Chemotherapy is currently the mainstay of systemic management for triple-negative breast cancer (TNBC), but chemoresistance significantly impacts patient outcomes. Our research indicates that Doxorubicin (Dox)-resistant TNBC cells exhibit increased glycolysis and ATP generation compared to their parental cells, with this metabolic shift contributing to chemoresistance. We discovered that ALKBH3, an m¹A demethylase enzyme, is crucial in regulating the enhanced glycolysis in Dox-resistant TNBC cells. Knocking down ALKBH3 reduced ATP generation, glucose consumption, and lactate production, implicating its involvement in mediating glycolysis. Further investigation revealed that aldolase A (ALDOA), a key enzyme in glycolysis, is a downstream target of ALKBH3. ALKBH3 regulates ALDOA mRNA stability through m¹A demethylation at the 3'-untranslated region (3'UTR). This methylation negatively affects ALDOA mRNA stability by recruiting the YTHDF2/PAN2-PAN3 complex, leading to mRNA degradation. The ALKBH3/ALDOA axis promotes Dox resistance both in vitro and in vivo. Clinical analysis demonstrated that ALKBH3 and ALDOA are upregulated in breast cancer tissues, and higher expression of these proteins is associated with reduced overall survival in TNBC patients. Our study highlights the role of the ALKBH3/ALDOA axis in contributing to Dox resistance in TNBC cells through regulation of ALDOA mRNA stability and glycolysis.

Novel therapeutic approaches targeting key genes and regulatory molecules of hepatocellular carcinoma (HCC) have gradually been carried out in clinical practice. Hypoxia-inducible factor (HIF), as a critical factor for hepatocellular carcinoma cells to adapt to the hypoxic microenvironment, mediates changes in the transcription of many genes. HIF has a wide range of target genes and can promote metabolic reprogramming, angiogenesis, invasion and metastasis, and immune escape of cancer cells by regulating various signaling pathways. Hypoxia-inducible factor 1α (HIF-1α), as the main member of the HIF family, can provide new ideas and insights for exploring potential targets for HCC treatment.

Objective:To reassess the prognostic value of minimal residual disease (MRD) and IKZF1 gene deletions in adults with B-cell acute lymphoblastic leukemia (B-ALL) who received pediatric-specific chemotherapy regimens during the Nanfang Hospital PDT-ALL-2016 trial.Methods:We retrospectively analyzed the prognosis of 149 adult patients with B-ALL who were admitted to Nanfang Hospital from January 2016 to September 2020. Prognostic factors were identified using Cox regression models.Results:The complete remission rate was 93.2% in 149 patients, with a 5-year overall survival (OS) rate of (54.3±5.0) % and a cumulative incidence of relapse (CIR) of (47.5±5.2) %. The Cox regression analysis revealed that MRD positivity at day 45 (MRD 3) after induction therapy was independently associated with relapse risk ( HR=2.535, 95% CI 1.122-5.728, P=0.025). Deletion of IKZF1 gene was independently associated with mortality risk ( HR=1.869, 95% CI 1.034-3.379, P=0.039). Based on MRD 3 and IKZF1 gene status, we categorized adult patients with B-ALL into the low-risk (MRD 3-negative and IKZF1 gene deletion-negative) and high-risk (MRD 3-positive and/or IKZF1 gene wild type) groups. The 5-year OS and CIR rates were (45.5±6.0) % vs (69.4±8.6) % ( P<0.001) and (61.6±8.3) % vs (25.5±6.5) % ( P<0.001), respectively, in the high-risk and low-risk groups, respectively. The multivariate analysis showed that the high-risk group was an independent risk factor for OS ( HR=3.937, 95% CI 1.975-7.850, P<0.001) and CIR ( HR=4.037, 95% CI 2.095-7.778, P<0.001) . Conclusion:The combined use of MRD and IKZF1 gene in prognostic stratification can improve clinical outcome prediction in adult patients with B-ALL, helping to guide their treatment.

