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Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility., Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry., Design, Setting, and Participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry., Outcome Measurements and Statistical Analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness., Results and Limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10 -4 )., Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry., Patient Summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10 -4 ), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 × 10 -5 ; stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 × 10 -4 ; metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry., (Copyright © 2022. Published by Elsevier B.V.)

Background: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease., Objective: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa., Design, Setting, and Participants: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls., Outcome Measurements and Statistical Analysis: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls., Results and Limitations: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa., Conclusions: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease., Patient Summary: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa., (Copyright © 2020 European Association of Urology. All rights reserved.)

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Despite the paramount importance of patient-reported outcomes, little is known about the evolution of patient-reported urinary and sexual function over time., Objective: To evaluate differences in pretreatment urinary and sexual function in two population-based cohorts of men with prostate cancer enrolled nearly 20 yr apart., Design, Setting, and Participants: Patients were enrolled in the Prostate Cancer Outcomes Study (PCOS) or the Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study, two population-based cohorts that enrolled patients with incident prostate cancer from 1994 to 1995 and from 2011 to 2012, respectively. Participants completed surveys at baseline and various time points thereafter., Outcome Measurements and Statistical Analysis: We performed multivariable logistic and linear regression analysis to investigate differences in pretreatment function between studies., Results and Limitations: The study comprised 5469 men of whom 2334 (43%) were enrolled in PCOS and 3135 (57%) were enrolled in CEASAR. Self-reported urinary incontinence was higher in CEASAR compared with PCOS (7.7% vs 4.7%; adjusted odds ratio [OR]: 1.83; 95% confidence interval [CI], 1.39-2.43). Similarly, self-reported erectile dysfunction was more common among CEASAR participants (44.7% vs 24.0%) with an adjusted OR of 3.12 (95% CI, 2.68-3.64). Multivariable linear regression models revealed less favorable self-reported baseline function among CEASAR participants in the urinary incontinence and sexual function domains. The study is limited by its observational design and possibility of unmeasured confounding., Conclusions: Reporting of pretreatment urinary incontinence and erectile dysfunction has increased over the past two decades. These findings may reflect sociological changes including heightened media attention and direct-to-consumer marketing, among other potential explanations., Patient Summary: Patient reporting of urinary and sexual function has evolved and is likely contingent on continually changing societal norms. Recognizing the evolving nature of patient reporting is essential in efforts to conduct high-quality, impactful comparative effectiveness research., (Copyright © 2014 European Association of Urology. All rights reserved.)

Background: No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS)., Objective: To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer., Design, Setting, and Participants: SNPs implicated in any phenotype other than prostate cancer (p≤10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24,534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium., Outcome Measurements and Statistical Analysis: Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated., Results and Limitations: A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p=1.6×10(-6)), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95% CI 1.16-1.27; p=3.22×10(-18)). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86-0.94; p=2.5×10(-6)). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12, 95% CI 1.06-1.19; p=4.67×10(-5)); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL., Conclusions: We did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in prostate cancer etiology., Patient Summary: We evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified., (Copyright © 2014 European Association of Urology. All rights reserved.)

Objective: To provide population-based estimates of other-cause mortality by age and comorbidity in men with prostate cancer for use at the point of care in shared decision making., Materials and Methods: We sampled 3183 men with nonmetastatic prostate cancer from the Prostate Cancer Outcomes Study, a US population-based prospective cohort. Survival analysis accounting for competing risks was used to provide predictions of other-cause and cancer-specific mortality by age, comorbidity, and tumor risk through 14 years of follow-up., Results: Older men had a higher absolute risk of other-cause mortality associated with comorbidity. For men with comorbidity counts of 0, 1, 2, and 3+, cumulative incidence of other-cause mortality at 14 years was 9%, 18%, 30%, and 35% for those younger than 60 years; 26%, 26%, and 48%, and 52% for those aged 60-70 years; and 49%, 57%, 66%, and 74% for those older than 70 years. Prostate cancer mortality at 14 years was 5%, 8%, and 23% for men with low-, intermediate-, and high-risk disease. Competing risk pictograms for each age/comorbidity/tumor-risk pair provide visual characterization of these risks over time., Conclusion: Our survival tables may be used at the point of care as part of shared decision making. Men aged >60 years with multiple comorbidities have substantial risk of other-cause mortality within 15 years of diagnosis and should consider conservative management for low-risk disease, given its low incidence of cancer-specific mortality. Men with high-risk disease, regardless of age or comorbidity, are at greater risk for cancer mortality and may still be appropriate candidates for aggressive treatment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

