The efficacy and safety of fexuprazan in treating erosive esophagitis: a phase III, randomized, double-blind, multicenter study.

BACKGROUND AND AIM: Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). This study aimed to explore the noninferior efficacy and safety of fexuprazan to esomeprazole in treating erosive esophagitis (EE). METHODS: This was a phase III, randomized, double-blind multicenter study. Patients with endoscopically confirmed EE were randomized to receive fexuprazan 40 mg or esomeprazole 40 mg once a daily for 4-8 weeks. The healing rates of EE, symptom response, GERD-health-related quality life (GERD-HRQL), and treatment-emergent adverse events (TEAEs) were compared between fexuprazan group and esomeprazole group. RESULTS: A total of 332 subjects were included in full analysis set (FAS) and 311 in per-protocol set (PPS). The healing rates of fexuprazan and esomeprazole groups at 8 weeks were 88.5% (146/165) and 89.0% (145/163), respectively, in FAS and 97.3% (145/149) and 97.9% (143/146), respectively, in PPS. Noninferiority of fexuprazan compared with esomeprazole according to EE healing rates at 8 weeks was demonstrated in both FAS and PPS analysis. No significant difference was found between groups in EE healing rates at 4 weeks, symptom responses, and changes of GERD-HRQL. The incidence of drug-related AEs was 19.4% (32/165) in fexuprazan arm and 19.6% (32/163) in esomeprazole arm. CONCLUSION: This study demonstrated noninferior efficacy of fexuprazan to esomeprazole in treating EE. The incidence of TEAEs was similar between fexuprazan and esomeprazole. Trial registration number NCT05813561.

Association between childhood trauma and Internet gaming disorder: a moderated mediation analysis with depression as a mediator and psychological resilience as a moderator.

BACKGROUND: The effect of childhood trauma on Internet gaming disorder remains unclear. In this study, we examined this association in Chinese students and explored the possible associated roles of psychological resilience and depression. METHODS: In total, 8,579 students from Hunan Province, China, provided information regarding their sociodemographic factors, history of childhood trauma, any symptoms of depression, psychological resilience, and characteristics of Internet gaming disorder for this cross-sectional study. The impact of childhood trauma on Internet gaming disorder, as well as the extent to which it was mediated by depression and moderated by psychological resilience was evaluated. RESULTS: The influence of childhood trauma on Internet gaming disorder was partially mediated by depression (B = 0.07, 95% CI [0.04, 0.05], p < 0.001), with psychological resilience acting as a mitigating factor (B = -0.002, 95% CI [13.74, 21.72], p < 0.001). Psychological resilience also moderated the association between childhood trauma and depression (B = - 0.003, 95% CI [22.17, 28.10], p < 0.001). Our moderated mediation model elucidated psychosocial mechanisms, revealing the underlying link between childhood trauma and Internet gaming disorder. It also demonstrated the partial mediating role of depression and modulating role of psychological resilience among Chinese students. CONCLUSIONS: Education and interventions, along with effective social support, should be provided to enhance students' psychological resilience and prevent childhood trauma and depression.

Outcome and characteristics of nonsecretory multiple myeloma compared with secretory multiple myeloma: a retrospective multicenter study from China.

BACKGROUND: Nonsecretory multiple myeloma (NSMM) is a rare type of multiple myeloma (MM). Few studies have described the clinical features and outcomes of NSMM in novel agents. Additionally, the prognostic characteristics have remained controversial in recent years. PURPOSE: To investigate the clinical and prognostic features of NSMM and explore the prognostic value of involved free light chain (FLC) levels in NSMM patients in the Chinese population. METHODS: We retrospectively enrolled 176 newly diagnosed NSMM cases between January 2005 and December 2021 from 19 clinical centers in China. The control group was selected using a 1:4 propensity score matching technique of newly diagnosed secretory MM, with age, sex and diagnosis time as the matching variables. RESULTS: The median age of NSMM patients was 60 years, and 22.6% of patients were classified as ISS stage 3. The ORR of the NSMM patients was 87.4%, and the CR was 65.8%. Compared to the matched secretory MM patients, more NSMM patients achieved CR after first-line treatment (65.8% vs. 36%, p = 0.000). The ORR of first-line treatment was not significantly different between NSMM and secretory MM (89.45% vs. 84.7%, p = 0.196). The first-line PFS was 27.5 m and 23 m (p = 0.063), and the median OS was 81 m and 70 months (p = 0.401). However, for CR-achieved NSMM and CR-not-achieved NSMM patients, the median PFS was 37 m vs. 16 m (p = 0.021), while the median OS showed no difference (107 m vs. 87 m, p = 0.290). In multivariate analysis, the significant factors for PFS were age ≥ 65 and ISS-3. ISS-3 was the only independent prognostic factor of OS. The iFLC ≥ 50 mg/L group had a high ORR of 97.3%, and the median PFS and OS were 48 m and NR, respectively. Compared to the matched secretory MM, the iFLC ≥ 50 mg/L group also showed more CR and longer OS (NR vs. 70 m, p = 0.006) and PFS (48 m vs. 23 m, p = 0.003). CONCLUSIONS: Our results revealed that Chinese NSMM patients are younger and have a higher CR but not superior survival. The subgroup of NSMM patients with iFLC ≥ 50 mg/L had better outcomes than secretory MM.

