HIV-1 subtype-specific drug resistance on dolutegravir-based antiretroviral therapy: protocol for a multicentre study (DTG RESIST).

INTRODUCTION: HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was endorsed by the WHO in 2019 for first-line, second-line and third-line antiretroviral therapy (ART). This multiplicity of roles of dolutegravir in ART may facilitate the emergence of dolutegravir resistance. METHODS AND ANALYSIS: Nested within the International epidemiology Databases to Evaluate AIDS (IeDEA), DTG RESIST is a multicentre study of adults and adolescents living with HIV in sub-Saharan Africa, Asia, and South and Central America who experienced virological failure on dolutegravir-based ART. At the time of virological failure, whole blood will be collected and processed to prepare plasma or dried blood spots. Laboratories in Durban, Mexico City and Bangkok will perform genotyping. Analyses will focus on (1) individuals who experienced virological failure on dolutegravir and (2) those who started or switched to such a regimen and were at risk of virological failure. For population (1), the outcome will be any InSTI drug resistance mutations, and for population (2) virological failure is defined as a viral load >1000 copies/mL. Phenotypic testing will focus on non-B subtype viruses with major InSTI resistance mutations. Bayesian evolutionary models will explore and predict treatment failure genotypes. The study will have intermediate statistical power to detect differences in resistance mutation prevalence between major HIV-1 subtypes; ample power to identify risk factors for virological failure and limited power for analysing factors associated with individual InSTI drug resistance mutations. ETHICS AND DISSEMINATION: The research protocol was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, South Africa and the Ethics Committee of the Canton of Bern, Switzerland. All sites participate in International epidemiology Databases to Evaluate AIDS and have obtained ethics approval from their local ethics committee to collect additional data. TRIAL REGISTRATION NUMBER: NCT06285110.

A comprehensive insight from molecular docking and dynamics with clinical investigation on the impact of direct oral anticoagulants on atheroprotective protein in atrial fibrillation.

BACKGROUND: Direct oral anticoagulants (DOACs) have high potency against their therapeutic target and are widely used in the treatment of atrial fibrillation (AF). Most DOACs are often claimed to have adverse effects due to off-target inhibition of essential proteins. Human serum paraoxonase 1 (PON1), one of the essential proteins, known for its anti-inflammatory and antioxidant properties, could be affected by DOACs. Thus, a comparative evaluation of DOACs and their effect on PON1 protein will aid in recommending the most effective DOACs for AF treatment. This study aimed to assess the impact of DOACs on PON1 through a combination of computational and experimental analyses. METHODS: We focus on apixaban, dabigatran, and rivaroxaban, the most recommended DOACs in AF treatment, for their impact on PON1 through molecular docking and molecular dynamics (MD) simulation to elucidate the binding affinity and drug-protein structural stability. This investigation revealed the most influential DOACs on the PON1 protein. Then experimental validation was performed in DOAC-treated AF participants (n = 42; 19 treated with dabigatran and 23 treated with rivaroxaban) compared to a healthy control group (n = 22) through gene expression analysis in peripheral blood mononuclear cells (PBMC) and serum enzyme concentration. RESULTS: Our computational investigation showed rivaroxaban (-4.24 kcal/mol) exhibited a lower affinity against the PON1 protein compared to apixaban (-5.97 kcal/mol) and dabigatran (-9.03 kcal/mol) through molecular docking. Dabigatran holds complex interactions with PON1 at GLU53, TYR197, SER193, and ASP269 by forming hydrogen bonds. Additionally, MD simulation revealed that dabigatran disrupts PON1 stability, which may contribute functional changes. Further experimental validation revealed a significant down-regulation (p < 0.05) of PON1 gene expression in PBMC and decreased serum PON1 enzyme concentration on DOAC treatment. Rivaroxaban as about 48% has inhibitory percentage and dabigatran as about 75% of inhibitory percentage compared to healthy control. CONCLUSION: Overall, our computational and experimental results clearly show the higher inhibitory effect of dabigatran than rivaroxaban. Hence, rivaroxaban will be a better drug candidate for improving the outcome of AF.

