Chaperone-mediated autophagy degrade Dicer to promote breast cancer metastasis.

Metastasis in breast cancer usually lead to the majority of deaths on clinical patients. Accordingly, diagnosis of metastasis at the early stage in breast cancer is important to improve the prognosis. We observed that Dicer protein levels are significant decrease in highly invasive breast cancer cells and usually correlated with poor clinical outcomes. Following, we aim to clarify the molecular regulatory mechanism of this phenomenon in breast cancer to provide a new therapeutic target. In this study, we obtained that Dicer expression correlated with metastasis and invasion without affect cell stability in breast cancer cells. Importantly, we identified the regulatory mechanism of Dicer protein degradation, the chaperone-mediated autophagy (CMA)-mediated degradation that is major mechanism to decrease Dicer protein expression and lead to cancer metastasis. We discovered that heat shock cognate 71-kDa protein (Hsc70) which as a CMA-related factor interacts with the CMA-targeting motif I333A/K334A on Dicer to promote degradation through CMA. Taken together, our findings hint that Dicer highly correlated with cancer metastasis, we reveal the tumor-promoting effect of CMA-mediated Dicer degradation in breast cancer.

ERK-mediated transcriptional activation of Dicer is involved in gemcitabine resistance of pancreatic cancer.

Gemcitabine has been a commonly used therapeutic agent for treatment of pancreatic cancer. In the clinic, a growing resistance to gemcitabine has been observed in patients with pancreatic cancer, and investigation of the underlying mechanism of gemcitabine resistance is urgently required. The microRNA (miRNA)-producing enzyme, Dicer, is crucial for the maturation of miRNAs, and is involved in clinical aggressiveness, poor prognosis, and survival outcomes in various cancers, however, the role of Dicer in acquired gemcitabine resistance of pancreatic cancer is still not clear. Here, we found that Dicer expression was significantly increased in gemcitabine-resistant PANC-1 (PANC-1/GEM) cells compared with parental PANC-1 cells and observed a high level of Dicer correlated with increased risk of pancreatic cancer. Suppression of Dicer obviously decreased gemcitabine resistance in PANC-1/GEM cells; consistently, overexpression of Dicer in PANC-1 cells increased gemcitabine resistance. Moreover, we identified that transcriptional factor Sp1 targeted the promoter region of Dicer and found ERK/Sp1 signaling regulated Dicer expression in PANC-1/GEM cells, as well as positively correlated with pancreatic cancer progression and suggest that targeting the ERK/Sp1/Dicer pathway has potential therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Long-term outcomes of metabolic surgery in overweight and obese patients with type 2 diabetes in Asia.

AIM: To assess the outcomes of metabolic surgery in overweight and obese patients in Asia with type 2 diabetes (T2D). MATERIALS AND METHODS: The treatment outcomes of 1999 patients from the Asian Diabetes Surgery Summit database were analysed. The changes in treatment effects across time were assessed with respect to the surgical procedures performed by using generalized estimating equations. RESULTS: The most commonly performed procedure was the single-anastomosis gastric bypass (32.6%). Weight (from 106.2 ± 25.1 to 77.9 ± 18.8 kg), body mass index (BMI; from 38.7 ± 7.9 to 28.5 ± 5.9 kg/m2 ), blood sugar (from 9.3 ± 4.1 to 5.7 ± 1.8 mmol/L) and HbA1c (from 8.4% ± 1.8% to 6.0% ± 1.1%) significantly improved from baseline to 1 year (P < .001) and remained stable at 5 years (weight, 86.3 ± 23.3 kg; BMI, 31.7 ± 7.9 kg/m2 ; blood sugar, 5.8 ± 1.8 mmol/L, and HbA1c, 6.4% ± 1.2%; all P < .001 vs. baseline). Blood pressure and most lipid disorders also improved significantly. Of the treatment procedures, single-anastomosis gastric bypass had the most satisfactory outcomes with statistical significance for most disorders, whereas adjustable gastric banding displayed the least satisfactory outcomes. CONCLUSIONS: Metabolic surgery remarkably improved body weight, T2D and other metabolic disorders in Asian patients. However, the efficacy of individual procedures varied substantially.

AXL is crucial for E1A-enhanced therapeutic efficiency of EGFR tyrosine kinase inhibitors through NFI in breast cancer.

