Publications by authors named "Arnab Chowdhury"

23 Publications

  • Page 1 of 1

The impact of gender, age, race/ethnicity, and stage on quality of life in a spectrum of cutaneous lymphomas.

Support Care Cancer 2021 May 7. Epub 2021 May 7.

Division of Dermatology, City of Hope, Duarte, USA.

Purpose: Cutaneous lymphomas (CLs) are a group of rare, potentially disfiguring and disabling cancers that can have a significant impact on quality of life (QoL). While previous studies have shown that mycosis fungoides (MF) and Sézary syndrome (SS) impair QoL, the effect of other types of CL on QoL has not been evaluated.

Objective: To determine the impact of disease on QoL in all CL patients and to assess how QoL between the CL sub-types varies by demographic and clinical factors.

Methods: The Cutaneous Lymphoma Distress Questionnaire (CL-DQ) was used to assess QoL. All CL patients seen in a multidisciplinary CL clinic were screened for eligibility. Questionnaire responses were collected over a 22-month period between 2017 and 2019. A cross-sectional analysis of CL-DQ scores from an initial visit was performed to determine the effect of disease on QoL across CL sub-types and the potential impact of patient demographics, CL sub-type, and type of treatment.

Results: The study population consisted of 151 patients presenting with distinct types of cutaneous B- and T-cell lymphomas. Notable across the study population were the findings of frustration (44%), worry about progress/spread (43%), itching/pruritus (32%), and embarrassment/shame (28%). QoL was found to be most negatively affected in SS patients, females, younger patients, Black patients, and those with advanced stages of MF/SS.

Conclusions: Impairment of QoL due to CL correlates with gender, age, race/ethnicity, and stage of MF/SS. While the negative impact on QoL is most pronounced in SS patients, other CL sub-types also affect QoL and impact psychosocial distress. Our findings highlight the need for QoL assessment in all CL patients and further examination of disparities noted across demographic groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-021-06241-6DOI Listing
May 2021

A Case of Sheehan Syndrome 7 Years Postpartum with Transaminitis and Hyperlipidemia.

Am J Case Rep 2021 May 5;22:e930908. Epub 2021 May 5.

Internal Medicine, Mayo Clinic Health System - Southwest Minnesota region, Mankato, MN, USA.

BACKGROUND Sheehan syndrome (pituitary necrosis after postpartum hemorrhage) can present in various ways, depending on the hormones that are deficient. There may be a long delay to diagnosis of over a decade because symptoms are often vague and pituitary dysfunction progresses gradually. We describe a case of a patient with acute presentation of Sheehan syndrome 7 years after the obstetric event and with no clear precipitating event. CASE REPORT A 46-year-old woman with a history of hyperlipidemia and transaminitis came to the clinic for evaluation of hypotension and syncope. She had a history of longstanding anhedonia, fatigue, and postpartum hemorrhage 7 years previously and had undergone medical evaluations with her primary doctor with no cause found. Laboratory results showed anemia, central hypothyroidism, and adrenal insufficiency. A diagnosis of Sheehan syndrome was made. CONCLUSIONS Sheehan syndrome is a rare condition of progressive pituitary dysfunction, which can present with nonspecific symptoms and a myriad of laboratory abnormalities until an adrenal crisis is triggered years after the precipitating event. Screening patients for hypopituitarism by free thyroxine levels and adrenocorticotropic hormone (ACTH) stimulation testing is vital for determining whether hypopituitarism is the cause in the appropriate clinical scenario. Use of thyroid-stimulating hormone levels and morning cortisol testing alone will miss this diagnosis, and free thyroxine levels and ACTH stimulation testing are vital.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12659/AJCR.930908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112285PMC
May 2021

Pyruvate kinase M2 in chronic inflammations: a potpourri of crucial protein-protein interactions.

Cell Biol Toxicol 2021 Apr 17. Epub 2021 Apr 17.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India.

Chronic inflammation (CI) is a primary contributing factor involved in multiple diseases like cancer, stroke, diabetes, Alzheimer's disease, allergy, asthma, autoimmune diseases, coeliac disease, glomerulonephritis, sepsis, hepatitis, inflammatory bowel disease, reperfusion injury, and transplant rejections. Despite several expansions in our understanding of inflammatory disorders and their mediators, it seems clear that numerous proteins participate in the onset of CI. One crucial protein pyruvate kinase M2 (PKM2) much studied in cancer is also found to be inextricably woven in the onset of several CI's. It has been found that PKM2 plays a significant role in several disorders using a network of proteins that interact in multiple ways. For instance, PKM2 forms a close association with epidermal growth factor receptors (EGFRs) for uncontrolled growth and proliferation of tumor cells. In neurodegeneration, PKM2 interacts with apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) to onset Alzheimer's disease pathogenesis. The cross-talk of protein tyrosine phosphatase 1B (PTP1B) and PKM2 acts as stepping stones for the commencement of diabetes. Perhaps PKM2 stores the potential to unlock the pathophysiology of several diseases. Here we provide an overview of the notoriously convoluted biology of CI's and PKM2. The cross-talk of PKM2 with several proteins involved in stroke, Alzheimer's, cancer, and other diseases has also been discussed. We believe that considering the importance of PKM2 in inflammation-related diseases, new options for treating various disorders with the development of more selective agents targeting PKM2 may appear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10565-021-09605-0DOI Listing
April 2021