Characterizing HIV drug resistance in cases of vertical transmission in the VESTED randomized antiretroviral treatment trial.

Introduction: VESTED (NCT03048422) compared the safety and efficacy of three antiretroviral treatment (ART) regimens in pregnant and postpartum women: dolutegravir+emtricitabine/tenofovir alafenamide fumarate; dolutegravir+emtricitabine/tenofovir disoproxil fumarate (TDF); efavirenz/emtricitabine/TDF. Vertical HIV transmission (VT) occurred to 4/617 (0.60%) live-born infants, who were evaluated for HIV drug resistance (HIVDR) and other risk factors. Setting: In 2018-2020, pregnant (weeks-14-28) women living with HIV and ≤14 days of ART were enrolled at 22 international sites and followed with their infants through 50 weeks postpartum. Methods: HIV sequences derived by single genome amplification (SGA) from longitudinally collected specimens were assessed from VT Cases for HIVDR in protease, reverse transcriptase, integrase, and the nef 3'polypurine tract (3'PPT). Results: The four Case mothers were prescribed efavirenz-based-ART for 1-7 days prior to randomization to study ART. Their infants received postnatal nevirapine+/-zidovudine prophylaxis and were breastfed. A total of 833 SGA sequences were derived. The "major" (Stanford HIVDR Score ≥60) non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation (K103N) was detected persistently in one viremic mother, and likely contributed to VT of HIVDR. Major NNRTI HIVDR mutations were detected in all three surviving infants. No integrase, nor high frequencies of 3'PPT mutations conferring dolutegravir HIVDR were detected. The timing of HIV infant diagnosis, plasma HIV RNA levels and HIVDR suggests one in utero, one peripartum, one early, and one late breastfeeding transmission. Conclusions: VT was rare. New-onset NNRTI HIVDR in Case mothers was likely from efavirenz-ART prescribed prior to study dolutegravir-ART, and in one case appeared transmitted to the infant despite nevirapine prophylaxis.

Management of apixaban anticoagulation in a patient requiring therapeutic plasma exchange: a case report and a literature review.

Therapeutic plasma exchange (TPE) is used as an effective treatment modality for a variety of autoimmune disorders. Apart from its desired effect of removing pathological blood components, it also can remove coagulation factors and drugs. Currently, there is an insufficient amount of information regarding the use of direct oral anticoagulants in this setting. In this article, we present a case report of a patient with myasthenia gravis and chronic anticoagulation with apixaban who underwent a series of TPE while continuing apixaban treatment. We observed that only 10% of daily dose was removed by the procedure and plasma levels of apixaban corresponded with expected range. TPE was not associated with shortened drug plasma half-life. We did not observe any significant alteration of apixaban pharmacokinetics during the period of TPE therapy, as well as no thrombotic or bleeding events. This case report supports the use of apixaban in patients treated by TPE, nevertheless, to firmly establish apixaban efficacy and safety profile in this clinical setting further research is needed.

Effectiveness and Safety of Extended Treatment Apixaban Versus Low-Molecular-Weight Heparin in Cancer-Associated Venous Thromboembolism.

BACKGROUND: Limited real-world evidence is available comparing the safety and effectiveness of apixaban and low-molecular-weight heparins (LMWHs) for preventing recurrent venous thromboembolism (VTE) in patients with active cancer receiving anticoagulation in an extended treatment setting. This study evaluated the risk of bleeding and recurrent VTE in patients with cancer-associated VTE who were prescribed apixaban or LMWH for ≥3 months. METHODS: A US commercial claims database was used to identify adult patients with VTE and active cancer who initiated apixaban or LMWH 30 days following the first VTE diagnosis and had ≥3 months of continuous enrollment and 3 months of primary anticoagulation treatment. Patients were followed from the day after the end of primary anticoagulation treatment until the earliest of: date of disenrollment, discontinuation of index anticoagulant, switch to another anticoagulant, or end of the study period. Inverse-probability treatment weighting (IPTW) was used to balance treatment cohorts. Incidence rates (IRs) for the outcomes were calculated per 100 person-years (PY). Cox proportional hazard models were used to evaluate the adjusted risk of recurrent VTE, major bleeding (MB), and clinically relevant nonmajor bleeding (CRNMB). RESULTS: A total of 13,564 apixaban- and 2,808 LMWH-treated patients were analyzed. Post-IPTW, the treatment cohorts were balanced. Patients receiving apixaban had lower adjusted IRs for recurrent VTE (4.1 vs 9.6 per 100 PY), MB (6.3 vs 12.6), and CRNMB (26.1 vs 36.0) versus LMWH (P<.0001 for all comparisons) during the follow-up period. Patients on apixaban had a lower adjusted risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.34-0.53), MB (HR, 0.50; 95% CI, 0.41-0.61), and CRNMB (HR, 0.76; 95% CI, 0.68-0.85) versus LMWH. CONCLUSIONS: Extended anticoagulation treatment of ≥3 months with apixaban was associated with lower rates of recurrent VTE, MB, and CRNMB compared with LMWH in adults with cancer-associated VTE.

