What Kind of Dressing Is Important to Ensure Wound Healing With the Application of Platelet-Rich Plasma in Chronic Ulcers?

Wound healing is an intricate process of tissue regeneration that depends on the simultaneous presence of immunological and microenvironmental factors. The significant role of platelets and their granules in the wound-healing process has led to extensive research on their potential as a therapeutic intervention in different areas, including chronic wounds and aesthetic therapies. Saltwater aids in purification and promotes healing by utilizing osmosis. Sodium chloride, the chemical component present in salt, induces the extrusion of fluids from cells upon contact. If the liquids in issue are bacterial, they will also be ejected, assisting in the cleansing of the skin. Desiccation, often known as the drying out of injured cells, is well-known for its antibacterial properties and subsequent ability to reduce inflammation. This case series aims to investigate the advantages of using saltwater dressing following platelet-rich plasma therapy for chronic wounds.

Obesity Differs from Diabetes Mellitus in Antibody and T Cell Responses Post COVID-19 Recovery.

Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.

Assessing Trace Metal-Based Human Health Risks for Commonly Used Body Soaps in Bangladesh.

In Bangladesh, body soaps are very popular among consumers due to their flavors and low alkali content. The current study assesses the contamination of several trace metals (TMs) such as iron (Fe), copper (Cu), zinc (Zn), chromium (Cr), manganese (Mn), nickel (Ni), cadmium (Cd), and lead (Pb) in some of the body soaps most commonly used in Bangladesh. The concentrations of Fe, Cu, Zn, Cr, and Mn were found within the acceptable limits stipulated by the World Health Organization (WHO); however, in contrast, the concentrations of Ni, Cd, and Pb remained below the detection limit. Notably, the concentration of Cr in two soap samples (S-2, S-3) out of twenty-one soap samples exceeded the permissible limit stipulated by the WHO. Health risks associated with the TM intake via dermal routes were evaluated in terms of chronic daily intake (CDI) and hazard quotient (HQ). The results indicated that no non-carcinogenic risks (NCR) are likely to occur owing to the use of those body soaps. The carcinogenic risk (CR) estimated for Cr revealed no possibility of probable carcinogenic diseases. Though the NCR and CR are unlikely to occur resulting from the long-term uses of these soaps, the present study provides baseline information on the possible contaminations of TMs in the beauty soaps that do not seem to have been reported so far in Bangladesh. In light of the above information, it can be concluded that the presence of TMs in the body soaps could be a warning for people in general thereby suggesting continuous monitoring.

Does First-Use Syndrome Happen During Apheresis? A Case Report.

Steam, dry heat, radiation, ethylene oxide gas, evaporated hydrogen peroxide, and many other sterilization methods are used to sanitize medical equipment (e.g., chlorine dioxide gas, nitrogen dioxide, and vaporized peracetic acid). The benefits of ethylene oxide (EO) are its great processing capabilities, high ionic conductivity, high flexibility, low cost, and exceptional adhesive qualities. Patients on hemodialysis, those undergoing extracorporeal photopheresis, and plasmapheresis donors have all reported allergic reactions to EO. Differentiating between IgE-mediated anaphylaxis and anaphylactoid reactions is often impossible in practice due to the wide range of clinical symptoms. The infrequency of EO reactions coupled with healthcare personnel's lack of familiarity with this clinical phenomenon may result in their underdiagnosis. We describe the case of a platelet donor who developed an allergy, while donating at a transfusion facility, due to an ethylene oxide-sterilized apheretic kit. We aim to draw attention to the fact that care should be given while handling cases of this nature as they can become life-threatening.

Outcome of Intra-articular Injection of Total Stromal Cells and Platelet-Rich Plasma in Primary Knee Osteoarthritis: A Randomized Clinical Trial.

