Novel indolylarylsulfone derivatives as covalent HIV-1 reverse transcriptase inhibitors specifically targeting the drug-resistant mutant Y181C

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. However, emergent and transmitted drug resistance compromise their efficacy in the clinical setting. Y181C is selected in patients receiving nevirapine, etravirine and rilpivirine, and together with K103N is the most prevalent NNRTI-associated mutation in HIV-infected patients. Herein, we report on the design, synthesis and biological evaluation of a novel series of indolylarylsulfones bearing acrylamide or ethylene sulfonamide reactive groups as warheads to inactivate Cys181-containing HIV-1 RT via a Michael addition reaction. Compounds I-7 and I-9 demonstrated higher selectivity towards the Y181C mutant than against the wild-type RT, in nucleotide incorporation inhibition assays. The larger size of the NNRTI binding pocket in the mutant enzyme facilitates a better fit for the active compounds, while stacking interactions with Phe227 and Pro236 contribute to inhibitor binding. Mass spectrometry data were consistent with the covalent modification of the RT, although off-target reactivity constitutes a major limitation for further development of the described inhibitors.by grants PID2019-104176RB-I00/AEI/10.13039/501100011033) (Spanish Ministry of Science and Innovation) and 2019AEP001 (CSIC), as well as an institutional grant of Fundación Ramón Areces (awarded to the CBMSO)

Analysis of factors influencing the outpatient workload at Chinese health centres

<p>Abstract</p> <p>Background</p> <p>Although the community health service system is now established in China, the utilisation of the community health service institutions is low due to the lack of a gate-keeping role of the primary health service providers and referrals among the three-tiered health service institutions. In addition to this, patients who can afford to pay, often seek best services in big hospitals to guarantee the quality of care. Thus, the need of guiding the patients to the community health services and increasing the utilisation of the community health service institutions is becoming an urgent problem, which hinders the future development of community health services. This study focuses on the question of how to increase the utilisation of Chinese community health centres (HCs).</p> <p>Methods</p> <p>A cross-sectional Base-line Survey of Chinese City Community Health Service System Building using the multi-staged cluster sampling was conducted to collect data from all HCs in 28 key contact cities. Relevant indicators of totally 1790 HCs were analysed. The statistical methods included ANONVA and logistic regression.</p> <p>Results and Conclusions</p> <p>The analysis suggested several key factors for increasing the outpatient workload (OW) at the HCs: establishing an adequate referral system among the different levels of the health system; enhancing the qualification of health personnel and increasing the compensation by the health insurance for services provided at HCs. Other key factors with a positive effect on the OW included: the government ownership of the HCs, the scale of the institutions, the medical equipment used, the mix of health services provided, and the women in childbearing age in the residence.</p

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Advances in Diagnosis and Treatment of Multiple Primary Lung Cancer

Recently, the incidence and detection rates of multiple primary lung cancer (MPLC) are increasing. The diagnosis of MPLC depends mainly on the Martini-Melamed criterion and ACCP criterion at present, taking all features (histological, genetic, radiologic and clinical) into account. It may be easy to diagnose cases of MPLC that exhibit different histological types, but it is difficult to diagnose cases that exhibit similar histological type. DNA polity, gene mutations, microsatellite alteration and so on provide new methods for the accurate diagnosis of MPLC. They can evaluate the clonal relationship and help differential diagnosis between MPLC and metastasis. The first therapeutic choice for MPLC is curative operation. The surgical approach includes lobectomy, wedge resection and segmentectomy. For those which cannot be resected, we can synthesize chemotherapy, radiotherapy, stereotactic ablative radiotherapy (SABR), radiofrequency ablation (RFA), molecular targeted therapy, etc

Effect of Material Properties on the Foaming Behaviors of PP-Based Wood Polymer Composites Prepared with the Application of Spherical Cavity Mixer

For the low weight and high strength, the microcellular extrusion foaming technology was applied in the preparation of polypropylene (PP)-based wood polymer composites, and the spherical cavity mixer was used to construct an experimental platform for the uniform dispersion of wood flour (WF). The effects of PP molecular configuration on the composite properties and cell morphology of samples were also investigated. The experimental results indicated that the application of a spherical cavity mixer with a cavity radius of 5 mm could effectively improve the mixing quality and avoid the agglomeration of WF. In addition, compared with the branched molecule, the linear molecule not only increased the melting temperature by about 10 °C, but also endowed composites with a higher complex viscosity at a shear rate lower than 100 s−1, which contributed to the cell morphology of more microporous samples

