Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).

Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION.

BACKGROUND: Tepotinib, a MET inhibitor approved for the treatment of MET exon 14 (METex14) skipping NSCLC, demonstrated durable clinical activity in VISION (Cohort A + C; N = 313): objective response rate (ORR) 51.4% (95% CI: 45.8, 57.1); median duration of response (mDOR) 18.0 months (95% CI: 12.4, 46.4). We report outcomes in Asian patients from VISION (Cohort A + C) (cut-off: November 20, 2022). METHODS: Patients with advanced METex14 skipping NSCLC, detected by liquid or tissue biopsy, received tepotinib 500 mg (450 mg active moiety) once daily. PRIMARY ENDPOINT: objective response (RECIST 1.1) by independent review. Secondary endpoints included: DOR, progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: Across treatment lines in 106 Asian patients (39.6% female, 43.4% smoking history, 79.2% adenocarcinoma, 47.2% treatment-naive), ORR was 56.6% (95% CI: 46.6, 66.2), mDOR 18.5 months (10.4, ne), mPFS 13.8 months (10.8, 22.0), and mOS 25.5 months (19.3, 36.4). Consistent efficacy observed, regardless of baseline characteristics. HRQoL remained stable during treatment. Treatment-related adverse events (TRAEs) occurred in 95.3% of patients (39.6% Grade ≥3). Most common TRAEs: peripheral edema (62.3%), creatinine increase (38.7%). CONCLUSIONS: Tepotinib demonstrated robust and durable efficacy, with a manageable safety profile, in Asian patients with METex14 skipping NSCLC. CLINICAL TRIAL REGISTRATION: NCT02864992.

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Contamination status, partitioning behavior, ecological risks assessment of legacy and emerging per- and polyfluoroalkyl substances in a typical heavily polluted semi-enclosed bay, China.

The contaminant status, spatial distribution, partitioning behavior, and ecological risks of 26 legacy and emerging perfluoroalkyl and polyfluoroalkyl substances (PFASs) in Laizhou Bay, China were investigated. The concentrations of ∑PFASs in surface and bottom seawater ranged from 37.2 to 222 ng/L and from 34.2 to 305 ng/L with an average of 116 ± 62.7 and 138 ± 93.8 ng/L, respectively. There were no significant differences in the average concentrations between the surface and bottom seawater (P > 0.05). Perfluorooctanoic acid (PFOA) and short-chain PFASs dominated the composition of PFASs in seawater. The concentrations of ∑PFASs in sediments ranged from 0.997 to 7.21 ng/g dry weight (dw), dominated by perfluorobutane sulfonate (PFBS), perfluorobutanoic acid (PFBA), and long-chain PFASs. The emerging alternatives of perfluoro-1-butane-sulfonamide (FBSA) and 6:2 fluorotelomer sulfonic acid (6:2 FTSA) were detected for the first time in Laizhou Bay. The ∑PFASs in seawater in the southwest of the bay were higher than those in the northeast of the bay. The ∑PFASs in sediments in the northeast sea area were higher than those in the inner area of the bay. Log Kd and log Koc values increased with increasing carbon chain length for PFASs compounds. Ecological risk assessments indicated a low ecological risk associated with HFPO-DA but a moderate risk associated with PFOA contamination in Laizhou Bay. Positive matrix factorization (PMF) analysis revealed that fluoropolymer manufacturing, metal plating plants, and textile treatments were identified as major sources contributing to PFASs contamination.

[Mechanisms of NLRP3 inflammasome-mediated pyroptosis in chronic heart failure and research progress in traditional Chinese medicine].

