A5039021620- Amyloidosis: Diagnosis, Treatment, Outcomes
- Renal Diseases and Glomerulopathies
- Trace Elements in Health
- Mitochondrial Function and Pathology
- Parathyroid Disorders and Treatments
- Biomedical Research and Pathophysiology
- Pneumocystis jirovecii pneumonia detection and treatment
- Cell death mechanisms and regulation
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Heat shock proteins research
- Chronic Kidney Disease and Diabetes
- Systemic Sclerosis and Related Diseases
- Autophagy in Disease and Therapy
- Acute Kidney Injury Research
- Epigenetics and DNA Methylation
- Blood Pressure and Hypertension Studies
- Antifungal resistance and susceptibility
- Palliative Care and End-of-Life Issues
- Drug-Induced Hepatotoxicity and Protection
- Global Health Care Issues
- Renal and related cancers
- Metabolism and Genetic Disorders
- Patient-Provider Communication in Healthcare
- Cancer Genomics and Diagnostics
- Stress Responses and Cortisol
Boston University
2012-2024
Boston Medical Center
2013-2024
Alnylam Pharmaceuticals (United States)
2022-2024
University of Regensburg
2012-2023
Amyloidosis Foundation
2015-2022
University Medical Center
2016-2020
Metabolism and Renal Physiology
2014
Bridgeport Hospital
2003-2005
Yale University
2005
University Hospital Regensburg
2004
Hsp27 inhibits mitochondrial injury and apoptosis in both normal cancer cells by an unknown mechanism. To test the hypothesis that decreases inhibiting Bax, expression was manipulated renal epithelial before transient metabolic stress, insult activates induces injury, causes apoptosis. Compared with control, enhanced inhibited conformational Bax activation, oligomerization, translocation to mitochondria, reduced leakage of cytochrome c apoptosis-inducing factor, significantly improved cell...
Ischemia activates Bax, a proapoptotic BCL2 protein, as well the prosurvival beta-catenin/Wnt signaling pathway. To test hypothesis that regulates Bax-mediated apoptosis after induction of metabolic stress, which occurs during renal ischemia, we infected immortalized and primary proximal tubular epithelial cells with adenovirus to express either constitutively active or dominant negative beta-catenin constructs. Constitutively significantly decreased improved cell survival stress....
The mechanism by which the serine-threonine kinase glycogen synthase kinase-3beta (GSK3beta) affects survival of renal epithelial cells after acute stress is unknown. Using in vitro and vivo models, we tested hypothesis that GSK3beta promotes Bax-mediated apoptosis, contributing to tubular injury organ dysfunction ischemia. Exposure metabolic activated GSK3beta, Bax, caspase 3 induced apoptosis. Expression a constitutively active mutant Bax decreased cell stress. In contrast, pharmacologic...
<b><i>Background:</i></b> The extent of interstitial fibrosis on kidney biopsy is regarded as a prognostic indicator and guide to treatment. Patients with extensive are assigned supportive treatments the expectation that they have advanced beyond point at which immunosuppressive or other disease-modifying therapies would be benefit. Our study highlights some limitations using predict who will develop end-stage renal disease (ESRD)....
Objective: Zilebesiran is an investigational RNA interference therapeutic that targets hepatic angiotensinogen, the most upstream precursor of renin-angiotensin system. In Phase 2 KARDIA-1 study, single subcutaneous (SC) doses zilebesiran monotherapy significantly reduced 24-hr mean ambulatory and office systolic blood pressure (SBP) from baseline to Months 3 6 versus placebo. The objective KARDIA-2, a randomized, double-blind, placebo-controlled was assess efficacy, safety, pharmacodynamics...
The role of mitofusin 2 (MFN2), a key regulator mitochondrial morphology and function in the renal stress response is unknown. To assess its role, MFN2 floxed gene was conditionally deleted kidney mice (MFN2 cKO) by Pax2 promoter driven Cre expression (Pax2Cre). cKO caused severe fragmentation epithelial cells that are critical for normal tubular function. However, despite small (20%) decrease nephron number, newborn pups had organ or did not differ from littermate Cre-negative pups....
