A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice.

INTRODUCTION: Fruquintinib is approved in China for patients with metastatic colorectal cancer (CRC) who progressed after 2 lines of chemotherapy. This postmarketing study was conducted to evaluate the safety of fruquintinib in the Chinese population, including previously treated patients with advanced CRC and other solid tumors. METHODS: Patients in the first cycle of fruquintinib or expected to start fruquintinib within a week were enrolled. Fruquintinib was administrated according to the label or per physicians' discretion. Patient characteristics and safety information were collected at baseline, 1 month, and 6 months after consent (or 30 days after the last dose). RESULTS: Overall, 3005 patients enrolled between April 24, 2019 and September 27, 2022. All enrolled patients received at least one dose of fruquintinib. Most patients had metastases at baseline. The median age was 60 years. More than half (64.0%) of the patients started fruquintinib at 5 mg, and the median treatment exposure was 2.7 months. Nearly one-third (32.5%) of patients with CRC received fruquintinib with concomitant antineoplastic agents. Treatment-emergent adverse events (TEAEs) leading to dose modification were reported in 626 (20.8%) patients, and 469 (15.6%) patients experienced TEAEs leading to treatment discontinuation. The most common grade ≥ 3 TEAEs were hypertension (6.6%), palmar-plantar erythrodysesthesia syndrome (2.2%), and platelet count decreased (1.0%). Combination therapy did not lead to excessive toxicities. CONCLUSIONS: The safety profile of fruquintinib in the real world was generally consistent with that in clinical studies, and the incidence of TEAEs was numerically lower than known VEGF/VEGFR inhibitor-related AEs. Fruquintinib exhibited manageable safety and tolerability in Chinese patients in the real-world setting.

Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase IV study.

BACKGROUND: Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. METHODS: Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan-Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. RESULTS: Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6-5.4%), and DCR was 35.8% (95% CI, 33.7-38.0%). The median PFS was 2.7 months (95% CI 2.2-2.8), and the median OS was 5.8 months (95% CI 5.4-6.1). CONCLUSIONS: The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.

An artificial neural network model based on DNA damage response genes to predict outcomes of lower-grade glioma patients.

Although the prognosis of lower-grade glioma (LGG) patients is better than others, outcomes are highly heterogeneous. Isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion status can identify patient subsets with different prognosis. However, in the era of precision medicine, there is still a lack of biomarkers that can accurately predict the individual prognosis of each patient. In this study, we found that most DNA damage response (DDR) genes were aberrantly expressed in LGG patients and were associated with their prognosis. Consequently, we developed an artificial neural network (ANN) model based on DDR genes to predict outcomes of LGG glioma patients. Then, we validated the predictive ability in an independent external dataset and found that the concordance indexes and area under time-dependent receiver operating characteristic curves of the predict index (PI) calculated based on the model were superior to those of the mutation markers. Subgroup analyses demonstrated that the model could accurately identify patients with the same mutation status but different prognosis. Moreover, the model can also identify patients with favorable prognostic mutation status but poor prognosis or vice versa. Finally, we also found that the PI was associated with the mutation status and with the altered immune microenvironment. These results demonstrated that the ANN model can accurately predict outcomes of LGG patients and will contribute to individualized therapies. In addition, a web-based application program for the model was developed.

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model.

