Anti-PD-L1 antibody TQB2450 combined with tyrosine kinase receptor inhibitor AL2846 for immunotherapy-refractory advanced hepatocellular carcinoma and esophageal squamous cell carcinoma: A prospective phase 1b cohort study.

BACKGROUND: Effective systemic therapy remains limited for advanced esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC), particularly after prior failed treatment with immune checkpoint inhibitors (ICIs). Theoretically, a combination of tyrosine kinase inhibitors (TKIs) with ICIs may restore immunotherapy sensitivity. METHODS: In this phase 1b study, patients received AL2846, an antiangiogenic TKI with multiple targets (c-MET, VEGFR1, c-KIT, Axl, RET, KDR, and VEGFR3), in combination with an anti-PD-L1 antibody (TQB2450) until disease progression, intolerable toxicity, death, or discontinuation for any cause. The primary end points included overall response rate (ORR) and safety, with secondary end points encompassing progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response. RESULTS: Between November 2021 and September 2022, 18 patients with ESCC and 15 patients with HCC, whose ORR was 11.1% (95% confidence interval [CI], 3.1%-32.8%) and 0%, respectively, were enrolled. Adverse events (AEs) of any grade and treatment-related AEs were documented in 32 patients (97.0%) and 31 patients (93.9%), respectively. Grade 3 or higher AEs were observed in 10 patients (30.3%), with vomiting (6.1%) and infectious pneumonia (9.1%) being the most prevalent. Median PFS and OS values were 3.22 months (95% CI, 1.35-5.68 months) and 5.98 months (95% CI, 3.71-8.87 months), respectively, in patients with ESCC, and 5.55 months (95% CI, 2.66 months to not evaluable [NE]) and 16.72 months (95% CI, 4.86 months to NE), respectively, in patients with HCC. The DCRs were 66.7% (95% CI, 43.75%-83.72%) in patients with ESCC and 73.3% (95% CI, 48.05%-89.10%) in patients with HCC. CONCLUSIONS: Combined TQB2450 and AL2846 therapy exhibited a favorable safety profile in immunotherapy-refractory patients with advanced ESCC and HCC.

Combinational zimberelimab plus lenvatinib and chemotherapy for alpha-fetoprotein elevated, advanced gastric cancer patients (AFPGC): a phase 1 dose-escalation study.

BACKGROUND: Alpha-fetoprotein elevated gastric cancer (AFPGC) got growing interests for its aggressive nature and unfavorable prognosis. Here, a phase 1 dose escalation study was conducted to evaluate safety and efficacy of zimberelimab (GLS-010, anti-PD-1) plus lenvatinib and chemotherapy (XELOX) as the first-line treatment for AFPGC. METHODS: Histologically confirmed HER2-negative, advanced GC patients with elevated serum AFP level (≥ 20 ng/ml) were screened. Using a 3 + 3 dose escalation design, patients were administered varying doses of lenvatinib (12, 16, 20 mg) with GLS-010 and XELOX. The primary endpoints were safety and determination of recommended phase II dose (RP2D). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and disease control rate. RESULTS: Nine patients were enrolled with no dose-limiting toxicities observed. Most frequent treatment-related AEs were fatigue (55.6%), hand-foot syndrome (55.6%) and rash (55.6%), and no grade ≥ 4 AEs were reported. All patients exhibited disease control with ORR reaching 33.3%. The median PFS and OS reached 7.67 months (95% CI 4.07-11.27) and 13.17 months (95% CI 2.78-23.56), respectively. Serum AFP level was found correlated with therapeutic responses. Further 16s rRNA sequencing analysis demonstrated altered gut microbiota with elevated abundance of Lachnospiraceae bacterium-GAM79 and Roseburia hominis A2-183. CONCLUSIONS: GLS-010 plus lenvatinib and XELOX demonstrated a manageable safety profile with promising efficacy for AFPGC. With RP2D of lenvatinib determined as 16 mg, further expansion cohort is now ongoing. Translational investigation suggested that serum AFP can be indictive for therapeutic responses and certain microbiota species indicating favorable responses to immunotherapy was elevated after the combinational treatment.

Combined score based on plasma fibrinogen and platelet-lymphocyte ratio as a prognostic biomarker in esophageal squamous cell carcinoma.

