Search

The morbidity and mortality of gastric cancer are high, while the overall therapeutic effect is poor without satisfactory. Clinical obstacles, such as low early-diagnosis rate, tumor heterogeneity, lack of accurate classification and precise treatment, therapeutic resistance, recurrence and metastasis, are the key point issues to the lower efficacy in treatment of gastric cancer. In order to solve these clinical problems, it is necessary to devote more energy to the basic research of gastric cancer, including tumor genomics; gene editing; tumor microenvironment; inflammation, aging and tumor; cell differentiation disorders; autophagy and cell death; metabolic disorders; immunotherapy and drug development. This paper will summarize the clinical obstacles in the treatment of gastric cancer, and describe the directions of basic research on these clinical problems in future, so as to provide notions for the translational research of gastric cancer.

Esophageal cancer (EC) is the seventh most common cancer worldwide. Patients with EC have a generally poor prognosis mainly due to the lack of effective treatments. Cancer immunotherapy is a promising novel treatment option for EC. This literature review investigated the clinical efficacy of immunotherapy either alone or in combination with chemotherapy or targeted therapy. In addition, we analyzed the adverse events associated with immune checkpoint inhibitors (ICIs). In conclusion, ICIs increase the efficacy of EC treatments, thereby improving the outcomes of EC patients. The findings of this study may help enhance the response to immunotherapy, diminish toxicity, and thus eventually improve medical care for patients with EC. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have shown that immune checkpoint inhibitors can improve the survival of patients with advanced non‐small cell lung cancer with KRAS mutations; however, there is a lack of comparisons between treatment regimens associated with immune checkpoint inhibitors, and our study aims to compare several treatment parties to find a more effective treatment regimen. Method: A comprehensive literature search was conducted across multiple databases, namely PubMed, Web of Science, Embase, and Cochrane Library, to identify relevant studies. The screened studies were thoroughly examined, and data were collected to establish a Bayesian framework. The study focused on two primary endpoints: overall survival (OS) and progression‐free survival (PFS). Data analysis and graphical plotting using R software and Revman (version 5.3). It is worth mentioning that the study protocol was registered with the International Prospective Registry for Systematic Reviews, ensuring transparency and adherence to predetermined protocols (CRD42022379595). Result: In total, our analysis included six RCTs involving 469 patients with KRAS mutations. Among these patients, 224 received chemotherapy, while 245 were treated with immune checkpoint inhibitors. Meta‐analysis results showed that the addition of ICIs could significantly improve OS and PFS (0.69, 95% CI 0.55, 0.86; 0.57, 95% CI 0.42, 0.77). The results of the network meta‐analysis showed that Pembrolizumab could improve OS (HR 0.42, 95% CI 0.22–0.80) and Pembrolizumab emerged as the most effective treatment option for enhancing OS in patients (SUCRA 65.03%). Additionally, pembrolizumab in combination with chemotherapy showed improvement in PFS (HR 0.47, 95% CI 0.29–0.76). Conclusion: Our analysis found that among advanced NSCLC patients with KRAS gene mutations, first‐line treatment with pembrolizumab alone demonstrated greater efficacy. Similarly, second‐line treatment with nivolumab alone was found to be more effective in this patient population. However, the sample size of this study was limited, Therefore, additional clinical data is necessary to validate this finding in subsequent research. [ABSTRACT FROM AUTHOR]

