Racial and Ethnic Underserved Populations Prescription Analgesic Use Before and After Lower Extremity Amputation in US Medicare.

BACKGROUND: Racial disparities exist in access to health care and management of multiple health conditions including chronic pain; however, racial disparities in pre- and postoperative pain management in lower extremity amputation are not well-studied. Our objective was to examine the association between different racial and ethnic groups and prescription opioid and other analgesics use before and after lower extremity amputation. We hypothesize prescription opioid and other analgesic use among Black, Hispanic, and Native American US Medicare beneficiaries undergoing lower extremity amputations will be lower compared to White US Medicare beneficiaries. METHODS: This retrospective cohort study included a 5% national sample of all Medicare beneficiaries from 2011 to 2015 and 15% national sample of fee-for-service Medicare beneficiaries from 2016 to 2018 undergoing nontraumatic, lower extremity amputations. The exposure of interest was racial and ethnic group membership (ie, Black, Hispanic, Native American, White, and others-with others being the combination of the categories Asian and other) as provided in Medicare claims data. Using multivariable generalized estimating equations with a logistic link to account for repeated measurements over time, we estimated the odds of prescription opioid use within 6 months before and after lower extremity amputation across different racial and ethnic groups separately, adjusting for sociodemographic and health status factors (eg, Elixhauser index). Adjusted odds ratios (aORs) and 95% confidence intervals (95% CI) were reported. RESULTS: Among 16,068 eligible beneficiaries who underwent major and minor amputations (mean age = 65.1 ± 12.7 years; female = 36.1%), 10,107 (62.9%) were White, 3462 (21.5%) were Black, 1959 (12.2%) were Hispanic, 247 (1.5%) were Native American, and 151 (2.9%) were beneficiaries of other races. During the 6 months before lower extremity amputation, Hispanic beneficiaries (aOR, 0.71, 95% CI, 0.65-0.78) and beneficiaries of other races (aOR, 0.60, 95% CI, 0.47-0.76) had significantly lower odds of using prescription opioids compared to White beneficiaries. Similarly, Hispanic beneficiaries (aOR, 0.78, 95% CI, 0.71-0.84) and beneficiaries of other races (aOR, 0.63, 95% CI, 0.51-0.78) were associated with lower odds of opioid use in the 6 months after amputation compared to White beneficiaries. CONCLUSIONS: Among fee-for-service Medicare beneficiaries, Hispanic and other (eg, Asian) fee-for-service Medicare beneficiaries had lower odds of prescription opioid use than their White counterparts before and after nontraumatic, lower extremity amputations. Efforts to determine the underlying reasons are needed to ensure equitable health care access.

Trajectories of Oral Anticoagulation Adherence and Associated Clinical Outcomes During Long-Term Anticoagulation Among Medicare Beneficiaries With Venous Thromboembolism.

BACKGROUND: Little is known about anticoagulation medication nonadherence patterns impacting effectiveness and safety outcomes in clinical practice. OBJECTIVE: We identified adherence trajectories of extended therapy with direct-acting oral anticoagulants (DOACs) and warfarin after 6 months initial anticoagulant therapy among Medicare beneficiaries with venous thromboembolism (VTE). We further assessed the associated recurrent VTE and major bleeding risks. METHODS: Using group-based trajectory models, this retrospective cohort study identified distinct beneficiary subgroups with similar adherence patterns of extended-phase anticoagulant treatment (DOACs or warfarin) for patients with VTE who completed 6 months of initial anticoagulant treatment. We examined associations between adherence trajectories and risks of recurrent VTE and major bleeding using inverse probability treatment weighted Cox proportional hazards models. RESULTS: Compared with no extended treatment, consistently high DOAC adherence was associated with decreased recurrent VTE risk (hazard ratio [HR] = 0.33, 95% confidence interval [CI] = 0.21-0.51) without increased major bleeding risk, and consistently high warfarin adherence was associated with decreased recurrent VTE risk (HR = 0.62, 95% CI = 0.40-0.95) and increased major bleeding risk (HR = 1.64, 95% CI = 1.12-2.41). Gradually declining adherence to DOACs (HR = 1.80, 95% CI = 1.07-3.03) or warfarin (HR = 2.34, 95% CI = 1.57-3.47) was associated with increased bleeding risk with no change in recurrent VTE risk. CONCLUSION AND RELEVANCE: This real-world evidence suggests persistently adhering to extended DOAC therapy is associated with lower recurrent VTE risk without increasing major bleeding among Medicare beneficiaries with VTE. Persistently adhering to extended warfarin therapy was associated with lower recurrent VTE risk but higher major bleeding risk.

