil extracellular traps in highly lethal pancreatic cancer, where a noncanonical TIMP1/CD63/ERK signaling axis induces NET formation. GRAPHICAL ABSTRACT http//cancerres.aacrjournals.org/content/canres/81/13/3568/F1.large.jpg.Long noncoding RNAs (lncRNA) have been shown to play critical regulatory roles in the onset and progression of human cancers. However, the functions of a large proportion of lncRNAs are still unexplored. Here we describe a novel lncRNA, CTD-2245E15.3, that promotes lung tumorigenesis by regulating the anabolic enzymes acetyl-CoA carboxylase 1 (ACC1, encoded by the ACACA gene) and pyruvate carboxylase (PC). Differentially expressed lncRNAs between non-small cell lung cancer (NSCLC) and paired adjacent nontumor tissues were identified by a microarray and validated using quantitative real-time polymerase chain reaction. CTD-2245E15.3 was significantly upregulated in NSCLC and was mainly located in the cytoplasm. Knockdown of CTD-2245E15.3 by specific antisense oligonucleotides suppressed cell growth in vitro and in vivo, largely due to cell-cycle arrest and induction of apoptosis. Overexpression of CTD-2245E15.3 in an orthotopic model of lung cancer led to a significant increase in total tumor burden. CTD-2245E15.3 exerted its oncogenic function by binding ACC1 and PC, which are key anabolic factors for biomolecule synthesis in rapidly proliferating tumor cells. Knockdown of CTD-2245E15.3 increased phosphorylation of ACC1 at an inhibitory site for enzymatic activity and promoted PC degradation via ubiquitination. Supplements of palmitate or oxaloacetate, products of ACC1 and PC, alleviated the suppression of cell growth caused by loss of CTD-2245E15.3. These findings reveal the important role of CTD-2245E15.3 as an oncogenic lncRNA in the anabolic process for tumor growth. SIGNIFICANCE These findings demonstrate a novel lncRNA CTD-2245E15.3 that binds and positively regulates anabolic enzymes ACC1 and PC to promote tumor growth. GRAPHICAL ABSTRACT http//cancerres.aacrjournals.org/content/canres/81/13/3509/F1.large.jpg.Proteolysis is a fundamental property of all living cells. In the bacterium Salmonella enterica serovar Typhimurium, the HspQ protein controls the specificities of the Lon and ClpAP proteases. Upon acetylation, HspQ stops being a Lon substrate and no longer enhances proteolysis of the Lon substrate Hha. The accumulated HspQ protein binds to the protease adaptor ClpS, hindering proteolysis of ClpS-dependent substrates of ClpAP, such as Oat, a promoter of antibiotic persistence. HspQ is acetylated by the protein acetyltransferase Pat from acetyl coenzyme A (acetyl-CoA) bound to the acetyl-CoA binding protein Qad. We now report that low cytoplasmic Mg2+ promotes qad expression, which protects substrates of Lon and ClpSAP by increasing HspQ amounts. The qad promoter is activated by PhoP, a regulatory protein highly activated in low cytoplasmic Mg2+ that also represses clpS transcription. Both the qad gene and PhoP repression of the clpS promoter are necessary for antibiotic persistence. PhoP also promotes qad transcription in Escherichia coli, which shares a similar PhoP box in the qad promoter region with S. Typhimurium, Salmonella bongori, and Enterobacter cloacae. Our findings identify cytoplasmic Mg2+ and the PhoP protein as critical regulators of protease specificity in multiple enteric bacteria. IMPORTANCE The bacterium Salmonella enterica serovar Typhimurium narrows down the spectrum of substrates degraded by the proteases Lon and ClpAP in response to low cytoplasmic Mg2+, a condition that decreases protein synthesis. This control is exerted by PhoP, a transcriptional regulator activated in low cytoplasmic Mg2+ that governs proteostasis and is conserved in enteric bacteria. The uncovered mechanism enables bacteria to control the abundance of preexisting proteins.

Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts.

We performed medical records-based genome-wide and phenome-wide association studies for plasma C3 and C4 levels among participants of the Electronic Medical Records and Genomics (eMERGE) network.

