Amelioration of the physicochemical properties enhanced the resilience of bacteria in bauxite residues.

Bacteria-driven strategies have gained attention because of their effectiveness, viability, and cost-efficiency in the soil formation process of bauxite residues. However, further investigation is needed to enhance the extreme environment of bauxite residues and facilitate long-term sustainable development of bacteria. Here, soil, phosphogypsum, and leaf litter were selected as amendments, and soil and leaf litter were also used as bacterial inoculants in a 12-month microcosm experiment with bauxite residues. The results showed significant improvements in physicochemical properties, including alkalinity, organic carbon content, nutrient availability, and physical structure, when bauxite residue was mixed with amendments, particularly when different amendments were combined. The diversity, structure, and function of the bacterial community were significantly enhanced with the amelioration of the physicochemical properties. In the treated samples, especially those treated with a combination of different amendments, the relative abundance (RA) of alkali-resistant bacterial taxa decreased, whereas the RA of some common taxa found in normal soil increased, and the structure of the bacterial community gradually changed towards that of normal soil. A strong correlation between physicochemical and biological properties was found. These findings suggest that rational application of soil, phosphogypsum, and leaf litter effectively improves the environmental conditions of bauxite residues and facilitate long-term sustainable bacterial communities.

ERS International Congress 2023: highlights from the Respiratory Intensive Care Assembly.

Early career members of Assembly 2 (Respiratory Intensive Care) attended the 2023 European Respiratory Society International Congress in Milan, Italy. The conference covered acute and chronic respiratory failure. Sessions of interest to our assembly members and to those interested in respiratory critical care are summarised in this article and include the latest updates in respiratory intensive care, in particular acute respiratory distress syndrome and mechanical ventilation.

Renewing Halogen Substitution Strategy for the Rational Design of High-Curie Temperature Metal-Free Molecular Antiferroelectrics.

Metal-free molecular antiferroelectric (AFE) holds a promise for energy storage on account of its unique physical attributes. However, it is challenging to explore high-curie temperature (Tc) molecular AFEs, due to the lack of design strategies regarding the rise of phase transition energy barriers. By renewing the halogen substitution strategy, we have obtained a series of high-Tc molecular AFEs of the halogen-substituted phenethylammonium bromides (x-PEAB, x=H/F/Cl/Br), resembling the binary stator-rotator system. Strikingly, the p-site halogen substitution of PEA+ cationic rotators raises their phase transition energy barrier and greatly enhances Tc up to ~473 K for Br-PEAB, on par with the record-high Tc values for molecular AFEs. As a typical case, the member 4-fluorophenethylammonium bromide (F-PEAB) shows notable AFE properties, including high Tc (~374 K) and large electric polarization (~3.2 µC/cm2). Further, F-PEAB also exhibits a high energy storage efficiency (η) of 83.6 % even around Tc, catching up with other AFE oxides. This renewing halogen substitution strategy in the molecular AFE system provides an effective way to design high-Tc AFEs for energy storage devices.

Th9/IL-9 may participate in the pathogenesis of multiple myeloma.

INTRODUCTION: This research is aimed to evaluate the correlation between Th9-associated cytokine levels in MM patients, clinical features, and therapy. METHODS: Peripheral blood samples were taken in 52 MM patients and 20 healthy volunteers matched by sex and age. The patients with MM were separated into two groups: the untreated group (27) and the remission group (25). An enzyme-linked immunosorbent assay (ELISA) was used to measure the IL-9 plasma levels. The levels of Th9-associated cytokines' mRNA expression (IL-9, PU.1, and IRF4) were measured in RT-qPCR. We also analyzed the correlations between the IL-9 plasma levels and the clinical parameters of newly diagnosed MM patients. RESULTS: The IL-9 plasma levels and the Th9-associated cytokines (IL-9, PU.1, and IRF4) mRNA levels in newly diagnosed MM patients were significantly elevated than those in healthy volunteers and significantly decreased after achieving remission. Moreover, PU.1 and IRF4 had a positive correlation with the IL-9 mRNA expression. Then, we found that the upregulation of IL-9 plasma levels correlates with the severity of anemia and decreased albumin Levels. CONCLUSION: The results demonstrate that Th9/IL-9 may be involved in the pathogenesis of MM and is correlated with worse patient conditions such as lower hemoglobin and serum albumin. More work is necessary to confirm whether they might serve as a useful therapeutic target and prognostic marker for MM.

