The CoFeNC@NC Catalyst with Numerous Surface Cracks Bidirectionally Catalyzes the Conversion of Polysulfides to Accelerate the Reaction Kinetics of Lithium-Sulfur Batteries.

More and more attention has been paid to lithium-sulfur (Li─S) batteries due to their high energy density and low cost. However, the intractable "shuttle effect" and the low conductivity of S and its reaction product, Li2 S, compromise battery performance. To address the inherent challenges, a hollow composite catalyst as a separator coating material is designed, in which CoFe alloy is embedded in a carbon skeleton (CoFeNC@NC). In the hybrid structure, the carbon layer can endow the batteries with high electrical conductivity, while the CoFe alloy can effectively bidirectionally catalyze the conversion between lithium polysulfides (LiPSs) and Li2 S, accelerating the reaction kinetics and reducing the dissolution of LiPSs. Furthermore, the distinctive hollow structure with a cracked surface can facilitate the exposure of a more accessible catalytically active site and enhance Li+ diffusion. Benefiting from the synergistic effects, Li─S batteries with a CoFeNC@NC catalyst achieve a high sulfur utilization (1250.8 mAh g-1 at 0.2 C), superior rate performance (756 mAh g-1 at 2 C), and excellent cycling stability (an ultralow capacity fading of 0.054% per cycle at 1 C for 1000 cycles). Even at a sulfur loading of 5.3 mg cm-2 , a high area capacity of 4.05 mAh cm-2 can still be achieved after 100 cycles, demonstrating its potential practicality.

Novel GSH-responsive prodrugs derived from indole-chalcone and camptothecin trigger apoptosis and autophagy in colon cancer.

Antineoplastic agents that target tubulin have shown efficacy as chemotherapeutic drugs, yet they are often constrained by multidrug resistance (MDR) and unwanted side effects. A multi-targeted strategy demonstrates great potency in reducing toxicity and enhancing efficacy and provides an alternative way for attenuating MDR. In this study, a series of dual-targeted anti-cancer agents based on indole-chalcone derivatives and the camptothecin (CPT) scaffold were synthesized. Among them, 14-1 demonstrated superior anti-proliferative activity than its precursor 13-1, CPT or their physical mixtures against tested cancer cells, including multidrug-resistant variants, while exhibited moderate cytotoxicity toward human normal cells. Mechanistic studies revealed that 14-1 acted as a glutathione-responsive prodrug, inducing apoptosis by substantially enhancing intracellular uptake of CPT, inhibiting tubulin polymerization, increasing the accumulation of intracellular reactive oxygen species, and initiating a mitochondrion-dependent apoptotic pathway. Moreover, 14-1 notably induced autophagy and suppressed topoisomerase I activity to further promote apoptosis. Importantly, 14-1 displayed potent inhibitory effect on tumor growth in paclitaxel (PTX)-resistant colorectal cancer (HCT-116/PTX) xenograft models without inducing obvious toxicity compared with CPT- or combo-treated group. These results suggest that 14-1 holds promise as a novel candidate for anti-cancer therapy, particularly in PTX-resistant cancers.

Immune checkpoint inhibitors enhanced the antitumor efficacy of disitamab vedotin for patients with HER2-positive or HER2-low advanced or metastatic gastric cancer: a multicenter real-world study.

BACKGROUND: Novel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients. METHODS: This was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities. RESULTS: 45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3-4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively. CONCLUSION: Compared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

Transcriptome analysis of PK-15 cells expressing CSFV NS4A.

BACKGROUND: Classical swine fever (CSF) is a severe disease of pigs that results in huge economic losses worldwide and is caused by classical swine fever virus (CSFV). CSFV nonstructural protein 4 A (NS4A) plays a crucial role in infectious CSFV particle formation. However, the function of NS4A during CSFV infection is not well understood.  RESULTS: In this study, we used RNA-seq to investigate the functional role of CSFV NS4A in PK-15 cells. A total of 3893 differentially expressed genes (DEGs) were identified in PK-15 cells expressing NS4A compared to cells expressing the empty vector (NC). Twelve DEGs were selected and further verified by RT‒qPCR. GO and KEGG enrichment analyses revealed that these DEGs were associated with multiple biological functions, including cell adhesion, apoptosis, host defence response, the inflammatory response, the immune response, and autophagy. Interestingly, some genes associated with host immune defence and inflammatory response were downregulated, and some genes associated with host apoptosis and autophagy were upregulated. CONCLUSION: CSFV NS4A inhibits the innate immune response, and suppresses the expression of important genes associated with defence response to viruses and inflammatory response, and regulates cell adhesion, apoptosis and autophagy.

