Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype.

Diffuse large B-cell lymphoma (DLBCL) has been categorized into two molecular subtypes that have prognostic significance, namely germinal center B-cell like (GCB) and activated B-cell like (ABC). Although ABC-DLBCL has been associated with NF-κB activation, the relationships between activation of specific NF-κB signals and DLBCL phenotype remain unclear. Application of novel gene expression classifiers identified two new DLBCL categories characterized by selective p100 (NF-κB2) and p105 (NF-κB1) signaling. Interestingly, our molecular studies showed that p105 signaling is predominantly associated with GCB subtype and histone mutations. Conversely, most tumors with p100 signaling displayed ABC phenotype and harbored ABC-associated mutations in genes such as MYD88 and PIM1. In vitro, MYD88 L265P mutation promoted p100 signaling through TAK1/IKKα and GSK3/Fbxw7a pathways, suggesting a novel role for this protein as an upstream regulator of p100. p100 signaling was engaged during activation of normal B cells, suggesting p100's role in ABC phenotype development. Additionally, silencing p100 in ABC-DLBCL cells resulted in a GCB-like phenotype, with suppression of Blimp, IRF4 and XBP1 and upregulation of BCL6, whereas introduction of p52 or p100 into GC cells resulted in differentiation toward an ABC-like phenotype. Together, these findings identify specific roles for p100 and p105 signaling in defining DLBCL molecular subtypes and posit MYD88/p100 signaling as a regulator for B-cell activation.

A cross-sectional study of Mycoplasma genitalium infection and correlates in women undergoing population-based screening or clinic-based testing for Chlamydia infection in London.

OBJECTIVE: To determine Mycoplasma genitalium infection and correlates among young women undergoing population-based screening or clinic-based testing for Chlamydia infection. DESIGN: Cross-sectional study. SETTING: National Chlamydia Screening Programme (NCSP) and two London sexually transmitted infection (STI) clinics. PARTICIPANTS: 2441 women aged 15-64 years who participated in the NCSP and 2172 women who attended two London STI clinics over a 4-month period in 2009. OUTCOME MEASURES: (1) M genitalium prevalence in defined populations (%). (2) Age-adjusted ORs (aORs) for correlates of M genitalium infection. RESULTS: The overall frequency of M genitalium and Chlamydia trachomatis was 3% and 5.4%, respectively. Co-infection was relatively uncommon (0.5% of all women); however 9% of women with C trachomatis also had M genitalium infection. M genitalium was more frequently detected in swab than urine samples (3.9 vs 1.3%, p<0.001) with a significantly higher mean bacterial load (p ≤ 0.001). Among NCSP participants, M genitalium was significantly more likely to be diagnosed in women of black/black British ethnicity (aOR 2.3, 95% CI 1.2 to 4.5, p=0.01). M genitalium and C trachomatis and were both significantly associated with multiple sexual partners in the past year (aOR 2.4, 95% CI 1.3 to 4.4, p=0.01 and aOR 2.0, 95% CI 1.4 to 2.8, p<0.01). Among STI clinic attendees, M genitalium was more common in women who were less than 25 years in age. CONCLUSIONS: M genitalium is a relatively common infection among young women in London. It is significantly more likely to be detected in vulvovaginal swabs than in urine samples. Co-infection with Chlamydia is uncommon. The clinical effectiveness of testing and treatment strategies for M genitalium needs further investigation.

The need for innovative sexually transmitted infection screening initiatives for young men: evidence from genitourinary medicine clinics across England.

The study objectives were to ascertain behavioural, access-related, health-seeking factors and sexually transmitted infection (STI) prevalence in young men (<25 years) attending genitourinary (GU) medicine clinics and compare them with older men (≥ 25 years) and young women (<25 years). Between October 2004 and March 2005, 4600 new attendees at seven sociodemographically and geographically contrasting GU medicine clinics across England completed questionnaires, which were linked to routine clinical data. Young men waited significantly less time to be seen in clinic compared with older men and young women. They were less likely to report symptoms than older men (P = 0.021) yet more likely to be diagnosed with chlamydia (P = 0.001) and gonorrhoea (P = 0.007). They were also more likely to be diagnosed with an acute STI relative to young women (P = 0.007). Our data confirm the need to make comprehensive STI screening readily available for young men and to develop effective and innovative screening strategies in different settings.

Immunophenotypic and gene expression analysis of monoclonal B-cell lymphocytosis shows biologic characteristics associated with good prognosis CLL.

Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.

Stromal gene signatures in large-B-cell lymphomas.

BACKGROUND: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear. METHODS: We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group. RESULTS: A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density. CONCLUSIONS: Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.

Sexual behaviour, condom use, and disclosure of HIV status in HIV infected heterosexual individuals attending an inner London HIV clinic.

BACKGROUND: The National Strategy for Sexual Health and HIV for England (2001) emphasised the role of HIV services in reducing secondary transmission of HIV through prevention work with HIV infected people. OBJECTIVE: To determine the sexual behaviour, condom use, and disclosure of HIV status of HIV infected heterosexuals attending an inner London HIV clinic. DESIGN: Cross sectional questionnaire study of heterosexual HIV infected individuals attending an HIV outpatient clinic. METHODS: We collected demographic data for all respondents and sexual behaviour data for those sexually active over the past year using a self administered questionnaire. Viral load and CD4 count for responders and age, sex, ethnicity, viral load, and CD4 count for non-responders were obtained from the clinic database. RESULTS: The response rate was 47.3% (n = 142). 100 participants reported being sexually active in the past year, of whom 73% used condoms when they last had vaginal sex. Knowledge of partner's HIV status was the only variable significantly associated with the participant disclosing their HIV status to their partner (p<0.001). In those who had disclosed their status, only knowledge of partner's HIV status was significantly associated with condom use (p = 0.03). CONCLUSIONS: Issues relating to non-disclosure and partner notification in HIV infected heterosexuals will need to be better understood to improve sexual health in this group and to reduce onward transmission of HIV.

Progressive neuropsychiatric problems following institution of highly active antiretroviral therapy.

A 31 year old HIV infected woman developed neuropsychiatric problems soon after starting highly active antiretroviral therapy (HAART). Despite modifying and subsequently stopping HAART her condition progressively worsened. Cranial magnetic resonance imaging revealed multiple areas of abnormal signal suggestive of either a vasculitis or demyelination.

Recalcitrant Trichomonas vaginalis infection--a case series.

The objective of this study was (1) to estimate the prevalence of recalcitrant Trichomonas vaginalis (TV) infection in a UK genitourinary medicine clinic; (2) to use a case series and literature review to suggest an algorithm for management of recalcitrant TV (rTV). A retrospective review of laboratory records, case-notes and literature review was conducted. Fifteen patients were studied, representing 1.16% of the cases presenting during the study period. A wide variety of therapeutic agents was used, the treatment regimen differed for each patient. No treatment was universally effective in achieving cure, but the use of acetarsol pessaries vaginally appeared to be the most frequently successful strategy. Based on these results, an algorithm for treatment of rTV is presented, although clinical trials will be needed to elucidate the best clinical approaches to this problem.