Association between exposure to organophosphate flame retardants and epidermal growth factor receptor expression in lung cancer patients.

BACKGROUND: Organophosphate flame retardants (OPFRs) are extensively distributed in our environment, prompting concerns about potential health hazards, including lung injuries resulting from OPFR exposure. METHODS: The present study recruited 125 lung cancer patients, assessing their exposure to 10 OPFR compounds through urine samples. The final analysis comprised 108 participants after excluding those lacking epidermal growth factor receptor (EGFR) status and those with chronic kidney disease. Demographic and clinical characteristics, as well as urinary OPFR concentrations, were compared based on OPFR detection. Spearman correlation was conducted to explore the relationship between OPFR compounds, while logistic regression was used to identify OPFR compounds associated with EGFR mutation. RESULTS: The study revealed widespread OPFR exposure among lung cancer patients, with an overall detection frequency of 99.07%. Tris(2-butoxyethyl) phosphate (TBEP) exhibited a strong correlation to its metabolite bis(2-butoxyethyl) phosphate (r = 0.88, p < 0.01). Patients with TBEP in their urine had higher percentage of wild-type EGFR and the detection of TBEP was associated with a reduced likelihood of mutant EGFR expression. CONCLUSIONS: OPFR exposure was prevalent in lung cancer patients, with TBEP detection identified as a factor with lower EGFR mutation expression. This study contributes to the understanding of OPFR exposure in lung cancer patients and underscores the significance of TBEP in evaluating EGFR mutation in this population.

Tumor Location Is an Independent Prognostic Factor in Completely Resected Pathological Stage I Non-Small Cell Lung Cancer: A Multicenter Retrospective Study.

Previous studies suggested that the location of the primary tumor in non-small cell lung cancer (NSCLC) is associated with clinical features and prognosis, but results are conflicting. The purpose of this study was to explore tumor location as an independent risk factor of survival for patients with completely resected pathological stage I NSCLC. This was a multicenter retrospective study conducted in Taiwan. Included patients were diagnosed with stage I NSCLC and had undergone primary tumor resection. Variables including tumor location, pathological stage, histological differentiation, and International Association for the Study of Lung Cancer (IASLC) grade were evaluated for predictive ability for disease-free survival (DFS) and overall survival (OS). A total of 208 patients were included, with 123 (59.1%) patients having a primary tumor in the upper and middle lobes. The median duration of follow-up for survivors was 60.5 months. Compared to patients with IASLC Grade 3 disease, patients with Grade 1 disease had significantly longer DFS. Tumor location and IASLC grade were independent predictors for OS in multivariate analysis. Specifically, patients with NSCLC in the lower lobe and patients who are histologically classified as IASLC Grade 3 may have poorer prognosis and require greater attention to improve outcomes.

The safety and response of CT guided percutaneous cryoablation for lung nodules by 17-gauge needles.

BACKGROUND: The safety and efficacy of 17-gauge needles used in CT-guided percutaneous cryoablation for lung nodules were explored in this study. The purpose of the study was to compare the findings with earlier research and multi-center clinical trials that used various needle sizes. METHODS: Between 2016 and 2020, a retrospective study was conducted with approval from the institutional review board. A total of 41 patients were enrolled, and 71 lung nodules were treated in 63 cryoablation procedures using local anesthesia. Complication rates were recorded, and overall survival rates as well as tumor progression-free rates were calculated using the Kaplan-Meier method. RESULTS: Self-limited hemoptysis was caused by 12.9% of the procedures, and drainage was required for pneumothoraces resulting from 11.3% of them. The overall survival rates at one, two, three, and four years were 97%, 94%, 82%, and 67%, respectively. The tumor progression-free rates at one, two, three, and four years were 86.2%, 77%, 74%, and 65%, respectively. CONCLUSION: Cryoablation for lung nodules using 17-Gauge needles can achieve similar rates of survival and tumor control rates, similar or even lower complication rates as compared with other studies and multi-center trials using mixed sized needles.