Efficacy of regorafenib combined with PD-1 inhibitors in elderly patients with advanced metastatic colorectal cancer.

OBJECTIVE: This is the first clinical study that wants to investigate the treatment patterns, clinical outcomes, and prognostic factors of regorafenib plus PD-1 inhibitors therapy in Chinese elderly patients with advanced colorectal cancer. METHODS: A cohort of metastatic colorectal cancer patients 60 years or older who received treatment with regorafenib combined with PD-1 inhibitors was included in our analysis. The endpoints included overall survival (OS), progression-free survival (PFS), and prognostic factors. RESULTS: In total, 24 patients were enrolled with the median age of 68 years, and 62.5% were female. The median OS and PFS were 15.03 months (95% CI 7.0-23.0) and 4.0 months (95% CI 1.8-6.2), respectively. The objective response rate was 8.3%, and the disease control rate was 70.8%. Patients previously treated with regorafenib had a longer median PFS than those without (6.3 versus 2.8 months). In terms of final daily doses, it showed a trend toward better PFS (median PFS was 10.0 months) in high-dose group (daily dose above 80 mg of regorafenib) compared to low-dose group (daily dose no more than 80 mg of regorafenib) (median PFS was 3.5 months). CONCLUSIONS: This real-world evidence confirms that Chinese elderly patients with advanced colorectal cancer may benefit from the treatment of regorafenib combined with PD-1 inhibitors, similarly with this combination therapy strategies in all age patients.

The efficacy and safety of apatinib treatment for patients with advanced or recurrent biliary tract cancer: a retrospective study.

INTRODUCTION: The present study aims to evaluate the efficacy and safety of apatinib monotherapy or combination therapy for patients with advanced or recurrent biliary tract cancer (BTC). METHODS: Twenty-eight patients with advanced or recurrent BTC who progressed after prior systemic therapies and treated with apatinib from January 2017 to June 2019 were enrolled in this retrospective and observational study. The primary end point was progression free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity. RESULTS: A total of 28 patients with advanced or recurrent BTC who progressed after prior systemic therapies received apatinib monotherapy or combination therapy (with capecitabine, S-1, oxaliplatin, irinotecan or PD-1 inhibitor), including 9 cases of gallbladder cancer and 19 cases of cholangiocarcinoma. Six patients achieved PR, 15 patients had SD and 7 patients had PD. Median progression-free survival (PFS) and overall survival (OS) was 4.3 months (95%CI = 1.8-6.8) and 6.2 months (95% CI = 4.6-7.8) respectively. The ORR and DCR were 21.4% (6/28) and 75.0% (21/28), respectively. Most of the adverse events were grade 1-2 in severity, apatinib treatment was well tolerated. CONCLUSIONS: Apatinib monotherapy or combination therapy can improve PFS in patients with advanced or recurrent BTC who progressed after prior systemic therapies, and adverse reactions can be well tolerated. Our study support apatinib therapy as a feasible therapeutic strategy in advanced or recurrent BTC.

Transcriptomic analysis of gene expression in normal goat ovary and intersex goat gonad.

Intersexuality is a congenital reproductive disorder that usually occurs in hornless goats, hindering breeding of goats with hornless traits and the development of the goat industry. In this study, we aimed to identify differentially expressed genes in intersex and normal goat gonads by comparing gene transcription profiles of intersex and normal goat gonads. As intersex goats are genetically based on females, we chose female goats as controls. The goats in the control group and the experimental group were both over one-year old. We evaluated the anatomical characteristics of the reproductive organs of five intersex goats using histopathological methods. The gonads were found to be ovarian and testicular types. RNA-Seq technology was used to identify differentially expressed genes in gonads and normal goat ovary tissues. Transcription analysis results were verified by qPCR. The results showed that 2,748 DEGs were upregulated and 3,327 DEGs were downregulated in intersex ovaries unlike in controls, whereas 2006 DEGs were upregulated and 2032 DEGs were downregulated in the interstitial testes. Many of these genes play important roles in mammalian sex determination and sex differentiation, such as SOX9, WT1, GATA4, DMRT1, DHH, AMH, CYP19A1 and FST. We found that many DEGs are involved in biological developmental regulation by GO and KEGG enrichment analyses, and that most genes associated with the steroid synthesis pathway were downregulated. The DEGs identified in this study may be involved in the regulation of intersex goat sex determination and differentiation, and may increase our understanding of the molecular mechanisms of mammalian sex differentiation.