This study aims to investigate the mechanisms through which fructose diphosphate (FDP) causes anti-hypoxia and anti-fatigue effects and improves learning and memory. Mice were divided into three groups: low-dose FDP (FDP-L), high-dose FDP (FDP-H), and a control group. Acute toxic hypoxia induced by carbon monoxide, sodium nitrite, and potassium cyanide and acute cerebral ischemic hypoxia were used to investigate the anti-hypoxia ability of FDP. The tests of rod-rotating, mouse tail suspension, and swimming endurance were used to explore the anti-fatigue effects of FDP. The Morris water maze experiment was used to determine the impact of FDP on learning and memory ability. Poisoning-induced hypoxic tests showed that mouse survival time was significantly prolonged in the FDP-L and FDP-H groups compared with the control group (p < 0.05). In the exhaustive swimming test, FDP significantly shortened struggling time and prolonged the time of mass-loaded swimming; the rod-rotating test showed that endurance time was significantly prolonged by using FDP (p < 0.05). FDP significantly decreased lactate and urea nitrogen levels and increased hepatic and muscle glycogen and glucose transporter-4 and [Na.sup.+]-[K.sup.+]-ATPase (p < 0.05). To conclude, FDP enhances hypoxia tolerance and fatigue resistance and improves learning and memory ability through regulating glucose and energy metabolism. Key words: fatigue resistance, fructose diphosphate, glucose metabolism, hypoxia tolerance, learning and memory ability. Cette etude porte sur les modes d'action par lesquels le diphosphate de fructose (DPF) entraine des effets anti-hypoxie et anti-fatigue, et ameliore l'apprentissage et la memoire. Nous avons reparti des souris dans les trois groupes suivants : DPF-A, DPF-M et temoin. Nous avons etudie la capacite anti-hypoxie du DPF en creant une hypoxie toxique aigue a l'aide de monoxyde de carbone, de nitrite de sodium et de cyanure de potassium, ainsi qu'une hypoxie cerebrale ischemique aigue. Nous avons etudie les effets anti-fatigues du DPF a l'aide des tests de la tige rotative, de suspension caudale et d'endurance a la nage. Nous avons etabli l'incidence du DPF sur l'apprentissage et les capacites mnesiques a l'aide de l'experience du labyrinthe aquatique de Morris. Les tests d'hypoxie engendree par un empoisonnement ont montre que le temps de survie augmentait nettement dans les groupes DPF-A et DPF-M par rapport aux temoins (p < 0,05). Dans le test de nage jusqu'a l'epuisement, le DPF entrainait une abreviation notable du temps de lutte avec un prolongement du temps de nage avec charge; le test de la tige rotative a montre que le temps d'endurance augmentait de facon marquee avec l'utilisation de DPF (p < 0,05). Le DPF entrainait une diminution importante des taux de lactate et d'azote ureique, avec une augmentation des taux de glycogene hepatique et musculaire, ainsi que du transporteur du glucose 4 et de la [Na.sup.+]-[K.sup.+]-ATPase (p < 0,05). Pour conclure, le DPF permet d'ameliorer la tolerance a l'hypoxie et la resistance a la fatigue, ainsi que d'ameliorer l'apprentissage et les capacites mnesiques par l'intermediaire de la regulation du metabolisme energetique et du glucose. [Traduit par la Redaction] Mots-cles: resistance a la fatigue, diphosphate de fructose, metabolisme du glucose, tolerance a l'hypoxie, apprentissage et capacites mnesiques., Introduction Chronic hypoxia can cause inadequate oxygen supply to various organs, which inhibits oxidation and promotes glycolysis in different tissues, resulting in insufficient adenosine triphosphate (ATP) generation. Some vital organ [...]

Erlotinib, an EGFR tyrosine kinase inhibitor, is used for treating patients with cancer exhibiting EGFR overexpression or mutation. However, the response rate of erlotinib is low among patients with gastric cancer (GC). The findings of this study illustrated that the overexpression of bromodomain PHD finger transcription factor (BPTF) is partially responsible for erlotinib resistance in GC, and the combination of the BPTF inhibitor AU‐1 with erlotinib synergistically inhibited tumor growth both in vivo and in vitro. AU‐1 inhibited the epigenetic function of BPTF and decreased the transcriptional activity of c‐MYC on PLCG1 by attenuating chromosome accessibility of the PLCG1 promoter region, thus decreasing the expression of p‐PLCG1 and p‐Erk and eventually improving the sensitivity of GC cells to erlotinib. In patient‐derived xenograft (PDX) models, AU‐1 monotherapy exhibited remarkable tumor‐inhibiting activity and is synergistic anti‐tumor effects when combined with erlotinib. Altogether, the findings illustrate that BPTF affects the responsiveness of GC to erlotinib by epigenetically regulating the c‐MYC/PLCG1/pErk axis, and the combination of BPTF inhibitors and erlotinib is a viable therapeutic approach for GC. [ABSTRACT FROM AUTHOR]

In recent years, immunotherapy has become a major research focus in the field of cancer treatment. Because of its good efficacy and lasting immune response, immune checkpoint inhibitors have benefited the long-term survival of many types of cancer patients. However, overactivation of the immune system may attack normal organs and cause a series of immune related adverse reactions. Among them, due to the high incidence of immune-related colitis, it deserves special attention. Camrelizumab is a programmed cell death 1 (PD-1) inhibitor that was developed by Jiangsu Hengrui Medicine Company. We reported the clinical data of a case of hepatocellular carcinoma with immune-related colitis after treatment with camrelizumab. A 63-year-old man with hepatocellular carcinoma developed diarrhea and hematochezia after receiving 4 cycles of camrelizumab. Endoscopy showed multiple flake congestion and edema in the terminal ileum and total colon mucosa with bright red surface. Pathological evaluation showed chronic inflammation of colonic mucosa. After giving 0.25g bid of enteric-coated sulfasalazine tablets orally for 6 weeks, his colitis improved. Camrelizumab can induce immune-related colitis. Sulfasalazine could be used to reduce adverse reactions of glucocorticoids. [ABSTRACT FROM AUTHOR]