Noninvasive Monitoring of Immunotherapy in Lung Cancer by Lymphocyte Activation Gene 3 PET Imaging of Tumor-Infiltrating Lymphocytes.

Although immunotherapy has revolutionized the entire cancer treatment landscape, small fractions of patients respond to immunotherapy. Early identification of responders may improve patient management during immunotherapy. In this study, we evaluated a PET approach for monitoring immunotherapy in lung cancer by imaging the upregulation of lymphocyte activation gene 3 (LAG-3)-expressing (LAG-3+) tumor-infiltrating lymphocytes (TILs). Methods: We synthesized a LAG-3-targeted molecular imaging probe, [68Ga]Ga-NOTA-C25 and performed a series of in vitro and in vivo assays to test its specificity. Next, [68Ga]Ga-NOTA-C25 PET was used to monitor immunotherapy in murine lung cancer-bearing mice and in humanized mouse models for assessing clinical translational potential, with confirmation by immunostaining and flow cytometry analysis. Results: [68Ga]Ga-NOTA-C25 PET could noninvasively detect intertumoral differences in LAG-3+ TIL levels in different tumor models. Importantly, in Lewis lung carcinoma tumor models treated with an agonist of a stimulator of interferon genes, [68Ga]Ga-NOTA-C25 PET also detected an immunophenotyping transition of the tumor from "cold" to "hot" before changes in tumor size. Meanwhile, animals carrying "hot" tumor showed more significant tumor inhibition and longer survival than those carrying "cold" tumor. [68Ga]Ga-NOTA-C25 PET also showed markedly higher tumor uptake in immune system-humanized mice carrying human non-small cell lung cancer than immunodeficient models. Conclusion: [68Ga]Ga-NOTA-C25 PET could be used to noninvasively monitor the early response to immunotherapy by imaging LAG-3+ TILs in lung cancer. [68Ga]Ga-NOTA-C25 PET also exhibited excellent translational potential, with great significance for the precise management of lung cancer patients receiving immunotherapy.

Effects of treatment with stem cell-derived extracellular vesicles in preclinical rodent models of intrauterine adhesion: A meta-analysis.

Background: Intrauterine adhesion (IUA) results from serious complications of intrauterine surgery or infection and mostly remains incurable. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have emerged as a potential new approach for the treatment of IUA; however, their impact is not fully understood. Here, we performed a meta-analysis summarizing the effects of sEVs on IUA in preclinical rodent models. Methods: This meta-analysis included searches of PubMed, EMBASE, Cochrane, and the Web of Science databases from January 1, 1997, to April 1, 2022, to identify studies reporting the therapeutic effect of sEVs on rodent preclinical animal models of IUA. We compared improvements in endometrial thickness, endometrial gland number, fibrosis area, embryo number, vascular endothelial growth factor (VEGF), transforming growth factor ß1 (TGFß1), and leukemia inhibitory factor (LIF) levels after treatment. Results: Our search included 100 citations, of which 7 met the inclusion criteria, representing 231 animals. Compared with that in the control group, the fibrosis area in the sEV-treated group was significantly reduced (standardized mean difference (SMD) = -6.87，95 % confidence interval (CI) = -9.67 to -4.07). The number of glands increased after the intervention (95 % CI, 3.72-7.68; P = 0.000). Endometrial thickness was significantly improved in the sEV-treated group (SMD = 2.57, 95 % CI, 1.62-3.52). Conclusions: This meta-analysis is highlighting that sEV treatment can improve the area of endometrial fibrosis, as well as VEGF, and LIF level, in a mouse IUA model. This knowledge of these findings will provide new insights into future preclinical research.

Lipidomics analysis of impaired glucose tolerance and type 2 diabetes mellitus in overweight or obese elderly adults.