Antiviral activity of ISG15 against classical swine fever virus replication in porcine alveolar macrophages via inhibition of autophagy by ISGylating BECN1.

Interferons (IFNs) induce the expression of interferon-stimulated genes (ISGs) for defense against numerous viral infections, including classical swine fever virus (CSFV). However, the mechanisms underlying the effect of ISGs on CSFV infection are rarely reported. In this study, we demonstrate that IFN-α treatment induces upregulation of ISG15 and thus attenuates CSFV replication. To determine whether ISG15 is critical for controlling CSFV replication, we established porcine alveolar macrophages (PAMs) with stable overexpression or knockdown of ISG15. Overexpression of Flag-ISG15 significantly prevented CSFV replication, whereas loss of ISG15 led to abnormal proliferation of CSFV. Furthermore, upregulated ISG15 promoted beclin-1 (BECN1) ISGylation and dysfunction and subsequently inhibited autophagy, which is indispensable for CSFV replication. In addition, HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5), which functions to catalyze conjugation of ISG15 protein, was confirmed to interact with BECN1. Collectively, these results indicate that IFN-α restricts CSFV replication through ISG15-mediated BECN1 ISGylation and autophagy inhibition, providing insight into the mechanism of CSFV replication control by type I IFN. This mechanism may not be the only antiviral mechanism of ISG15; nonetheless, this study may contribute to the development of CSFV treatment and prevention strategies.

Long non-coding RNA NNT-AS1 sponges miR-424/E2F1 to promote the tumorigenesis and cell cycle progression of gastric cancer.

Long non-coding RNAs (lncRNAs) have been illustrated to function as important regulators in carcinogenesis and cancer progression. However, the roles of lncRNA NNT-AS1 in gastric cancer remain unclear. In the present study, we investigate the biological role of NNT-AS1 in gastric cancer tumorigenesis. Results revealed that NNT-AS1 expression level was significantly up-regulated in GC tissue and cell lines compared with adjacent normal tissue and normal cell lines. The ectopic overexpression of NNT-AS1 indicated the poor prognosis of GC patients. In vitro experiments validated that NNT-AS1 knockdown suppressed the proliferation and invasion ability and induced the GC cell cycle progression arrest at G0/G1 phase. In vivo xenograft assay, NNT-AS1 silencing decreased the tumour growth of GC cells. Bioinformatics online program predicted that miR-424 targeted the 3'-UTR of NNT-AS1. Luciferase reporter assay, RNA-immunoprecipitation (RIP) and RNA pull-down assay validated the molecular binding within NNT-AS1 and miR-424, therefore jointly forming the RNA-induced silencing complex (RISC). Moreover, E2F1 was verified to act as the target gene of NNT-AS1/miR-424, indicating the NNT-AS1/miR-424/E2F1 axis. In conclusion, our study indicates that NNT-AS1 sponges miR-424/E2F1 to facilitate GC tumorigenesis and cycle progress, revealing the oncogenic role of NNT-AS1 for GC.

MAVS induces a host cell defense to inhibit CSFV infection.

Classical swine fever virus (CSFV) infection results in highly significant economic losses. Previous studies have suggested that CSFV can be recognized by RIG-I-like receptors (RLRs) to trigger innate defenses. However, the role of mitochondrial antiviral signaling protein (MAVS), the adaptor of RLRs, is still unknown during CSFV infection. Here, we showed that CSFV infection increased MAVS expression in porcine alveolar macrophages (PAMs). Additionally, intracellular reactive oxygen species (ROS) were involved in MAVS expression in CSFV-infected PAMs. Moreover, MAVS enhanced the induction of antiviral and pro-inflammatory cytokines and apoptosis, and inhibited CSFV replication. However, CSFV still establishes a persistent infection in the host. Thus, how CSFV antagonises MAVS-mediated host cell defense was investigated. Importantly, CSFV Npro inhibited MAVS-induced interferons and pro-inflammatory cytokines and apoptosis. Furthermore, IRF3-knockdown also suppressed MAVS-induced host cell defense. Taken together, these results demonstrate that intracellular ROS is involved in CSFV-induced MAVS expression and MAVS induces antiviral cytokines and apoptosis to inhibit CSFV replication while CSFV Npro inhibits MAVS-mediated host cell defenses possibly through degradation of IRF3. These data offer novel insights into the immunomodulatory effects of CSFV infection on the host innate response.

uS10, a novel Npro-interacting protein, inhibits classical swine fever virus replication.

