Design and Construction of Carbon-Coated Bimetallic Selenide Heterostructures Loaded on Reduced Graphene Oxide Substrate for Superior Lithium-Ion Storage.

In this work, carbon-coated bimetallic tin-nickel selenide heterostructures loaded on reduced graphene oxide composites were prepared through a metal-organic framework-assisted strategy. The carbon coating mitigates the volume expansion and maintains the structural stability, while the introduction of reduced graphene oxide and heterojunction enhances electrical conductivity and reaction kinetics, thereby together contributing to the enhanced lithium-ion storage performance. As expected, the optimal material delivers excellent lithium-ion storage performance in terms of a high reversible capacity of 1033.4 mAh g-1 at 0.2 A g-1, outstanding rate capability, and long-term cyclability with the capacity of 726.2 mAh g-1 after 500 cycles at 1.0 A g-1 and 452.4 mAh g-1 after 1000 cycles at 2.0 A g-1. Furthermore, the electrochemical reaction mechanism of the composite is analyzed.

Prevalence and risk factors for subclinical hypothyroidism in older patients with major depressive disorder.

BACKGROUND: Subclinical hypothyroidism (SCH) is highly correlated with major depressive disorder (MDD). However, the prevalence and risk factors for SCH in older patients with MDD have rarely been reported in China. METHODS: This cross-sectional study included 266 older MDD patients with SCH was performed. Clinical and anthropometric, biochemical, and thyroid function data were collected. Depression, anxiety, and psychotic symptoms were assessed using the Hamilton Depression Scale, the Hamilton Anxiety Scale, and the Positive and Negative Syndrome Scale positive subscale, respectively. RESULTS: Among older patients with MDD, the prevalence of SCH was 64.7% (172/266). Compared to patients without SCH, older MDD patients with SCH had a longer disease course and higher TSH, A-TG, A-TPO, HDL-C, LDL-C, TC, FPG, and systolic pressure levels (all P ≤ 0.002). Furthermore, disease progression (OR 1.082, 95% CI 1.020-1.147, P = 0.009), A-TG (OR 1.005, 95% CI 1.001-1.009, P = 0.017), TC (OR 2.024, 95% CI 1.213-3.377, P = 0.007), FPG (OR 2.916, 95% CI 1.637-5.194, P < 0.001), systolic pressure (OR 1.053, 95% CI 1.008-1.100, P = 0.022) were independently associated with SCH, in older patients with MDD. CONCLUSIONS: Our findings suggest a high prevalence of SCH in older patients with MDD. Several demographic and clinical variables were independently associated with SCH in older patients with MDD.

[Mechanism of Mailuo Shutong Pills on posterior limb muscle swelling caused by femoral fracture in rats based on network pharmacology and experimental verification].

This study aims to investigate the mechanism of Mailuo Shutong Pills(MLST) on posterior limb muscle swelling caused by femoral fracture(SCFF) through network pharmacology and animal experiments. The plasma components of MLST were analyzed by LC-MS, and the target and signal pathway of SCFF were predicted by network pharmacology and verified by molecular docking. SCFF model rats were established through animal experiments, and different doses of MLST were administered to detect the degree of limb swelling. Hematoxylin-eosin(HE) staining was used to observe pathological changes in muscle tissue, and interleukin-6(IL-6), interleukin-1ß(interleukin-1ß), and tumor necrosis factor-α(TNF-α) in peripheral blood were determined by enzyme-linked immunosorbent assay(ELISA). The expression of relevant signaling pathways was measured by Western blot. Network pharmacological results showed that MLST and SCFF had a total of 153 disease targets, and the key targets were IL-6, TNF, etc., involving mitogen-activated protein kinase(MAPK) signaling pathway, phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT) signaling pathway, etc. The binding energies of the main components and key targets were lower than-7.0 kcal·mol~(-1), indicating that the network analysis results were reliable. The results of animal experiments showed that MLST could reduce the swelling degree and pathological damage of the posterior limb muscles of SCFF rats compared with the model group. ELISA results showed that MLST could reduce the levels of IL-6, IL-1ß, and TNF-α in the serum of SCFF rats. Western blot results showed that MLST can reduce the expression of p-AKT, p-PI3K, p-NF-κB, p-p38 MAPK, and p-ERK in SCFF rats. MLST may reduce the content of inflammatory factors in serum by regulating the expression of PI3K/AKT and MAPK-related signaling pathway protein and improving posterior limb muscle SCFF in rats.

