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PURPOSE: Next-generation sequencing (NGS) has enabled the detection of concomitant driver alterations in non–small cell lung cancer (NSCLC). However, the magnitude and clinical relevance of concomitant drivers remain to be explored. METHODS: We profiled concomitant driver alterations of EGFR + NSCLC by using targeted NGS. The associated genomic and clinical features were analyzed and validated in an independent The Cancer Genome Atlas cohort of patients with EGFR + NSCLC. RESULTS: Out of the total patient population, 334 patients had EGFR mutations along with concomitant driver mutations, comprising 3.09% of the entire cohort. The most frequent co-occurring mutations with sensitizing EGFR mutations include KRAS at 53.9%, followed by ERBB2 at 24.3%, MET at 16.5%, and BRAF at 3.3%. KRAS mutations in concomitant drivers were frequently hyperexchange mutations (25.6% v 8.2%, P <.001), compared with KRAS single drivers. EGFR / ERBB2 drivers exhibited a higher incidence of ERBB2 amplification (40.7% v 16.5%, P <.001) and p.S310F/Y mutations (44.4% v 4.3%, P <.001) compared with ERBB2 alone. EGFR / MET drivers had a higher frequency of MET amplification (71.4% v 43.3%) than MET single drivers. At the genomic level, the median number of additional concurrent mutations was four, with TSC2 (4%), CD274 (1%), and TP53 (63%) being the most frequently coaltered genes in concomitant driver tumors. Interestingly, clonality analysis indicated that EGFR mutations were more likely to occur as clonal events, whereas the codrivers were more often subclonal. Patients with concomitant drivers or with concomitant MET amplification exhibited worse prognosis. CONCLUSION: These findings might aid in the selection of effective therapeutic regimens and facilitate the development of combination therapies. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that Bcl2-associated athanogene 2 (BAG2) serves as a crucial regulator for tumorigenesis in multiple tumors. However, little is known about the effect of BAG2 on esophageal squamous cell carcinoma (ESCC). This study focused on investigating whether BAG2 functions as a cancer-promoting gene in ESCC. In this work, gene expression data and clinical information from the NCBI Gene Expression Omnibus (GEO), Oncomine and The Cancer Genome Atlas (TCGA) were collected and analyzed. Expression of BAG2 in ESCC was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). BAG2 was knocked down using small interference RNA (si-RNA) approach. Cell proliferation, migration and invasion were assessed by Cell Counting Kit-8 (CCK-8) and transwell assays. Molecular mechanism was detected by western blotting assay. The expression of BAG2 both in ESCC tissues and cells was upregulated and overexpression was associated with worsened prognosis. BAG2 silencing inhibited ESCC cell proliferation, migration and invasion, which was regulated by the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway. These results reveal contributions of BAG2 as a predictor and potential therapeutic target in ESCC.

Polo‐like kinase 1 (PLK1) inhibitor NMS‐P937 is a targeted therapeutic agent with good preclinical efficacy in various human cancers, and its therapeutic effect on nasopharyngeal carcinoma (NPC) remains to be determined. Here, to explore biological activity of NMS‐P937 in NPC, multiple types of NPC cells were utilized. We tested IC50 values, carried out flow cytometry, western blot analysis analysis, immunofluorescence, and constructed subcutaneous xenograft mouse models. We found that treatment with NMS‐P937 increased the proportion of G2/M phase NPC cells, where CyclinB1 expression was upregulated and CyclinE1 expression was downregulated. Besides, NMS‐P937 treatment‐induced NPC cell apoptosis with increased cleavage of PARP and caspase‐3. Mechanistically, NMS‐P937 treatment led to aberrant mitosis, causing increased reactive oxygen species (ROS) levels. ROS scavenger N‐acetylcysteine partially reversed ROS levels induced by NMS‐P937. Furthermore, NMS‐P937 administration restrained NPC xenografts growth in nude mice. Overall, NMS‐P937 suppressed NPC cell proliferation and increased ROS levels, causing cell cycle abnormalities and apoptosis. NMS‐P937 holds great promise as a therapeutic agent for treating nasopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated from Piper kadsura, can be used to treat sepsis, models of bacterial lipopolysaccharide (LPS)-activated macrophages and LPS-induced endotoxemia mice were used. Galgravin suppressed NF-κB activation in LPS-activated RAW 264.7 macrophages without causing significant cytotoxicity, in which proinflammatory molecules like TNF-α, IL-6, iNOS, and COX-2 were downregulated. In addition, the expression of TNF-α and IL-6 was also suppressed by galgravin in LPS-activated murine bone marrow-derived macrophages. Moreover, galgravin significantly downregulated the mRNA expression of TNF-α, IL-6, and iNOS in the lungs and decreased TNF-α and IL-6 in the serum and IL-6 in the bronchoalveolar lavage fluid of LPS-challenged mice. The COX-2 expression in tissues, including the lung, liver, and kidney, as well as the lung alveolar hemorrhage, was also reduced by galgravin. The present study reveals the anti-inflammatory effects of galgravin in mouse models and implies its potential application in inflammation diseases. [ABSTRACT FROM AUTHOR]

The experience of a physician at a clinical center is among the critical factors in managing chronic myeloid leukemia (CML) during its treatment with tyrosine kinase inhibitors (TKIs). The authors conducted a cross-sectional questionnaire to investigate barriers to physician use of published evidence-based guidelines in CML management in a real-world setting. Among the participating physicians (N = 407), 99.8% of physicians reported that CML guidelines were useful; however, only 62.9% of physicians reported that they follow guidelines in real-time. Although 90.7% of physicians prefer second-generation TKIs as the first-line treatment, imatinib (88.2%) remains the most widely administered TKI in the first-line setting. Only 50.6% of physicians switched the treatment when patients failed to achieve early molecular response (at 3 months), whereas 70.3% of physicians switched the treatment when patients' response to TKI was inadequate at 6 months and/or 12 months. Moreover, only 43.5% of physicians considered treatment-free remission (TFR) as one of the top 3 goals for their patients. The major concern to obtain TFR was patients' adherence. This study demonstrated that CML management was generally in line with the current guidelines, but some of the details at the point of care are needed to be improved in CML. [ABSTRACT FROM AUTHOR]

Myopia and keratoconus have become common corneal diseases that threaten the quality of human vision, and keratoconus is one of the most common indications for corneal transplantation worldwide. Collagen crosslinking (CXL) using riboflavin and ultraviolet A (UVA) light is an effective approach for treating ophthalmic disorders and has been shown clinically not only to arrest further progression of keratoconus but also to improve refractive power for cornea. However, CXL surgery irradiated by UVA has various potential risks such as surface damage and endothelial cell damage. Here, near‐infrared femtosecond laser‐based two‐photon CXL was first applied to ex vivo human corneal stroma, operating at low photon energy with high precision and stability. After two‐photon CXL, the corneal stiffness can be enhanced by 300% without significantly reducing corneal transparency. These findings illustrate the optimized direction that depositing high pulses energy in corneal focal volume (not exceeding damage threshold), and pave the way to 3D CXL of in vivo human cornea with higher safety, precision, and efficacy. [ABSTRACT FROM AUTHOR]