Summary Pancreatic ductal adenocarcinoma (PDA) is characterized by immune-tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine-protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T-helper cell differentiation towards a mixed Th1/Th17 phenotype, leading to tumor-immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1- and ICOS-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor-immunity.

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Background The effectiveness of amlodipine has been reported in clinical trials in India. However, real-world data on the effectiveness of amlodipine in India is limited. Objective To provide real-world evidence regarding the effectiveness of amlodipine as monotherapy or in combination with other antihypertensive drugs (AHDs) in Indian patients with essential hypertension. Methods Electronic medical record data of adult patients who were diagnosed with essential hypertension (≥ 140/90 mmHg) and were prescribed amlodipine as monotherapy or add-on therapy were retrospectively analyzed. Patients were classified based on the number of AHD classes prescribed on initiation of amlodipine. Change in systolic (SBP) and diastolic (DBP) blood pressure from baseline was the primary endpoint. Evaluation of proportion of patients who achieved treatment goals as per 2018 European Society of Cardiology/European Society of Hypertension guidelines was the secondary endpoint. Readings were obtained before initiating amlodipine and after at least a month of therapy with amlodipine. Results Among the 462 included patients, the majority (90.7%) were on amlodipine monotherapy or amlodipine + 1AHD. Mean (95% confidence interval [CI]) change in the amlodipine monotherapy group was: SBP (− 12.1 [− 14.9, − 9.3] mmHg) and DBP (− 7.5 [− 8.9, − 6.1] mmHg) and mean (95% CI) change in the amlodipine + 1AHD group was: SBP (− 17.8 [− 21.0, − 14.6] mmHg) and DBP (− 9.5 [− 11.0, − 8.0] mmHg) ( P < 0.001 for all). SBP and DBP goals were achieved by 31.4% and 42.9% of patients on amlodipine monotherapy and by 38.9% and 51.8% of patients on amlodipine + 1AHD, respectively. Among patients aged ≤ 45 years, mean (95% CI) change in the amlodipine monotherapy group was: SBP (− 11.7 [− 16.0, − 7.4] mmHg; P < 0.001) and DBP (− 7.2 [− 9.7, − 4.7] mmHg; P < 0.001) and mean (95% CI) change in the amlodipine + 1AHD group was: SBP (− 14.6 [− 21.9, − 7.3] mmHg; P < 0.05) and DBP (− 10.6 [− 14.8, − 6.4] mmHg; P < 0.01). SBP and DBP goals were achieved by 35.4% and 33.8% of patients on amlodipine monotherapy and by 48.0% and 56.0% of patients on amlodipine + 1AHD, respectively. Among patients aged ≥ 65 years, mean (95% CI) change in the amlodipine monotherapy group was: SBP (− 13.9 [− 20.2, − 7.6] mmHg; P < 0.01) and DBP (− 8.5 [− 11.4, − 5.7] mmHg; P < 0.001) and mean (95% CI) change in the amlodipine + 1AHD group was: SBP (− 22.4 [− − 28.8, − 16.0] mmHg; P < 0.001) and DBP (− 10.8 [− 14.0, − 7.6] mmHg; P < 0.001). SBP and DBP goals were achieved by 25.5% and 13.7% of patients on amlodipine monotherapy and by 29.8% and 14.0% of patients on amlodipine + 1AHD. Conclusion Amlodipine prescribed as mo...

Introduction: The effectiveness of telmisartan has been reported in Indian clinical trials; however, real-world data are limited. We aimed to provide real-world evidence regarding the effectiveness of telmisartan as monotherapy or in combination with other antihypertensive drugs (AHDs) in Indian patients with essential hypertension. Methods: Electronic medical record data of adult patients diagnosed with essential hypertension (C 140/90 mmHg) and who were prescribed telmisartan as mono-or add-on therapy were retrospectively analyzed. Patients were classified according to the number of AHD classes prescribed on initiating telmisartan. Change in systolic and diastolic blood pressure (SBP and DBP) after a month of treatment and the proportion of patients who achieved treatment goals according to the 2018 European Society of Cardiology/European Society of Hypertension guidelines were evaluated. Results: A majority (90.6%) of the 1304 patients included in the study were on telmisartan monotherapy or telmisartan ? 1 AHD. The mean (95% confidence interval [CI]) change in the telmisartan monotherapy group was SBP (-13.3 [-14.6, -12.0] mmHg) and DBP (-7.2 [-7.9, -6.5] mmHg), and the mean (95% CI) change in the telmisartan ? 1 AHD group was SBP (-10.8 [-13.1, -8.5] mmHg) and DBP (-6.5 [-7.7, -5.3] mmHg) (P \ 0.001 for all). SBP and DBP goals were achieved by 35.9% and 47.3% of patients on telmisartan monotherapy and by 35.9% and 46.8% of patients on telmisartan ? 1 AHD. Among patients with comorbid diabetes, the mean (95% CI) change in the telmisartan monotherapy group was SBP (-13.3 [-15.0, -11.6] mmHg) and DBP (-7.3 [-8.2, -6.5] mmHg), and the mean (95% CI) change Suyog Mehta was an employee of Dr. Reddy's Laboratories when the study was conducted

Introduction: The renoprotective effects of dihydropyridine calcium channel blockers (CCBs) have been established as non-inferior to other classes of antihypertensive drugs. Studying their effect on renal outcome parameters, specifically for amlodipine as monotherapy, in real-world settings can further help in expanding its usage among Indian patients. This study was performed to assess the effects of amlodipine and other dihydropyridine CCBs (cilnidipine, benidipine and azelnidipine) on renal parameters and effectiveness in blood pressure reduction in Indian patients. Methods: The retrospective data of adult patients ([ 18 years) with essential hypertensive who were prescribed amlodipine (n = 92), cil-Supplementary Information The online version contains supplementary material available at