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Lung cancer is the leading cause of cancer-related death. The identification of epidermal growth factor receptor (EGFR) somatic mutations defined a new, molecularly classified subgroup of non-small-cell lung cancer (NSCLC). Classic EGFR activating mutations, such as inframe deletions in exon 19 or the Leu858Arg (L858R) point mutation in exon 21 are associated with sensitivity to first generation quinazoline reversible EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 20 insertion mutations, which are typically located after the C-helix of the tyrosine kinase domain of EGFR, may account for up to 4% of all EGFR mutations. Preclinical models have shown that the most prevalent EGFR exon 20 insertion mutated proteins are resistant to clinically achievable doses of reversible (gefitinib, erlotinib) and irreversible (neratinib, afatinib, PF00299804) EGFR TKIs. Growing clinical experience with patients whose tumours harbour EGFR exon 20 insertions corresponds with the preclinical data; very few patients have had responses to EGFR TKIs. Despite the prevalence and biological importance of EEGFR exon 20 insertions, few reports have summarised all preclinical and clinical data on these mutations. Here, we review the literature and provide an update with an emphasis on the structural, molecular, and clinical implications of EGFR exon 20 insertions.

Peptidylarginine deiminase 2 (PAD2) is an enzyme that converts arginine to citrulline and is involved in diseases, such as Alzheimer’s diseases, fibrosis and cancer. However, its role in inflammatory bowel disease remains unclear. In this study, we investigated the pathogenic effects of PAD2 on inflammatory bowel disease using a trinitrobenzene sulfonic acid (TNBS)-induced murine colitis model. PAD2-deficient (PAD2KO) mice were generated using CRISPR/Cas9-mediated genomic editing. TNBS injection resulted in body weight loss, extensive colonic erosion, and ulceration in wild-type (WT) mice. However, these responses were significantly attenuated in PAD2KO mice. TNBS-induced increases in myeloperoxidase activity, inflammatory cytokine expression, and macrophage extracellular traps (METs) induction in the colon were significantly reduced in PAD2KO. Furthermore, METs were triggered in peritoneal macrophages obtained from WT mice by A23187 and phorbol myristate acetate, and notably, these responses were not abolished in PAD2KO mice. Moreover, inflammatory cytokine expression and M1 macrophage polarization in peritoneal macrophages obtained from PAD2KO mice was lower than that in peritoneal macrophages from WT mice. Overall, PAD2 contributes to the pathogenesis of TNBS-induced colitis by regulating inflammatory cytokine expression in macrophages through METs-independent pathways. Therefore, PAD2 is a promising target for treating inflammatory bowel disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the disease COVID-19 can lead to serious symptoms, such as severe pneumonia, in the elderly and those with underlying medical conditions. While vaccines are now available, they do not work for everyone and therapeutic drugs are still needed, particularly for treating life-threatening conditions. Here, we showed nasal delivery of a new, unmodified camelid single-domain antibody (VHH), termed K-874A, effectively inhibited SARS-CoV-2 titers in infected lungs of Syrian hamsters without causing weight loss and cytokine induction. In vitro studies demonstrated that K-874A neutralized SARS-CoV-2 in both VeroE6/TMPRSS2 and human lung-derived alveolar organoid cells. Unlike other drug candidates, K-874A blocks viral membrane fusion rather than viral attachment. Cryo-electron microscopy revealed K-874A bound between the receptor binding domain and N-terminal domain of the virus S protein. Further, infected cells treated with K-874A produced fewer virus progeny that were less infective. We propose that direct administration of K-874A to the lung could be a new treatment for preventing the reinfection of amplified virus in COVID-19 patients.

