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Background: Thiazide-type diuretics are associated with an increased incidence of diabetes compared with other antihypertensive medications. In this study, we determined the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use.Methods and Results: A total of 22 418 participants from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years posttrial) through the use of national databases. The primary outcome was CVD mortality (death from coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction or fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, nonsignificant risk for CVD mortality (hazard ratio [HR], 1.04; 95% CI, 0.74-1.47), all-cause mortality (HR, 1.04; 95% CI, 0.82-1.30), and non-CVD mortality (HR, 1.05; 95% CI, 0.77-1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range, 1.22-1.53). Participants with incident diabetes had elevated CHD risk compared with those with no diabetes (HR, 1.46; 95% CI, 1.09-1.96), but those on chlorthalidone had significantly lower risk than those on lisinopril (HR, 1.18 versus 2.57; P=0.04 for interaction).Conclusions: The findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops while on other antihypertensive medications. [ABSTRACT FROM AUTHOR]

Background: The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial reported that treatment initiated with doxazosin compared with chlorthalidone doubled the risk for heart failure in high-risk hypertensive patients (relative risk, 2.04 [95% CI, 1.79 to 2.32]). Patients assigned to doxazosin therapy had a mean in-trial systolic/diastolic blood pressure 3/0 mm Hg higher than that in patients assigned to chlorthalidone. Sixty-eight percent (6167 of 9061) of the former patients and 59% (9081 of 15 256) of the latter patients were given additional medications to achieve a target blood pressure of less than 140/90 mm Hg.Objective: To ascertain the influence of open-label antihypertensive drugs and subsequent blood pressure on relative risk for heart failure.Design: Randomized, double-blind, active-controlled clinical trial.Setting: 623 sites in the United States and Canada.Patients: Hypertensive patients 55 years of age or older with at least one additional risk factor for cardiovascular disease.Intervention: Chlorthalidone (12.5 to 25 mg/d) or doxazosin (2 to 8 mg/d) for a planned follow-up of 4 to 8 years.Measurements: Data on blood pressure, medication, and incident heart failure (treated outside hospital, hospitalized, or fatal) from February 1994 through December 1999.Results: After the treatment groups were categorized as having no exposure to open-label medications (monotherapy) or exposure to open-label therapy, the relative risk for heart failure with doxazosin versus chlorthalidone was 3.10 (CI, 2.51 to 3.82) and 1.42 (CI, 1.20 to 1.69), respectively. After adjustment for follow-up systolic/diastolic blood pressure, the overall relative risk was 2.00 (CI, 1.72 to 2.32).Conclusion: In high-risk patients with hypertension, the higher risk for heart failure while taking doxazosin compared with chlorthalidone is attenuated but not eliminated by adding other antihypertensive drugs. The small observed difference in systolic blood pressure does not explain this increased risk. [ABSTRACT FROM AUTHOR]

Context: Although evidence suggests that homocysteine is a risk factor for cardiovascular disease in adults, little information exists on homocysteine levels in children.Objectives: To describe the distribution of serum homocysteine concentrations among children and to examine the association between homocysteine levels and several characteristics, including serum levels of folic acid and vitamins B12 and B6.Design: Cross-sectional analysis.Setting: School-based cohort from California, Louisiana, Minnesota, and Texas.Participants: A total of 3524 US schoolchildren, aged 13 and 14 years, from the Child and Adolescent Trial for Cardiovascular Health (completed in 1994). Measurement was conducted in 1997.Main Outcome Measure: Nonfasting serum total homocysteine concentration.Results: The distribution of homocysteine values ranged from 0.1 to 25.7 micromol/L (median, 4.9 micromol/L). Geometric mean homocysteine concentration was significantly higher in boys (5.22 micromol/L) than girls (4.84 micromol/L); blacks (5.51 micromol/L) than whites (4.96 micromol/L) or Hispanics (4.93 micromol/L); nonusers of multivitamins (5.09 micromol/L) than users (4.82 micromol/L); and smokers (5.19 micromol/L) than nonsmokers (5.00 micromol/ L). Serum homocysteine was significantly inversely correlated with serum levels of folic acid (r= -0.36; P = .001), vitamin B12 (r = -0.21; P = .001), and vitamin B6 (r = -0.18; P = .001). Serum homocysteine was not significantly associated with serum lipid levels or family history of cardiovascular disease and was only weakly related to body mass index and systolic blood pressure. After multivariate adjustment, homocysteine remained independently associated with sex, race, serum folic acid and vitamin B12 levels, and systolic blood pressure.Conclusions: The distribution of homocysteine levels in children is substantially lower than that observed for adults; however, a small percentage of children are still potentially at elevated risk for future cardiovascular disease. Serum folic acid may be an important determinant of homocysteine levels in children. [ABSTRACT FROM AUTHOR]

