ABSTRACT
BACKGROUND: Quality of chronic care for cardiovascular disease (CVD) remains suboptimal worldwide. The Collaborative Quality ImProvement (C-QIP) trial aims to develop and test the feasibility and clinical effect of a multicomponent strategy among patients with prevalent CVD in India. METHODS: The C-QIP is a clinic-based, open randomized trial of a multicomponent intervention versus usual care that was locally developed and adapted for use in Indian settings through rigorous formative research guided by Consolidated Framework for Implementation Research (CFIR). The C-QIP intervention consisted of 5 components: 1) electronic health records and decision support system for clinicians, 2) trained non-physician health workers (NPHW), 3) text-message based lifestyle reminders, 4) patient education materials, 5) quarterly audit and feedback reports. Patients with CVD (ischemic heart disease, ischemic stroke, or heart failure) attending outpatient CVD clinics were recruited from September 2022 to September 2023 and were randomized to the intervention or usual care arm for at least 12 months follow-up. The co-primary outcomes are implementation feasibility, fidelity (i.e., dose delivered and dose received), acceptability, adoption and appropriateness, measured at multiple levels: patient, provider and clinic site-level, The secondary outcomes include prescription of guideline directed medical therapy (GDMT) (provider-level), and adherence to prescribed therapy, change in mean blood pressure (BP) and LDL-cholesterol between the intervention and control groups (patient-level). In addition, a trial-based process and economic evaluations will be performed using standard guidelines. RESULTS: We recruited 410 socio-demographically diverse patients with CVD from four hospitals in India. Mean (SD) age was 57.5 (11.7) years, and 73.0% were males. Self-reported history of hypertension (48.5%) and diabetes (41.5%) was common. At baseline, mean (SD) BP was 127.9 (18.2) /76.2 (11.6) mm Hg, mean (SD) LDLc: 80.3 (37.3) mg/dl and mean (SD) HbA1c: 6.8% (1.6%). At baseline, the GDMT varied from 62.4% for patients with ischemic heart disease, 48.6% for ischemic stroke and 36.1% for heart failure. CONCLUSION: This study will establish the feasibility of delivering contextually relevant, and evidence-based C-QIP strategy and assess whether it is acceptable to the target populations. The study results will inform a larger scale confirmatory trial of a comprehensive CVD care model in low-resource settings. TRIAL REGISTRATION: Clinical Trials Registry India: CTRI/2022/04/041847; Clinicaltrials.gov number: NCT05196659.
ABSTRACT
Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 (ATP binding cassette subfamily B member 1) overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.
Subject(s)
Adenosine Triphosphatases , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Rats , Mice , Animals , Adenosine Triphosphatases/genetics , Adenosine Triphosphatases/metabolism , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Cell Line , Chromatin , Mammals/genetics , Androgen Receptor Antagonists , DNA Helicases/genetics , Nuclear Proteins/genetics , Transcription Factors/geneticsABSTRACT
Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 (BRD4) and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.
ABSTRACT
Introduction: Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis; and it plays a central role in the development of cardiovascular diseases and many types of human diseases (diabetes, kidney failure, cancer, and viral infections). Strategies that are effective in protecting vascular endothelial function and retard or reversing endothelial dysfunction in the early stage appear to be potential in the prevention of vascular, cardiac, and many human diseases. Several studies have been carried out on the effects of yoga on endothelial function, but the results of these studies have not been synthesized. This study aimed at conducting a systematic review and meta-analysis to determine the effectiveness of yoga on endothelial function. Methods: A systematic review and meta-analysis of studies that assessed the effect of yoga practice on vascular endothelial function was done as per the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed, Scopus, Google Scholar, and Cochrane controlled register of trials (CENTRAL) were searched from inception to August 2022. The search strategy was constructed around yoga-based techniques and endothelial function. All the yoga-based interventional studies on endothelial function or dysfunction were included in this review. A narrative synthesis and descriptive analysis were done due to the diverse methodology of selected studies. We carried out a formal meta-analysis of controlled trials that assessed the effect of yoga on flow-mediated dilatation (FMD), a measure of endothelial function. Results: A total of 18 studies were included for review involving 1043 participants. Yoga training showed improved endothelial function in 12 studies, whereas 6 studies did not find any statistically robust effect. Meta-analysis (n = 395 participants, 6-studies, 7 comparisons) showed an increase in brachial FMD by yoga practice (mean difference = -1.23%; 95% confidence interval -2.23 to -0.23; p = 0.02). The heterogeneity between the studies was 43% (Tau2 = 0.70, χ2 = 10.49). The risk of bias was low to moderate in these studies. No adverse effects were reported. Conclusions: Yoga practice improved endothelial function. Yoga could be a safe and potential integrative medicine to improve endothelial function. However, as the statistical heterogeneity, that is, variation in the FMD among the studies was moderate, large clinical trials are necessary for its clinical recommendations.
Subject(s)
Atherosclerosis , Cardiovascular Diseases , Yoga , Humans , Cardiovascular Diseases/prevention & controlABSTRACT
Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy-resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). SUMMARY: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors.