Background: Sepsis, which could cause a systemic inflammatory response, is a life-threatening disease with a high morbidity and mortality rate. There is evidence that brain injury may be related to severe systemic infection induced by sepsis. The brain injury caused by sepsis could increase the risk of mortality in septic patients, which seriously affects the septic patient's prognosis of survival. Although there remains a focus on sepsis research, clinical measures to prevent and treat brain injury in sepsis are not yet available, and the high mortality rate is still a big health burden. Therefore, it is necessary to investigate the new molecules or regulated pathways that can effectively inhibit the progress of sepsis. Objective: NLR family pyrin domain-containing 3 (NLRP3) increased in the procession of sepsis and functioned as the key regulator of pyroptosis. Heat shock factor 1 (HSF1) can protect organs from multiorgan dysfunction syndrome induced by lipopolysaccharides in mice, and NLRP3 could be inhibited by HSF1 in many organs. However, whether HSF1 regulated NLRP3 in sepsis-induced brain injury, as well as the detailed mechanism of HSF1 in brain injury, remains unknown in the sepsis model. In this research, we try to explore the relationship between HSF1 and NLRP3 in a sepsis model and try to reveal the mechanism of HSF1 inhibiting the process of brain injury. Methods: In this study, we used wild-type mice and hsf1 -/- mice for in vivo research and PC12 cells for in vitro research. Real-time PCR and Western blot were used to analyze the expression of HSF1, NLRP3, cytokines, and pyrolytic proteins. EthD-III staining was chosen to detect the pyroptosis of the hippocampus and PC12 cells. Results: The results showed that HSF1 is negatively related to pyroptosis. The pyroptosis in cells of brain tissue was significantly increased in the hsf1 -/- mouse model compared to hsf1 +/+ mice. In PC12 cells, hsf1 siRNA can upregulate pyroptosis while HSF1-transfected plasmid could inhibit the pyroptosis. HSF1 could negatively regulate the NLRP3 pathway in PC12 cells, while hsf1 siRNA enhanced the pyroptosis in PC12 cells, which could be reversed by nlrp3 siRNA. Conclusion: These results imply that HSF1 could alleviate sepsis-induced brain injury by inhibiting pyroptosis through the NLRP3-dependent pathway in brain tissue and PC12 cells, suggesting HSF1 as a potential molecular target for treating brain injury in sepsis clinical studies.

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

Establishment of predicting equation for individual sufentanil dosage postoperatively based on gene polymorphisms.

BACKGROUND: Postoperative analgesia is widely used for patients undergoing major surgeries. Individual differences in genetic polymorphisms may be obstructive factors for accurately anesthetics using. However, the equation for predicting sufentanil dosage postoperatively based on genetic design has been established yet. Our aim was to establish sufentanil dosage postoperatively prediction equation based on patients' genetic polymorphisms. METHODS: One hundred forty patients with total gastrectomy and radical resection of pulmonary carcinoma were included. To establish sufentanil dosage postoperatively for patients with gastric cancer, we collected patients' basic information and CYP3A4*1G, COMTVal158Met, OPRM1A118G, and ABCB1C3435T gene sequencing results. To verify this equation, we put patients' with lung cancer surgeries information into it. RESULTS: The sufentanil dosage prediction equation postoperatively was y = 4.104 - 0.222 × (gender) + 0.021 × (OPRM1A118G) + 0.249 × (ABCB1C3435T). Patients' with lung cancer surgeries information were substituted into it. The results showed no significant differences between predicted and actual sufentanil dosage (p > 0.05). CONCLUSION: We established the prediction equation for individual sufentanil dosage postoperatively based on gene polymorphisms. The results showed this prediction equation was valid, which might be used for different types of surgeries. We established an equation for individual dosage of sufentanil for postoperative analgesia based on gene polymorphisms. The results show that the prediction equation is valid, the information might be used for different types of postoperative analgesia, and the painful patients will have great potential safe and personalized pain control after analgesic therapy. It might also have potential as a clinical tool.

Knockdown of CENPK inhibits cell growth and facilitates apoptosis via PTEN-PI3K-AKT signalling pathway in gastric cancer.

Previous studies have indicated that centromere protein K (CENPK) is upregulated in several cancers and related to tumorigenesis. Nevertheless, the potential function of CENPK in gastric cancer (GC) remains unknown. Here, we investigated the function of CENPK on oncogenicity and explored its underlying mechanisms in GC. Our results showed that CENPK was dramatically overexpressed in GC and was associated with poor prognosis through bioinformatics analysis. We demonstrated that CENPK is upregulated in GC tissues and cell lines. Moreover, knockdown of CENPK significantly inhibited proliferation in vitro and attenuated the growth of implanted GCs in vivo. In addition, CENPK silencing induced G1 phase cell cycle arrest and facilitated apoptosis of GC cells. KEGG pathway analysis indicated that the PI3K-AKT signalling pathway was considerably enriched. Knockdown of CENPK decreased the expression of PI3K, p-Akt (Ser437) and p-GSK3ß (Ser9) in GC cells, and increased the expression of PTEN. In conclusion, this study indicated that CENPK was overexpressed in GC and may promote gastric carcinogenesis through the PTEN-PI3K-AKT signalling pathway. Thus, CENPK may be a potential target for cancer therapeutics in GC.