Comparison of effectiveness and safety for low versus full dose of apixaban during extended phase oral anticoagulation in patients with venous thromboembolism.

BACKGROUND: The optimal dose of apixaban therapy to prevent asecondary venous thromboembolism (VTE) event remains unconfirmed. To investigate the effects of extended phase use of apixaban (2.5 vs. 5 mg twice daily) beyond 6 months of initial treatment on the risk of recurrent VTE and major bleeding events among patients with a history of VTE. METHODS: A retrospective cohort analysis of two large national insurance claims databases was conducted for patients diagnosed with VTE. Cox proportional hazard models after propensity score matching were used to compare the risk of recurrent VTE and major bleeding. RESULTS: There were no detected differences in recurrent VTE or major bleeding events between patients prescribed low versus full dose apixaban. CONCLUSION: This study provides evidence that apixaban 2.5 mg twice daily is an alternative option for extended phase therapy for risk reduction of VTE recurrence compared to apixaban 5 mg twice daily.

Fatty acid synthase (FASN) levels in serum of colorectal cancer patients: correlation with clinical outcomes.

Fatty acid synthase (FASN) is a common phenotype to many kinds of human cancers, such as those of the breast, ovary, pancreas, prostate, colon, and so on. Increased FASN levels have been detected in the serum of the patients with breast and pancreatic cancers. The relationship between the FASN level in serum and the clinicopathological characteristics of colorectal cancer is investigated in this study. FASN levels in serum were examined with enzyme-linked immunosorbent assay (ELISA) in 74 patients with colorectal cancer and 40 healthy persons. Pathological and clinical factors associated with FASN concentrations in serum were investigated and analyzed by statistical analysis. The FASN level in colorectal cancer patients' serum is significantly higher than that in healthy persons' serum. FASN levels in the serum of colorectal cancer patients are associated with tumor extent, lymph node metabasis status, distant metastasis, and tumor clinical stage. The 5-year overall survival rate and 5-year disease-free survival rate among patients with low FASN levels in serum are significantly higher than those among patients with high FASN levels in serum (log-rank P = 0.003). The high FASN level in serum is a promising independent predictor of colorectal cancers with advanced phases, late clinical stages, and shorter survival. These results suggest that FASN concentration in serum may be a potential and useful tumor marker.

Trajectories of adherence to extended treatment with direct oral anticoagulants and risks of recurrent venous thromboembolism and major bleeding.

BACKGROUND: Little is known about medication adherence patterns and their association with effectiveness and safety among patients with venous thromboembolism (VTE) receiving direct oral anticoagulant (DOAC) therapy beyond 3-6 months of initial treatment. OBJECTIVE: To examine the associations between adherence trajectories of extended treatment with DOAC and the risks of recurrent VTE and major bleeding among patients with VTE. METHODS: We conducted a retrospective cohort study of patients with incident VTE who completed 6 months of initial anticoagulant treatment and received either DOAC extended therapy or no extended therapy using MarketScan Commercial and Medicare Supplemental databases (2013-2019). We used group-based trajectory models to identify distinct adherence patterns during extended treatment. Using inverse probability treatment weighted Cox proportional hazards models, we examined the association between the adherence trajectories and the risks of recurrent VTE and major bleeding. RESULTS: Among 10,960 patients with extended treatment with DOACs (rivaroxaban, apixaban, dabigatran, edoxaban) and 5,133 patients with no extended treatment, we identified 4 distinct trajectories (consistently high, gradually declining, rapidly declining, and no extended treatment). Compared with the no extended treatment group, the groups with consistently high adherence (hazard ratio = 0.09, 95% CI = 0.05-0.17) and with gradually declining adherence (0.13, 0.03-0.53) showed decreased recurrent VTE risk without increased major bleeding risk (consistently high adherence 1.19, 0.71-1.99; gradually declining adherence 1.96, 0.81-4.70). There was no difference in the risk of recurrent VTE (0.34, 0.10-1.16) for the group with rapidly declining adherence, but this group was associated with increased major bleeding risk (2.65, 1.01-6.92). CONCLUSIONS: Our findings underscore the clinical importance of continuing and remaining adherent to extended DOAC treatment without increased major bleeding risk for patients with VTE. DISCLOSURES: This research was supported by the BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program. The funding source had no role in the design, collection, analysis, or interpretation of the data or the decision to submit the article for publication. Dr Lo-Ciganic reported receiving research funding from Merck Sharp & Dohme Corp. Dr Dietrich reported receiving honorarium for training and education from BMS/Pfizer. Dr DeRemer is a stockholder of Portola Pharmaceuticals and reported receiving personal fees for advisory board meeting from BMS. No other disclosures were reported.

Comparative effectiveness and safety of direct oral anticoagulants versus warfarin among patients with recurrent venous thromboembolism.