For eradication of tuberculosis (TB) by 2050, the declared aim of the Stop TB Partnership, novel treatment strategies are indispensable. The emerging epidemic of multi-drug resistant (MDR) TB has fuelled the debate about TB vaccines, as increasing numbers of patients can no longer be cured by pharmacotherapy. Of several proposed modalities, TB vaccines administered in therapeutic manner represents a promising alternative, despite the controversial history due to the occurrence of exacerbated immune response. A modified concept of immunotherapy is required in order to justify further exploration. In this paper we systematically reviewed the most advanced therapeutic vaccines for TB. We address the rationale of immunotherapeutic vaccination combined with optimized pharmacotherapy in active TB. We summarize preclinical and patient data regarding the five most advanced therapeutic vaccines currently in the pipeline. Of the five products that have been tested in animal models and in humans during active or latent TB, the quality of the published clinical reports of two of these products justify further studies in patients with active TB. This systematic review fuels further clinical evaluation eventually including head-to-head comparative studies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A heat-killed preparation of Mycobacterium vaccae (SRL172) has been shown, in recent studies, to be effective in the treatment of adenocarcinoma of the lung and renal cell cancer. It is postulated that the mechanisms of this form of immunotherapy is, at least in part, due to immune regulation, reflected in the selective enhancement of Th1 and down-regulation of Th2 T cell activity. These beneficial effects are attributed to the ability of adjuvants in the bacterial cell walls to modify and optimise the response to antigens shared by the bacteria and stressed host tissues, resulting in the destruction of cancer cells by programmed cell death or apoptosis. The M. vaccae-induced apoptosis appears to be most effective against carcinomas, perhaps especially those of glandular tissue, in contrast to pyrexia-induced necrosis which is most effective against tumours of mesodermal origin. In view of the great range of adjuvants, especially in the genus Mycobacterium and related genera, it may prove possible to develop a range of immunotherapeutic agents with useful activity against a wide range of cancers.

The well-established model of Chagas' disease in "l" rats was used to evaluate the effects of three injections of heat-killed Gordonia bronchialis, Rhodococcus coprophilus or saline on Trypanosoma cruzi parasitaemia and acute and chronic myocarditis, sequelae of the infection. Two vaccinating injections were given prior to challenge with T. cruzi, and the third, immunotherapeutic, injection was given 7 days after challenge. Treatment with either actinomycete significantly reduced acute parasitaemia (p<0.04), modified cellular infiltration during acute myocarditis and limited chronic myocarditis (p<0.03) in comparison with the saline-treated control animals. Immunological investigations showed that both bacterial preparations achieved their results through different mechanisms. The relevance of our findings to human Chagas' disease is discussed.

Objectives: To determine the risk factors for the self-reported history of prostatitis and to determine whether a self-reported history of prostatitis is related to the diagnosis of prostate cancer., Methods: Random digit dialing was used to select a group of controls aged 40 to 64 years without prostate cancer matched by age with a group of patients with prostate cancer in a study on the epidemiology of prostate cancer. Controls were divided into those who reported a diagnosis of prostatitis (cases) and those who denied ever having had prostatitis (controls). We adjusted for the time from a prostatitis diagnosis to the in-person interview. We also compared the number of men with a prostatitis diagnosis to the number of men diagnosed and not diagnosed with prostate cancer., Results: Of the 645 control men without a history of prostate cancer, 58 (9.0%) reported a diagnosis of prostatitis. The men with prostatitis had a mean age of 39.5 years at diagnosis. The urinary symptoms among prostatitis cases and controls was similar. Prostatitis cases more frequently reported urinary (P < or =0.05) or urethral infections (P < or =0.01) before diagnosis. Men with prostatitis were more likely to have procedures aimed at diagnosing both prostatic and other diseases. Men with prostate cancer reported a diagnosis of prostatitis more often than the noncancer controls (13.6% versus 9.0%). After controlling for the number of prostate-specific antigen tests this difference disappeared., Conclusions: Nine percent of a randomly selected group of middle-aged men reported they had been diagnosed with prostatitis. The prevalence of a prostatitis diagnosis is similar in men with and without prostate cancer.