BACKGROUND: Increasing evidence has showed that inflammatory biomarkers, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and fibrinogen can be used as predictors in the prognosis of esophageal squamous cell carcinoma (ESCC). The aim of this study was to explore prognostic value of these biomarkers and evaluate the clinicopathological and prognostic significance of combined score based on plasma fibrinogen and platelet-lymphocyte ratio (F-PLR score). METHODS: A total of 506 patients with ESCC were enrolled in this study. Harrell's concordance index (c-index) was used to determine the optimal cut-off values of these markers and evaluate their prognostic significance. The relationship between factors with survival rates (including overall survival [OS] and disease-free survival [DFS]) was explored by Kaplan-Meier curve, univariate analysis and multivariate cox hazard analysis. RESULTS: Our result indicated that high F-PLR score was significantly associated with longer tumor length and deeper depth of tumor invasion (p < 0.01). The result of Cox multivariable analysis showed that F-PLR score was an independent prognostic factor for OS (p = 0.002) and DFS (p = 0.003). In addition, F-PLR score presented the greater c-index values for OS and DFS compared with NLR, PLR and fibrinogen level. Our result also showed that the c-index values for OS and DFS were both greater in TNM + F-PLR than those in TNM stage alone. CONCLUSIONS: In conclusion, F-PLR score is a predictive biomarker for prognosis in patients with ESCC.

Chemotherapy re-use versus anti-angiogenic monotherapy as the third-line treatment of patients with metastatic colorectal cancer: a real-world cohort study.

BACKGROUND: There are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use in third-line setting is a common option in clinical practice. This study aimed to investigate the efficacy of third-line chemotherapy re-use by the comparison with that of anti-angiogenic monotherapy, and further find the population more suitable for third-line chemotherapy. METHODS: Using electronic medical records of patients with mCRC, a retrospective cohort study was conducted. A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting as control group were retrospectively collected. Baseline characteristics were analyzed using the χ² test or the Fisher's exact test. ROC curve and surv_cutpoint function of 'survminer' package in R software were used to calculate the cut-off value. Survival curves were plotted with the Kaplan-Meier method and were compared using the log-rank test. The Cox proportional hazard regression model was used to analyze the potential risk factors. RESULTS: A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting were retrospectively collected. Chemotherapy rechallenge was recorded in 93 patients (93/143, 65.0%), and the remaining patients chose new chemotherapeutic drugs that had not been previously used, including irinotecan-based (22/50), oxaliplatin-based (9/50), raltitrexed (9/50), gemcitabine (5/50) and other agents (5/50). The ORR and DCR of third-line chemotherapy reached 8.8%, 61.3%, respectively (anti-angiogenic monotherapy group: ORR 2.6%, DCR 47.4%). The mPFS and mOS of patients receiving chemotherapy were 4.9 and 12.0 m, respectively (anti-angiogenic monotherapy group: mPFS 2.7 m, mOS 5.2 m). Subgroup analyses found that patients with RAS/RAF mutation, longer PFS (greater than 10.6 m) in front-line treatment or larger tumor burden had better prognosis with third-line chemotherapy rather than anti-angiogenic monotherapy. CONCLUSIONS: Third-line chemotherapy re-use was effective in mCRC. Those with more aggressive characteristics (RAS/RAF mutant, larger tumor burden) or better efficacy of previous chemotherapy (longer PFS) were more appropriate for third-line chemotherapy, rather than anti-angiogenic monotherapy.

Prusogliptin (DBPR108) monotherapy in treatment-naïve patients with type 2 diabetes: A randomized, double-blind, active and placebo-controlled, phase 3 study.