The comparative effectiveness and safety of oral anticoagulant therapies to prevent a second recurrent venous thromboembolism (VTE) remains undetermined. We aimed to compare the benefits and harms of direct oral anticoagulant (DOAC) and warfarin therapies in preventing second recurrent VTE and major bleeding events among patients with a recurrent VTE episode following anticoagulation therapy for incident VTE. A retrospective cohort analysis of two large national insurance claims databases was conducted for patients with two episodes of VTE. Cox proportional hazards models were used after inverse probability treatment weighting to compare risks of second recurrent VTE and major bleeding events. Compared with warfarin, DOAC therapy was associated with significantly decreased risk of second recurrent VTE with no significant difference in risk of major bleeding events. Our findings suggest that, compared with warfarin, DOACs may reduce risk of second VTE recurrence among patients who have experienced one recurrence.

Trajectories of adherence to extended treatment with warfarin and risks of recurrent venous thromboembolism and major bleeding.

Background: Little is published about warfarin therapy adherence patterns beyond 6 months of initial anticoagulant treatment and their association with effectiveness and safety for patients with venous thromboembolism (VTE). Objectives: To compare the risks of recurrent VTE and major bleeding during extended treatment between adherence patterns using MarketScan Commercial and Medicare Supplemental databases (2013-2019). Methods: In a retrospective cohort study, we included patients with incident VTE who completed an initial 6-month anticoagulant treatment and received either warfarin or no extended therapy. Group-based trajectory models were used to identify distinct extended treatment trajectories. Associations between the trajectories and risk of hospitalization due to recurrent VTE and major bleeding were assessed using inverse probability treatment-weighted Cox proportional hazards models. Results: Compared with no extended treatment, consistently high warfarin adherence was associated with a significantly decreased risk of hospitalization due to recurrent VTE (hazard ratio [HR] = 0.23; 95% CI, 0.12-0.45), but gradually (HR = 0.29; 95CI, 0.08-1.06) or rapidly declining (HR = 0.14; 95% CI, 0.02-1.24) adherence showed no association with the risk of hospitalization due to recurrent VTE. Compared with no extended treatment, warfarin extended therapy was associated with an increased risk of hospitalization due to major bleeding regardless of adherence patterns (consistently high: HR = 2.08; 95% CI, 1.18-3.64, gradually declining: HR = 2.10; 95% CI, 0.74-5.95, and rapidly declining: HR = 9.19; 95% CI, 4.38-19.29). However, compared with rapidly declining adherence, consistently high (HR = 0.23; 95% CI, 0.11-0.47) and gradually declining (HR = 0.23; 95% CI, 0.08-0.64) adherence were associated with decreased risk of hospitalization due to major bleeding. Conclusion: The findings indicated that consistently high adherence to extended warfarin treatment was associated with a decreased risk of hospitalization due to recurrent VTE but an increased risk of hospitalization due to major bleeding compared with no extended treatment.

Comparative effectiveness and safety of extended anticoagulant therapy among Medicare beneficiaries with venous thromboembolism.

Guidelines recommend an extended course of anticoagulation therapy for patients who experienced venous thromboembolism (VTE) without transient provocation, however, optimal duration remains uncertain. We assessed effectiveness and safety of extended use of apixaban and warfarin greater than 6 months of initial treatment in patients with VTE. We conducted a retrospective cohort study of Medicare beneficiaries aged greater than or equal to 18 years with deep vein thrombosis or pulmonary embolism. Patients were required to have initiated anticoagulants within 30 days of their first VTE diagnosis, completed 6 months of initial anticoagulant treatment, and received extended phase treatment with apixaban (the apixaban group) or warfarin (the warfarin group) or no extended therapy. Multivariable Cox proportional hazards modeling with inverse probability treatment weighting was used to compare recurrent VTE, mortality, and major bleeding risks among the three groups. Mean extended-treatment duration was up to 10 months and 14 months in apixaban and warfarin groups, respectively. Compared with no extended treatment, apixaban use was associated with decreased risks of recurrent VTE (hazard ratio [HR] = 0.08, [95% confidence interval [CI]: 0.01-0.41]) and mortality (HR = 0.37, [95% CI: 0.27-0.51]) without increased major bleeding risk (HR = 1.29, [95% CI: 0.68-2.45]); warfarin use was associated not with recurrent VTE risk change but with increased major bleeding risk (HR = 2.14, [95% CI: 1.26-3.65]) and decreased mortality risk (HR = 0.39, [95% CI: 0.29-0.51]). Compared with warfarin, apixaban use was associated with decreased recurrent VTE (HR = 0.13, [95% CI: 0.03-0.63]) and major bleeding (HR = 0.56, [95% CI: 0.32-0.98]) risks. Subgroup and sensitivity analyses (e.g., intention-to-treat) findings remained consistent. Compared with warfarin or no extended therapy, extended-apixaban use was associated with reduced risk of recurrent VTE without increased major bleeding risk. Continuing anticoagulant therapy with apixaban greater than 6 months may be effective and safe.