Objective:To evaluate the efficacy and safety of vedolizumab (VDZ) in the treatment of active ulcerative colitis (UC).Methods:From November 1, 2020 to October 30, 2022, at the Department of Gastroenterology, the Sixth Affiliated Hospital of Sun Yat-sen University, 81 UC patients who received VDZ treatment and completed a 14-week follow-up were retrospectively selected. The clinical data of patients, including age, disease duration, disease activity of UC were collected. The VDZ efficacy evaluation included primary and secondary efficacy indicators. The primary efficacy indicator was the clinical remission rate after 14 weeks of VDZ treatment, and the secondary efficacy indicators included the clinical response rate, steroids-free remission rate, endoscopic remission rate after 14 weeks of treatment as well as the clinical response rate, clinical remission rate, steroids-free remission rate, secondary loss of response rate after 52 weeks of treatment. The adverse reactions during the treatment were recored. Taking clinical remission after 14 weeks of treatment as the dependent variable, univariate analysis was performed to identify the risk factors affecting clinical remission of VDZ. Binary logistic regression analysis was used for multivariate analysis to determine the independent risk factors of VDZ-included clinical remission. Chi-square test and Wilcoxon signed-rank test were used for statistical analysis.Results:Among the 81 UC patients, the age was 40.0 years old (29.0 years old, 53.5 years old) and the disease duration was 42.5 months (22.5 months, 94.7 months). The proportion of patients with mild active UC was 21.0% (17/81), the proportion of patients with moderate active UC was 64.2% (52/81), and the proportion of patients with severe active UC was 14.8% (12/81). After 14 weeks of treatment, the total Mayo score decreased from baseline level of 7.0 (6.0, 9.0) to 1.0 (0.0, 3.0), and the difference was statistically significant ( Z=-6.87, P<0.001). The clinical response rate was 84.0% (68/81) and the clinical remission rate was 69.1% (56/81) after 14 weeks of treatment. Of the 17 patients treated with combination of corticosteroid therapy, 10 achieved steroid-free remission, and the endoscopic remission rate was 34.8% (23/66). Of the 43 patients followed up to 52 weeks, the total Mayo score of UC patients decreased from baseline level of 7.0 (6.0, 9.0) to 0.0 (0.0, 1.0) after 52 weeks of treatment, and the difference was statistically significant ( Z=-3.25, P<0.001). The clinical response rate was 69.8% (30/43), and the clinical remission rate was 65.1% (28/43). Of the 13 patients treated with combination of corticosteroid therapy, 10 patients achieved steroid-free remission. The secondary loss of response rate was 15.2%(5/33) .The result of the univariate analysis showed that previous use of glucocorticoids was a risk factor of clinical remission after 14 weeks of VDZ treatment ( χ2=5.88, P=0.015). The result of multivariate logistic regression analysis showed that previous use of glucocorticoids was an independent risk factor of clinical remission after 14 weeks of VDZ treatment ( OR=3.429, 95% confidence interval 1.235 to 9.517, P=0.014). During the follow-up period, 12.3% (10/81) of patients developed Clostridium difficile infections, except for 1 case stopped VDZ treatment because the clinical response was not reached, remaining 9 cases continued VDZ treatment after received anti- Clostridium difficile treatment. Conclusion:VDZ has good clinical efficacy and safety in the treatment of Chinese UC patients, and patients with no history of glucocorticoid use may be more likely to achieve clinical remission after 14 weeks of treatment.

Humans ; Neoplasms, Second Primary/epidemiology* ; Neoplasms/epidemiology* ; Risk Factors ; Prognosis