The association between adherence to antiretroviral therapy and viral suppression under dolutegravir-based regimens: an observational cohort study from Uganda.

INTRODUCTION: Millions of people living with HIV (PLWH) take oral antiretroviral therapy (ART), which requires a lifetime of consistent medication adherence. The relationship between adherence and poor HIV outcomes is well documented. Newer ART regimens that include dolutegravir (DTG) could be more forgiving, but empirical evidence on the relationship between adherence and viral suppression under DTG is only emerging. METHODS: In this observational cohort study (secondary analysis of data from a randomized trial), we used data from 313 ART clients from a large HIV clinic in Kampala, Uganda. Over the 4-year study period (January 2018-January 2022), 91% switched from non-DTG regimens to DTG regimens. We measured adherence using Medication Event Monitoring Systems-caps and extracted prescription information and viral load measures from electronic health records. We estimated unadjusted linear regressions and adjusted models that included individual and time fixed-effects. RESULTS: Under non-DTG regimens, 96% of participants were virally suppressed (defined as viral load < 200 copies/ml) when adherence was 90% or higher in the 3 months before viral load measurement. Viral suppression was 32 percentage points lower when adherence was between 0% and 49% (95% CI -0.44, -0.20, p < 0.01), 12 percentage points lower when adherence was between 50% and 79% (95% CI -0.23, -0.02, p < 0.01), and not significantly different when adherence was between 80% and 89% (effect of 0.00, 95% CI -0.06, 0.07, p = 0.81). In contrast, for participants taking DTG, there was no statistically significant difference in viral suppression among any of the four adherence levels; more than 95% were virally suppressed at each adherence level. On average, switching to DTG increased viral suppression by 6 percentage points in our adjusted models (95% CI 0.00, 0.13, p = 0.03). CONCLUSIONS: There was no significant association between adherence levels and viral suppression among PLWH taking DTG regimens, suggesting a high degree of forgiveness for missed doses. The use of DTG should be prioritized over older regimens, particularly for those with low adherence. CLINICAL TRIAL NUMBER: NCT03494777.

An observational cohort study to investigate the impact of dolutegravir in pregnancy and its obesogenic effects on the metabolic health of women living with HIV and their children: Study protocol.

INTRODUCTION: Dolutegravir (DTG)-based antiretroviral therapy is the World Health Organization's preferred first-line regimen for all persons with HIV, including pregnant women. While DTG has been implicated as an obesogen associated with greater weight gain compared to other antiretrovirals, there is a paucity of data in pregnant women and their children. The Obesogenic oRigins of maternal and Child metabolic health Involving Dolutegravir (ORCHID) study is investigating associations between DTG, weight gain, and metabolic outcomes in the context of HIV. MATERIALS & METHODS: ORCHID is a prospective observational study taking place in Cape Town, South Africa (NCT04991402). A total of 1920 pregnant women with and without HIV infection are being followed from ≤18 weeks gestational age to 24 months postpartum with their children. Participants attend eleven study visits: 3 antenatal, delivery, and 7 postnatal visits. Several embedded sub-studies address specific scientific aims. Primary outcome measurements in mothers include anthropometry, blood pressure, body composition, dysglycemia, insulin resistance (IR), and dyslipidemia. Other maternal measures include demographics, resting energy expenditure, viral load, physical activity, dietary intake, hepatic steatosis, and repository specimens. Sub-study measurements include markers of adipose inflammation, gut integrity, and satiety/hunger, subcutaneous adipose tissue morphology and mitochondrial function, and metabolomics. Primary outcome measurements in children include anthropometry, adipose tissue mass, dysglycemia, IR, and dyslipidemia. Other variables include fetal growth, birth outcomes, medical/breastfeeding history, caloric intake, neurodevelopment, and repository specimens. Sub-study measurements include metabolites/lipid subspecies in umbilical cord blood, as well as breast milk composition and DTG exposure. DISCUSSION: ORCHID will play a pivotal role in defining obesogenic mechanisms and clinical consequences of DTG use in pregnancy in women with HIV and their children. It will provide insights into metabolic disease risk reduction in the context of HIV/DTG, identify intervention targets, and inform public health approaches to diminish chronic metabolic co-morbidities for women and children.