AXL which is a chemosensitizer protein for breast cancer cells in response to epidermal growth factor receptor-tyrosine kinase inhibitor and suppresses tumor growth. The clinical information show nuclear factor I (NFI)-C and NFI-X expression correlate with AXL expression in breast cancer patients. Following, we establish serial deletions of AXL promoter to identify regions required for Adenovirus-5 early region 1A (E1A)-mediated AXL suppression. All of the NFI family members were extensively studied for their expression and functions in regulating AXL. Moreover, E1A post-transcriptionally downregulates AXL expression through NFI. NFI-C and NFI-X, not NFI-A and NFI-B, resulting in cell death in response to EGFR-TKI. Our finding suggests that NFI-C and NFI-X are crucial regulators for AXL and significantly correlated with poor survival of breast cancer patients.

Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer.

There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-ß-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.

Postoperative recovery after anesthesia in morbidly obese patients: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Obese patients present a challenge to safe general anesthesia because of impaired cardiopulmonary physiology and increased risks of aspiration and acute upper airway obstruction. Since studies are lacking regarding the postoperative effects on recovery from general anesthesia in morbidly obese patients, we conducted a systematic review and meta-analysis of recovery outcomes in morbidly obese patients who had undergone general anesthesia. SOURCE: We systematically searched the PubMed, EMBASE™, Cochrane, and Scopus™ databases for randomized controlled trials that evaluated the outcome of anesthesia with desflurane, sevoflurane, isoflurane, or propofol in morbidly obese patients. Using a random effects model, we conducted meta-analyses to assess recovery times (eye opening, hand squeezing, tracheal extubation, and stating name or birth date), time to discharge from the postanesthesia care unit (PACU), and the incidence and severity of postoperative nausea and vomiting (PONV). PRINCIPAL FINDINGS: We reviewed results for 11 trials and found that patients given desflurane took less time: to respond to commands to open their eyes (weighted mean difference [WMD] -3.10 min; 95% confidence interval (CI): -5.13 to -1.08), to squeeze the investigator's hand (WMD -7.83 min; 95% CI: -8.81 to -6.84), to be prepared for tracheal extubation (WMD -3.88 min; 95% CI: -7.42 to -0.34), and to state their name (WMD -7.15 min; 95% CI: -11.00 to -3.30). We did not find significant differences in PACU discharge times, PONV, or the PACU analgesic requirement. CONCLUSION: Postoperative recovery was significantly faster after desflurane than after sevoflurane, isoflurane, or propofol anesthesia in obese patients. No clinically relevant differences were observed regarding PACU discharge time, incidence of PONV, or postoperative pain scores. The systematic review was registered with PROSPERO (CRD42014009480).

Suppression of Dicer increases sensitivity to gefitinib in human lung cancer cells.

BACKGROUND: Accumulating evidence is revealing an important role of microRNA (miRNA) in tumor progression and chemotherapeutic resistance. Dicer is a cytoplasmic endoribonuclease type III crucial for production of mature miRNAs. The aberrant expression of Dicer has also been reportedly associated with clinical aggressiveness, prognosis, and patient survival in various cancer types. However, the molecular mechanisms of Dicer in acquired gefitinib resistance are still not clear. METHODS: In this study, we analyzed the protein level of Dicer between gefitinib-sensitive (PC9) and gefitinib-resistant (PC9/GR) non-small-cell lung cancer (NSCLC) cell lines by Western blot analysis. Silence and overexpression of the Dicer were performed to investigate the effects on gefitinib sensitivity, as assessed by (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay and sub-G1 assay of flow cytometry. To further explore the mechanism of chemoresistance, we examined whether Dicer knockdown led to modulating specific miRNAs and its miRNA target genes. RESULTS: Dicer expression was significantly increased in PC9/GR compared with PC9 cells. Knockdown of Dicer restores gefitinib sensitivity in resistant cells, and overexpression of Dicer enhances resistance to gefitinib in sensitive cells. Silencing of Dicer induces sensitivity to gefitinib in NSCLC cells through the downregulation of miR-30b/c and miR-221/222 to increase the protein level of caspase-3, resulting in an increase in gefitinib-induced apoptosis. CONCLUSIONS: Dicer contributes to the resistance to gefitinib in lung cancer. These results indicate that Dicer may be a target for diagnosis and therapy of patients with resistance to gefitinib.