Chronic heart failure(CHF) is a severe cardiovascular disease characterized by a complex pathogenesis involving myocardial structural and functional abnormalities and the activation of inflammatory responses. The NOD-like receptor thermal protein domain-associated protein 3(NLRP3) inflammasome, acting as a sensor for inflammatory cells, plays a pivotal role in the development of CHF. Research indicates that the activation of the NLRP3 inflammasome can induce inflammatory responses, leading to cardiac inflammation and impairing myocardial function, and it is correlated with the severity of CHF. Traditional Chinese medicine(TCM) has garnered increasing attention as a traditional therapeutic approach in recent years. Various TCM drugs and treatment methods have exhibited potential efficacy in suppressing inflammatory responses, alleviating myocardial cell pyroptosis, improving myocardial structure and function, and inhibiting myocardial fibrosis. Several TCM drugs and their extracts have been utilized in CHF treatment, with mechanisms potentially involving the inhibition of NLRP3 inflammasomes and the mitigation of inflammatory responses. The article provided an overview of the composition, structural characteristics, initiation, and activation modes of the NLRP3 inflammasome, its mechanisms in CHF, and the research progress of TCM in CHF treatment. It aims to offer references and foundations for a deeper understanding of CHF pathogenesis and subsequent development of new therapeutic strategies.

Boryl Radical as a Catalyst in Enabling Intra- and Intermolecular Cascade Radical Cyclization Reactions: Construction of Polycyclic Molecules.

Cascade radical cyclization constitutes an atom- and step-economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox-active metal catalysts has recently shown robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium-based N-heterocyclic carbene (NHC)-boryl radical is capable of catalyzing cascade cyclization reactions in both intra- and intermolecular pathways, assembling [5,5] fused bicyclic and [6,6,6] fused tricyclic molecules, respectively. The catalytic reactions start with the chemo- and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal [3+2] or an intermolecular [2+2+2] cycloaddition process to construct bicyclo[3.3.0]octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a ß-elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.

The Clinical Efficacy Evaluation of Thigh Liposuction Based on 3-Dimensional Digital Technology: A Quantitative Study.

BACKGROUND: There is a lack of convenient and accurate objective methods to evaluate the clinical efficacy of thigh liposuction. METHODS: This retrospective study involved the 3-dimensional images of 19 patients who underwent bilateral thigh liposuction. Data such as volume change and volume change rate before and after surgery, circumference change, and circumference change rate of 3 planes (upper, middle, and lower) were analyzed. The correlation between body mass index and volume change rate and between preoperative circumference and circumference change rate of different planes were determined. RESULTS: There were significant differences between the preoperative and postoperative volume and circumference of 3 planes of 19 patients (38 thighs). The rate of change in total volume (16.90 ± 5.55%) correlated with the circumference change rate at the top of the thigh. There was also a linear relationship between body mass index and volume change rate, but not between preoperative circumference and circumference change rate. CONCLUSIONS: Three-dimensional imaging technology can accurately quantify the volume and circumference change of the thigh to objectively evaluate the clinical efficacy of thigh liposuction.

Clinicopathological features and resistance mechanisms in HIP1-ALK-rearranged lung cancer: A multicenter study.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) respond well to ALK tyrosine kinase inhibitors (TKIs), and echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged NSCLC accounts for the majority of those patients. However, few studies have evaluated ALK-TKIs treatment for patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions. This retrospective study evaluated the clinicopathological characteristics, genomic features, response to ALK-TKIs, and resistance mechanisms in 11 cases with HIP1-ALK fusions from five Chinese centers. Patients who received crizotinib at the Chinese centers had an objective response rate of 90% [9/10 cases, 95% confident index (CI): 54.1%-99.5%], median progression-free survival of 17.9 months (95% CI: 5.8-NA months), and median overall survival of 58.8 months (95% CI: 24.7-NA months). One patient who received first-line lorlatinib treatment achieved partial response for > 26.5 months. Despite the small sample size, HIP1-ALK (H21:A20) variant was the most common variant (four of 11 cases, 36.4%) and associated with better outcomes. Among the 11 cases, there were eight patients having available specimens for genetic testing before ALK-TKIs treatment and four patients undergoing biopsy after ALK-TKIs failure. The most common coexisting gene was TP53 among 11 patients and two of four patients after crizotinib failure harbored acquired ALK mutations (e.g., L1152V/Q1146K and L1196M). Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants. Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.