Aims: Aging, obesity, and type 2 diabetes mellitus (T2DM) form a metabolic disease continuum that has a continuously increasing prevalence. Lipidomics explains the complex interactions between lipid metabolism and metabolic diseases. We aimed to systematically investigate the plasma lipidome changes induced by newly diagnosed impaired glucose tolerance (IGT) and T2DM in overweight/obese elderly individuals and to identify potential biomarkers to differentiate between the IGT, T2DM, and control groups. Methods: Plasma samples from 148 overweight/obese elderly individuals, including 52 patients with IGT, 47 patients with T2DM, and 49 euglycemic controls, were analyzed using a high-coverage nontargeted absolute quantitative lipidomics approach. Results: We quantified 1840 lipids from thirty-eight classes and seven lipid categories. Among overweight/obese elderly individuals, the lipidomic profiles of IGT and T2DM patients were significantly different from those of controls, while they were similar in the IGT and T2DM groups. The concentrations of diglycerides, triglycerides, phosphatidylcholines, and ceramides were obviously altered in the IGT and T2DM groups. Particularly, IGT and T2DM induced the accumulation of triglycerides with longer carbon atom numbers (C44-50) and saturated or lower double bond numbers (n (C=C) = 0-2). Furthermore, a total of 17 potential lipidic biomarkers were identified to successfully differentiate between the IGT, T2DM, and control groups. Conclusions: In overweight/obese elderly patients, IGT and T2DM induced apparent lipidome-wide changes. This study's results may contribute to explaining the complex dysfunctional lipid metabolism in aging, obesity, and diabetes.

Subplenones A-J: Dimeric Xanthones with Antibacterial Activity from the Endophytic Fungus Subplenodomus sp. CPCC 401465.

Subplenones A-J (1-10), 10 new xanthone dimers, have been isolated and characterized from the endophytic fungus Subplenodomus sp. CPCC 401465, which resides within the Chinese medicinal plant Gentiana straminea. The isolation process was guided by antibacterial assays and molecular-networking-based analyses. The chemical structures of these compounds were elucidated through the interpretation of nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HRESIMS) data. Furthermore, the relative configuration of the compounds was determined using NMR and single-crystal X-ray diffraction analyses, and the absolute configuration was established using electronic circular dichroism calculations. All of the isolated compounds exhibited significant inhibitory activity against Gram-positive bacteria. Notably, compounds 1, 5, and 7 displayed remarkable inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 700698, with a minimum inhibitory concentration (MIC) of 0.25 µg/mL, and against vancomycin-resistant Enterococcus faecium (VRE) ATCC 700221, with MIC values ranging from 0.5 to 1.0 µg/mL.

Assessing the Association of Self-Reported Sleep Duration and Metabolic Syndrome Among Middle-Aged and Older Adults in China from the China Health and Retirement Longitudinal Survey.

Objectives: We aim to investigate the correlation between sleep and metabolic syndrome (MS) among a community population 45 years of age and older in China. Methods: A cross-sectional analysis of 9096 participants from China health and longitudinal study was carried out. MS was defined by consensus criteria. Sleep durations were assessed by self-reported questionnaire. Odds ratio (OR) and 95% confidence intervals (CIs) for MS were obtained using multivariable-adjusted regression analysis. Results: Long habitual daytime sleep had a positive influence on MS (OR = 1.50, 95% CI = 1.10-2.06). For elderly, short daytime sleep significantly increased risk of MS (OR = 2.14, 95% CI = 1.25-3.67). Females with long daytime sleep was associated with increased risk of MS (OR = 1.54, 95% CI = 1.04-2.29). Conclusions: Daytime sleep significantly increased risk of MS for middle-aged and elderly Chinese. The hazard role of daytime sleep on MS was various between age and sex groups. Results of this study needed to be verified by future longitudinal studies.

Polymyxin resistance caused by large-scale genomic inversion due to IS26 intramolecular translocation in Klebsiella pneumoniae.

Polymyxin B and polymyxin E (colistin) are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales, Acinetobacter baumannii, and Klebsiella pneumoniae. Yet resistance to this last-line drugs is a major public health threat and is rapidly increasing. Polymyxin S2 (S2) is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and colistin. To predict the possible resistant mechanism of S2 for wide clinical application, we experimentally induced bacterial resistant mutants and studied the preliminary resistance mechanisms. Mut-S, a resistant mutant of K. pneumoniae ATCC BAA-2146 (Kpn2146) induced by S2, was analyzed by whole genome sequencing, transcriptomics, mass spectrometry and complementation experiment. Surprisingly, large-scale genomic inversion (LSGI) of approximately 1.1 Mbp in the chromosome caused by IS26 mediated intramolecular transposition was found in Mut-S, which led to mgrB truncation, lipid A modification and hence S2 resistance. The resistance can be complemented by plasmid carrying intact mgrB. The same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146 (Mut-B and Mut-E, respectively). This is the first report of polymyxin resistance caused by IS26 intramolecular transposition mediated mgrB truncation in chromosome in K. pneumoniae. The findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics.

Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs.

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with ß-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C ß-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of ß-lactamase-producing MDR Gram-negative bacterial infections.

Protective effect of the novel cyclic peptide ASK0912 on mice with sepsis induced by Acinetobacter baumannii.

BACKGROUND: Sepsis has become a global health concern owing to its increasing incidence and high mortality rate. In the present study, we investigated a novel drug candidate ASK0912 on its protective effects in mice with Acinetobacter baumannii 20-1-induced sepsis, and studied the related mechanisms. MATERIAL AND METHODS: To analyze the protective effect of ASK0912 on septic mice, survival rates, body temperature, organ and blood bacterial loads, white blood cell and platelet counts, organ damage, and cytokine levels were determined. RESULTS: ASK0912 remarkably increased the survival rate of mice with sepsis induced by A. baumannii 20-1 at a low dose of 0.6 mg/kg. Rectal temperature measurements showed that ASK0912 treatment prevented the body temperature decrease of septic mice to some extent. Treatment with ASK0912 can notably reduce the organ and blood bacterial loads and alleviate platelet count reduction due to sepsis. ASK0912 attenuated organ damage, including reduced levels of total bile acids, urea, and creatinine, aggregation of inflammatory cells, and mitigation of structural changes in septic mice, as demonstrated by biochemical analysis and hematoxylin & eosin staining. Additionally, multiplex assay showed that abnormally increased cytokine levels (IL-1ß, IL-3, IL-5, IL-6, IL-10, IL-13, MCP-1, RANTES, KC, MIP-1α, MIP-1ß, and G-CSF) in septic mice decreased after ASK0912 treatment. CONCLUSIONS: ASK0912 can not only improve the survival rate, hypothermia, lower the bacterial loads in the organs and blood, but also alleviate the pathophysiological manifestations such as intravascular coagulation abnormalities, organ damages, and immune system disorder of sepsis mice induced by A. baumannii 20-1.

Comprehensive Lipid Profile of Eight Echinoderm Species by RPLC-Triple TOF-MS/MS.

Echinoderms are of broad interest for abundant bioactive lipids. The comprehensive lipid profiles in eight echinoderm species were obtained by UPLC-Triple TOF-MS/MS with characterization and semi-quantitative analysis of 961 lipid molecular species in 14 subclasses of 4 classes. Phospholipids (38.78-76.83%) and glycerolipids (6.85-42.82%) were the main classes in all investigated echinoderm species, with abundant ether phospholipids, whereas the proportion of sphingolipids was higher in sea cucumbers. Two sulfated lipid subclasses were detected in echinoderms for the first time; sterol sulfate was rich in sea cucumbers, whereas sulfoquinovosyldiacylglycerol existed in the sea star and sea urchins. Furthermore, PC(18:1/24:2), PE(16:0/14:0), and TAG(50:1e) could be used as lipid markers to distinguish eight echinoderm species. In this study, the differentiation of eight echinoderms was achieved by lipidomics and revealed the uniqueness of the natural biochemical fingerprints of echinoderms. The findings will help evaluate the nutritional value in the future.

In vivo pharmacodynamic study of contezolid acefosamil, a prodrug of contezolid for oral and intravenous administration.

OBJECTIVES: Contezolid acefosamil is a novel O-acyl phosphoramidate prodrug of contezolid. In the current study, we aimed to systemically evaluate the efficacy of contezolid acefosamil against infections caused by multiple Gram-positive pathogens, and compare the efficacy of the prodrug by oral and intravenous administrations. METHODS: The in vivo pharmacodynamic efficacy of contezolid acefosamil was evaluated in mouse models of systemic (with five S. aureus, three S. pneumoniae and two S. pyogenes bacterial isolates) and thigh (with two S. aureus isolates) infections using linezolid as the reference agent. RESULTS: In both models, contezolid acefosamil administrated either orally or intravenously, demonstrated high antibacterial efficacy similar to linezolid, and the antibacterial efficacy of oral and intravenous contezolid acefosamil were comparable. CONCLUSIONS: The high aqueous solubility and great efficacy of contezolid acefosamil support its clinical development as an injectable and oral antibiotic suitable for serious Gram-positive infections.

Progress and opportunities for metal-organic framework composites in electrochemical sensors.