Novel key genes in triple-negative breast cancer identified by weighted gene co-expression network analysis.

Triple-negative breast cancer (TNBC) is a special subtype of breast cancer (BC) with poor prognosis. Although some molecular mechanisms of TNBC have been elucidated, the efficacy of current treatments is limited. Therefore, it is urgently demanded to screen for novel biomarkers and drug targets for TNBC. In this study, we obtained four independent data sets (GSE76250, GSE31448, GSE43358, and METABRIC) from the Gene Expression Omnibus (GEO) database and the cBioPortal website. In the GSE76250 data set, 890 differentially expressed genes were identified and weighted gene co-expression network analysis was performed based on them. Then, two preserved modules associated with the KI67 score were detected. Gene ontology and pathway enrichment analyses showed genes in the modules participated in some cancer-related biological processes or pathways. Non-SMC condensin I complex subunit G (NCAPG) and ATP-binding cassette subfamily A member 9 (ABCA9) were identified as hub genes of the modules, and the significance of hub genes was validated in the GSE43358 data set. Finally, their prognostic value was assessed by survival analysis. These findings suggested that NCAPG and ABCA9 may be the key genes of TNBC. Moreover, ABCA9 was first reported in TNBC. They deserved further studies.

Knockdown of AGGF1 inhibits the invasion and migration of gastric cancer via epithelial-mesenchymal transition through Wnt/ß-catenin pathway.

BACKGROUND: Angiogenic factor with G-patch and FHA domain 1 (AGGF1), as a newly identified human angiogenic factor, is overexpressed in some types of malignant tumors and closely associated with patient's prognosis. However, the mechanisms involved in the regulation of AGGF1 in gastric cancer (GC) still remain unclear. METHODS: In this study, AGGF1 level in GC tissues and cell lines was analyzed by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). After knockdown of AGGF expression by RNA interference in GC cell lines MKN-45 and MGC-803, wound healing and transwell assays were conducted to examine the effects of AGGF1 on migration and invasion. Tumor growth was assessed in a mouse xenograft model in vivo. Furthermore, expression levels of epithelial-mesenchymal transition (EMT) biomarkers and involvement of the Wnt/ß-catenin pathway were detected by western blot and qRT-PCR. RESULTS: Compared to those in normal groups, the protein and mRNA of AGGF1 expression levels were significantly higher both in GC tissues and cell lines (all P < 0.05). Knockdown of AGGF1 dramatically inhibited the invasion and migration of MKN-45 and MGC-803 cells (all P < 0.01) in vitro, and suppressed the tumor growth of nude mice xenograft model in vivo. Western blot revealed alterations in EMT biomarkers, suggesting the role of AGGF1 in EMT. Moreover, we found that downregulated expression of AGGF1 attenuated Wnt/ß-catenin related protein expression. CONCLUSIONS: Collectively, knockdown of AGGF1 inhibits the invasion and migration of gastric cancer via epithelial-mesenchymal transition through Wnt/ß-catenin pathway.

Paraoxonase 3 is involved in the multi-drug resistance of esophageal cancer.