Classical swine fever (CSF) is a severe, febrile and highly contagious disease caused by classical swine fever virus (CSFV) that has resulted in huge economic losses in the pig industry worldwide. CSFV Npro has been actively studied but remains incompletely understood. Few studies have investigated the cellular proteins that interact with Npro and their participation in viral replication. Here, the yeast two-hybrid (Y2H) system was employed to screen Npro-interacting proteins from a porcine alveolar macrophage (PAM) cDNA library, and a blast search of the NCBI database revealed that 15 cellular proteins interact with Npro. The interaction of Npro with ribosomal protein S20, also known as universal S10 (uS10), was further confirmed by co-immunoprecipitation and glutathione S-transferase pull-down assays. Furthermore, uS10 overexpression inhibited CSFV replication, whereas the knockdown of uS10 promoted CSFV replication in PAMs. In addition, Npro or CSFV reduced uS10 expression in PAMs in a proteasome-dependent manner, indicating that Npro-uS10 interaction might contribute to persistent CSFV replication. Our previous research showed that CSFV decreases Toll-like receptor 3 (TLR3) expression. The results showed that uS10 knockdown reduced TLR3 expression, and that uS10 overexpression increased TLR3 expression. Notably, uS10 knockdown did not promote CSFV replication following TLR3 overexpression. Conversely, uS10 overexpression did not inhibit CSFV replication following TLR3 knockdown. These results revealed that uS10 inhibits CSFV replication by modulating TLR3 expression. This work addresses a novel aspect of the regulation of the innate antiviral immune response during CSFV infection.

Effects of wheat intercropping on growth and occurrence of Fusarium wilt in watermelon.

Watermelon is commonly affected by Fusarium wilt in a monoculture cropping system. Wheat intercropping alleviates the affection of Fusarium wilt of watermelon. The objective of this study was to determine the effects of wheat and watermelon intercropping on watermelon growth and Fusarium wilt. Our results showed that wheat and watermelon intercropping promoted growth, increased chlorophyll content, and photosynthesis of watermelon. Meanwhile, wheat and watermelon intercropping inhibited watermelon Fusarium wilt occurrence, decreased spore numbers, increased root vigor, increased antioxidant enzyme activities, and decreased malondialdehyde (MDA) content in watermelon roots. Additionally, wheat and watermelon intercropping enhanced the bacterial colonies and total microbes growth in soil, decreased fungi and Fusarium oxysporum f. sp. niveum (FON) colonies, and increased soil enzyme activities in watermelon rhizosphere soil. Our results indicated that wheat and watermelon intercropping enhanced watermelon growth and decreased the incidence of Fusarium wilt in watermelon. These effects could be due to intercropping inducing physiological changes, regulating soil enzyme activities, and/or modulating soil microbial communities.

Individual Irinotecan Therapy Under the Guidance of Pre-Treated UGT1A1*6 Genotyping in Gastric Cancer.

Background: Severe delayed diarrhea and hematological toxicity limit the use of irinotecan. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is a critical enzyme in irinotecan metabolism. The study aims to investigate the safety and efficacy of irinotecan under the guidance of the pre-treatment UGT1A1 genotype in the second-line treatment of gastric cancer. Methods: This study involved 110 patients. Irinotecan was injected intravenously every 3 weeks, and the dose of irinotecan was determined by polymorphism of the UGT1A1 gene, which was divided into three groups (125 mg/m2: GG type; 100 mg/m2: GA type; 75 mg/m2: AA type). The primary end point was overall survival (OS), the secondary end points were progression-free survival (PFS) and safety. Results: One hundred and seven patients received irinotecan treatment and three patients with AA type received paclitaxel treatment. Among 107 patients, there were no significant differences in PFS (4.8 m vs 4.9 m vs 4.4 m; p = 0.5249) and OS (9.3 m vs 9.3 m vs NA; p = 0.6821) among patients with GG/GA/AA subtypes after dose adjustment. For the patient with homozygosity mutation, treatment was switched to paclitaxel. There were no significant differences in PFS and OS among patients with different alleles or after dose adjustment (p > 0.05). There was a significant difference in the risk of delayed diarrhea (p = 0.000), leukopenia (p = 0.003) and neutropenia (p = 0.000) in patients with different UGT1A1*6 genotypes, while no difference in patients with different UGT1A1*28 genotypes. Additionally, grade 3/4 diarrhea, neutropenia, and leukopenia were significantly more common in AA genotype patients compared to GG (2%, 19%, 24%) or GA (23%, 31%, 31%) genotype patients. Conclusion: Individual irinotecan treatment shows encouraging survival and tolerability outcomes in patients with GG/GA subtype. Irinotecan may be not suitable for patients with AA subtype.

Roles and inhibitors of FAK in cancer: current advances and future directions.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that exhibits high expression in various tumors and is associated with a poor prognosis. FAK activation promotes tumor growth, invasion, metastasis, and angiogenesis via both kinase-dependent and kinase-independent pathways. Moreover, FAK is crucial for sustaining the tumor microenvironment. The inhibition of FAK impedes tumorigenesis, metastasis, and drug resistance in cancer. Therefore, developing targeted inhibitors against FAK presents a promising therapeutic strategy. To date, numerous FAK inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, and APG-2449, have been developed, which have demonstrated positive anti-tumor effects in preclinical studies and are undergoing clinical trials for several types of tumors. Moreover, many novel FAK inhibitors are currently in preclinical studies to advance targeted therapy for tumors with aberrantly activated FAK. The benefits of FAK degraders, especially in terms of their scaffold function, are increasingly evident, holding promising potential for future clinical exploration and breakthroughs. This review aims to clarify FAK's role in cancer, offering a comprehensive overview of the current status and future prospects of FAK-targeted therapy and combination approaches. The goal is to provide valuable insights for advancing anti-cancer treatment strategies.

In era of immunotherapy: the value of trastuzumab beyond progression in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer.

Background: For patients with human epidermal growth factor receptor-2 (HER2)-positive advanced or metastatic gastric cancer who have progressed on first-line trastuzumab therapy, the clinical value of the continuous use of trastuzumab beyond progression (TBP) is controversial. Objectives: The present study was conducted to evaluate the efficacy and explore new treatment strategies of TBP for patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer in the era of cancer immunotherapy. Design: Retrospective analysis. Methods: Patients with HER2-positive advanced or metastatic gastric cancer who have failed first-line treatment based on trastuzumab-targeted therapy from June 2019 to December 2020 were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival curves of patients were estimated by the Kaplan-Meier method and compared using the log-rank test. Results: In all, 30 patients received TBP with chemotherapy, immunotherapy, or anti-angiogenic therapy, and the other 26 patients received treatment of physician's choice without trastuzumab. The median PFS in the TBP and non-TBP population was 6.0 [95% confidence interval (CI) = 3.8-8.2] and 3.5 (95% CI = 2.2-4.8) months, respectively (p = 0.038), and the median OS was 12.3 (95% CI = 10.4-14.2) and 9.0 (95% CI = 6.6-11.4) months (p = 0.008). The patients who received TBP treatment had more favorable PFS and OS than the non-TBP population. In the TBP group, patients who received trastuzumab plus chemotherapy and immunotherapy had higher ORR (40.0% versus 16.7%), DCR (90.0% versus 50.0%), and showed a significant improvement in PFS (7.0 versus 1.9 m) compared to TBP with chemotherapy alone. Subgroup analysis suggested that patients with male, HER2 positive with immunohistochemistry score 3+ and PFS of first-line treatment less than 6 months had a greater benefit from TBP. The incidence of Grade 3-4 adverse events in the TBP and non-TBP groups was 43.3% and 38.5%. Conclusion: The continuous use of TBP improves PFS and OS in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer with well-tolerated toxicity. In the era of immunotherapy, TBP combined with chemotherapy and immunotherapy may further enhance the clinical benefit and provide a new treatment strategy. Trial registration: This study is a retrospective study, which does not require clinical registration.

