Investigation on the Coaxial-Annulus-Argon-Assisted Water-Jet-Guided Laser Machining of Hard-to-Process Materials.

In this study, the novel coaxial-annulus-argon-assisted (CAAA) atmosphere is proposed to enhance the machining capacity of the water-jet-guided laser (WJGL) when dealing with hard-to-process materials, including ceramic matrix composites (CMCs) and chemical-vapor-deposition (CVD) diamond. A theoretical model was developed to describe the two-phase flow of argon and the water jet. Simulations and experiments were conducted to analyze the influence of argon pressure on the working length of the WJGL beam, drainage circle size, and extreme scribing depth on ceramic matrix composite (CMC) substrates. A comparative experiment involving coaxial annulus and helical atmospheres revealed that the coaxial annulus atmosphere disrupts the water jet proactively, while effectively maintaining the core velocity within the confined working length and enhancing the processing capability of the WJGL beam. Single-point percussion drilling experiments were performed on a CMC substrate to evaluate the impact of machining parameters on hole morphology. The maximum depth-to-width ratio of the groove and depth-to-diameter ratio of the hole reached up to 41.2 and 40.7, respectively. The thorough holes produced by the CAAAWJGL demonstrate superior roundness and minimal thermal damage, such as fiber drawing and delamination. The average tensile strength and fatigue life of the CMCs specimens obtained through CAAAWJGL machining reached 212.6 MPa and 89,463.8 s, exhibiting higher machining efficiency and better mechanical properties compared to femtosecond (194.2 MPa; 72,680.2 s) and picosecond laser (198.6 MPa; 80,451.4 s) machining. Moreover, groove arrays with a depth-to-width ratio of 11.5, good perpendicularity, and minimal defects on a CVD diamond were fabricated to highlight the feasibility of the proposed machining technology.

Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.

Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized B-factors and optimization of lipophilic efficiency.

Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants.

First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.

Knowledge and perceptions of sexual and reproductive health and HIV among perinatally HIV-infected adolescents in rural China.

Due to the success of highly active antiretroviral therapy, more children infected with HIV perinatally are living to adolescence. This brings new challenges on sexual and reproductive health (SRH) needs and psychosocial support specific to adolescents. To improve such efforts on long-term care of this vulnerable population, we assessed SRH and HIV knowledge and perceptions among perinatally HIV-infected adolescents (PHIVA). This descriptive cross-sectional study was conducted between July and September 2013 in a rural HIV clinic. A structured questionnaire focusing on SRH and HIV was administered to 124 PHIVA attending quarterly medical visit. Multivariable logistic regression was used to detect associated factors with knowledge acquisition. Among participants, 79% had never discussed puberty development or sexuality with parents. Over 50% had never heard of condoms and 20% reported not having any informational source of SRH and HIV knowledge. Only 5% correctly answered all questions regarding HIV knowledge and pregnancy, with 18% correctly answered questions regarding contraception. Adolescents older than age of 15 and who had been disclosed of HIV status were more likely to acquire correct knowledge of SRH and HIV. Most PHIVA did not report having access to comprehensive information on SRH and HIV, in part because of the early death of caretakers or unfavorable family status. Further integration of SRH services with HIV treatment programs is needed to provide comprehensive care for adolescents and prepare them for the transition to adult care.

A higher correlation of HCV core antigen with CD4+ T cell counts compared with HCV RNA in HCV/HIV-1 coinfected patients.

Development of HCV infection is typically followed by chronic hepatitis C (CHC) in most patients, while spontaneous HCV viral clearance (SVC) occurs in only a minority of subjects. Compared with the widespread application of HCV RNA testing by quantitative RT-PCR technique, HCV core antigen detection may be an alternative indicator in the diagnosis of hepatitis C virus infections and in monitoring the status of infectious individuals. However, the correlation and differences between these two indicators in HCV infection need more investigation, especially in patients coinfected by HIV-1. In this study, a total of 354 anti-HCV and/or anti-HIV serum positive residents from a village of central China were enrolled. Besides HCV-related hepatopathic variables including clinical status, ALT, AST, anti-HCV Abs, as well as the altered CD4+/CD8+ T cell counts, HCV core antigen and HCV viral load were also measured. The concentration of serum HCV core antigen was highly correlated with level of HCV RNA in CHC patients with or without HIV-1 coinfection. Of note, HCV core antigen concentration was negatively correlated with CD4+ T cell count, while no correlation was found between HCV RNA level and CD4+ T cell count. Our findings suggested that quantitative detection of plasma HCV core antigen may be an alternative indicator of HCV RNA qPCR assay when evaluating the association between HCV replication and host immune status in HCV/HIV-1 coinfected patients.

[Study on the natural history of HIV among former commercial plasma donors caused by contaminated plasma donation in central China].

OBJECTIVE: To investigate the natural history of HIV infection caused by contaminated plasma donation among former commercial plasma donors in China. METHODS: Ambispective cohort study among HIV/AIDS cases and suspected AIDS deaths was conducted from January 1, 1995 to March 31, 2008 in 7 administrative villages in Shangcai county of Henan province. Information regarding diagnostic criteria, deaths and anti-retrovirus treatment was collected. Incubation and survival time were calculated using Kaplan-Meier and life-tables method. Sensitive analysis on the time of outcome was conducted. RESULTS: A total number of 2569 cases of HIV infection including 483 suspected AIDS deaths were involved in a cohort. 200 patients with rapid progress (7.8%) and 337 long-term but non-progressive patients (13.1%) were identified. Results from the sensitive analysis showed that the median incubation period from HIV infection to AIDS was between 8.5 and 8.9 years, with incidence as 11.7 - 12.0 cases/100 person-years and the median survival time for HIV progression to death was from 8.8 to 10.7 years, with the death rate as 6.9 - 8.3 cases/100 person-years. The median survival time for AIDS patient was from 1.2 to 2.0 years, with death rate as 34.9 - 51.5 cases/100 person-years. CONCLUSION: According to sensitive analysis, the incubation period for HIV progression to AIDS, the median survival time for HIV progression to death and the median survival time for AIDS patient to death were 8.8 years, 1.2 years and 9.8 years, respectively.

Mortality survey on HIV/AIDS-related deaths in HIV epidemic regions caused by contaminated plasma donation in central China.

The objective of our study was to understand the trend of AIDS deaths and the impact of AIDS-related deaths on the local mortality rate in seven villages in Shangcai County, Henan Province. A retrospective study survey among all deaths was conducted through household visits from 1 January 1995 to 31 October 2007 in seven administrative villages in Shangcai County of Henan Province. The cause of death and characteristics of the deceased were analyzed. There were a total of 2546 deaths, of which 521 (20.5%) were HIV/AIDS-related, 525 (20.6%) were suspected AIDS deaths, and 1500 (58.9%) were unrelated HIV/AIDS deaths. The proportion of deaths among people aged 20-49 years was less than 20% from 1995 to 1997, but increased to 27.4% in 1998, and reached 49.2% in 2001, followed by a decrease in succeeding years, dropping to 29.5% in 2007. HIV/AIDS-related and suspected deaths among those aged 20-49 years accounted for 63.9% and 70.9% of all deaths, respectively. The overall mortality rate was 7 per thousand from 1995 to 1999, and 14.9 per thousand in 2002. Our study shows that confirmed HIV/AIDS-related deaths and suspected AIDS deaths were the main cause of deaths at the local level after 1998, especially among those aged 20-49.