Vascular endothelial growth factor-C upregulates cortactin and promotes metastasis of esophageal squamous cell carcinoma.

BACKGROUND: Vascular endothelial growth factor-C (VEGF-C) plays an important role during cancer progression and metastasis through activation of VEGF receptors. However, the role of VEGF-C in esophageal squamous cell carcinoma (ESCC) remains unclear. METHODS: The expression of VEGF-C in advanced stages of esophageal cancer was examined by immunohistochemistry and its expression was correlated with the protein level of cortactin (CTTN) by Western blot. Knockdown and overexpression of the CTTN protein were respectively performed to investigate the effects on VEGF-C-enhanced ESCC migration/invasion by in vitro transwell assay, cell tracing assay, and tumor growth/experimental metastasis in animal models. RESULTS: The expression of VEGF-C was positively correlated with tumor status and poor clinical prognosis in patient with esophageal cancer. VEGF-C-upregulated CTTN expression contributed the migration/invasive abilities of ESCC cell lines through Src-mediated downregulation of miR-326. Moreover, knockdown of CTTN expression significantly abolished VEGF-C-induced tumor growth and experimental lung metastasis in vivo. CONCLUSIONS: Upregulation of CTTN is critical for VEGF-C-mediated tumor growth and metastasis of ESCC. These finding suggest that VEGF-C upregulated CTTN expression through Src-mediated downregulation of miR-326. CTTN may be a crucial mediator of VEGF-C-involved ESCC metastasis, which provides a potential target for diagnosis and individualized treatment in clinical practice.

The clinicopathological and genetic differences among gastric cancer patients with no recurrence, early recurrence, and late recurrence after curative surgery.

BACKGROUND: To date, few reports have investigated the genetic alterations and clinicopathological features among gastric cancer (GC) patients with no tumor recurrence, early recurrence, and late recurrence following curative surgery. METHODS: A total of 473 GC patients undergoing curative surgery were included. The clinicopathological characteristics, patient prognosis, recurrence patterns, and genetic alterations were compared between GC patients with early recurrence and late recurrence. RESULTS: Among the 473 GC patients, 119 had early recurrence (<2 years) and 45 had late recurrence (≥2 years). Patients with early recurrence had tumor size larger than 5 cm, fewer superficial-type tumors, more lymphovascular invasion, more advanced pathological T and N categories and Tumor, Node, Metastasis (TNM) stages, and worse 5-year overall survival than patients with late recurrence and no recurrence. For intestinal-type GC, patients with no tumor recurrence had more Helicobacter pylori infection than patients with early recurrence and late recurrence; for diffuse-type GC patients, the frequency of PIK3CA amplification was the highest in early recurrence, followed by late recurrence and no recurrence. GC patients with single-site recurrence had more ARID1A mutations than those with multiple-site recurrence. Multivariate analysis demonstrated that age, tumor recurrence, and pathological N categories were independent prognostic factors. CONCLUSION: PIK3CA amplifications were more common in diffuse-type GC with early recurrence, whereas ARID1A mutations were more common in patients with single-site recurrence. Targeted therapy and immunotherapy might be helpful for these patients.

Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis.

Sorafenib, a small-molecule inhibitor targeting several tyrosine kinase pathways, is the standard treatment for advanced hepatocellular carcinoma (HCC). However, not all patients with HCC respond well to sorafenib, and 30% of patients develop resistance to sorafenib after short-term treatment. Galectin-1 modulates cell-cell and cell-matrix interactions and plays a crucial role in HCC progression. However, whether Galectin-1 regulates receptor tyrosine kinases by sensitizing HCC to sorafenib remains unclear. Herein, we established a sorafenib-resistant HCC cell line (Huh-7/SR) and determined that Galectin-1 expression was significantly higher in Huh-7/SR cells than in parent cells. Galectin-1 knockdown reduced sorafenib resistance in Huh-7/SR cells, whereas Galectin-1 overexpression in Huh-7 cells increased sorafenib resistance. Galectin-1 regulated ferroptosis by inhibiting excessive lipid peroxidation, protecting sorafenib-resistant HCC cells from sorafenib-mediated ferroptosis. Galectin-1 expression was positively correlated with poor prognostic outcomes for HCC patients. Galectin-1 overexpression promoted the phosphorylation of AXL receptor tyrosine kinase (AXL) and MET proto-oncogene, receptor tyrosine kinase (MET) signaling, which increased sorafenib resistance. MET and AXL were highly expressed in patients with HCC, and AXL expression was positively correlated with Galectin-1 expression. These findings indicate that Galectin-1 regulates sorafenib resistance in HCC cells through AXL and MET signaling. Consequently, Galectin-1 is a promising therapeutic target for reducing sorafenib resistance and sorafenib-mediated ferroptosis in patients with HCC.