Clinician barriers, perceptions, and practices in treating patients with hepatitis C virus and substance use disorder in the United States.

The likelihood of clinicians prescribing direct-acting antiviral (DAA) therapy for patients with chronic hepatitis C virus (HCV) and substance use disorder (SUD) was assessed via a survey emailed throughout the United States to clinicians (physicians and advanced practice providers) in gastroenterology, hepatology, and infectious disease specialties. Clinicians' perceived barriers and preparedness and actions associated with current and future DAA prescribing practices of HCV-infected patients with SUD were assessed. Of 846 clinicians presumably receiving the survey, 96 completed and returned it. Exploratory factor analyses of perceived barriers indicated a highly reliable (Cronbach alpha = 0.89) model with five factors: HCV stigma and knowledge, prior authorization requirements, and patient- clinician-, and system-related barriers. In multivariable analyses, after controlling for covariates, patient-related barriers (P < 0.01) and prior authorization requirements (P < 0.01) were negatively associated with the likelihood of prescribing DAAs. Exploratory factor analyses of clinician preparedness and actions indicated a highly reliable (Cronbach alpha = 0.75) model with three factors: beliefs and comfort level; action; and perceived limitations. Clinician beliefs and comfort levels were negatively associated with the likelihood of prescribing DAAs (P = 0.01). Composite scores of barriers (P < 0.01) and clinician preparedness and actions (P < 0.05) were also negatively associated with the intent to prescribe DAAs. Conclusion: These findings underscore the importance of addressing patient-related barriers and prior authorization requirements-significant problematic barriers-and improving clinicians' beliefs (e.g., medication-assisted therapy should be prescribed before DAAs) and comfort levels for treating patients with HCV and SUD to enhance treatment access for patients with both HCV and SUD.

Deprescribing Strategies for Opioids and Benzodiazepines with Emphasis on Concurrent Use: A Scoping Review.

While the Food and Drug Administration's black-box warnings caution against concurrent opioid and benzodiazepine (OPI-BZD) use, there is little guidance on how to deprescribe these medications. This scoping review analyzes the available opioid and/or benzodiazepine deprescribing strategies from the PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library databases (01/1995-08/2020) and the gray literature. We identified 39 original research studies (opioids: n = 5, benzodiazepines: n = 31, concurrent use: n = 3) and 26 guidelines (opioids: n = 16, benzodiazepines: n = 11, concurrent use: n = 0). Among the three studies deprescribing concurrent use (success rates of 21-100%), two evaluated a 3-week rehabilitation program, and one assessed a 24-week primary care intervention for veterans. Initial opioid dose deprescribing rates ranged from (1) 10-20%/weekday followed by 2.5-10%/weekday over three weeks to (2) 10-25%/1-4 weeks. Initial benzodiazepine dose deprescribing rates ranged from (1) patient-specific reductions over three weeks to (2) 50% dose reduction for 2-4 weeks, followed by 2-8 weeks of dose maintenance and then a 25% reduction biweekly. Among the 26 guidelines identified, 22 highlighted the risks of co-prescribing OPI-BZD, and 4 provided conflicting recommendations on the OPI-BZD deprescribing sequence. Thirty-five states' websites provided resources for opioid deprescription and three states' websites had benzodiazepine deprescribing recommendations. Further studies are needed to better guide OPI-BZD deprescription.

Clinicopathological Significance of Mucin 2 Immuno-histochemical Expression in Colorectal Cancer: A Meta-Analysis.

OBJECTIVE: To evaluate the association between mucin 2 (MUC2) expression and clinicopathological characters of colorectal cancer. METHODS: A literature search was performed on December 31, 2010 according to defined selection criteria. We evaluated the correlation between MUC2 (detected by immunohistochemistry) and clinicopathological characters of colorectal cancer. According to the tumor histological type, differentiation, location and TNM staging of colorectal carcinoma, we divided the clinicopathological characteristics into different subgroups. Fixed and random effects models were applied for estimation of the summarized risk ratios (RRs) and 95% confidence intervals (CIs) in different subgroups. Finally, forest plots and funnel plots were created to allow for visual comparison of the results or the effect of publication bias. RESULTS: According with the inclusive criteria, fourteen studies (n=1,558) were eligible for the meta-analysis. We observed a trend towards a correlation of MUC2 higher positivity in mucinous than non-mucinous carcinoma (RR, 2.10; 95% CI, 1.30-3.40; P=0.002) and less positivity in distal than proximal colon (RR, 0.74; 95% CI, 0.64-0.85; P=0.000). There was no statistically significance for the association between MUC2 expression and differentiation or TNM staging of colorectal cancer, but MUC2 overexpression tended to be associated with the presence of T stage tumor (RR, 1.17; P=0.052). CONCLUSION: MUC2 overexpression was associated with the mucinous and proximal colorectal cancer.