Efficacy and safety of iruplinalkib (WX-0593) in ALK-positive crizotinib-resistant advanced non-small cell lung cancer patients: a single-arm, multicenter phase II study (INTELLECT).

BACKGROUND: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. METHODS: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). RESULTS: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. CONCLUSIONS: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. TRIAL REGISTRATION: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.

Dysregulation of memory B cells and circulating T follicular helper cells is a predictor of poor immune recovery in HIV-infected patients on antiretroviral therapy.

T follicular helper (Tfh) cells and their interactions with B cells within the germinal center play extensive roles in human immunodeficiency virus (HIV) pathology. However, their association with immune reconstitution during antiretroviral therapy (ART) is still unclear. The aim of this study was to determine the impact of Tfh and memory B cell function on T helper cell recovery in patients with acute or chronic HIV infection. A total of 100 HIV-infected individuals were enrolled in our study, classified into acute and chronic HIV infection groups (60 and 40, respectively), and subsequently classified into immunological responder (IR) and immunological nonresponder (INR) subgroups according to immune recovery outcomes after 96 weeks of ART. Liquid chromatography-mass spectrometry was used to quantify the temporal regulation patterns of B and CD4+ T-cell profiles among patients, and flow cytometry was used to investigate certain subsets of B and T cells. Here we showed that the prevalence of Tfh cells in the T helper cell population correlated negatively with CD4+ T-cell recovery. The proportion of CXCR3-  Tfh cells in patients with acute or chronic infection was associated with CD4+ T-cell count recovery, and the proportion of CD21+ memory B cells at baseline was significantly higher in those with improved immune recovery outcomes. Universal proteomic dysregulation of B and CD4+ T cells at baseline was detected in patients with acute infected and poor CD4+ T-cell recovery. Proteomics analysis revealed distinct temporal regulation profiles of both T helper cells and B cells between IRs and INRs among patients with acute infection. Our results suggest that the functions of memory B cells in INRs are dysregulated at the early stage of ART, possibly through disruption of Tfh cell function. The frequency and function of Tfh cells and their subsets are potential predictors of poor immune recovery.

Reuse of osimertinib after small cell lung cancer transformation in lung adenocarcinoma with de-novo epidermal growth factor receptor T790M mutation: case report.

Osimertinib is a third-generation tyrosine kinase inhibitor for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-sensitizing mutations and acquired drug-resistant mutation T790M. Despite promising treatment benefits of osimertinib in first- and second-line settings, drug resistance has been an inevitable clinical issue. The resistance to osimertinib is heterogeneous, which may involve EGFR-dependent and independent mechanisms as well as histological transformation from NSCLC to small cell lung cancer (SCLC). Current clinical studies of NSCLC were mainly focused on patients with EGFR-sensitizing mutations or acquired T790M mutation or both. The treatments and drug-resistant mechanisms in patients with de-novo T790M mutation remain undefined. Herein, we reported the presence of the less common de-novo EGFR T790M mutation in a stage IV NSCLC patient. The patient received osimertinib as first-line treatment and achieved durable progression-free survival (PFS) for 24 months. After osimertinib resistance, tumor biopsy indicated histologic transformation from NSCLC to SCLC. Given persistent presence of de-novo T790M mutation, osimertinib was used in combination with etoposide and cisplatin as second-line treatment and the patient achieved partial response with PFS of 7 months. Our study suggested that NSCLC patients with de-novo T790M mutation could also benefit from osimertinib and the SCLC transformation may be a potential resistance mechanism that could be targeted through the combination of targeted therapy and chemotherapy.

Asymmetric Ligands of a Metal-Organic Framework on Enhanced Photocatalytic CO2 Reduction.