RASSF1A inhibits epithelial-mesenchymal transition of gastric cancer cells by downregulating P-JNK.

Gastric cancer (GC) is one of the most common gastrointestinal tumors. In this study, we assessed the biological role of Ras association domain family 1 isoform A (RASSF1A) in GC cells. Expressions of RASSF1A and the relationship of RASSF1A with epithelial-mesenchymal transformation (EMT)-related proteins were assessed in five cell lines using Western blot. GC cells with RASSF1A overexpression were used to study sensitivity to cisplatin, migration, invasion, and the expression of EMT-associated biomarkers. GC cells showed profound downregulation of RASSF1A expression compared with normal human gastric mucosal cells. High RASSF1A expression was associated with increased overall survival. Overexpression of RASSF1A regulates GC cells activity and the expression of EMT-associated biomarkers. RASSF1A regulates E-cadherin and Vimentin through P-JNK pathway. Our results revealed that RASSF1A can inhibit the proliferation, migration, and invasion of GC cells via E-cadherin. Our study provides insights for further research on GC.

Application of pyroptosis score in the treatment and prognosis evaluation of gastric cancer. / 细胞焦亡评分在胃癌治疗和预后评估中的应用.

Pyroptosis is a kind of proinflammatory programmed cell death mediated by inflammasome. It affects the occurrence and development of gastric cancer through different ways, showing dual effects. On the one hand, inflammasome-mediated inflammatory response is highly likely to participate in the formation and development of early tumors; on the other hand, drugs can inhibit the deterioration process of tumor proliferation, invasion and metastasis through activating the pathways of inflammasome and pyroptosis. Recently, many agents based on pyroptosis have been found to inhibit gastric cancer by promoting the secondary pyroptosis pathway, regulating NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and inhibiting caspase-1. The establishment of cell pyrodeath models can predict the prognosis of gastric cancer patients. Most of the models show that gastric cancer patients with high pyroptosis level have better prognosis and longer overall survival. Pyroptosis scores can also be used to predict the response of gastric cancer patients to immunotherapy and to screen potential anti-gastric cancer drugs. Therefore, in-depth understanding of the potential mechanism of pyroptosis affecting the progression of gastric cancer and the role of pyroptosis score in the treatment and prognosis assessment of gastric cancer will be helpful to find a new and effective method for the treatment of gastric cancer.

Aberrant SPOP-CHAF1A ubiquitination axis triggers tumor autophagy that endows a therapeutical vulnerability in diffuse large B cell lymphoma.