High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 amyloidosis treated HDM/SCT over 25 years. Hematologic CR was achieved by 39% patients. The median duration hematologic 12.3 years, 45% a had no evidence recurrent plasma dyscrasia at 15 years after HDM/SCT. With follow-up interval 8 event-free survival (EFS) overall (OS) were 3.3 7.6 respectively. Patients OS 30% these...
Abstract Effective systemic therapies suppress toxic light chain production leading to an increased proportion of patients with (AL) amyloidosis who survive longer albeit end-stage renal disease. There is a critical need identify in this population benefit from transplantation. This multicenter, observational study five countries includes 237 AL underwent transplantation between 1987 and 2020. With median follow-up 8.5 years, the overall survival was 8.6 years significantly complete very...
Proximal tubule (PT) cells are critical targets of acute ischemic injury. Elimination the mitochondrial fusion protein mitofusin 2 (Mfn2) sensitizes PT to apoptosis in vitro. However, role Mfn2 AKI vivo is unknown. To test its role, we evaluated effects conditional KO (cKO-PT-Mfn2) on animal survival after transient bilateral renal ischemia associated with severe AKI. Forty-eight hours ischemia, 28% control mice survived compared 86% cKO-PT-Mfn2 animals (P<0.001 versus control). Although no...
Proteinuria is a major risk factor for chronic kidney disease progression. Furthermore, exposure of proximal tubular epithelial cells to excess albumin promotes atrophy and fibrosis, key predictors progressive organ dysfunction. However, the link between proteinuria damage unclear. We propose that pathological impairs autophagy, an essential process recycling damaged organelles toxic intracellular macromolecules. In both mouse primary tubule immortalized human cells, decreased number...
HBO1 acetylates lysine residues of histones and is involved in DNA replication gene transcription. Two isoforms JADE1, JADE1S JADE1L, bind promote acetylation chromatin context. We characterized the role JADE1-HBO1 complexes vitro vivo during epithelial cell replication. Down-regulation JADE1 by siRNA diminished rate synthesis cultured cells, decreased endogenous protein expression, prevented recruitment factor Mcm7, demonstrating that required for proliferation. used a murine model acute...
The kidney is the most common organ affected by immunoglobulin light-chain (AL) amyloidosis and monoclonal deposition disease (MIDD), often leading to end-stage renal (ESRD). High-dose melphalan stem cell transplantation (HDM/SCT) effective for selected patients with AL amyloidosis, high rates of complete hematologic response potential improved dysfunction. Data on tolerability HDM/SCT in ESRD due MIDD are limited. We analyzed data toxicity, efficacy, 32 4 who were dialysis-dependent treated...
Abstract Gentamicin is a nephrotoxic antibiotic that causes acute kidney injury (AKI) primarily by targeting the proximal tubule epithelial cell. The development of an effective therapy for gentamicin-induced renal cell limited incomplete mechanistic insight. To address this challenge, we propose RNAi signal pathway screening could identify unifying mechanism and suggest therapeutic strategy to ameliorate it. Computational analysis screens in gentamicin-exposed human cells suggested...
Significance Statement CKD is defined by both functional changes (such as in eGFR and proteinuria) renal histologic alterations. Although kidney function acutely regulated, such interstitial fibrosis, tubular atrophy, glomerulosclerosis could represent chronic damage, thus might provide additional information about disease severity. In an analysis of 859 tissue samples, the authors found that relationship between not linear. At stages 3–5, correlates with fibrosis/tubular atrophy reasonably...
Objective: Zilebesiran is an investigational subcutaneous (SC) RNA interference therapeutic that targets synthesis of hepatic angiotensinogen, the most upstream precursor renin-angiotensin system. In phase 2 KARDIA-1 (NCT04936035) study, a single dose zilebesiran monotherapy significantly reduced 24-hr mean ambulatory and office systolic blood pressure (SBP) from baseline to 3 6 months versus placebo in patients with mild moderate hypertension. KARDIA-3, randomized, double-blind,...