Enhanced laccase production by mutagenized Myrothecium verrucaria using corn stover as a carbon source and its potential in the degradation of 2-chlorophen.

Chlorophenols are widely used in industry and are known environmental pollutants. The degradation of chlorophenols is important for environmental remediation. In this study, we evaluated the biodegradation of 2-chlorophenol using crude laccase produced by Myrothecium verrucaria. Atmospheric and room temperature plasma technology was used to increase laccase production. The culture conditions of the M-6 mutant were optimized. Our results showed that corn stover could replace glucose as a carbon source and promote laccase production. The maximum laccase activity of 30.08 U/mL was achieved after optimization, which was a 19.04-fold increase. The biodegradation rate of 2-chlorophenol using crude laccase was 97.13%, a positive correlation was determined between laccase activity and degradation rate. The toxicity of 2-CP was substantially reduced after degradation by laccase solution. Our findings show the feasibility of the use of corn stover in laccase production by M. verrucaria mutant and the subsequent biodegradation of 2-chlorophenol using crude laccase.

[Sphingosine kinase 1 enhances the proliferation and invasion of human colon cancer LoVo cells through up-regulating FAK pathway and the expression of ICAM-1 and VCAM-1].

OBJECTIVE: To investigate the effects of sphingosine kinase 1 (SphK1) on the proliferation, migration and invasion of human colon cancer LoVo cells, and to explore the related mechanisms. METHODS: Human colon cancer LoVo cells were divided into three groups: phorbol 12-myristate 13-acetate (PMA) was used to induce the activation of SphK1 in the PMA group, N,N-dimethylsphingosine (DMS) used to suppress the activity of SphK1 in DMS group, and the cells treated with equal amount of 0.9 % NaCl instead of drugs served as the control group. The activity of SphK1 was assayed by autoradiography, the cell proliferation was assessed by MTT assay, cell migration and invasion were examined by Boyden chamber assay, concentrations of sICAM-1 and sVCAM-1 were assayed by ELISA, and RT-PCR and Western blot were used to evaluate the mRNA and protein expression in the cells. RESULTS: The activity of SphK1 was efficiently induced by PMA and significantly suppressed by DMS. PMA induced cell proliferation in a time- and dose-dependent manner. On the contrast, DMS suppressed cell proliferation in a time- and dose-dependent manner. After treating with PMA, the number of migrating and invasing cells were increased to 143.36 ± 8.73 and 118.46 ± 6.25, significantly higher than those of the control group (75.48 ± 6.12 and 64.19 ± 5.36). After treating with DMS, the number of migrating and invasing cells were decreased to 38.57 ± 3.24 and 32.48 ± 4.27, significantly lower than those of the control group (P < 0.01). The relative expression levels of FAK, ICAM-1 and VCAM-1 mRNA in the PMA group were 0.82 ± 0.06, 0.74 ± 0.05 and 0.89 ± 0.09, and those in the DMS group were 0.23 ± 0.02, 0.26 ± 0.03 and 0.37 ± 0.04, with significant differences between the PMA, DMS and control groups (P < 0.01). Compared with the control group, the relative expression levels of FAK and p-FAK proteins in the PMA group (0.52 ± 0.06 and 0.51 ± 0.06) were significantly elevated, and those of the DMS group (0.20 ± 0.03 and 0.09 ± 0.02) were significantly decreased. In addition, the concentrations of sICAM-1 and sVCAM-1 were significantly elevated with the activation of SphK1. On the contrary, those of the DMS group were significantly reduced with the suppression of SphK1 (Both P < 0.01). CONCLUSIONS: SphK1 may enhance the proliferation, migration and invasion of colon cancer LoVo cells through activating FAK pathway and up-regulating the expression of ICAM-1 and VCAM-1.

Adherence to endocrine therapy in patients with hormone receptor-positive early-stage breast cancer: a retrospective study.