Subject(s)
Breast Neoplasms , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Clinical Trials as Topic , Estrogen Receptor alpha/genetics , Female , Fulvestrant/therapeutic use , Humans , Indazoles , Neoplasm Recurrence, Local , PyridinesABSTRACT
Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK1/2 inhibitor with efficacy in wildtype (WT) and mutant MEK12 models. Starting from a HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK1/2 and a panel of MEK1/2 mutant cell lines. Using a structure-based approach, the optimization addressed the liabilities by systematic analysis of molecular matched pairs (MMPs) and ligand conformation. Addition of only three heavy atoms to early tool compound 6 removed Cyp3A4 liabilities and increased the cellular potency by 100-fold, while reducing log P by 5 units. Profiling of MAP855, compound 30, in pharmacokinetic-pharmacodynamic and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK1/2 inhibitors. Compound 30 is a novel highly potent and selective MEK1/2 kinase inhibitor with equipotent inhibition of WT and mutant MEK1/2, whose drug-like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy.
Subject(s)
Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Adenosine Triphosphate/metabolism , Cell Line, Tumor , MAP Kinase Kinase 1 , Mitogen-Activated Protein Kinase Kinases/metabolism , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/geneticsABSTRACT
The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.
Subject(s)
Adenosine Triphosphatases , DNA Helicases , Nuclear Proteins , Prostatic Neoplasms , Transcription Factors , Adenosine Triphosphatases/metabolism , Animals , Benzamides , DNA Helicases/genetics , Enhancer Elements, Genetic , Genes, myc , Hepatocyte Nuclear Factor 3-alpha , Humans , Male , Nitriles , Nuclear Proteins/genetics , Oncogenes , Phenylthiohydantoin , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Receptors, Androgen , Transcription Factors/genetics , Transcriptional Regulator ERG , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: India has ratified with the United Nations Convention on the Rights of Persons with Disabilities and has passed the Rights of People with Disabilities Act in 2016. There is need for training healthcare professionals in disability competencies as people with disabilities are many and marginalized. Disability competencies were introduced in the foundation course of revised competency based medical curriculum for Indian medical graduates by the Medical Council of India (MCI) just prior to the rollout of the programme. We intend describing our center's experience in implementing the same. METHODS: FC 4.5.1 TO 4.5.8 of MCI foundation course guidelines were resource material. Eight faculty members participated. Setting was the lecture theatre. The suggested and actual teaching learning methods are compared for each competency. Notes made from delivering disability competencies, photographs, videos and reflections from students were source of data. RESULTS: We used sensitizing lectures of 15 min each for FC 4.5.1, 4.5.2 and 4.5.4 [cognitive] with interesting set induction, student narratives of family members with disability, buzz groups for interaction and self-directed learning activity using mobile phones. We facilitated FC 4.5.3 and 4.5.5 [skill/affective domain] demonstrating unacceptable and acceptable disability etiquettes using standardized patients and role play. We conducted a forum theatre of the oppressed for FC 4.5.6. We introduced our learners to universal design in our campus for teaching 4.5.7. As a part of the principle of inclusivity we involved two staff members with motor disabilities for delivering FC 4.5.8 in an interview. We assessed the learners using written reflections and obtained feedback on a rating scale.
ABSTRACT
Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERαWT and ERαMUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERαWT and ERαY537S breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERαWT and ERαMUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs.Significance: Nearly 30% of endocrine therapy-resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERαWT and ERαMUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176-93. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.
Subject(s)
Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm/drug effects , Estrogen Receptor Antagonists/administration & dosage , Estrogen Receptor alpha/antagonists & inhibitors , Indazoles/administration & dosage , Mutation , Administration, Oral , Animals , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cysteine/antagonists & inhibitors , Drug Screening Assays, Antitumor , Drug Synergism , Estrogen Receptor Antagonists/chemistry , Estrogen Receptor Antagonists/pharmacology , Estrogen Receptor alpha/chemistry , Estrogen Receptor alpha/genetics , Female , Humans , Indazoles/chemistry , Indazoles/pharmacology , MCF-7 Cells , Mice , Protein Conformation/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