Coordinated Targeting of S6K1/2 and AXL Disrupts Pyrimidine Biosynthesis in PTEN-Deficient Glioblastoma.

Intrinsic resistance to targeted therapeutics in PTEN-deficient glioblastoma (GBM) is mediated by redundant signaling networks that sustain critical metabolic functions. Here, we demonstrate that coordinated inhibition of the ribosomal protein S6 kinase 1 (S6K1) and the receptor tyrosine kinase AXL using LY-2584702 and BMS-777607 can overcome network redundancy to reduce GBM tumor growth. This combination of S6K1 and AXL inhibition suppressed glucose flux to pyrimidine biosynthesis. Genetic inactivation studies to map the signaling network indicated that both S6K1 and S6K2 transmit growth signals in PTEN-deficient GBM. Kinome-wide ATP binding analysis in inhibitor-treated cells revealed that LY-2584702 directly inhibited S6K1, and substrate phosphorylation studies showed that BMS-777607 inactivation of upstream AXL collaborated to reduce S6K2-mediated signal transduction. Thus, combination targeting of S6K1 and AXL provides a kinase-directed therapeutic approach that circumvents signal transduction redundancy to interrupt metabolic function and reduce growth of PTEN-deficient GBM. SIGNIFICANCE: Therapy for glioblastoma would be advanced by incorporating molecularly targeted kinase-directed agents, similar to standard of care strategies in other tumor types. Here, we identify a kinase targeting approach to inhibit the metabolism and growth of glioblastoma.

HIV viral suppression in the era of dolutegravir use: Findings from a national survey in Tanzania.

BACKGROUND: Tanzania has made significant progress in improving access to HIV care and treatment. However, virologic suppression among people living with HIV (PLHIV) has not been fully realized. In March 2019, Tanzania introduced a World Health Organization (WHO)-recommended dolutegravir-based regimen as the default first-line regimen. Eighteen months later we investigated the HIV viral suppression rates and the factors associated with lack of viral suppression among PLHIV (children and adults) in Tanzania. METHODOLOGY: A cross-sectional survey was conducted from September to December 2020 among PLHIV on antiretroviral therapy (ART) in Tanzania. Whole blood samples, demographic data and clinical information were obtained from eligible adults (≥15 years) and children (< 15 years) attending thirty-six HIV care and treatment centres located in 22 regions of Tanzania mainland. A whole blood sample from each participant was processed into plasma and HIV viral load was estimated using real-time PCR. HIV viral suppression was defined at a cut-off of < 50 copies/mL as recommended by WHO. Analyses were conducted using descriptive statistics to establish the national representative prevalence of viral suppression, and logistic regression analyses to determine independent factors associated with non-suppression. RESULTS: A total of 2,039 PLHIV on ART were recruited; of these, adults and children were 57.5% (n = 1173) and 42.5% (n = 866), respectively. Among the adult population, the mean age and standard deviation (SD) was 42.1 ± 12.4 years, with 64.7% being female. Among children, the mean age and SD were 9.6 ± 3 years, and 53.2% were female. Overall viral suppression at < 50 copies/mL (undetectable) was achieved in 87.8% of adults and 74.4% of children. Adults and children on dolutegravir-based regimen recorded viral suppression rates of 89.7% and 85.1% respectively. Factors independently associated with lack of viral suppression status in the adult population were age and ART adherence while in the children population, the factors were sex, ART adherence, and current ART regimen (p<0.05). CONCLUSION: Dolutegravir-based regimens are promising to help attain epidemic control in Tanzania. More efforts especially on ART adherence are needed to attain optimal treatment outcomes for children and adults PLHIV in Tanzania.