Community-Based Screening for Hepatitis B and C Infectivity Using Two Quantitative Antigens to Identify Endemic Townships.

Screening and linkage to care are essential to achieve viral hepatitis elimination before 2030. The accurate identification of endemic areas is important for controlling diseases with geographic aggregation. Viral activity drives prognosis of chronic hepatitis B and hepatitis C virus infection. This screening was conducted in Chiayi County from 2018-2019. All residents aged 30 years or older were invited to participate in quantitative HBsAg (qHBsAg) and HCV Ag screening. Among the 4010 participants (male:female = 1630:2380), the prevalence of qHBsAg and HCV Ag was 9.9% (396/4010) and 4.1% (163/4010), respectively. High-prevalence townships were identified, three for qHBsAg > 15% and two for HCV Ag > 10%. The age-specific prevalence of qHBsAg was distributed in an inverse U-shape with a peak (16.0%, 68/424) for subjects in their 40 s; for HCV, prevalence increased with age. Concentrations of qHBsAg < 200 IU/mL were found in 54% (214/396) of carriers. The rate of oral antiviral treatment for HCV was 75.5% (114/151), with subjects younger than 75 years tending to undergo treatment (85.6% vs. 57.4%, p < 0.001). QHBsAg and HCV Ag core antigens can reflect the concentration of the viral load, which serves as a feasible screening tool. Using quantitative antigen screening for hepatitis B and C in community-based screening, two hyperendemic townships were identified from an endemic county.

Unusual synchronous double primary treatment-naïve lung adenocarcinoma harboring T790M and L858R mutations in early-stage lung cancer.

BACKGROUND: Concurrent mutations of synchronous multiple primary non-small cell lung cancer (SMPNSCLC) is rare, and only a few cases have been reported. Herein, we present a case of early-stage SMPNSCLC with T790M and L858R mutations. CASE PRESENTATION: A 68-year-old male patient presented to the Thoracic Surgery Department due to a tumor in the right lower lung. The tumor was detected more than 5 years previously during a health examination; however, the patient ignored the problem because the clinician at that time stated that the lesion was highly likely to be benign. Chest computed topography (CT) was ordered and the images showed a well-defined tumor in the right lower lung and a faint nodular lesion over the left lower lung field. A CT-guided biopsy results showed the presence of atypical cells and positive staining of TTF-1 and CK7. Surgical intervention was performed. The right- and left-sided tumors disclosed micropapillary predominant adenocarcinoma and acinar-predominant adenocarcinoma, respectively. Both tumors were positive for TTF-1 but negative for ALK and p40. Real-time PCR analysis showed that the right-sided tumor had an epidermal growth factor receptor (EGFR) mutation presenting as point mutation T790M in exon 20, while the left-sided tumor had a point mutation L858R in exon 21 of EGFR. CONCLUSIONS: Our patient's case suggests that tumors resembling a benign pattern with central calcification may be misdiagnosed. Thus, early screening for lung cancer is important, and intensive efforts to make a diagnosis through surgical resection or biopsies to allow for tailored optimal treatment may be preferential for the best patient outcomes.

AChRs Are Essential for the Targeting of Rapsyn to the Postsynaptic Membrane of NMJs in Living Mice.