Effectiveness and Safety of Extended Oral Anticoagulant Therapy in Patients with Venous Thromboembolism: A Retrospective Cohort Study.

Limited real-world evidence exists for effectiveness and safety of extended oral anticoagulation beyond 6 months of initial treatment in prevention of recurrent venous thromboembolism (VTE) and adverse major bleeding events among patients with VTE. Using MarketScan Commercial and Medicare Supplemental databases (2013-2019), we conducted a retrospective cohort study to compare the risk of recurrent VTE and major bleeding events during extended treatment among patients with VTE who completed the 6-month initial treatment and received extended oral anticoagulant treatment with apixaban, warfarin, or no extended treatment. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards modeling with inverse probability treatment weighting. We identified 14,818 patients with extended treatment of apixaban (n = 4,338), warfarin (n = 5,298), or no extended treatment (n = 5,182). Compared with no extended treatment, apixaban use was associated with decreased risk of recurrent VTE (HR: 0.10, 95% CI: 0.04-0.26) without increased risk of major bleeding events (HR: 1.06, 95% CI: 0.52-2.17); warfarin use was associated with decreased risk of recurrent VTE (HR: 0.23, 95% CI: 0.12-0.44) but with increased risk of major bleeding events (HR: 2.64, 95% CI: 1.51-4.59). Compared with warfarin, apixaban use was associated with decreased risk of major bleeding events (HR: 0.42, 95% CI: 0.22-0.80) but no difference in risk of recurrent VTE (HR: 0.46, 95% CI: 0.15-1.36). In a real-world clinical setting, extended anticoagulation with apixaban or warfarin was associated with decreased risk of recurrent VTE compared with no extended treatment, and apixaban had a better safety profile with fewer major bleeding events compared with warfarin among commercially insured patients with VTE.

Dosing profiles of concurrent opioid and benzodiazepine use associated with overdose risk among US Medicare beneficiaries: group-based multi-trajectory models.

BACKGROUND AND AIMS: One-third of opioid (OPI) overdose deaths involve concurrent benzodiazepine (BZD) use. Little is known about concurrent opioid and benzodiazepine use (OPI-BZD) most associated with overdose risk. We aimed to examine associations between OPI-BZD dose and duration trajectories, and subsequent OPI or BZD overdose in US Medicare. DESIGN: Retrospective cohort study. SETTING: US Medicare. PARTICIPANTS: Using a 5% national Medicare data sample (2013-16) of fee-for-service beneficiaries without cancer initiating OPI prescriptions, we identified 37 879 beneficiaries (age ≥ 65 = 59.3%, female = 71.9%, white = 87.6%, having OPI overdose = 0.3%). MEASUREMENTS: During the 6 months following OPI initiation (i.e. trajectory period), we identified OPI-BZD dose and duration patterns using group-based multi-trajectory models, based on average daily morphine milligram equivalents (MME) for OPIs and diazepam milligram equivalents (DME) for BZDs. To label dose levels in each trajectory, we defined OPI use as very low (< 25 MME), low (25-50 MME), moderate (51-90 MME), high (91-150 MME) and very high (>150 MME) dose. Similarly, we defined BZD use as very low (< 10 DME), low (10-20 DME), moderate (21-40 DME), high (41-60 DME) and very high (> 60 DME) dose. Our primary analysis was to estimate the risk of time to first hospital or emergency department visit for OPI overdose within 6 months following the trajectory period using inverse probability of treatment-weighted Cox proportional hazards models. FINDINGS: We identified nine distinct OPI-BZD trajectories: group A: very low OPI (early discontinuation)-very low declining BZD (n = 10 598; 28.0% of the cohort); B: very low OPI (early discontinuation)-very low stable BZD (n = 4923; 13.0%); C: very low OPI (early discontinuation)-medium BZD (n = 4997; 13.2%); D: low OPI-low BZD (n = 5083; 13.4%); E: low OPI-high BZD (n = 3906; 10.3%); F: medium OPI-low BZD (n = 3948; 10.4%); G: very high OPI-high BZD (n = 1371; 3.6%); H: very high OPI-very high BZD (n = 957; 2.5%); and I: very high OPI-low BZD (n = 2096; 5.5%). Compared with group A, five trajectories (32.3% of the study cohort) were associated with increased 6-month OPI overdose risks: E: low OPI-high BZD [hazard ratio (HR) = 3.27, 95% confidence interval (CI) = 1.61-6.63]; F: medium OPI-low BZD (HR = 4.04, 95% CI = 2.06-7.95); G: very high OPI-high BZD (HR = 6.98, 95% CI = 3.11-15.64); H: very high OPI-very high BZD (HR = 4.41, 95% CI = 1.51-12.85); and I: very high OPI-low BZD (HR = 6.50, 95% CI = 3.15-13.42). CONCLUSIONS: Patterns of concurrent opioid and benzodiazepine use most associated with overdose risk among fee-for-service US Medicare beneficiaries initiating opioid prescriptions include very high-dose opioid use (MME > 150), high-dose benzodiazepine use (DME > 40) or medium-dose opioid with low-dose benzodiazepine use.

