Lung cancer is the second most common and the deadliest type of cancer worldwide. Clinically, non‐small cell lung cancer (NSCLC) is the most common pathological type of lung cancer; approximately one‐third of affected patients have locally advanced NSCLC (LA‐NSCLC, stage III NSCLC) at diagnosis. Because of its heterogeneity, LA‐NSCLC often requires multidisciplinary assessment. Moreover, the prognosis of affected patients is much below satisfaction, and the efficacy of traditional therapeutic strategies has reached a plateau. With the emergence of targeted therapies and immunotherapies, as well as the continuous development of novel radiotherapies, we have entered an era of novel treatment paradigm for LA‐NSCLC. Here, we reviewed the landscape of relevant therapeutic modalities, including adjuvant, neoadjuvant, and perioperative targeted and immune strategies in patients with resectable LA‐NSCLC with/without oncogenic alterations; as well as novel combinations of chemoradiation and immunotherapy/targeted therapy in unresectable LA‐NSCLC. We addressed the unresolved challenges that remain in the field, and examined future directions to optimize clinical management and increase the cure rate of LA‐NSCLC.

Background Metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF) has the potential to improve the pathogen identification in severe community-acquired pneumonia (SCAP). Methods In this 1.5-year, multicenter, prospective study, we investigated the usefulness of mNGS of BALF for identifying pathogens of SCAP in hospitalized adults, comparing it with other laboratory methods. Results Of 329 SCAP adults, a microbial etiology was established in 304 cases (92.4%). The overall microbial yield was 90.3% for mNGS versus 39.5% for other methods (P < 0.05). The most frequently detected pathogens in immunocompetent patients were Streptococcus pneumoniae (14.8%), rhinovirus (9.8%), Haemophilus influenzae (9.1%), Staphylococcus aureus (8.7%), and Chlamydia psittaci (8.0%), while in immunocompromised patients they were Pneumocystis jirovecii (44.6%), Klebsiella pneumoniae (18.5%), Streptococcus pneumoniae (15.4%), Haemophilus influenzae (13.8%), and Pseudomonas aeruginosa (13.8%). Notably, novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified from two patients solely by mNGS in January 2020; uncommon pathogens including Orientia tsutsugamushi and Nocardia otitidiscaviarum were identified from one patient, respectively. Furthermore, mixed infections were detected in 56.8% of the patients. Conclusions A high microbial detection rate was achieved in SCAP adults using mNGS testing of BALF. The most frequently detected pathogens of SCAP differed between immunocompetent and immunocompromised patients. mNGS testing may be an powerful tool for early identification of potential pathogens for SCAP to initiate a precise antimicrobial therapy.

Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive channel in pulmonary arterial smooth muscle cells (PASMCs). Its upregulation by chronic hypoxia is associated with enhanced myogenic tone, and genetic deletion of trpv4 suppresses the development of chronic hypoxic pulmonary hypertension (CHPH). Here we further examine the roles of TRPV4 in agonist-induced pulmonary vasoconstriction and in the enhanced vasoreactivity in CHPH. Initial evaluation of TRPV4-selective antagonists HC-067047 and RN-1734 in KCl-contracted pulmonary arteries (PAs) of trpv4 ^−/− mice found that submicromolar HC-067047 was devoid of off-target effect on pulmonary vasoconstriction. Inhibition of TRPV4 with 0.5 μM HC-067047 significantly reduced the sensitivity of serotonin (5-HT)-induced contraction in wild-type (WT) PAs but had no effect on endothelin-1 or phenylephrine-activated response. Similar shift in the concentration-response curve of 5-HT was observed in trpv4 ^−/− PAs, confirming specific TRPV4 contribution to 5-HT-induced vasoconstriction. 5-HT-induced Ca²⁺ response was attenuated by HC-067047 in WT PASMCs but not in trpv4 ^−/− PASMCs, suggesting TRPV4 is a major Ca²⁺ pathway for 5-HT-induced Ca²⁺ mobilization. Nifedipine also attenuated 5-HT-induced Ca²⁺ response in WT PASMCs but did not cause further reduction in the presence of HC-067047, suggesting interdependence of TRPV4 and voltage-gated Ca²⁺ channels in the 5-HT response. Chronic exposure (3–4 wk) of WT mice to 10% O₂ caused significant increase in 5-HT-induced maximal contraction, which was partially reversed by HC-067047. In concordance, the enhancement of 5-HT-induced contraction was significantly reduced in PAs of CH trpv4 ^−/− mice and HC-067047 had no further effect on the 5-HT induced response. These results suggest unequivocally that TRPV4 contributes to 5-HT-dependent pharmaco-mechanical coupling and plays a major role in the enhanced pulmonary vasoreactivity to 5-HT in CHPH.

Background: Pneumonia is usually presented as a forgotten killer, and an early diagnosis could largely improve the prognostic outcomes. Lung ultrasound (LUS) has been universally applied in evaluating multiple pulmonary diseases including pneumonia. However, the diagnosis accuracy of LUS for pneumonia in adults is still uncertain. Hence, we performed a systematic review of the current literature to assess the diagnosis accuracy of LUS for pneumonia in adults. Methods: PubMed and EMBASE were searched for clinical trials that assessed the detection accuracy of LUS for pneumonia in adult patients. We extracted descriptive and quantitative information from eligible studies that met strict inclusion criteria and calculated pooled sensitivity, specificity and pooled diagnostic likelihood ratios (LR). Summary receiver operating characteristic (sROC) curve was used to assess the overall performance of LUS-based assays. Results: We reviewed 1,072 articles and selected 38 for detailed review. 14 articles containing 1,911 participants met all inclusion criteria and were included in the final analysis. LUS exhibited a pooled sensitivity of 0.904 (0.884–0.921), specificity of 0.884 (0.861–0.904), positive LR of 6.6 (3.7–11.7), negative LR of 0.08 (0.04–0.19) and the area under curve (AUC) was 0.9611. Interestingly, when CT alone, CT combined with clinical presentations, and microbiology was set as the gold standard of pneumonia respectively, LUS demonstrated a pooled sensitivity of 90.9%, 95.0%, 53.3%, and a pooled specificity of 89.7%, 91.3% and 67.9%. In extension, we compared the diagnostic efficiency of LUS for pneumonia with chest X-ray (CXR) in 1,343 patients. The AUC for LUS and CXR was 0.972 and 0.867 respectively and the Z statistic of the two sROC curves was 2.31. Conclusions: Our study indicated that LUS is a robust diagnostic tool for pneumonia with high accuracy. Utilization of LUS would facilitate the estimation of pneumonia at bedside.