AIM: This study aimed to assess the efficacy and safety of prusogliptin (DBPR108), a novel and highly selective dipeptidyl peptidase-4 inhibitor, in individuals with type 2 diabetes who had not been using glucose-lowering agents regularly for the 8 weeks before the screening period. MATERIALS AND METHODS: In this multicentre, randomized, double-blind, phase 3 study, adult patients with type 2 diabetes were randomly assigned to receive either DBPR108 100 mg, sitagliptin 100 mg, or placebo once daily during the initial 24-week double-blind treatment period, followed by a 28-week open-label extension period during which all patients received DBPR108 100 mg once daily. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) levels from baseline to week 24. RESULTS: In total, 766 patients were enrolled and received DBPR108 100 mg (n = 462), sitagliptin 100 mg (n = 152), or placebo (n = 152). The mean age of all patients was 54.3 ± 10.5 years, with 58% being men. The median duration of type 2 diabetes was 0.38 (0.02, 2.65) years, and the mean HbA1c (SD) at baseline was 7.94% (0.62), 7.88% (0.61) and 7.83% (0.59) for DBPR108, sitagliptin and placebo groups, respectively. At week 24, the least square mean (SE) changes from baseline in HbA1c were -0.63% (0.04%) for DBPR108, -0.60% (0.07%) for sitagliptin and -0.02% (0.07%) for placebo. The mean treatment difference between DBPR108 and placebo was -0.61% (95% CI -0.77% to -0.44%), and between DBPR108 and sitagliptin was -0.03% (95% CI -0.19% to 0.13%). These results indicate that DBPR108 was superior to placebo and non-inferior to sitagliptin. DBPR108 also significantly reduced fasting and postprandial plasma glucose levels and had little effect on body weight. The mean (SD) changes in HbA1c from baseline to week 52 were -0.50% (0.97%) for the DBPR108 group, -0.46% (0.96%) for the sitagliptin group and -0.41% (0.95%) for the placebo group. The incidence of adverse events was comparable across all three groups. CONCLUSIONS: DBPR108 showed superiority to placebo and non-inferiority to sitagliptin in terms of glycaemic control over the initial 24 weeks in treatment-naïve patients with type 2 diabetes. Furthermore, its efficacy was sustained for up to 52 weeks.

Sintilimab Plus Apatinib and Chemotherapy as Second­/Third-Line treatment for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a prospective, Single-Arm, phase II trial.

BACKGROUND: The prognosis of patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer remains poor. Given the robust development of immunotherapy and targeted therapy during the last decades, we aimed to investigate if the combination of traditional second-line chemotherapy with sintilimab and apatinib could bring survival benefits for these patients. METHODS: In this single-center, single-arm, phase II trial, patients with previously treated advanced gastric or GEJ adenocarcinoma received specific dose level of intravenous paclitaxel or irinotecan (investigator's choice), 200 mg intravenous sintilimab on day 1, and 250 mg oral apatinib once daily continuously in each cycle until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoints were objective response rate and progression-free survival. The secondary endpoints were mainly overall survival and safety. RESULTS: From May 2019 to May 2021, 30 patients were enrolled. At the data cutoff date (March 19, 2022), the median follow-up duration was 12.3 months and 53.6% (95% CI, 33.9-72.5%) patients achieved objective response. The median progression-free survival and overall survival were 8.5 months (95% CI, 5.4-11.5) and 12.5 months (95% CI, 3.7-21.3), respectively. Grade 3-4 adverse events included hematological toxicities, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated alkaline phosphatase, elevated gamma-glutamyl transpeptidase, hyperbilirubinemia and proteinuria. The most frequent grade 3-4 adverse event was neutropenia (13.3%). No serious treatment-related adverse events or treatment-related deaths occurred. CONCLUSION: Sintilimab plus apatinib and chemotherapy demonstrates promising anti-tumor activity with manageable safety profile in patients with previously treated advanced gastric or GEJ cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05025033, 27/08/2021.

The optimal time of starting adjuvant chemotherapy after curative surgery in patients with colorectal cancer.

BACKGROUND: Postoperative adjuvant chemotherapy (AC) is now well-accepted as standard for high-risk stage II and stage III colorectal cancer (CRC) patients, however the optimal time to initiate AC remains elusive. METHODS: A comprehensive literature search was performed using the PubMed and Embase databases. The Hazard ratio (HR) with the corresponding 95% confidence interval (CI) was used as an effect measure to evaluate primary endpoints. All analyses were conducted using Stata software version 12.0 with the Random-effects model. RESULTS: A total of 30 studies were included in our study. Upon comparison on overall survival (OS), we identified that delaying the initiation of AC for > 8 weeks after operation was significantly associated with poor OS (HR: 1.37; 95% CI: 1.27-1.48; P < 0.01). The poor prognostic value of AC delay for > 8 weeks was not undermined by subgroup analysis based on region, tumor site, sample size and study quality. No obvious differences were observed in survival between AC within 5-8 weeks and ≤ 4 weeks (HR: 1.03; 95% CI: 0.96 -1.10; P = 0.46). Moreover, two studies both highlighted that the survival benefit of AC was still statistically significant when AC was applied 5-6 months after surgery compared with the non-chemotherapy group. CONCLUSIONS: Delaying the initiation of AC for > 8 weeks after surgery was significantly associated with poor OS. AC started within 8 weeks after surgery brought more benefits to CRC patients. There were no obvious differences in survival benefits between AC within 5-8 weeks and ≤ 4 weeks. Compared to patients not receiving AC after surgery, a delay of approximately 5-6 months was still useful to improve prognosis.

