Mechanisms Targeting the Unfolded Protein Response in Asthma.

Lung cells are constantly exposed to various internal and external stressors that disrupt protein homeostasis. To cope with these stimuli, cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR). UPR stressors can impose greater protein secretory demands on the endoplasmic reticulum (ER), resulting in the development, differentiation, and survival of these cell types to meet these increasing functional needs. Dysregulation of the UPR leads to the development of the disease. The UPR and ER stress are involved in several human conditions, such as chronic inflammation, neurodegeneration, metabolic syndrome, and cancer. Furthermore, potent and specific compounds that target the UPR pathway are under development as future therapies. The focus of this review is to thoroughly describe the effects of both internal and external stressors on the ER in asthma. Furthermore, we discuss how the UPR signaling pathway is activated in the lungs to overcome cellular damage. We also present an overview of the pathogenic mechanisms, with a brief focus on potential strategies for pharmacological interventions.

Therapeutic targeting of TGF-ß in lung cancer.

Transforming growth factor-ß (TGF-ß) plays a complex role in lung cancer pathophysiology, initially acting as a tumor suppressor by inhibiting early-stage tumor growth. However, its role evolves in the advanced stages of the disease, where it contributes to tumor progression not by directly promoting cell proliferation but by enhancing epithelial-mesenchymal transition (EMT) and creating a conducive tumor microenvironment. While EMT is typically associated with enhanced migratory and invasive capabilities rather than proliferation per se, TGF-ß's influence on this process facilitates the complex dynamics of tumor metastasis. Additionally, TGF-ß impacts the tumor microenvironment by interacting with immune cells, a process influenced by genetic and epigenetic changes within tumor cells. This interaction highlights its role in immune evasion and chemoresistance, further complicating lung cancer therapy. This review provides a critical overview of recent findings on TGF-ß's involvement in lung cancer, its contribution to chemoresistance, and its modulation of the immune response. Despite the considerable challenges encountered in clinical trials and the development of new treatments targeting the TGF-ß pathway, this review highlights the necessity for continued, in-depth investigation into the roles of TGF-ß. A deeper comprehension of these roles may lead to novel, targeted therapies for lung cancer. Despite the intricate behavior of TGF-ß signaling in tumors and previous challenges, further research could yield innovative treatment strategies.

4D in vivo dose verification for real-time tumor tracking treatments using EPID dosimetry.

The use of sophisticated techniques such as gating and tracking treatments requires additional quality assurance to mitigate increased patient risks. To address this need, we have developed and validated an in vivo method of dose delivery verification for real-time aperture tracking techniques, using an electronic portal imaging device (EPID)-based, on-treatment patient dose reconstruction and a dynamic anthropomorphic phantom. Using 4DCT scan of the phantom, ten individual treatment plans were created, 1 for each of the 10 separate phases of the respiratory cycle. The 10 MLC apertures were combined into a single dynamic intensity-modulated radiation therapy (IMRT) plan that tracked the tumor motion. The tumor motion and linac delivery were synchronized using an RPM system (Varian Medical Systems) in gating mode with a custom breathing trace. On-treatment EPID frames were captured using a data-acquisition computer with a dedicated frame-grabber. Our in-house EPID-based in vivo dose reconstruction model was modified to reconstruct the 4D accumulated dose distribution for a dynamic MLC (DMLC) tracking plan using the 10-phase 4DCT dataset. Dose estimation accuracy was assessed for the DMLC tracking plan and a single-phase (50% phase) static tumor plan, represented a static field test to verify baseline accuracy. The 3%/3 mm chi-comparison between the EPID-based dose reconstruction for the static tumor delivery and the TPS dose calculation for the static plan resulted in 100% pass rate for planning target volume (PTV) voxels while the mean percentage dose difference was 0.6%. Comparing the EPID-based dose reconstruction for the DMLC tracking to the TPS calculation for the static plan gave a 3%/3 mm chi pass rate of 99.3% for PTV voxels and a mean percentage dose difference of 1.1%. While further work is required to assess the accuracy of this approach in more clinically relevant situations, we have established clinical feasibility and baseline accuracy of using the transmission EPID-based, in vivo patient dose verification for MLC-tracking treatments.

Association Between miR-146a rs2910164 Polymorphism and Breast Cancer Susceptibility: An Updated Meta-Analysis of 9545 Cases and 10030 Controls.

BACKGROUND: Several studies have reported a possible association of miR-146a rs2910164 polymorphism with Breast Cancer (BC) development. However, the correlation between this polymorphism and susceptibility to BC is under debate. The current meta-analysis was designed and performed to more conclusively evaluate the miR-146a rs2910164 polymorphism and its potential link to BC. METHODS: Our team has selected eligible studies (published up to October 2, 2020) from several electronic databases, including Web of Science, PubMed, Scopus and Google Scholar. A total number of 9,545 BC cases and 10,030 controls extracted from 26 eligible articles were included in this study. We utilized pooled Odds Ratios (ORs) as well as 95% confidence intervals (95% CIs) under five genetic models for quantitative estimation of any possible association between miR-146a rs2910164 polymorphism and BC. RESULTS: Based on this meta-analysis, our findings suggest that there is no significant association between miR-146a rs2910164 polymorphism and BC risk. However, stratified analysis revealed that the rs2910164 polymorphism significantly increased the risk of BC in hospital-based studies using the homozygous genetic model (OR=1.37, 95%CI=1.01-1.86, p=0.043, CC vs. GG). Neither Asian nor Caucasian populations showed any significant association between rs2910164 polymorphism and BC susceptibility. CONCLUSION: In summary, our findings suggest that BC development is not associated with miR-146a rs2910164 polymorphism. However, larger ingenious future investigations might be needed for a more precise estimation of any association between miR-146a rs2910164 polymorphism and BC.

