Publications by authors named "Thomas G Martin"

65 Publications

Evaluation of subcutaneous daratumumab injections in the ambulatory care setting.

J Oncol Pharm Pract 2021 Oct 14:10781552211046911. Epub 2021 Oct 14.

Department of Pharmaceutical Services, 43166San Francisco Medical Center, University of California, San Francisco, CA, USA.

Introduction: Subcutaneous daratumumab is non-inferior to intravenous daratumumab for the treatment of multiple myeloma and significantly reduced incidence of systemic reactions. However, manufacturer for subcutaneous daratumumab has not provided guidance regarding optimal methods for monitoring for hypersensitivity reactions following subcutaneous daratumumab administration.

Methods: A retrospective analysis was performed in two cohorts of patients who received at least two doses of subcutaneous daratumumab for the treatment of plasma cell disorders: patients with previous exposure to intravenous daratumumab (dara-exposed) and patients without history of intravenous daratumumab (dara-naïve). The primary outcome was incidence of systemic and injection-site reactions following first dose of subcutaneous daratumumab. Secondary analysis included time to systemic and injection-site reactions, grading of adverse reaction, and incidence of second systemic reaction.

Results: Thirty-one patients were dara-naïve and 49 patients were dara-exposed. Differences in incidence of systemic (dara-naïve: 9.7% vs dara-exposed: 6.1%, = 0.67) and injection-site reactions (dara-naïve: 12.9% vs dara-exposed: 14.3%, = 0.99) did not reach statistical significance. Difference in median time to systemic reaction (dara-naïve: 3 h vs dara-exposed: 12 h, = 0.18) was clinically important but did not reach statistical significance. Median time to injection-site reactions (dara-naïve: 6 h vs dara-exposed: 24 h,  = 0.03) was shorter in the dara-naïve cohort. No clinically meaningful difference was observed for incidence of second systemic reaction.

Conclusion: Most reactions were mild and did not require medical intervention. Following first subcutaneous daratumumab dose, monitoring for 3 h for dara-naïve patients and no monitoring time for dara-exposed patients for hypersensitivity reactions may be a safe and reasonable practice.
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http://dx.doi.org/10.1177/10781552211046911DOI Listing
October 2021

Isatuximab, carfilzomib and dexamethasone (Isa-Kd) for the management of relapsed multiple myeloma.

Future Oncol 2021 Sep 23. Epub 2021 Sep 23.

Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA 94143, USA.

The treatment of relapsed multiple myeloma remains challenging. Based on interim data from the randomized Phase III IKEMA study demonstrating a progression-free survival benefit with a combination of isatuximab (Isa, a CD38-targeted monoclonal antibody) and carfilzomib/dexamethasone (Kd) versus Kd alone, Isa-Kd recently received regulatory approval in the USA and Europe for patients with multiple myeloma who have received at least one prior line of therapy (in the USA, up to three prior lines). In this review we discuss the rationale and clinical trial experience to date with Isa-Kd. Although final IKEMA results are pending, Isa-Kd has emerged as an effective and tolerable therapy for patients with relapsed multiple myeloma. Given the growing number of antibody-containing triplet regimens in this setting, potential niches and limitations for Isa-Kd are also discussed.
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http://dx.doi.org/10.2217/fon-2021-0778DOI Listing
September 2021

Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis.

Blood Cancer Discov 2021 Sep 16;2(5):434-449. Epub 2021 Jul 16.

Department of Medicine, University of California, San Francisco, CA 94158, USA.

Acute myeloid leukemia patients refractory to induction therapy or relapsed within one year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in pre-clinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single cell RNA sequencing using prospectively acquired patient specimens identified interferon response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well-tolerated with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.
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http://dx.doi.org/10.1158/2643-3230.bcd-21-0055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425277PMC
September 2021

Pharmacological inhibition of BAG3-HSP70 with the proposed cancer therapeutic JG-98 is toxic for cardiomyocytes.

J Cell Biochem 2021 Sep 6. Epub 2021 Sep 6.

Department of Cell and Molecular Physiology, Loyola University Stritch School of Medicine, Maywood, Illinois, USA.

The co-chaperone Bcl2-associated athanogene-3 (BAG3) maintains cellular protein quality control through the regulation of heat shock protein 70 (HSP70). Cancer cells manipulate BAG3-HSP70-regulated pathways for tumor initiation and proliferation, which has led to the development of promising small molecule therapies, such as JG-98, which inhibit the BAG3-HSP70 interaction and mitigate tumor growth. However, it is not known how these broad therapies impact cardiomyocytes, where the BAG3-HSP70 complex is a key regulator of protein turnover and contractility. Here, we show that JG-98 exposure is toxic in neonatal rat ventricular myocytes (NRVMs). Using immunofluorescence microscopy to assess cell death, we found that apoptosis increased in NRVMs treated with JG-98 doses as low as 10 nM. JG-98 treatment also reduced autophagy flux and altered expression of BAG3 and several binding partners involved in BAG3-dependent autophagy, including SYNPO2 and HSPB8. We next assessed protein half-life with disruption of the BAG3-HSP70 complex by treating with JG-98 in the presence of cycloheximide and found BAG3, HSPB5, and HSPB8 half-lives were reduced, indicating that complex formation with HSP70 is important for their stability. Next, we assessed sarcomere structure using super-resolution microscopy and found that disrupting the interaction with HSP70 leads to sarcomere structural disintegration. To determine whether the effects of JG-98 could be mitigated by pharmacological autophagy induction, we cotreated NRVMs with rapamycin, which partially reduced the extent of apoptosis and sarcomere disarray. Finally, we investigated whether the effects of JG-98 extended to skeletal myocytes using C2C12 myotubes and found again increased apoptosis and reduced autophagic flux. Together, our data suggest that nonspecific targeting of the BAG3-HSP70 complex to treat cancer may be detrimental for cardiac and skeletal myocytes.
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http://dx.doi.org/10.1002/jcb.30140DOI Listing
September 2021

Individualized genetic makeup that controls natural killer cell function influences the efficacy of isatuximab immunotherapy in patients with multiple myeloma.

