Esophageal cancer is one of the deadliest cancers in the world, and the main subtype is esophageal squamous cell carcinoma (ESCC), which comprises 90% of cases. Expression of tryptophan ...2,3-dioxygenase (TDO2), an enzyme involved in tryptophan catabolism, has been linked with tumor survival and poor prognosis of brain and breast cancer. However, no studies have investigated the potential role of TDO2 in esophageal cancer. Here we explored the expression and biological significance of TDO2 in ESCC.
TDO2 protein expression was evaluated in 90 ESCC tissue samples by immunohistochemistry. TDO2 function in ESCC cell lines and spheroid colony formation were evaluated by RNA interference (RNAi).
TDO2 overexpression was associated with tumor stage, recurrence status, and the CD44 cancer stem cell marker in ESCC. TDO2 overexpression was correlated with poor outcome of ESCC patients. Inhibition of TDO2 expression by RNAi in TE-10 and TE-11 cell lines reduced both the number and the size of spheroid colonies as well as cell proliferation. Knockdown of TDO2 expression also induced inactivation of the epidermal growth factor receptor signaling pathway.
Our results imply that TDO2 could play an important role in the progression of ESCC. Furthermore, TDO2 may be a potential therapeutic target in ESCC.
ABSTRACT
The utility of Schlafen 11 (SLFN11) expression as a predictive biomarker for platinum‐based chemotherapy has been established for cancers from different histologies. However, the therapeutic ...relevance of SLFN11 in bladder cancer (BC) is unknown. Here, we examined the clinicopathologic significance of SLFN11 expression across 120 BC cases by immunohistochemistry. We divided the cases into two cohorts, one including 50 patients who received adjuvant or neoadjuvant platinum‐based chemotherapy, and the other including 70 BC patients treated by surgical resection without chemotherapy. In the cohort of 50 BC cases treated with platinum‐based chemotherapy, the SLFN11‐positive group (n = 25) showed significantly better overall survival than the SLFN11‐negative group (n = 25, P = .012). Schlafen 11 expression correlated significantly with the expression of luminal subtype marker GATA3. Multivariate analyses identified SLFN11 expression as an independent prognostic predictor (odds ratio, 0.32; 95% confidence interval, 0.11‐0.91; P = .033). Conversely, in the cohort of 70 BC cases not receiving platinum‐based chemotherapy, the SLFN11‐positive group (n = 29) showed significantly worse overall survival than the SLFN11‐negative group (n = 41, P = .034). In vitro analyses using multiple BC cell lines confirmed that SLFN11 KO rendered cells resistant to cisplatin. The epigenetic modifying drugs 5‐azacytidine and entinostat restored SLFN11 expression and resensitized cells to cisplatin and carboplatin in SLFN11‐negative BC cell lines. We conclude that SLFN11 is a predictive biomarker for BC patients who undergo platinum‐based chemotherapy and that the combination of epigenetic modifiers could rescue refractory BC patients to platinum derivatives by reactivating SLFN11 expression.
Schlafen 11 (SLFN11) is a predictive biomarker for bladder cancer patients who undergo platinum‐based chemotherapy. A combination of epigenetic modifiers could rescue bladder cancer patients who are refractory to platinum derivatives, by reactivating SLFN11 expression.
Background
The attainment of drug resistance in gastric cancer (GC) is a problematic issue. Although many studies have shown that cancer stem cells (CSCs) play an important role in the acquisition of ...drug resistance, there is no clinically available biomarker for predicting oxaliplatin (L-OHP) resistance in relation to CSCs. Organoid technology, a novel 3D cell culture system, allows harboring of patient-derived cancer cells containing abundant CSCs using niche factors in a dish.
Methods
In this study, we established L-OHP-resistant gastric cancer organoids (GCOs) and evaluated their gene expression profile using microarray analysis. We validated the upregulated genes in the L-OHP-resistant GCOs compared to their parental GCOs to find a gene responsible for L-OHP resistance by qRT-PCR, immunohistochemistry, in vitro, and in vivo experiments.
Results
We found myoferlin (MYOF) to be a candidate gene through microarray analysis. The results from cell viability assays and qRT-PCR showed that high expression of MYOF correlated significantly with the IC50 of L-OHP in GCOs. Immunohistochemistry of MYOF in GC tissue samples revealed that high expression of MYOF was significantly associated with poor prognosis, T grade, N grade, and lymphatic invasion, and showed MYOF to be an independent prognostic indicator, especially in the GC patients treated with platinum-based chemotherapy. The knockdown of MYOF repressed L-OHP resistance, cell growth, stem cell features, migration, invasion, and in vivo tumor growth.