Metal-Organic Framework Supported Copper Photoredox Catalysts for Iminyl Radical-Mediated Reactions.

Visible-light copper photocatalysis has recently emerged as a viable technology for building sustainable synthetic processes. To broaden the applications of phosphine-ligated copper(I) complexes, we describe herein an effective metal-organic framework (MOF)-supported copper(I) photocatalyst for multiple iminyl radical-mediated reactions. Due to site isolation, the heterogenized copper photosensitizer has a significantly higher catalytic activity than its homogeneous counterpart. Using a hydroxamic acid linker to immobilize copper species on MOF supports affords the heterogeneous catalysts with high recyclability. The post-synthetic modification sequence on MOF surfaces allows for the preparation of previously unavailable monomeric copper species. Our findings highlight the potential of using MOF-based heterogeneous catalytic systems to address fundamental challenges in the development of synthetic methodologies and mechanistic investigations of transition-metal photoredox catalysis.

Camrelizumab in different PD-L1 expression cohorts of pre-treated advanced or metastatic non-small cell lung cancer: a phase II study.

BACKGROUND: This phase II study evaluated camrelizumab in different PD-L1 expression cohorts of patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC; NCT03085069, registered March 21, 2017). METHODS: Patients who progressed during/after chemotherapy were enrolled and divided into four cohorts based on PD-L1 tumor proportion score (TPS). Patients with EGFR/ALK alterations and PD-L1 TPS ≥ 50% were also eligible. All enrolled patients received camrelizumab at 200 mg IV Q2W. The primary endpoint was objective response rate. RESULTS: A total of 146 patients were enrolled. As of data cutoff on Aug 20, 2020, the median follow-up was 29.5 months (95% CI 27.4-30.8). Objective response rate was 17.8% (95% CI 12.0-25.0) and improved with the increasing PD-L1 TPS (TPS < 1%, 12.2% [95% CI 5.7-21.8]; ≥ 1-< 25%, 19.4% [95% CI 7.5-37.5]; ≥ 25-< 50%, 36.4% [95% CI 10.9-69.2]; ≥ 50%, 23.3% [95% CI 9.9-42.3]). No response was observed in the five patients harboring EGFR mutations. Median progression-free survival was 3.2 months (95% CI 2.0-3.4), and patients with positive PD-L1 TPS had longer progression-free survival. Median overall survival was 14.8 months (95% CI 10.2-18.7). Treatment-related adverse events (TRAEs) of any grade occurred in 87.7% of patients, and 21.2% had grade ≥ 3 TRAEs. CONCLUSION: Camrelizumab showed improved efficacy compared with historical data of the second-line chemotherapy in pre-treated advanced/metastatic NSCLC. Patients with positive PD-L1 expression derived greater benefit from camrelizumab. Camrelizumab has a manageable safety profile.

Subsequent treatments beyond progression on osimertinib in EGFR-mutated NSCLC and leptomeningeal metastases.

BACKGROUND: Despite the reported efficacy of osimertinib, central nervous system (CNS) progression is still frequent in EGFR-mutated NSCLC. This study aimed to reveal site-specific resistant mechanisms to osimertinib and investigate subsequent treatments for leptomeningeal metastases (LM). METHODS: EGFR-mutated NSCLC with LM who progressed on osimertinib were included. Molecular analysis of cerebrospinal fluid (CSF) at osimertinib progression was performed. Subsequent treatments of LM were collected and analyzed. RESULTS: A total of 246 patients were identified. Only those with LM as a progression site on osimertinib were included (n=81). In 58 CSF-plasma pairs, more alterations were uniquely detected in CSF (77%) than in plasma (7%). These mechanisms led to 22 patients receiving matched targeted therapy. Among them, 16 (72.7%) had a clinical response. The median overall survival was 7.2 months. For non-matched therapy (n=59), the osimertinib combination had a longer median overall survival than the regimen switch in CNS-only progression (15.3 vs. 7 months, p=0.03). Finally, serial monitoring by CSF revealed the potential evolution of LM. CONCLUSIONS: Private resistant mechanisms in CSF might match osimertinib-resistant LM for targeted therapy. Besides, continuing osimertinib with intensification strategy might prolong survival, especially for those with CNS-only progression. Prospective  exploration is needed.