[Implantation brachytherapy with 32P-chromic phosphate-poly (L-lactide) delayed-release particles for prostate cancer in nude mice].

OBJECTIVE: To study the effects of implantation brachytherapy with delayed-release particles of 32P-chromic phosphate-poly (L-lactide) (32P-CP-PLLA) on prostate cancer (PCa) in nude mice. METHODS: We established a subcutaneous transplantable PCa model in nude mice, and randomly divided them into six groups, Groups A, B and C implanted intratumorally with 32P-CP-PLLA delayed-release particles at 3.7, 7.4 and 14.8 MBq, Groups D, E and F with 125I particles at the same doses as the former three, and another six nude mice were included in Group G as the blank control. Then we killed the mice at 21 days after the treatment, observed the effects of the particles on the morphology of the tumor and their inhibition of tumor growth, counted WBCs and platelets (PLTs) in the peripheral blood, and detected the toxic reaction of the blood. RESULTS: At 21 days after the treatment, the solid tumor tissues exhibited bleeding and necrotic changes, and the rates of tumor inhibition were positively correlated with the doses of administration. Groups A, B and C showed statistically significant differences from Groups D, E, F and G in the rate of tumor inhibition ([ 65.72 +/- 6.95]%, [77.58 +/- 4.32]% and [82.64 +/- 4.03]% versus [35.61 +/- 5.61]%, [43.30 +/- 6.94]% and [69.01 +/- 4.98]%), WBC count ([1.72 +/- 0.37] x 10(9)/L, [1.23 +/- 0.27] x 10(9)/L and [0.86 +/- 0.25] x 10(9)/L versus [1.45 +/- 0.40] x 10(9)/L, [0.51 +/- 0.24] x 10(9)/L, [0.37 +/- 0.26] x 10(9)/L and [3.96 +/- 0.26] x 10(9)/L), PLT count ([1.18 +/- 0.11] x 10(11)/L, [0.97 +/- 0.10] x 10(11)/L and [0.72 +/- 0.11] x 10(11)/L versus [0.97 +/- 0.15] x 10(11)/L, [0.76 +/- 0.16] x 10(11)/L, [0.64 +/- 0.12] x 10(11)/L and [2.89 +/- 0.21] x 10(11)/L) and body weight ([18.60 +/- 0.66] g, [17.60 +/- 0.39] g and [16.90 +/- 0.68] g versus [17.86 +/- 0.60] g, [15.56 +/- 0.39] g, [14.61 +/- 0.65] g and [19.95 +/- 0.73] g) (P < 0.01). CONCLUSION: Intratumoral implantation of 32P-CP-PL-LA is a safe, simple and effective radionuclide interventional therapy for prostate cancer.

Protective effects of acarbose against vascular endothelial dysfunction through inhibiting Nox4/NLRP3 inflammasome pathway in diabetic rats.