Abstract.: It has been known that oxidative stress plays an important role in the development of diabetic nephropathy (DN). The antioxidative effects of Astragalus saponin I (AS I) were studied in vitro and in vivo. In the presence of high glucose and H2O2, the total antioxidative capability, catalase, reduced glutathione, and superoxide dismutase level of rat mesangial cells were significantly decreased, and transforming growth factor β1 (TGF-β1) mRNA level, collagen IV, and laminin level were significantly increased. When compared with those in the high glucose group, these 4 indexes of cells incubated in 2.0 and/or 20 µmol/L of AS I were significantly enhanced, and levels of TGF-β1 mRNA, collagen IV and laminin were statistically decreased. By flowcytomery, percentages of S phase of cells incubated in high glucose and H2O2 were lowered, while those in AS I were increased. Furthermore, the physical behaviors of rats treated with 12 mg/kg of AS I restored with vigor and weight gaining, while the level of HbAlC was significantly reduced. Thus, AS I has antioxidative effects and is a potential compound worth further study because it may prevent the development of DN. Keywords:: Astragalus saponin I, diabetic nephropathy, antioxidative, mesangial cell

Importance. Following the research, we discovered that other meta-analyses contained incomplete genes or did not include a sufficient number of trials. To address these limitations, this meta-analysis sought to find studies examining the extent toward epidermal growth factor receptor (EGFR) or KRAS or mutation status gives data on both the probability of a specific illness outcome very independent of treatment (prognostic factor) and possibility of advantage from a particular therapy (predictive factor) in non-small-cell lung cancer (NSCLC) patients. Objective. To assess and compare the effectiveness of immune checkpoint inhibitors vs. chemotherapy for KRAS-mutant or EGFR-mutant non-small-cell lung cancers. Methods. Until February 19, 2022, Cochrane Library, PubMed, Web of Science, and Embase were searched for relevant randomized controlled trials (RCTs) in NSCLC. Progression-free survival (PFS) and overall survival (OS) were used as outcome measures. The studies were conducted using the Cochrane methodology for meta-analyses, and all statistical analyses were made with Review Manager Software (RevMan version 5.4). Results. Our meta-analysis included nine clinical trials including 5633 participants with NSCLC. Immune checkpoint drugs extended OS (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.60–0.76) and PFS (HR, 0.44; 95% CI, 0.35-0.56) in patients with EGFR wild-type compared to chemotherapy alone, whereas programmed cell death 1 ligand 1 (PD-L1)/programmed cell death-1 (PD-1) inhibitors with chemotherapy versus chemotherapy extended PFS in NSCLC patients with EGFR mutations (HR, 0.63; 95% CI, 0.42-0.94). Meanwhile, immune checkpoint inhibitors vs. chemotherapy improved the OS (HR, 0.65; 95% CI, 0.48–0.88) and PFS (HR, 0.49; 95% CI, 0.36–0.66) of NSCLC patients with KRAS mutation. NSCLCs with KRAS G12C mutation had a much better PFS with ICIs than with chemotherapy (HR, 0.38; 95% CI, 0.21–0.71). Conclusion. This research revealed that individuals with EGFR wild-type NSCLC or KRAS mutation may benefit from PD-L1/PD-1 inhibitors and that PD-L1/PD-1 inhibitors in combination with chemotherapy seem to be more successful than chemotherapy alone in NSCLC patients with EGFR mutation. [ABSTRACT FROM AUTHOR]

Abstract: Astragaloside IV (AGS-IV), a new glycoside of cycloartane-type triterpene isolated from the root of Astragalus membranaceus (Fisch.) Bunge, has been used experimentally for its potent immune-stimulating, anti-inflammatory, and antioxidative [...]