To promote the use of γ-TiAl alloys in various domains, such as the aerospace industry, it is pivotal to investigate the unusual phase transformation from rapidly solidified and metastable γ-TiAl toward the equilibrium state. In this study, the microstructure characteristics of gas-atomized β-solidifying Ti-44Al-6Nb-1.2Cr alloy powder, in terms of the effect of rapid solidification on microstructure evolution, were explored in comparison with cast materials. The phase constitution, morphology, and crystallographic orientation between phases were noted to be distinct. Furthermore, subsequent heat treatment was conducted at different temperatures using gas-atomized powder. The transition from the metastable to equilibrium state was observed, wherein firstly, the γ phase precipitated from the retained α2 phase, forming an α2/γ lamellar microstructure. In intensified heat-treatment conditions adequate for cellular reaction, β/γ cells were formed at the grain boundaries of α2/γ lamellar colonies. The findings highlight the overall phase transformation during rapid solidification and continuous microstructural evolution from the nonequilibrium to the equilibrium state. This research can bridge the gap in understanding the effect of the solidification rate on microstructural evolution and contribute to enhanced comprehension of the microstructure in other domains involving rapid solidification, such as the additive manufacturing of γ-TiAl alloys.

Background Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. Materials and Methods Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. Results Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P = .005 and .044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P = .428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P = .028). Conclusion This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis. Despite favorable outcomes, immune checkpoint inhibitors are associated with a unique set of toxicities, known as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study investigated whether pre-existing interstitial lung abnormality is a potential risk factor for ICI-related pneumonitis.

Neutrophil extracellular traps (NETs) are induced in the innate immune response against infectious agents and are also implicated in the pathogenesis of various cancers and autoimmune diseases. Peptidylarginine deiminase 4 (PAD4), an enzyme that converts arginine to citrulline, is also involved in NET formation. In this study, we investigated the pathogenic effect of PAD4 on NETs in inflammatory bowel disease using a trinitrobenzene sulfonic acid (TNBS)-induced murine colitis model. PAD4-deficient (PAD4KO) mice were generated by CRISPR-Cas9-mediated genomic editing. NETs were triggered in peritoneal neutrophils obtained from wild-type mice by A23187 (a calcium ionophore), but these responses were completely abolished in the PAD4KO mice. Experimental colitis was induced in wild-type and PAD4KO mice via an intrarectal injection of TNBS. TNBS injection resulted in body weight loss, extensive colonic erosion, and ulceration in wildtype mice. However, these responses were significantly attenuated following the administration of Cl-amidine (an inhibitor of pan-PADs) and DNase I (an inhibitor of NET formation), in combination with PAD4KO in mice. TNBS-induced increases in myeloperoxidase activity, inflammatory cytokine expression, and NET formation in the colon were significantly reduced following the administration of Cl-amidine, DNase I injection, and PAD4KO. These findings suggest that NET formation contributes to the pathogenesis of TNBS-induced colitis via PAD4. Thus, PAD4 is a promising target for the treatment of inflammatory bowel disease.

The next-generation sequencing (NGS)–based Oncomine Dx Target Test (ODxTT) is the standard tool for guiding postoperative adjuvant therapy in patients with non-small cell lung cancer (NSCLC) in Japan. To advance precision oncology, we evaluated the clinical utility of an in-house comprehensive genomic profiling (CGP) assay, Rapid-Neo, as a complementary approach to ODxTT in surgically resected NSCLC. Patients with pathological stage II–III NSCLC who underwent anatomical surgical resection between December 2019 and May 2024 were included. Resected specimens underwent genomic analysis using both ODxTT and Rapid-Neo CGP. We evaluated the mutational concordance and the frequency of additional actionable alterations identified by CGP. Among 68 eligible patients, driver mutation results were concordant in 64 (94.1%) cases. Crucially, CGP rescued one patient for targeted therapy by detecting an EGFR mutation where ODxTT failed due to insufficient DNA. CGP also identified rare EGFR variants not covered by ODxTT in two cases, although it failed to detect a RET fusion in one patient. Furthermore, CGP revealed additional actionable alterations, such as tumor suppressor gene mutations, in 57 patients (83.8%). Our in-house CGP shows high concordance with ODxTT and serves as a powerful complementary tool. These findings support a strategic testing algorithm where CGP is incorporated for patients with negative or inconclusive ODxTT results, or at the time of recurrence, to maximize opportunities for individualized therapy in resected NSCLC.