The cardiovascular efficacy of glucose-lowering drugs is needed due to the cardiovascular complication in type 2 diabetes mellitus (T2DM). Acarbose is an α-glucosidase inhibitor that suppresses postprandial hyperglycemia, however, the cardiovascular protection of acarbose has still remained controversial. NLRP3 inflammasome activation mediated tight junction disruption, a hallmark event of endothelial barrier dysfunction leading to endothelial hyperpermeability in diabetes. Given the anti-inflammatory property of acarbose, it was investigated that acarbose protected against vascular endothelial barrier dysfunction through inhibiting NLRP3 inflammasome in vascular endothelial cells in T2DM rats. The rat aortic endothelial cells (RAECs) were incubated with high glucose (HG, 30 mM) for 24 h in vitro. It was found that HG significantly induced the formation and activation of NLRP3 inflammasome, which was markedly blocked by acarbose treatment. Furthermore, acarbose blocked the Nox4-dependent superoxide (O2.-) generation, which regulated NLRP3 inflammasome in RAECs. Importantly, we found that acarbose remarkably enhanced the junction protein expression of ZO-1 and VE-Cadherin and consequently abolished vascular hyperpermeability, which was associated with inhibiting NLRP3 inflammasome in RAECs. In vivo, acarbose intervention relieved vascular leakage in the heart of diabetic rats injected with Evans blue dye and the vasodilatory response to acetylcholine, which was accompanied with the restoration of ZO-1, VE-Cadherin, Nox4 and NLRP3 inflammasome in the aortal endothelium of diabetic rats. Taken together, our data indicated that acarbose ameliorated endothelial barrier dysfunction by directly inhibiting NLRP3 inflammasome which was dependent on inhibiting Nox4 oxidase-dependent O2.- production. These properties might carry a potential significance for acarbose in cardiovascular protection in diabetic patients.

Polymorphisms in metabolic GSTP1 and DNA-repair XRCC1 genes with an increased risk of DNA damage in pesticide-exposed fruit growers.

Pesticide exposure is associated with various neoplastic diseases and congenital malformations. Previous studies have indicated that pesticides may be metabolized by cytochrome P450 3A5 or glutathione S-transferases. DNA-repair genes, including X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD), may also be implicated in the process of pesticide-related carcinogenesis. Thus, we investigated whether various metabolic and DNA-repair genotypes increase the risk of DNA damage in pesticide-exposed fruit growers. Using the comet assay, the extent of DNA damage was evaluated in the peripheral blood of 135 pesticide-exposed fruit growers and 106 unexposed controls. The metabolic genotypes CYP3A5 (A(-44)G) and GSTP1 (Ile105Val) and DNA-repair genotypes XRCC1 (Arg399Gln, Arg194Trp, T(-77)C) and XPD (Asp312Asn, Lys751Gln) were identified by polymerase chain reaction. Our multiple regression model for DNA tail moment showed that age, high pesticide exposure, low pesticide exposure, GSTP1 Ile-Ile, and XRCC1 399 Arg-Arg genotype were associated with increased DNA tail moment (DNA damage). Further analysis of interaction between GSTP1 and XRCC1 genes that increase susceptibility revealed a significant difference in DNA tail moment for high pesticide-exposed subjects carrying both GSTP1 Ile-Ile with XRCC1 399 Arg-Arg genotypes (2.49+/-0.09 microm/cell; P=0.004), compared to those carrying GSTP1 Ile-Val/Val-Val with XRCC1 399 Arg-Gln/Gln-Gln genotypes (1.98+/-0.15 microm/cell). These results suggest that individuals with susceptible metabolic GSTP1 and DNA-repair XRCC1 genotypes may be at increased risk of DNA damage due to pesticide exposure.

GSTP1 genetic polymorphism is associated with a higher risk of DNA damage in pesticide-exposed fruit growers.

Pesticide exposure is associated with various neoplastic diseases and congenital malformations. Animal studies also indicated that pesticides may be metabolized by cytochrome P450 3A5 (CYP3A5) enzymes, paraoxonases (PON1 and PON2), or glutathione S-transferases (GSTM1, GSTT1, and GSTP1). However, little is known about the genotoxicity of pesticides in people with various genetic polymorphisms of human CYP3A5, PON1, PON2, GSTM1, GSTT1, and GSTP1. Thus, this study was designed to investigate whether various metabolic genotypes are more susceptible to DNA damage in pesticide-exposed fruit growers. Using the Comet assay, the extent of DNA damage was evaluated in the peripheral blood of 91 fruit growers who experienced pesticide exposure and 106 unexposed controls. Questionnaires were administered to obtain demographic data, cigarette smoking habits, medical, and occupational histories. The genotypes for CYP3A5, PON1, PON2, GSTM1, GSTT1, and GSTP1 genes were identified by PCR. The results showed that subjects experiencing high or low pesticide exposure had a significantly greater DNA tail moment (DAN damage) than did controls. The multiple regression model also revealed that age (P < 0.01), high pesticide exposure (P < 0.01), low pesticide-exposure (P < 0.01), and CYP3A5 (P = 0.04) and GSTP1 (P = 0.02) genotypes were significantly associated with an increased DNA tail moment. Further analysis of environmental and genetic interactions revealed a significant interaction for GSTP1 genotypes to influence DNA tail moment for the high pesticide exposure group. These results suggest that individuals with susceptible metabolic GSTP1 genotypes may experience an increased risk of DNA damage elicited by pesticide exposure.