In a GWAS for C3 levels in 3949 individuals, we detected two genome-wide significant loci chr.1q31.3 (CFH locus; rs3753396-A;

=0.20; 95% CI, 0.14 to 0.25;

=1.52×10

) and chr.19p13.3 (C3 locus; rs11569470-G;

=0.19; 95% CI, 0.13 to 0.24;

=1.29×10

). These two loci explained approximately 2% of variance in C3 levels. GWAS for C4 levels involved 3998 individuals and revealed a genome-wide significant locus at chr.6p21.32 (C4 locus; rs3135353-C;

=0.40; 95% CI, 0.34 to 0.45;

=4.58×10

). link2 This locus explained approximately 13% of variance in C4 levels. The multiallelic copy number vaelations across the spectrum of complement-related diseases in humans.

Patients with CKD are at high risk for thrombotic and hemorrhagic complications. Abnormalities in platelet function are central to these complications, but reports on platelet function in relation to CKD are conflicting, and vary from decreased platelet reactivity to normal or increased platelet responsiveness. The direct effects of uremic toxins on platelet function have been described, with variable findings.

To help clarify how CKD affects platelet function, we conducted a systematic review and meta-analysis of platelet activity in CKD, with a focus on nondialysis-induced effects. We also performed an extensive literature search for the effects of individual uremic toxins on platelet function.

We included 73 studies in the systematic review to assess CKD’s overall effect on platelet function in patients; 11 of them described CKD’s effect on

platelet aggregation and were included in the meta-analysis. Although findings on platelet abnormalities in CKD are inconsistent, bleeding time was mostly prolring different CKD stages, is warranted.Coronary revascularization has matured as a field since coronary artery bypass grafting (CABG) was first developed over 50 years ago, with diagnostic and treatment methods having advanced dramatically. CABG remains the standard of care for obstructive coronary artery disease, particularly for patients with multivessel disease or diabetes. It is now recognized that not all CABG is created equal-operative strategy, including conduit choice for bypass grafts and target coronary selection, affects survival. A multidisciplinary approach including surgeons with a special interest in CABG is recommended to optimize treatment selection and outcomes.The second-generation antipsychotic drug quetiapine (Seroquel) is increasingly being used off-label for treating insomnia in the general population, possibly to avoid standard medications with known addictive qualities and adverse side effects. However, evidence to support using it in this way is scant, and quetiapine is associated with weight gain and other metabolic effects. It must be used cautiously and with appropriate monitoring for adverse effects and abuse.The percent of US children who are not vaccinated has been increasing, and so have the rates of communicable diseases. As the unvaccinated and undervaccinated population ages, practitioners are likely to see more adult patients who have never been vaccinated. This article reviews the recommendations for vaccinating previously unvaccinated patients and addresses potential barriers and concerns adult patients may have about vaccines.An estimated 10% of COVID-19 survivors continue to experience symptoms several weeks to months after the appearance of initial symptoms, a condition termed post-acute sequelae of SARS-CoV-2 infection (PASC). These patients, also called “long-haulers,” most commonly report protracted symptoms of fatigue, cough, dyspnea, chest tightness, difficulty concentrating, arthralgia, olfactory dysfunction, and headache. While age, comorbid medical conditions, and COVID-19 severity are risk factors, young and previously healthy individuals with mild COVID-19 are also at risk. Recognition of symptoms, evaluation, supportive treatment, and attention to medical comorbidities are the cornerstones of medical management.Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (ERBB2) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from 2 locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in > 5% but less then 50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the non-heterogenous subgroup and 0% in the heterogenous group (p less then 0.0001, adjusted for hormone receptor status). Single cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 non-amplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies.CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8 T cells during early stages of activation. Mice receiving tumor-specific CD8 T cells treated with CDK4/6 inhibitors displayed increased T cell persistence and immunologic memory. CDK4/6 inhibition upregulated Mxd4, a negative regulator of Myc, in both mouse and human CD8 T cells. link3 Silencing of Mxd4 or Myc in mouse CD8 T cells demonstrated the importance of this axis for memory formation. We used single cell transcriptional profiling and TCR clonotype tracking to evaluate recently activated human CD8 T cells in breast cancer patients before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8 memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in cancer patients may augment long-term protective immunity.