Three vaccines, BCG alone, BCG + 10(7) killed Mycobacterium vaccae and 10(8) killed M. vaccae alone, were studied in children living in close contact with leprosy. In the year before vaccination, 14/446 (3.1%) children had developed leprosy. Among those who were not vaccinated, 9/74 (12.2%) developed the disease in the first 4 years of the study and 5/65 (7.7%) developed the disease in the second 4 years. In comparison with this, among those vaccinated, 20/343 (5.8%) developed leprosy in the first 4 years and 5/323 (1.5%) developed leprosy in the second 4 years. This represents 52.5% protection in the first 4 years and 80.5% in the second 4 years. There were no significant differences in protection afforded by each of the three vaccines but the success of the killed preparation of M. vaccae is an important finding.

Immunological responses of wildfowl (Order Anseriformes: ducks, geese, swans and screamers) to mycobacteria have been investigated as part of studies to develop a vaccine and diagnostic assay for avian tuberculosis. 10(9) killed Mycobacterium vaccae protected the Cairinini (perching ducks) from avian tuberculosis (p<0.02) but did not achieve statistically significant protection in the other taxonomic tribes. The Cairinini includes the threatened, yet highly susceptible, white-winged duck (Cairina scutulata).Together, loss of cell-mediated responses to common mycobacterial antigens, increased responsiveness to the species specific antigens of M. avium, and increased antibody production are reminiscent of the T(H1) to T(H2) shift seen in mammalian mycobacterial infections. It is speculated that excessive exposure to environmental mycobacteria prior to vaccination is detrimental and common antigens play an important role in wildfowl immunity to mycobacteria. A new vaccination trial using killed M. vaccae is being undertaken. Antibody responses are a useful ante mortem diagnostic indicator in most taxonomic tribes with the exception of the primitive Dendrocygnini (whistling ducks).

Research into immunity to complex intracellular parasites has recently placed emphasis on the identification of peptide sequences recognised by T-cells, often with the dual objectives of finding species-specific protective epitopes, and of understanding selection of Th1 versus Th2 response patterns. In this review it is suggested that although such work is interesting, it will not achieve these objectives, which must, however, be addressed before we can design the new generation of therapeutic vaccines which may eventually replace antimicrobial drugs in the treatment of infection. First, we suggest that the balance of Th1 to Th2 lymphocyte activity is not determined by epitopes, but rather by adjuvant effects of microbial components which we have barely begun to define, and local endocrine effects mediated by conversion of prohormones into active metabolites by enzymes in lymph node macrophages. Cytokines play a role as mediators within these pathways. In chronic disease states there is a tendency for T-cell function to shift towards Th2. We describe immunopathological consequences of this tendency, including a putative role for agalactosyl IgG, and review evidence for involvement of changes in the endocrine system, brought about not only by the cytokine-hypothalamus-pituitary-adrenal axis, but also by direct actions on peripheral endocrine organs of excess levels of cytokines such as TNF alpha, TGF beta and IL-6. We summarise evidence that the epitopes that are targets for protective cell-mediated responses to complex organisms are usually not species specific. In tuberculosis, cellular responses to species-specific components appear to be associated with immunopathology rather than protection. Finally, we discuss how application of these principles has led to remarkable results in the immunotherapy of tuberculosis, including multidrug-resistant disease.

Both leprosy and tuberculosis present continuing problems in their control, especially in the developing world, despite the availability of drugs effective in producing a bacteriological cure. Improved immunoprophylaxis, and an effective immunotherapy to be used with chemotherapy are urgently required. Intradermal injection of a suspension of killed Mycobacterium vaccae promotes cell-mediated responses to antigens common to all mycobacteria, and switches off the tissue-necrotizing aspects of the Koch phenomenon. These properties led to the use of the suspensions as an improved vaccine, either alone or in combination with BCG. The same properties led to the employment of the suspension in immunotherapy as an adjunct to chemotherapy in the treatment of both leprosy and tuberculosis. The evidence leading to these conclusions is reviewed and discussed.