Dysregulation of the “intrinsic” apoptotic pathway is associated with the development of cancer and autoimmune disease. Bak and Bax are two proapoptotic members of the Bcl-2 protein family with overlapping, essential roles in the intrinsic apoptotic pathway. Their activity is critical for the control of cell survival during lymphocyte development and homeostasis, best demonstrated by defects in thymic T-cell differentiation and peripheral lymphoid homeostasis caused by their combined loss. Because most bak −/− bax −/− mice die perinatally, the roles of Bax and Bak in immunological tolerance and prevention of autoimmune disease remain unclear. We show that mice reconstituted with a Bak/Bax doubly deficient hematopoietic compartment develop a fatal systemic lupus erythematosus-like autoimmune disease characterized by hypergammaglobulinemia, autoantibodies, lymphadenopathy, glomerulonephritis, and vasculitis. Importantly, these mice also develop a multiorgan autoimmune disease with autoantibodies against most solid glandular structures and evidence of glandular atrophy and necrotizing vasculitis. Interestingly, similar albeit less severe pathology was observed in mice containing a hematopoietic compartment deficient for only Bak, a phenotype reminiscent of the disease seen in patients with point mutations in BAK . These studies demonstrate a critical role for Bak and an ancillary role for Bax in safeguarding immunological tolerance and prevention of autoimmune disease. This suggests that direct activators of the intrinsic apoptotic pathway, such as BH3 mimetics, may be useful for treatment of diverse autoimmune diseases.
Acute generalized exanthematous pustulosis (AGEP) is characterized by the rapid development of nonfollicular sterile pustules on an erythematous base, most often after drug exposure to anti-infectious agents.1 It can occur at any age but is most commonly seen in middle aged to older adults, with a female predominance.2 Common offenders include antibiotics, antifungals, antimalarials, and diltiazem, and AGEP eruption typically develops within 3 days of drug administration.2 Here we present a case of naltrexone-induced AGEP—an agent that has been previously reported to induce pustular psoriasis, urticaria, and eosinophilic pustular folliculitis.
Molluscum contagiosum (MC) is a common viral infection that affects the skin of children. This study compared demographic data and treatment patterns for MC patients across US medical specialties. Using the National Ambulatory Medical Care Survey database from 2000 to 2016, we found an average of 471,383 pediatric MC visits yearly. Most visits were made by Caucasians (91.0%) or non-Hispanics (82.9%). Pediatricians handled most cases (46.5%), followed by dermatologists (36.8%) and family medicine physicians (10.6%). Dermatologists saw more Caucasian patients (95% vs. 84%) and more patients with private insurance (83% vs. 73%) than pediatricians. Patients living in non-metropolitan areas were more likely to visit family medicine physicians (55.0%) than pediatricians (26.4%) or dermatologists (16.3%). Pediatricians favored spontaneous resolution (70%) over dermatologists (38%). Pediatricians mainly used terpenoids (12%), steroids (4%), and imiquimod (4%), while dermatologists preferred terpenoids (20%), imiquimod (12%), and curettage (10%). Pediatricians oversee most MC cases, but treatment strategies significantly differ from the best-practice guidelines.
Abstract Screening patient peripheral blood using our proposed non-invasive method can boost the accuracy in selecting proper candidates for immune checkpoint therapy in the clinical setting, thereby leading to higher success in treatment. The immune system is regulated by a sophisticated network of modulatory molecules. In chronic infections and cancers, T cell exhaustion can arise when clearance of antigens is incomplete due to sustained expression of co-inhibitory molecules. T cell exhaustion has been exploited by some cancers, and also described in chronic infections with latency. Such exhausted T cells may be reversed with the right immune checkpoint blockade, thereby restoring effector T cell function. We have optimized a T cell Exhaustion Recall Antigen Assay, demonstrating T cell exhaustion may be reversed by immune checkpoint blockades in certain hosts. We hypothesize that understanding of the capacity and expressions of co-inhibitory molecules assist in predicting responders for specific immune checkpoint therapies. We have used a flow cytometry-based approach to examine changes in an array of immune checkpoint molecules on activated T cells and antigen presenting cells. We first tested the effect of anti-PD1 on tumor antigen-specific activated T cells using splenocytes from PMEL T cell receptor (TCR) transgenic mouse, which expresses mouse homologue of human premelanosome protein, or gp100. Activated CD3+CD8+ gp100-specific T cell population and IFNγ production were measured by flow cytometry. Secondly, we evaluated the expression levels of various immune checkpoint molecules post anti-CD3 stimulation of human peripheral blood mononuclear cells (PBMC) from characterized healthy hosts. Surprisingly, we found high expressions of co-inhibitory and co-stimulatory molecules including CTLA-4, PD1, PDL-1/PDL2, TIGIT, LAG3, TIM3, GITR, are associated with poor response to immune checkpoint blockades. Levels of activated T cells and cytokine production in donors with high checkpoint receptors showed lower T cell activations and cytokine production. Screening patient peripheral blood using our proposed non-invasive method can boost the accuracy in selecting proper candidates for immune checkpoint therapy in the clinical setting, thereby leading to higher success in treatment. Citation Format: Pirouz M. Daftarian, Marybeth George, Eden Kleiman, Wushouer Ouerkaxi, Amy Yamamura, Zhongliang Li, Mingfa Zang, Derron Yu, Eunmi Hwang, Annie X. An, Ann E. Lin, Henry Li. Expressions of co-inhibitory / co-stimulatory molecules may impact immune checkpoint therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4124.
Syphilis is known as the great mimicker because of its variable clinical manifestations. Diffuse symmetric papulosquamous eruption is the most common presentation of secondary syphilis.1 Skin bullae and vesicles have been reported in the congenital form but, to our knowledge, have not been previously documented in adults. We report an adult male with secondary syphilis presenting with pemphigus-like lesions.
Abstract The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy. Genetic or pharmacological inhibition of MDR1 increased intracellular levels of birinapant and sensitized AML cells from leukemia murine models, human leukemia cell lines, and primary AML samples to killing by birinapant. The combination of clinical MDR1 and IAP inhibitors was well tolerated in vivo and more effective against leukemic cells, compared with normal hematopoietic progenitors. Importantly, birinapant combined with third-generation MDR1i effectively killed murine leukemic stem cells (LSCs) and prolonged survival of AML-burdened mice, suggesting a therapeutic opportunity for AML. This study identified a drug combination strategy that, by efficiently killing LSCs, may have the potential to improve outcomes in patients with AML.
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