BACKGROUND: The persistence and adherence to endocrine therapy (ET) in hormone receptor-positive (HR +) breast cancer patients remain far less than optimal. AIM: This retrospective study aimed to evaluate adherence to ET and to identify influencing factors in early-stage HR + breast cancer patients. METHOD: A stratified random sampling method was used to select patients admitted for breast cancer surgery at a university hospital in Shanghai, China. Patients who received ET medications in the hospital information system (HIS) were included. The primary outcomes were early discontinuation of and adherence to ET. Potential factors influencing the discontinuation and adherence were assessed using univariate and multivariate logistic regression analyses. RESULTS: In total, 706 patients were included, and 161 (22.8%) discontinued ET in less than five years from the first prescription. The discontinuation rates from the one-year to the five-year treatment were 5.38, 16.70, 32.27, 51.52, and 50.00%, respectively (P < 0.001). The rates of adherence (defined as medication possession ratio ≥ 80%) from the first to the fifth year were 85.18, 82.25, 82.18, 72.92, and 73.68%, respectively (P = 0.18). Age, insurance, and surgery type impacted ET discontinuation and adherence. However, the type of medication only impacted the adherence to ET. CONCLUSION: Persistence and adherence to ET in patients with breast cancer remain far from optimal and decrease over time. More attention should be paid to patients aged ≥ 70 years and those without insurance who tend to have early discontinuation of ET.

Sphingosine kinase 1 enhances colon cancer cell proliferation and invasion by upregulating the production of MMP-2/9 and uPA via MAPK pathways.

PURPOSE: Sphingosine kinase (SphK) 1 is an oncogenic enzyme promoting transformation, proliferation, and survival of a number of human tumor cells. However, its effect on colon cancer cell behavior has not been fully clarified. METHODS: SphK1 plasmid or SphK1 shRNA transfection and N,N-dimethylsphingosine (DMS) was used to regulate the expression and activity of SphK1 in colon cancer line LOVO. Cell proliferation, apoptosis, invasion, and protein expression were detected by MTT, flow cytometry, transwell chambers model, and western blot. The levels of metalloproteinases-2/9 (MMP-2/9) and urokinase plasminogen activator (uPA) were detected by ELISA. RESULTS: Overexpression of SphK1 after plasmid transfection markedly enhanced LOVO cell viability and invasiveness and reduced cell apoptosis. In contrast, inhibition of SphK1 by DMS and shRNA significantly suppressed cell viability and invasiveness but promoted cell apoptosis. SphK1 increased the constitutive expression of extracellular signal-regulated kinase1/2 (ERK1/2) but reduced the constitutive expression of p38 mitogen-activated protein kinase (MAPK). Blocking ERK1/2 pathway inhibited the biological effects induced by overexpression of SphK1. Blocking p38 MAPK pathway reversed the effects of DMS and SphK1 shRNA. Moreover, SphK1 was required for the production of MMP-2/9 and uPA in tumor cells, which was suppressed by ERK1/2 inhibitor U0126, but enhanced by the p38 MAPK inhibitor SB203580. CONCLUSIONS: SphK1 enhances colon cancer cell proliferation and invasiveness, meanwhile suppressing cell apoptosis. SphK1 promoting the secretion of MMP-2/9 and uPA via activation of ERK1/2 and suppression of p38 MAPK pathways maybe the molecular mechanisms for its regulation of the malignant behavior of colon cancer cell.

[The expression and clinical significance of SphK1 and nuclear factor-κB p65 in human colon carcinoma].