PURPOSE: Aberrant epigenetic changes, like DNA methylation, histone modifications, or ubiquitination, could trigger metabolic disorders in human cancer cells. This study planed to uncover the biological roles of epigenetic SPOP/CHAF1A axis in modulating tumor autophagy during Diffuse large B-cell lymphoma (DLBCL) tumorigenesis. MATERIALS AND METHODS: The Immunohistochemistry (IHC) was performed to assess the CHAF1A expressions. The expression data of CHAF1A was derived from The Cancer Genome Atlas (TCGA), GSE32918 and GSE83632 datasets. Bioinformatic assays contain differential analysis, functional enrichment analysis and Kaplan-Meier survival curve analysis. The colony generation assay, Transwell assay and CCK-8 assays were conducted for the in vitro assays. The in vivo ubiquitination assays were used to assess regulations of SPOP on CHAF1A. The Chromatin immunoprecipitation (ChIP) assays were used to uncover epigenetic regulations of CHAF1A on TFEB. The relevant DLBCL cells were subcutaneously injected to SCID beige mice to establish the xenograft models. RESULTS: Bioinformatic results revealed that CHAF1A expressed highly in DLBCL that were validated in patients samples. Patients with high CHAF1A suffered from inferior prognosis with shorter survival months relative to those with low CHAF1A. High CHAF1A enhanced DLBCL aggressiveness, including cell proliferation, migration and in vivo growth. Mechanistically, E3 ubiquitin ligase SPOP binds to and induces the degradative ubiquitination of CHAF1A via recognizing a consensus SPOP-binding motif in CHAF1A. SPOP is down-regulated in DLBCL and habours two DLBCL-associated mutations. Deficient SPOP leads to accumulated CHAF1A proteins that promote malignant features of DLBCL. Subsequently, ChIP-qPCR assay revealed that CHAF1A directly binds to TFEB promoters to activate the expressions. High CHAF1A could enhance the transcriptional activity of TFEB and downstream genes. The SPOP/CHAF1A axis modulates TFEB-dependent transactivation to regulate the lysosomal biogenesis and autophagy. The in vivo models suggested that TFEB inhibition is effective to suppress growth of SPOP-deficient DLBCLs. CONCLUSIONS: CHAF1A is aberrantly elevated in SPOP-deficient DLBCL. The in-depth mechanism understanding of SPOP/CHAF1A/TFEB axis endows novel targets for DLBCL treatment.

Efficacy and safety of pomalidomide and low-dose dexamethasone in Chinese patients with relapsed or refractory multiple myeloma: a multicenter, prospective, single-arm, phase 2 trial.

BACKGROUND: Pomalidomide in combination with dexamethasone has demonstrated positive results in patients with relapsed or refractory multiple myeloma (RRMM), but no data are available in China. We conducted a multicenter, single-arm trial to examine the efficacy and safety of bioequivalent generic pomalidomide plus low-dose dexamethasone in Chinese RRMM patients. METHODS: Adult (≥ 18 years of age) RRMM patients who progressed after at least two previous treatments, including bortezomib and lenalidomide, were eligible. Pomalidomide was given orally at 4 mg/day on days 1 to 21 of a 28-day cycle. Dexamethasone was given at 40 mg/day (either orally or intravenously; 20 mg/day at 75 years or older) on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression or intolerable adverse events (AEs). The primary end point was objective response rate (ORR). RESULTS: Seventy-four patients were enrolled between February 2017 and February 2019. All patients had progressed within 60 days of their last therapy. 74.3% of the patients were resistant to lenalidomide, 31.1% had renal insufficiency and 33.8% had high-risk cytogenetic RRMM. The median follow-up duration was 33.0 months (range 31.1-34.8 months). The ORR was 37.8% in the overall analysis, 32.7% in lenalidomide-refractory patients, 36.0% in patients with high-risk cytogenetics and 34.8% in RRMM patients with renal impairment. The median progression-free survival was 5.7 months (95% CI 3.7-8.8 months). The median overall survival was 24.3 months (95% CI 14.4-41.1 months). The most common grade 3 and 4 treatment-emergent adverse events (TEAEs) were neutropenia (63.5%), leukopenia (37.8%), thrombocytopenia (28.4%), and anemia (31.1%). Pulmonary infection (27.0%) was the most frequent grade 3 and 4 nonhematologic TEAE. No previously unreported AEs were observed. No venous thromboembolism was reported. CONCLUSIONS: Pomalidomide in combination with low-dose dexamethasone is effective and safe in Chinese RRMM patients. TRIAL REGISTRATION: The study is registered at Chinese Clinical Trial Registry (ChiCTR) ( ChiCTR-OIC-17013234 , first registered on 03/11/2017).

Efficacy of keverprazan for duodenal ulcer: A phase II randomized, double-blind, parallel-controlled trial.

