Treatment of Relapsing HPV Diseases by Restored Function of Natural Killer Cells.

Human papillomavirus (HPV) infections underlie a wide spectrum of both benign and malignant epithelial diseases. In this report, we describe the case of a young man who had encephalitis caused by herpes simplex virus during adolescence and currently presented with multiple recurrent skin and mucosal lesions caused by HPV. The patient was found to have a pathogenic germline mutation in the X-linked interleukin-2 receptor subunit gamma gene (IL2RG), which was somatically reverted in T cells but not in natural killer (NK) cells. Allogeneic hematopoietic-cell transplantation led to restoration of NK cytotoxicity, with normalization of the skin microbiome and persistent remission of all HPV-related diseases. NK cytotoxicity appears to play a role in containing HPV colonization and the ensuing HPV-related hyperplastic or dysplastic lesions. (Funded by the National Institutes of Health and the Herbert Irving Comprehensive Cancer Center Flow Cytometry Shared Resources.).

Polyfunctional Antigen Specific CD4+ T cell Responses in Patients With Human Immunodeficiency Virus/AIDS and Histoplasmosis Immune Reconstitution Inflammatory Syndrome.

In the combination antiretroviral era, there are limited data regarding the pathogenesis of histoplasmosis immune reconstitution inflammatory syndrome (IRIS) in people with human immunodeficiency virus (HIV). We immunologically characterized 10 cases of histoplasmosis, 4 of whom developed histoplasmosis IRIS. CD4+ T cells in histoplasmosis IRIS demonstrated a significant polyfunctional cytokine response to histoplasma antigen.

Identification of rare HIV-1-infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression.

BACKGROUND: The goal of antiretroviral therapy (ART) is to suppress HIV-1 replication and reconstitute CD4+ T cells. Here, we report on HIV-infected individuals who had a paradoxical decline in CD4+ T cells despite ART-mediated suppression of plasma HIV-1 load (pVL). We defined such an immunological outcome as extreme immune decline (EXID). METHODS: EXID's clinical and immunological characteristics were compared to immunological responders (IRs), immunological nonresponders (INRs), healthy controls (HCs), and idiopathic CD4+ lymphopenia (ICL) patients. T cell immunophenotyping and assembly/activation of inflammasomes were evaluated by flow cytometry. PBMC transcriptome analysis and genetic screening for pathogenic variants were performed. Levels of cytokines/chemokines were measured by electrochemiluminescence. Luciferase immunoprecipitation system and NK-mediated antibody-dependent cellular cytotoxicity (ADCC) assays were used to identify anti-lymphocyte autoantibodies. RESULTS: EXIDs were infected with non-B HIV-1 subtypes and after 192 weeks of consistent ART-mediated pVL suppression had a median CD4+ decrease of 157 cells/µl, compared with CD4+ increases of 193 cells/µl and 427 cells/µl in INR and IR, respectively. EXID had reduced naive CD4+ T cells, but similar proportions of cycling CD4+ T cells and HLA-DR+CD38+CD8+ T cells compared with IR and INR. Levels of inflammatory cytokines were also similar in EXID and INR, but the IL-7 axis was profoundly perturbed compared with HC, IR, INR, and ICL. Genes involved in T cell and monocyte/macrophage function, autophagy, and cell migration were differentially expressed in EXID. Two of the 5 EXIDs had autoantibodies causing ADCC, while 2 different EXIDs had an increased inflammasome/caspase-1 activation despite consistently ART-suppressed pVL. CONCLUSIONS: EXID is a distinct immunological outcome compared with previously described INR. Anti-CD4+ T cell autoantibodies and aberrant inflammasome/caspase-1 activation despite suppressed HIV-1 viremia are among the mechanisms responsible for EXID.

Manufactured populations: what do contemporary reference skeletal collections represent? A comparative study using the Maxwell Museum documented collection.

The extent to which archaeological or cemetery skeletal collections accurately represent the population from which they were drawn cannot be known. The creation of documented or forensic skeletal collections, derived from donation or autopsy, was intended to overcome many of the problems inherent in archaeological populations, yet it is misleading to assume such collections represent a specific or defined population. This study compares the documented skeletal collection curated at the Maxwell Museum to annual demographic information from three relevant populations: (i) the living population of New Mexico (NM), (ii) the deceased of NM, and (iii) the subset of decedents who undergo a medicolegal death investigation or autopsy. Results indicate that the Maxwell Documented collection differs significantly from all three populations in every variable examined: age, sex, ethnicity/race, cause, and manner of death. Collection development that relies on body donation or retention of unclaimed bodies under coroner/medical examiner statutes results in a biased sample, with significant overrepresentation of males, Whites, the elderly, those who die unnatural deaths and individuals with antemortem traumatic injury or surgical intervention. Equally problematic is the perception that the collection has documented race or ethnicity, when in fact only 17% was self-reported, while the affinity of the remaining individuals was determined by pathologists or other observers. Caution is warranted in how this and similar collections are used and interpreted by researchers. Although documented reference collections are useful in developing methods of estimating age or sex, they are not a proxy for modern or racially/ethnically defined populations.

Strigolactone analogs act as new anti-cancer agents in inhibition of breast cancer in xenograft model.

Strigolactones (SLs) are a novel class of plant hormones. Previously, we found that analogs of SLs induce growth arrest and apoptosis in breast cancer cell lines. These compounds also inhibited the growth of breast cancer stem cell enriched-mammospheres with increased potency. Furthermore, strigolactone analogs inhibited growth and survival of colon, lung, prostate, melanoma, osteosarcoma and leukemia cancer cell lines. To further examine the anti-cancer activity of SLs in vivo, we have examined their effects on growth and viability of MDA-MB-231 tumor xenografts model either alone or in combination with paclitaxel. We show that strigolactone act as new anti-cancer agents in inhibition of breast cancer in xenograft model. In addition we show that SLs affect the integrity of the microtubule network and therefore may inhibit the migratory phenotype of the highly invasive breast cancer cell lines that were examined.

Kumho, Daubert, and the nature of scientific inquiry: implications for forensic anthropology.

In the last 15 years, the US Supreme Court has implemented major changes concerning the admittance of expert testimony. In 1993, Daubert v. Merrell Dow Pharmaceuticals superseded the Frye ruling in federal courts and established judges, not the scientific community, as the gatekeepers regarding the credibility of scientific evidence. In 1999, a lesser-known but equally important decision, Kumho Tire v. Carmichael, ruled that technical expert testimony needed to employ the same rigor as outlined in Daubert, but experts can develop theories based on observations and apply such theories to the case before the court. Anthropology has never been defined as a hard science. Yet, many recent publications have modified existing techniques to meet the Daubert criteria, while none have discussed the significance of Kumho to anthropological testimony. This paper examines the impact of Daubert and Kumho on forensic anthropology and illustrates areas of anthropological testimony best admitted under Kumho's guidance.