UNLABELLED: Rapsyn, a 43 kDa scaffold protein, is required for the clustering of acetylcholine receptors (AChRs) at synaptic sites between mammalian motor neurons and muscle cells. However, the mechanism by which rapsyn is inserted and retained at postsynaptic sites at the neuromuscular junction (NMJ) in vivo remains largely unknown. We found that neither the N-terminal myristoylation nor the cysteine-rich RING H2 domain of rapsyn is required for its stable association with the postsynaptic membrane of NMJs. When N-myristoylation-defective rapsyn-EGFP mutant (G2A) and RING-H2 domain truncated rapsyn-EGFP were electroporated into sternomastoid muscles, a strong rapsyn fluorescent signal was observed selectively at synapses, similar to WT rapsyn-EGFP. The targeting of rapsyn-EGFP (WT and mutants) is independent of synaptic activity because they were inserted at denervated NMJs. However, when the coiled-coil domain (the AChR-binding domain of rapsyn) is deleted, rapsyn fails to associate with AChRs at NMJs of living mice. In cultured myoblasts (in which AChRs are absent), myristoylated WT rapsyn mostly localizes to lysosomes and is not associated with the plasma membrane. However, in the presence of AChR subunits, rapsyn molecules were targeted to the cell surface and formed aggregates with AChRs. The targeting of AChRs to the cell membrane, in contrast, does not require rapsyn because expressed AChRs are visible on the cell membranes of rapsyn-deficient myoblasts. These results provide evidence for an active role of AChRs in the targeting of rapsyn to the NMJ in vivo SIGNIFICANCE STATEMENT: Rapsyn is required for the clustering of acetylcholine receptors (AChRs) at postsynaptic sites. However, the mechanism by which rapsyn is targeted to synaptic sites at the vertebrate neuromuscular junction remains unclear. In this study, we showed that the coiled-coil domain of rapsyn is required for its targeting to the cell surface via its interaction with AChRs. In contrast, the targeting of AChRs to the cell membrane does not require rapsyn. These results indicate that AChRs play a critical role in the insertion and/or association of rapsyn with the plasma membrane of synaptic sites.

Hypoxia-inducible factor 3 is an oxygen-dependent transcription activator and regulates a distinct transcriptional response to hypoxia.

Hypoxia-inducible factors (HIFs) play key roles in the cellular response to hypoxia. It is widely accepted that whereas HIF-1 and HIF-2 function as transcriptional activators, HIF-3 inhibits HIF-1/2α action. Contrary to this idea, we show that zebrafish Hif-3α has strong transactivation activity. Hif-3α is degraded under normoxia. Mutation of P393, P493, and L503 inhibits this oxygen-dependent degradation. Transcriptomics and chromatin immunoprecipitation analyses identify genes that are regulated by Hif-3α, Hif-1α, or both. Under hypoxia or when overexpressed, Hif-3α binds to its target gene promoters and upregulates their expression. Dominant-negative inhibition and knockdown of Hif-3α abolish hypoxia-induced Hif-3α-promoter binding and gene expression. Hif-3α not only mediates hypoxia-induced growth and developmental retardation but also possesses hypoxia-independent activities. Importantly, transactivation activity is conserved and human HIF-3α upregulates similar genes in human cells. These findings suggest that Hif-3 is an oxygen-dependent transcription factor and activates a distinct transcriptional response to hypoxia.

Gut microbiota protects against gastrointestinal tumorigenesis caused by epithelial injury.

Inflammation is a critical player in the development of both colitis-associated and sporadic colon cancers. Several studies suggest that the microbiota contribute to inflammation and tumorigenesis; however, studies to understand the role of the microbiota in colon tumor development in germ-free (GF) mice are limited. We therefore studied the effects of the microbiota on the development of inflammation and tumors in GF and conventionally raised specific pathogen-free (SPF) mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS). We discovered that GF mice developed significantly more and larger tumors compared with that in SPF mice after AOM and DSS treatment despite the lack of early acute inflammation in response to chemically induced injury by DSS. Although the extent of intestinal epithelial damage and apoptosis was not significantly different in GF and SPF mice, there was a delay in intestinal epithelial repair to DSS-induced injury in GF mice resulting in a late onset of proinflammatory and protumorigenic responses and increased epithelial proliferation and microadenoma formation. Recolonization of GF mice with commensal bacteria or administration of lipopolysaccharide reduced tumorigenesis. Thus, although commensal bacteria are capable of driving chronic inflammation and tumorigenesis, the gut microbiota also have important roles in limiting chemically induced injury and proliferative responses that lead to tumor development.