BACKGROUND AND AIM: Considering the limitation of varying acid suppression of proton pump inhibitors, this study was aimed to assess the efficacy, safety, and dose-effect relationship of keverprazan, a novel potassium-competitive acid blocker, in the treatment of duodenal ulcer (DU) compared with lansoprazole. METHODS: A randomized, double-blind, double-dummy, multicenter, low-dose, high-dose, and positive-drug parallel-controlled study was conducted to verify the non-inferiority of keverprazan (20 or 30 mg) to lansoprazole of 30 mg once daily for 4 to 6 weeks and dose-effect relationship of keverprazan in the treatment of patients with active DU confirmed by endoscopy. RESULTS: Of the 180 subjects randomized, including 55 cases in the keverprazan_20 mg group, 61 cases in the keverprazan_30 mg group, and 64 cases in the lansoprazole_30 mg group, 168 subjects (93.33%) completed the study. The proportions of healed DU subjects in the keverprazan_20 mg, keverprazan_30 mg, and lansoprazole_30 mg groups were respectively 87.27%, 90.16%, and 79.69% at week 4 (P = 0.4595) and were respectively 96.36%, 98.36%, and 92.19% at week 6 (P = 0.2577). The incidence of adverse events in the keverprazan_20 mg group was lower than that in the lansoprazole_30 mg (P = 0.0285) and keverprazan_30 mg groups (P = 0.0398). CONCLUSIONS: Keverprazan was effective and non-inferior to lansoprazole in healing DU. Based on the comparable efficacy and safety data, keverprazan of 20 mg once daily is recommended for the follow-up study of acid-related disorders. (Trial registration number: ChiCTR2100043455.).

Comprehensive geriatric assessment in newly diagnosed older myeloma patients: a multicentre, prospective, non-interventional study.

BACKGROUND: Multiple myeloma is a disease of the older people, whose prognoses are highly heterogeneous. The International Myeloma Working Group (IMWG) proposed a geriatric assessment (GA) based on age, functional status and comorbidities to discriminate between fit and frail patients. Given the multidimensional nature of frailty and the relatively recent exploration of frailty in the field of MM, reaching a consensus on the measurement of frailty in MM patients remains challenging. OBJECTIVE: We sought to assess the feasibility of performing a comprehensive GA (CGA) in older MM patients in a real-world and multicentre setting and to evaluate their baseline CGA profiles. RESULTS: We studied 349 older patients with newly diagnosed MM (age range, 65-86 years). Our results showed that a CGA is feasible for older MM patients. Using the IMWG-GA criteria, we identified significantly more frail patients in our cohort comparing to in the IMWG cohort (43% vs 30%, P = 0.002). In the IMWG-GA 'fit' group, risk of malnutrition, depression and cognitive impairment remains. The median follow-up time was 26 months (range 1-38). The median overall survival (OS) was 34.7 months, and the estimated 3-year OS rate was 50%. A high MNA-SF score (MNA-SF ≥ 12), low GDS score (GDS ≤ 5) and high CCI score (CCI ≥ 2) can be used to predict the OS of older patients with newly diagnosed MM. This study is registered at www.clinicaltrials.gov (NCT03122327). CONCLUSIONS: Our study justifies the need for a CGA in older patients with newly diagnosed MM.

Watch-and-wait or immediate immunotherapy/immunochemotherapy in patients with phase IE primary pulmonary MALT lymphoma? A multicenter retrospective study.

Primary pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is rare, and the optimal frontline treatment has not taken shape so far. It is still debatable whether the watch-and-wait (W&W) policy is beneficial to patients, especially in the early stage. This study was to compare the efficacy of W&W with rituximab single agent or combined chemotherapy (R/R-Chemo) on primary pulmonary MALT patients with localized disease. Clinical characters and effect on 28 patients with primary pulmonary MALT (IE phase) were analyzed. Among the 28 patients, 14 were grouped into W&W cohort, and 14 were immediately treated with R/R-Chemo. The median follow-up duration was 62 months. The estimated median time to treatment failure (TTF) in the W&W cohort and immediate R/R-Chemo cohort was 29 months and 59 months, which were not significantly different (P = 0.667). The estimated median time of overall survival (OS) in the W&W cohort and immediate R/R-Chemo cohort was 78 months and 76 months, which were also not statistically significant (P = 0.696). Concerning prognosis, there is no difference between patients with primary pulmonary MALT (IE phase) treated with W&W and with timely R/R-Chemo.

Linc00483 as ceRNA regulates proliferation and apoptosis through activating MAPKs in gastric cancer.