Silencing of Dicer enhances dacarbazine resistance in melanoma cells by inhibiting ADSL expression.

Dacarbazine (DTIC) is the primary first-line treatment for advanced-stage metastatic melanoma; thus, DTIC resistance is poses a major challenge. Therefore, investigating the mechanism underlying DTIC resistance must be investigated. Dicer, a type III cytoplasmic endoribonuclease, plays a pivotal role in the maturation of miRNAs. Aberrant Dicer expression may contribute to tumor progression, clinical aggressiveness, and poor prognosis in various tumors. Dicer inhibition led to a reduction in DTIC sensitivity and an augmentation in stemness in melanoma cells. Clinical analyses indicated a low Dicer expression level as a predictor of poor prognosis factor. Metabolic alterations in tumor cells may interfere with drug response. Adenylosuccinate lyase (ADSL) is a crucial enzyme in the purine metabolism pathway. An imbalance in ADSL may interfere with the therapeutic efficacy of drugs. We discovered that DTIC treatment enhanced ADSL expression and that Dicer silencing significantly reduced ADSL expression in melanoma cells. Furthermore, ADSL overexpression reversed Dicer silencing induced DTIC resistance and cancer stemness. These findings indicate that Dicer-mediated ADSL regulation influences DTIC sensitivity and stemness in melanoma cells.

Prediction of 5-Year Weight Loss and Weight Regain According to Early Weight Loss after Sleeve Gastrectomy.

BACKGROUND: Patients with morbid obesity exhibit sustained weight loss after sleeve gastrectomy (SG), but some individuals exhibit subsequent weight regain in the following years. Early weight loss was proven as a predictor of short- and mid-term weight loss and regain. However, the long-term effects of early weight loss have yet to be fully investigated. This study investigated the predictive effects of early weight loss on long-term weight loss and regain after SG. METHODS: Data of patients who underwent SG from November 2011 to July 2016 and followed through July 2021 were collected retrospectively. Weight regain was defined by weight increase more than 25% of their lost weight at the first postoperative year. Linear regression analysis and Cox proportional hazards analysis were performed to evaluate the correlations among early weight loss, weight loss, and weight regain. RESULTS: Data of 408 patients were included. The percentages of total weight loss (%TWL) at postoperative months 1, 3, 12, and 60 were 10.6%, 18.1%, 29.3%, and 26.6%, respectively. The %TWL at months 1 and 3 were significantly correlated with %TWL after 5 years (P < .01). The weight regain rate was 29.8% at 5 years. The %TWL at months 1 and 3 significantly influenced weight regain (hazard ratio: 0.87 and 0.89, P = .017 and .008). CONCLUSION: Early weight loss may be used to predict weight loss and regain 5 years after SG. Patients with poor early weight loss are recommended to receive early interventions to achieve long-term weight loss and prevent weight regain.

Predictors of diabetes relapse after metabolic surgery in Asia.

BACKGROUND: Limited studies have focused on diabetes relapse after metabolic surgery, especially among Asians. OBJECTIVES: To identify the predictors of diabetes relapse following initial postoperative remission in Asia. SETTING: Four tertiary hospitals METHODS: We assessed 342 patients (age, 41.0 ± 10.8 yr; body mass index [BMI], 39.6 ± 7.3 kg/m2) with complete diabetes data before and 1 and 3 years after metabolic surgery. A total of 290 (84.8%) and 277 (81.0%) patients had diabetes remission at 1 and 3 years after surgery. Logistic regressions were performed to identify the independent predictors of diabetes relapse. Two published predictive models for diabetes remission were also tested for relapse. RESULTS: Of the 290 patients with 1-year diabetes remission, 29 (10%) experienced a relapse at 3 years after surgery. The area under the receiver operating characteristic curve of the ABCD score in predicting 1-year remission, 3-year remission, and 3-year relapse were .814, .793, and .795, while those of the DiaRem2 score were .823, .774, and .701, respectively. The baseline age, BMI, and insulin use were independent predictors for relapse. The most powerful predictive model for relapse was composed of preoperative insulin use, 1-year A1C, and a change in BMI between the first and third year (C-statistic: .919). CONCLUSION: The ABCD score predicted both mid-term postoperative diabetes remission and relapse in Asians. Initial older age, lower BMI, insulin use, higher 1-year A1C, and weight regain were independent predictors of relapse. Personalized strategies should be proposed for those at risk of relapse to optimize diabetes outcomes after surgery.

