Cytokine receptor IL27RA is an NF-κB-responsive gene involved in CD38 upregulation in multiple myeloma.

Multiple myeloma (MM) shows constitutive activation of canonical and noncanonical nuclear factor κB (NF-κB) signaling via genetic mutations or tumor microenvironment (TME) stimulations. A subset of MM cell lines showed dependency for cell growth and survival on the canonical NF-κB transcription factor RELA alone, suggesting a critical role for a RELA-mediated biological program in MM pathogenesis. Here, we determined the RELA-dependent transcriptional program in MM cell lines and found the expression of the cell surface molecules interleukin-27 receptor-α (IL-27Rα) and the adhesion molecule JAM2 to be responsive to RELA at the messenger RNA and protein levels. IL-27Rα and JAM2 were expressed on primary MM cells at higher levels than on healthy long-lived plasma cells (PCs) in the bone marrow. IL-27 activated STAT1, and to a lesser extent STAT3, in MM cell lines and in PCs generated from memory B cells in an IL-21-dependent in vitro PC differentiation assay. Concomitant activity of IL-21 and IL-27 enhanced differentiation into PCs and increased the cell-surface expression of the known STAT target gene CD38. In accordance, a subset of MM cell lines and primary MM cells cultured with IL-27 upregulated CD38 cell-surface expression, a finding with potential implications for enhancing the efficacy of CD38-directed monoclonal antibody therapies by increasing CD38 expression on tumor cells. The elevated expression of IL-27Rα and JAM2 on MM cells compared with that on healthy PCs may be exploited for the development of targeted therapeutic strategies that modulate the interaction of MM cells with the TME.

A Playbook for Implementing Medicaid Expansion: Louisiana's Experience.

Policy Points Twelve states have yet to expand Medicaid under the Affordable Care Act (ACA). Louisiana offers a model of steps that states and counties can take to rapidly enroll eligible persons while balancing eligibility integrity and doing so within a limited administrative budget. In a post-COVID-19 health care landscape, Medicaid expansion can improve and protect population health and boost state economies, even amid budget shortfalls. Even though Louisiana compares well with other states in eligibility and enrollment efforts, future expansions may integrate other social support programs into their implementation strategies.

"B" aware: Memory lane access is restricted!

Understanding the molecular mechanisms that govern the differentiation of high-affinity germinal center (GC) B cells into memory B cells versus plasma cells is a major quest of adaptive immunity. In this issue, Toboso-Navasa et al. (https://doi.org/10.1084/jem.20191933) provide evidence that the MYC-MIZ1 transcriptional repressor complex restricts the differentiation of GC B cells into MBCs.

Clinical outcomes and financial impacts of malnutrition in sepsis.

BACKGROUND: In the United States in 2014 approximately 1.7 million adults were hospitalized with sepsis, resulting in about 270,000 deaths. Malnutrition in hospitalized patients contributes to increased morbidity, mortality, and costs, especially in the critically ill population. AIM: Our goal was to investigate the prevalence of malnutrition in sepsis and the impact it has on clinical and financial outcomes in our most critically ill patients. METHODS: We implemented nutritional screening by a registered dietitian of 1000 patients admitted with sepsis to specialized care units. We calculated the prevalence of malnutrition, and compared outcomes including mortality, length of stay, and financial costs. RESULTS: About 10% of patients with sepsis admitted to our specialized care units were diagnosed with malnutrition on admission after implementation of mandatory assessment. CONCLUSIONS: Although mortality did not reach statistical significance, these patients had more comorbidities, longer hospital stays, and higher total costs.

A T Cell-B Cell Tumor-Suppressive Axis in the Germinal Center.

TNFRSF14, encoding the receptor HVEM, is frequently mutated in germinal center (GC)-derived B cell lymphomas. In this issue, Mintz et al. demonstrate that the HVEM-BTLA axis restrains T cell help to GC B cells. Mutation-associated loss of this interaction promotes B cell proliferation through exaggerated T cell help, explaining how HVEM loss contributes to GC lymphomagenesis and revealing a cell-extrinsic tumor-suppressor role for BTLA.

Aberrant Activation of NF-κB Signalling in Aggressive Lymphoid Malignancies.