Metal-organic frameworks (MOFs) have been studied extensively in the catalytic field. However, the role of ligands in catalysis has been less well investigated. Here, an asymmetric ligand photocatalytic strategy for CO2 reduction in MOFs is first proposed. MOF-303(Al) with asymmetric ligands (pyrazolyldicarboxylic acid) exhibits synergistic catalytic effects. Specifically, pyrazoles participate in CO2 activation; i.e., pyrazole and µ2-OH form hydrogen bonds with CO2 to polarize C═O bonds. Furthermore, the lowest unoccupied molecular orbital (LUMO; A pyrazole) and highest occupied molecular orbital (HOMO; B pyrazole) act as the electron donor and acceptor to spatially separate the excited electron-hole, with A and B pyrazoles for CO2 and H2O adsorption to avoid competition, respectively. Owing to its advantages, MOF-303-modified g-C3N4 achieves nonsacrificial and transition-metal-free photocatalytic CO2 reduction to CO of 16.19 µmol·g-1·h-1, significantly higher than that of g-C3N4. This work provides fresh insights into asymmetric ligands in photocatalytic CO2 reduction.

The role and mechanism of tumor necrosis factor-alpha in alcohol-induced bone loss.

AIM: It is well known that alcohol can cause bone loss and that bone mineral density has an inverse relationship with bone marrow adipocyte (BMA). However, little is known about the mechanisms that link alcohol and bone loss, and existing studies lack data on BMA in alcohol-induced bone loss. Here, wild-type (WT) and tumor necrosis factor-alpha knockout (TNF-α KO) mice were used to examine the effects of alcohol on bone metabolism. METHODS: The effects of alcohol on bone metabolism were demonstrated in vivo by feeding WT and TNF-α KO mice with alcohol. The osteogenesis and adipogenesis of primary bone marrow stromal cells (BMSCs) derived from WT and TNF-α KO mice under alcohol intervention were compared in vitro. Tissue staining, cell staining, micro-CT, and quantitative RT-PCR were used to explore the potential mechanism. RESULTS: Alcohol induced trabecular bone loss, increased BMA, and promoted the mRNA expression of Adipoq, Fabp4, visfatin， Pparg, TNF-α, IL-1ß, and IL-6 in BMA in WT mice, but not in TNF-α KO mice. In addition, alcohol promoted BMSC adipogenesis and inhibited BMSC osteogenesis, while TNF-α knockout could restrain this situation. CONCLUSION: Our study demonstrated that alcohol may reduce bone mass by disrupting the balance of osteogenesis and adipogenesis in bone marrow, and TNF-α plays an important role in this process.

Efficacy of immune checkpoint inhibitors in non-small cell lung cancer with NTRK family mutations.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients harboring neurotrophin receptor kinase (NTRK) family mutations remains obscure. METHODS: The Zehir cohort from cBioPortal was used to analyze the mutations (MT) frequency of NTRK family in patients with NSCLC, and their correlation with clinical characteristics and patient survival. The influence of NTRK MT on ICIs efficacy was evaluated in ICIs-treated patients from Samstein cohort and further validated by use of data from OAK/POPLAR cohort. RESULTS: In the Zehir cohort, a significant difference was observed in median overall survival (mOS) between patients with NTRK MT and wild-type (WT) (mOS: 18.97 vs. 21.27 months, HR = 1.34, 95%CI 1.00-1.78; log-rank P = 0.047). In Samstein cohort, the mOS of NTRK mutant patients receiving ICIs has improved compared to WT patients (mOS: 21.00 vs. 11.00 months, log-rank P = 0.103). Notably, in subgroup analysis, ICIs significantly prolonged mOS in patients with NTRK3 MT than in WT patients (mOS: not available vs. 11.00 months, HR = 0.36, 95%CI 0.16-0.81; log-rank P = 0.009). Identical mOS between NTRK MT and WT patients receiving ICIs treatment (mOS: 13.24 vs. 13.50 months, log-rank P = 0.775) was observed in OAK/POPLAR cohort. Moreover, a similar programmed death ligand 1 (PD-L1) expression, but higher tumor mutational burden (TMB), blood TMB (bTMB) and enriched anti-tumor immunity were observed in NTRK MT compared to WT (P < 0.05). CONCLUSION: Taking high TMB or bTMB into consideration, patients with NTRK mutant NSCLC could benefit from ICIs treatment.