A Comparison of Oxygenation Efficacy between High-Flow Nasal Cannulas and Standard Facemasks during Elective Tracheal Intubation for Patients with Obesity: A Randomized Controlled Trial.

Obese patients are predisposed to rapid oxygen desaturation during tracheal intubation. We aimed to compare the risk of desaturation between high-flow nasal oxygenation (HFNO) and classical facemask oxygenation (FMO) during rapid sequence intubation for elective surgery in obese patients. Adults with a body mass index ≥30 kg·m−2 undergoing laparoscopic sleeve gastrectomy at a medical center were randomized into the HFNO group (n = 40) and FMO group (n = 40). In the HFNO group, patients used a high-flow nasal cannula to receive 30 to 50 L·min−1 flow of heated and humidified 100% oxygen. In the FMO group, patients received a fitting facemask with 15 L·min−1 flow of 100% oxygen. After 5-min preoxygenation, rapid sequence intubation was performed. The primary outcome was arterial desaturation during intubation, defined as a peripheral capillary oxygen saturation (SpO2) <92%. The risk of peri-intubation desaturation was significantly lower in the HFNO group compared to the FMO group; absolute risk reduction: 0.20 (95% confidence interval: 0.05−0.35, p = 0.0122); number needed to treat: 5. The lowest SpO2 during intubation was significantly increased by HFNO (median 99%, interquartile range: 97−100) compared to FMO (96, 92−100, p = 0.0150). HFNO achieved a higher partial pressure of arterial oxygen (PaO2) compared to FMO, with medians of 476 mmHg (interquartile range: 390−541) and 397 (351−456, p = 0.0010), respectively. There was no difference in patients' comfort level between groups. Compared with standard FMO, HFNO with apneic oxygenation reduced arterial desaturation during tracheal intubation and enhanced PaO2 among patients with obesity.

Morphometric and ultrasonographic determinants of difficult laryngoscopy in obese patients: A prospective observational study.

BACKGROUND: Obese people have a higher risk of difficult laryngoscopy due to their thick neck, large tongue, and redundant pharyngeal soft tissue. However, there is still no established predictive factor for difficult laryngoscopy in obese population. METHODS: We conducted a prospective assessor-blind observational study to enroll adult patients with a body mass index of 30 kg·m-2 or higher undergoing laparoscopic sleeve gastrectomy at a medical center between May 2020 and August 2021. Conventional morphometric characteristics along with ultrasonographic airway parameters were evaluated before surgery. The primary outcome was difficult laryngoscopy, defined as a Cormack and Lehane's grade III or IV during direct laryngoscopy. Logistic regression analyses were performed to evaluate the association between included factors and difficult laryngoscopy. Discrimination performance of predictive factors was assessed using area under the receiver operating characteristic curve (AUC). RESULTS: A total of 80 patients were evaluated, and 17 (21.3%) developed an event of difficult laryngoscopy. Univariate analyses identified five factors associated with difficult laryngoscopy, including age, sex, hypertension, neck circumference, and cross-sectional area of tongue base. After adjusting for these variables, neck circumference was the only independent influential factor, adjusted odds ratio: 1.227 (95% confidence interval, 1.009-1.491). Based on Youden's index, the optimal cutoff of neck circumference was 49.1 cm with AUC: 0.739 (sensitivity: 0.588, specificity: 0.889; absolute risk difference: 0.477, and number needed to treat: 3). CONCLUSION: Greater neck circumference was an independent risk factor for difficult laryngoscopy in obese patients. This finding provides a way of reducing unanticipated difficult airway in this high-risk population.