Purpose: To assess the effect of dietary calcium supplementation on blood pressure.Data Sources: Published reports of trials studying the effect of dietary calcium supplementation on blood pressure were identified by a search of previous reviews, a MEDLINE search, a manual review of journal articles, and a review of abstracts from scientific meetings.Study Selection: Randomized clinical trials in which dietary calcium intake varied by intervention group were selected. Multifactorial trials were not included.Data Synthesis: Data from 28 active treatment arms or strata from 22 randomized clinical trials were pooled using a weighted average method, with weights proportional to the inverse of the variance of the treatment effect. The total sample comprised 1231 persons. Because trials of both normotensive and hypertensive persons were included, subgroup analyses could be done. Pooled estimates of the effect of calcium supplementation on blood pressure were -0.18 mm Hg for diastolic blood pressure (95% CI, -0.75 to 0.40 mm Hg) and -0.89 mm Hg for systolic blood pressure (CI, -1.74 to -0.05 mm Hg). Pooled estimates for systolic blood pressure were -0.53 mm Hg (CI, -1.56 to 0.49 mm Hg) for trials of normotensive persons and -1.68 mm Hg (CI, -3.18 to -0.18 mm Hg) for trials of hypertensive persons. Diastolic blood pressure was not significantly affected in either subgroup.Conclusion: The pooled estimate shows a statistically significant decrease of systolic blood pressure with calcium supplementation, both for hypertensive persons and for the overall sample. However, the effect is too small to support the use of calcium supplementation for preventing or treating hypertension. [ABSTRACT FROM AUTHOR]

Hypertension is preventable, and lifestyle changes may reduce a patient's medication requirements. Why this renewed emphasis on prevention? After decades of medical progress against it, hypertension threatens public health more than ever. [ABSTRACT FROM AUTHOR]

Context: Nonpharmacologic interventions are frequently recommended for treatment of hypertension in the elderly, but there is a paucity of evidence from randomized controlled trials in support of this recommendation.Objective: To determine whether weight loss or reduced sodium intake is effective in the treatment of older persons with hypertension.Design: Randomized controlled trial.Participants: A total of 975 [corrected] men and women aged 60 to 80 years with systolic blood pressure lower than 145 mm Hg and diastolic blood pressure lower than 85 mm Hg while receiving treatment with a single antihypertensive medication.Setting: Four academic health centers.Intervention: The 585 obese participants were randomized to reduced sodium intake, weight loss, both, or usual care, and the 390 nonobese participants were randomized to reduced sodium intake or usual care. Withdrawal of antihypertensive medication was attempted after 3 months of intervention.Main Outcome Measure: Diagnosis of high blood pressure at 1 or more follow-up visits, or treatment with antihypertensive medication, or a cardiovascular event during follow-up (range, 15-36 months; median, 29 months).Results: The combined outcome measure was less frequent among those assigned vs not assigned to reduced sodium intake (relative hazard ratio, 0.69; 95% confidence interval [CI], 0.59-0.81; P<.001) and, in obese participants, among those assigned vs not assigned to weight loss (relative hazard ratio, 0.70; 95% CI, 0.57-0.87; P<.001). Relative to usual care, hazard ratios among the obese participants were 0.60 (95% CI, 0.45-0.80; P<.001) for reduced sodium intake alone, 0.64 (95% CI, 0.49-0.85; P=.002) for weight loss alone, and 0.47 (95% CI, 0.35-0.64; P<.001) for reduced sodium intake and weight loss combined. The frequency of cardiovascular events during follow-up was similar in each of the 6 treatment groups.Conclusion: Reduced sodium intake and weight loss constitute a feasible, effective, and safe nonpharmacologic therapy of hypertension in older persons. [ABSTRACT FROM AUTHOR]