Efficacy and safety of janagliflozin monotherapy in Chinese patients with type 2 diabetes mellitus inadequately controlled on diet and exercise: A multicentre, randomized, double-blind, placebo-controlled, Phase 3 trial.

AIMS: To evaluate the efficacy and safety of janagliflozin, a selective renal sodium-glucose cotransporter-2 inhibitor, as monotherapy in drug-naive Chinese patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This Phase 3 trial included a 24-week, multicentre, randomized, double-blind, placebo-controlled period, followed by a 28-week extension period. A total of 432 patients with glycated haemoglobin (HbA1c) levels ≥7.0% (53 mmol/mol) and ≤10.5% (91 mmol/mol) were randomized (1:1:1) to receive once-daily placebo, 25 mg or 50 mg janagliflozin. After 24 weeks, patients on placebo were switched and re-randomized (1:1) to 25 mg or 50 mg janagliflozin, whereas patients on janagliflozin maintained the initial therapy. The primary endpoint was change from baseline in HbA1c after 24 weeks. RESULTS: At Week 24, the placebo-adjusted least squares mean changes in HbA1c were -0.80% (95% confidence interval [CI] -0.98% to -0.62%)/-8.7 mmol/mol (95% CI -10.7 mmol/mol to -6.8 mmol/mol) and -0.88% (95% CI -1.06% to -0.70%)/-9.6 mmol/mol (95% CI -11.6 mmol/mol to -7.7 mmol/mol), respectively (P < 0.001 for both). A higher proportion of patients achieved HbA1c <7.0% (53 mmol/mol) with janagliflozin 25 mg and janagliflozin 50 mg compared with placebo (47.2%, 49.3%, and 23.5%, respectively). Both janagliflozin doses significantly decreased fasting plasma glucose, 2-hour postprandial glucose, body weight and systolic blood pressure, as well as increased high-density lipoprotein (HDL) cholesterol and insulin sensitivity compared with placebo (P < 0.05 for all). The trends in improvement of these variables were sustained during the 28-week extension period. Overall incidences of adverse events were 67.8%, 71.5% and 60.7% with janagliflozin 25 mg, janagliflozin 50 mg and placebo, respectively. The incidence of urinary tract infections and genital fungal infections was low. No severe hypoglycaemia or ketoacidosis occurred. CONCLUSIONS: Janagliflozin 25 mg and 50 mg monotherapy once-daily effectively improved glycaemic control, reduced body weight and blood pressure, improved HDL cholesterol and insulin sensitivity, and was generally well tolerated.

Treatment of Morel-Lavallée Lesions (MLLs) with Mesh Incisions Combined with Quilting Sutures and Negative Pressure Wound Therapy (NPWT).

Purpose: The objective of this retrospective study was to evaluate the clinical effects of a novel treatment approach for Morel-Lavallée lesions (MLL) using a combination of suturing techniques and Negative Pressure Wound Therapy (NPWT) with mesh incisions. To summarize the clinical effects of a combination of suturing techniques and (Negative Pressure Wound Therapy) NPWT on the wall of Morel-Lavallée lesions (MLL) fibrotic pseudocapsules with mesh incisions in the treatment of MLLs. A retrospective analysis was performed on MLL patients from April 2017 to March 2021. Methods: This a retrospective case-control study and thirteen MLL patients were included in this retrospective analysis conducted between April 2017 and March 2021, who were treated with mesh incisions on the wall of the pseudocapsule, quilting suturing to degloved soft tissues, and NPWT. Physical examination, MRI, or ultrasound before surgery confirmed the diagnosis. Wound healing, secondary infection, recurrence, visual analog scale (VAS) scores before and after surgery, and skin and soft tissue condition were observed and evaluated. Results: The combination of mesh incisions, quilting sutures, and NPWT led to successful wound healing in 11 out of 13 cases without recurrent hematoma or secondary infection. Visual analog scale (VAS) scores significantly decreased after the operation, and the aesthetic and tactile qualities of the injured area improved. One case of skin and soft tissue necrosis infection before the operation, which healed after second-stage full-thickness skin grafting, 1 case healed after a dressing change, and the remaining 11 cases had wounds that healed by the first stage without secondary infection or recurrent hematoma formation. VAS scores decreased significantly after the operation, the appearance of the injured area was as expected, and the skin feel and elasticity recovered satisfactorily. Conclusion: The study demonstrates that the mesh incision technique, along with mattress sutures and NPWT, presents a feasible and effective approach for treating MLL with fibrotic pseudocapsules. This could shorten healing times, reduce risk of complications, and improve patient satisfaction.