Progress in Research on the Alleviation of Glucose Metabolism Disorders in Type 2 Diabetes Using Cyclocarya paliurus

Globally, the incidence of diabetes is increasing annually, and China has the largest number of patients with diabetes. Patients with type 2 diabetes need lifelong medication, with severe cases requiring surgery. Diabetes treatment may cause complications, side-effects, and postoperative sequelae that could lead to adverse health problems and significant social and economic burdens; thus, more efficient hypoglycemic drugs have become a research hotspot. Glucose metabolism disorders can promote diabetes, a systemic metabolic disease that impairs the function of other organs, including the heart, liver, and kidneys. Cyclocarya paliurus leaves have gathered increasing interest among researchers because of their effectiveness in ameliorating glucose metabolism disorders. At present, various compounds have been isolated from C. paliurus, and the main active components include polysaccharides, triterpenes, flavonoids, and phenolic acids. C. paliurus mainly ameliorates glucose metabolism disorders by reducing glucose uptake, regulating blood lipid levels, regulating the insulin signaling pathway, reducing &beta;-cell apoptosis, increasing insulin synthesis and secretion, regulating abundances of intestinal microorganisms, and exhibiting &alpha;-glucosidase inhibitor activity. In this paper, the mechanism of glucose metabolism regulation by C. paliurus was reviewed to provide a reference to prevent and treat diabetes, hyperlipidaemia, obesity, and other metabolic diseases

Preparation and Application of Self-Curing Magnesium Phosphate Cement Concrete with High Early Strength in Severe Cold Environments

The early strength of magnesium phosphate cement (MPC) decreases sharply in severe cold environments &le;&minus;10 &deg;C, with the 2 h compressive strength falling to 3.5 MPa at&minus;20 &deg;C. Therefore, it cannot be used as a repair material for emergency repair construction in such environments. In this study, MPC is adapted for use in such cold environments by replacing part of the dead-burned magnesia (M) in the mixture with a small amount of light-burned magnesia (LBM) and introducing dilute phosphoric acid (PA) solution as the mixing water. The heat released by the highly active acid&ndash;base reaction of PA and LBM stimulates an MPC reaction. Moreover, the early strength of the MPC significantly improves with the increase in the Mg2+ concentration and the initial reaction temperature of the MPC paste, which enables MPC hardening in severe cold environments. Although the morphology of the reaction products of the MPC is poor and the grain plumpness and size of the struvite crystals are remarkably reduced, the early strength of MPC prepared in the severe cold environment is close to that of MPC prepared under normal temperature. Furthermore, the increases in the early reaction temperature and early strength of magnesium phosphate cement concrete (MPCC) are significantly improved when the PA concentration in the mixing water and the LBM/M ratio are 10% and 4&ndash;6% at &minus;10 &deg;C and 20% and 6&ndash;8% at &minus;20 &deg;C, respectively. Moreover, self-curing of MPCC can be realized even at &minus;20 &deg;C, at which temperature the 2 h and 24 h compressive strength of MPCC reach 36 MPa and 45 MPa, respectively

Electroacupuncture Alleviates Pain Responses and Inflammation in a Rat Model of Acute Gout Arthritis

Acute gout arthritis is one of the most painful inflammatory conditions. Treatments for gout pain are limited to colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids, which oftentimes result in severe adverse effects. Electroacupuncture (EA) has been proved to be effective in relieving many inflammatory pain conditions with few side effects. Here, we aim to investigate the therapeutic potentials of EA on pain and inflammation of a rat model of acute gout arthritis and underlying mechanisms. We found that 2/100 Hz EA produced the most robust analgesic effect on mechanical hyperalgesia of acute gout arthritis rat model compared with 2 and 100 Hz. EA produced similar analgesic effect compared with indomethacin. 2/100 Hz EA also significantly alleviates the ongoing pain behavior, thermal hyperalgesia, and ankle edema. Locally applied μ and κ-opioid receptor antagonists but not adenosine A1 receptor antagonist significantly abolished the analgesic effect of EA. Locally applied μ and κ-opioid receptor agonists produced significant antiallodynia on acute gout arthritis rats, mimicking EA. Furthermore, 2/100 Hz EA upregulated β-endorphin expression in inflamed ankle skin tissue. Our results demonstrated, for the first time, that EA can be used for relieving acute gout arthritis with effect dependent on peripheral opioid system and comparable with the one obtained with indomethacin