Hyperbaric Oxygen and Ginkgo Biloba Extract Ameliorate Cognitive and Memory Impairment via Nuclear Factor Kappa-B Pathway in Rat Model of Alzheimer's Disease.

BACKGROUND: Hyperbaric oxygen (HBO) and Ginkgo biloba extract (e.g., EGB 761) were shown to ameliorate cognitive and memory impairment in Alzheimer's disease (AD). However, the exact mechanism remains elusive. The aim of the present study was to investigate the possible mechanisms of HBO and EGB 761 via the function of nuclear factor kappa-B (NF-κB) pathway. METHODS: AD rats were induced by injecting ß-amyloid 25-35 into the hippocampus. All animals were divided into six groups: Normal, sham, AD model, HBO (2 atmosphere absolute; 60 min/d), EGB 761 (20 mg·kg-1·d-1 ), and HBO/EGB 761 groups. Morris water maze tests were used to assess cognitive, and memory capacities of rats; TdT-mediated dUTP Nick-End Labeling staining and Western blotting were used to analyze apoptosis and NF-κB pathway-related proteins in hippocampus tissues. RESULTS: Morris water maze tests revealed that EGB 761 and HBO significantly improved the cognitive and memory ability of AD rats. In addition, the protective effect of combinational therapy (HBO/EGB 761) was superior to either HBO or EGB 761 alone. In line, reduced apoptosis with NF-κB pathway activation was observed in hippocampus neurons treated by HBO and EGB 761. CONCLUSIONS: Our results suggested that HBO and EGB 761 improve cognitive and memory capacity in a rat model of AD. The protective effects are associated with the reduced apoptosis with NF-κB pathway activation in hippocampus neurons.

Thymidine kinase 1 is a better prognostic marker than Ki-67 for pT1 adenocarcinoma of the lung.

OBJECTIVES: The sensitivity and reliability of the biomarkers thymidine kinase 1 (TK1) and Ki-67 were studied in relation to clinical features and prognosis of survival for pathological-T1 (pT1) lung adenocarcinoma patients. METHODS: TK1 and Ki-67 expression was determined in 80 patients with pT1 adenocarcinoma of the lung and in 20 specimens from normal lung tissues, using immunohistochemistry. RESULTS: TK1 was found in most lung tumor cells both in the cytoplasm and the nuclei. The positive labelling index (LI) for total TK1 was significantly higher than that for Ki-67. There was a significant correlation between the LI of total TK1 and lymph node metastasis, degree of tumor invasion and pathologic stages, which was not found for Ki-67. In addition, the overall 5-year survival of patients was statistically significant different between low and high levels of TK1 expression, but not in cases of Ki-67. A multivariate analysis revealed that expression of TK1, lymph node involvement and TNM pathology staging could serve as independent prognostic factors for the disease progression of pT1 lung adenocarcinoma patients. CONCLUSIONS: Compared with Ki-67, TK1 is a more reliable proliferation index in pT1 adenocarcinoma of lung, which can evaluate the invasion and the prognosis of tumor.

Tumor necrosis factor alpha affect hydrocortisone expression in mice adrenal cortex cells mainly through tumor necrosis factor alpha-receptor 1.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) is important in promoting relative adrenal insufficiency (RAI) due to systemic inflammatory response syndrome (SIRS). We identified the TNF-α receptor involved in the inhibition of adrenal corticotrophin (ACTH)-stimulated hydrocortisone release by studying the expression of TNF-α receptors in adrenal cortex Y1 cells and the effect of downregulating TNF receptors on ACTH-stimulated hydrocortisone release. METHODS: We used real-time PCR and immunocytochemistry to evaluate the expression of TNF receptors on Y1 cells. TNF-receptor 1 (TNF-R1) DNA fragments corresponding to the short hairpin RNA (shRNA)-sequences were synthesized and cloned into pcDNA(TM) 6.2-GW/EmGFP expression vector. Knockdown efficiency of TNF-R1 expression was evaluated in miRNA transfected and mock-miRNA transfected Y1 cells by quantitative real-time PCR (Q-PCR). Hydro-cortisone expression levels were determined in TNF-R1-knockdown and control Y1 cells treated with TNF-α and ACTH. RESULTS: Mouse adrenal cortex Y1 cells were positive for type I TNF-R1, but not type II TNF-receptor (TNF-R2). Blocking TNF-R1 expression resulted in loss of TNF-α-mediated inhibition of ACTH-stimulated hydrocortisone expression, suggesting a role for the TNF-R1 related signaling pathway in ACTH-stimulated hydrocortisone synthesis. CONCLUSION: The inhibitory effect of TNF-α on ACTH-stimulated hydrocortisone synthesis was mediated via TNF-R1 in adrenal cortex.