Mixed-Linker Isoreticular Zn(II) Metal-Organic Frameworks as Brønsted Acid-Base Bifunctional Catalysts for Knoevenagel Condensation Reactions.

Multicomponent metal-organic frameworks (MOFs) have received an increasing amount of attention due to their potential to produce new topologies, pore metrics, and functionalities compared to MOFs with a single metal cluster and one organic linker. Herein, five isoreticular Zn MOFs were obtained by mixing two types of linear ditopic linkers in a one-pot solvothermal synthesis. Interestingly, in the resulting Zn MOFs a six-connected cyclic trinuclear Zn(II) cluster and an eight-connected linear trinuclear Zn(II) cluster coexist, leading to an uncommon (6,8)-connected network. Catalytic activities toward the solvent-free Knoevenagel reactions were observed for all of these MOFs. Further experimental and computational studies suggest that they are Brønsted acid-base bifunctional catalysts. Through chemical modifications of dicarboxylate ligands, including their aromatic backbones and substituents, we have successfully implemented reticular chemistry for the modulations of pore sizes, surface areas, and catalytic performances in a series of four-component isoreticular MOFs.

Development of a fluorescent nanoprobe based on an amphiphilic single-benzene-based fluorophore for lipid droplet detection and its practical applications.

Lipid droplets (LDs) are crucial biological organelles connected with metabolic pathways in biological systems and diseases. To monitor the locations and accumulation of LDs in lipid-related diseases, the development of a visualization tool for LDs has gained importance. In particular, LD visualization using fluorescent probes has gained attention. Herein, a new fluorescent nanoprobe, BMeS-Ali, is developed that can sense LDs based on an amphiphilic single benzene-based fluorophore (SBBF). BMeS-Ali consists of hydrophilic (-NH2) and hydrophobic (-C12H25) moieties and exists as a micelle nanostructure in aqueous media. BMeS-Ali has a weak fluorescence, but its emission was dramatically enhanced upon exposure to the LD components such as oleic acids (OA) by reassembling its nano-formulation. BMeS-Ali showed a selective LD staining ability and great biocompatibility in cells (cancer cells and stem cells). It also showed a practical sensing ability towards biologically derived lipids and can be applied to the visualization of human fingerprints. We found that the nanoprobe BMeS-Ali has significant potential to serve as a practical dye and sensor for lipids, especially for LD imaging in the biomedical research area and broader industrial applications.

Analgesic Effect of Ropivacaine Pumped in the Sub Rectus Abdominis Muscle Sheath after Abdominoplasty.

BACKGROUND: Abdominoplasty is a major surgical procedure in plastic surgery. It removes excess skin and fat, tightens abdominal muscles and fascia, restores normal abdominal anatomy and reshapes the distorted abdominal contour. According to the statistics released annually by International Society of Aesthetic Plastic Surgery (ISAPS) in 2020, there are more than 900, 000 abdominal wall plastic surgeries performed every year worldwide. However, the most commonly used analgesic methods, such as oral administration, intravenous analgesia and local infiltration anesthesia, do not provide the satisfactory analgesic results. We found that intra-sheath injection of ropivacaine of the rectus abdomen was effective in reducing postoperative pain. OBJECTIVES: To retrospectively study the analgesic effect of continuous pumping ropivacaine into the intra-sheath space of rectus abdominis after abdominoplasty. METHODS: A retrospective study was conducted on 67 patients with total abdominal wall plastic surgery admitted to Plastic Surgery Hospital of Chinese Academy of Medical Sciences from February 2020 to August 2021. The patients were from 25 to 56 years old, with a mean age of 38.5, ASA grade 1-2, BMI 27-33kg/m2, and rectus abdominis muscle separation range of 4-8cm. Based on the methods of postoperative analgesia, we divided patients into the following two groups: 29 patients in the conventional intravenous analgesic group (group A) and 38 patients in the rectus abdominis intrathecal analgesic group (group B). Group A received PCA with sufentanil 1.0µg/kg+ normal saline diluted to 100ml. Group B received continuous pumping of ropivacaine (0.2625%) through the rectus sheath internal tube in 100mL of normal saline and continued pumping at a rate of 2mL /h. Visual analog pain score (VAS score), analgesic pump pressure times and the degree of postoperative satisfaction were recorded at T1 (24h) and T2 (48h). The incidence of adverse drug reactions and complications related to nerve block within one week after operation were also recorded. RESULTS: The clinical data of patients with total abdominal wall plastic surgery in two groups were collected and analyzed. The patients in group B overall had lower postoperative VAS score, less analgesic pump usage, less nausea, vomiting, drowsiness and restlessness and a higher degree of postoperative satisfaction than those in group A. CONCLUSION: Continuous pumping of ropivacaine through rectus sheath can effectively relieve postoperative pain, reduce postoperative adverse reactions and improve postoperative satisfaction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online instructions to Authors www.springer.com/00266 . Body Contouring LOE IV.