Emergency logistics network optimization with time window assignment.

During natural disasters or accidents, an emergency logistics network aims to ensure the distribution of relief supplies to victims in time and efficiently. When the coronavirus disease 2019 (COVID-19) emerged, the government closed the outbreak areas to control the risk of transmission. The closed areas were divided into high-risk and middle-/low-risk areas, and travel restrictions were enforced in the different risk areas. The distribution of daily essential supplies to residents in the closed areas became a major challenge for the government. This study introduces a new variant of the vehicle routing problem with travel restrictions in closed areas called the two-echelon emergency vehicle routing problem with time window assignment (2E-EVRPTWA). 2E-EVRPTWA involves transporting goods from distribution centers (DCs) to satellites in high-risk areas in the first echelon and delivering goods from DCs or satellites to customers in the second echelon. Vehicle sharing and time window assignment (TWA) strategies are applied to optimize the transportation resource configuration and improve the operational efficiency of the emergency logistics network. A tri-objective mathematical model for 2E-EVRPTWA is also constructed to minimize the total operating cost, total delivery time, and number of vehicles. A multi-objective adaptive large neighborhood search with split algorithm (MOALNS-SA) is proposed to obtain the Pareto optimal solution for 2E-EVRPTWA. The split algorithm (SA) calculates the objective values associated with each solution and assigns multiple trips to shared vehicles. A non-dominated sorting strategy is used to retain the optimal labels obtained with the SA algorithm and evaluate the quality of the multi-objective solution. The TWA strategy embedded in MOALNS-SA assigns appropriate candidate time windows to customers. The proposed MOALNS-SA produces results that are comparable with the CPLEX solver and those of the self-learning non-dominated sorting genetic algorithm-II, multi-objective ant colony algorithm, and multi-objective particle swarm optimization algorithm for 2E-EVRPTWA. A real-world COVID-19 case study from Chongqing City, China, is performed to test the performance of the proposed model and algorithm. This study helps the government and logistics enterprises design an efficient, collaborative, emergency logistics network, and promote the healthy and sustainable development of cities.

Baseline radiologic features as predictors of efficacy in patients with pancreatic neuroendocrine tumors with liver metastases receiving surufatinib.

Objective: Currently, pre-treatment prediction of patients with pancreatic neuroendocrine tumors with liver metastases (PNELM) receiving surufatinib treatment was unsatisfying. Our objective was to examine the association between radiological characteristics and efficacy/prognosis. Methods: We enrolled patients with liver metastases in the phase III, SANET-p trial (NCT02589821) and obtained contrast-enhanced computed tomography (CECT) images. Qualitative and quantitative parameters including hepatic tumor margins, lesion volumes, enhancement pattern, localization types, and enhancement ratios were evaluated. The progression-free survival (PFS) and hazard ratio (HR) were calculated using Cox's proportional hazard model. Efficacy was analyzed by logistic-regression models. Results: Among 152 patients who had baseline CECT assessments and were included in this analysis, the surufatinib group showed statistically superior efficacy in terms of median PFS compared to placebo across various qualitative and quantitative parameters. In the multivariable analysis of patients receiving surufatinib (N=100), those with higher arterial phase standardized enhancement ratio-peri-lesion (ASER-peri) exhibited longer PFS [HR=0.039; 95% confidence interval (95% CI): 0.003-0.483; P=0.012]. Furthermore, patients with a high enhancement pattern experienced an improvement in the objective response ratio [31.3% vs. 14.7%, odds ratio (OR)=3.488; 95% CI: 1.024-11.875; P=0.046], and well-defined tumor margins were associated with a higher disease control rate (DCR) (89.3% vs. 68.2%, OR=4.535; 95% CI: 1.285-16.011; P=0.019) compared to poorly-defined margins. Conclusions: These pre-treatment radiological features, namely high ASER-peri, high enhancement pattern, and well-defined tumor margins, have the potential to serve as predictive markers of efficacy in patients with PNELM receiving surufatinib.

Tumor-infiltrating neutrophils and peripheral neutrophil-to-lymphocyte ratio conversely predicted the prognosis of patients with non-small cell lung cancer.