Conclusions
Our results suggest that MYOF is highly involved in L-OHP resistance and tumor progression in GC. MYOF could be a promising biomarker and therapeutic target for L-OHP-resistant GC cases.
Patients with end-stage renal failure are susceptible to dry eye disease. This study explores the relationship between dry eye disease and influence factors.
The control group consisted of 57 healthy ...subjects who were kidney donors. They were of the same age and sex as the kidney transplant recipients. The outcome variable was the dry eye condition of the participants. The Schirmer test confirmed dry eye disease, TBUT (breakup time test), and the Eye Surface Disease Index (OSDI) questionnaire, using linear regression to evaluate the association.
The total number of subjects was 146 (89 kidney recipients and 57 kidney donors). When univariate analysis found the level of visual acuity, the age group involved was statistically significant, while the other factors were not statistically significant. In multivariable logistic regression analysis, age (odds ratio: 2.8, p<0.05), smoking history (odd ratio: 0.1, p<0.05), corneal conjunctival calcification (odd ratio: 0.2, p<0.05); central corneal thickness (odd ratio: 1.02, p<0.05) is considered to be an influence factor for disease progression.
Age group, smoking history, corneal central thickness, and conjunctival calcification are factors for dry eye disease in patients preparing to receive a kidney. These results reinforce the evidence for multifactorial dry eye disease in patients with renal impairment.
Colorectal cancer (CRC) is the second leading cause of cancer‐related mortality worldwide. Kinesin Family Member C1 (KIFC1) has been proposed as a promising therapeutic target due to its pivotal role ...in centrosome clustering to mediate cancer cell progression. This study aimed to analyze the expression and biological function of KIFC1 in CRC. Immunohistochemically, 67 (52%) of 129 CRC cases were positive for KIFC1 and statistically associated with poorer overall survival. KIFC1 small interfering RNA (siRNA)‐transfected cells demonstrated lower cell proliferation as compared to the negative control cells. A specific KIFC1 inhibitor, kolavenic acid analog (KAA) drastically inhibited CRC cell proliferation. Microarray analysis revealed that KAA‐treated CRC cells presented reduced ZW10 interacting kinetochore protein (ZWINT) expression as compared to control cells. Immunohistochemical analysis demonstrated that 61 (47%) of 129 CRC cases were positive for ZWINT and ZWINT expression was significantly correlated with KIFC1 expression. ZWINT‐positive cases exhibited significantly worse overall survival. KIFC1 siRNA‐transfected cells showed reduced ZWINT expression while ZWINT siRNA‐transfected cells decreased cell proliferation. Both KIFC1 and ZWINT knockdown cells attenuated spheroid formation ability. This study provides new insights into KIFC1 regulating ZWINT in CRC progression and its potential as a therapeutic target.
Although docetaxel (DTX) confers significant survival benefits in patients with castration‐resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms ...of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S‐phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin‐positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan–Meier analysis showed that high claspin expression was related to poor prostate‐specific antigen (PSA) relapse‐free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse‐free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX‐resistant DU145 (DU145‐DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145‐DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance.
Claspin overexpression was related to poor PSA relapse‐free prognosis. Claspin knockdown significantly upregulated the sensitivity to docetaxel in DU145 docetaxel‐resistant cells.
The severe heatwaves and hot spells in Vietnam were observed more frequently in intensity and duration due to global warming and climate change impacts. The hot days and extreme summer events make ...the weather harsh and significantly affect human health and the environment. This study presents the spatiotemporal distribution of the number of hot days (NHDs) in Vietnam. The variability of NHD in seven climate subregions is also examined in association with the large-scale drivers. The European Center for Medium-Range Weather Forecasts (ECMWF) reanalysis version 5 (ERA5) data for the period 1981–2020 are used. Principal component analysis is also applied to the observed monthly NHD to obtain spatial patterns and time series. The results show that the NHD in the Highland and South subregions from March to May is linked with the subtropical high associated with decreased 500hPa-level vertical velocity (VV500). From May to June, the North and Central subregions seem related to deepening the Asiatic low and enhancement of southwest flows across the Indochina Peninsula. Finally, both increased southwest flows and decreased VV500 can partly contribute to the intensification of NHD in the North and Central subregions during July and August. The long trends of NHD are also examined. The results reveal that the increasing trends in NHD occur in most subregions, except for the Central Highland, and changing trends of NHD in June greatly contribute to the annual trend of NHD. Finally, the examinations with the El Niño-Southern Oscillation events show that NHD is significantly higher in El Niño events than in La Niña events in March and April for the Northwest, South Central, Central Highlands, and South, in May and June for all subregions, and in July and August for only the Red River Delta subregion. This suggests that ENSO can provide the potential for improving seasonal climate forecasts and mitigating natural disaster risks for the community.