Risk of Major Bleeding, Stroke/Systemic Embolism, and Death Associated With Different Oral Anticoagulants in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease.

BACKGROUND: Patients with atrial fibrillation and severe chronic kidney disease have higher risks of bleeding, thromboembolism, and mortality. However, optimal anticoagulant choice in these high-risk patients remains unclear. METHODS AND RESULTS: Using deidentified electronic health records from the Optum Labs Data Warehouse, adults with atrial fibrillation and severe chronic kidney disease (estimated glomerular filtration rate <30 mL/min per 1.73 m2) initiating warfarin, apixaban, or rivaroxaban between 2011 and 2021 were included. Using inverse probability of treatment weighting, adjusted risks of major bleeding, stroke/systemic embolism, and death were compared among agents. A total of 6794 patients were included (mean age, 78.5 years; mean estimated glomerular filtration rate, 24.7 mL/min per 1.73 m2; 51% women). Apixaban versus warfarin was associated with a lower risk of major bleeding (incidence rate, 1.5 versus 2.9 per 100 person-years; subdistribution hazard ratio [sub-HR], 0.53 [95% CI, 0.39-0.70]), and similar risks for stroke/systemic embolism (incidence rate, 1.9 versus 2.4 per 100 person-years; sub-HR, 0.80 [95% CI, 0.59-1.09]) and death (incidence rate, 4.6 versus 4.5 per 100 person-years; HR, 1.03 [95% CI, 0.82-1.29]). Rivaroxaban versus warfarin was associated with a higher risk of major bleeding (incidence rate, 4.9 versus 2.9 per 100 person-years; sub-HR, 1.65 [95% CI, 1.10-2.48]), with no difference in risks for stroke/systemic embolism and death. Apixaban versus rivaroxaban was associated with a lower risk of major bleeding (sub-HR, 0.53 [95% CI, 0.36-0.78]). CONCLUSIONS: These real-world findings are consistent with potential safety advantages of apixaban over warfarin and rivaroxaban for patients with atrial fibrillation and severe chronic kidney disease. Further randomized trials comparing individual oral anticoagulants are warranted.

BRAF and MEK inhibitor targeted therapy in papillary craniopharyngiomas: a cohort study.

OBJECTIVE: Targeted therapy (TT) with BRAF/MEK inhibitors has emerged as a potential treatment in papillary craniopharyngiomas (PCPs). However, standardized data on large cohorts are lacking. Our study aimed to assess real-life efficacy and safety of BRAF/MEK inhibition in patients with PCPs. DESIGN: Retrospective French multicenter study involving BRAF V600E-mutated PCP patients, treated with BRAF/MEK inhibitor combination dabrafenib and trametinib, from April 2019 to July 2023. METHODS: Objective response and clinical and safety outcomes were assessed after 3 months and at the last available follow-up during TT. RESULTS: Sixteen patients (8 females, mean age 50.5 ± 15.75 years), receiving either neoadjuvant therapy (NEO) for non-resectable tumors (n = 6), post-surgical adjuvant therapy (ADJ; n = 8), or palliative therapy (PAL) following failure of multimodal treatment (n = 2), were included.At the last follow-up (mean 7.6 ± 5.3 months), 12 patients showed subtotal response, 3 exhibited partial response, and 1 maintained stable disease. Mean volume reduction was 88.9 ± 4.4%, 73.3 ± 23.4%, and 91.8 ± 4.3% in the NEO, ADJ, and PAL groups, respectively.Targeted therapy resolved headaches in 5/5 patients and visual impairment in 6/9; 2/3 patients had improved neurological symptoms, 1/4 presented weight loss, and 2/14 recovered endocrine function.Targeted therapy was well-tolerated in 62.5% of cases; adverse events led to treatment discontinuation in 5 patients and definitive discontinuation in 3 cases. CONCLUSIONS: In this study, 94% of patients showed partial response or better to TT. Adverse events were acceptable. Further research is needed to establish standardized protocols; however, these results advocate for a NEO approach in invasive PCPs.

Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer.

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.

HIV-1 resistance and virological failure to treatment with the integrase inhibitors bictegravir, cabotegravir, and dolutegravir: a systematic literature review.

We describe and analyze resistance-associated mutations (RM) and virological failures (VF) on antiretroviral therapy using the latest approved integrase inhibitors (INIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB), together with their companion drugs in fixed-dose formulations: BIC/emtricitabine/tenofovir; CAB/rilpivirine; DTG/abacavir/lamivudine; DTG/emtricitabine/tenofovir; and DTG/lamivudine. Systematic literature searches were conducted in PubMed and other electronic databases for clinical studies published between January 2010 and May 2023, according to preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA), which analyzed VFs and RMs of INIs. Fifty clinical studies were included in the synthesis. VF in antiretroviral treatment (ART)-naïve patients occurred in 0.7-4.0%, 0.6-1.4%, and 0.6-9.0% of patients treated with DTG, BIC, and CAB, respectively. VF was reported in patients with previous ART in 0-8.1%, 0-2.0%, and 0.4-2.3% of those treated with DTG, BIC, and CAB, respectively. RMs were detected in ART-naïve patients in only one study with DTG (0.3%), none of the studies with BIC, and three of the studies with CAB (0.1-5.4%). In ART-experienced patients, RMs were detected in 0-1.9% of DTG-treated patients. No cases of RM were detected in the 11 BIC studies reviewed. In the case of CAB, RMs were detected in eight studies, ranging from 0.3% to 1.9% of patients. In conclusion, RM rates in the studies reviewed were generally low using the latest INIs. This review identified BIC as the INI with the lowest number of observed VF and lack of RM.

MET alterations as resistance mechanisms of dabrafenib-trametinib in BRAF p.V600E mutated non-small cell lung cancer patient.

The combination of BRAF and MEK inhibitors demonstrated significant clinical benefit in patients with BRAF-mutant non-small cell lung cancer (NSCLC). However, the molecular mechanisms of acquired resistance to BRAF and MEK inhibition in NSCLC are still unknown. Herein, we report a case of a 76-year-old man with a history of smoking who was diagnosed with BRAF V600E-mutant lung adenocarcinoma (PD-L1 > 50%) and subsequently candidate to first-line therapy with pembrolizumab. After 18 months since the start of immunotherapy, computed tomography scan showed disease progression and a second-line therapy with dabrafenib and trametinib was initiated. Seven months later, due to a suspect disease progression, a left supraclavicular lymphadenectomy was performed and next-generation sequencing analysis revealed the appearance of MET exon 14 skipping mutation, while fluorescence in situ hybridization analysis showed MET amplification. The patient is still on BRAF and MEK inhibitor treatment. Our case highlights the relevance of performing tumor tissue rebiopsy at the time of progression during treatment with BRAF/MEK inhibition with the aim of identifying putative mechanisms of resistance.

Evidence from recent clinical trials in fibrotic interstitial lung diseases.