aims to study the combinatory antitumor effect of apatinib and raltitrexed on human esophageal squamous carcinoma cells (ESCC). Materials and Methods: Two VEGFR-2-positive human ESCC lines, KYSE-30 and TE-1, were treated with apatinib or raltitrexed, or both, then the cell proliferation rate was measured by MTS assay; cell migration and invasion were studied by transwell assays; cell apoptosis rate was determined by flow cytometry; cellular autophagy level affected was analyzed by Western blot analysis; finally, quantitative polymerase chain reaction (qPCR) was used to monitor transcription and Western blot was performed to check phosphorylation of apoptotic proteins after treatment. Results: Both apatinib and raltitrexed significantly inhibited KYSE-30 and TE-1 cell proliferation in a dose-dependent manner. Treatment with both drugs showed enhanced inhibitory effects on cell proliferation, migration, and invasiveness compared with apatinib monotherapy. Apoptosis percentages in both cell lines were also remarkably increased by the combined treatment. Moreover, the combination of apatinib and raltitrexed down-regulated mRNA level of the anti-apoptotic protein Bcl-2, while up-regulated pro-apoptotic protein PARP, Bax, and caspase-3 transcription. Western blot analysis showed that phosphorylation levels of Erk, Akt, and invasiveness-associated protein matrix metalloproteinases-9 (MMP-9) were decreased in the combination group. Conclusion: Taken together, these results indicate that raltitrexed enhances the antitumor effects of apatinib on human ESCC cells by down-regulating phosphorylation of Akt and Erk, implying a combination of raltitrexed and apatinib might be an effective option for treating esophageal squamous cell carcinoma patients. [ABSTRACT FROM AUTHOR]

background and relatively low resolution of photos captured for the wound healing assay. For Figure 3A on page 2691, all Transwell images were captured and saved in one folder labelled by experimental date. Two overlapping images from different visual fields were captured from one well but labelled incorrectly and inadvertently selected for Figure 3A. The correct Figures 2 and 3 are shown in Download Article. The authors apologize for these errors and advise they do not affect the results of the paper. Read the original article [ABSTRACT FROM AUTHOR]

Background. Bismuth-containing quadruple therapy achieves higher eradication rate of Helicobacter pylori. High level of bismuth in blood may result in damage of many organs. Wei Bi Mei is a new bismuth-containing drug combining chemicals and Chinese medicine portions. The present research is to study the pharmacokinetics of bismuth to evaluate the safety and rational use of Wei Bi Mei granules. Material and Methods. Seven healthy Chinese adult subjects were enrolled in this research, which included a single-dose study and a multiple-dose study. Wei Bi Mei granules were administered orally to the subjects at corresponding time. Blood and urine were collected. All samples were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). Results. For single-dose Wei Bi Mei granules administration, the mean time to peak concentration (tmax) of bismuth was 2.29 ± 0.76 h, and the mean peak concentration (Cmax) of bismuth was 0.85 ± 0.55 ng/mL. For multiple-dose Wei Bi Mei granules administration, the Cmax was 2.25 ± 1.18 ng/mL at day two, and the volume of distribution (Vd) was (22.97 ± 9.82) × 103 L. The urinary excretion of bismuth was the fastest during the first two days, with a mean excretion rate of 3.84 ± 1.23 ng/h. The bismuth concentration in urine was significantly reduced at day 16. Conclusion. Bismuth has a washout period of approximately two months. The concentration of bismuth in blood was far less than the "safe level." Thus, Wei Bi Mei is a highly safe therapeutic medicine, with a good clinical application value. Wei Bi Mei should be recommended more widely for use in bismuth-containing quadruple therapy for the treatment of Helicobacter pylori infection. [ABSTRACT FROM AUTHOR]

The current study aimed to investigate the antitumor and antiangiogenesis effects of apatinib in triple-negative breast cancer in vitro and also whether the combination of docosahexaenoic acid (DHA) and apatinib is more effective than apatinib monotherapy. The cell counting kit-8 assay was used to measure cell proliferation. Flow cytometry was utilized to determine the cell apoptosis rate. A wound healing assay was utilized to assess cell migration. Western blot analysis was carried out to determine the effects of apatinib and DHA on Bcl-2, BAX, cleaved caspase-3, caspase-3, phosphorylated protein kinase B (p-Akt), and Akt expression. DHA in combination with apatinib showed enhanced inhibitory effects on cell proliferation and migration compared with apatinib or DHA monotherapy. Meanwhile, DHA combined with apatinib strongly increased the cell apoptosis percentage. DHA was observed to enhance the antitumor and antiangiogenesis effects of apatinib via further downregulation of p-Akt expression. Abbreviations: FITC: fluorescein isothiocyanate; PI: propidium iodide Apatinib showed antitumor and antiangiogenesis effects by decreasing p-Akt/Akt ration and increasing BAX and cleaved caspase-3 expression, which can be synergistically enhanced by DHA. [ABSTRACT FROM AUTHOR]