Objective: To assess the effects of supplementation with oral potassium on blood pressure in humans.Design: Meta-analysis of randomized controlled trials.Data Sources: English-language articles published before July 1995.Study Selection: Thirty-three randomized controlled trials (2609 participants) in which potassium supplementation was the only difference between the intervention and control conditions.Data Extraction: Using a standardized protocol, 2 of us independently abstracted information on sample size, duration, study design, potassium dose, participant characteristics, and treatment results.Results: By means of a random-effects model, findings from individual trials were pooled, after results for each trial were weighted by the inverse of its variance. An extreme effect of potassium in lowering blood pressure was noted in 1 trial. After exclusion of this trial, potassium supplementation was associated with a significant reduction in mean (95% confidence interval) systolic and diastolic blood pressure of -3.11 mm Hg (-1.91 to -4.31 mm Hg) and -1.97 mm Hg (-0.52 to -3.42 mm Hg), respectively. Effects of treatment appeared to be enhanced in studies in which participants were concurrently exposed to a high intake of sodium.Conclusions: Our results support the premise that low potassium intake may play an important role in the genesis of high blood pressure. Increased potassium intake should be considered as a recommendation for prevention and treatment of hypertension, especially in those who are unable to reduce their intake of sodium. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of low-dose, diuretic-based antihypertensive treatment on major cardiovascular disease (CVD) event rates in older, non-insulin-treated diabetic patients with isolated systolic hypertension (ISH), compared with nondiabetic patients.Design: Double-blind, randomized, placebo-controlled trial: the Systolic Hypertension in the Elderly Program (SHEP).Setting: Multiple clinical and support centers in the United States.Participants: A total of 4736 men and women aged 60 years and older at baseline with ISH (systolic blood pressure [BP], > or = 160 mm Hg; diastolic BP, <90 mm Hg) at baseline, 583 non-insulin-dependent diabetic patients and 4149 nondiabetic patients (4 additional patients not so classifiable were randomized but not included in these analyses). Diabetes mellitus defined as physician diagnosis, taking oral hypoglycemic drugs, fasting glucose level of 7.8 mmol/L or more (> or = 140 mg/dL), or any combination of these characteristics.Intervention: The active treatment group received a low dose of chlorthalidone (12.5-25.0 mg/d) with a step-up to atenolol (25.0-50.0 mg/d) or reserpine (0.05-0.10 mg/d) if needed. The placebo group received placebo and any active antihypertensive drugs prescribed by patient's private physician for persistently high BP.Main Outcome Measures: The 5-year rates of major CVD events, nonfatal plus fatal stroke, nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD), major CHD events, and all-cause mortality.Results: The SHEP antihypertensive drug regimen lowered BP of both diabetic and nondiabetic patients, with few adverse effects. For both diabetic and nondiabetic patients, all outcome rates were lower for participants randomized to the active treatment group than for those randomized to the placebo group. Thus, 5-year major CVD rate was lower by 34% for active treatment compared with placebo, both for diabetic patients (95% confidence interval [CI], 6%-54%) and nondiabetic patients (95% CI, 21%-45%). Absolute risk reduction with active treatment compared with placebo was twice as great for diabetic vs nondiabetic patients (101/1000 vs 51/1000 randomized participants at the 5-year follow-up), reflecting the higher risk of diabetic patients.Conclusion: Low-dose diuretic-based (chlorthalidone) treatment is effective in preventing major CVD events, cerebral and cardiac, in both non-insulin-treated diabetic and nondiabetic older patients with ISH. [ABSTRACT FROM AUTHOR]

Objective: - To compare long-term plasma lipid changes among 6 antihypertensive treatment interventions for stage I (mild) hypertension.Design: - Multicenter, randomized, double-blind, parallel-group clinical trial.Setting: - Four academic clinical research units in the United States.Participants: - A total of 902 men and women, aged 45 to 69 years, with stage I diastolic hypertension (diastolic blood pressure <100 mm Hg), recruited from 11914 persons screened in their communities.Interventions: - Participants were randomized to 1 of 6 treatment groups: (1) placebo, (2) beta-blocker (acebutolol), (3) calcium antagonist (amlodipine), (4) diuretic (chlorthalidone), (5) alpha1-antagonist (doxazosin), and (6) angiotensin-converting enzyme inhibitor (enalapril). All groups received intensive lifestyle counseling to achieve weight loss, dietary sodium and alcohol reduction, and increased physical activity.Main Outcome Measures: - Changes in plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides from baseline to annual visits through 4 years.Results: - Mean changes in all plasma lipids were favorable in all groups. The degree of weight loss with fat-modified diet and exercise was significantly related to favorable lipid changes. Significant differences (P<.01) among groups for average changes during follow-up in each lipid were observed. Decreases in plasma total cholesterol and LDL cholesterol were greater with doxazosin and acebutolol (for plasma total cholesterol, 0.36 and 0.30 mmol/L [13.8 and 11.7 mg/dL], respectively), less with chlorthalidone and placebo (0.12 and 0.13 mmol/L [4.5 and 5.1 mg/dL], respectively). Decreases in triglycerides were greater with doxazosin and enalapril, least with acebutolol. Increases in HDL cholesterol were greater with enalapril and doxazosin, least with acebutolol. Significant relative increases in plasma total cholesterol with chlorthalidone compared with placebo at 12 months were no longer present at 24 months and beyond, when mean plasma total cholesterol for the chlorthalidone group fell below baseline. Analyses of participants continuing to receive chlorthalidone throughout the 4 years of follow-up indicated this was not due solely to an increasing percentage of participants changing or discontinuing use of medication during follow-up.Conclusions: - Weight loss with a fat-modified diet plus increased exercise produces favorable long-term effects on blood pressure and all plasma lipid fractions of adults with stage I hypertension; blood pressure reduction is enhanced to a similar degree by addition of a drug from any one of 5 classes of antihypertensive medication. These drugs differ quantitatively in influencing the degree of long-term favorable effects on blood lipids obtained with nutritional-hygienic treatment. [ABSTRACT FROM AUTHOR]