OBJECTIVE: To investigate the expression of sphingosine kinase 1 (SphK1) and NF-κB in colon carcinoma tissues and their correlation with clinicopathologic features. METHODS: Sixty-six paraffin-embedded colon carcinoma samples and 66 fresh colon carcinoma samples were tested using immunohistochemistry, RT-PCR and Western blot, respectively. RESULTS: In 66 fresh colon carcinoma samples, the positive rate of SphK1 and NF-κB mRNA expression were 84.85%(56/66) and 74.24% (49/66), while the positive rate of SphK1 and NF-κB protein detected by Western blot were 78.79% (52/66) and 69.70% (46/66). The positive rates were higher than those in the adjacent tissues [mRNA: 63.64% (42/66), 48.49% (32/66); protein: 57.58% (38/66), 45.45% (30/66)] and the normal mucosa [mRNA: 42.42% (28/66), 25.76% (17/66); protein: 36.36% (24/66), 24.24% (16/66)], with statistical significances (all P values < 0.05). The mean expressive levels of SphK1 and NF-κB mRNA and protein in colon carcinoma were both significantly higher than those in the adjacent tissues and the normal mucosa (mRNA: 0.55 ± 0.06 vs 0.35 ± 0.05 vs 0.25 ± 0.05, 0.75 ± 0.06 vs 0.43 ± 0.05 vs 0.30 ± 0.04; protein: 0.77 ± 0.05 vs 0.38 ± 0.06 vs 0.12 ± 0.03, 0.45 ± 0.08 vs 0.23 ± 0.05 vs 0.13 ± 0.03; all P values < 0.05). There was a close correlation between SphK1 and NF-κB expression levels (r = 0.459, P = 0.036). The results of immunohistochemistry were similar to those of RT-PCR and Western blot. Overexpression of SphK1 and NF-κB in colon carcinoma was related with depth of invasion, distant and lymph node metastasis and Dukes' stages (all P values < 0.05). The expression of SphK1 was also related with differentiation (P < 0.05). CONCLUSIONS: Overexpression of SphK1 and NF-κB may be involved in the pathogenesis and progression of colon carcinoma. Moreover, SphK1 and NF-κB may be correlated with the invasion and metastasis of colon carcinoma.

Toxicity spectrum of immunotherapy in advanced lung cancer: A safety analysis from clinical trials and a pharmacovigilance system.

Background: With the increased use of immune checkpoint inhibitors (ICIs) in advanced lung cancer, adverse events (AEs), particularly immune-related AEs (irAEs), have garnered considerable interest. We conducted a comprehensive assessment of the toxicity profile in advanced lung cancer using multi-source medical data. Methods: First, we systematically searched the PubMed, Embase, and Cochrane Library databases (from inception to 10 August 2021) for relevant randomised controlled trials (RCTs) involving ICI-based treatments for advanced lung cancer. The primary outcomes were treatment-related AEs and irAEs, including events that were assigned grade 1-5 and 3-5. The secondary outcomes were grade 5 AEs and irAEs (grade 1-5 and grade 3-5) in specific organs. Network comparisons were conducted for 11 treatments, including chemotherapy (CT), ICI monotherapy (three regimens: programmed death-1 receptor [PD-1] inhibitors, programmed death ligand-1 [PD-L1] inhibitors, and cytotoxic T lymphocyte-associated antigen [CTLA-4] inhibitors), dual-ICI combination therapy (two regimens), and treatment using one or two ICI drugs administered in combination with CT (five regimens). We also conducted a disproportionality analysis by extracting reports of various irAEs associated with ICIs from the FDA Adverse Event Reporting System (FAERS) database. The reporting odds ratios and fatality proportions of different irAEs were calculated and compared. PROSPERO: CRD42021268650. Findings: Overall, 41 RCTs involving 23,121 patients with advanced lung cancer were included. Treatments containing chemotherapy increased the risk of treatment-related AEs compared to ICI-based regimens without chemotherapy. Concerning irAEs, PD-L1 + CTLA-4 + CT was associated with the highest risk of grade 1-5 irAEs, followed by two regimens of dual ICI combination, three regimens of ICI monotherapy, and three regimens of one ICI combined with CT. For 3-5 irAEs, CTLA-4 accounted for most AEs. Detailed comparisons of ICI-based treatment options provided irAE profiles based on specific organs/systems and AE severity. Insights from the FAERS database revealed that signals corresponding to pneumonitis, colitis, thyroiditis, and hypophysitis were observed across all ICI regimens. Further analyses of the outcomes indicated that myocarditis (163 of 367, 44.4%), pneumonitis (1610 of 4497, 35.8%), and hepatitis (290 of 931, 31.1%) had high fatality rates. Interpretation: Included RCTs showed heterogeneity in a few clinical factors, and reports derived from the FAERS database might have involved inaccurate data. Our results can be used as a basis for improving clinical treatment strategies and designing preventive methods for ICI treatment in advanced lung cancer. Funding: This study was supported by the Research Project of Drug Clinical Comprehensive Evaluation and Drug Treatment Pathway (SHYXH-ZP-2021-001, SHYXH-ZP-2021-006), Clinical Research Innovation and Cultivation Fund of Ren Ji Hospital (RJPY-LX-008), Ren Ji Boost Project of National Natural Science Foundation of China (RJTJ-JX-001), and Shanghai "Rising Stars of Medical Talent" Youth Development Program - Youth Medical Talents - Clinical Pharmacist Program (SHWJRS (2019) 072).