Phosphomimetic Dicer S1016E triggers a switch to glutamine metabolism in gemcitabine-resistant pancreatic cancer.

OBJECTIVE: Dicer is an enzyme that processes microRNAs (miRNAs) precursors into mature miRNAs, which have been implicated in various aspects of cancer progressions, such as clinical aggressiveness, prognosis, and survival outcomes. We previously showed that high expression of Dicer is associated with gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC); thus, in this study, we aimed to focus on how Dicer is involved in GEM resistance in PDAC, including cancer prognosis, cell proliferation, and metabolic regulation. METHODS: We generated stable shRNA knockdown of Dicer in GEM-resistant PANC-1 (PANC-1 GR) cells and explored cell viability by MTT and clonogenicity assays. Metabolomic profiling was employed to investigate metabolic changes between parental cells, PANC-1, and PANC-1 GR cells, and further implied to compare their sensitivity to the glutaminase inhibitor, CB839, and GEM treatments. To identify putative phosphorylation site involves with Dicer and its effects on GEM resistance in PDAC cells, we further generated phosphomimetic or phosphomutant Dicer at S1016 site and examined the changes in drug sensitivity, metabolic alteration, and miRNA regulation. RESULTS: We observed that high Dicer levels in pancreatic ductal adenocarcinoma cells were positively correlated with advanced pancreatic cancer and acquired resistance to GEM. Metabolomic analysis indicated that PANC-1 GR cells rapidly utilised glutamine as their major fuel and increased levels of glutaminase (GLS): glutamine synthetase (GLUL) ratio which is related to high Dicer expression. In addition, we found that phosphomimetic Dicer S1016E but not phosphomutant Dicer S1016A facilitated miRNA maturation, causing an imbalance in GLS and GLUL and resulting in an increased response to GLS inhibitors. CONCLUSION: Our results suggest that phosphorylation of Dicer on site S1016 affects miRNA biogenesis and glutamine metabolism in GEM-resistant pancreatic cancer.

Dicer-mediated miR-200b expression contributes to cell migratory/invasive abilities and cancer stem cells properties of breast cancer cells.

Distant metastasis is the leading cause of death in patients with breast cancer. Despite considerable treatment advances, the clinical outcomes of patients with metastatic breast cancer remain poor. CSCs can self-renew, enhancing cancer progression and metastasis. Dicer, a microRNA (miRNA) processing-related enzyme, is required for miRNA maturation. Imbalanced Dicer expression may be pivotal in cancer progression. However, whether and how Dicer affects the stemness of metastatic breast cancer cells remains unclear. Here, we hypothesized that Dicer regulates the migration, invasion, and stemness of breast cancer cells. We established highly invasive cell lines (MCF-7/I-3 and MDA-MB-231/I-3) and observed that Dicer expression was conspicuously lower in the highly invasive cells than in the parental cells. The silencing of Dicer significantly enhanced the cell migratory/invasive abilities and CSCs properties of the breast cancer cells. Conversely, the overexpression of Dicer in the highly invasive cells reduced their migration, invasion, and CSCs properties. Our bioinformatics analyses demonstrated that low Dicer levels were correlated with increased breast cancer risk. Suppression of Dicer inhibited miR-200b expression, whereas miR-200b suppression recovered Dicer knockdown-induced migration, invasion, and cancer stem cells (CSCs) properties of the breast cancer cells. Thus, our findings reveal that Dicer is a crucial regulator of the migration, invasion, and CSCs properties of breast cancer cells and is significantly associated with poor survival in patients with breast cancer.

Organic cation transporter 2 activation enhances sensitivity to oxaliplatin in human pancreatic ductal adenocarcinoma.

Oxaliplatin, a third-generation platinum derivative, has become one of the main chemotherapeutic treatments for esophagus, gastric and colorectal cancer; however, it is still unclear the potential effectiveness for pancreatic ductal adenocarcinoma (PDAC) with gemcitabine resistance. Here, we observed that PDAC tumors have low level of organic cation transporter 2 (OCT2, also known as SLC22A2) compared with non-tumor tissues and identified that OCT2 expression is positively correlated with oxaliplatin sensitivity in PDAC cells. Treatment of OCT2 inhibitors or knockdown of OCT2 expression significantly decreased the sensitivity to oxaliplatin in PANC-1 cells. In addition, bisulfite sequencing polymerase chain reaction analysis revealed that higher methylation frequency represses OCT2 expression in gemcitabine-resistant PANC-1 (PANC-1/GR) cells. Moreover, we found that treatment of DNA methyltransferase (DNMT) inhibitors, decitabine or 5-azacytidine recover OCT2 expression and oxaliplatin sensitivity in PANC-1/GR cells, and DNMT1 level has inverse correlation with OCT2 expression in PDAC cells and tumors. Our findings jointly suggest that OCT2 expression is a potential and predictive marker for evaluating oxaliplatin sensitivity and developing alternative treatments for PDAC patients with gemcitabine resistance.