Objective: - To review published and presented data on the relationship between dietary protein and blood pressure in humans and animals.Data Sources: - Bibliographies from review articles and books on diet and blood pressure that had references to dietary protein. The bibliographies were supplemented with computerized MEDLINE search restricted to English language and abstracts presented at epidemiologic meetings.Study Selection: - Observational and intervention studies in humans and experimental studies in animals.Data Extraction: - In human studies, systolic or diastolic blood pressure were outcome measures, and dietary protein was measured by dietary assessment methods or by urine collections. In animal studies, blood pressure and related physiological effects were outcome measures, and experimental treatment included protein or amino acids.Data Synthesis: - Historically, dietary protein has been thought to raise blood pressure; however, studies conducted in Japan raised the possibility of an inverse relationship. Data analyses from subsequent observational studies in the United States and elsewhere have provided evidence of an inverse relationship between protein and blood pressure. However, intervention studies have mostly found no significant effects of protein on blood pressure. Few animal studies have specifically examined the effects of increased dietary protein on blood pressure.Conclusions: - Because of insufficient data and limitations in previous investigations, better controlled and adequately powered human studies are needed to assess the effect of dietary protein on blood pressure. In addition, more research using animal models, in which experimental conditions are highly controlled and detailed mechanistic studies can be performed, is needed to help provide experimental support for or against the protein-blood pressure hypothesis. [ABSTRACT FROM AUTHOR]

The Multiple Risk Factor Intervention Trial (MRFIT) was one of the coronary heart disease prevention trials recommended to the National Heart and Lung Institute in 1971 as an alternative to a national single-factor dietary trial, which was judged to be infeasible. MRFIT was a randomized, primary prevention trial, conducted at 22 US clinical centers from 1973 to 1982 to test whether lowering elevated serum cholesterol and diastolic blood pressure and ceasing cigarette smoking would reduce coronary heart disease mortality. Men 35-57 y of age (n = 12866) with one or more of these risk factors were randomly assigned to the special intervention (SI) or usual care (UC) group and followed for 6-8 y. UC men were given information on risk factors, referred to their usual sources of care, and reexamined annually. SI participants received group and individual counseling on a fat-modified diet, a stepped-care drug treatment program for diastolic hypertension (after an initial attempt at blood pressure control by weight reduction, if indicated), and, for cigarette smokers, counseling aimed at cessation. SI men had risk factor assessments every 4 mo and annual examinations that were generally identical to those given to UC men and that always included measurement of blood cholesterol concentration. A listing of variables measured at each visit along with the design and major mortality results of MRFIT are included in this chapter. (c) 1997 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Background: It is known that obesity, sodium intake, and alcohol consumption factors influence blood pressure. In this clinical trial, Dietary Approaches to Stop Hypertension, we assessed the effects of dietary patterns on blood pressure.Methods: We enrolled 459 adults with systolic blood pressures of less than 160 mm Hg and diastolic blood pressures of 80 to 95 mm Hg. For three weeks, the subjects were fed a control diet that was low in fruits, vegetables, and dairy products, with a fat content typical of the average diet in the United States. They were then randomly assigned to receive for eight weeks the control diet, a diet rich in fruits and vegetables, or a "combination" diet rich in fruits, vegetables, and low-fat dairy products and with reduced saturated and total fat. Sodium intake and body weight were maintained at constant levels.Results: At base line, the mean (+/-SD) systolic and diastolic blood pressures were 131.3+/-10.8 mm Hg and 84.7+/-4.7 mm Hg, respectively. The combination diet reduced systolic and diastolic blood pressure by 5.5 and 3.0 mm Hg more, respectively, than the control diet (P<0.001 for each); the fruits-and-vegetables diet reduced systolic blood pressure by 2.8 mm Hg more (P<0.001) and diastolic blood pressure by 1.1 mm Hg more than the control diet (P=0.07). Among the 133 subjects with hypertension (systolic pressure, > or =140 mm Hg; diastolic pressure, > or =90 mm Hg; or both), the combination diet reduced systolic and diastolic blood pressure by 11.4 and 5.5 mm Hg more, respectively, than the control diet (P<0.001 for each); among the 326 subjects without hypertension, the corresponding reductions were 3.5 mm Hg (P<0.001) and 2.1 mm Hg (P=0.003).Conclusions: A diet rich in fruits, vegetables, and low-fat dairy foods and with reduced saturated and total fat can substantially lower blood pressure. This diet offers an additional nutritional approach to preventing and treating hypertension. [ABSTRACT FROM AUTHOR]