BACKGROUND: Drug resistance prevents the effective treatment of cancers. DNA methylation has been found to participate in the development of cancer drug resistance. METHODS: We performed the wound-healing and invasion assays to test the effect of the paraoxonase gene PON3 on esophageal cancer (EC) cells. In addition, in vivo EC-derived tumor xenografts in nude mice were generated to test the effect of PON3 on the chemoresistance of EC cells. RESULTS: We found that PON3 is hypermethylated in drug-resistant EC cell line K150, which in-return down-regulates its expression. The following experiments by the forced changes of PON3 level in vitro and in vivo demonstrated that the PON3 expression negatively correlates with drug resistance in EC cells. Further wound-healing and invasion assays showed that PON3 suppresses the migration and invasion of EC cells. CONCLUSION: Our data established that PON3 is associated with the EC drug resistance, which may serve as a biomarker for the potential therapeutic treatment of EC.

Martrilin-3 (MATN3) Overexpression in Gastric Adenocarcinoma and its Prognostic Significance.

BACKGROUND The aim of this study was to investigate the expression level of martrilin-3 (MATN3) in patients with gastric adenocarcinoma (GAC) and to investigate the prognostic significance of MATN3. MATERIAL AND METHODS Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data were used to predict the expression and prognostic value of MATN3 mRNA in GAC patients. Seventy-six GAC patients had GAC tissue samples and paired adjacent normal tissue samples collected retrospectively to examine the MATN3 protein expression level by immunohistochemical staining. Furthermore, Kaplan-Meier univariate and Cox multivariate analyses were used to verify the correlation between MATN3 expression and clinicopathological parameters of GAC patients and the prognostic significance of MATN3. RESULTS The GEO and TCGA data predicted that MATN3 mRNA levels were significantly higher in GAC tissue compared to normal tissue (all p<0.05). Further survival analyses showed that GAC patients with high mRNA expression of MATN3 had significantly lower disease-free survival (DFS) and overall survival (OS) time than those with low mRNA expression of MATN3 (all p<0.05). Subsequent immunohistochemical staining results confirmed that the MATN3 protein levels in GAC tissues were highly expressed (p=0.000) compared to normal tissues. In addition, GAC patients with high protein expression of MATN3 had remarkably decreased OS compared to patients with low protein expression of MATN3 (p=0.000). Univariate and multivariate survival analyses revealed that MATN3 high expression could be used as an independent predictor of poor prognosis in GAC patients (all p=0.000). CONCLUSIONS This study confirmed that MATN3 protein was highly expressed in GAC patients, and MATN3 overexpression could be used as an independent predictor of poor prognosis in GAC patients.

Overexpression of Coiled-Coil Domain-Containing Protein 34 (CCDC34) and its Correlation with Angiogenesis in Esophageal Squamous Cell Carcinoma.

BACKGROUND The coiled-coil domain-containing proteins have been shown to have a series of functions in biological synthesis. Recent studies have found that CCDC34 is highly expressed in bladder cancer, but the underlying molecular mechanisms still remain unclear. Therefore, we performed the present study to assess the expression of the coiled-coil domain-containing protein 34 (CCDC34) in esophageal squamous cell carcinoma (ESCC) patients. We also explored the relationships between CCDC34 expression and clinicopathologic characteristics, tumor angiogenesis, and prognosis. MATERIAL AND METHODS We detected the expressions of CCDC34, VEGF, and MVD by immunohistochemical technique in 100 cases of ESCC and 80 cases of corresponding paracarcinomatous normal tissues. The relationship between CCDC34 expression and clinicopathologic characteristics, tumor angiogenesis, and prognosis were also explored. RESULTS The expression of CCDC34 protein was obviously increased in ESCC tissues, which was significantly correlated with sex (p=0.038), TNM stage (p=0.003), and lymphatic metastasis (p=0.024). In addition, we found that the expression of CCDC34 was an independent prognostic factor for ESCC patients. The overexpression of CCDC34 protein in ESCC was associated with tumor progression, angiogenesis, and poor survival. CONCLUSIONS Our results demonstrate that CCDC34 is overexpressed in ESCC and can be used as an independent parameter for indicating the poor prognosis of ESCC patients, suggesting that CCDC34 might be a new potential therapeutic target for ESCC patients in the future.

Prognostic Significance of Periostin and Mammalian Target of Rapamycin (mTOR) in Locally Advanced Esophageal Squamous Cell Carcinoma.