Lymphoid malignancies frequently harbor genetic mutations leading to aberrant activation of nuclear factor-κB (NF-κB) signaling; in normal cells, this pathway has important roles in the control of cell growth, survival, stress responses, and inflammation. Malignancies with mutations in NF-κB pathway components can derive from all cell stages of mature B-cell development; however, aberrant NF-κB activity is particularly prevalent in aggressive subtypes of non-Hodgkin lymphoma and myeloma. NF-κB activation is mediated by two separate pathways, the canonical and alternative pathway, and five downstream transcription factor subunits. Recent findings implicate a predominant role for distinct NF-κB pathways and subunits in certain lymphoma subtypes and myeloma; findings which are complemented by the realization that individual NF-κB subunits can have unique, non-redundant biological roles in the putative tumor precursor cells, including activated B cells, germinal center B cells and plasma cells. The knowledge gained from these studies may be exploited for the development of therapeutic strategies to inhibit aberrant NF-κB activity at the level of the transcription-factor subunits and their target genes, as global inhibition of the pathway is toxic. Here, we provide an overview on the role of aberrant NF-κB activation in aggressive lymphoid malignancies and discuss the potential importance of individual NF-κB subunits in the pathogenesis of tumor subtypes.

Hirmi Valley liver disease: a disease associated with exposure to pyrrolizidine alkaloids and DDT.

BACKGROUND & AIMS: Hirmi Valley liver disease was first reported in 2001 in Tigray, Ethiopia. 591 cases, including 228 deaths, were reported up to December 2009. The pyrrolizidine alkaloid acetyllycopsamine was detected in stored grain and residents reported adding the pesticide DDT (dichlorodiphenyldichloroethylene) directly to their food stores. We aimed to characterise the clinical features of the disease, and explore the role of these chemicals in its aetiology. METHODS: 32 cases were examined and full clinical histories taken. Nine cases underwent liver biopsy in hospitals. Serum and urine samples were collected from cases and controls. Urine was analysed for acetyllycopsamine by UPLC-MS. Total DDT in serum was measured by ELISA. Hepatotoxicity of DDT and acetyllycopsamine alone or in combination was explored in C57BL/6J mice. RESULTS: Clinical presentation included epigastric pain, abdominal swelling, bloody diarrhoea, hepatomegaly, splenomegaly, and ascites. Histology revealed acute injury characterised by centrilobular necrosis or chronic injury with bile ductular reaction, cytomegaly and fibrosis but no hepatic vein occlusion. Acetyllycopsamine was detected in urine samples taken in the affected area with significantly greater concentrations in 45 cases than in 43 controls (p=0.02). High levels of DDT (>125 ppb) were detected in 78% of serum samples. In mice, DDT (3 × 75 mg/kg) significantly increased the hepatotoxicity (plasma ALT, p=0.0065) of acetyllycopsamine (750 mg/kg), and in combination induced liver pathology similar to Hirmi Valley liver disease including centrilobular necrosis and cytomegaly. CONCLUSIONS: This novel form of disease appears to be caused by co-exposure to acetyllycopsamine and DDT.

Health and social problems encountered by treated and untreated obstetric fistula patients in rural Ethiopia.

OBJECTIVE: To assess health, social, and psychological problems encountered by women with treated and untreated obstetric fistula (OF). METHODS: A cross-sectional study consisting of quantitative and qualitative components was conducted in seven administrative regions of rural Ethiopia. Fifty-two women with OF were interviewed on the subjects of their socioeconomic status and history of the development of OF. Qualitative in-depth interviews were conducted with 27 of the untreated women and seven of the treated women. RESULTS: A total of 19 153 houses were surveyed, and 55 women with fistulae were identified, of whom 52 were interviewed. Thirty-six of the interviewed women (69.2%) were divorced, 10 (19.2%) were not allowed to eat with family members, and 23 (44.2%) were not members of any community associations. Of the 48 women with feelings of depression, 28 (54.2%) had suicidal ideation. Twenty-four women attributed their development of a fistula to evil spirits, to a curse, or to sin. The in-depth interviews revealed that treatment improved family and social life; however, some health, social, and sexual problems remained. CONCLUSION: Women with OF encounter health, psychological, and social consequences that are not completely resolved by repairing the fistula. The care of women with OF should go beyond surgical treatment and should include support for their reintegration into the community with proper follow-up.