Abstract: The interaction between menin and histone-lysine N-methyltransferase 2A (KMT2A) is a critical dependency for KMT2A- or nucleophosmin 1 (NPM1)-altered leukemias and an emerging opportunity for therapeutic development. JNJ-75276617 (bleximenib) is a novel, orally bioavailable, potent, and selective protein-protein interaction inhibitor of the binding between menin and KMT2A. In KMT2A-rearranged (KMT2A-r) and NPM1-mutant (NPM1c) acute myeloid leukemia (AML) cells, JNJ-75276617 inhibited the association of the menin-KMT2A complex with chromatin at target gene promoters, resulting in reduced expression of several menin-KMT2A target genes, including MEIS1 and FLT3. JNJ-75276617 displayed potent antiproliferative activity across several AML and acute lymphoblastic leukemia (ALL) cell lines and patient samples harboring KMT2A or NPM1 alterations in vitro. In xenograft models of AML and ALL, JNJ-75276617 reduced leukemic burden and provided a significant dose-dependent survival benefit accompanied by expression changes of menin-KMT2A target genes. JNJ-75276617 demonstrated synergistic effects with gilteritinib in vitro in AML cells harboring KMT2A-r. JNJ-75276617 further exhibited synergistic effects with venetoclax and azacitidine in AML cells bearing KMT2A-r in vitro, and significantly increased survival in mice. Interestingly, JNJ-75276617 showed potent antiproliferative activity in cell lines engineered with recently discovered mutations (MEN1M327I or MEN1T349M) that developed in patients refractory to the menin-KMT2A inhibitor revumenib. A cocrystal structure of menin in complex with JNJ-75276617 indicates a unique binding mode distinct from other menin-KMT2A inhibitors, including revumenib. JNJ-75276617 is being clinically investigated for acute leukemias harboring KMT2A or NPM1 alterations, as a monotherapy for relapsed/refractory acute leukemia (NCT04811560), or in combination with AML-directed therapies (NCT05453903)., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Small molecules that target the menin-KMT2A protein-protein interaction (menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A or MLL1)-rearranged (KMT2A-r) and nucleophosmin-mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with menin inhibitors. Recently, the novel IKAROS degrader mezigdomide was developed with greatly enhanced IKAROS protein degradation. In this study, we show that mezigdomide has increased preclinical activity in vitro as a single-agent in KMT2A-r and NPM1c AML cell lines, including sensitivity in cell lines resistant to lenalidomide and iberdomide. Further, we demonstrate that mezigdomide has the greatest capacity to synergize with and induce apoptosis in combination with menin inhibitors, including in MEN1 mutant models. We show that the superior activity of mezigdomide compared with lenalidomide or iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent mezigdomide was efficacious in 5 patient-derived xenograft models of KMT2A-r and 1 NPM1c AML. The combination of mezigdomide with the menin inhibitor VTP-50469 increased survival and prevented and overcame MEN1 mutations that mediate resistance in patients receiving menin inhibitor monotherapy. These results support prioritization of mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single agent or in combination with menin inhibitors., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription., Competing Interests: Declaration of interests B.L.E. has received research funding from Celgene, Deerfield, Novartis, and Calico and consulting fees from GRAIL. He is a member of the Scientific Advisory Board and shareholder for Neomorph Inc., TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. A.S.S. received consulting fees from Adaptive Technologies. N.H.T. receives funding from the Novartis Research Foundation and is a member of the Scientific Advisory Board of Monte Rosa Therapeutics. K.A.D. is a consultant to Kronos Bio and Neomorph Inc. E.S.F. is a founder, Scientific Advisory Board (SAB) member, and equity holder of Civetta Therapeutics, Lighthorse Therapeutics, Proximity Therapeutics, and Neomorph, Inc. (also board of directors). B.L.E. and M.S. have received research funding from Calico Life Sciences LLC. E.S.F. is an equity holder and SAB member for Avilar Therapeutics and Photys Therapeutics and a consultant to Odyssey, Novartis, Sanofi, EcoR1 Capital, Ajax Therapeutics, and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, and Astellas., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Myelodysplastic syndromes (MDS) are a heterogenous collection of clonal bone marrow diseases characterized by cytopenias, abnormal karyotypes, molecular abnormalities, and dysplasia by flow cytometry and/or morphology. The progression of MDS to severe cytopenias and/or overt leukemia is associated with the accumulation of additional cytogenetic abnormalities, suggesting clonal evolution. The impact of these accumulated abnormalities on myeloid maturation and the severity of the disease is poorly understood., Methods: Bone marrow specimens from 16 patients with cytogenetic abnormalities were flow cytometrically sorted into three myeloid populations: progenitors, immature myeloid cells, and mature myeloid cells. Fluorescence in situ hybridization analysis was performed on each to determine the distribution of chromosomal abnormalities during myeloid maturation., Results: Our findings revealed three distinct distributions of cytogenetic abnormalities across myeloid maturation, each of which corresponded to specific cytogenetic abnormalities. Group 1 had continuous distribution across all maturational stages and contained patients with a single cytogenetic aberration associated with good-to-intermediate prognosis; Group 2 had accumulation of abnormalities in immature cells and contained patients with high-risk monosomy 7; and Group 3 had abnormalities defining the founding clone equally distributed across maturational stages while subclonal abnormalities were enriched in progenitor cells and contained patients with multiple, non-monosomy 7, abnormalities with evidence of clonal evolution., Conclusions: Our findings demonstrate that low-risk abnormalities (e.g., del(20q) and trisomy 8) occurring in the founding clone display a markedly different disease etiology, with respect to myeloid maturation, than monosomy 7 or abnormalities acquired in subclones, which result in a disruption of myeloid cell maturation in MDS., (© 2021 International Clinical Cytometry Society.)