A Modified Negative Pressure Wound Therapy Reduces the Occurrence of Tension Blisters Around Negative Pressure Dressings.

Background: To date, there is no effective solution for preventing the formation of blisters around negative-pressure wound dressings. In this study, we aim to address this problem and identify techniques to improve the negative-pressure drainage technique. Methods: A total of 129 patients from 2021.11 to 2022.11 who were previously treated in Fuyang People's Hospital were included in this retrospective analysis. All patients had negative-pressure drainage dressings applied to their wounds after undergoing thorough wound debridement. The patients were divided into the following groups: a traditional treatment group and a modified treatment group. The traditional treatment group comprised 60 patients who received negative-pressure wound therapy (NPWT) and a modified treatment group comprised 69 patients who received NPWT plus Vaseline gauze. The dressing coverage area, wound location, incidence of blisters around the dressing 3 days after NPWT, wound infection rate, and length of hospitalization were recorded. The incidence of blisters, wound infection rate, and wound location in the 2 groups were included as the categorical data and were compared using a chi-squared test. The dressing coverage area and length of hospitalization in the 2 groups were included as the quantitative data and were compared using an independent samples t test or with the Mann-Whitney test if the data were abnormally distributed. Results: The incidence rates of blisters in the traditional and modified treatment groups were 33.3% (20/60) and 13.0% (9/69), respectively, displaying a statistically significant difference (χ2 = 7.581, P = .006). The infection rates of the 2 groups were 38.3% (23/60) and 20.3% (14/69), respectively, showing a statistically significant difference (χ2 = 5.108; P = .024). The lengths of hospitalization in the 2 groups were 26.05 ± 14.74 days and 18.17 ± 7.54 days, respectively, showing a statistically significant difference (t = 3.892; P = .000). The dressing coverage areas were 150 cm2 (88.75 cm2, 600 cm2) and 150 cm2 (124 cm2, 600 cm2), respectively, showing no statistical difference (P = .759). Conclusion: Modified NPWT can effectively reduce the incidence of blisters, length of hospitalization, and infection rate of patients.

HSP90 promotes radioresistance of cervical cancer cells via reducing FBXO6-mediated CD147 polyubiquitination.

HSP90 inhibition might be a promising strategy to overcome the radioresistance of some cancers. In the current study, we further explored the mechanisms of HSP90 in regulating the radiosensitivity of cervical cancer cells. Bioinformatic analysis was performed based on data from TCGA-CESC. Cellular and molecular studies were conducted using CaSki and SiHa and the derived radioresistant (RR) subclones. Through a proteomics screen, we identified HSP90 chaperones (both HSP90α and HSP90ß) as CD147-binding partners supporting its stabilization. Targeting HSP90 sensitized CaSki-RR and SiHa-RR cancer cells to irradiation partially through CD147 destabilization. Mechanistically, HSP90 interacts with FBXO6 and reduces FBXO6-mediated proteasomal degradation of CD147. Enforced FBXO6 overexpression also sensitized CaSki-RR and SiHa-RR cancer cells to irradiation. These effects were enhanced using 17-AAG treatment but were weakened by CD147 overexpression. Survival analysis further confirmed the association between high FBXO6 expression and favorable progression-free survival among patients with cervical cancer. In conclusion, this study showed that HSP90 promotes radioresistance of cervical cancer cells partially via reducing FBXO6 mediated CD147 polyubiquitination. These findings help to explain why HSP90 inhibitor exerts radio-sensitizing effects in cervical cancer.

Exosomal miR-208b related with oxaliplatin resistance promotes Treg expansion in colorectal cancer.

