Biochemical and Genetic Basis of Guanacastane Diterpene Biosynthesis in Basidiomycete Fungi.

Guanacastane diterpenoids with an unusual 5/7/6 tricyclic skeleton mainly produced by basidiomycete fungi represent a structurally intriguing class of natural products. While the chemical synthesis of several members has been achieved, the biochemical and genetic basis of their biosynthesis remain unknown. Herein, we present the identification and characterization of two crucial enzymes in the biosynthesis of guanacastane diterpenoids in .

Clinical targeting of HIV capsid protein with a long-acting small molecule.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections.

Psathyrins: Antibacterial Diterpenoids from .

Two skeletally novel tetracyclic diterpenoids, psathyrins A () and B (), have been characterized from cultures of the basidiomycete . Their structures including absolute configurations were established by means of spectroscopic methods, as well as ECD calculations. They possess a novel 5/5/4/6-fuesd ring system, for which the biosynthetic pathway is proposed.

Sesquiterpenoids from Cultures of the Basidiomycetes .

Eight previously undescribed sesquiterpenoids, tremutins A-H (-), together with three known ones (-), were isolated from cultures of the basidiomycetes . Structures of the new compounds together with absolute configurations were elucidated on the basis of extensive spectroscopic methods, as well as single-crystal X-ray diffractions and equivalent circulating density calculations. Compounds and possess an unusual 6/7-fused ring system that might be derived from a tremulane framework.

Switching to bictegravir/emtricitabine/tenofovir alafenamide maintained HIV-1 RNA suppression in participants with archived antiretroviral resistance including M184V/I.

Objectives: Studies 1878 and 1844 demonstrated non-inferior efficacy of switching suppressed HIV-1-infected adults to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) versus continuing boosted PI-based triple regimens or dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). Here, detailed analyses of pre-existing resistance in the two BIC/FTC/TAF switch studies and efficacy at week 48 are described.

Methods: Pre-existing resistance was assessed from historical genotypes (documented resistance to study drugs was excluded) and by retrospective baseline proviral archive DNA genotyping from whole blood.

Cytotoxic ergosterols from cultures of the basidiomycete Psathyrella candolleana.

Three newly isolated ergosterols, psathergosterols A-C (1-3), together with two known ones (4 and 5), have been isolated from cultures of the basdiomycete Psathyrella candolleana. Their structures with the absolute configuration were elucidated by means of spectroscopic methods and the single crystal X-ray diffraction. Compounds 2-4 exhibited certain cytotoxicities to five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480).

Efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in Asian participants with human immunodeficiency virus 1 infection: A sub-analysis of phase 3 clinical trials.

The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) was analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naive and ART-experienced Asian participants infected with human immunodeficiency virus (HIV)-1 through 96 or 144 weeks. In Asian population requiring treatment, it is imperative to have data specific to this group, particularly as there is a general concern that Asians with lower body weight have increased risk of tenofovir disoproxil fumarate (TDF)-related renal dysfunction. Studies -104 and 111 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naive participants, comparing E/C/F/TAF versus E/C/F/TDF.

Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial.

Background: Switching from therapy based on a boosted protease inhibitor to bictegravir, emtricitabine, and tenofovir alafenamide could avoid drug interactions and unwanted side-effects in virologically suppressed adults with HIV-1 infection, while maintaining a high barrier to resistance and providing a simplified once-daily, single-tablet regimen. Here, we report 48 week results of a phase 3 study investigating this switch.

Methods: In this multicentre, randomised, open-label, active-controlled, non-inferiority, phase 3 trial, adults with HIV-1 infection were enrolled at 121 outpatient centres in ten countries.

Superior Efficacy and Improved Renal and Bone Safety After Switching from a Tenofovir Disoproxil Fumarate- to a Tenofovir Alafenamide-Based Regimen Through 96 Weeks of Treatment.

We previously demonstrated superior efficacy and safety advantages in HIV-infected, virologically suppressed adults switched to a regimen containing tenofovir alafenamide (TAF) as compared with those remaining on a tenofovir disoproxil fumarate (TDF) regimen through week 48. We now report long-term data through week 96. In this randomized, active-controlled, multicenter, open-label, noninferiority trial (ClinicalTrials.

Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.