nSite-Selective, Chemical Modification of Protein at Aromatic Side Chain and Their Emergent Applications.

Protein Pept Lett 2021 Jan 29. Epub 2021 Jan 29.

Biomimetic Peptide Engineering Laboratory, Department of Chemistry, Indian Institute of Technology, Ropar, Birla Farms, Punjab-781039. India.

Site-selective chemical modification of protein side chain has probed enormous opportunities in the fundamental understanding of cellular biology and therapeutic applications. Primarily, in the field of biopharmaceutical where formulation of bioconjugates is found to be potential medicine than an individual constituent. In this regard, Lysine and Cysteine are the most widely used endogenous amino acid for these purposes. Recently, the aromatic side chain residues (Trp, Tyr, and His) that are low abundant in protein have gained more attention in therapeutic applications due to their advantages of chemical reactivity and specificity. This review discusses the site-selective bioconjugation methods for aromatic side chains (Trp, Tyr and His) and highlights the developed strategies in the last three years, along with their applications. Also, the review highlights the prevalent methods published earlier. We have examined that metal-catalyzed and photocatalytic reactions are gaining more attention for bioconjugation, though their practical operation is under development. The review has been summarized with the future perspective of protein and peptide conjugations contemplating therapeutic applications and challenges.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/0929866528666210129152535DOI Listing
January 2021

Postoperative Atypical Hemolytic Uremic Syndrome in a 67-Year-Old Woman Associated with Hemolytic Anemia, Thrombocytopenia, and Acute Renal Failure.

Am J Case Rep 2020 Dec 8;21:e925662. Epub 2020 Dec 8.

Department of Hospital Medicine, Mayo Clinic Health System in Mankato, Mankato, MN, USA.

BACKGROUND Hemolytic uremic syndrome (HUS) develops from uncontrolled complement activation leading to intravascular hemolysis and thrombotic microangiopathy. Atypical HUS is diagnosed by excluding a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13 deficiency, and infection-associated HUS. Patients with atypical HUS may respond to eculizumab. We present a case of a 67-year-old woman who developed atypical HUS with hemolytic anemia, renal failure, and thrombocytopenia following an elective hip arthroplasty. CASE REPORT An otherwise healthy 67-year-old woman was admitted to our hospital after an elective right total hip arthroplasty. In the postoperative course, she developed vomiting and acute renal failure that was initially attributed to a prerenal cause. She continued to have worsened renal failure in spite of intravenous hydration, and she also developed mild thrombocytopenia. A peripheral blood smear was performed and showed the presence of schistocytes (red blood cell fragments) consistent with microangiopathic hemolytic anemia. In the context of anemia, thrombocytopenia, and renal failure, this finding led to a prompt and early referral to a tertiary care center and a timely diagnosis of atypical HUS. The patient underwent treatment with plasmapheresis, hemodialysis, and eculizumab. CONCLUSIONS This report highlights the importance of examination of the peripheral blood smear in the diagnosis of thrombotic microangiopathy. As shown in our case, the presence of schistocytes indicates the need for prompt clinical management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12659/AJCR.925662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733150PMC
December 2020

Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64-labeled daratumumab.

Blood Adv 2020 10;4(20):5194-5202

The Judy and Bernard Briskin Center for Multiple Myeloma Research.

18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and nonmalignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with 64Cu via the chelator DOTA (64Cu-daratumumab), led to improved sensitivity and specificity over that of FDG. Here, we report the results of a phase 1 trial designed to (1) assess the safety and feasibility of 64Cu-daratumumab PET/CT and (2) preliminarily evaluate and characterize the ability of 64Cu-daratumumab to accurately detect or exclude MM lesions. A total of 12 daratumumab-naive patients were imaged. Prior to the injection of 15 mCi/5 mg of 64Cu-daratumumab, patients were treated with 0 (n = 3), 10 (n = 3), 45 (n = 3), or 95 mg (n = 3) of unlabeled daratumumab to assess its effect on image quality. No significant adverse events were observed from either unlabeled daratumumab or 64Cu-daratumumab. Of the dose levels tested, 45 mg unlabeled daratumumab was the most optimal in terms of removing background signal without saturating target sites. 64Cu-daratumumab PET/CT provided safe whole-body imaging of MM. A trial comparing the sensitivity and specificity of 64Cu-daratumumab PET/CT with that of FDG PET/CT is planned. This trial was registered at www.clinicaltrials.gov as #NCT03311828.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594407PMC
October 2020

An Analysis and Comparison of Survival and Functional Outcomes in Oropharyngeal Squamous Cell Carcinoma Patients Treated with Concurrent Chemoradiation Therapy within City of Hope Cancer Center Sites.