INTRODUCTION:  Mesenchymal stem cell (MSC) therapy appeared promising in knee osteoarthritis (OA). We examined if a single intra-articular (IA) autologous total stromal cells (TSC) and platelet-rich plasma (PRP) injection improved knee pain, physical function, and articular cartilage thickness in knee OA. METHODS:  The study was performed in the physical medicine and rehabilitation department of Bangabandhu Shaikh Mujib Medical University, Dhaka, Bangladesh. Knee OA was diagnosed according to the American College of Rheumatology criteria and randomly assigned to treatment (received TSC and PRP) and control groups. Kallgreen-Lawrance (KL) scoring system was used to grade primary knee OA. The Visual Analogue Scale (VAS, 0-10 cm) for pain, WOMAC (Western Ontario and McMaster Universities Arthritis Index) for physical function, and medial femoral condylar cartilage (MFC) thickness (millimeters) under ultrasonogram (US) were documented and compared between groups before and after treatment. Statistical Package analyzed data for Social Scientists (SPSS 22.0; IBM Corp, Armonk, NY) was used for data analysis. Pre- and post-intervention outcomes were measured using the Wilcoxon-sign test, whereas Mann-Whitney U-test calculated the difference between groups; a p-value <0.05 was considered statistically significant.  Result: In the treatment group, 15 received IA-TSC and PRP preparation, and in the control group, 15 patients received no injection, but quadricep muscle-strengthening exercise. There was no significant difference between groups regarding VAS for pain, WOMAC physical function, and cartilage thickness before starting the treatment and two weeks after intervention. VAS for pain and WOMAC physical function scores improved profoundly in the treatment group after 12 and 24 weeks of intervention; the pain and physical function scores difference between groups was also significant. However, significant mean femoral cartilage thickness was not changed until the end of 24 weeks (U=175.00, p=0.009 two-tailed and U= 130.00, p=0.016 two-tailed, respectively, for right and left knee). CONCLUSION:  Single TSC and PRP injection reduces knee pain and improves physical function and cartilage thickness in knee OA. While pain and physical function improvement happen earlier, cartilage thickness change takes more time.

Knowledge, Attitude, and Practices on Antimicrobial Use and Antimicrobial Resistance among Commercial Poultry Farmers in Bangladesh.

Antimicrobial resistance (AMR) has become an emerging health issue globally, posing a threat to zoonotic pathogens and foodborne diseases. In Bangladesh, the poultry sector supplies the majority of the demand for animal-source protein. The irrational and excessive use of antimicrobials (AMU) has been observed in the poultry sector. The development of AMR is associated with many factors, including the knowledge and attitudes of poultry farmers. Therefore, AMR reduction requires intervention from all the stockholders, including the farmers who are considered as end users of antimicrobials. This current research conducted a cross-sectional study to assess the knowledge, attitudes, and practices (KAP) of poultry farmers on AMU and AMR in Bangladesh. We determined the KAP of poultry farmers (broiler and layer farmers) of some selected districts of the country using a tested and paper-based questionnaire. The results demonstrated that most of the respondents have insufficient KAP regarding AMU and AMR. The respondents used a variety of antimicrobials primarily in the treatment of various diseases in poultry. One-third of the farmers did not seek antimicrobials from registered vets. Instead, they depended on others or themselves. The factor score analysis further revealed that the farmers' demographic and socioeconomic variables were significant factors influencing the KAP. An adjusted logistic regression analysis showed that older farmers with 9-12 years of farming experience and graduate-level education, engaging in medium-sized layer farming, were more likely to have correct KAP on AMU and AMR. Further, farmers from the Cox's Bazar region showed correct knowledge, whereas farmers of the Chattogram region showed a correct attitude towards AMU and AMR. A Spearman's rank-order correlation revealed a positive association between knowledge-attitudes and knowledge-practices. The findings of the current investigation provide baseline evidence about the KAP of poultry farmers from low-income resources and offer insights into designing interventions and policies for the use of AMU and AMR in Bangladesh.

