A Recurrent ADPRHL1 Germline Mutation Activates PARP1 and Confers Prostate Cancer Risk in African American Families.

African American (AA) families have the highest risk of prostate cancer. However, the genetic factors contributing to prostate cancer susceptibility in AA families remain poorly understood. We performed whole-exome sequencing of one affected and one unaffected brother in an AA family with hereditary prostate cancer. The novel non-synonymous variants discovered only in the affected individuals were further analyzed in all affected and unaffected men in 20 AA-PC families. Here, we report one rare recurrent ADPRHL1 germline mutation (c.A233T; p.D78V) in four of the 20 families affected by prostate cancer. The mutation co-segregates with prostate cancer in two families and presents in two affected men in the other two families, but was absent in 170 unrelated healthy AA men. Functional characterization of the mutation in benign prostate cells showed aberrant promotion of cell proliferation, whereas expression of the wild-type ADPRHL1 in prostate cancer cells suppressed cell proliferation and oncogenesis. Mechanistically, the ADPRHL1 mutant activates PARP1, leading to an increased H2O2 or cisplatin-induced DNA damage response for prostate cancer cell survival. Indeed, the PARP1 inhibitor, olaparib, suppresses prostate cancer cell survival induced by mutant ADPRHL1. Given that the expression levels of ADPRHL1 are significantly high in normal prostate tissues and reduce stepwise as Gleason scores increase in tumors, our findings provide genetic, biochemical, and clinicopathological evidence that ADPRHL1 is a tumor suppressor in prostate tissue. A loss of function mutation in ADPRHL1 induces prostate tumorigenesis and confers prostate cancer susceptibility in high-risk AA families. IMPLICATIONS: This study highlights a potential strategy for ADPRHL1 mutation detection in prostate cancer-risk assessment and a potential therapeutic application for individuals with prostate cancer in AA families.

Correction: Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor.

[This corrects the article DOI: 10.1371/journal.pone.0226464.].

Poly(hydroxybutyrate-co-hydroxyvalerate) Porous Matrices from Thermally Induced Phase Separation.

Thermally induced phase separation followed by freeze drying has been used to prepare biodegradable and biocompatible scaffolds with interconnected 3D microporous structures from poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) copolymers containing 5 and 12 wt % of 3-hydroxyvalerate (HV). Solutions of PHBV in 1,4-dioxane, underwent phase separation by cooling under two different thermal gradients (at -25 °C and -5 °C). The cloud point and crystallization temperature of the polymer solutions were determined by turbidimetry and differential scanning calorimetry, respectively. Parameters affecting the phase separation mechanism such as variation of both the cooling process and the composition of the PHBV copolymer were investigated. Afterwards, the influence of these variables on the morphology of the porous structure and the final mechanical properties (i.e., rigidity and damping) was evaluated via scanning electron microscopy and dynamic mechanical thermal analysis, respectively. While the morphology of the scaffolds was considerably affected by polymer crystallization upon a slow cooling rate, the effect of solvent crystallization was more evident at either high hydroxyvalerate content (i.e., 12 wt % of HV) or high cooling rate. The decrease in the HV content gave rise to scaffolds with greater stiffness because of their higher degree of crystallinity, being also noticeable the greater consistency of the structure attained when the cooling rate was higher. Scaffolds were fully biocompatible supports for cell adhesion and proliferation in 3D cultures and show potential application as a tool for tissue regeneration.

Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies.

Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T-cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies.

Manejo del paciente politraumatizado y emergencia masiva en el banco de sangre / Politraumatism patient management and mass emergency in the blood bank

Se presenta un programa establecido en el Banco de Sangre del Hospital Nacional de Niños de Costa Rica para situaciones de emergencia. Consiste en el envío de GRE o Rho (D) positivo reconstituidos con suero fisiológico tibio sin que aun se haya hecho la determinación del grupo sanguíneo y pruebas de compatibilidad. El procedimiento agiliza la transfusión de sangre pues se disminuye la viscosidad considerablemente, se evita la sensibilización innecesaria por otros antígenos sanguíneos y a la vez disminuye los errores clericales que ocurren en estas situaciones de emergencia. Se presenta la experiencia obtenida entre octubre de 1993 y abril de 1994.

Prueba cruzada incompatible contra el sistema M N S S / Testing cross incompatible against the system M N S S

Se presentan 6 casos de pacientes de 1 a 22 años de edad, atendidos entre 1985 y 1994, sensibilizados post transfusión: 4 por anti M y 2 por anti S. 4 con IgM. 2 de ellos tenían además componetne IgG. A estos pacientes con historia de anemias, quemaduras o neoplasias y transfusiones previas se les solicitó sangre para cirugía; al realizar las pruebas cruzadas se encontró que 40 sangres fueron incompatibles. Se identificó la especificidad y se procedió a fenotipear sangres para este sistema y finalmente los pacientes se transfundieron sin problema