Drug-related problems among hospitalized cancer pain patients: an investigative single-arm intervention trial.

BACKGROUND: To evaluate the characteristics of drug-related problems (DRPs) in cancer pain patients, and to identify the impact of pharmacists' intervention in cancer pain associated DRPs. METHODS: In this investigative, single-arm intervention study, clinical pharmacists identified DRPs in cancer pain patients and provided interventions based on medication information, direct patient-pharmacist interview, and ward rounds with multi-disciplinary team (MDT). Types and causes of DRPs, interventions, acceptance and outcome were sorted based on Pharmaceutical Care Network Europe (PCNE) DRP classification V9.0, which includes 3 primary domains for problems, 9 for causes, 5 for interventions, 3 for acceptance, and 4 for DRPs status. RESULTS: Totally, 42 cancer pain patients were enrolled, and 47 DRPs in 33 (78.6%) patients were identified by clinical pharmacists. The major type of DRPs was treatment effectiveness (30; 63.8%) and treatment safety (17; 36.2%). For the "treatment effectiveness" category, the "effect of drug treatment not optimal" was dominant category (27/30; 90%). A total of 66 DRP causes were identified, and most of DRPs were caused by "drug selection" (27; 40.9%) and "dose selection" (16; 24.2%). Within the "drug selection" category, "no or incomplete drug treatment in spite of existing indication" was dominant category (25/27; 92.6%). According to DRPs, 159 interventions were provided by clinical pharmacists and 99.4% of interventions were accepted by prescribers or patients. Finally, 44 (93.6%) DRPs were solved. CONCLUSIONS: In cancer pain patients, insufficient pain control mainly caused by inappropriate selection and dosage of analgesics. Clinical pharmacists' interventions dramatically ameliorate these problems and bring about positive effects in cancer pain pharmacotherapy.

High FAM189B Expression and Its Prognostic Value in Patients with Gastric Cancer.

The clinical significance of the family with sequence similarity 189 member B (FAM189B) gene remains largely unknown in gastric cancer (GC). A comprehensive investigation combining multiple detection methods was carried out in the current study to unveil the clinical implications and prospective molecular characterization of FAM189B protein and mRNA in GC. The protein level of FAM189B was clearly upregulated in the tumor tissues of GC as compared to noncancerous gastric tissues with 179 GC cases and 147 noncancerous gastric controls assessed by immunohistochemistry. The upregulation of the FAM189B protein was also found in the more deteriorating period of the tumor, as there were increasing trends in the groups of larger tumors, with lymph node metastasis, a further advanced clinical stage, and a higher histological grade. Next, we focused on the mRNA level of FAM189B in GC tissues using various high-throughput data. After the screening of GEO, ArrayExpress, and SRA, we finally achieved 18 datasets, including an RNA sequencing dataset of TCGA. Altogether, 1095 cases of GC tissue samples were collected, with 305 unique examples of noncancerous controls. Concerning the mRNA level of FAM189B in GC, the final standard mean difference (SMD) was 0.46 and the area under the curve (AUC) was 0.79 for the upregulation of FAM189B mRNA, which confirmed that the FAM189B mRNA level was also markedly upregulated in GC tissues and comparable to its protein level. The survival analysis showed that the higher expression of FAM189B was a risk factor for the overall survival, first progression, and postprogression survival of GC. For the Affymetrix ID 1555515_a_at of FAM189B, the higher expression level of FAM189B predicted a lower overall survival, first progression survival, and postprogression survival with the hazard ratio (HR) being 1.56 (1.24, 1.95), 1.69 (1.32, 2.17), and 1.97 (1.5, 2.6), respectively. For the Affymetrix ID 203550_s_at of FAM189B, a similar result could be found with corresponding HR being 1.49 (1.24, 1.8), 1.49 (1.21, 1.83), and 1.66 (1.32, 2.08), respectively. The interaction of MEM, COXPRESdb coexpressed genes, and DEGs of GC finally generated 368 genes, and the pathway of the cell cycle was the top pathway enriched by KEGG. In conclusion, the overexpression of the FAM189B protein and mRNA might enhance the incidence of GC.