Sarcopenia has been associated with poor clinical outcomes in several diseases. Herein, the clinical results of balloon kyphoplasty (BKP) for acute osteoporotic vertebral fracture (OVF) treatment were assessed and compared between sarcopenia and non-sarcopenia patients. Sixty patients who underwent BKP for treatment of acute OVF with poor prognostic factors between April 2016 and September 2017 and were assessed for sarcopenia were enrolled. Clinical results (back pain on visual analogue scale [VAS]; short-form [SF] 36; vertebral deformity; activities of daily living levels; and incidence of adjacent vertebral fractures) were compared between the two groups at 6 months post-BKP. Data analysis revealed that back pain on VAS, SF-36 scores, and vertebral deformity improved from baseline to 6 months after BKP. Thirty-nine patients (65.0%) were diagnosed with sarcopenia and demonstrated a lower body mass index (21.2 vs. 23.3 kg/m 2 , p = 0.02), skeletal muscle mass index (5.32 vs. 6.55 kg/m 2 , p < 0.01), hand-grip strength (14.7 vs. 19.2 kg, p = 0.01), and bone mineral density of the femoral neck (0.57 vs. 0.76 g/cm 2 , p < 0.01) than those of patients without sarcopenia. However, no significant differences were observed in the clinical results between these groups. Therefore, BKP’s clinical results for the treatment of acute OVF are not associated with sarcopenia.

UV-B radiation induces sunburn, and neutrophils are pivotal in this inflammation. In this study, we examined the potential involvement of neutrophil extracellular traps (NETs) in ultraviolet B (UVB)-induced skin inflammation, correlating the skin inflammation-mitigating effects of Hochu-ekki-to on UV-B irradiation and NETs. To elucidate NET distribution in the dorsal skin, male ICR mice, exposed to UVB irradiation, were immunohistologically analyzed to detect citrullinated histone H3 (citH3) and peptidylarginine deiminase 4 (PAD4). Reactive oxygen species (ROS) production in the bloodstream was analyzed. To establish the involvement of NET-released DNA in this inflammatory response, mice were UV-B irradiated following the intraperitoneal administration of DNase I. In vitro experiments were performed to scrutinize the impact of Hochu-ekki-to on A23187-induced NETs in neutrophil-like HL-60 cells. UV-B irradiation induced dorsal skin inflammation, coinciding with a significant increase in citH3 and PAD4 expression. Administration of DNase I attenuated UV-B-induced skin inflammation, whereas Hochu-ekki-to administration considerably suppressed the inflammation, correlating with diminished levels of citH3 and PAD4 in the dorsal skin. UV-B irradiation conspicuously augmented ROS and hydrogen peroxide (H2O2) production in the blood. Hochu-ekki-to significantly inhibited ROS and H2O2 generation. In vitro experiments demonstrated that Hochu-ekki-to notably inhibited A23187-induced NETs in differentiated neutrophil-like cells. Hence, NETs have been implicated in UV-B-induced skin inflammation, and their inhibition reduces cutaneous inflammation. Additionally, Hochu-ekki-to mitigated skin inflammation by impeding neutrophil infiltration and NETs in the dorsal skin of mice.

The effect of a two-step heat treatment on the microstructure and high-temperature tensile properties of β-containing Ti-44Al-4Cr (at%) alloys fabricated by electron beam powder bed fusion were examined by focusing on the morphology of α2/γ lamellar grains and β/γ cells precipitated at the lamellar grain boundaries by a cellular precipitation reaction. The alloys subjected to the first heat treatment step at 1573 K in the α + β two-phase region exhibit a non-equilibrium microstructure consisting of the α2/γ lamellar grains with a fine lamellar spacing and a β/γ duplex structure located at the grain boundaries. In the second step of heat treatment, i.e., aging at 1273 K in the β + γ two-phase region, the β/γ cells are discontinuously precipitated from the lamellar grain boundaries due to excess Cr supersaturation in the lamellae. The volume fraction of the cells and lamellar spacing increase with increasing aging time and affect the tensile properties of the alloys. The aged alloys exhibit higher strength and comparable elongation at 1023 K when compared to the as-built alloys. The strength of these alloys is strongly dependent on the volume fraction and lamellar spacing of the α2/γ lamellae. In addition, the morphology of the β/γ cells is also an important factor controlling the fracture mode and ductility of these alloys.