Increasing evidence indicates that neutrophil-associated prognostic markers, such as, tumor-associated neutrophils (TANs), neutrophil-to-T cell ratio (NTR) and neutrophil-to-lymphocyte ratio (NLR), are strongly correlated with the survival of patients with non-small cell lung cancer (NSCLC). However, either the association or the difference in their predictive efficacies remains unknown. To this aim, we investigated the influence of intratumoural TANs and peripheral NLR on the clinical outcome of NSCLC patients using tumor tissues, peripheral blood indexes, and clinicopathological data of 133 patients diagnosed with NSCLC. Additionally, Kendall correlation analysis was performed to identify the association between TANs and NLR. Our results revealed that intratumoural TANs were effective prognostic factors for favorable overall survival (OS), but were not associated with disease-free survival (DFS) in the subgroup analysis of 84 postoperative patients and progression-free survival (PFS) in 49 non-resectable NSCLC patients. Elevated NTR also indicated favorable prognosis, with high intratumoural NTR being correlated with prolonged OS and high stromal NTR being correlated with prolonged DFS. In contrast, peripheral NLR predicted dismal OS and DFS of patients receiving curative surgery. Furthermore, neither intratumoural nor stromal TANs were found to be associated with NLR, indicating that they were independent inflammatory indexes in predicting the prognosis of NSCLC. In conclusion, we discovered that TANs and NLR independently and oppositely predicted the clinical outcome of NSCLC patients, providing new sights on the role of neutrophil in tumor biology and survival prediction.

Identification of a major facilitator superfamily protein that is beneficial to L-lactic acid production by Bacillus coagulans at low pH.

BACKGROUND: Product inhibition is one of the major problems in lactic acid (LA) fermentation. Our previous study revealed that Bacillus coagulans 2-6 was an efficient producer of high-optical-purity L-LA. Its mutant strain B. coagulans Na-2 has better resistance to sodium lactate stress but the resistance mechanism has not been understood. RESULTS: In this study, the whole-genome sequencing of B. coagulans Na-2 was performed and one mutant gene mfs coding for the major facilitator superfamily (MFS) protein was revealed by comparative genome analysis. Ten mutation sites were identified between the wild (MFS-2-6) and mutant (MFS-Na-2) proteins, among which T127A and N154T were predicted locating in the center of the transmembrane transport channel. The MFS-2-6 and MFS-Na-2 were expressed separately in a genetically operable strain, B. coagulans DSM1, using the genes' native promoter. The expression of the two MFS proteins had no effect and a negative effect on L-LA production when the pH was controlled at 6.0 and 7.0 by sodium hydroxide, respectively. However, 4.2 and 4.6-fold of L-LA concentrations were obtained at pH 5.0 by the strains expressing MFS-2-6 and MFS-Na-2 than that by the control strain, respectively. The intracellular pH values of the strains expressing MFS-2-6 and MFS-Na-2 were approximately 0.69 and 0.45 higher than that of the control strain during pH-controlled fermentation at 5.0. Results suggest that the expression of MFS-2-6 and MFS-Na-2 were both conducive to L-LA production at low pH, while the better performance of the latter was probably due to the more appropriate intracellular pH during the whole fermentation process. CONCLUSIONS: The MFS protein identified here can improve the ability of B. coagulans to resist acidic environments and produce more L-LA at low pH. The MFS protein has an application potential in environment-friendly L-LA production.

T-cell responses to SARS-CoV-2 Omicron spike epitopes with mutations after the third booster dose of an inactivated vaccine.

The rapidly spreading severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant contains more than 30 mutations that mediate escape from antibody responses elicited by prior infection or current vaccines. Fortunately, T-cell responses are highly conserved in most individuals, but the impacts of mutations are not clear. Here, we showed that the T-cell responses of individuals who underwent booster vaccination with CoronaVac were largely protective against the SARS-CoV-2 Omicron spike protein. To specifically estimate the impact of Omicron mutations on vaccinated participants, 16 peptides derived from the spike protein of the ancestral virus or Omicron strain with mutations were used to stimulate peripheral blood mononuclear cells (PBMCs) from the volunteers. Compared with the administration of two doses of vaccine, booster vaccination substantially enhanced T-cell activation in response to both the ancestral and Omicron epitopes, although the enhancement was slightly weakened by the Omicron mutations. Then, the peptides derived from these spike proteins were used separately to stimulate PBMCs. Interestingly, compared with the ancestral peptides, only the peptides with the G339D or N440K mutation were detected to significantly destabilize the T-cell response. Although more participants need to be evaluated to confirm this conclusion, our study nonetheless estimates the impacts of mutations on T-cell responses to the SARS-CoV-2 Omicron variant.