A Network Comparison on Safety Profiling of Immune Checkpoint Inhibitors in Advanced Lung Cancer.

Background: Immune checkpoint inhibitors (ICIs) have become one of the standard treatment options for advanced lung cancer. However, adverse events (AEs), particularly immune-related AEs (irAEs), caused by these drugs have aroused public attention. The current network meta-analysis (NMA) aimed to compare the risk of AEs across different ICI-based regimens in patients with advanced lung cancer. Methods: We systematically searched the PubMed, EMBASE, and Cochrane Library databases (from inception to 19 April 2021) for relevant randomized controlled trials (RCTs) that compared two or more treatments, with at least one ICI administered to patients with advanced lung cancer. The primary outcomes were treatment-related AEs and irAEs, including grade 1-5 and grade 3-5. The secondary outcomes were grade 1-5 and grade 3-5 irAEs in specific organs. Both pairwise and network meta-analyses were conducted for chemotherapy, ICI monotherapy, ICI monotherapy + chemotherapy, dual ICIs therapy, and dual ICIs + chemotherapy for all safety outcomes. Node-splitting analyses were performed to test inconsistencies in network. Sensitivity analyses were adopted by restricting phase III RCTs and studies that enrolled patients with non-small cell lung cancer. Results: Overall, 38 RCTs involving 22,178 patients with advanced lung cancer were enrolled. Both pooled incidence and NMA indicated that treatments containing chemotherapy increased the risk of treatment-related AEs when compared with ICI-based regimens without chemotherapy. As for grade 1-5 irAEs, dual ICIs + chemotherapy was associated with the highest risk of irAEs (probability in ranking first: 50.5%), followed by dual-ICI therapy (probability in ranking second: 47.2%), ICI monotherapy (probability in ranking third: 80.0%), ICI monotherapy + chemotherapy (probability in ranking fourth: 98.0%), and finally chemotherapy (probability in ranking fifth: 100.0%). In grade 3-5 irAEs, subtle differences were observed; when ranked from least safe to safest, the trend was dual ICIs therapy (60.4%), dual ICIs + chemotherapy (42.5%), ICI monotherapy (76.3%), ICI monotherapy + chemotherapy (95.0%), and chemotherapy (100.0%). Furthermore, detailed comparisons between ICI-based options provided irAE profiles based on specific organ/system and severity. Conclusions: In consideration of overall immune-related safety profiles, ICI monotherapy + chemotherapy might be a better choice among ICI-based treatments for advanced lung cancer. The safety profiles of ICI-based treatments are various by specific irAEs and their severity. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42021268650.

A fatal myelosuppression, diarrhea and neurotoxicity induced by combination of irinotecan and tegafur-gimeracil-oteracil potassium in the treatment of colon cancer: a case report.