5-FU is one of the key drugs in the treatment of gastric cancer (GC). Much evidence has shown that cancer stem cells (CSCs) play a key role in the acquisition of drug resistance. The organoid is a ...novel 3D cell culture system technology that sustains stem-cell-driven formation of near-physiological, self-renewing tissues using specific niche factors in a dish. In this study, we established GC organoids (GCOs) and gradually treated them with higher concentrations of 5-FU. We successfully harvested four 5-FU-resistant GCOs, which were supported by significant changes in the expression of molecules related to 5-FU metabolism. We then performed microarray analysis using three normal gastric organoids and three pairs of 5-FU-resistant and parental GCOs. Through the comparison of expression profiles and further validation, we chose KHDRBS3 as a target gene. We found KHDRBS3 to be an independent prognostic factor in GC patients, especially in GC patients treated with 5-FU chemotherapy. We also determined that KHDRBS3 might play an important role in the acquisition of stem cell-like features, such as multi-drug resistance and organoid formation, by regulating CD44 variant expression. We found KHDRBS3, which is thought to play an important role in the acquisition of characteristics of CSCs in GC, to be a promising candidate marker for predicting therapeutic effect and prognosis in GC patients.
Beta2-microglobulin (β2-M) is recognized as a surrogate marker relating to the mechanisms of dialysis-associated amyloidosis. Few studies have evaluated the association of serum β2-M with clinical ...outcome in hemodialysis patients using high-flux type. However, study on patients using low-flux dialyzer reuse has not been done yet.
Using serum β2-M level on predicting long-term mortality of hemodialysis patients was examined in 326 prevalent hemodialysis patients (45.59±14.46 years, hemodialysis duration of 47.5 (26-79) months, 186 males and 140 females). The patients were divided into 3 groups with equal number of patients, according to their serum β2-M levels: group A (n=109, serum β2-M concentration ≤55.7 mg/L), group B (n=109, serum β2-M level from 55.8 mg/L to 75.4 mg/L) and group C (n=108, serum β2-M concentration >75.4 mg/L).
During the follow-up period of 5 years, there were 75 all-cause deaths (23.0%). Kaplan-Meier analysis revealed that all-cause mortality in the higher β2-M group was significantly higher compared to that in the lower β2-M groups (
<0.001). Serum β2-M level was a significant predictor for all-cause mortality (AUC =0.898;
<0.001; Cut-off value: 74.9 mg/L, Se=93.3%, Sp=92.9%).
Serum β2-M levels were a significant predictor of long-term mortality in hemodialysis patients, who use only low-flux dialyzers and reuse 6 times.
Purpose
Deoxycholic acid (DCA), a secondary bile acid, is reportedly increased in the serum of patients with nonalcoholic steatohepatitis and animals with experimentally induced hepatocellular ...carcinoma (HCC), but its contribution to malignant behaviors of HCC has not been precisely clarified. This study aimed to examine the effect of DCA on hepatic stellate cells (HSCs), a major component of nonparenchymal cells in the liver, and its subsequent indirect effect on HCC cells.
Methods
LX2 cells, a human HSC line, were treated with DCA in vitro. Then, HuH7 cells, a human hepatoma cell line, were incubated in conditioned media of DCA-treated LX2 to investigate the subsequent effect focusing on malignant behaviors.
Results
DCA resulted in cellular senescence in LX2 with the decreased cell proliferation via cell cycle arrest at G0/1 phase, together with the induction of senescence-associated secretory phenotype (SASP) factors. To investigate the influence of SASP factors secreted by HSCs in response to DCA, HCC cells were treated with conditioned media that promoted cell migration and invasion via induction of epithelial mesenchymal transition. These changes were attenuated in the presence of neutralizing antibody against IL8 or TGFβ. Pathological analysis of surgical specimens from HCC patients revealed that senescent HSCs were detected in the stroma surrounding HCC.
Conclusion
Our data suggest an important role of HSC senescence caused by DCA for the malignant biological behaviors of HCC via induction of SASP factors, particularly IL8 and TGFβ.
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