J Immunother Cancer 2021 07;9(7)

Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California, USA

Background: Phase IIb clinical trial with isatuximab (Isa)-lenalidomide (Len)-dexamethasone (Dex) showed an improved progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (RRMM), but the efficacy varied by patient. Antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells plays a crucial role in arbitrating antitumor activities of therapeutic-antibodies. We tested if patient-specific genetic makeup known to set NK cell functional threshold influence response to Isa-Len-Dex therapy.

Methods: We characterized 57 patients with RRMM receiving Isa-Len-Dex for polymorphisms of killer-cell immunoglobulin-like receptors (KIR), human leukocyte antigen (HLA) class I, and FCGR3A loci. In vitro ADCC assay, coincubating primary NK cells expressing specific KIR repertoire with multiple myeloma cell lines (MM cells) expressing selected HLA class I ligands, was used to confirm the identified genetic correlatives of clinical response.

Results: Patients with KIR3DL2+ and its cognate-ligand HLA-A3/11+ had superior PFS than patients missing this combination (HR=0.43; p=0.02), while patients carrying KIR2DL1+ and HLA-C2C2+ compared with to patients missing this pair showed short PFS (HR=3.54; p=0.05). Patients with KIR3DL2+ and HLA-A3/11+ plus high-affinity FCGR3A-158V allele showed the most prolonged PFS (HR=0.35; p=0.007). Consistent with these clinical data, mechanistic experiments demonstrated that NK cells expressing KIR3DL2 trigger greater ADCC when MM cells express HLA-A3/11. Inversely, NK cells expressing KIR2DL1 do not kill if MM cells express the HLA-C2C2 ligand. NK cells expressing high-affinity FCGR3A-158VV-induced greater ADCC compared with those with low-affinity FCGR3A-158FF.

Conclusions: Our results suggest that KIR3DL2+ and HLA-A3/11+ with FCGR3A-158V markers lead to enhanced Isa-dependent NK-mediated cytolysis against MM cells and results in improved PFS in patients with RRMM treated by Isa-Len-Dex. Moreover, the presence of KIR2DL1+ and HLA-C2C2+ identifies patients who may have a lower response to Isa-Len-Dex therapy linked to a reduced NK-mediated ADCC. These biomarkers could potentially identify, via precision medicine, patients more likely to respond to Isa-Len-Dex immunotherapy.

Trial Registration Number: NCT01749969.
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http://dx.doi.org/10.1136/jitc-2021-002958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287616PMC
July 2021

Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.

Nat Commun 2021 05 19;12(1):2942. Epub 2021 May 19.

Department of Cell and Molecular Physiology, Loyola University Stritch School of Medicine, Maywood, IL, USA.

The association between reduced myofilament force-generating capacity (F) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired F arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with F. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced F and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/F, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued F and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.
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http://dx.doi.org/10.1038/s41467-021-23272-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134551PMC
May 2021

BAG3 expression and sarcomere localization in the human heart are linked to HSF-1 and are differentially affected by sex and disease.

Am J Physiol Heart Circ Physiol 2021 06 14;320(6):H2339-H2350. Epub 2021 May 14.

Department of Cell and Molecular Physiology, Loyola University Stritch School of Medicine, Maywood, Illinois.

Mutations to the sarcomere-localized cochaperone protein Bcl2-associated athanogene 3 (BAG3) are associated with dilated cardiomyopathy (DCM) and display greater penetrance in male patients. Decreased protein expression of BAG3 is also associated with nongenetic heart failure; however, the factors regulating cardiac BAG3 expression are unknown. Using left ventricular (LV) tissue from nonfailing and DCM human samples, we found that whole LV BAG3 expression was not significantly impacted by DCM or sex; however, myofilament localized BAG3 was significantly decreased in males with DCM. Females with DCM displayed no changes in BAG3 compared with nonfailing. This sex difference appears to be estrogen independent, as estrogen treatment in ovariectomized female rats had no impact on BAG3 expression. BAG3 gene expression in noncardiac cells is primarily regulated by the heat shock transcription factor-1 (HSF-1). We show whole LV HSF-1 expression and nuclear localized/active HSF-1 each displayed a striking positive correlation with whole LV BAG3 expression. We further found that HSF-1 localizes to the sarcomere -disc in cardiomyocytes and that this myofilament-associated HSF-1 pool decreases in heart failure. The decrease of HSF-1 was more pronounced in male patients and tightly correlated with myofilament BAG3 expression. Together our findings indicate that cardiac BAG3 expression and myofilament localization are differentially impacted by sex and disease and are linked to HSF-1. Myofilament BAG3 expression decreases in male patients with nonischemic DCM but is preserved in female patients with DCM. BAG3 expression in the human heart is tightly linked to HSF-1 expression and nuclear translocation. HSF-1 localizes to the sarcomere Z-disc in the human heart. HSF-1 expression in the myofilament fraction decreases in male patients with DCM and positively correlates with myofilament BAG3.
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http://dx.doi.org/10.1152/ajpheart.00419.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289355PMC
June 2021

Epidermal growth factor receptor-dependent maintenance of cardiac contractility.