Oxaliplatin resistance is a challenge in the treatment of colorectal cancer (CRC) patients. Regulatory T cells (Tregs) are well known for their immunosuppressive roles, and targeting Tregs is an effective way to improve chemosensitivity. Exosome-delivered microRNA (miRNA) might be used as a potential biomarker for predicting chemosensitivity. However, the relationship between Tregs and exosomal miRNAs remains largely unknown. TaqMan low-density array was performed to screen the differentially expressed serum miRNAs from pooled serum of patients who had FOLFOX treatment. Differential expression was validated using qRT-PCR in individual samples. Exosomes were isolated by sequential differential centrifugation, and they were verified by transmission electron microscopy. The RNA and protein levels were determined by quantitative real-time PCR and western blotting. A mouse xenograft model was adopted to evaluate the correlation between exosome-derived miR-208b and Tregs in vivo. We demonstrated that circulating miR-208b is a non-invasive marker for predicting FOLFOX sensitivity in CRC. miR-208b in colon cancer was secreted by tumor cells in the pattern of exosomes, and oxaliplatin-resistant cells showed the most obvious phenomenon of miR-208b increase. Colon cancer cell-secreted miR-208b was sufficiently delivered into recipient T cells to promote Treg expansion by targeting programmed cell death factor 4 (PDCD4). Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-208b resulted in tumor growth and oxaliplatin resistance. Our results demonstrate that tumor-secreted miR-208b promotes Treg expansion by targeting PDCD4, and it may be related to a decrease of oxaliplatin-based chemosensitivity in CRC. These findings highlight a potential role of exosomal miR-208b as a predictive biomarker for oxaliplatin-based therapy response, and they provide a novel target for immunotherapy.

CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer.

BACKGROUND: Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including exosomes. Yet, the role of CAFs in regulating lipid metabolism as well as ferroptosis of cancer cells is still unexplored and remains enigmatic. METHODS: Ferroptosis-related genes in gastric cancer (GC) were screened by using mass spectrum; exosomes were isolated by ultra-centrifugation and CAF secreted miRNAs were determined by RT-qPCR. Erastin was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring lipid-ROS, cell viability and mitochondrial membrane potential. RESULTS: Here, we provide clinical evidence to show that arachidonate lipoxygenase 15 (ALOX15) is closely related with lipid-ROS production in gastric cancer, and that exosome-miR-522 serves as a potential inhibitor of ALOX15. By using primary stromal cells and cancer cells, we prove that exosome-miR-522 is mainly derived from CAFs in tumor microenvironment. Moreover, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was found to mediate miR-522 packing into exosomes, and ubiquitin-specific protease 7 (USP7) stabilizes hnRNPA1 through de-ubiquitination. Importantly, cisplatin and paclitaxel promote miR-522 secretion from CAFs by activating USP7/hnRNPA1 axis, leading to ALOX15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately result in decreased chemo-sensitivity. CONCLUSIONS: The present study demonstrates that CAFs secrete exosomal miR-522 to inhibit ferroptosis in cancer cells by targeting ALOX15 and blocking lipid-ROS accumulation. The intercellular pathway, comprising USP7, hnRNPA1, exo-miR-522 and ALOX15, reveals new mechanism of acquired chemo-resistance in GC.

Rational design and synthesis of magnetic covalent organic frameworks for controlling the selectivity and enhancing the extraction efficiency of polycyclic aromatic hydrocarbons.

A series of three-dimensional magnetic covalent organic frameworks were designed and synthesized via monomer selection, coating thickness optimization, and composite strategy transformation. Their structure properties including morphology, functional group, surface area, and pore size were characterized. The relationship between the structural properties and analytical performance was systematically investigated by density functional theory calculation and batch extraction experiments for polycyclic aromatic hydrocarbons. It is proven that the extractant modified by monomer 1,4-phthalaldehyde provides a hizgh affinity for high molecule weight polycyclic aromatic hydrocarbons and the right balance between extraction and elution efficiency. The relationship between coating thickness and mass transfer rate of polycyclic aromatic hydrocarbons was studied by accurate tuning of coating layers via layer-by-layer method. A mathematical model was derived and employed to determine that two coating layers were sufficient to provide the highest extraction efficiency with the shortest equilibrium time. The extractants synthesized by two different composite strategies (layer-by-layer and one-step) show opposite selectivity for polycyclic aromatic hydrocarbons. After optimization of the extraction conditions, dispersed solid-phase extraction coupled with gas chromatography-mass spectroscopy method was developed providing a wide linear range (5-500 ng L-1), good linearity (R2 > 0.9923), high precision in intra-day (RSD% < 8.2%) and inter-day (RSD% < 12.3%) detection, and low detection limits (1.5-15.1 ng L-1). The method was applied to the simultaneous determination of 16 polycyclic aromatic hydrocarbons with acceptable recoveries, which were 87-109% for groundwater, 83-116% for East Lake water, and 82-116% for Yangtze River water samples.

Increasing soluble dietary fiber content and antioxidant activity of wheat bran through twin-screw extrusion pretreatment.