Chromatin-binding proteins are critical regulators of cell state in haematopoiesis 1,2 . Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs 3-5 . In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. 6 ). Here we identified somatic mutations in MEN1 at the revumenib-menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor-menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reductions in major cardiovascular disease events and mortality with an intensive systolic blood pressure (SBP) goal intervention. However, a detailed description of the blood pressure intervention, antihypertensive medication usage, blood pressure levels, and rates and predictors of blood pressure control has not been reported previously., Methods: Hypertensive participants (n=9361) 50 years and older with elevated cardiovascular disease risk were randomized 1:1 to SBP goal <120 mm Hg or SBP goal <140 mm Hg. Guideline-recommended antihypertensive medications and dosing were provided at no cost. Intensive group participants were started on at least 2 medications, and medications were adjusted monthly until SBP goal was achieved, if feasible. Standard group participants were treated to achieve SBP 135 to 139 mm Hg., Results: Baseline blood pressure (median±interquartile range) was 138±19/78±16 mm Hg. For intensive group participants, percent at goal rose from 8.9% at baseline to 52.4% at 6 months and average antihypertensive medications rose from 2.2 to 2.7; SBP was <120 mm Hg in 61.6% and <130 mm Hg in 80.0% at their final visit. For the standard group participants, percent at goal rose from 53.0% at baseline to 68.6% at 6 months, while antihypertensive medications fell from 1.9 to 1.8. From 6 to 36 months, median SBP was stable at 119±14 mm Hg for intensive and 136±15 mm Hg for standard participants, with stable numbers of medications. Few predictors of SBP control were found in multiple regression models., Conclusions: These results may inform and help replicate the benefits of SPRINT in clinical practice., Registration: URL: http://www., Clinicaltrials: gov; Unique identifier: NCT01206062.