Cardiovasc Res 2021 Apr 23. Epub 2021 Apr 23.

Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.

Aims: Epidermal growth factor receptor (EGFR) is essential to the development of multiple tissues and organs and is a target of cancer therapeutics. Due to the embryonic lethality of global EGFR deletion and conflicting reports of cardiac-overexpressed EGFR mutants, its specific impact on the adult heart, normally or in response to chronic stress, has not been established. Using complimentary genetic strategies to modulate cardiomyocyte-specific EGFR expression, we aim to define its role in the regulation of cardiac function and remodeling.

Methods And Results: A floxed EGFR mouse model with α-myosin heavy chain-Cre-mediated cardiomyocyte-specific EGFR downregulation (CM-EGFR-KD mice) developed contractile dysfunction by 9 weeks of age, marked by impaired diastolic relaxation, as monitored via echocardiographic, hemodynamic and isolated cardiomyocyte contractility analyses. This contractile defect was maintained over time without overt cardiac remodeling until 10 months of age, after which the mice ultimately developed severe heart failure and reduced lifespan. Acute downregulation of EGFR in adult floxed EGFR mice with adeno-associated virus 9 (AAV9)-encoded Cre with a cardiac troponin T promoter (AAV9-cTnT-Cre) recapitulated the CM-EGFR-KD phenotype, while AAV9-cTnT-EGFR treatment of adult CM-EGFR-KD mice rescued the phenotype. Notably, chronic administration of the β-adrenergic receptor (βAR) agonist isoproterenol effectively and reversibly compensated for the contractile dysfunction in the absence of cardiomyocyte hypertrophy in CM-EGFR-KD mice. Mechanistically, EGFR downregulation reduced the expression of protein phosphatase 2 A (PP2A) regulatory subunit Ppp2r3a/PR72, which was associated with decreased phosphorylation of phospholamban (PLB) and Ca2+ clearance, and whose re-expression via AAV9-cTnT-PR72 rescued the CM-EGFR-KD phenotype.

Conclusions: Altogether our study highlights a previously unrecognized role for EGFR in maintaining contractile homeostasis under physiologic conditions in the adult heart via regulation of PR72 expression.

Translational Perspective: Our study highlights a previously unrecognized role for EGFR in maintaining contractile homeostasis under physiologic conditions in the adult heart via regulation of PR72, a PP2A regulatory subunit with an unknown impact on cardiac function. Further, we have shown that cardiomyocyte-expressed EGFR is required for the promotion of cardiac hypertrophy under conditions of chronic catecholamine stress. Altogether, our study provides new insight into the dynamic nature of cardiomyocyte-specific EGFR.
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http://dx.doi.org/10.1093/cvr/cvab149DOI Listing
April 2021

Early Time-to-Tocilizumab after B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy in Myeloma.

Transplant Cell Ther 2021 06 6;27(6):477.e1-477.e7. Epub 2021 Mar 6.

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California.

Preemptive administration of tocilizumab (toci) to manage cytokine release syndrome (CRS) after chimeric antigen receptor T cell (CAR-T) therapy may reduce rates of serious CRS but conversely may worsen neurotoxicity or risk of infections. Optimal toci administration strategies for patients with relapsed/refractory multiple myeloma (RRMM) receiving B cell maturation antigen (BCMA)-directed CAR-T therapies have not been evaluated. The objective of this study was to identify whether shorter time-to-toci intervals (hours between first fever attributed to CRS and first dose of toci) have any impact on therapy-related toxicities or clinical outcomes among patients with RRMM receiving BCMA-directed CAR-T therapies. We retrospectively analyzed our institution's experience with 4 BCMA-directed CAR-T therapies (idecabtagene vicleucel, bb21217, ciltacabtagene autoleucel, and orvacabtagene autoceucel) for RRMM over a 3-year period ending in June 2020. We divided patients based on the administration of toci and median time-to-toci interval into early-toci (time-to-toci ≤50th percentile), late-toci (time-to-toci >50th percentile), and no-toci (no toci received) groups. We compared the early-toci and late-toci groups with regard to patient characteristics, weight-based CAR-T toxicities, selected toxicities (CRS, neurotoxicity, macrophage activation syndrome, or infections), and clinical outcomes. Of 50 analyzed patients with a median follow-up of 15.3 months, 76% (n = 38) received ≥1 dose of toci (range, 1 to 3) and were classified into early-toci (time-to-toci ≤12 hours) or late-toci (time-to-toci >12 hours) groups. The 2 groups (n = 19 each) had similar CRS grade distributions, hours to CRS onset, CRS-related biomarkers, and incidences of neurotoxicity or severe infections; however, weight-adjusted CAR-T cell doses were higher in the early-toci group (median 5.99 versus 3.80 × 10 cells/kg, P < 0.01). Peak CRS grades (range, 0 to 2) using American Society for Transplantation and Cellular Therapy consensus criteria, neurotoxicity rates, and rates of severe infections were similar between groups; however, the median CRS duration was 18.6 hours for the early-toci group versus 84.7 hours for the late-toci group. The median progression-free survival was 35.7 months in the early-toci group and 13.2 months in the late-toci group. While limited by small sample size and known confounders such as CAR-T cell dose, our analysis suggests that preemptive toci strategies for CRS management with BCMA-directed CAR-T therapy-specifically, toci administration within 12 hours of the first fever attributed to CRS-do not appear to increase rates of therapy-related toxicities or compromise efficacy. However, total CRS duration may be shorter with early-toci workflows. Prospective validation of our findings may lead to improved safety and cost-effectiveness profiles for CAR-T therapy in RRMM.
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http://dx.doi.org/10.1016/j.jtct.2021.03.004DOI Listing
June 2021

Phase 1b trial of isatuximab, an anti-CD38 monoclonal antibody, in combination with carfilzomib as treatment of relapsed/refractory multiple myeloma.