Knowledge, Attitude, and Practices on Antimicrobial Use and Antimicrobial Resistance among Poultry Drug and Feed Sellers in Bangladesh.

Poultry production has boomed in Bangladesh in recent years. The poultry sector has contributed significantly to meet the increased demand for animal source proteins in the country. However, increased use of antimicrobials appeared to be a significant threat to food safety in the poultry sector. The poultry drug and feed sellers are at the frontline position involving selecting and delivering the antimicrobials to the poultry farmers. Studies assessing the poultry drug and feed sellers' knowledge, attitudes, and practices (KAPs) are limited. The current study aimed to assess the community poultry drug and feed sellers' KAPs of antimicrobial use (AMU) and antimicrobial resistance (AMR) in some selected areas of Bangladesh. We determined the respondents' (drug and the feed sellers) KAPs of AMU and AMR using a tested and paper-based questionnaire. The study demonstrated that most respondents have insufficient knowledge, less positive attitudes, and inappropriate practices regarding AMU and AMR. The factor score analysis further showed that the type of respondents and their years of experience, level of education, and training on the drug were the significant factors impacting the current knowledge, attitudes, and practices of AMU and AMR. The adjusted logistic regression analysis revealed that the drug sellers who completed their education up to 12th grade and had training on the drug had adequate knowledge of AMU and AMR. The data also showed that the drug sellers belong to the age group 31-35 and 36-40 years and who completed 12th grade had good attitudes on the same. Likewise, the analysis further determined that drug sellers belonging to the age category 18-25 and 26-30 years, and interestingly, the respondents who completed education up to 12th grade, had better practices. Spearman's rank-order correlation revealed a positive association between each pair of the KAPs scores for the respondents. The correlation was fair between knowledge-attitudes, knowledge-practices, and attitudes-practices. Based on the current study results, we recommend educational interventions and appropriate training for the poultry drug and feed sellers to raise awareness and to upgrade their current knowledge on the appropriate use of antimicrobials. This will ultimately lead to reducing the chances of developing AMR in the poultry sectors of the country.

Antibody Response to ChAdOx1-nCoV-19 Vaccine Among Recipients in Bangladesh: A Prospective Observational Study.

PURPOSE: The aim of the study was to assess the antibody response to the ChAdOx1-nCoV vaccine in individuals who were not previously infected by COVID-19. PATIENTS AND METHODS: All people aged 18-65 years who received their first vaccination with ChAdOx1-nCoV from March to May 2021 were approached for inclusion. Individuals with sufficient antibody titers against SARS-CoV-2 infection before vaccination were considered previously infected and were excluded from the analysis. We observed viral spike protein RBD-S1-specific IgG antibody levels at day 28 of the first dose of vaccination and day 14 of the second dose of vaccination (74 days from index vaccination). An optical density ratio (ODR) of >1.1 was considered to have a positive antibody response, 0.8 to 1.1 borderline and <0.8 was denoted as negative. Informed consent was ensured before enrollment, and ethical principles conformed with the current Declaration of Helsinki. RESULTS: This observational study comprised 769 infection-naïve individuals (mean age 40.5 years, 38.9% female). Spike-specific IgG antibody responses elicited after the first and second doses of vaccine were 99.9% and 100%, respectively. The median ODR was 5.43 (interquartile range [IQR]: 4.32-6.98) and 10.90 (IQR 9.02-11.90) after the first and second doses. Higher age was associated with lower antibody levels after both dosages. However, no sex-specific variation was seen. People with comorbidity had a lower antibody level after the second dose. Tenderness (51.46%) and fever (19.30%) were the most common local and systemic side effects after vaccination. CONCLUSION: This study was one of the earlier attempts in the country to assess the antibody response to ChAdOx1-nCoV vaccine recipients. The results imply that general people should be encouraged to take the vaccine at their earliest.

Convalescent plasma transfusion therapy in severe COVID-19 patients- a safety, efficacy and dose response study: A structured summary of a study protocol of a phase II randomized controlled trial.