Background: Tenofovir alafenamide is a prodrug that reduces tenofovir plasma concentrations by 90% compared with tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine, and tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and tenofovir disoproxil fumarate.

Methods: In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe.

Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial.

Objectives: Cobicistat (COBI) enhances atazanavir (ATV) pharmacokinetic parameters similarly to ritonavir (RTV) in both healthy volunteers and HIV-infected adults. Primary efficacy and safety outcomes of this Phase 3, international, randomized, double-blind, double-dummy, active- controlled trial in HIV-1-infected treatment-naïve adults (GS-US-216-0114/NCT01108510) demonstrated that ATV+COBI was non-inferior to ATV+RTV, each in combination with emtricitabine/ tenofovir disoproxil fumarate (FTC/TDF), at Weeks 48 and 144, with high rates of virologic success for both regimens (85.2% and 87.

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study.

Background: Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate.

Long-term efficacy and safety of tenofovir disoproxil fumarate in HIV-1-infected adolescents failing antiretroviral therapy: the final results of study GS-US-104-0321.

Background: Reports of long-term tenofovir disoproxil fumarate (TDF) treatment in HIV-infected adolescents are limited. We present final results from the open-label (OL) TDF extension following the randomized, placebo (PBO)-controlled, double-blind phase of GS-US-104-0321 (Study 321).

Methods: HIV-infected 12- to 17-year-olds treated with TDF 300 mg or PBO with an optimized background regimen (OBR) for 24-48 weeks subsequently received OL TDF plus OBR in a single arm study extension.

Elvitegravir/cobicistat/emtricitabine/tenofovir DF in HIV-infected patients with mild-to-moderate renal impairment.

In HIV-1-infected treatment-naive patients with mild-to-moderate renal impairment [creatinine clearance (CrCl): 50-89 mL/min], elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB, n = 33) achieved high rates of virologic success (78.8%; 95% confidence interval: 61.1% to 91.

A randomized phase 3 study comparing once-daily elvitegravir with twice-daily raltegravir in treatment-experienced subjects with HIV-1 infection: 96-week results.

: This 96-week, double-blind, active-controlled, phase 3 study, randomized subjects to elvitegravir once daily or raltegravir twice daily with a fully active, ritonavir-boosted protease inhibitor plus a third agent. The proportion of subjects randomized to elvitegravir that achieved and maintained HIV-1 RNA < 50 copies/mL through week 96 was 47.6% (167/351) compared with 45.

[ABA signaling mediated by PYR/PYL/RCAR in plants].

Abscisic acid (ABA) is a phytohormone that plays critical roles in numerous developmental stages as well as in adaptive responses to biotic and abiotic stresses. Recent breakthroughs in the field of ABA signaling have indicated that there are three major components, PYR/PYL/RCAR (an ABA receptor), type 2C protein phosphates (PP2C, a negative regulator), and SNF1-related protein kinase 2 (SnRK2, a positive regulator). Further results show that these three proteins construct a double negative regulatory system, PYR/PYL/RCAR-| PP2C-| SnRK2, to regulate ABA signal responses in plant cells.

A randomized study of tenofovir disoproxil fumarate in treatment-experienced HIV-1 infected adolescents.

Background: There are few data on the safety and antiviral activity of tenofovir disoproxil fumarate (TDF) in HIV-1 infected adolescents.

Methods: A randomized, double-blinded, placebo-controlled study was conducted. Ninety adolescents (12 to <18 years) who were viremic while receiving antiretroviral treatment were randomized to receive TDF 300 mg (mean, 216.

Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study.

Background: Elvitegravir is a once daily inhibitor of HIV-1 integrase boosted by ritonavir. We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 integrase inhibitor, in patients in whom previous antiretroviral treatment failed.

Methods: We conducted a randomised, double-blind, double-dummy, phase 3 study at 234 sites in 13 countries.

Comparison of intravenous pamidronate to standard therapy for osteoporosis: use in patients unable to take oral bisphosphonates.

Background: Bisphosphonates are potent therapies for osteoporosis, but some patients cannot tolerate oral forms. Our study sought to examine the effectiveness and safety of intravenous pamidronate as an alternate osteoporotic therapy in these patients.

Methods: We conducted a retrospective study of 26 patients treated with intermittent, intravenous pamidronate (30 mg every 3 months) and 52 matched controls treated with standard therapy, all with osteoporosis.