Chemical treatment is the vital pattern for colon cancer patients after surgery. Irinotecan and tegafur-gimeracil-oteracil potassium (S-1) combined chemotherapy is effective on metastatic colorectal cancer (mCRC). Nevertheless, patients receiving this combined chemotherapy might suffer the adverse drug reaction (ADR), such as myelosuppression and/or diarrhea, which could lead to poor prognosis. Here, we report a 76-year-old Chinese female who died due to the toxicity of combined therapy with irinotecan and S-1. This patient received irinotecan and S-1 combined therapy for 6 sessions after laparoscopic radical operation on colon cancer. After 6 sessions of chemotherapy, myelosuppression and severe diarrhea appeared with delirious accompanied. Antineoplastic agents were stopped immediately due to the appearance of III grade myelosuppression and IV grade diarrhea. Loperamide and octreotide were used to stop diarrhea, while granulocyte colony-stimulating factor (G-CSF) and recombinant human IL (IL-11) were used to improve blood cell count. Meanwhile, intravenous fluid replacement was continuously transfused to maintain water electrolyte balance. The patient remained continuous insanity and died 4 days after admission because of multiple organ failure, cardiac insufficiency, sever myelosuppression and ascending colon cancer. Myelosuppression is the principal toxicity associated with chemotherapy. And delayed-onset diarrhea is most frequently reported ADR of irinotecan, which could also be induced by S-1. Moreover, neurotoxicity is rarely reported as ADR for both irinotecan and S-1. Postoperative adjuvant chemotherapy should be carefully selected according to specific condition of patient. Blood routine examination should be monitored, and clinical manifestations should be carefully observed to ensure the safety and effectiveness of chemotherapy during the treatment.

Preliminary exploration on the role of clinical pharmacists in cancer pain pharmacotherapy.

BACKGROUND: More than half of cancer patients affected by cancer experience pain of moderate-tosevere intensity. Therefore, facilitating appropriate and safe administration of analgesics is crucial to the comprehensive management of cancer patients. In this article, we assessed medication adherence, pain relief, drug related problems (DRPs) and analgesics adverse events (AEs) in cancer pain patients based on a model of clinical pharmacy services. METHODS: In this prospective, single-arm intervention study, cancer pain patients admitted to our institution were eligible. According to different adherence, heterogeneity of pain, and individual treatment strategy, clinical pharmacists (CPs) provided comprehensive pain assessment and medication education for patients, as well as provided consultation and recommendation for physicians. CPs' pharmacy services were assessed through medication adherence, numbers of DRPs, acceptance of recommendation, pain intensity (PI), daily interference and AEs. RESULTS: A total of 42 patients were enrolled between November, 2018 and November, 2019. Compared to baseline, patients' medication adherence evaluated with a medication adherence scale showed a significantly improvement at 14 and at 28 days after receiving CPs' interventions (8 score vs. 7 score at 14 days and at 28 days, P<0.01). During the 28-day follow-up, a total of 63 interventions were put forward according to 57 identified DRPs in 33 patients (78.6%), and approximately 95% (60/63) of the interventions were accepted by physicians. PI and daily interference significantly improved on the third day after the interventions of CPs, and the improvement continued until day 28 (P<0.01). AEs caused by opioids occurred in 19 patients (45.2%), and the most common one was constipation (14 patients, 33.3%). CONCLUSIONS: CPs' comprehensive interventions for cancer pain patients were efficacious in improving their medication adherence and pain relief, as well as reducing incidence of AEs. Therefore, this promising model should be replicated in other medical centers.

Relationship of vasculogenic mimicry, SphK1 expression, and Cx43 expression to metastasis and prognosis in colorectal cancer.