OBJECTIVES: General: To assess the safety, efficacy and dose response of convalescent plasma (CP) transfusion in severe COVID-19 patients Specific: a. To identify the appropriate effective dose of CP therapy in severe patients b. To identify the efficacy of the therapy with their end point based on clinical improvement within seven days of treatment or until discharge whichever is later and in-hospital mortality c. To assess the clinical improvement after CP transfusion in severe COVID-19 patients d. To assess the laboratory improvement after CP transfusion in severe COVID-19 patients TRIAL DESIGN: This is a multicentre, multi-arm phase II Randomised Controlled Trial. PARTICIPANTS: Age and sex matched COVID-19 positive (by RT-PCR) severe cases will be enrolled in this trial. Severe case is defined by the World Health Organization (W.H.O) clinical case definition. The inclusion criteria are 1. Respiratory rate > 30 breaths/min; PLUS 2. Severe respiratory distress; or SpO2 ≤ 88% on room air or PaO2/FiO2≤ 300 mm of Hg, PLUS 3. Radiological (X-ray or CT scan) evidence of bilateral lung infiltrate, AND OR 4. Systolic BP < 90 mm of Hg or diastolic BP <60 mm of Hg. AND/OR 5. Criteria 1 to 4 AND or patient in ventilator support Patients' below18 years, pregnant and lactating women, previous history of allergic reaction to plasma, patients who have already received plasma from a different source will be excluded. Patients will be enrolled at Bangabandhu Sheikh Mujib Medical University (BSMMU) hospital, Dhaka medical college hospital (DMCH) and Mugda medical college hospital (MuMCH). Apheretic plasma will be collected at the transfusion medicine department of SHNIBPS hospital, ELISA antibody titre will be done at BSMMU and CMBT and neutralizing antibody titre will be checked in collaboration with the University of Oxford. Patients who have recovered from COVID-19 will be recruited as donors of CP. The recovery criteria are normality of body temperature for more than 3 days, resolution of respiratory symptoms, two consecutively negative results of sputum SARS-CoV-2 by RT-PCR assay (at least 24 hours apart) 22 to 35 days of post onset period, and neutralizing antibody titre ≥ 1:160. INTERVENTION AND COMPARATOR: This RCT consists of three arms, a. standard care, b. standard care and 200 ml CP and c. standard care and 400 ml CP. Patients will receive plasma as a single transfusion. Intervention arms will be compared to the standard care arm. MAIN OUTCOMES: The primary outcome will be time to clinical improvement within seven days of treatment or until discharge whichever is later and in-hospital mortality. The secondary outcome would be improvement of laboratory parameters after therapy (neutrophil, lymphocyte ratio, CRP, serum ferritin, SGPT, SGOT, serum creatinine and radiology), length of hospital stay, length of ICU stay, reduction in proportion of deaths, requirement of ventilator and duration of oxygen and ventilator support. RANDOMISATION: Randomization will be done by someone not associated with the care or assessment of the patients by means of a computer generated random number table using an allocation ratio of 1:1:1. BLINDING (MASKING): This is an open level study; neither the physician nor the patients will be blinded. However, the primary and secondary outcome (oxygen saturations, PaO2/FiO2, BP, day specific laboratory tests) will be recorded using an objective automated method; the study staff will not be able to influence the recording of these data. NUMBER TO BE RANDOMISED (SAMPLE SIZE): No similar study has been performed previously. Therefore no data are available that could be used to generate a sample size calculation. This phase II study is required to provide some initial data on efficacy and safety that will allow design of a larger study. The trial will recruit 60 participants (20 in each arm). TRIAL STATUS: Protocol version 1.4 dated May 5, 2020 and amended version 1.5, dated June 16, 2020. First case was recruited on May 27, 2020. By August 10, 2020, the trial had recruited one-third (21 out of 60) of the participants. The recruitment is expected to finish by October 31, 2020. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT04403477 . Registered 26 May, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trial's website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Circadian genes and risk of prostate cancer in the prostate cancer prevention trial.