Association of CASP8 polymorphisms and cancer susceptibility: A meta-analysis.

Caspase-8 plays is an essential enzyme in apoptosis pathway. Several investigation have been done to identify the relation between CASP8 polymorphisms and different human cancers, but, the findings are still debated. The aim of the current investigation is to assess if CASP8 rs3834129 (-652 6N insertion/deletion), rs1045485 G > C, rs3769818 G > A, rs6723097 A > C, rs3769821 T > C, rs13113 T > A, rs3769825 G > A, rs2293554 A > C, and rs10931936 C > T polymorphisms are linked to susceptibility of cancer. Our team has extracted the eligible studies up to July 4, 2019, from different sources. Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were estimated to quantitatively evaluate the association between CASP8 polymorphisms and cancer susceptibility. Our results showed that the rs3834129 and rs1045485 polymorphisms meaningfully reduced the risk of cancer, while the rs3769818, rs3769821 and rs3769825 polymorphisms considerably increased cancer susceptibility. No association of rs6723097, rs13113, rs2293554 and rs10931936 polymorphisms was observed with cancer susceptibility. The CASP8 rs3834129 polymorphism reduced the risk of gastrointestinal, digestive tract, colorectal, breast and lung cancers. Furthermore, the cancer risk was decreased in Asian and Caucasian populations as well as population- and hospital-based studies due to this polymorphism. There was not any relation between this gene polymorphism and the risk of prostate and cervical cancer development. Regarding the CASP8 rs1045485 polymorphism, the reduced breast cancer risk along with the risk of cancer in Caucasians, population- and hospital-based studies were observed.

Genetic association between HOTAIR gene and the risk of cancer: an updated meta-analysis.

Several recent investigations show that HOX transcript antisense intergenic RNA (HOTAIR) play an important role in the pathogenesis of different cancers. HOTAIR polymorphisms has been widely studied in the context of association between with the risk of cancer pathogenesis. However, there is no certain conclusion about the role of HOTAIR polymorphisms in different cancer initiation and progression. Our team has selected eligible studies up to 1 May 2019, from several electronic databases, including Web of Science, PubMed, Scopus, and Google Scholar databases. We have included total number of 102 case-control investigations extracted from 41 eligible articles for the current meta-analysis. We calculated pooled odds ratio (ORs) with their corresponding 95% confidence intervals (CIs) using either fixed-effect or random-effect models for quantitative evaluation of the strength for the association between HOTAIR gene polymorphisms and the risk of cancer. Our current meta-analysis investigation showed that HOTAIR rs4759314 polymorphism particularly increased the overall risk of cancer in different models including homozygous, recessive and allele genetic. HOTAIR rs920778 significantly raised the cancer risk only in recessive genetic model. HOTAIR rs12826786 polymorphism was associated with cancer development in heterozygous, homozygous, dominant, recessive and allele genetic models. Also, an increase in cancer risk was observed with rs874945 polymorphism of HOTAIR gene in heterozygous, dominant and allele genetic models. The rs12427129 polymorphism showed correlation with cancer susceptibility only in recessive model. Subgroup analysis based on cancer type suggested that rs4759314 polymorphism significantly increased the risk of gastric and cervical cancers, and the rs920778 polymorphism increased the risk of gastrointestinal, cervical and gastric cancers. In summary, this study found that HOTAIR polymorphisms are significantly associated with cancer development.

The ER Stress/UPR Axis in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis.

Cellular protein homeostasis in the lungs is constantly disrupted by recurrent exposure to various external and internal stressors, which may cause considerable protein secretion pressure on the endoplasmic reticulum (ER), resulting in the survival and differentiation of these cell types to meet the increased functional demands. Cells are able to induce a highly conserved adaptive mechanism, known as the unfolded protein response (UPR), to manage such stresses. UPR dysregulation and ER stress are involved in numerous human illnesses, such as metabolic syndrome, fibrotic diseases, and neurodegeneration, and cancer. Therefore, effective and specific compounds targeting the UPR pathway are being considered as potential therapies. This review focuses on the impact of both external and internal stressors on the ER in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) and discusses the role of the UPR signaling pathway activation in the control of cellular damage and specifically highlights the potential involvement of non-coding RNAs in COPD. Summaries of pathogenic mechanisms associated with the ER stress/UPR axis contributing to IPF and COPD, and promising pharmacological intervention strategies, are also presented.