Long non-coding RNAs (lncRNAs) are important regulators of many cellular processes, and their aberrant expression and/or function is associated with many different diseases, including cancer. However, the identification of functional lncRNAs in gastric cancer is still a challenge. In this study, we describe a novel functional lncRNA, linc00483, that is upregulated and associated with tumorigenesis, tumour size, metastasis and poor prognosis in gastric cancer. In our study, linc00483 promoted gastric cancer cell proliferation, invasiveness and metastasis in vitro and in vivo. Mechanistically, upregulated expression of linc00483 in gastric cancer acts as a sponge to absorb endogenous tumour suppressor miR-30a-3p. Furthermore, it restores SPAG9 expression, which is negatively regulated by miR-30a-3p, and actives MAPK signaling pathway in gastric cancer cells. Thus, linc00483 is an oncogenic lncRNA in gastric cancer and targeting linc00483 or its pathway can potentially be useful in development of targeted therapies for patients with gastric cancer. Our results show that linc00483 is an important regulator in carcinogenesis and may be a useful biomarker to predict prognosis of gastric cancer patients. We believe our findings are novel and will be of interest to scientists working in many areas related to biomarkers in cancer.

Hypomethylation agent decitabine restores drug sensitivity by depressing P-glycoprotein activity through MAPK signaling pathway.

The multidrug resistance (MDR) continues to be an obstacle in the treatment of both hematological and solid tumors. Hypomethylation agent, decitabine (5-Aza-dC), is an experimental agent in MDR therapy, while the mechanism is not very clear. In the present study, we demonstrated 5-Aza-dC may reverse MDR induced by P-glycoprotein (P-gp) coded by mdr1 gene in both hematologic K562/ADR cells and solid tumor MCF-7/ADR cells with time and dose-dependent manner. 5-Aza-dC significantly increased drug sensitivity in patients' leukemic cells which had higher expression of mdr1 gene. Both total protein and membrane P-gp expression were up-regulated with 5-Aza-dC treatment in K562/ADR and MCF-7/ADR cells. However, accumulation of adriamycin and rhodamine 123 were increased which suggested the depression of P-gp activity. Gene expression profiling was performed and activation of MAPK signaling pathway was identified as the most significant change affected by 5-Aza-dC. Inhibition of MAPK pathway could increase P-gp activity. Our data suggested that hypomethylation agent decitabine restores drug sensitivity in the P-gp-induced MDR phenotype by depressing of P-gp activity as drug pump partly through MAPK signaling pathway.

Live kinase B1 maintains CD34+CD38- AML cell proliferation and self-renewal.

Live kinase B1 (LKB1) has been recognized as a tumor suppressor in many human cancers; however, LKB1 maintains self-renewal of hematopoietic stem cells (HSCs). The existence of leukemia stem cells (LSCs) is responsible for drug resistance and leukemia relapse. In acute myeloid leukemia (AML), CD34+CD38- fraction is the most enriched compartment for LSCs. We found that LKB1 was upregulated in CD34+CD38- AML cells. LKB1 downregulation suppressed the long-term proliferation of CD34+CD38- AML cells, induced CD34+CD38- AML cells into G2/M phase, and enhanced the sensitivity of CD34+CD38- AML cells to chemotherapy. Furthermore, LKB1 downregulation in CD34+CD38- AML cells inhibited tumor formation in NOD-SCID mice. Downregulation of LKB1 gene makes LSCs partly loose the characters as stem cells. Gene expression microarray showed that MAPK/ERK pathway was implicated in the regulation of CD34+CD38- AML cell proliferation by LKB1. Together, these findings demonstrate that LKB1 plays an important role in the maintenance of LSCs, which may be responsible for drug resistance and AML relapse.

The effect of S1P receptor signaling pathway on the survival and drug resistance in multiple myeloma cells.

Multiple myeloma (MM) remains incurable by conventional chemotherapy. Sphingosine-1-phosphate (S1P) receptor-mediated signaling has been recently demonstrated to have critical roles in cell survival and drug resistance in a number of hematological malignancies. To dissect the roles of S1P receptor pathway in MM, we systematically examined cell viability and protein expression associated with cell survival and drug resistance in MM cell lines upon treatment with either pathway activator (S1P) or inhibitor (FTY720). Our results reveal that FTY720 inhibits cell proliferation by downregulating expression of target genes, while S1P has an opposite effect. Knocking down of S1P receptor S1P5R results in a reduction of cell survival-related gene expression; however, it does not have impacts on expression of drug resistance genes. These results suggest that S1P signaling plays a role in cell proliferation and drug resistance in MM, and targeting this pathway will provide a new therapeutic direction for MM management.

Down-regulation of long non-coding RNA MALAT1 by RNA interference inhibits proliferation and induces apoptosis in multiple myeloma.