Objective:To evaluate the efficacy and safety of vedolizumab (VDZ) in the treatment of active Crohn′s disease (CD) .Methods:A retrospective cohort study was conducted. Clinical data of 45 patients with active CD at the Sixth Affiliated Hospital of Sun Yat-sen University from November 2020 to May 2022 were analyzed. All of the patients received VDZ at the dose of 300 mg per time at 0, 2th, 6th weeks and subsequently once every 8 weeks. The clinical response and remission were evaluated by Crohn′s disease activity index (CDAI) . The endoscopic response and remission were evaluated by simple endoscopic score for Crohn′s disease (SES-CD) . All of the adverse effects occurred during the treatment of VDZ were recorded in order to evaluate the safety. The primary endpoint was the clinical remission rate at 22 weeks after treatment. The secondary endpoints included the clinical response rate at 22 weeks after treatment, the clinical response rate and clinical remission rate at 52 weeks after treatment, the endoscopic response rate and remission rate at (22 ± 8) weeks after treatment. Thirty-one patients who had previously used infliximab (IFX) and adalimumab (ADA) were set as non-Bio-Na?ve group, and 14 patients who had not previously used biologics were set as Bio-Na?ve group. The differences of the primary endpoint and some secondary endpoints between the two groups were compared.Results:At 22 weeks after treatment, the CDAI score of 45 patients decreased from baseline (261.4 ± 98.3) points to (166.6 ± 93.5) points, the difference was statistically significant ( t = 4.6, P<0.01) . Among them, 64.4% (29/45) patients achieved clinical response and 46.7% (21/45) patients achieved clinical remission. There were no significant difference in clinical response rate [71.4% (10/14) vs. 61.3% (19/31) , χ 2 = 0.4, P = 0.4] and clinical remission rate [42.9% (6/14) vs. 48.4% (15/31) , χ 2 = 0.1, P = 0.8] between the Bio-Na?ve group and non-Bio-Na?ve group at 22 weeks after treatment. At 52 weeks after treatment, the CDAI score of 33 patients decreased from baseline (306.9 ± 130.7) points to (126.6 ± 92.7) points, the difference was statistically significant ( t = 8.5, P<0.01) . Among them, 39.4% (13/33) of the patients achieved clinical response, 33.3% (11/33) of the patients achieved clinical remission, but 41.4% (12/29) of the patients had secondary loss of response. At (22 ± 8) weeks after treatment, the SES-CD score of 25 patients in active phase under endoscopy at baseline decreased from baseline 13.0 (7.0, 19.0) points to 8.0 (2.5, 18.5) points, the difference was statistically significant ( Z = -2.6, P<0.05) . Among them, 40.0% (10/25) patients achieved endoscopic response and 20.0% (5/25) patients achieved endoscopic remission. The new facial rash occurred in 1 patient (2.2%) , new joint pain in 2 (4.4%) and there was no new active tuberculosis and hepatitis B virus infection during the treatment of VDZ for 45 patients. Conclusions:Single drug of VDZ has a good effect on inducing remission in patients with mild to moderate CD and has a good safety. The previous use of IFX or ADA does not affect the efficacy of VDZ, but part of patients still have secondary loss of response.

Objective:To evaluate the efficacy and safety of vedolizumab (VDZ) in the treatment of active Crohn′s disease (CD) .Methods:A retrospective cohort study was conducted. Clinical data of 45 patients with active CD at the Sixth Affiliated Hospital of Sun Yat-sen University from November 2020 to May 2022 were analyzed. All of the patients received VDZ at the dose of 300 mg per time at 0, 2th, 6th weeks and subsequently once every 8 weeks. The clinical response and remission were evaluated by Crohn′s disease activity index (CDAI) . The endoscopic response and remission were evaluated by simple endoscopic score for Crohn′s disease (SES-CD) . All of the adverse effects occurred during the treatment of VDZ were recorded in order to evaluate the safety. The primary endpoint was the clinical remission rate at 22 weeks after treatment. The secondary endpoints included the clinical response rate at 22 weeks after treatment, the clinical response rate and clinical remission rate at 52 weeks after treatment, the endoscopic response rate and remission rate at (22 ± 8) weeks after treatment. Thirty-one patients who had previously used infliximab (IFX) and adalimumab (ADA) were set as non-Bio-Na?ve group, and 14 patients who had not previously used biologics were set as Bio-Na?ve group. The differences of the primary endpoint and some secondary endpoints between the two groups were compared.Results:At 22 weeks after treatment, the CDAI score of 45 patients decreased from baseline (261.4 ± 98.3) points to (166.6 ± 93.5) points, the difference was statistically significant ( t = 4.6, P<0.01) . Among them, 64.4% (29/45) patients achieved clinical response and 46.7% (21/45) patients achieved clinical remission. There were no significant difference in clinical response rate [71.4% (10/14) vs. 61.3% (19/31) , χ 2 = 0.4, P = 0.4] and clinical remission rate [42.9% (6/14) vs. 48.4% (15/31) , χ 2 = 0.1, P = 0.8] between the Bio-Na?ve group and non-Bio-Na?ve group at 22 weeks after treatment. At 52 weeks after treatment, the CDAI score of 33 patients decreased from baseline (306.9 ± 130.7) points to (126.6 ± 92.7) points, the difference was statistically significant ( t = 8.5, P<0.01) . Among them, 39.4% (13/33) of the patients achieved clinical response, 33.3% (11/33) of the patients achieved clinical remission, but 41.4% (12/29) of the patients had secondary loss of response. At (22 ± 8) weeks after treatment, the SES-CD score of 25 patients in active phase under endoscopy at baseline decreased from baseline 13.0 (7.0, 19.0) points to 8.0 (2.5, 18.5) points, the difference was statistically significant ( Z = -2.6, P<0.05) . Among them, 40.0% (10/25) patients achieved endoscopic response and 20.0% (5/25) patients achieved endoscopic remission. The new facial rash occurred in 1 patient (2.2%) , new joint pain in 2 (4.4%) and there was no new active tuberculosis and hepatitis B virus infection during the treatment of VDZ for 45 patients. Conclusions:Single drug of VDZ has a good effect on inducing remission in patients with mild to moderate CD and has a good safety. The previous use of IFX or ADA does not affect the efficacy of VDZ, but part of patients still have secondary loss of response.