BACKGROUND Periostin and the mammalian target of rapamycin (mTOR) are involved in several cancers. This study aimed to evaluate the expression level of periostin and mTOR in locally advanced esophageal squamous cell carcinoma (ESCC) and to analyze their correlations with prognostic value. MATERIAL AND METHODS Expression levels of periostin and mTOR were examined by immunohistochemistry in locally advanced ESCC and corresponding adjacent normal tissue of 71 patients. The expression of periostin and mTOR were correlated with clinicopathologic characteristics by χ² test or Kruskal-Wallis analysis. The prognostic factors of periostin and mTOR on overall survival (OS) and disease-free survival (DFS) were assessed using Kaplan-Meier and Cox regression methods, respectively. RESULTS The high expression of periostin was significantly correlated to tumor stage (P=0.000), vascular invasion (P=0.027), differentiation (P=0.002), invasion depth (P=0.023), and lymph node metastasis (P=0.017). The high expression of mTOR was associated with tumor stage (P=0.001), lymphatic metastasis (P=0.014), and differentiation (P=0.036). Expression levels of periostin and mTOR was positively correlated (r=0.416, P=0.000). The OS and DFS in patients in the high-periostin group were significantly shorter than those in the low-periostin group, (both P<0.001). Similar results were found in mTOR analysis. Moreover, Cox regression analysis showed that the expressions of periostin and mTOR, along with tumor stage, were the independent factors affecting the survival time of ESCC patients. CONCLUSIONS Expressions of periostin and mTOR are related to multiple clinicopathologic features. High expression of periostin and mTOR were independent risk factors of ESCC patients, which might offer a potential target strategy for ESCC treatment in the future.

Relationship between Helicobacter pylori infection and vomiting induced by gastrointestinal cancer chemotherapy.

BACKGROUND: Nausea and vomiting are the most common adverse reactions to chemotherapy. AIM: To discuss the relationship between Helicobacter pylori and chemotherapy-induced nausea and vomiting (CINV). METHODS: A total of 112 patients with malignant tumours of the gastrointestinal tract was selected. Based on the 14C-urea breath test results, the patients were divided into H. pylori-positive (n = 59) and H. pylori-negative (n = 53) groups. Both groups received prophylactic antiemetic treatment during chemotherapy. The incidence of nausea and vomiting and their effects on the patients' life functions was recorded using the Multinational Association of Supportive Care in Cancer (MASCC) Antiemetic Tool (MAT) and the Functional Living Index Emesis (FLIE) from 0-120 h after chemotherapy. Records of the H. pylori-positive and H. pylori-negative groups were compared. RESULTS: The rates of nausea and vomiting remission were higher in the H. pylori -negative group than in the H. pylori -positive group. The proportions of no effect in daily life (NIDL) patients in the nausea and vomiting section were 73.4 and 75.5% in the H. pylori -negative group respectively. There was a higher proportion of NIDL patients in the H. pylori -negative group than in the H. pylori -positive group (P < 0.001, P = 0.046). A multivariate unconditional logistic regression analysis was performed, and the results showed that H. pylori infection was a factor affecting the nausea scores on the FLIE (odds ratio = 0.757, 95% confidence interval 0.597-0.960, P = 0.021). CONCLUSION: H. pylori infection in patients with cancer may be a factor that increases CINV.

[Prevalence of vitamin D insufficiency/deficiency among overweight and obese preschool children in Yuelu District of Changsha].