Circadian genes have been considered as a possible biological mechanism for the observed relationship between circadian rhythm disruptions and increased risk of hormone-related cancers. In the current study, we investigated the relationship between circadian gene variants and prostate cancer risk and whether reducing bioavailable testosterone modifies the circadian genes-prostate cancer relationship. We conducted a nested case-control study among Caucasian men in the Prostate Cancer Prevention Trial (PCPT), a randomized placebo-controlled clinical trial to assess if finasteride (an androgen bioactivation inhibitor) could prevent prostate cancer. We evaluated the associations between 240 circadian gene variations and prostate cancer risk among 1092 biopsy-confirmed prostate cancer cases and 1089 biopsy-negative controls in the study (642 cases and 667 controls from the placebo group; 450 cases and 422 controls from the finasteride group), stratified by treatment group. Among men in the finasteride group, there were suggestive associations between NPAS2 variants and total prostate cancer risk, with one SNP remaining statistically significant after Bonferroni correction (rs746924, odds ratio [OR] = 1.5, P = 9.6 × 10-5 ). However, we found little evidence of increased prostate cancer risk (overall or by low/high grade) associated with circadian gene variations in men of the placebo group, suggesting potential modification of genetic effects by treatment. We did not find strong evidence that circadian gene variants influenced prostate cancer risk in men who were not on finasteride treatment. There were suggestive associations between NPAS2 variants and prostate cancer risk among men using finasteride, which warrants further investigations.

Stem Cell Therapy for Cirrhosis of Liver in Bangladesh: Specific Design Compatible for Developing Country.

AIMS AND OBJECTIVES: To assess the safety and efficacy of stem cell therapy in patients with cirrhosis of the liver (LC) in the context of developing country with limited facilities for cell-based therapy and advanced technologies. MATERIALS AND METHODS: A total of 34 patients received granulocyte colony-stimulating factor at a dose of 30 IU, daily for 2 to 11 days to upregulate the numbers of white blood cells and stem cells. Subsequently, stem cells were isolated from the peripheral blood of LC patients in a closed chamber using a harvesting machine. Variable amounts of autologous stem cells were injected to LC patients for once. The patients were followed for 3 months and various factors related to safety and parameters of efficacy were analyzed in this interim report. RESULTS: Out of 34 patients available for final analysis, 3 months after the start of stem therapy, 4 patients died within this period. There was no significant alteration in biochemical parameters due to stem cell therapy, and patients also did not develop any features of acute liver failure indicating that short-term safety parameters of stem cell therapy may be acceptable. Stem cell therapy had a dominant effect on ascites of in this cohort. Although 24 of 34 patients had ascites at the start of therapy,ascites were found in 11 patients after one month and only 4 patients had ascites after 3 months. The positive role of stem cell therapy on ascites in LC patients may be attributed, even in part, to increased serum levels of albumin after therapy compared to basal levels (p <0.001). CONCLUSION: This first study about stem cell therapy in Bangladesh indicates that cell therapy may be accomplished in general hospitals of developing countries if the proper design and mild to moderate types of invasive approach is utilized. The apparent safety of administered stem cells in LC patients and the observed effect on ascites of LC patients inspire optimism about the installation of new and innovative therapy in Bangladesh. Future studies with phase I/II may with stem cell and others cell may be planned at Bangladesh in patients with LC and other intractable diseases with suitable control arms.How to cite this article: Mahtab MA, Akbar SMF, Begum M, Islam MA, Rahim MA, Noor-E-Alam SM, Alam MA, Khondaker FA, Moben AL, Mohsena M, Khan SI, Huq MZ, Munshi S, Hoque A, Haque SA. Stem Cell Therapy for Cirrhosis of Liver in Bangladesh: Specific Design Compatible for Developing Country. Euroasian J Hepatogastroenterol, 2018;8(2):121-125.

Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer.

BACKGROUND: In the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride. METHODS: From 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERß, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers. FINDINGS: We found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups. INTERPRETATION: We showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT.

Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the Prostate Cancer Prevention Trial.

BACKGROUND: Prostate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment. METHODS: A nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. RESULTS: There were significant associations of genetic polymorphisms in steroid 5α-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend < .05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; Ptrend < .05) were significantly associated with both circulating hormone levels and prostate cancer risk. CONCLUSIONS: Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. Cancer 2016;122:2332-2340. © 2016 American Cancer Society.

Serum androgens and prostate cancer risk: results from the placebo arm of the Prostate Cancer Prevention Trial.

BACKGROUND: Compelling and long-standing data suggest that androgens play an important role in the development of both normal prostate epithelium and prostate cancer. Although testosterone administration can induce prostate cancer (PCA) in laboratory animals, serum-based epidemiologic studies examining androgens in humans have not consistently supported a role for androgens in prostate carcinogenesis. We examined whether pre-diagnostic serum androgens were associated with PCA risk in the placebo arm of the Prostate Cancer Prevention Trial. METHODS: In this nested case-control study, cases (n = 1,032) were primarily local-stage, biopsy-detected cancers, and controls (n = 1,025) were biopsy-confirmed to be PCA-free. Pre-diagnostic serum androgens (total testosterone, 3α-androstanediol glucuronide, free testosterone), estrogen-to-testosterone ratio, and sex hormone-binding globulin (SHBG) concentrations were measured in pooled (baseline and year 3) blood samples. RESULTS: We found no significant associations between serum androgens, estrogen-to-testosterone ratios, or SHBG and risk of total, low (Gleason <7) or high-grade (Gleason 7-10) PCA. CONCLUSION: Much remains to be learned about the role of androgens in prostate carcinogenesis. Further research is needed to evaluate the role of androgens, timing of exposure, genetic modulators of androgen metabolism, or environmental exposures that may affect androgen influence on prostate carcinogenesis.

Finasteride concentrations and prostate cancer risk: results from the Prostate Cancer Prevention Trial.

OBJECTIVE: In the Prostate Cancer Prevention Trial (PCPT), finasteride reduced the risk of prostate cancer by 25%, even though high-grade prostate cancer was more common in the finasteride group. However, it remains to be determined whether finasteride concentrations may affect prostate cancer risk. In this study, we examined the association between serum finasteride concentrations and the risk of prostate cancer in the treatment arm of the PCPT and determined factors involved in modifying drug concentrations. METHODS: Data for this nested case-control study are from the PCPT. Cases were drawn from men with biopsy-proven prostate cancer and matched controls. Finasteride concentrations were measured using a liquid chromatography-mass spectrometry validated assay. The association of serum finasteride concentrations with prostate cancer risk was determined by logistic regression. We also examine whether polymorphisms in the enzyme target and metabolism genes of finasteride are related to drug concentrations using linear regression. RESULTS AND CONCLUSIONS: Among men with detectable finasteride concentrations, there was no association between finasteride concentrations and prostate cancer risk, low-grade or high-grade, when finasteride concentration was analyzed as a continuous variable or categorized by cutoff points. Since there was no concentration-dependent effect on prostate cancer, any exposure to finasteride intake may reduce prostate cancer risk. Of the twenty-seven SNPs assessed in the enzyme target and metabolism pathway, five SNPs in two genes, CYP3A4 (rs2242480; rs4646437; rs4986910), and CYP3A5 (rs15524; rs776746) were significantly associated with modifying finasteride concentrations. These results suggest that finasteride exposure may reduce prostate cancer risk and finasteride concentrations are affected by genetic variations in genes responsible for altering its metabolism pathway. TRIAL REGISTRATION: ClinicalTrials.gov NCT00288106.