Gastrointestinal stromal tumor (GIST) is commonly characterized by activating mutations in the receptor tyrosine kinase KIT. Tyrosine kinase inhibitors are the only approved therapy for GIST, and complementary treatment strategies are urgently needed. As GIST lacks oncogene amplification and relies upon an established network of transcription factors, we hypothesized that unique chromatin-modifying enzymes are essential in orchestrating the GIST epigenome. We identified through genome-scale CRISPR screening that MOZ and Menin-MLL chromatin regulatory complexes are cooperative and unique dependencies in GIST. These complexes were enriched at GIST-relevant genes and regulated their transcription. Inhibition of MOZ and Menin-MLL complexes decreased GIST cell proliferation by disrupting interactions with transcriptional/chromatin regulators, such as DOT1L. MOZ and Menin inhibition caused significant reductions in tumor burden in vivo, with superior effects observed with combined Menin and KIT inhibition. These results define unique chromatin regulatory dependencies in GIST and identify potential therapeutic strategies for clinical application., Significance: Although many malignancies rely on oncogene amplification, GIST instead depends upon epigenetic regulation of KIT and other essential genes. Utilizing genome-scale CRISPR dependency screens, we identified complementary chromatin-modifying complexes essential to GIST and characterize the consequences of their disruption, elucidating a novel therapeutic approach to this disease. This article is highlighted in the In This Issue feature, p. 1599., (©2022 American Association for Cancer Research.)

Acute myeloid leukemia (AML) remains difficult to treat and requires new therapeutic approaches. Potent inhibitors of the chromatin-associated protein MENIN have recently entered human clinical trials, opening new therapeutic opportunities for some genetic subtypes of this disease. Using genome-scale functional genetic screens, we identified IKAROS (encoded by IKZF1) as an essential transcription factor in KMT2A (MLL1)-rearranged (MLL-r) AML that maintains leukemogenic gene expression while also repressing pathways for tumor suppression, immune regulation and cellular differentiation. Furthermore, IKAROS displays an unexpected functional cooperativity and extensive chromatin co-occupancy with mixed lineage leukemia (MLL)1-MENIN and the regulator MEIS1 and an extensive hematopoietic transcriptional complex involving homeobox (HOX)A10, MEIS1 and IKAROS. This dependency could be therapeutically exploited by inducing IKAROS protein degradation with immunomodulatory imide drugs (IMiDs). Finally, we demonstrate that combined IKAROS degradation and MENIN inhibition effectively disrupts leukemogenic transcriptional networks, resulting in synergistic killing of leukemia cells and providing a paradigm for improved drug targeting of transcription and an opportunity for rapid clinical translation., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The SPRINT (Systolic Blood Pressure Intervention Trial) results have influenced clinical practice but have also generated discussion regarding the validity, generalizability, and importance of the findings. Following the SPRINT primary results manuscript in 2015, additional results and analyses of the data have addressed these concerns. The primary objective of this article is to respond to key questions that have been raised.

Nonreceptor tyrosine kinases (NRTKs) represent an important class of signaling molecules driving diverse cellular pathways. Aberrant expression and hyperphosphorylation of TNK2, an NRTK, have been implicated in multiple cancers. However, the exact proteins and cellular events that mediate phenotypic changes downstream of TNK2 are unclear. Biological systems that employ proximity-dependent biotinylation methods, such as BioID, are being increasingly used to map protein-protein interactions, as they provide increased sensitivity in discovering interaction partners. In this study, we employed stable isotope labeling with amino acids in cell culture and BioID coupled to the biotinylation site identification technology (BioSITe) method that we recently developed to quantitatively explore the interactome of TNK2. By performing a controlled comparative analysis between full-length TNK2 and its truncated counterpart, we were able to not only identify site-level biotinylation of previously well-established TNK2 binders and substrates including NCK1, NCK2, CTTN, and STAT3, but also discover several novel TNK2 interacting partners. We also performed co-immunoprecipitation and immunofluorescence analysis to validate the interaction between TNK2 and CLINT1, a novel TNK2 interacting protein. Overall, this work reveals the power of the BioSITe method coupled to BioID and highlights several molecules that warrant further exploration to assess their functional significance in TNK2-mediated signaling.

Valencia-Sánchez et al. have demonstrated that two histone post-translational modifications (PTMs) - H4K16 acetylation (H4K16ac) and H2BK120 ubiquitination (H2Bub) - enhance the methylation of H3K79 (H3K79me) by Dot1. This breakthrough indicates crosstalk between H4Kac/H2Bub/H3K79me and may improve our understanding of the role that Dot1/Dot1L plays in developmental processes and disease, including MLL1/KMT2A(MLL-r) leukemia., Competing Interests: Declaration of Interests S.A.A. has been a consultant and/or shareholder for Neomorph Inc, Imago BioSciences, Vitae/Allergan Pharma, Cyteir Therapeutics, C4 Therapeutics, Accent Therapeutics, and Mana Therapeutics. S.A.A. has received research support from Janssen, Novartis, and Syndax. J.A.C. and F.P. have no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier Ltd.)

