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Burkitt lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies. We used high throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways that cooperate with MYC, the defining oncogene of this cancer. In 38% of sporadic BL (sBL) cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. In 70% of sBL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival PI(3) kinase pathway in BL, in part by augmenting constitutive B cell receptor signaling. These findings suggest opportunities to improve therapy for patients with BL.

BACKGROUND Male circumcision significantly reduced the incidence of human immunodeficiency virus (HIV) infection among men in three clinical trials. We assessed the efficacy of male circumcision for the prevention of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis in HIV-negative adolescent boys and men. METHODS We enrolled 5534 HIV-negative, uncircumcised male subjects between the ages of 15 and 49 years in two trials of male circumcision for the prevention of HIV and other sexually transmitted infections. Of these subjects, 3393 (61.3%) were HSV-2–seronegative at enrollment. Of the seronegative subjects, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). At baseline and at 6, 12, and 24 months, we tested subjects for HSV-2 and HIV infection and syphilis, along with performing physical examinations and conducting interviews. In addition, we evaluated a subgroup of subjects for HPV infection at baseline and at 24 months. RESULTS At 24 months, the cumulative probability of HSV-2 seroconversion was 7.8% in the intervention group and 10.3% in the control group (adjusted hazard ratio in the intervention group, 0.72; 95% confidence interval [CI], 0.56 to 0.92; P = 0.008). The prevalence of high-risk HPV genotypes was 18.0% in the intervention group and 27.9% in the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 to 0.90; P = 0.009). However, no significant difference between the two study groups was observed in the incidence of syphilis (adjusted hazard ratio, 1.10; 95% CI, 0.75 to 1.65; P = 0.44). CONCLUSIONS In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure.

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Background-A randomized trial of male circumcision (MC) was conducted among HIVinfected males to test the hypothesis that MC would reduce HIV transmission to female sexual partners.

Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

BACKGROUNDTo assess the impact of combination HIV prevention (CHP) on HIV incidence, we analyzed the association between HIV incidence and scale-up of antiretroviral therapy (ART) and medical male circumcision in Rakai, Uganda. Changes in population-level viral load suppression and sexual behaviors were also examined.METHODSBetween 1999 and 2016, data were collected through 12 surveys from 30 communities in the Rakai Community Cohort Study, an open population-based cohort of persons aged 15-49 years. We assessed HIV incidence trends based on observed seroconversion data, self-reported ART and male circumcision coverage, viral load suppression, and sexual behaviors.RESULTSIn total, 33,937 study participants contributed 103,011 person-visits (HIV prevalence ~13%). Follow-up of 17,870 HIV-negative persons contributed 94,427 person-years with 931 seroconversions. ART was introduced in 2004; by 2016 coverage was 69% (72% in women vs. 61% in men, p<0.001). HIV viral load suppression among all HIV-positive persons increased from 42% in 2009 to 75% by 2016 (p<0.001). Male circumcision coverage increased from 15% in 1999 to 59% by 2016 (p<0.001). Persons 15-19 years reporting n 71 ever having sex increased from 30% to 55% (p<0.0001). HIV incidence declined by 42% in 2016 relative to the pre-CHP period prior to 2010 (1.17/100 py to 0.66/100 py; adjIRR:0.58: 95%CI: 0.45-0.76); declines were greater in men (adjIRR=0.46; 95%CI: 0.29-0.73) than women (adjIRR=0.68, 95%CI: 0.50-0.94).CONCLUSIONSIn this longitudinal study, HIV incidence significantly declined with CHP scale-up, providing empiric evidence that HIV control interventions can have substantial population-level impact. However, additional efforts are needed to overcome gender disparities and achieve HIV elimination.

Although it is a standard practice in high-income countries, determination of the human immunodeficiency virus (HIV) load is not recommended in developing countries because of the costs and technical constraints. As more and more countries establish capacity to provide second-line therapy, and as costs and technological constraints associated with viral load testing decrease, the question of whether determination of the viral load is necessary deserves attention. Viral load testing could increase in importance as a guide for clinical decisions on when to switch to second-line treatment and on how to optimize the duration of the first-line treatment regimen. In addition, the viral load is a particularly useful tool for monitoring adherence to treatment, performing sentinel surveillance, and diagnosing HIV infection in children aged <18 months. Rather than considering viral load data to be an unaffordable luxury, efforts should be made to ensure that viral load testing becomes affordable, simple, and easy to use in resource-limited settings.