Background: Traditional chemotherapy and molecular targeted therapy have shown modest effects on the survival of patients with pancreatic cancer. The current study aimed to investigate the antitumor effects of apatinib, Astragalus polysaccharide (APS), and the combination of both the drugs in pancreatic cancer cells and further explore the molecular mechanisms in vitro. Materials and methods: Expression of vascular endothelial growth factor receptor-2 (VEGFR-2) in human pancreatic cancer cell lines ASPC-1, PANC-1, and SW1990 was detected by Western blotting. Cell proliferation was measured by MTS, and migration and invasion were detected by wound-healing and Transwell assays, respectively. Cell apoptosis rate was determined by flow cytometry and cellular autophagy level affected by apatinib, and APS was analyzed by Western blotting. Results: Human pancreatic cancer cell lines ASPC-1 and PANC-1 expressed VEGFR-2, but VEGFR-2 was not detected in SW1990. Either apatinib or APS inhibited cell proliferation in a dose-dependent manner in ASPC-1 and PANC-1. APS in combination with apatinib showed enhanced inhibitory effects on cell migration and invasion compared with apatinib monotherapy in ASPC-1 and PANC-1. Meanwhile, APS combined with apatinib strongly increased cell apoptosis percentage. Western blotting showed that the combination of APS and apatinib significantly enhanced the downregulation of phosphorylated protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) (p-AKT and p-ERK) as well as matrix metalloproteinases-9 (MMP-9) expression. In addition, both apatinib and APS induced cellular autophagy. However, the expression of autophagy-related proteins was not further elevated in the combination group. Conclusion: The study first demonstrated that apatinib showed potentially inhibitory effects in pancreatic cancer cells and that APS enhanced the antitumor effects of apatinib through further downregulating the expression of phosphorylation of AKT and ERK as well as MMP-9. [ABSTRACT FROM AUTHOR]

Apatinib has been proved effective in the treatment of advanced gastric cancer. Traditional Chinese medicine is often considered as adjuvants which could increase the effects and counteract the side effects of chemotherapy. The present study aims to explore the antitumor effects of Astragalus polysaccharide (AsPs) in combination with Apatinib in gastric cancer AGS cells. Our results demonstrated that the expression of VEGFR-2 was observed in human gastric cancer line AGS. Both Apatinib and AsPs could significantly inhibit the proliferation of AGS cells in a dose-dependent manner and Apatinib in combination with AsPs showed enhanced inhibitory effects on cell proliferation, migration and invasion compared with Apatinib monotherapy. Moreover, there was a remarkable increase in apoptosis following Apatinib treatment which could be enhanced by the addition of AsPs. Western blotting showed that the combination of Apatinib and AsPs could inhibit the expression of phosphorylated AKT (p-AKT) and MMP-9 expression. In addition, both Apatinib alone and Apatinib in combination with AsPs induced celluar autophagy which could be attenuated by the autophagy inhibitor 3-MA. The suppression of autophagy leaded to further apoptosis induction and cell proliferation suppression. In conclusion, the current study showed AsPs enhanced antitumor effects of Apatinib on AGS cells by the mechanism which includes inhibition of AKT signaling pathway. Apatinib-induced autophagy could be attenuated by 3-MA, which subsequently increased the apoptosis rate. On the basis of our study, the combination of Apatinib and AsPs could be considered as a potential candidate in the gastric cancer treatment. [ABSTRACT FROM AUTHOR]

Objective To investigate the protective effects and potential mechanism of the compound 25-OH-PPD (PPD) on the glomerular mesangial cells (GMC) under high glucose condition. Methods The hypertrophic GMC cells were established by DMEM containing glucose and randomly divided into five groups, including the normal control group (Control), the high glucose model group (HG, 25 mmol L −1 ), the PPD low dose group (1 μmol L −1 , PPD-L), the PPD middle dose group (5 μmol L −1 , PPD −M) and the PPD high dose group (10 μmol L −1 , UCN-H). The GMC were incubated for 48 h under different treatment factors. Total protein content was determined by Lowry method. The diameter of the single GMC and volume were measured by computer photograph analysis system. The GMC cell viability was analyzed by MTT assay. The level of malondialdehyde (MDA), the content of glutathione (GSH) and superoxide dismutase (SOD) activity were measured by ELISA. [Ca 2+ ] і transient was measured by Till image system and by cell-loading Fura-2/AM. The expression of COX-1 and COX-2 were also determined using ELISA method. Results The viability of GMC and the total protein content were decreased in HG group, different dosage PPD group could increase these indexes ( P < 0.05). The level of MDA was increased, the content of GSH and SOD was decreased in HG group, while PPD could reduce the MDA and enhance GSH and SOD ( P < 0.05). Following treatment with different dosage (PPD-L, PPD-M or PPD-H), the [Ca 2+ ] і transient was reduced ( P < 0.05 or P < 0.01). Moreover, the expression of COX-1 was decreased while COX-2 expression was increased in different dosage PPD groups. Conclusion The protective effects of PPD on GMC from HG-induced hypertrophy may be associated with the inhibition of [Ca 2+ ] і transient and decreasing expression of COX-1 via the oxidative-stress injure pathway. [ABSTRACT FROM AUTHOR]

