Nicotinic acetylcholine receptor expression in human airway correlates with lung function

Nicotine and its derivatives, by binding to nicotinic acetylcholine receptors (nAChRs) on bronchial epithelial cells, can regulate cellular signaling and inflammatory processes. Delineation of nAChR subtypes and their responses to nicotine stimulation in bronchial epithelium may provide information for therapeutic targeting in smoking-related inflammation in the airway. Expression of nAChR subunit genes in 60 bronchial epithelial biopsies and immunohistochemical staining for the subcellular locations of nAChR subunit expression were evaluated. Seven human bronchial epithelial cell lines (HBECs) were exposed to nicotine in vitro for their response in nAChR subunit gene expression to nicotine exposure and removal. The relative normalized amount of expression of nAChR α4, α5, and α7 and immunohistochemical staining intensity of nAChR α4, α5, and β3 expression showed significant correlation with lung function parameters. Nicotine stimulation in HBECs resulted in transient increase in the levels of nAChR α5 and α6 but more sustained increase in nAChR α7 expression. nAChR expression in bronchial epithelium was found to correlate with lung function. Nicotine exposure in HBECs resulted in both short and longer term responses in nAChR subunit gene expression. These results gave insight into the potential of targeting nAChRs for therapy in smoking-related inflammation in the airway.postprin

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma

Publisher Copyright: © 2021, The Author(s).Background: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016). Patients and methods: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments. Results: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1–617) and 71 days (range, 1–490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1–24.5) in the HNSCC cohort and 19% (90% CI, 9.2–32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7–4.7) and 1.9 months (95% CI, 1.7–3.7) in the HNSCC and NSCLC cohorts. Conclusions: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing.Peer reviewe

Triggering a Cell Shape Change by Exploiting Preexisting Actomyosin Contractions

Apical constriction changes cell shapes, driving critical morphogenetic events including gastrulation in diverse organisms and neural tube closure in vertebrates. Apical constriction is thought to be triggered by contraction of apical actomyosin networks. We found that apical actomyosin contractions began before cell shape changes in both C. elegans and Drosophila. In C. elegans, actomyosin networks were initially dynamic, contracting and generating cortical tension without significant shrinking of apical surfaces. Apical cell-cell contact zones and actomyosin only later moved increasingly in concert, with no detectable change in actomyosin dynamics or cortical tension. Thus, apical constriction appears to be triggered not by a change in cortical tension but by dynamic linking of apical cell-cell contact zones to an already contractile apical cortex

Rare solid and cystic presentation of hemangiopericytoma/ solitary fibrous tumor: A case report

Hemangiopericytoma/Solitary Fibrous Tumor (HPC/SFT) is a rare fibroblastic sarcoma characterized by hyper-vasculature and STAT6 trans-nuclear localization. Cystic HPC/SFT is extremely rare. Due to the scarcity of cystic HPC/SFT cases, diagnostic and treatment guidelines are not well established. To our knowledge, we present the first case of cystic HPC/SFT observed in the liver. In addition, the patient had over 6 years of recurrent hypervascular solid HPC/SFT in the brain, bone, leptomeninges, liver and lung prior to developing a cystic HPC/SFT. Briefly, a 37-year-old Caucasian female with a history of HPC/SFT presented with several enlarging cystic hepatic lesions on surveillance MRI. The cystic/nonenhancing nature of these liver metastases were confirmed by contrast-enhanced ultrasound. Due to diagnostic uncertainty, two of these hepatic cysts were removed laparoscopically and pathology confirmed cystic HPC/SFT with a high MIB-1 index. Previously, in 2014, the patient was diagnosed with solid intracranial grade III pseudopapillary mesenchymal HPC/SFT in the posterior fossa and underwent subtotal resection followed by external beam radiation. In 2017, she had recurrent intracranial, vertebral, and intraspinal intradural extramedullary HPC/SFTs followed by surgery, proton therapy, and SRS radiotherapy. In 2019, after an uneventful pregnancy and birth, routine surveillance revealed metastases in the liver requiring an extended right hepatectomy. In 2020-2021 two solid hypervascular hepatic HPC/SFT were found and treated with microwave ablation. Shortly afterwards, several rapidly growing hepatic cystic HPC/SFT lesions developed. Of note, she has not taken any systemic therapy, indicating the cystic tumors are from metastases rather than cystic degradation as a sequela of therapy. Overall, this case highlights that cystic metastasis are a potential clinical manifestation of solid HPC/SFT. Moreover, cystic HPC/SFT can co-exist with the more typical primary solid hypervascular HPC/SFTs in the same patient. Lastly, in this case cystic HPC/SFT had a higher growth rate and propensity to metastasize as compared to the solid equivalent.Peer reviewe

A Genome-Wide Screen for Promoter Methylation in Lung Cancer Identifies Novel Methylation Markers for Multiple Malignancies

BACKGROUND: Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The “rules” governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor type-specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype would identify pathways important as therapeutic targets. METHODS AND FINDINGS: In an effort to identify new cancer-specific methylation markers, we employed a high-throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5′ CpG islands, are induced from undetectable levels by 5-aza-2′-deoxycytidine in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (n = 20) and adjacent nonmalignant tissue (n = 20) showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. We studied the eight most frequently and specifically methylated genes from our lung cancer dataset in breast cancer (n = 37), colon cancer (n = 24), and prostate cancer (n = 24) along with counterpart nonmalignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. CONCLUSIONS: By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation pattern we observed for these novel markers suggests that we have identified a partial promoter hypermethylation signature for these common malignancies. These data suggest that while tumors in different tissues vary substantially with respect to gene expression, there may be commonalities in their promoter methylation profiles that represent targets for early detection screening or therapeutic intervention

Genome-wide characterization of circulating metabolic biomarkers

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases

Genome-wide characterization of circulating metabolic biomarkers

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8,9,10,11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases