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Need for Multidisciplinary Research and Data-Driven Guidelines for the Cardiovascular Care of Patients With Cancer.
Meijers WC, Moslehi JJ
(2019) JAMA 322: 1775-1776
MeSH Terms: Antineoplastic Agents, Cardiac Resynchronization Therapy, Cardiomyopathies, Humans, Interdisciplinary Research, Neoplasms, Patient Care Team, Stroke Volume
Added January 15, 2020
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MeSH Terms
Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma.
Cornell RF, Ky B, Weiss BM, Dahm CN, Gupta DK, Du L, Carver JR, Cohen AD, Engelhardt BG, Garfall AL, Goodman SA, Harrell SL, Kassim AA, Jadhav T, Jagasia M, Moslehi J, O'Quinn R, Savona MR, Slosky D, Smith A, Stadtmauer EA, Vogl DT, Waxman A, Lenihan D
(2019) J Clin Oncol 37: 1946-1955
MeSH Terms: Adult, Aged, Aged, 80 and over, Bortezomib, Cardiovascular Diseases, Disease-Free Survival, Electrocardiography, Female, Heart Diseases, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Molecular Targeted Therapy, Multiple Myeloma, Natriuretic Peptide, Brain, Neoplasm Recurrence, Local, Oligopeptides, Prospective Studies, Proteasome Inhibitors, Risk Factors, Time-to-Treatment, Treatment Outcome, Troponin I, Troponin T
Show Abstract · Added November 12, 2019
PURPOSE - Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs.
PATIENTS AND METHODS - Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs.
RESULTS - Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib ( = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; < .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank = .01) and overall survival (log-rank < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications.
CONCLUSION - CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.
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25 MeSH Terms
Green tea intake and risk of incident kidney stones: Prospective cohort studies in middle-aged and elderly Chinese individuals.
Shu X, Cai H, Xiang YB, Li H, Lipworth L, Miller NL, Zheng W, Shu XO, Hsi RS
(2019) Int J Urol 26: 241-246
MeSH Terms: Adult, Aged, China, Feeding Behavior, Female, Follow-Up Studies, Humans, Kidney Calculi, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Risk Factors, Self Report, Sex Factors, Tea
Show Abstract · Added February 26, 2019
OBJECTIVES - To investigate the association between green tea intake and incident stones in two large prospective cohorts.
METHODS - We examined self-reported incident kidney stone risk in the Shanghai Men's Health Study (n = 58 054; baseline age 40-74 years) and the Shanghai Women's Health Study (n = 69 166; baseline age 40-70 years). Information on the stone history and tea intake was collected by in-person surveys. Multivariable Cox proportional hazards models were adjusted for baseline demographic variables, medical history and dietary intakes including non-tea oxalate from a validated food frequency questionnaire.
RESULTS - During 319 211 and 696 950 person-years of follow up, respectively, 1202 men and 1451 women reported incident stones. Approximately two-thirds of men and one-quarter of women were tea drinkers at baseline, of whom green tea was the primary type consumed (95% in men, 88% in women). Tea drinkers (men: hazard ratio 0.78, 95% confidence interval 0.69-0.88; women: hazard ratio 0.8, 95% confidence interval 0.77-0.98) and specifically green tea drinkers (men: hazard ratio 0.78, 95% confidence interval 0.69-0.88; women: hazard ratio 0.84, 95% confidence interval 0.74-0.95) had lower incident risk than never/former drinkers. Compared with never/former drinkers, a stronger dose-response trend was observed for the amount of dried tea leaf consumed/month by men (hazard ratio 0.67, 95% confidence interval 0.56-0.80, P  < 0.001) than by women (hazard ratio 0.87, 95% confidence interval 0.70-1.08, P  = 0.041).
CONCLUSIONS - Green tea intake is associated with a lower risk of incident kidney stones, and the benefit is observed more strongly among men.
© 2018 The Japanese Urological Association.
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16 MeSH Terms
Comparing Auditory-Only and Audiovisual Word Learning for Children With Hearing Loss.