Cancer 2021 Jun 18;127(11):1816-1826. Epub 2021 Mar 18.

Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.

Background: Isatuximab (Isa), an anti-CD38 monoclonal antibody, and carfilzomib (K), a next-generation proteasome inhibitor (PI), both have potent single-agent activity in relapsed and refractory multiple myeloma (RRMM).

Methods: This phase 1b study evaluated the combination of Isa and K in 33 patients with RRMM. Isa was administered by intravenous infusion in 3 dosing cohorts: dose level 1 (Isa at 10 mg/kg biweekly), dose level 2 (DL2; Isa at 10 mg/kg weekly for 4 doses and then biweekly), and dose level 3 (Isa at 20 mg/kg weekly for 4 doses and then biweekly) and all patients received K (20 mg/m intravenously for cycle 1, days 1 and 2, and then 27 mg/m for all subsequent doses). A standard 3+3 dose-escalation design was used, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. An expansion cohort of 18 patients was enrolled at DL2 to further evaluate safety and efficacy. Responses were assessed with the International Myeloma Working Group response criteria, and patients continued treatment until disease progression or unacceptable toxicity.

Results: With a median follow-up of 26.7 months, in this heavily pretreated population with a median of 3 prior lines (refractory to PIs and immunomodulatory drugs, 76%; refractory to K, 27%), the overall response rate was 70% (stringent complete response/complete response, 4; very good partial response, 8; partial response, 11). The median progression-free survival was 10.1 months, and the 2-year survival probability was 76%. The most common treatment-related adverse events (grade 2 or higher) were anemia, leukopenia, neutropenia, thrombocytopenia, hypertension, and infection. Infusion reactions were common (55%) but did not limit dosing.

Conclusions: Treatment with Isa plus K was well tolerated with no unexpected toxicity. The combination was effective despite the enrollment of heavily pretreated patients with RRMM.

Lay Summary: This phase 1b study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of isatuximab and carfilzomib in patients with relapsed and refractory multiple myeloma. Thirty-three patients were treated: 15 in dose escalation and 18 in dose expansion. Patients received an average of 10 cycles. The treatment was safe and effective. No unexpected toxicity or drug-drug interactions were noted. Seventy percent of the subjects responded to therapy, and the progression-free survival was 10.1 months.
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http://dx.doi.org/10.1002/cncr.33448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252002PMC
June 2021

Revealing the structures of megadalton-scale DNA complexes with nucleotide resolution.

Nat Commun 2020 12 4;11(1):6229. Epub 2020 Dec 4.

Physik Department, Technische Universität München, Garching, Germany.

The methods of DNA nanotechnology enable the rational design of custom shapes that self-assemble in solution from sets of DNA molecules. DNA origami, in which a long template DNA single strand is folded by many short DNA oligonucleotides, can be employed to make objects comprising hundreds of unique DNA strands and thousands of base pairs, thus in principle providing many degrees of freedom for modelling complex objects of defined 3D shapes and sizes. Here, we address the problem of accurate structural validation of DNA objects in solution with cryo-EM based methodologies. By taking into account structural fluctuations, we can determine structures with improved detail compared to previous work. To interpret the experimental cryo-EM maps, we present molecular-dynamics-based methods for building pseudo-atomic models in a semi-automated fashion. Among other features, our data allows discerning details such as helical grooves, single-strand versus double-strand crossovers, backbone phosphate positions, and single-strand breaks. Obtaining this higher level of detail is a step forward that now allows designers to inspect and refine their designs with base-pair level interventions.
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http://dx.doi.org/10.1038/s41467-020-20020-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718922PMC
December 2020

Serial comprehensive geriatric and quality of life assessments in adults age ≥ 50 years undergoing autologous hematopoietic cell transplantation.

J Geriatr Oncol 2021 05 13;12(4):531-539. Epub 2020 Oct 13.

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 400 Parnassus Avenue, San Francisco, CA 94131, USA. Electronic address:

Objectives: We sought to examine the natural history of geriatric assessment (GA) and quality of life (QOL) domains among adults age ≥ 50 years undergoing autologous hematopoietic cell transplantation (autoHCT).

Materials And Methods: A QOL tool and cancer-specific GA were completed before autoHCT in patients ≥50 years, and at 100 days, six months, and one year post-transplant.

Results: One hundred eighty-four patients completed the pre-transplant QOL/GA assessment, 169 (92%) completed the 100-day assessment, 162 (88%) completed the six-month assessment, and 145 (79%) completed the twelve-month assessment. Functional status, as measured by instrumental activities of daily living (IADL), decreased from baseline to day 101 (mean change -0.42 points, 95% CI, -0.75 to -0.09, p = 0.01) but returned to baseline by one year. Physical function as measured by Medical Outcomes Study-Physical Health (MOS-PH) increased by mean of 3.27 points (95% CI, -0.02 to 6.56, p = 0.05) by one year. Physician-rated KPS improved by one year, but patient-rated KPS did not. No QOL metric deteriorated from baseline. Baseline factors predictive of IADL and MOS-PH as measured over time included comorbidities and disease status at transplant. IADL and MOS-PH as measured over time were not significantly associated with age.

Conclusions: AutoHCT for adults age ≥ 50 years resulted in an initial decrease in functional status, with subsequent improvement back to baseline by one year. Physical health and QOL measures were improved or unchanged over time. AutoHCT is well tolerated in well selected older patients, using patient reported geriatric metrics as outcomes.
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http://dx.doi.org/10.1016/j.jgo.2020.09.027DOI Listing
May 2021

Deletion of cardiac polycystin 2/PC2 results in increased SR calcium release and blunted adrenergic reserve.

Am J Physiol Heart Circ Physiol 2020 11 18;319(5):H1021-H1035. Epub 2020 Sep 18.

Department of Cell and Molecular Physiology, Loyola University Chicago, Chicago, Illinois.

Transient receptor potential proteins (TRPs) act as nonselective cation channels. Of the TRP channels, PC2 (also known as polycystin 2) is localized to the sarcoplasmic reticulum (SR); however, its contribution to calcium-induced calcium release and overall cardiac function in the heart is poorly understood. The goal of this study was to characterize the effect of cardiac-specific PC2 deletion in adult cardiomyocytes and in response to chronic β-adrenergic challenge. We used a temporally inducible model to specifically delete PC2 from cardiomyocytes (Pkd2 KO) and characterized calcium and contractile dynamics in single cells. We found enhanced intracellular calcium release after Pkd2 KO, and near super-resolution microscopy analysis suggested this was due to close localization of PC2 to the ryanodine receptor. At the organ level, speckle-tracking echocardiographical analysis showed increased dyssynchrony in the Pkd2 KO mice. In response to chronic adrenergic stimulus, cardiomyocytes from the Pkd2 KO had no reserve β-adrenergic calcium responses and significantly attenuated wall motion in the whole heart. Biochemically, without adrenergic stimulus, there was an overall increase in PKA phosphorylated targets in the Pkd2 KO mouse, which decreased following chronic adrenergic stimulus. Taken together, our results suggest that cardiac-specific PC2 limits SR calcium release by affecting the PKA phosphorylation status of the ryanodine receptor, and the effects of PC2 loss are exacerbated upon adrenergic challenge. Our goal was to characterize the role of the transient receptor potential channel polycystin 2 (PC2) in cardiomyocytes following adult-onset deletion. Loss of PC2 resulted in decreased cardiac shortening and cardiac dyssynchrony and diminished adrenergic reserve. These results suggest that cardiac-specific PC2 modulates intracellular calcium signaling and contributes to the maintenance of adrenergic pathways.
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http://dx.doi.org/10.1152/ajpheart.00302.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789970PMC
November 2020

Under construction: The dynamic assembly, maintenance, and degradation of the cardiac sarcomere.

J Mol Cell Cardiol 2020 11 10;148:89-102. Epub 2020 Sep 10.

Department of Cell and Molecular Physiology, Loyola University Stritch School of Medicine, Maywood, IL, United States of America. Electronic address:

The sarcomere is the basic contractile unit of striated muscle and is a highly ordered protein complex with the actin and myosin filaments at its core. Assembling the sarcomere constituents into this organized structure in development, and with muscle growth as new sarcomeres are built, is a complex process coordinated by numerous factors. Once assembled, the sarcomere requires constant maintenance as its continuous contraction is accompanied by elevated mechanical, thermal, and oxidative stress, which predispose proteins to misfolding and toxic aggregation. To prevent protein misfolding and maintain sarcomere integrity, the sarcomere is monitored by an assortment of protein quality control (PQC) mechanisms. The need for effective PQC is heightened in cardiomyocytes which are terminally differentiated and must survive for many years while preserving optimal mechanical output. To prevent toxic protein aggregation, molecular chaperones stabilize denatured sarcomere proteins and promote their refolding. However, when old and misfolded proteins cannot be salvaged by chaperones, they must be recycled via degradation pathways: the calpain and ubiquitin-proteasome systems, which operate under basal conditions, and the stress-responsive autophagy-lysosome pathway. Mutations to and deficiency of the molecular chaperones and associated factors charged with sarcomere maintenance commonly lead to sarcomere structural disarray and the progression of heart disease, highlighting the necessity of effective sarcomere PQC for maintaining cardiac function. This review focuses on the dynamic regulation of assembly and turnover at the sarcomere with an emphasis on the chaperones involved in these processes and describes the alterations to chaperones - through mutations and deficient expression - implicated in disease progression to heart failure.
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http://dx.doi.org/10.1016/j.yjmcc.2020.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736463PMC
November 2020

Potent Activity of an Anti-ICAM1 Antibody-Drug Conjugate against Multiple Myeloma.

Clin Cancer Res 2020 11 11;26(22):6028-6038. Epub 2020 Sep 11.

Department of Anesthesia, University of California at San Francisco, California.

Purpose: New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody-drug conjugate (ADC).

Experimental Design: Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines , orthotopic xenografts , and patient samples . The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state.

Results: The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity and . In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples.

Conclusions: We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669584PMC
November 2020

CRISPR-based screens uncover determinants of immunotherapy response in multiple myeloma.

Blood Adv 2020 07;4(13):2899-2911

Institute for Neurodegenerative Diseases and.

Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference- and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell surface expression of the multiple myeloma immunotherapy antigen B-cell maturation antigen (BCMA). We discovered that pharmacologic inhibition of HDAC7 and the Sec61 complex increased cell surface BCMA, including in primary patient cells. Pharmacologic Sec61 inhibition enhanced the antimyeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference chimeric antigen receptor T cells (CAR-T cells) coculture screen enabled us to identify both antigen-dependent and antigen-independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study shows the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies.
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http://dx.doi.org/10.1182/bloodadvances.2019001346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362346PMC
July 2020

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma.