OBJECTIVE: To investigate the prevalence of vitamin D insufficiency/deficiency among 3-5 years old overweight and obese children in Yuelu district of Changsha and to give scientific suggestion for children health promotion.
 Methods: Based on the stratified cluster sampling method, 2 872 children aged 3-5 years old from Yuelu district were enrolled from Oct to Dec 2015. All participants have received biochemical and physical examination. According to the body mass index, the prevalence rates of vitamin D insufficiency [serum 25(OH)D level 20-<30 ng/mL] and deficiency [serum 25(OH)D level<20 ng/mL] among normal weight, overweight/obese children were calculated, respectively. Multivariate logistic regression was used to evaluate the association between overweight/obese and vitamin D insufficiency/deficiency.
 Results: The prevalence rates of vitamin D insufficiency/deficiency among children aged 3-5 years old were 39.6% (95% CI 37.8% to 41.4%) and 19.5% (95% CI 18.1% to 21.0%), respectively. Compared to children with normal weight, overweight/obese children had higher prevalence rate of vitamin D insufficiency [48.6% (95% CI 44.4% to 52.9%)] and deficiency [24.6% (95% CI 21.1% to 28.4%)] (P<0.017). After adjustment with confounding variables, the associations between overweight/obese and vitamin D insufficiency/deficiency were still statistically significant [for insufficiency ORadj=1.17 (95% CI 1.06 to 1.43); for deficiency ORadj=1.22 (95% CI 1.12 to 1.51)].
 Conclusion: Compared with normal weight children, overweight/obese children have higher prevalence rate of vitamin D insufficiency/deficiency. More attention should be paid to those populations for prevention of vitamin D insufficiency/deficiency.

Xanthohumol Promotes Skp2 Ubiquitination Leading to the Inhibition of Glycolysis and Tumorigenesis in Ovarian Cancer.

Ovarian cancer is a common, highly lethal tumor. Herein, we reported that S-phase kinase-associated protein 2 (Skp2) is essential for the growth and aerobic glycolysis of ovarian cancer cells. Skp2 was upregulated in ovarian cancer tissues and associated with poor clinical outcomes. Using a customized natural product library screening, we found that xanthohumol inhibited aerobic glycolysis and cell viability of ovarian cancer cells. Xanthohumol facilitated the interaction between E3 ligase Cdh1 and Skp2 and promoted the Ub-K48-linked polyubiquitination of Skp2 and degradation. Cdh1 depletion reversed xanthohumol-induced Skp2 downregulation, enhancing HK2 expression and glycolysis in ovarian cancer cells. Finally, a xenograft tumor model was employed to examine the antitumor efficacy of xanthohumol in vivo. Collectively, we discovered that xanthohumol promotes the binding between Skp2 and Cdh1 to suppress the Skp2/AKT/HK2 signal pathway and exhibits potential antitumor activity for ovarian cancer cells.

Multivariate prognostic index and triplet regimen efficacy predictive index in locally advanced and metastatic gastric cancer: pooled analysis from three clinical trials using individual patient data.

Background: To construct an effective prognostic index to predict overall survival (OS) and triplet regimen efficacy for advanced gastric cancer (AGC) patients treated with platinum-based and fluorouracil-based chemotherapy. Objectives: Between 2011 and 2021, 679 patients from two randomized phase III trials and one phase II trial were enrolled. Designs: We collected 11 baseline clinicopathological and 14 hematological parameters to establish a prognostic index. Methods: Univariate and multivariate Cox analyses were used to screen prognostic factors, and a prognostic index nomogram was conducted. Results: Seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic nomogram named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in the low-risk group (median OS, 15.5 versus 8.0 months, p < 0.001). The areas under the curve of the FARS index for 1-, 2-, and 3-year OS were 0.70, 0.72, and 0.77, respectively. A validation and external cohort verified the prognostic value of the FARS index. Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (p = 0.018). Conclusion: The constructed FARS index to predict the OS of AGC patients and the TRIS index to screen out the dominant population for triplet regimens can be used to aid clinical decision-making and individual risk stratification.

A prognostic index in locally advanced and metastatic gastric cancer To date, no recognized systematic prognostic score has been established for advanced gastric cancer (AGC). Our research aims to construct an effective prognostic index to predict overall survival (OS) for AGC patients to aid clinical decision-making and individual risk stratification. In our research, seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic index named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in low-risk group (median OS, 15.5 months vs. 8.0 months, P < 0.001). Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (P = 0.018).

Correlation between the CD4+CD25high regulatory T cells and the outcome of chemotherapy in advanced esophageal carcinoma.