Efficacy of Fibrin Sealant in Reducing Complication Risk After Bariatric Surgery: a Systematic Review and Meta-analysis.

BACKGROUND: Complications including staple-line leakage and bleeding may occur after sleeve gastrectomy and Roux-en-Y gastric bypass. In this meta-analysis, the efficacy of fibrin sealant in strengthening the staple line and reducing complication risk after bariatric surgery was evaluated. METHODS: We searched PubMed, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) published up to October 2020. Pooled estimates of the outcomes were computed using a random effects model. The primary outcomes were bleeding and leakage; secondary outcomes were gastric stricture, length of hospital stay, reoperation rate, and total operation time. RESULTS: In total, 9 RCTs including 2136 patients were reviewed. Our meta-analysis revealed that compared with controls, fibrin sealants decreased incidence of bleeding significantly (risk ratio [RR] = 0.42; 95% confidence interval [CI], 0.18-0.97), but did not demonstrate significant differences in reducing the incidence of leakage (RR = 0.62; 95% CI, 0.23-1.73), gastric stricture (RR = 1.16; 95% CI, 0.46-2.91), reoperation rate (RR = 0.85; CI, 0.14-5.14), or length of hospital stay (weighted mean difference = 0.62; 95% CI, - 0.31 to 1.55). Compared with oversewing, fibrin sealant use reduced the operation time; however, their efficacies in reducing the incidence of postoperative bleeding and leakage did not differ significantly. CONCLUSIONS: Although applying fibrin sealants to the staple line in bariatric surgery may provide favorable results, but it may not reduce postoperative leakage and stricture incidence significantly. Nevertheless, the application of fibrin sealants as a method for reducing risks of complications after bariatric surgery warrant further investigation.

Efficacy of Different Procedures of Metabolic Surgery for Type 2 Diabetes in Asia: a Multinational and Multicenter Exploratory Study.

INTRODUCTION: Asian patients with diabetes exhibit different characteristics from Western patients. However, limited large-scale data are available on metabolic surgery procedures in Asia. We compared the short-term efficacies of metabolic surgery procedures for the management of Asian patients with different severities of diabetes. METHODS: We included patients undergoing metabolic surgery in five Asian institutions from January 2008 to December 2015 with at least 1-year postoperative follow-up. Outcomes of weight loss and diabetes control were determined. Diabetes remission rates in different ABCD scores and factors affecting diabetes remission were analyzed. RESULTS: A total of 1016 patients (mean BMI, 39.0 ± 7.2 kg/m2; HbA1c, 8.3% ± 1.7%) underwent metabolic surgery (197, Roux-en-Y gastric bypass [RYGB]; 171, one anastomosis gastric bypass [OAGB]; 437, sleeve gastrectomy [SG]; 130, SG with duodenal-jejunal bypass [SG-DJB]; and 81, single anastomosis duodenal-jejunal bypass with SG [SA-DJBSG]). The OAGB group exhibited significantly higher 1-year total weight loss (30.5%) and type 2 diabetes mellitus (T2DM) remission (78.4%) rates than did the other groups (p < .001). The patients with higher preoperative ABCD scores exhibited higher T2DM remission rates (81.8-100% and 9.5-46.2% in ABCD score subgroups of 9-10 and 1-2, respectively). In multivariate analysis, bypass was found to be an independent predictor of T2DM remission compared with SG (odds ratio of OAGB vs SG, 3.72; RYGB vs SG, 1.96; SG-DJB vs SG, 2.73; SA-DJBSG vs SG, 2.12). CONCLUSION: The metabolic surgeries are highly effective in T2DM treatment. However, SG may not be as effective as gastric bypass and duodenal-jejunum bypass.