Nat Commun 2020 04 22;11(1):1931. Epub 2020 Apr 22.

Department of Laboratory Medicine, University of California, San Francisco, CA, USA.

Enhancing the efficacy of proteasome inhibitors (PI) is a central goal in myeloma therapy. We proposed that signaling-level responses after PI may reveal new mechanisms of action that can be therapeutically exploited. Unbiased phosphoproteomics after treatment with the PI carfilzomib surprisingly demonstrates the most prominent phosphorylation changes on splicing related proteins. Spliceosome modulation is invisible to RNA or protein abundance alone. Transcriptome analysis after PI demonstrates broad-scale intron retention, suggestive of spliceosome interference, as well as specific alternative splicing of protein homeostasis machinery components. These findings lead us to evaluate direct spliceosome inhibition in myeloma, which synergizes with carfilzomib and shows potent anti-tumor activity. Functional genomics and exome sequencing further support the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.
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http://dx.doi.org/10.1038/s41467-020-15521-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176739PMC
April 2020

A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.

Blood Adv 2020 01;4(1):181-190

Division of Cancer Genetics and Epidemiology, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.
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http://dx.doi.org/10.1182/bloodadvances.2019000491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960456PMC
January 2020

Impact of Plerixafor Use at Different Peripheral Blood CD34 Thresholds on Autologous Stem Cell Collection in Patients with Multiple Myeloma.

Biol Blood Marrow Transplant 2020 05 27;26(5):876-883. Epub 2019 Nov 27.

Department of Medicine, Division of Hematology/Oncology/Blood and Marrow Transplant, University of California, San Francisco, California. Electronic address:

Patients with multiple myeloma (MM) scheduled for autologous stem cell transplantation must undergo autologous stem cell mobilization; unfortunately, however, many do not obtain an adequate collection yield. Despite the availability of plerixafor, its widespread and uniform use is limited by its cost, and consequently, many institutions have adopted various risk-adapted algorithms. We report our mobilization experience as we have modified our plerixafor algorithm to a more liberal one, with the expectation of greater collection efficiency and mobilization success with higher plerixafor use. A total of 344 mobilization attempts were analyzed over 3 time periods and using 3 different peripheral blood CD34 cell counts to guide plerixafor use: <15/µL (n = 66), <20/µL (n = 130), and <40/µL (n = 148). The primary endpoints were evaluation of changes in mean plerixafor utilization and apheresis days and assessment of the impact on overall mobilization costs. Secondary endpoints were a description of the impact of lenalidomide use on mobilization and evaluation of the rate of mobilization failure. We found that mean plerixafor use increased from 1.32 to 1.65 to 1.74 doses per mobilization (P = .026) and the mean days of apheresis decreased from 2.15 to 2.17 to 1.89 days per mobilization for the <15/µL, <20/µL, and <40/µL cohorts, respectively (P = .011). The combined cost of plerixafor and apheresis procedures at a threshold of 40/µL is close to that at a threshold of 15/µL, while saving 26 apheresis days per 100 patients. In general, there were low rates of mobilization failure across all thresholds. Patients who received more than 6 cycles of lenalidomide demonstrated impaired mobilization and required more apheresis sessions (P < .013) and greater plerixafor use (P < .001) to achieve target stem cell yields. Overall, using plerixafor in patients with MM, with a day 4 pCD34 count of <40/µL is a reasonable and cost-effective strategy to optimize apheresis utilization.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.024DOI Listing
May 2020

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab.

Cells 2019 11 26;8(12). Epub 2019 Nov 26.

Dana-Farber Cancer Institute, Boston, MA 02215, USA.

CD38 is a transmembrane glycoprotein with ectoenzymatic activity involved in regulation of migration, signal transduction, and receptor-mediated adhesion. CD38 is highly expressed on various malignant cells, including multiple myeloma (MM), and at relatively low levels in other tissues, making it a suitable target for therapeutic antibodies. Several anti-CD38 therapies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab (SAR650984), respectively. Studies have shown that anti-CD38 therapies are effective in the treatment of relapsed/refractory MM and are well tolerated, with infusion reactions being the most common side effects. They can be used as monotherapy or in combination with immunomodulatory agents, such as pomalidomide, or proteasome inhibitors to potentiate their activity. Here we examine isatuximab and several anti-CD38 agents in development that were generated using new antibody engineering techniques and that may lead to more effective CD38 targeting. We also summarize trials assessing these antibodies in MM, other malignancies, and solid organ transplantation. Finally, we propose that further research on the mechanisms of resistance to anti-CD38 therapy and the development of biomarkers and new backbone regimens with CD38 antibodies will be important steps in building more personalized treatment for patients with MM.
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http://dx.doi.org/10.3390/cells8121522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953105PMC
November 2019

Functional Status as Measured by Geriatric Assessment Predicts Inferior Survival in Older Allogeneic Hematopoietic Cell Transplantation Recipients.

Biol Blood Marrow Transplant 2020 01 5;26(1):189-196. Epub 2019 Sep 5.