The present study aimed at evaluating the anticancer and radiosensitizing potential of juglone against a chemoresistant and radioresistant tumor (B16F1 melanoma) growing on C57BL/6J mice. Volume doubling time, growth delay, and median survival were used to assess the in vivo anticancer and radiosensitizing potential of juglone. In vitro radiosensitizing potential of juglone was studied using clonogenic, comet, and reactive oxygen species induction assays. Treatment of tumor-bearing mice with sublethal doses of juglone caused a dose-dependent inhibition of tumor growth as evident from the growth delay and median survival values. Comet assay using tumor tissue and blood showed differential toxicity of juglone, where higher levels of DNA damage was seen in tumor tissue compared with blood cells. Pretreatment of tumor-bearing mice with optimum dose of juglone before radiation resulted in significant tumor growth inhibition compared with radiation alone. From the clonogenic assay, the authors observed a sensitization enhancement ratio of 1.37 for the combination treatment compared with radiation alone. Furthermore, comet assay studies revealed the potential of juglone to enhance the radiation-induced DNA damage and cause a delay in its repair. Juglone pretreatment before radiation also resulted in a significant elevation in the intracellular reactive oxygen species levels compared with radiation alone. In conclusion, the results of this study show the potential of juglone to inhibit the growth of melanoma in vivo. The study also revealed the potential of juglone to augment the radiation-induced cell death of melanoma cells, which may be attributed to oxidative stress-mediated DNA damage and its delayed repair.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , DNA Damage/drug effects , Naphthoquinones/pharmacology , Radiation-Sensitizing Agents/pharmacology , Animals , Cell Survival/drug effects , Female , Male , Melanoma, Experimental/drug therapy , Melanoma, Experimental/metabolism , Melanoma, Experimental/radiotherapy , Mice , Mice, Inbred C57BL , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolismABSTRACT
We report the design and development of an optical fiber probe-based Helium-Neon (He-Ne) low-level laser therapy system for tissue regeneration. Full thickness excision wounds on Swiss albino mice of diameter 15 mm were exposed to various laser doses of 1, 2, 3, 4, 6, 8 and 10 J cm(-2) of the system with appropriate controls, and 2 J cm(-2) showing optimum healing was selected. The treatment schedule for applying the selected laser dose was also standardized by irradiating the wounds at different postwounding times (0, 24 and 48 h). The tissue regeneration potential was evaluated by monitoring the progression of wound contraction and mean wound healing time along with the hydroxyproline and glucosamine estimation on wound ground tissues. The wounds exposed to 2 J cm(-2) immediately after wounding showed considerable contraction on days 5, 9, 12, 14, 16 and 19 of postirradiation compared with the controls and other treatment schedules, showing significant (P < 0.001) decrease in the healing time. A significant increase in hydroxyproline and glucosamine levels was observed for the 2 J cm(-2) irradiation group compared with the controls and other treatment groups. In conclusion, the wounds treated with 2 J cm(-2) immediately after the wounding show better healing compared with the controls.
Subject(s)
Lasers, Gas/therapeutic use , Low-Level Light Therapy/methods , Regeneration/radiation effects , Animals , Dose-Response Relationship, Radiation , Female , Hydroxyproline/metabolism , Low-Level Light Therapy/instrumentation , Male , Mice , Optical Fibers , Regeneration/physiology , Skin/injuries , Skin/metabolism , Skin/radiation effects , Wound Healing/physiology , Wound Healing/radiation effectsABSTRACT
The present study was aimed to evaluate the anti-tumor efficacy and systemic toxicity of chitosan-based plumbagin microspheres in comparison to free plumbagin. The optimized formulation had a mean particle size of 106.35 mum with an encapsulation efficiency of 80.12%. Pharmacokinetic studies showed a 22.2-fold increase in elimination half-life (t(1/2)) of plumbagin from chitosan microspheres as compared to free plumbagin. Administration of plumbagin microspheres resulted in a significant tumor growth inhibition and reduced systemic toxicity. These results suggest that chitosan-based microspheres could be a promising strategy for the systemic delivery of anti-cancer agents like plumbagin.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/pharmacokinetics , Melanoma, Experimental/drug therapy , Naphthoquinones/administration & dosage , Naphthoquinones/pharmacokinetics , Animals , Antineoplastic Agents, Phytogenic/chemistry , Blood Cell Count , Calorimetry, Differential Scanning , Chemistry, Pharmaceutical , Chitosan , Chromatography, High Pressure Liquid , Cross-Linking Reagents , Delayed-Action Preparations , Drug Compounding , Glutaral/chemistry , Half-Life , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Microscopy, Electron, Scanning , Microspheres , Naphthoquinones/chemistry , Particle Size , Spectrophotometry, UltravioletABSTRACT
Quinones have diverse pharmacological properties including antibacterial, antifungal, antiviral, anti-inflammatory, antipyretic and anticancer activity. The cytotoxic potential of 1,4-naphthoquinone (NQ14) was studied against B16F1 melanoma cells grown in vitro. NQ14 treatment resulted in a concentration-dependent cytotoxicity as indicated by MTT assay and lactate dehydrogenase leakage assay. Depletion in cellular glutathione levels after 1h incubation with NQ14 correlated with the corresponding increase in reactive oxygen species generation as determined by 2',7'-dicholorofluorescein diacetate assay suggests the role of oxidative stress in cell death. The frequency of micronucleated binucleate cells increased with increasing doses of NQ14 with a corresponding decrease in the cytokinesis block proliferation index indicating the drug induced genotoxicity and cell division delay. Further, a dose-dependent decrease in the clonogenic cell survival indicated the potential of NQ14 to inhibit cell proliferation contributing to cell death. The cell death after NQ14 treatment may be attributed to apoptosis as seen in DNA ladder pattern along with necrosis as indicated in flow cytometric analysis of Annexin V/PI stained cells. Results of the present study demonstrate the cytotoxic and genotoxic potential of NQ14 by the induction of oxidative stress mediated mechanisms leading to tumor cell kill.