Objective:To transfer the interleukin 37 (IL-37) gene to cervical cancer Hela cells,and to explore the killing effect of IL-37 on the HeLa cells and its enhancement in the chemotherapy sensitivity of HeLa cells.Methods:The pIRES2-EGFP (NC group) and pIRES2-EGFP/IL-37 (IL-37 group) plasmids were transfected into the HeLa cells.Q-PCR and Western blotting methods were used to detect the expression levels of IL-37 mRNA and protein.The activities of HeLa cells in NC group,IL-37 group,DDP group and IL-37+DDP group were detected by CCK8 method,and the inhibitory rates of cells were calculated.The gene expressions of signal transducer and activator of transcription 3 (STAT3) and Cyclin D1 were detected by RT-PCR method.Results:Compared with NC group,the expression levels of IL-37 mRNA and protein in IL-37 group were significantly increased (P＜0.01).The activities of HeLa cells in DDP (5-15 mg · L-1) groups were inhibited after administration for 24-72 h (P＜ 0.01);the inhibitory rates in IL-37 + DDP group were higher than those in DDP group within 48 h after administration (P＜0.05).Compared with IL-37 group,the inhibitory rates in IL-37+DDP group was increased with 96 h after administration (P＜0.05).Compared with NC group,the expression levels of STAT3 and Cyclin D1 mRNA in IL-37 group were significantly decreased (P＜0.01).Conclusion:The over-expression of IL-37 can inhibit the proliferation of cervical cancer cells and enhance the effect of DDP on the chemotherapy of cervical cancer cells which may be related to the down-regulation of the expressions of STAT3 and Cyclin D1 by IL-37.

Objective To investigate the effect of HBP-A on meniscal injuries and the expressions of genes associated with pathological hypertrophy and calcification of the meniscusinduced by abnormal loading. Methods Bovine meniscus explants were subjected to 25%strain at 0.3 Hz for 3 h and treated with 0.6 mg/mL of HBP-A. The cell viability in the meniscus explants after 72 hin culture was determined using live/dead staining and the expression levels of genes associated with pathological hypertrophy and calcification of the meniscus (ANKH, ENPP1, ALP, MMP13, and IL-1) were measured using real-time PCR and Western blotting. The conditioned medium was collected for testing sulfated glycosaminoglycan (GAG) release. Results The number of dead cells, loss of proteoglycan content, and the expressions of ANKH, ENPP1, ALP and MMP13, and IL-1 at both the mRNA and protein levels were all significantly lower in the meniscus explants treated with 0.6 mg/mL HBP-A than in the explants with only 25%abnormal pressure stimulation (n=3, P<0.05). Conclusion HBP-A can effectively alleviate meniscal injuries induced by abnormal loading and suppress the expressions of genes related with pathological hypertrophy and calcification of the meniscus, and can serve as a potential drug for treatment of knee osteoarthritis.

Objective To investigate the effect of HBP-A on meniscal injuries and the expressions of genes associated with pathological hypertrophy and calcification of the meniscusinduced by abnormal loading. Methods Bovine meniscus explants were subjected to 25%strain at 0.3 Hz for 3 h and treated with 0.6 mg/mL of HBP-A. The cell viability in the meniscus explants after 72 hin culture was determined using live/dead staining and the expression levels of genes associated with pathological hypertrophy and calcification of the meniscus (ANKH, ENPP1, ALP, MMP13, and IL-1) were measured using real-time PCR and Western blotting. The conditioned medium was collected for testing sulfated glycosaminoglycan (GAG) release. Results The number of dead cells, loss of proteoglycan content, and the expressions of ANKH, ENPP1, ALP and MMP13, and IL-1 at both the mRNA and protein levels were all significantly lower in the meniscus explants treated with 0.6 mg/mL HBP-A than in the explants with only 25%abnormal pressure stimulation (n=3, P<0.05). Conclusion HBP-A can effectively alleviate meniscal injuries induced by abnormal loading and suppress the expressions of genes related with pathological hypertrophy and calcification of the meniscus, and can serve as a potential drug for treatment of knee osteoarthritis.