OBJECTIVE: To determine the presence of vasculogenic mimicry (VM) and expression of Sphingosine kinase 1 (SphK1) and Connexin43 (Cx43) in colorectal cancer (CRC) tissues, and to identify their inter-relationships and associations with multiple pathologic parameters. METHODS: Ninety-two CRC specimens and normal pericarcinoma tissues were analyzed for expression of SphK1 and Cx43 using immunohistochemistry, and for identification of VM using CD34-periodic acid-Schiff dual staining. RESULTS: The positive rate of SphK1 expression was greater in CRC cells than pericarcinoma cells (85.87% vs. 33.70%, P < 0.05). In contrast, the positive rate of Cx43 expression was greater in pericarcinoma cells than in CRC cells (58.70% vs. 92.39%, P < 0.05). Analysis of CRC tissues indicated that expression of SphK1 was associated with poor differentiation, advanced tumor stage, lymph node metastasis, and the presence of VM (P < 0.05 for each comparison). Expression of Cx43 was associated with high differentiation and the presence of VM (P < 0.05 for each comparison). Patient sex, age, tumor size, depth of invasion, and distant metastasis were unrelated to the expression of either protein. There was a significant correlation between the expression of SphK1 and Cx43 (P < 0.05). Analysis of overall patient survival indicated that SphK1 positivity and the presence of VM were significantly associated with poor survival, but Cx43 positivity had no relationship with survival. CONCLUSION: SphK1 protein expression was significantly greater in CRC tissues than pericarcinoma tissues, suggesting this protein may be associated with the pathogenesis of CRC. In addition, the significant correlation between expression of SphK1 and Cx43 in CRC tissues suggests their interaction may impact the pathogenesis of CRC.

Net Clinical Benefit of Non-vitamin K Antagonist Oral Anticoagulants for Venous Thromboembolism Prophylaxis in Patients With Cancer: A Systematic Review and Trade-Off Analysis From 9 Randomized Controlled Trials.

Venous thromboembolism (VTE) is highly prevalent in patients with cancer. Non-vitamin K antagonist oral anticoagulants (NOACs), directly targeting the enzymatic activity of thrombin or factor Xa, have been shown to be as effective as and safer than traditional anticoagulation for VTE prophylaxis in no-cancer patients. However, related studies that focused on the anticoagulation in cancer patients are lacked, and almost no net clinical benefit (NCB) analyses that quantified both VTE events and bleeding events have been addressed in this fragile population. Therefore, we aim to investigate this issue using a systematic review and NCB analysis. A comprehensive search of Medline, Embase, and Cochrane Library were performed for randomized controlled trials (RCTs) that reported the VTE events and major bleeding of NOACs and traditional anticoagulants in patients with or without cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) of VTE and bleeding events were calculated using a random-effects model. The primacy outcome of narrow NCB was calculated by pooling ORs of VTE and major bleeding, with a weighting of 1.0. Similarly, the broad NCB was calculated by pooling ORs of VTE and clinically relevant bleeding. Heterogeneity was assessed through I2 test and Q statistic, and subgroup analyses were performed on the basis of different patients (VTE patients or acutely ill patients), comparators (vitamin-K antagonists or low-molecular-weight heparin), and follow-up duration (≤6 months or >6 months). Overall, 9 RCTs including 41,454 patients were enrolled, of which 2,902 (7%) were cancer patients, and 38,552 (93%) were no-cancer patients; 20,712 (50%) were administrated with NOACs and 20,742 (50%) were administrated with traditional anticoagulants. The use of NOACs had a superior NCB than traditional anticoagulation in both cancer patients (OR: 0.68, 95%CI: 0.50-0.85 for narrow NCB; OR: 0.76, 95%CI: 0.61-0.91 for broad NCB) and no-cancer patients (OR: 0.75, 95%CI: 0.54-0.96 for narrow NCB; OR: 0.85, 95%CI: 0.67-1.04 for broad NCB), with the estimates mainly from VTE patients receiving long-term warfarin treatment. In conclusion, NOACs may represent a better NCB property compared to traditional anticoagulants in cancer patients who need long-term anticoagulation treatment.