PURPOSE OF REVIEW: Idiopathic pulmonary fibrosis (IPF) is the prototype of fibrosing interstitial lung diseases. It is mirrored by progressive pulmonary fibrosis (PPF), an umbrella term which characterizes disease behavior of various fibrotic interstitial lung diseases with irreversible progression, accounting for loss of lung function, exercise intolerance and respiratory failure leading to early mortality. Pirfenidone and nintedanib halve the decline in lung function but do not halt disease progression. RECENT FINDINGS: Since the publication in 2014 of pivotal pirfenidone and nintedanib studies, a number of clinical trials were conducted, many of them did not reach their primary endpoints. In IPF, promising phase 2 trials were followed by large phase 3 trials that did not confirm a favorable efficacy to tolerability favorable profile, including those with ziritaxestat, an autotaxin-1 inhibitor, zinpentraxin-alpha (human recombinant pentraxin-2), and the monoclonal antibody pamrevlumab targeting connective tissue growth factor. Nevertheless, newer compounds that hold promise are currently being evaluated in phase 3 or phase 2b randomized controlled trials, including: nerandomilast, a preferential phosphodiesterase 4B inhibitor; admilparant, a lysophosphatidic acid receptor antagonist; inhaled treprostinil, a prostacyclin agonist; and bexotegrast, a dual-selective inhibitor of αvß6 and αvß1 integrins. Nerandomilast, admilparant, inhaled treprostinil, and inhaled AP01 (pirfenidone), are currently studied in patients with PPF. SUMMARY: Despite recent frustrating negative results, there is a growing portfolio of candidate drugs developed in both IPF and PPF.

Efficacy of Trametinib in Neurofibromatosis Type 1-Associated Gastrointestinal Stromal Tumors: A Case Report.

Trametinib, an MEK inhibitor, may offer a new therapeutic option for patients with NF1-related GIST.

Pirfenidone Alleviates Inflammation and Fibrosis of Acute Respiratory Distress Syndrome by Modulating the Transforming Growth Factor-ß/Smad Signaling Pathway.

Acute respiratory distress syndrome (ARDS) occurs as an acute onset condition, and patients present with diffuse alveolar damage, refractory hypoxemia, and non-cardiac pulmonary edema. ARDS progresses through an initial exudative phase, an inflammatory phase, and a final fibrotic phase. Pirfenidone, a powerful anti-fibrotic agent, is known as an agent that inhibits the progression of fibrosis in idiopathic pulmonary fibrosis. In this study, we studied the treatment efficiency of pirfenidone on lipopolysaccharide (LPS) and bleomycin-induced ARDS using rats. The ARDS rat model was created by the intratracheal administration of 3 mg/kg LPS of and 3 mg/kg of bleomycin dissolved in 0.2 mL of normal saline. The pirfenidone treatment group was administered 100 or 200 mg/kg of pirfenidone dissolved in 0.5 mL distilled water orally 10 times every 2 days for 20 days. The administration of LPS and bleomycin intratracheally increased lung injury scores and significantly produced pro-inflammatory cytokines. ARDS induction increased the expressions of transforming growth factor (TGF)-ß1/Smad-2 signaling factors. Additionally, matrix metalloproteinase (MMP)-9/tissue inhibitor of metalloproteinase (TIMP)-1 imbalance occurred, resulting in enhanced fibrosis-related factors. Treatment with pirfenidone strongly suppressed the expressions of TGF-ß1/Smad-2 signaling factors and improved the imbalance of MMP-9/TIMP-1 compared to the untreated group. These effects led to a decrease in fibrosis factors and pro-inflammatory cytokines, promoting the recovery of damaged lung tissue. These results of this study showed that pirfenidone administration suppressed inflammation and fibrosis in the ARDS animal model. Therefore, pirfenidone can be considered a new early treatment for ARDS.

Dihydrothiazolo ring-fused 2-pyridone antimicrobial compounds treat Streptococcus pyogenes skin and soft tissue infection.

We have developed GmPcides from a peptidomimetic dihydrothiazolo ring-fused 2-pyridone scaffold that has antimicrobial activities against a broad spectrum of Gram-positive pathogens. Here, we examine the treatment efficacy of GmPcides using skin and soft tissue infection (SSTI) and biofilm formation models by Streptococcus pyogenes. Screening our compound library for minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations identified GmPcide PS757 as highly active against S. pyogenes. Treatment of S. pyogenes biofilm with PS757 revealed robust efficacy against all phases of biofilm formation by preventing initial biofilm development, ceasing biofilm maturation and eradicating mature biofilm. In a murine model of S. pyogenes SSTI, subcutaneous delivery of PS757 resulted in reduced levels of tissue damage, decreased bacterial burdens, and accelerated rates of wound healing, which were associated with down-regulation of key virulence factors, including M protein and the SpeB cysteine protease. These data demonstrate that GmPcides show considerable promise for treating S. pyogenes infections.