The value of TBP in trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer Patients with human epidermal growth factor receptor-2 (HER2) positive advanced or metastatic gastric cancer who have failed from first-line treatment based on trastuzumab targeted therapy from June 2019 to December 2020 were retrospectively analyzed. 30 patients received TBP with chemotherapy, immunotherapy or anti-angiogenic therapy, and the other 26 patients received treatment of physician's choice without trastuzumab. The median PFS in the TBP and non-TBP population was 6.0(95% CI = 3.8-8.2) and 3.5 (95% CI = 2.2-4.8) months, respectively (P = 0.038), and the median OS was 12.3 (95% CI = 10.4-14.2) and 9.0 (95% CI = 6.6-11.4) months (P = 0.008). In TBP group, patients who received trastuzumab plus chemotherapy and immunotherapy had higher ORR, DCR and showed a significant improvement in PFS compared to TBP with chemotherapy-alone (p = 0.024). Subgroup analysis suggested that patients with male, HER2-positive with IHC score 3+ and PFS of first-line treatment less than 6 months had a greater benefit from TBP. The continuous use of TBP does not increase the incidence of adverse events (AEs). The continuous use of TBP improve PFS and OS in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer with well tolerated toxicity. In the era of immunotherapy, TBP combined with chemotherapy and immunotherapy further enhanced the clinical benefit and provide new treatment strategy.

Construction of an auxiliary scoring model for myelosuppression in patients with lung cancer chemotherapy based on random forest algorithm.

OBJECTIVE: To construct an auxiliary scoring model for myelosuppression in patients with lung cancer undergoing chemotherapy based on a random forest algorithm, and to evaluate the predictive performance of the model. METHODS: Patients with lung cancer who received chemotherapy in Shanxi Province Cancer Hospital from January 2019 to January 2022 were retrospectively selected as research subjects, and their general demographic information, disease-related indicators, and laboratory test results before chemotherapy were collected. Patients were divided into a training set (136 cases) and a validation set (68 cases) in a ratio of 2:1. R software was used to establish a scoring model of myelosuppression in lung cancer patients in the training set, and the receiver operating characteristic curve, accuracy, sensitivity, and balanced F-score were used in the two data sets to evaluate the predictive performance of the model. RESULTS: Among the 204 lung cancer patients enrolled, 75 patients developed myelosuppression during the follow-up period after chemotherapy, with an incidence of 36.76%. The factors in the constructed random forest model were ranked in order of age (23.233), bone metastasis (21.704), chemotherapy course (19.259), Alb (13.833), and gender (11.471) according to the mean decrease accuracy. The areas under the curve of the model in the training and validation sets were 0.878 and 0.885, respectively (all P < 0.05). The predictive accuracy of the validated model was 82.35%, the sensitivity and specificity were 84.00% and 81.40%, respectively, and the balanced F-score was 77.78% (all P < 0.05). CONCLUSION: The risk assessment model for the occurrence of myelosuppression in patients with lung cancer chemotherapy based on a random forest algorithm can provide a reference for the accurate identification of high-risk patients.

Corrigendum: Self-assembling and pH-Responsive protein nanoparticle as potential platform for targeted tumor therapy.

[This corrects the article DOI: 10.3389/fmolb.2023.1172100.].

Self-assembling and pH-responsive protein nanoparticle as potential platform for targeted tumor therapy.

Frequent injections at high concentrations are often required for many therapeutic proteins due to their short in vivo half-life, which usually leads to unsatisfactory therapeutic outcomes, adverse side effects, high cost, and poor patient compliance. Herein we report a supramolecular strategy, self-assembling and pH regulated fusion protein to extend the in vivo half-life and tumor targeting ability of a therapeutically important protein trichosanthin (TCS). TCS was genetically fused to the N-terminus of a self-assembling protein, Sup35p prion domain (Sup35), to form a fusion protein of TCS-Sup35 that self-assembled into uniform spherical TCS-Sup35 nanoparticles (TCS-Sup35 NP) rather than classic nanofibrils. Importantly, due to the pH response ability, TCS-Sup35 NP well retained the bioactivity of TCS and possessed a 21.5-fold longer in vivo half-life than native TCS in a mouse model. As a result, in a tumor-bearing mouse model, TCS-Sup35 NP exhibited significantly improved tumor accumulation and antitumor activity without detectable systemic toxicity as compared with native TCS. These findings suggest that self-assembling and pH responding protein fusion may provide a new, simple, general, and effective solution to remarkably improve the pharmacological performance of therapeutic proteins with short circulation half-lives.