Transcriptomic and metabolomic analyses for providing insights into the influence of polylysine synthetase on the metabolism of Streptomyces albulus.

ε-poly-L-lysine (ε-PL) is the main secondary metabolite of Streptomyces albulus, and it is widely used in the food industry. Polylysine synthetase (Pls) is the last enzyme in the ε-PL biosynthetic pathway. Our previous study revealed that Pls overexpressed in S. albulus CICC11022 result in the efficient production of ε-PL. In this study, a Pls gene knockout strain was initially constructed. Then, genomic, transcriptomic and metabolomic approaches were integrated to study the effects of the high expression and knockout of Pls on the gene expression and metabolite synthesis of S. albulus. The high expression of Pls resulted in 598 significantly differentially expressed genes (DEGs) and 425 known differential metabolites, whereas the inactivation of Pls resulted in 868 significant DEGs and 374 known differential metabolites. The expressions of 8 and 35 genes were negatively and positively associated with the Pls expression, respectively. Subsequently, the influence mechanism of the high expression and inactivation of Pls on the ε-PL biosynthetic pathway was elucidated. Twelve metabolites with 30% decreased yield in the high-expression strain of Pls but 30% increased production in the Pls knockout strain were identified. These results demonstrate the influence of Pls on the metabolism of S. albulus. The present work can provide the theoretical basis for improving the production capacity of ε-PL by means of metabolic engineering or developing bioactive substances derived from S. albulus.

ANK2 as a novel predictive biomarker for immune checkpoint inhibitors and its correlation with antitumor immunity in lung adenocarcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been shown to significantly improve the survival of patients with advanced lung adenocarcinoma (LUAD). However, only limited proportion of patients could benefit from ICIs. Novel biomarkers with strong predictability are needed for clinicians to maximize the efficacy of ICIs. Our study aimed to identify potential biomarkers predicting ICIs efficacy in LUAD. METHODS: The Cancer Genome Atlas (TCGA) PanCancer Atlas studies in cBioportal were used to evaluate the mutation frequency of ANK2 across multiple cancers. Clinical and mutational data for LUAD from ICIs-treated cohorts (Hellmann et al. and Rizvi et al.) were collected to explore the correlation between ANK2 mutation and clinical outcomes. In addition, the relationship between ANK2 expression and clinical outcomes was analyzed using LUAD data from TCGA and Gene Expression Omnibus. Furthermore, the impact of ANK2 mutation and expression on the tumor immune microenvironment of LUAD was analyzed using TCGA and TISIDB databases. RESULTS: Patients with ANK2 mutation benefited more from ICIs. In ICIs-treated cohort, prolonged progression-free survival (PFS) (median PFS: NR (not reached) vs. 5.42 months, HR (hazard ratio) 0.31, 95% CI 0.18-0.54; P = 0.0037), improved complete response rate (17.65% vs. 1.85%, P = 0.0402), and improved objective response rate (64.71% vs. 24.07%, P = 0.0033) were observed in LUAD patients with ANK2 mutation compared to their wild-type counterparts. Regarding ANK2 expression, it was observed that ANK2 expression was decreased in LUAD (P < 0.05) and a higher level of ANK2 expression was associated with longer overall survival (HR 0.69, 95% CI 0.52-0.92; P = 0.012) in TCGA LUAD cohort. Moreover, ANK2 mutation or higher ANK2 expression correlated with enhanced antitumor immunity and "hot" tumor microenvironment in LUAD, which could be potential mechanisms that ANK2 mutation facilitated ICIs therapy and patients with higher ANK2 expression survived longer. CONCLUSION: Our findings suggest that ANK2 mutation or increased ANK2 expression may serve as a favorable biomarker for the efficacy of ICIs in patients with LUAD.