Tasquinimod efficacy and S100A9 expression in glucose-treated HREC cells.

PURPOSE: Diabetic retinopathy (DR) is one of the leading causes of blindness in working-aged people. Few studies were on the relationship between S100 Calcium Binding Protein A9 (S100A9) protein and DR, and none on endothelial cells induced by tasquinimod in high glucose. Therefore, we assessed the relationship between tasquinimod and S100A9 in DR. METHODS: DR pathogenesis was simulated using high-glucose-induced human retinal endothelial cells (HRECs) to study the mRNA expression of s100a9, thrombospondin-1 (tsp-1), hypoxia-inducible factor 1-alpha (hif1-α), intercellular adhesion molecule 1 (icam-1), and vascular endothelial growth factor (vegf) after tasquinimod treatment. The protein expression of S100A9, TSP-1, extracellular signal-regulated kinase (ERK), ICAM-1 and VEGF was also analyzed. RESULT: A total of 28 eyes of 26 patients were included in this experiment. A significantly higher expression of S100A9 as well as enhanced proliferation and mobility was observed in the high-glucose-treated HRECs compared with that in low-glucose-treated cells. However, these were significantly inhibited when treated with high glucose with 50 µM tasquinimod. The mRNA expression of tsp-1 was increased, whereas that of hif1-α, icam-1 and vegf was decreased after tasquinimod treatment. Western blot indicated the increased TSP-1 but decreased ERK, ICAM-1 and VEGF expression after treating with tasquinimod. CONCLUSION: High glucose promoted the expression of s100a9, S100A9 protein in DR patients and HRECs. Tasquinimod inhibited the proliferation, migration and lumen formation of HRECs under a high glucose environment. Tasquinimod might play a vital role in inhibiting angiogenesis through inducing TSP-1 and inhibiting VEGF, ICAM-1 and ERK.

Building a Pyrazole-Benzothiadiazole-Pyrazole Photosensitizer into Metal-Organic Frameworks for Photocatalytic Aerobic Oxidation.

Charge separation plays a crucial role in regulating photochemical properties and therefore warrants consideration in designing photocatalysts. Metal-organic frameworks (MOFs) are emerging as promising candidates for heterogeneous photocatalysis due to their structural designability and tunability of photon absorption. Herein, we report the design of a pyrazole-benzothiadiazole-pyrazole organic molecule bearing a donor-acceptor-donor conjugated π-system for fast charge separation. Further attempts to integrate such a photosensitizer into MOFs afford a more effective heterogeneous photocatalyst (JNU-204). Under visible-light irradiation, three aerobic oxidation reactions involving different oxygenation pathways were achieved on JNU-204. Recycling experiments were conducted to demonstrate the stability and reusability of JNU-204 as a robust heterogeneous photocatalyst. Furthermore, we illustrate its applications in the facile synthesis of pyrrolo[2,1-a]isoquinoline-containing heterocycles, core skeletons of a family of marine natural products. JNU-204 is an exemplary MOF platform with good photon absorption, suitable band gap, fast charge separation, and extraordinary chemical stability for proceeding with aerobic oxidation reactions under visible-light irradiation.