Objectives: The primary objective of this pilot study was to investigate whether the therapeutic drug monitoring of imipenem could be performed with spent effluent instead of blood sampling collected from critically ill patients under continuous renal replacement therapy. Methods: A prospective open-label study was conducted in a real clinical setting. Both blood and effluent samples were collected pairwise before imipenem administration and 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after imipenem administration. Plasma and effluent imipenem concentrations were determined by reversed-phase high-performance liquid chromatography with ultraviolet detection. Pharmacokinetic and pharmacodynamic parameters of blood and effluent samples were calculated. Results: Eighty-three paired plasma and effluent samples were obtained from 10 patients. The Pearson correlation coefficient of the imipenem concentrations in plasma and effluent was 0.950 (P<0.0001). The average plasma-to-effluent imipenem concentration ratio was 1.044 (95% confidence interval, 0.975 to 1.114) with Bland-Altman analysis. No statistically significant difference was found in the pharmacokinetic and pharmacodynamic parameters tested in paired plasma and effluent samples with Wilcoxon test. Conclusion: Spent effluent of continuous renal replacement therapy could be used for therapeutic drug monitoring of imipenem instead of blood sampling in critically ill patients. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis is a major public health problem especially in developing countries, the comparative efficacy and safety of fluroquinolones (FQs) for adult patients with newly diagnosed, sputum-positive tuberculosis remains controversial. We aimed to investigate the benefits and risks of FQs-containing (addition/substitution) regimens in this population. Methods: A network meta-analysis was performed to compare FQs (C: ciprofloxacin; O: ofloxacin; Lo: levofloxacin; M: moxifloxacin; G: gatifloxacin) addition/substitution regimen with standard HRZE regimen (ie isoniazid, rifampicin, pyrazinamide and ethambutol) in newly diagnosed, sputum-positive tuberculosis. Medline, Embase and Cochrane Central Register of Controlled Trials were systematically searched, randomized trials with duration longer than 8 weeks were included. The primary outcome was week-8 sputum negativity, and secondary outcomes included treatment failure, serious adverse events and death from all cause. Results: Twelve studies comprising 6465 participants were included in the network meta-analysis. Löwenstein-Jensen culture method showed that HRZEM (OR 4.96, 95% CI 2.83–8.67), MRZE (OR 1.48, 95% CI 1.19–1.84) and HRZM (OR 1.32, 95% CI 1.08–1.62) had more sputum conversion than HRZE by the eighth week, whereas HRC (OR 0.39, 95% CI 0.19–0.77) and HRZO (OR 0.47, 95% CI 0.24–0.92) were worse than HRZE. Moxifloxacin-containing regimens showed more conversion than HRZE by liquid method at the end of two months. But by the end of treatment, FQs-containing regimens didn’t show superiority than HRZE on treatment failure. There were no significant differences between any regimens on other outcomes like serious adverse events and all-cause death. Conclusion: This comprehensive network meta-analysis showed that compared with HRZE, moxifloxacin-containing regimens could significantly increase sputum conversion by the eighth week for patients with newly diagnosed pulmonary tuberculosis while HRC and HRZO regimens were inferior. But all the FQs-containing regimens did not show superiority in other outcomes (such as treatment failure, serious adverse events and all-cause death). Thus, HRZE is still an effective regimen for this population. Although moxifloxacin-containing regimens have deomonstrated their potential, FQs-containing regimens should be used with great caution to avoid widespread FQs-resistance worldwide. [ABSTRACT FROM AUTHOR]