Metal-organic framework composites have the advantages of large surface area, high porosity, strong catalytic efficiency and good stability, which provide a great possibility of finding excellent electrode materials for electrochemical sensors. However, MOF composites still face various challenges and difficulties, which limit their development and application. This paper reviews the application of MOF composites in electrochemical sensors, including MOF/carbon composites, MOF/metal nanoparticle composites, MOF/metal oxide composites and MOF/enzyme composites. In addition, the application challenges of MOF composites in electrochemical sensors are summarized. Finally, the application prospect for MOF composites is considered to promote the synthesis of more MOF composites with excellent properties.

Fucoxanthin protects retinal ganglion cells and promotes parkin-mediated mitophagy against glutamate excitotoxicity.

OBJECTIVE: To clarify whether fucoxanthin plays a protective role and regulates parkin-mediated mitophagy on retinal ganglion cells (RGCs) against glutamate excitotoxicity. METHODS: The excitotoxicity model of primary RGCs was carried out with glutamate. Mitochondrial membrane potential was measured by JC-1 kit (Abcam, USA). The apoptotic rate and cytotoxicity were detected by Hoechst staining and lactate dehydrogenase (LDH) kit (Takara, Japan). Mitochondria was assessed by MitoTracker staining and confocal microscopy. The mRNA levels and protein expression levels of Bax, Bcl-2, parkin, optineurin, LC3, and LAMP1 in RGCs were analyzed by quantitative PCR and immunoblotting. Finally, the mitochondrial health score and mitophagy were assessed by transmission electron microscopy. RESULTS: Fucoxanthin increased the mitochondrial membrane potential of RGCs, reduced cytotoxicity, and decreased apoptosis in RGCs under glutamate excitotoxicity. It also enhanced expression levels of parkin, optineurin, and LAMP1, and upgraded the ratio of LC3-II to LC3-I. Meanwhile, fucoxanthin increased LC3 and MitoTracker co-localization staining. In addition, up-regulated mitochondrial health score, and the number of autophagosomes and mitophagosomes were observed in fucoxanthin-treated RGCs under glutamate excitotoxicity. CONCLUSION: Fucoxanthin may exert its neuroprotective effect on RGCs via promoting parkin-mediated mitophagy under glutamate excitotoxicity. The neuroprotective effect of fucoxanthin in glaucomatous neurodegeneration and ocular diseases characterized by impaired mitophagy warrants further investigation.

Centimeter-Sized Single Crystals of Dion-Jacobson Phase Lead-Free Double Perovskite for Efficient X-ray Detection.

2D Dion-Jacobson (DJ) phase hybrid perovskites have shown great promise in the photoelectronic field owing to their outstanding optoelectronic performance and superior structural rigidity. However, DJ phase lead-free double perovskites are still a virgin land with direct X-ray detection. Herein, we have designed and synthesized a new DJ phase lead-free layered double perovskite of (HIS)2 AgSbBr8 (1, HIS2+  = histammonium). Centimeter-sized (18 × 10 × 5 mm3 ) single crystals of 1 are successfully grown via the temperature cooling technique, exhibiting remarkable semiconductive characteristics such as a high resistivity (2.2 × 1011  Ω cm), a low trap state density (3.56 × 1010 cm-3 ), and a large mobility-lifetime product (1.72 × 10-3 cm2 V-1 ). Strikingly, its single-crystal-based X-ray detector shows a high sensitivity of 223 µC Gy-1 air cm-2 under 33.3 V mm-1 , a low detection limit (84.2 nGyair s-1 ) and superior anti-fatigue. As far as we know, we firstly demonstrates the potential of 2D DJ phase lead-free hybrid double perovskite in X-ray detection, showing excellent photoelectric response and operational stability. This work will pave a promising pathway to the innovative application of hybrid perovskites for eco-friendly and efficient X-ray detection.

Isolation, Structure Elucidation, and First Total Synthesis of Quinomycins K and L, Two New Octadepsipeptides from the Maowei Sea Mangrove-Derived Streptomyces sp. B475.

Mangrove actinomycetia have been proven to be one of the promising sources for discovering novel bioactive natural products. Quinomycins K (1) and L (2), two rare quinomycin-type octadepsipeptides without intra-peptide disulfide or thioacetal bridges, were investigated from the Maowei Sea mangrove-derived Streptomyces sp. B475. Their chemical structures, including the absolute configurations of their amino acids, were elucidated by a combination of NMR and tandem MS analysis, electronic circular dichroism (ECD) calculation, advanced Marfey's method, and further unequivocally confirmed by the first total synthesis. The two compounds displayed no potent antibacterial activity against 37 bacterial pathogens and had no significant cytotoxic activity against H460 lung cancer cells.