As a by-product during flour production, wheat bran is mainly used as raw material for fodder or fermentation. In the present work, wheat bran was extruded with different moisture conditions and the consequently chemical component, absorption capacity, and antioxidant activity of treated wheat bran were analyzed. Results showed that extrusion decreased the particle size and crystallinity of wheat bran, but increased the soluble dietary fiber content of which from 3.08% to 11.78%. Meanwhile, water holding capacity, oil holding capacity for peanut oil and lard, and swelling capacity of WB-W-G-Na reached 5.67 g/g, 3.34 g/g, 3.58 g/g and 4.3 mL/g, respectively. Moreover, DPPH radical scavenging activity of WB-W-G-Na increased from 6.8% to 18.4% and hydroxyl radical scavenging activity increased from 5.3% to 15.9%. Overall, this work provides an excellent pretreatment method for increasing the functional activities of wheat bran in the food industry.

Oral microbiome and risk of malignant esophageal lesions in a high-risk area of China: A nested case-control study.

OBJECTIVE: We aimed to prospectively evaluate the association of oral microbiome with malignant esophageal lesions and its predictive potential as a biomarker of risk. METHODS: We conducted a case-control study nested within a population-based cohort with up to 8 visits of oral swab collection for each subject over an 11-year period in a high-risk area for esophageal cancer in China. The oral microbiome was evaluated with 16S ribosomal RNA (rRNA) gene sequencing in 428 pre-diagnostic oral specimens from 84 cases with esophageal lesions of severe squamous dysplasia and above (SDA) and 168 matched healthy controls. DESeq analysis was performed to identify taxa of differential abundance. Differential oral species together with subject characteristics were evaluated for their potential in predicting SDA risk by constructing conditional logistic regression models. RESULTS: A total of 125 taxa including 37 named species showed significantly different abundance between SDA cases and controls (all P<0.05 & false discovery rate-adjusted Q<0.10). A multivariate logistic model including 11 SDA lesion-related species and family history of esophageal cancer provided an area under the receiver operating characteristic curve (AUC) of 0.89 (95% CI, 0.84-0.93). Cross-validation and sensitivity analysis, excluding cases diagnosed within 1 year of collection of the baseline specimen and their matched controls, or restriction to screen-endoscopic-detected or clinically diagnosed case-control triads, or using only bacterial data measured at the baseline, yielded AUCs>0.84. CONCLUSIONS: The oral microbiome may play an etiological and predictive role in esophageal cancer, and it holds promise as a non-invasive early warning biomarker for risk stratification for esophageal cancer screening programs.

Effectiveness of Intensive Endoscopic Screening for Esophageal Cancer in China: A Community-Based Study.

Evidence is required to evaluate the effectiveness of population-level endoscopic screening for esophageal cancer (EC). In this study, 5,632 permanent residents aged 25-65 years from 6 villages in Hua County, Henan Province, China, were defined as the screening cohort and were offered intensive endoscopic screening. Residents of all 914 remaining villages in Hua County were included as the control cohort, and age-sex standardization was used to calculate the expected numbers of EC and upper gastrointestinal (GI) tract cancer cases and deaths in the screening cohort. The effectiveness of screening was assessed by comparing observed numbers of cases and deaths with expected numbers after 9-year follow-up of these screened subjects (2007-2016). In the screening cohort, 23 upper GI cancers (including 16 ECs) and 10 upper GI cancer deaths (including 5 EC deaths) were identified, and 47% (standardized incidence ratio = 0.53, 95% confidence interval (CI): 0.33, 0.87) and 66% (standardized mortality ratio = 0.34, 95% CI: 0.14, 0.81) reductions in cumulative EC incidence and mortality were found. For upper GI cancers, incidence and mortality were lowered by 43% (standardized incidence ratio = 0.57, 95% CI: 0.38, 0.86) and 53% (standardized mortality ratio = 0.47, 95% CI: 0.25, 0.88), respectively. This study showed that upper GI tract endoscopy is an effective population-level screening test for EC in high-risk regions.

MiR-181a, a new regulator of TGF-ß signaling, can promote cell migration and proliferation in gastric cancer.