Background: Vacuolar protein sorting-associated protein 35 (VPS35) is a core component of the retromer complex which mediates intracellular protein transport. It is well known that dysfunctional VPS35 functions in the accumulation of pathogenic proteins. In our previous study, VPS35 was found to be a potential gene related to poor prognosis in gastric cancer. However, the biological functions of VPS35 in gastric cancer remain unclear., Methods: Cell viability assays were performed to examine whether VPS35 affected cell proliferation. Immunoprecipitation and biotin assays showed that VPS35 bound to epidermal growth factor receptor (EGFR) in the cytoplasm and recycled it to the cell surface. Patient-derived xenografts and organoids were used to evaluate the effect of VPS35 on the response of gastric cancer to EGFR inhibitors., Findings: VPS35 expression levels were upregulated in tumour tissues and correlated with local tumour invasion and poor survival in patients with gastric cancer. VPS35 promoted cell proliferation and increased tumour growth. Mechanistically, VPS35 selectively bound to endocytosed EGFR in early endosomes and recycled it back to the cell surface, leading to the downstream activation of the ERK1/2 pathway. We also found that high VPS35 expression levels increased the sensitivity of the xenograft and organoid models to EGFR inhibitors., Interpretation: VPS35 promotes cell proliferation by recycling EGFR to the cell surface, amplifying the network of receptor trafficking. VPS35 expression levels are positively correlated with gastric cancer sensitivity to EGFR inhibitors, which offers a potential method to stratify patients for EGFR inhibitor utilisation., Funding: National Natural Science Foundation of China., Competing Interests: Declaration of interests All the authors have declared no conflicts of interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Increasing evidence has elucidated that the tumor microenvironment (TME) shows a strong association with tumor progression and therapeutic outcome. We comprehensively estimated the TME infiltration patterns of 111 gastric cancer (GC) and 21 normal stomach mucosa samples based on bulk transcriptomic profiles based on which GC could be clustered as three subtypes, TME-Stromal, TME-Mix, and TME-Immune. The expression data of TME-relevant genes were utilized to build a GC prognostic model-GC&#95;Score. Among the three GC TME subtypes, TME-Stomal displayed the worst prognosis and the highest GC&#95;Score, while TME-Immune had the best prognosis and the lowest GC&#95;Score. Connective tissue growth factor (CTGF), the highest weighted gene in the GC&#95;Score, was found to be overexpressed in GC. In addition, CTGF exhibited a significant correlation with the abundance of fibroblasts. CTGF has the potential to induce transdifferentiation of peritumoral fibroblasts (PTFs) to cancer-associated fibroblasts (CAFs). Beyond characterizing TME subtypes associated with clinical outcomes, we correlated TME infiltration to molecular features and explored their functional relevance, which helps to get a better understanding of carcinogenesis and therapeutic response and provide novel strategies for tumor treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sang, Dai, Yu, Chen, Fan, Liu, Li, Li, Wu, Hou, Yu, Feng, Zhu, Su, Li and Liu.)