A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

Association Between Prediabetes and Retinopathy: A Meta-Analysis.

Diabetes confers an increased risk of microvascular complications, including retinopathy. However, whether prediabetes is also related to retinopathy has not been comprehensively examined. We performed a meta-analysis to evaluate the relationship between prediabetes and retinopathy. This meta-analysis included relevant observational studies from Medline, Embase, and Web of Science databases. A random-effect model after incorporation of the intra-study heterogeneity was selected to pool the results. Subgroup analyses were applied to evaluate the influences of study characteristics on relationship. Nine cross-sectional studies including 14 751 community dwelling adult participants were included; 3847 (26.1%) of them were prediabetic. Results showed that prediabetes was associated with a higher prevalence of retinopathy compared to normoglycemia [odds ratio (OR): 1.55, 95% confidence interval (CI): 1.10-2.20, p=0.01, I2=34%]. Sensitivity analysis by excluding one study at a time showed consistent result (OR: 1.35 to 1.73, p all<0.05). Subgroup analysis showed study characteristics such as definition of prediabetes, country of study, sample size, mean age of participants, or univariate or multivariate analyses may not significantly affect the association (p for subgroup difference all>0.05). Current evidence suggests that patients with prediabetes may be associated with higher prevalence of retinopathy as compared to those with normoglycemia. Although prospective cohort studies are needed to validate these findings, results of our meta-analysis highlighted the importance of early prevention of retinopathy in patients with prediabetes.

L-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling.

Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy. L-carnitine (LC) has been shown to protect against various types of renal injury. In this study, we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus (TAC) nephropathy. SD rats were injected with TAC (1.5 mg · kg-1 · d-1, sc) for 4 weeks. Renoprotective effects of LC were assessed in terms of renal function, histopathology, oxidative stress, expression of inflammatory and fibrotic cytokines, programmed cell death (pyroptosis, apoptosis, and autophagy), mitochondrial function, and PI3K/AKT/PTEN signaling. Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy. At a molecular level, TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney, induced oxidative stress, and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN. Coadministration of LC (200 mg · kg-1 · d-1, ip) caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats. Furthermore, LC exerted anti-inflammatory and antioxidant effects, prevented mitochondrial dysfunction, and modulated the expression of a series of apoptosis- and autophagy-controlling genes to promote cell survival. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TAC (50 µg/mL) in vitro, which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death (pyroptosis, apoptosis, and autophagy) through interfering with PI3K/AKT/PTEN signaling. The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002 (25 µM). In conclusion, LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling.

Continuous tension reduction to prevent keloid recurrence after surgical excision: Preliminary experience in Asian patients.

Surgical excision combined with postoperative radiotherapy is considered one of the most radical but most effective keloid therapeutic option. However, radiotherapy may not be appropriate for all keloid patients. In this study, we propose an alternate approach to prevent keloid recurrence and provide preliminary assessment in clinical efficacy of this treatment for keloids. Forty consecutive patients with different keloid sites underwent excision without postoperative radiation. After surgery, the tension offloading device was used at least 6 months for the purpose of continuous tension reduction at surgery incision. Scars were assessed independently using scar scale at before and 24-month follow-up. Overall, 38 patients completed this research. Clinical results showed that 35 patients achieved healing with an esthetic appearance at 24-month follow-up. Three patients showed relapse and the recurrence rate was 7.9%. Both of VSS (Vancouver Scar Scale) and JSW (Japan Scar Workshop Scar Scale) scores decreased significantly at 24-month follow-up visit than before. No severe complications were reported. Using the tension offloading device could greatly decrease tension on the surgical incision. The technique of continuous tension reduction could be used as an alternative method to prevent keloid recurrence under the condition of without radiotherapy.