Homologous and Heterologous Expression of Delta(12)-Desaturase in Mucor circinelloides Enhanced the Production of Linolenic Acid.

Linolenic acid (LA) is gaining more interest within the scientific community. This is because it has a potential medical role in reducing the risk of inflammation, carcinogenesis, atherosclerosis and diabetes and is a valuable nutraceutical for human health. The oleaginous fungus Mucor circinelloides produces a high lipid content (36%), including valuable polyunsaturated fatty acids (PUFAs). However, the critical step in which oleic acid (OA) is converted into LA is not efficient at supplying enough substrates for PUFA synthesis. Hence, we propose a method to increase LA production based on genetic engineering. The overexpression of the Δ12-desaturase gene from M. circinelloides and Mortierella alpina increased the LA content and improved the lipid accumulation (from 14.9% to 21.6% in the Δ12-desaturase gene of the M. circinelloides overexpressing strain (Mc-D12MC) and from 14.9% to 18.7% in the Δ12-desaturase gene of M. alpina overexpressing strain (Mc-D12MA)). Additionally, the up-regulated expression levels of these genes targeted the genes involved in NADPH production, implying that the elevated Δ12-desaturase gene may function as a critical regulator of NADPH and lipid synthesis in M. circinelloides. This study provides the first evidence to support the design of metabolic engineering related to LA and PUFA production in M. circinelloides for potential industrial applications.

Anlotinib Monotherapy for Refractory Metastatic Colorectal Cancer: A Double-Blinded, Placebo-Controlled, Randomized Phase III Trial (ALTER0703).

BACKGROUND: Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC. MATERIALS AND METHODS: This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1-14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety. RESULTS: A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4-4.5) over placebo group (1.5 months; 95% CI, 1.4-1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27-0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8-9.7 vs. 7.2 months; 95% CI, 6.2-8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%). CONCLUSION: Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients. IMPLICATIONS FOR PRACTICE: In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.

Larotinib in patients with advanced and previously treated esophageal squamous cell carcinoma with epidermal growth factor receptor overexpression or amplification: an open-label, multicenter phase 1b study.

BACKGROUND: Larotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This open-label, phase 1b study is aimed to evaluate the efficacy, safety of larotinib in patients with advanced esophageal squamous cell carcinoma (ESCC) with EGFR overexpression or amplification pretreated with one or more system regimens, and to recommend an appropriate dose for its further study. METHODS: Patients received larotinib orally at 3 doses (250, 300, 350 mg), once daily. Clinical response was evaluated every 8 weeks according to RECIST v1.1 criteria by both investigators and independent radiology review (IRC). RESULTS: 81 patients were enrolled. The investigator-assessed overall response rate (ORR) was 13.7% (10/73), all responses were observed in the 350 mg group of which ORR up to 20.0% (10/50), with 10 of them having EGFR overexpression and 4 having EGFR amplification. Per IRC assessment, ORR for all patients and 350 mg group were 13.9% (10/72) and 16.3% (8/50). In the 350 mg group, median overall survival (OS) and progression-free survival (PFS) were 8.0 (95% CI 4.9-10.2) months and 3.4 (95% CI 2.4-3.7) months, respectively. The most common treatment-related adverse events (TRAEs) were diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome, elevated AST/ALT, vomiting, similarly with other EGFR TKIs. CONCLUSIONS: Larotinib demonstrated promising antitumor activity and manageable safety profiles in patients with pre-treated advanced ESCC with EGFR overexpression or amplification, especially at the dose of 350 mg, which showed better efficacy and acceptable safety. A phase 3 study is underway on 350 mg larotinib in ESCC patients with EGFR overexpression. TRIAL REGISTRATION: This trial was retrospectively registered on 25/03/2019, NCT03888092. https://clinicaltrials.gov/ct2/show/NCT03888092 .

Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. METHODS: SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821. FINDINGS: Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3-19·4) in the surufatinib group and 11·1 months (5·7-35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5-13·8) for surufatinib versus 3·7 months (2·8-5·6) for placebo (hazard ratio 0·49, 95% CI 0·32-0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. INTERPRETATION: Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. FUNDING: Hutchison MediPharma.