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by abnormal proliferation of monoclonal plasma cells in the bone marrow. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an evolutionarily highly conserved long non-coding RNA was originally identified in metastatic non-small cell lung cancer and has been reported to be up-regulated in many other cancers. However, the function of MALAT1 in MM remains unknown. In the present study, by transfecting MM cells with MALAT1-specific short hairpin RNA (shRNA) expression plasmids, the role of MALAT1 in the proliferation and apoptosis of MM cells was investigated in vitro, and the tumorigenicity of MALAT1-silenced cells was evaluated in vivo. MALAT1 was found to be highly expressed in RPMI8226 and U266 cells. Down-regulation of MALAT1 via RNA interference significantly inhibited the proliferation of MM cells through cell cycle arrest at G1 phase. Moreover, knockdown of MALAT1 induced apoptosis, which was closely associated with the activation of caspase-3/-9, down-regulation of Bcl-2 and up-regulation of Bax. In addition, silencing of MALAT1 by intratumoral injection of MALAT1 shRNA attenuated the tumour growth in mice bearing myeloma xenograft and led to massive apoptosis in the xenograft tumour. Therefore, MALAT1 may serve as a promising target in the genetic therapeutic strategy for MM treatment.

Knockdown of RLIP76 expression by RNA interference inhibits proliferation, enhances apoptosis, and increases chemosensitivity to daunorubicin in U937 leukemia cells.

RLIP76 is known to play a role in cell growth, division, apoptosis, and chemosensitivity in various malignant cancer cells. However, few studies have been done on the role of RLIP76 in leukemia. In this study, human leukemia cell line U937 was transiently transfected with a RLIP76-targeted short hairpin RNA (shRNA) to investigate the effects of RLIP76 on cellular functions. Real-time PCR and western blot analysis revealed that the expression levels of RLIP76 mRNA and protein in U937 cells were significantly suppressed after transfection with shRNA-containing vector. Knockdown of RLIP76 significantly inhibited cell growth and decreased the colony formation rate, as assessed by trypan blue exclusion and colony formation assay. Flow cytometry analysis showed that reduced RLIP76 expression resulted in cell cycle arrest at G1 phase and induced apoptosis. Meanwhile, western blot analysis demonstrated that RLIP76 knockdown increased expression of Bax, cleaved caspase-3/-9, and cleaved poly (ADP-ribose) polymerase (PARP) but reduced the expression of cyclin D1, cyclin E, and Bcl-2 in U937 cells. Finally, knockdown of RLIP76 in U937 cells also enhanced their chemosensitivity to daunorubicin. Taken together, this study suggests that RLIP76 is a potential target for developing novel therapeutic strategies for leukemia.

High expression of Golgi phosphoprotein-3 is associated with poor survival in patients with hepatocellular carcinoma.

Golgi phosphoprotein 3 (GOLPH3) is recently demonstrated to function as an oncogene involved in the development and progression of cancers. However, little is known about GOLPH3 expression and its clinical significance in hepatocellular carcinoma (HCC). The levels of GOLPH3 messenger RNA (mRNA) and protein in HCC cell lines and fresh tissues were determined by quantitative RT-PCR and western blotting. Additionally, the protein expression of GOLPH3 was detected in 167 paraffin-embedded HCC samples by immunohistochemistry. GOLPH3 mRNA and protein was overexpressed in HCC cell lines and tissues than the immortalized normal hepatocyte cell line LO2 and the adjacent nontumorous live tissues, respectively. High GOLPH3 expression was positively correlated with high serum AFP level (P = 0.015) and more tumor recurrence or metastasis (P = 0.010). In addition, HCC patients with high GOLPH3 expression had poorer overall survival (hazard ratio (HR), 1.87; 95 % confidence interval (CI), 1.19-2.94; P = 0.006) and poorer disease-free survival (HR, 1.90; 95 % CI, 1.21-2.98; P = 0.005) than those with low GOLPH3 expression. The cumulative 5-year survival rate was only 35.19 % (95 % CI, 26.18-44.20 %) in the high GOLPH3 expression group, whereas it was 55.93 % (95 % CI, 43.26-68.60 %) in the low GOLPH3 expression group. Furthermore, multivariate Cox regression analysis demonstrated that the expression of GOLPH3, tumor size, and tumor multiplicity were independent prognostic predictors for HCC patients. GOLPH3 was overexpressed in HCC at both the mRNA and protein levels, and high expression of GOLPH3 could be served as a novel and potential prognostic biomarker for HCC patients.

MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis.

BACKGROUND: Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation. METHODS: We used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay. RESULTS: This study revealed that the downregulation of Mucin 20 (MUC20) could predict PI sensitivity and outcomes in MM patients. Besides, MUC20 attenuated PI resistance in MM cells by inducing cuproptosis via the inhibition of cyclin-dependent kinase inhibitor 2 A expression (CDKN2A), which was achieved by hindering MET proto-oncogene, receptor tyrosine kinase (MET) activation. Moreover, MUC20 suppressed MET activation by repressing insulin-like growth factor receptor-1 (IGF-1R) lactylation in PI-resistant MM cells. This study is the first to perform extrachromosomal circular DNA (eccDNA) sequencing for MM, and it revealed that eccDNA induced PI resistance by amplifying kinesin family member 3 C (KIF3C) to reduce MUC20 expression in MM. CONCLUSION: Our findings indicated that MUC20 regulated by eccDNA alleviates PI resistance of MM by modulating cuproptosis, which would provide novel strategies for the treatment of PI-resistant MM.

Impairment of olfactory identification ability in ultra-high risk for psychosis and drug-naïve first episode psychosis.

OBJECTIVE: Patients with psychotic diseases have been reported to exhibit abnormalities in their olfactory discrimination. These alterations have also been identified in people at high genetic or clinical risk for psychosis, suggesting olfactory discrimination dysfunction may be a potential risk factor for developing psychosis. Thus, the purpose of our study is to explore the difference in olfactory discrimination ability in the prosal stage and early stage of psychosis and to explore the potential risk factor of developed psychosis. METHODS: We compared olfactory identification and cognitive function in 89 ultra-high-risk (UHR) individuals, 103 individuals with Drug-naïve first-episode schizophrenia (FES), 81 genetic high-risk (GHR) individuals, and 97 healthy controls (HC). Additionally, we compared olfactory identification and cognitive function between two groups; UHR individuals who later transitioned to psychosis (UHR-T; n = 33) and those who did not transition (UHR-NT; n = 42)). Furthermore, we analyzed the correlations between olfactory discrimination ability and cognitive function and symptoms and compared the olfactory function between men and women. RESULTS: Patients with first-episode schizophrenia (FES) and those at ultra-high risk (UHR) for psychosis exhibited more significant deficits in olfactory identification than healthy controls (HC), while no differences in olfactory identification dysfunction were observed between the genetic high risk (GHR) and HC groups. Notably, individuals in the UHR group who later developed psyhchosis displayed a steeper marked decline in their baseline olfactory identification ability than that of those in the UHR group who did not develop psychosis. Cognitive dysfunction is widely observed in both the FES and UHR groups, with a distinct correlation identified between olfactory discrimination function and cognitive performance. Finally, overall, women exhibit significantly superior olfactory function than men. CONCLUSION: In conclusion, these findings suggest that impairment of olfactory identification exists in the early stage of psychosis. Olfactory identification dysfunction may therefore be a potential marker of predicting the transition to schizophrenia.

Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia.

NK-cell leukemia is a clonal expansion of NK cells. The illness can occur in an aggressive or chronic form. We studied cell lines from human and rat NK-cell leukemias (aggressive NK-cell leukemia) as well as samples from patients with chronic NK-cell leukemia to investigate pathogenic mechanisms. Here we report that Mcl-1 was overexpressed in leukemic NK cells and that knockdown of Mcl-1 induced apoptosis in these leukemic cells. In vitro treatment of human and rat NK leukemia cells with FTY720 led to caspase-dependent apoptosis and decreased Mcl-1 expression in a time- and-dose-dependent manner. These biologic effects could be inhibited by blockade of reactive oxygen species generation and the lysosomal degradation pathway. Lipidomic analyses after FTY720 treatment demonstrated elevated levels of sphingosine, which mediated apoptosis of leukemic NK cells in vitro. Importantly, systemic administration of FTY720 induced complete remission in the syngeneic Fischer rat model of NK-cell leukemia. Therapeutic efficacy was associated with decreased expression of Mcl-1 in vivo. These data demonstrate that therapeutic benefit of FTY720 may result from both altered sphingolipid metabolism as well as enhanced degradation of a key component of survival signaling.