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. Electronic address:

Allogeneic hematopoietic cell transplantation (alloHCT) has been increasingly offered to older adults with hematologic malignancies. However, optimal methods to determine fitness for alloHCT have yet to be defined. We evaluated the ability of a comprehensive geriatric assessment (CGA) to predict post-alloHCT outcomes in a single-center prospective cohort study of patients age 50 years and older. Outcomes included overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM). A total of 148 patients were included, with a median age of 62 years (range, 50 to 76 years). In multivariate regression analysis, several CGA measures of functional status were predictive of post-alloHCT outcomes, after adjusting for traditional prognostic factors. Any deficit in instrumental activities of daily living (IADL) was associated with inferior OS (hazard ratio [HR], 1.81, 95% confidence interval [CI], 1.07 to 3.08; P = .03) and PFS (HR, 1.85; 95% CI, 1.15 to 2.99; P = .01). A Medical Outcomes Study Physical Health scale (MOS-PH) score <85 was associated with inferior OS (HR, 1.96; 95% CI, 1.13 to 3.40; P = .02), PFS (HR, 1.75; 95% CI, 1.07 to 2.88; P = .03), and increased NRM (subdistribution HR, 2.57; 95% CI, 1.12 to 5.92; P = .03). MOS-PH score was also associated with the number of non-hematologic grade ≥3 adverse events within the first 100 days after alloHCT (rate ratio, 1.61; 95% CI, 1.04 to 2.49; P = .03). These findings support previous work suggesting that IADL is an important prognostic tool prior to alloHCT. MOS-PH is newly identified as an additional metric to identify older patients at higher risk of poor post-alloHCT outcomes, including toxicity and NRM.
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http://dx.doi.org/10.1016/j.bbmt.2019.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942208PMC
January 2020

Preclinical Efficacy and Safety Comparison of CD3 Bispecific and ADC Modalities Targeting BCMA for the Treatment of Multiple Myeloma.

Mol Cancer Ther 2019 11 21;18(11):2008-2020. Epub 2019 Aug 21.

Allogene Therapeutics, Research, South San Francisco, California.

The restricted expression pattern of B-cell maturation antigen (BCMA) makes it an ideal tumor-associated antigen (TAA) for the treatment of myeloma. BCMA has been targeted by both CD3 bispecific antibody and antibody-drug conjugate (ADC) modalities, but a true comparison of modalities has yet to be performed. Here we utilized a single BCMA antibody to develop and characterize both a CD3 bispecific and 2 ADC formats (cleavable and noncleavable) and compared activity both and with the aim of generating an optimal therapeutic. Antibody affinity, but not epitope was influential in drug activity and hence a high-affinity BCMA antibody was selected. Both the bispecific and ADCs were potent and , causing dose-dependent cell killing of myeloma cell lines and tumor regression in orthotopic myeloma xenograft models. Primary patient cells were effectively lysed by both CD3 bispecific and ADCs, with the bispecific demonstrating improved potency, maximal cell killing, and consistency across patients. Safety was evaluated in cynomolgus monkey toxicity studies and both modalities were active based on on-target elimination of B lineage cells. Distinct nonclinical toxicity profiles were seen for the bispecific and ADC modalities. When taken together, results from this comparison of BCMA CD3 bispecific and ADC modalities suggest better efficacy and an improved toxicity profile might be achieved with the bispecific modality. This led to the advancement of a bispecific candidate into phase I clinical trials.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0007DOI Listing
November 2019

The Role of Volume Regulation and Thermoregulation in AKI during Marathon Running.

Clin J Am Soc Nephrol 2019 09 14;14(9):1297-1305. Epub 2019 Aug 14.

Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland;

Background And Objectives: Marathon runners develop transient AKI with urine sediments and injury biomarkers suggesting nephron damage.

Design, Setting, Participants, & Measurements: To investigate the etiology, we examined volume and thermoregulatory responses as possible mechanisms in runners' AKI using a prospective cohort of runners in the 2017 Hartford Marathon. Vitals, blood, and urine samples were collected in 23 runners 1 day premarathon and immediately and 1 day postmarathon. We measured copeptin at each time point. Continuous core body temperature, sweat sodium, and volume were assessed during the race. The primary outcome of interest was AKI, defined by AKIN criteria.

Results: Runners ranged from 22 to 63 years old; 43% were men. Runners lost a median (range) of 2.34 (0.50-7.21) g of sodium and 2.47 (0.36-6.81) L of volume sweat. After accounting for intake, they had a net negative sodium and volume balance at the end of the race. The majority of runners had increases in core body temperature to 38.4 (35.8-41)°C during the race from their baseline. Fifty-five percent of runners developed AKI, yet 74% had positive urine microscopy for acute tubular injury. Runners with more running experience and increased participation in prior marathons developed a rise in creatinine as compared with those with lesser experience. Sweat sodium losses were higher in runners with AKI versus non-AKI (median, 3.41 [interquartile range (IQR), 1.7-4.8] versus median, 1.4 [IQR, 0.97-2.8] g; =0.06, respectively). Sweat volume losses were higher in runners with AKI versus non-AKI (median, 3.89 [IQR, 1.49-5.09] versus median, 1.66 [IQR, 0.72-2.84] L; =0.03, respectively). Copeptin was significantly higher in runners with AKI versus those without (median, 79.9 [IQR, 25.2-104.4] versus median, 11.3 [IQR, 6.6-43.7]; =0.02, respectively). Estimated temperature was not significantly different.

Conclusions: All runners experienced a substantial rise in copeptin and body temperature along with salt and water loss due to sweating. Sodium and volume loss sweat as well as plasma copeptin concentrations were associated with AKI in runners.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_08_13_CJASNPodcast_19_09_.mp3.
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http://dx.doi.org/10.2215/CJN.01400219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730516PMC
September 2019

The influence of non-modifiable and modifiable factors on cardiac biomarkers after marathon running.

J Sports Med Phys Fitness 2019 Oct 5;59(10):1771-1778. Epub 2019 Feb 5.

Frank H. Netter MD School of Medicine, Quinnipiac University, Hamden, CT, USA.