Transforming growth factor-beta (TGF-ß) signaling pathway plays pivotal roles in various types of cancer. TGF-ß receptor 2 (TGFßR2) contains a kinase domain that phosphorylates and activates the downstream of the TGF-ß signaling pathway. Our previous microarray analysis revealed marked changes in miR-181a expression in gastric cancers, and the bioinformatics analysis suggested that miR-181a negatively regulated TGFßR2. In order to verify the effect of miR-181a on TGFßR2 and clarify the influence of miR-181a on the migration and proliferation of gastric cancer, studies in gastric cancer cell lines and xenograft mouse models were carried out. We found that a reduced expression of TGFßR2 and an increased expression miR-181a in gastric cancer tissues compared to adjacent noncancerous tissues. A luciferase reporter assay confirmed that TGFßR2 was a target of miR-181a. In addition, we found that miR-181a mimics, which increased the level of miR-181a, downregulated the expression of TGFßR2 in the gastric cancer cell line SGC-7901. Moreover, both the overexpression of miR-181a and the downregulation of TGFßR2 promoted the migration and proliferation of SGC-7901 cells. Conversely, SGC-7901 cell migration and proliferation were inhibited by the downregulation of miR-181a and the overexpression of TGFßR2. Furthermore, the increased expression of miR-181a and the decreased expression of TGFßR2 also enhanced the tumor growth in mice bearing gastric cancer. Our results herein indicated that miR-181a promoted the migration and proliferation of gastric cancer cells by downregulating TGFßR2 at the posttranscriptional level. The present study suggests that miR-181a is a novel negative regulator of TGFßR2 in the TGF-ß signaling pathway and thus represents a potential new therapeutic target for gastric cancer.

Clinical use of tumor biomarkers in prediction for prognosis and chemotherapeutic effect in esophageal squamous cell carcinoma.

BACKGROUND: Growing evidence has indicated that tumor biomarkers, including cytokeratin 19 fragment antigen 21-1 (Cyfra21-1), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4), carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC-Ag) were reported to be commonly used in diagnosis and prognosis in esophageal squamous cell carcinoma (ESCC). However, which is the best marker for predicting prognosis remains unknown. Few papers focused on the relationship between tumor biomarkers and postoperative treatment in ESCC. METHODS: A total of 416 ESCC patients were enrolled in this study. The association between tumor markers and overall survival (OS) was analyzed using Kaplan-Meier method with log-rank test, followed by multivariate Cox regression models. RESULTS: The results of Cox multivariate analysis indicated that among these tumor biomarkers, CA19-9 (≥ 37 vs. < 37) [hazard ratio (HR) = 2.130, 95% confidence interval (CI) = 1.138-3.986, p = 0.018] and CEA (≥ 5 vs. < 5) (HR = 1.827, 95% CI = 1.089-3.064, p = 0.022) were the independent prognostic factors of poor OS. For the ESCC patients with CA19-9 < 37, CEA < 5 or SCC-Ag < 1.5, the surgery plus postoperative chemotherapy group had a significantly longer OS than the surgery group alone (p < 0.05), but this significant difference of OS between these two groups cannot be found in patients with CA19-9 ≥ 37, CEA ≥ 5 or SCC-Ag ≥ 1.5 (p > 0.05). CONCLUSIONS: CEA and CA19-9 maybe are superior to other tumor biomarkers as prognostic indicators in ESCC. CA19-9, CEA, SCC-Ag may be useful in predicting the therapeutic effect of postoperative chemotherapy in ESCC.

Exosomes Serve as Nanoparticles to Deliver Anti-miR-214 to Reverse Chemoresistance to Cisplatin in Gastric Cancer.

Chemoresistance is one of the causes of adverse effects in gastric cancer, including a poor response to cisplatin (DDP). Exosomes loaded with microRNA (miRNA), mRNA, and other non-coding RNAs could regulate drug resistance. Exo-anti-214 was extracted and verified. A Cell Counting Kit-8 (CCK-8) cell viability assay, flow cytometry, and transwell and immunofluorescence assays were performed to determine whether exo-anti-214 could sensitize cells to DDP in vitro. A combination of intravenously injected exo-anti-214 and intraperitoneal DDP was utilized in vivo. Additionally, potential targets of miR-214 were screened by mass spectrometry (MS) and confirmed via western blotting (WB). The levels of miR-214 in the human immortalized gastric epithelial cell line ges-1 and the human gastric adenocarcinoma cell lines SGC7901 and SGC7901/DDP gradually increased. Exo-anti-214 could fuse with cells and regulate potential targets, reducing cell viability, suppressing migration, and promoting apoptosis in vitro. Caudally injected exo-anti-214 was applied to reverse chemoresistance and repress tumor growth in vivo due to the downregulation of miR-214 and overexpression of possible target proteins in tumors. Exo-anti-214 could reverse the resistance to DDP in gastric cancer, which might serve as a potential alternative for the treatment of cisplatin-refractory gastric cancer in the future.