The safety of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension: Protocol for a systemic review and network meta-analysis.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease and ultimately leads to right heart failure. Endothelin receptor antagonists (ERAs) have been demonstrated to significantly improve prognosis in PAH. However, ERAs-induced side effects can result in poor patient tolerance. Thus, we aim to evaluate current safety evidence of ERAs in PAH. METHODS: An electronic search will be performed for randomized controlled trials (RCTs) that reported the interested safety data (abnormal liver function, peripheral edema, and anemia) of ERAs in PAH. Risk ratios (RRs) with their confidence intervals (CIs) and the surface under the cumulative ranking curve (SUCRA) will be calculated using a network analysis. RESULTS: This study will provide the safety evidence of ERAs in PAH by combining the results of individual studies based on direct- and network comparison, and to rank ERAs in the evidence network. CONCLUSIONS: The results will supplement missing evidence of head-to-head comparisons between different ERAs and guide both clinical decision-making and future research.

The optimal anticoagulant therapy for mechanical heart valves in a gallbladder cancer patient with hepatic metastases: A case report.

RATIONALE: Developing an optimal anticoagulant strategy poses a challenging task in patients with mechanical heart valves (MHVs) throughout their lifetime. We report an optimal anticoagulant therapy in a cancer patient with hepatic metastases after MHV replacement. PATIENT CONCERNS: A 68-year-old female with MHVs suffered from gallbladder cancer with hepatic metastases. Her international normalized ratio (INR) fluctuated owing to the declined hepatic function. DIAGNOSES: Gallbladder cancer and hepatic metastases, with a history of mechanic aortic valve replacement and mitral valve replacement. INTERVENTIONS: Warfarin was discontinued and Vitamin K1 was immediately administrated via intravenous infusion. low-molecular-weight heparin (LMWH) was regarded as a preferable option, and nadroparin at the dosage of 4100IU daily was administered. OUTCOMES: No adverse event occurred during the patient's hospitalization and two-week follow up after discharge. LESSONS: LMWH may represent a reasonable alternative regarding the inhibition of thrombus and bleeding in MHVs carriers with cancer and hepatic metastases.

Sphingosine kinase 1 promotes tumor progression and confers malignancy phenotypes of colon cancer by regulating the focal adhesion kinase pathway and adhesion molecules.

Studies suggest a tumor-promoting function of sphingosine kinase 1 (SphK1) in some types of human tumors, however, its effect on colon cancer is still unclear. The aims of this study were to investigate the roles of SphK1 in the progression and tumor cell phenotypic changes in colon cancer. Moreover, the focal adhesion kinase (FAK) pathway and the expression of intercellular adhesion molecule­1 (ICAM­1) and vascular cell adhesion molecule­1 (VCAM­1) were detected to explore the mechanisms of SphK1 action. In this study, the expression of SphK1, FAK and phospho-FAK (p-FAK) was analyzed in 66 surgical specimens of primary colon cancer and matched adjacent normal tissues by immunohistochemistry and western blotting. In addition, N,N-dimethylsphingosine (DMS), SphK1 DNA and shRNA transfection were used to regulate the expression and activity of SphK1 in the LOVO colon cancer cell line. Tumor cell phenotypic changes were analyzed by cell viability, invasion and apoptosis assays. Results showed that the expression of SphK1, FAK and p-FAK in colon cancer tissues were significantly stronger compared to those in matched normal tissues. There was a close correlation between the expression of SphK1 and FAK or p-FAK and the co-expression of SphK1, FAK and p-FAK significantly associated with histological grade, Dukes' stage, lymph node metastasis and distant metastasis. Overexpression of SphK1 after DNA transfection enhanced tumor cell viability and invasiveness, but suppressed cell apoptosis. In contrast, suppression of SphK1 by DMS and shRNA reduced tumor cell viability and invasiveness, but promoted cell apoptosis. The expression of FAK, p-FAK, ICAM-1 and VCAM-1 in LOVO cells were increased with the overexpression of SphK1 but decreased with the suppression of SphK1. These findings indicate that SphK1 regulates tumor cell proliferation, apoptosis and invasion, which ultimately contributes to tumor progression and malignancy phenotype in colon cancer. FAK pathway, ICAM-1 and VCAM-1 may play critical roles in this SphK1­mediated effect.