Background: This study investigated the influence of modifiable (training) and non-modifiable factors (age and gender) on cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP) levels post-marathon.

Methods: Thirteen female and nine male recreational runners participated in the 2015 Hartford Marathon. A venous blood draw was taken from each subject at 24 hours pre-race, immediately post-race and 24 hours post-race.

Results: Weekly mileage and weekly long runs were recorded for a 12-week period prior to the marathon. No association was found between age and BNP (P=0.11, P=0.50) or cTnI (P=0.69, P=0.28) for either post-race time points. No association was found between gender and cTnI for either post-race time points (P=0.09, P=0.57). However, BNP elevation, at 24 hours post-race was more pronounced in females than males (P=0.047). For cTnI levels immediately post-race, a negative association was found for average weekly mileage (P=0.006), while a positive association was found for the number of long runs exceeding 20 miles (P=0.05). No association between training and BNP were found.

Conclusions: These results suggest that female runners may experience greater cardiac stress than males. In addition, runners with greater weekly training mileage experienced less cardiac stress post-race, while runners who ran too many 20+ mile long runs, experienced more cardiac stress post-marathon.
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http://dx.doi.org/10.23736/S0022-4707.19.09247-8DOI Listing
October 2019

Limitation in Patient-Reported Function Is Associated with Inferior Survival in Older Adults Undergoing Autologous Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 06 30;25(6):1218-1224. Epub 2019 Jan 30.

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. Electronic address:

Although the use of geriatric assessment (GA) in the allogeneic hematopoietic cell transplantation (HCT) setting has been reported, few studies have evaluated the impact of patient-reported function on autologous HCT (autoHCT) outcomes. In this study, GA, including the administration of Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) quality of life tool, was performed in 184 patients age ≥50 years (median age, 61 years; range, 50 to 75 years) before autoHCT. Associations among GA findings, quality of life metrics, and post-transplantation outcomes were evaluated using Cox regression. Indications for autoHCT included multiple myeloma (73%), non-Hodgkin lymphoma (20%), and other disorders (7%). The median progression-free survival (PFS) was 28 months, whereas the median overall survival (OS) was not reached. In unadjusted analysis, both PFS and OS were significantly associated with 5 GA components: limitation in instrumental activities of daily living, patient-reported Karnofsky Performance Status (KPS), and the Physical, Functional, and BMT subscale scores of the FACT-BMT. In multivariate analysis, 3 components-limitation in instrumental activities of daily living, patient-reported KPS, and FACT-BMT Physical subscale-remained predictive of both PFS and OS when adjusted for age, provider-reported KPS, disease status, and HCT comorbidity index. In older adults undergoing autoHCT, limitation in any 1 of 3 patient-reported measures of functional status was independently associated with inferior PFS and OS, even after adjusting for known prognostic factors.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.028DOI Listing
June 2019

Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function.

JCI Insight 2018 10 18;3(20). Epub 2018 Oct 18.

Loyola University Chicago, Department of Cell and Molecular Physiology, Chicago, Illinois, USA.

Patients with diabetes are at significantly higher risk of developing heart failure. Increases in advanced glycation end products are a proposed pathophysiological link, but their impact and mechanism remain incompletely understood. Methylglyoxal (MG) is a glycolysis byproduct, elevated in diabetes, and modifies arginine and lysine residues. We show that left ventricular myofilament from patients with diabetes and heart failure (dbHF) exhibited increased MG modifications compared with nonfailing controls (NF) or heart failure patients without diabetes. In skinned NF human and mouse cardiomyocytes, acute MG treatment depressed both calcium sensitivity and maximal calcium-activated force in a dose-dependent manner. Importantly, dbHF myocytes were resistant to myofilament functional changes from MG treatment, indicating that myofilaments from dbHF patients already had depressed function arising from MG modifications. In human dbHF and MG-treated mice, mass spectrometry identified increased MG modifications on actin and myosin. Cosedimentation and in vitro motility assays indicate that MG modifications on actin and myosin independently depress calcium sensitivity, and mechanistically, the functional consequence requires actin/myosin interaction with thin-filament regulatory proteins. MG modification of the myofilament may represent a critical mechanism by which diabetes induces heart failure, as well as a therapeutic target to avoid the development of or ameliorate heart failure in these patients.
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http://dx.doi.org/10.1172/jci.insight.121264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237482PMC
October 2018

Role of Proteasome Inhibitors in Relapsed and/or Refractory Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2019 01 5;19(1):9-22. Epub 2018 Sep 5.

Department of Hematology, Mayo Clinic, Jacksonville, FL.

Proteasome inhibition is an established treatment strategy for patients with multiple myeloma as proteasome inhibitors (PIs) selectively target and disrupt the protein metabolism of aberrant plasma cells. Since the introduction of the first-in-class PIs bortezomib, the therapeutic landscape for multiple myeloma has shifted with the development of next-generation PIs (carfilzomib and ixazomib) and new classes of agents. Treatment with modern combination therapies has been shown to result in deep responses and improved outcomes, and these potent regimens are increasingly used as frontline therapy. As patients continue to live longer with modern frontline therapy, there will be an increased need for effective regimens after initial treatment failure. Several recent studies have shown that treatment with combination therapy incorporating PIs induces deep and durable responses in patients with relapsed and/or refractory multiple myeloma. In this review, we review pivotal data and discuss the role of PIs-based doublet and triplet regimens for the management of relapsed/refractory multiple myeloma in the era of modern combination therapy.
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http://dx.doi.org/10.1016/j.clml.2018.08.016DOI Listing
January 2019
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