Background: Due to the molecular mechanism complexity and heterogeneity of gastric cancer (GC), mechanistically interpretable biomarkers were required for predicting prognosis and discovering therapeutic targets for GC patients., Methods: Based on a total of 824 GC-specific fitness genes from the Project Score database, LASSOCox regression was performed in TCGA-STAD cohort to construct a GC Prognostic (GCP) model which was then evaluated on 7 independent GC datasets. Targets prioritization was performed in GC organoids. ARGLU1 was selected to further explore the biological function and molecular mechanism. We evaluated the potential of ARGLU1 serving as a promising therapeutic target for GC using patients derived xenograft (PDX) model., Findings: The 9-gene GCP model showed a statistically significant prognostic performance for GC patients in 7 validation cohorts. Perturbation of SSX4, DDX24, ARGLU1 and TTF2 inhibited GC organoids tumor growth. The results of tissue microarray indicated lower expression of ARGLU1 was correlated with advanced TNM stage and worse overall survival. Over-expression ARGLU1 significantly inhibited GC cells viability in vitro and in vivo. ARGLU1 could enhance the transcriptional level of mismatch repair genes including MLH3, MSH2, MSH3 and MSH6 by potentiating the recruitment of SP1 and YY1 on their promoters. Moreover, inducing ARGLU1 by LNP-formulated saRNA significantly inhibited tumor growth in PDX model., Interpretation: Based on genome-wide functional screening data, we constructed a 9-gene GCP model with satisfactory predictive accuracy and mechanistic interpretability. Out of nine prognostic genes, ARGLU1 was verified to be a potential therapeutic target for GC., Funding: National Natural Science Foundation of China., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Traditional chemotherapy and molecular targeted therapy have shown modest effects on the survival of patients with pancreatic cancer. The current study aimed to investigate the antitumor effects of apatinib, Astragalus polysaccharide (APS), and the combination of both the drugs in pancreatic cancer cells and further explore the molecular mechanisms in vitro., Materials and Methods: Expression of vascular endothelial growth factor receptor-2 (VEGFR-2) in human pancreatic cancer cell lines ASPC-1, PANC-1, and SW1990 was detected by Western blotting. Cell proliferation was measured by MTS, and migration and invasion were detected by wound-healing and Transwell assays, respectively. Cell apoptosis rate was determined by flow cytometry and cellular autophagy level affected by apatinib, and APS was analyzed by Western blotting., Results: Human pancreatic cancer cell lines ASPC-1 and PANC-1 expressed VEGFR-2, but VEGFR-2 was not detected in SW1990. Either apatinib or APS inhibited cell proliferation in a dose-dependent manner in ASPC-1 and PANC-1. APS in combination with apatinib showed enhanced inhibitory effects on cell migration and invasion compared with apatinib monotherapy in ASPC-1 and PANC-1. Meanwhile, APS combined with apatinib strongly increased cell apoptosis percentage. Western blotting showed that the combination of APS and apatinib significantly enhanced the downregulation of phosphorylated protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) (p-AKT and p-ERK) as well as matrix metalloproteinases-9 (MMP-9) expression. In addition, both apatinib and APS induced cellular autophagy. However, the expression of autophagy-related proteins was not further elevated in the combination group., Conclusion: The study first demonstrated that apatinib showed potentially inhibitory effects in pancreatic cancer cells and that APS enhanced the antitumor effects of apatinib through further downregulating the expression of phosphorylation of AKT and ERK as well as MMP-9., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Molecular subtypes and Nottingham Prognostic Index (NPI) are both prognostic models for breast cancer patients. We evaluated the association between molecular subtypes and NPI in 1042 breast cancer patients. The molecular subtypes indicating poorer prognosis were positively correlated to higher NPI ( r = 0.138, P = 0.001). ER positive expression and PR high expression were positively correlated with NPI ( r = 0.142, P = 0.001; r = 0.139, P = 0.001; respectively) and negatively correlated with histological grade ( r = -0.233, P < 0.001; r = -0.176, P < 0.001; respectively). Ki67 status was negatively correlated with NPI and positively correlated with histological grade ( r = -0.120, P =0.004; r = 0.197, P < 0.001; respectively). The percentages of cases with NPI score 2.00-3.40 were higher in the luminar A, ER+, PR high expression and Ki67 low expression group, and the percentages of cases with NPI > 5.40 were higher in the HER2 overexpression subtype, basal-like subtype, ER-, PR low/negative expression, and Ki67 high expression groups. The excellent consistence was observed between histological grade and molecular subtypes, ER, PR, Ki67. The difference of histological grade between the HER2 positive and negative group was statistically significant. In conclusion, there was closely association between molecular subtypes and NPI in breast cancer. For further comparing the prognostic significance of molecular subtypes and NPI, survival analyses should be performed on the same population in a large-scale prospective study., Competing Interests: CONFLICTS OF INTEREST The authors declare no financial or commercial conflicts of interest.

Preclinical investigation and clinical experience have provided evidence on the potential anticancer effect of artemisinin and its derivatives (ARTs) in the recent two decades. The major mechanisms of action of ARTs may be due to toxic-free radicals generated by an endoperoxide moiety, cell cycle arrest, induction of apoptosis, and inhibition of tumor angiogenesis. It is very promising that ARTs are expected to be a new class of antitumor drugs of wide spectrum due to their detailed information regarding efficacy and safety. For developing repurposed drugs, many other characteristics of ARTs should be studied, including through further investigations on possible new pathways of anticancer effects, exploration on efficient and specific drug delivery systems-especially crossing biological barriers, and obtaining sufficient data in clinical trials. The aim of this review is to highlight these achievements and propose the potential strategies to develop ARTs as a new class of cancer therapeutic agents.

Natural products with biodiversity and chemical variations present a rich source for the discovery and development of new therapeutic and preventive drugs. Bioactive components derived from natural medicines including traditional Chinese medicine have been widely used for the screening of effective and safe anticancer drugs. Meanwhile, the investigation on mechanism of action (MOA) of natural bioactive components has a critical role in identifying and validating new molecular targets of those anticancer agents. Considering the high complexity of pharmacodynamic (PD) and pharmacokinetic (PK) characteristics of natural product anticancer agents, there are several major challenges in understanding mechanisms of action in vitro and in vivo for these agents. The recent rapid progress made in molecular and cell biology, genetics and genomics, and translational medicine, preclinical investigations provides an impetus for a better understanding of mechanisms of action and structure-activity relationships (SAR) of natural products. In addition, the simultaneous evaluation of PD-PK characterizations would allow a full assessment of the safety, efficacy, and indication of natural product anticancer drugs in various regimens and in various clinical settings. In this review, we provide a brief summary for recent advances in translational pharmacology, focusing on target validation and PK-PD, MOA, and SAR. Several examples for clinically used agents, and cancer preventive agents and therapeutic agents under preclinical and clinical development are used to illustrate the importance of such translational research and challenges we are facing.