Effect of finasteride on serum androstenedione and risk of prostate cancer within the prostate cancer prevention trial: differential effect on high- and low-grade disease.

OBJECTIVE: To evaluate the effect of finasteride on serum androst-4-ene-3,17-dione (androstenedione) and its association with prostate cancer risk among subjects who participated in the Prostate Cancer Prevention Trial. METHODS: We analyzed serum androstenedione levels in 317 prostate cancer cases and 353 controls, nested in the Prostate Cancer Prevention Trial, a randomized placebo-controlled trial that found finasteride decreased prostate cancer risk. Androstenedione is the second most important circulating androgen in men besides testosterone and also a substrate for 5α-reductase enzyme. RESULTS: We observed a 22% increase in androstenedione levels compared with the baseline values in subjects who were treated with finasteride for 3 years. This significant increase did not vary by case-control status. Adjusted odds ratio and 95% confidence interval for the third tertile of absolute change in androstenedione levels compared with the first tertile were 0.42 (95% confidence interval, 0.19-0.94) for low-grade (Gleason score <7) cases. Similar results were observed when analyzed using percent change. There were no significant associations between serum androstenedione levels and the risk of high-grade disease. CONCLUSION: The results of this nested case-control study confirm that finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT) and of androstenedione to 5α-androstanedione-3,17-dione, which also leads to the reduction of DHT formation. This decrease in DHT may help reduce the risk of low-grade prostate cancer in men. Our data on a differential effect of androstenedione also suggest that some high-grade prostate cancers may not require androgen for progression.

Prospective study of human herpesvirus type 8 serostatus and prostate cancer risk in the placebo arm of the Prostate Cancer Prevention Trial.

BACKGROUND: Human herpesvirus type 8 (HHV-8), a gamma herpesvirus associated with Kaposi's sarcoma, has been proposed as a candidate risk factor for prostate cancer (PCa) because of its detection in benign and malignant prostate specimens, and its relation with histologic prostatic inflammation. We investigated the possible relation between pre-diagnostic HHV-8 infection and PCa risk in a case-control study sampled from the placebo arm of the Prostate Cancer Prevention Trial. METHODS: We defined cases as men with a confirmed diagnosis of PCa after visit 2 (n = 315) and controls as men not diagnosed with PCa during the trial who also had a negative end-of-study prostate biopsy (n = 315). We tested sera from visit 2 for IgG antibodies against HHV-8 using a monoclonal antibody-enhanced immunofluorescence assay against multiple lytic HHV-8 antigens. RESULTS: The adjusted seroprevalence of HHV-8 infection was 11.6 % for cases and 11.0 % for controls (p = 0.81). No association was observed between HHV-8 seropositivity and PCa risk (OR 1.06, 95 % CI 0.65-1.76). CONCLUSION: Our findings of a null association between HHV-8 seropositivity and PCa risk do not support an association between HHV-8 infection and PCa development, consistent with the general tendency of the epidemiologic literature to date.

Amiloride and guggulsterone suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts.

Esophageal adenocarcinoma is increasing in the US and Western countries and frequent gastresophageal reflux or gastresophageal reflux disease carrying gastric acid and bile acid could contribute to esophageal adenocarcinogenesis. This study was designed to detect the expression of gastric acid-inducing gene Na + /H + exchanger-1 (NHE-1) ex vivo and then to explore targeting of NHE-1 expression or activity to control esophageal cancer cell viability in vitro and in nude mouse xenografts. The data showed that NHE-1 was highly expressed in esophageal adenocarcinoma tissues (66 of 101 cases [65.3%], but not in normal esophageal squamous cell epithelium (1 of 26 cases [3.8%]). Knockdown of NHE-1 expression using NHE-1 shRNA or inhibition of NHE-1 activity using the NHE-1 inhibitor amiloride suppressed viability and induced apoptosis in esophageal cancer cells. Molecularly, amiloride inhibited expression of cyclooxygenase-2 and matrix metallopeptidase-9 but not NHE-1 mRNA in esophageal cancer cells. A combination of amiloride and guggulsterone (a natural bile acid receptor inhibitor) showed more than additive effects in suppressing esophageal cancer cell growth in vitro and in nude mouse xenografts. This study suggests that inhibition of NHE-1 expression or activity or combination of amiloride and guggulsterone could be useful in control of esophageal adenocarcinoma.

Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial.

BACKGROUND: Chronic inflammation is hypothesized to influence prostate cancer development, although a definitive link has not been established. METHODS: Prostate cancer cases (N = 191) detected on a for-cause (clinically indicated) or end-of-study (protocol directed) biopsy, and frequency-matched controls (N = 209), defined as negative for cancer on an end-of-study biopsy, were sampled from the placebo arm of the Prostate Cancer Prevention Trial. Inflammation prevalence and extent in benign areas of biopsy cores were visually assessed using digital images of hematoxylin and eosin-stained sections. Logistic regression was used to estimate associations. RESULTS: Of note, 86.2% of cases and 78.2% of controls had at least one biopsy core (of three assessed) with inflammation in benign areas, most of which was chronic. Men who had at least one biopsy core with inflammation had 1.78 [95% confidence interval (CI), 1.04-3.06] times the odds of prostate cancer compared with men who had zero cores with inflammation. The association was stronger for high-grade disease (Gleason sum 7-10, N = 94; OR, 2.24; 95% CI, 1.06-4.71). These patterns were present when restricting to cases and controls in whom intraprostatic inflammation was the least likely to have influenced biopsy recommendation because their prostate-specific antigen (PSA) was low (<2 ng/mL at biopsy). CONCLUSION: Inflammation, most of which was chronic, was common in benign prostate tissue, and was positively associated with prostate cancer, especially high grade. The association did not seem to be due to detection bias. IMPACT: This study supports an etiologic link between inflammation and prostate carcinogenesis, and suggests an avenue for prevention by mitigating intraprostatic inflammation.

Inhibition of farnesoid X receptor controls esophageal cancer cell growth in vitro and in nude mouse xenografts.

BACKGROUND: Gastroesophageal reflux is a risk factor for esophageal adenocarcinoma, and bile acid and its farnesoid X receptor (FXR) have been implicated in esophageal tumorigenesis. The authors investigated the role of FXR expression and activity in esophageal cancer initiation and growth. METHODS: FXR expression in esophageal adenocarcinoma tissues was assessed by immunohistochemistry. Knockdown of FXR expression in esophageal cancer cells in vitro and in nude mice xenografts was suppressed by FXR small hairpin RNA (shRNA) and guggulsterone (a natural FXR inhibitor). Esophageal cancer cells were treated with bile acids to demonstrate their effects on growth-promoting genes. RESULTS: FXR was expressed in 48 of 59 esophageal adenocarcinoma tissues (81.3%), and this overexpression was associated with higher tumor grade, larger tumor size, and lymph node metastasis; however, was inversely associated with retinoic acid receptor-ß2 (RAR-ß2 ) expression. Knockdown of FXR expression suppressed tumor cell growth in vitro and in nude mouse xenografts. Guggulsterone reduced the viability of esophageal cancer cells in a time-dependent and dose-dependent manner, whereas this effect was diminished after knockdown of FXR expression. Guggulsterone induced apoptosis through activation of caspase-8, caspase-9, and caspase-3 in tumor cells. FXR mediated bile acid-induced alterations of gene expression, eg, RAR-ß2 and cyclooxygenase-2 (COX-2). CONCLUSIONS: Inhibition of FXR by FXR shRNA or guggulsterone suppressed tumor cell viability and induced apoptosis in vitro, and it reduced tumor formation and growth in nude mouse xenografts. FXR also mediated bile acid-induced alterations of cell growth-related genes in esophageal cancer cells.