High DCR and Better Survival in Patients with Advanced or Metastatic Gastric Cancer Receiving Anti-Angiogenic TKI plus Chemotherapy: A Real-World Study.

Objectives: This study was carried out to assess the efficacy and drug toxicity of anti-angiogenic tyrosine kinase inhibitor (TKI) plus chemotherapy as second-line or above therapeutic regime in advanced or metastatic gastric cancer patients. Methods: From November 2017 to April 2020, advanced or metastatic gastric cancer patients who have failed from prior treatment and received apatinib combined with irinotecan or irinotecan treatment were analyzed. The primary observed indicator was progression-free survival (PFS). Objective: response rate (ORR), disease control rate (DCR), overall survival (OS), and drug toxicity were also evaluated. Results: 26 patients received apatinib combined with irinotecan and 29 patients received irinotecan. The ORR in the combination therapy and monotherapy population was 26.9% and 17.2%, respectively. The DCR in the apatinib combined with irinotecan group was higher than in irinotecan monotherapy population (80.8% vs 55.2%, P = .043). Median PFS was 4.2 months in the combination group and 3.3 months in the monotherapy group (P = .020). Median OS was 8.0 months in the combination group and 5.9 months in the monotherapy group (P = .048). Except for ECOG PS 2, PFS and OS were generally consistent across subgroups by sex, age, number of metastatic sites and primary tumor site. The incidence of Grade 3-4 adverse events in combination and monotherapy group was 23.1% and 20.7%, respectively. In apatinib combined with irinotecan group, adverse events that were attributed to apatinib were secondary hypertension (in seven patients, 26.9%), hand-foot syndrome (5,19.2%), and proteinuria (5, 19.2%). Univariate analysis demonstrated that secondary hypertension was considered to be a favorable factor (P = .040) for longer OS in combination therapy group. Conclusions: Compared with chemotherapy alone, anti-angiogenic TKI plus chemotherapy showed better PFS, OS and DCR in advanced or metastatic gastric cancer as second-line or above therapy, with a tolerable and manageable safety profile.

An Exploration of Trifluridine/Tipiracil Monotherapy and in Combination With Bevacizumab or Immune Checkpoint Inhibitors for Patients With Metastatic Colorectal Cancer: A Real-World Study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) has achieved modest efficacy in the late-line treatment of metastatic colorectal cancer. The present study aimed to explore the clinical efficacy and drug toxicities of TAS-102 for patients with metastatic colorectal cancer in real-world clinical setting. METHODS: From October 2020 to February 2022, patients with metastatic colorectal cancer who failed from 2 or more lines of prior therapy and treated with TAS-102 monotherapy, in combination with bevacizumab or immune checkpoint inhibitors (ICIs) were analyzed. The evaluation indicators were progression free survival (PFS), objective response rate , disease control rate (DCR), overall survival (OS) and drug toxicities. RESULTS: A total of 70 patients were enrolled. The objective response rate and DCR were 1.4% and 68.6%. The median PFS and OS were 6.0 (95% CI: 4.1-7.9) and 10.0 (95% CI: 8.3-11.7) months. Compared with TAS-102 monotherapy and TAS-102 plus ICIs, TAS-102 plus bevacizumab obtained superior DCR (75.9% vs. 50% vs. 40%, P = .047), PFS (6.3m vs. 3.0 m vs. 3.0 m, P = .041) and OS (12.0 m vs. 6.5 m vs. 6.0m, P = .013). Patients without prior regorafenib or fruquintinib therapy obtained better median PFS (6.3 vs. 4.3 m, P = .031) and OS (NR vs. 9.0 m, P = .036). Other indicators, including age, tumor site, KRAS status and use of fluoropyrimidine as last regimen before TAS-102, did not affect the clinical efficacy of TAS-102. The most frequent adverse events were leukopenia, neutropenia, anemia, fatigue, nausea, and vomiting. CONCLUSION: In real-world clinical setting, TAS-102 showed consistent clinical efficacy and manageable safety with previous prospective clinical studies. Compared with monotherapy and TAS-102 plus ICIs, TAS-102 plus bevacizumab demonstrated better clinical efficacy for metastatic colorectal cancer.