McDaniel J, Camarata S, Yoder P
(2018) J Deaf Stud Deaf Educ 23: 382-398
MeSH Terms: Child, Child, Preschool, Education of Hearing Disabled, Female, Hearing, Humans, Learning, Male, Persons With Hearing Impairments, Teaching, Vision, Ocular
Show Abstract · Added March 30, 2020
Although reducing visual input to emphasize auditory cues is a common practice in pediatric auditory (re)habilitation, the extant literature offers minimal empirical evidence for whether unisensory auditory-only (AO) or multisensory audiovisual (AV) input is more beneficial to children with hearing loss for developing spoken language skills. Using an adapted alternating treatments single case research design, we evaluated the effectiveness and efficiency of a receptive word learning intervention with and without access to visual speechreading cues. Four preschool children with prelingual hearing loss participated. Based on probes without visual cues, three participants demonstrated strong evidence for learning in the AO and AV conditions relative to a control (no-teaching) condition. No participants demonstrated a differential rate of learning between AO and AV conditions. Neither an inhibitory effect predicted by a unisensory theory nor a beneficial effect predicted by a multisensory theory for providing visual cues was identified. Clinical implications are discussed.
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Factors Associated With Insulin Resistance in Adults With HIV Receiving Contemporary Antiretroviral Therapy: a Brief Update.
Hulgan T
(2018) Curr HIV/AIDS Rep 15: 223-232
MeSH Terms: Adult, Anti-HIV Agents, HIV, HIV Infections, HIV Integrase Inhibitors, HIV Protease Inhibitors, Humans, Hyperglycemia, Inflammation, Insulin Resistance, Mitochondria, Obesity
Show Abstract · Added December 11, 2019
PURPOSE OF REVIEW - This narrative review summarizes recent data on factors associated with insulin resistance (IR) in adults with HIV, including contemporary antiretroviral therapy (ART).
RECENT FINDINGS - IR remains common in persons with HIV, even those receiving contemporary ART. Generalized and abdominal obesity and ectopic fat are correlates of IR, and emerging data have identified associations with biomarkers of inflammation and immune activation. Small studies suggest associations between mitochondria and IR. In ART-naïve individuals, IR increased within 4 weeks of starting ART in persons receiving contemporary boosted protease inhibitors or an integrase inhibitor. The importance of IR in non-diabetic persons with HIV will continue to grow as the population ages and obesity increases. Non-invasive estimates of IR appear to perform well in persons with HIV, but clinically relevant cutoffs are uncertain. Unexpected metabolic effects of newer HIV integrase inhibitors have been reported; thus, careful observation for and studies of IR are still warranted.
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Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations.
Huang H, Kuenze G, Smith JA, Taylor KC, Duran AM, Hadziselimovic A, Meiler J, Vanoye CG, George AL, Sanders CR
(2018) Sci Adv 4: eaar2631
MeSH Terms: Cell Membrane, HEK293 Cells, Humans, KCNQ1 Potassium Channel, Leupeptins, Long QT Syndrome, Loss of Function Mutation, Magnetic Resonance Spectroscopy, Mutant Proteins, Mutation, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Domains, Protein Folding, Protein Structure, Secondary, Proteolysis
Show Abstract · Added March 14, 2018
Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure. For each variant, the efficiency of trafficking to the plasma membrane, the impact of proteasome inhibition, and protein stability were assayed. The results of these experiments combined with channel functional data provided the basis for classifying each mutation into one of six mechanistic categories, highlighting heterogeneity in the mechanisms resulting in channel dysfunction or LOF. More than half of the KCNQ1 LOF mutations examined were seen to destabilize the structure of the VSD, generally accompanied by mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutation-induced destabilization of membrane proteins may be a common human disease mechanism. Finally, we observed that five of the folding-defective LQTS mutant sites are located in the VSD S0 helix, where they interact with a number of other LOF mutation sites in other segments of the VSD. These observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilize the KCNQ1 VSD and, most likely, the corresponding domain of many other ion channels.
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16 MeSH Terms
UNC-45a promotes myosin folding and stress fiber assembly.
