The etiologic, theory-based, ontogenetic hierarchical framework of alcohol use disorder: a translational systematic review of reviews.

Modern nosologies (e.g., ICD-11, DSM-5) for alcohol use disorder (AUD) and dependence prioritize reliability and clinical presentation over etiology, resulting in a diagnosis that is not always strongly grounded in basic theory and research. Within these nosologies, DSM-5 AUD is treated as a discrete, largely categorical, but graded, phenomenon, which results in additional challenges (e.g., significant phenotypic heterogeneity). Efforts to increase the compatibility between AUD diagnosis and modern conceptualizations of alcohol dependence, which describe it as dimensional and partially overlapping with other psychopathology (e.g., other substance use disorders) will inspire a stronger scientific framework and strengthen AUD's validity. We conducted a systematic review of 144 reviews to integrate addiction constructs and theories into a comprehensive framework with the aim of identifying fundamental mechanisms implicated in AUD. The product of this effort was the Etiologic, Theory-Based, Ontogenetic Hierarchical Framework (ETOH Framework) of AUD mechanisms, which outlines superdomains of cognitive control, reward, as well as negative valence and emotionality, each of which subsume narrower, hierarchically-organized components. We also outline opponent processes and self-awareness as key moderators of AUD mechanisms. In contrast with other frameworks, we recommend an increased conceptual role for negative valence and compulsion in AUD. The ETOH framework serves as a critical step towards conceptualizations of AUD as dimensional and heterogeneous. It has the potential to improve AUD assessment and aid in the development of evidence-based diagnostic measures that focus on key mechanisms in AUD, consequently facilitating treatment matching

KIR3DS1 directs NK cell-mediated protection against human adenovirus infections

Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1(+) NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein 19K, consistent with evasion from CD8(+) T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1(+)/HLA-Bw4(+) donor cells compared with children receiving non-KIR3DS1(+)/HLA-Bw4(+) cells. These findings identify the KIR3DS1/HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease

Her2/neu signaling blockade improves tumor oxygenation in a multifactorial fashion in Her2/neu+ tumors

PURPOSE: Tumor hypoxia reduces the efficacy of radiation and chemotherapy as well as altering gene expression that promotes cell survival and metastasis. The growth factor receptor, Her2/neu, is overexpressed in 25–30% of breast tumors. Tumors that are Her2(+) may have an altered state of oxygenation, relative to Her2(−)tumors, due to differences in tumor growth rate and angiogenesis. METHODS: Her2 blockade was accomplished using an antibody to the receptor (trastuzumab; Herceptin). This study examined the effects of Her2 blockade on tumor angiogenesis, vascular architecture, and hypoxia in Her2(+) and Her2(−) MCF7 xenograft tumors. RESULTS: Treatment with trastuzumab in Her2(+) tumors significantly improved tumor oxygenation, increased microvessel density, and improved vascular architecture compared with the control-treated Her2(+) tumors. The Her2(+) xenografts treated with trastuzumab also demonstrated decreased proliferation indices when compared with control-treated xenografts. These results indicate that Her2 blockade can improve tumor oxygenation by decreasing oxygen consumption (reducing tumor cell proliferation and inducing necrosis) and increasing oxygen delivery (vascular density and architecture). CONCLUSIONS: These results support the use of trastuzumab as an adjunct in the treatment of breast tumors with chemotherapy or radiotherapy, as improvements in tumor oxygenation should translate into improved treatment response