BACKGROUND/AIMS: In patients with esophageal carcinoma, local immune suppression and the expression of soluble immunosuppressive factors have been observed. We aimed to investigate the correlation between the level of CD4+CD25high regulatory T (Treg) cell and the outcome of chemotherapy in advanced esophageal carcinoma. METHODOLOGY: Forty-eight cases of advanced esophageal carcinoma patients were enrolled from June 2006 to December 2008. CD3+CD8+ T cell, CD3+CD4 T cell, CD4+CD25+ Treg cell and NK cell were determined before and after chemotherapy. After two cycles of chemotherapy, its effect was evaluated and the survival time was followed-up. RESULTS: Significant downregulation of CD4+CD25high Treg cell was noted in the advanced esophageal carcinoma patients after chemotherapy (p<0.05). However, there were no obvious differences in the CD3+CD8+ T cell, CD3+CD4+ T cell and NK cell before and after chemotherapy (p>0.05). Log-rank test showed age and the decrease of CD4+CD25high Treg cell after chemotherapy correlated with the median survival time (p<0.05). The COX multivariate analysis also suggested that the decrease of CD4+CD25high Treg cell after chemotherapy was an independent prognostic factor (p<0.05). CONCLUSIONS: Our results suggest that the downregulation of CD4+CD25high Treg cell after chemotherapy may be a predictor for the outcome of chemotherapy in advanced esophageal carcinoma patients.

Pretreatment lymphocyte-monocyte ratio (LMR) as a superior predictor of short-term progression outcomes in patients with gastric cancer receiving second- and later-line apatinib regimens.

PURPOSE: Lymphocyte-monocyte ratio (LMR) has previously been used as a prognostic predictor in various solid tumors. This research aims in comparing the prognostic predictive Please check and conability of several inflammatory parameters and clinical parameters to validate further the excellent prognostic value of LMR in patients with gastric cancer treated with apatinib. METHODS: Monitor inflammatory, nutritional parameters and tumor markers. Cutoff values of the parameters concerned were identified with the X-tile program. Subgroup analysis was made via Kaplan-Meier curves, and univariate and multivariate Cox regression analyses were used to find independent prognostic factors. The nomogram of logistic regression models was constructed according to the results. RESULTS: A total of 192 patients (115 divided into training group and 77 into validation group) who received the second- or later-line regimen of apatinib were retrospectively analyzed. The optimal cutoff value for LMR was 1.33. Patients with high LMR (LMR-H) were significantly longer than those with low LMR (LMR-L) in progression-free survival (median 121.0 days vs. median 44.5 days, P < 0.001). The predictive value of LMR was generally uniform across subgroups. Meanwhile, LMR and CA19-9 were the only hematological parameters with significant prognostic value in multivariate analysis. The area under the LMR curve (0.60) was greatest for all inflammatory indices. Adding LMR to the base model significantly enhanced the predictive power of the 6-month probability of disease progression (PD). The LMR-based nomogram showed good predictive power and discrimination in external validation. CONCLUSION: LMR is a simple but effective predictor of prognosis for patients treated with apatinib.

Pucotenlimab in patients with advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A multicenter phase 2 study.

We report a multicenter, phase 2 study evaluating the efficacy of pucotenlimab, an anti-PD-1 antibody, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, and potential biomarkers for response. Overall, 100 patients with previously treated, advanced solid tumors centrally confirmed as dMMR or MSI-H received pucotenlimab at 200 mg every 3 weeks. The most common cancer type is colorectal cancer (n = 71). With a median follow-up of 22.5 months, the objective response rate is 49.0% (95% confidence interval 38.86%-59.20%) as assessed by the independent review committee, while the median progression-free survival and overall survival have not been reached. Grade ≥3 treatment-related adverse events were observed in 18 patients. For the biomarker analysis, responders are enriched in patients with mutations in the KMT2D gene. Pucotenlimab is an effective treatment option for previously treated advanced dMMR/MSI-H solid tumors, and the predictive value of KMT2D mutation warrants further research. This study is registered with ClinicalTrials.gov: NCT03704246.