Background: In a previously reported randomized trial of standard and intensive systolic blood-pressure control, data on some outcome events had yet to be adjudicated and post-trial follow-up data had not yet been collected., Methods: We randomly assigned 9361 participants who were at increased risk for cardiovascular disease but did not have diabetes or previous stroke to adhere to an intensive treatment target (systolic blood pressure, <120 mm Hg) or a standard treatment target (systolic blood pressure, <140 mm Hg). The primary outcome was a composite of myocardial infarction, other acute coronary syndromes, stroke, acute decompensated heart failure, or death from cardiovascular causes. Additional primary outcome events occurring through the end of the intervention period (August 20, 2015) were adjudicated after data lock for the primary analysis. We also analyzed post-trial observational follow-up data through July 29, 2016., Results: At a median of 3.33 years of follow-up, the rate of the primary outcome and all-cause mortality during the trial were significantly lower in the intensive-treatment group than in the standard-treatment group (rate of the primary outcome, 1.77% per year vs. 2.40% per year; hazard ratio, 0.73; 95% confidence interval [CI], 0.63 to 0.86; all-cause mortality, 1.06% per year vs. 1.41% per year; hazard ratio, 0.75; 95% CI, 0.61 to 0.92). Serious adverse events of hypotension, electrolyte abnormalities, acute kidney injury or failure, and syncope were significantly more frequent in the intensive-treatment group. When trial and post-trial follow-up data were combined (3.88 years in total), similar patterns were found for treatment benefit and adverse events; however, rates of heart failure no longer differed between the groups., Conclusions: Among patients who were at increased cardiovascular risk, targeting a systolic blood pressure of less than 120 mm Hg resulted in lower rates of major adverse cardiovascular events and lower all-cause mortality than targeting a systolic blood pressure of less than 140 mm Hg, both during receipt of the randomly assigned therapy and after the trial. Rates of some adverse events were higher in the intensive-treatment group. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062.)., (Copyright © 2021 Massachusetts Medical Society.)

The nuclear lamina is a proteinaceous network of filaments that provide both structural and gene regulatory functions by tethering proteins and large domains of DNA, the so-called lamina-associated domains (LADs), to the periphery of the nucleus. LADs are a large fraction of the mammalian genome that are repressed, in part, by their association to the nuclear periphery. The genesis and maintenance of LADs is poorly understood as are the proteins that participate in these functions. In an effort to identify proteins that reside at the nuclear periphery and potentially interact with LADs, we have taken a two-pronged approach. First, we have undertaken an interactome analysis of the inner nuclear membrane bound LAP2β to further characterize the nuclear lamina proteome. To accomplish this, we have leveraged the BioID system, which previously has been successfully used to characterize the nuclear lamina proteome. Second, we have established a system to identify proteins that bind to LADs by developing a chromatin-directed BioID system. We combined the BioID system with the m6A-tracer system which binds to LADs in live cells to identify both LAD proximal and nuclear lamina proteins. In combining these datasets, we have further characterized the protein network at the nuclear lamina, identified putative LAD proximal proteins and found several proteins that appear to interface with both micro-proteomes. Importantly, several proteins essential for LAD function, including heterochromatin regulating proteins related to H3K9 methylation, were identified in this study., (© 2021 Wong et al.)

KRAS is one of the most frequently mutated genes across all cancer subtypes. Two of the most frequent oncogenic KRAS mutations observed in patients result in glycine to aspartic acid substitution at either codon 12 (G12D) or 13 (G13D). Although the biochemical differences between these two predominant mutations are not fully understood, distinct clinical features of the resulting tumors suggest involvement of disparate signaling mechanisms. When we compared the global phosphotyrosine proteomic profiles of isogenic colorectal cancer cell lines bearing either G12D or G13D KRAS mutation, we observed both shared as well as unique signaling events induced by the two KRAS mutations. Remarkably, while the G12D mutation led to an increase in membrane proximal and adherens junction signaling, the G13D mutation led to activation of signaling molecules such as nonreceptor tyrosine kinases, MAPK kinases, and regulators of metabolic processes. The importance of one of the cell surface molecules, MPZL1, which was found to be hyperphosphorylated in G12D cells, was confirmed by cellular assays as its knockdown led to a decrease in proliferation of G12D but not G13D expressing cells. Overall, our study reveals important signaling differences across two common KRAS mutations and highlights the utility of our approach to systematically dissect subtle differences between related oncogenic mutants and potentially lead to individualized treatments.