Lehtimäki JI, Fenix AM, Kotila TM, Balistreri G, Paavolainen L, Varjosalo M, Burnette DT, Lappalainen P
(2017) J Cell Biol 216: 4053-4072
MeSH Terms: Actomyosin, Cell Adhesion, Cell Line, Tumor, Cell Movement, Cell Polarity, Gene Expression, Humans, Intracellular Signaling Peptides and Proteins, Myosin Type II, Osteoblasts, Proteasome Endopeptidase Complex, Protein Folding, Protein Isoforms, Stress Fibers, Tetratricopeptide Repeat
Show Abstract · Added March 14, 2018
Contractile actomyosin bundles, stress fibers, are crucial for adhesion, morphogenesis, and mechanosensing in nonmuscle cells. However, the mechanisms by which nonmuscle myosin II (NM-II) is recruited to those structures and assembled into functional bipolar filaments have remained elusive. We report that UNC-45a is a dynamic component of actin stress fibers and functions as a myosin chaperone in vivo. UNC-45a knockout cells display severe defects in stress fiber assembly and consequent abnormalities in cell morphogenesis, polarity, and migration. Experiments combining structured-illumination microscopy, gradient centrifugation, and proteasome inhibition approaches revealed that a large fraction of NM-II and myosin-1c molecules fail to fold in the absence of UNC-45a. The remaining properly folded NM-II molecules display defects in forming functional bipolar filaments. The C-terminal UNC-45/Cro1/She4p domain of UNC-45a is critical for NM-II folding, whereas the N-terminal tetratricopeptide repeat domain contributes to the assembly of functional stress fibers. Thus, UNC-45a promotes generation of contractile actomyosin bundles through synchronized NM-II folding and filament-assembly activities.
© 2017 Lehtimäki et al.
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15 MeSH Terms
Recurrent cardiotoxicity potentiated by the interaction of proteasome inhibitor and immunomodulatory therapy for the treatment of multiple myeloma.
Fradley MG, Groarke JD, Laubach J, Alsina M, Lenihan DJ, Cornell RF, Maglio M, Shain KH, Richardson PG, Moslehi J
(2018) Br J Haematol 180: 271-275
MeSH Terms: Adult, Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Cardiotoxicity, Electrocardiography, Female, Heart Diseases, Humans, Magnetic Resonance Imaging, Multiple Myeloma, Proteasome Inhibitors
Show Abstract · Added December 2, 2017
Patients with multiple myeloma (MM) have improved treatment options, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Despite their efficacy, increased rates of cardiovascular (CV) complications occur in patients exposed to some of these therapies. While previous research has focused on identifying the toxicities inherent to each specific agent, the CV side effects may be potentiated by the combination of PIs and IMiDs plus dexamethasone. We present a patient with MM with recurrent cardiotoxicity only when exposed to combination PI and IMiD-based therapy. We also review the literature in this context, and propose a potential algorithm for cardiotoxicity prevention in this population.
© 2017 John Wiley & Sons Ltd.
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11 MeSH Terms
A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.
Laubach JP, Moslehi JJ, Francis SA, San Miguel JF, Sonneveld P, Orlowski RZ, Moreau P, Rosiñol L, Faber EA, Voorhees P, Mateos MV, Marquez L, Feng H, Desai A, van de Velde H, Elliott J, Shi H, Dow E, Jobanputra N, Esseltine DL, Niculescu L, Anderson KC, Lonial S, Richardson PG
(2017) Br J Haematol 178: 547-560
MeSH Terms: Antineoplastic Agents, Benchmarking, Bortezomib, Cardiovascular Diseases, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Dyspnea, Heart Failure, Humans, Multiple Myeloma, Proteasome Inhibitors, Retrospective Studies, Risk Factors
Show Abstract · Added December 2, 2017
This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.
© 2017 John Wiley & Sons Ltd.
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13 MeSH Terms
Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway.
Ando K, Shah AK, Sachdev V, Kleinstiver BP, Taylor-Parker J, Welch MM, Hu Y, Salgia R, White FM, Parvin JD, Ozonoff A, Rameh LE, Joung JK, Bharti AK
(2017) Oncotarget 8: 43733-43751
MeSH Terms: BRCA1 Protein, Camptothecin, Cell Line, Tumor, DNA Topoisomerases, Type I, DNA-Binding Proteins, Drug Resistance, Neoplasm, Gene Editing, Humans, Ku Autoantigen, Multiprotein Complexes, PTEN Phosphohydrolase, Phosphorylation, Proteasome Endopeptidase Complex, Protein Binding, Protein Kinase C, Proteolysis, RNA Interference, Topoisomerase I Inhibitors, Ubiquitin
Show Abstract · Added November 26, 2018
Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. A higher basal level of topoI-pS10 ensures rapid topoI degradation leading to CPT resistance. Importantly, PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and CPT resistance.
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