Identification and Quantification of S-Sulfenylation Proteome of Mycobacterium tuberculosis under Oxidative Stress.

The ability to maintain redox homeostasis is critical for Mycobacterium tuberculosis (Mtb) to survive the redox stress of the host. There are many antioxidant systems in Mtb to ensure its normal replication and survival in the host, and cysteine thiols are one of them. S-sulfenylation is one of the reversible modifications of cysteine thiols to resist oxidative stress. In the study, we investigated the total cysteine thiols modification and S-sulfenylation modification of Mtb proteome under the oxidative stress provided by hydrogen peroxide. To determine and quantify the S-sulfenylation modified proteins, high specific IodoTMT6plex reagents and high resolution mass spectrometry were used to label and quantify the peptides and proteins modified. There are significant differences for the total cysteine modification levels of 279 proteins and S-sulfenylation modification levels of 297 proteins under hydrogen peroxide stress. Functional enrichment analysis indicated that these cysteine-modified proteins were involved in the oxidation-reduction process, fatty acid biosynthetic process, stress response, protein repair, cell wall, etc. In conclusion, our study provides a view of cysteine modifications of the Mtb proteome under oxidative stress, revealing a series of proteins that may play a role in maintaining redox homeostasis. IMPORTANCE With the continuous spread of drug-resistant tuberculosis, there is an urgent need for new antituberculosis drugs with new mechanisms. The ability of Mtb to resist oxidative stress is extremely important for maintaining redox homeostasis and survival in the host. The reversible modifications of cysteine residues have a dual role of protection from irreversible damage to protein functions and regulation, which plays an important role in the redox homeostasis system. Thus, to discover cysteine modification changes in the proteome level under oxidative stress is quintessential to elucidate its antioxidant mechanism. Our results provided a list of proteins involved in the antioxidant process that potentially could be considered targets for drug discovery and vaccine development. Furthermore, it is the first study to determine and quantify the S-sulfenylation-modified proteins in Mtb, which provided better insight into the Mtb response to the host oxidative defense and enable a deeper understanding of Mtb survival strategies.

Adjuvant icotinib versus observation in patients with completely resected EGFR-mutated stage IB NSCLC (GASTO1003, CORIN): a randomised, open-label, phase 2 trial.

Background: This phase 2 trial aimed to compare adjuvant icotinib with observation in patients with epidermal growth factor receptor (EGFR) mutation-positive resected stage IB non-small cell lung cancer (NSCLC). Methods: We performed a randomised, open-label, phase 2 trial from May 1, 2015 to December 29, 2020 at Sun Yat-sen University Cancer Center in China. Patients with completely resected, EGFR-mutant, stage IB (the 7th edition of TNM staging) NSCLC without adjuvant chemotherapy were randomised (1:1) to receive adjuvant therapy with icotinib (125 mg, three times daily) for 12 months or to undergo observation until disease progression or intolerable toxicity occurred. The primary endpoint was 3-year disease-free survival (DFS). CORIN (GASTO1003) was registered with Clinicaltrials.gov, with the number NCT02264210. Findings: A total of 128 patients were randomised, with 63 patients in the icotinib group and 65 patients in the observation group. The median duration of follow-up was 39.9 months. The three-year DFS was significantly higher in the icotinib group (96.1%, 95% confidence interval [CI], 91.3-99.9) than in the observation group (84.0%, 95% CI, 75.1-92.9; P = 0.041). The DFS was significantly longer in the icotinib group than in the observation group, with a hazard ratio (HR) of 0.23 (95% CI, 0.07-0.81; P = 0.013). The OS data were immature, with three deaths in the observation arm. In the icotinib group, adverse events (AEs) of any grade were reported in 49 patients (77.8%), and grade 3 or greater AEs occurred in four patients (6.3%). No treatment-related deaths occurred. Interpretation: Our findings suggested that adjuvant icotinib improved the 3-year DFS in patients with completely resected EGFR-mutated stage IB NSCLC with a manageable safety profile. Funding: This study was sponsored by Betta Pharmaceutical Co., Ltd.