J Clin Med 2020 Sep 24;9(10). Epub 2020 Sep 24.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.

Oropharyngeal squamous cell carcinoma (OPSCC) is a subset of head and neck cancers that can arise due to human papillomavirus (HPV) infection. We designed a retrospective analysis to determine differences in outcomes of OPSCC patients treated at City of Hope (COH) Cancer Center's main campus versus selected satellite sites with COH-associated faculty and facilities. Patients diagnosed with OPSCC and treated with concurrent chemoradiation therapy ( = 94) were identified and included in the study. Patients underwent treatment at the COH main campus site ( = 50) or satellite sites ( = 44). The majority of patients were Caucasian, male, and diagnosed with p16 positive stage IV locally advanced OPSCC by AJCC 7th edition. Most patients completed their prescribed cumulative radiation therapy dose and had a complete response to treatment. No significant difference in overall survival and progression-free survival was observed between the main campus and the satellite sites. Our study demonstrates successful treatment completion rates as well as comparable recurrence rates between the main campus and COH-associated satellite sites. A trend toward significant difference in feeding tube dependency at 6-months was observed. Differences in feeding tube placement and dependency rates could be addressed by the establishment of on-site supportive services in satellite sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9103083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601157PMC
September 2020

Design and in-silico screening of Peptide Nucleic Acid (PNA) inspired novel pronucleotide scaffolds targeting COVID-19.

Curr Comput Aided Drug Des 2020 Sep 23. Epub 2020 Sep 23.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, NIPER-Ahmedabad. India.

Introduction: The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned itself into a pandemic taking a heavy toll on human lives. The causal agent being SARS-CoV-2, a member of the long-known Coronaviridae family, is a positive sense single-stranded enveloped virus and quite closely related to SARS-CoV. It has become the need of the hour to understand the pathophysiology of this disease, so that drugs, vaccines, treatment regimens and plausible therapeutic agents can be produced.

Methods: In this regard, recent studies uncovered the fact that the viral genome of SARS-CoV-2 encodes nonstructural proteins like RNA dependent RNA polymerase (RdRp) which is an important tool for its transcription and replication process. A large number of nucleic acid based anti-viral drugs are being repurposed for treating COVID-19 targeting RdRp. Few of them are in the advanced stage of clinical trials including Remdesivir. While performing close investigation of the large set of nucleic acid based drugs, we were surprised to find that the synthetic nucleic acid backbone is explored very little or rare.

Results: We have designed scaffolds derived from peptide nucleic acid (PNA) and subjected them for in-silico screening systematically. These designed molecules have demonstrated excellent binding towards RdRp. Compound 12 was found to possess similar binding affinity as Remdesivir with comparable pharmacokinetics. However, the in-silico toxicity prediction indicates compound 12 may be a superior molecule which can be explored further due to its excellent safety-profile with LD50 (12,000mg/kg) as opposed to Remdesivir (LD50 =1000mg/kg).

Conclusion: Compound 12 falls in the safe category of class 6. Synthetic feasibility, equipotent binding and very low toxicity of this peptide nucleic acid derived compounds can serve as a leading scaffold to design, synthesize and evaluate many of similar compounds for the treatment of COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1573409916666200923143935DOI Listing
September 2020

Diffuse alveolar hemorrhage due to serogroup 3.

J Community Hosp Intern Med Perspect 2020 Jun 14;10(3):262-264. Epub 2020 Jun 14.

Department of Cardiovascular Medicine, Mayo Clinic Health System, Mankato, MN, USA.

Legionella pneumophilia remains an important cause of pneumonia that can cause substantial clinical morbidity and mortality. We describe a case involving a 67-year-old woman with legionella pneumonia who developed diffuse alveolar hemorrhage. We also highlight the pitfalls of commonly used legionella urine antigen testing. Furthermore, we explore the role of high-dose steroid therapy as a treatment option for patients with diffuse alveolar hemorrhage secondary to legionella pneumonia who continue to deteriorate in spite of adequate antimicrobial therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/20009666.2020.1767274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426976PMC
June 2020

Substance use disorders: diagnosis and management for hospitalists.

J Community Hosp Intern Med Perspect 2020 May 21;10(2):117-126. Epub 2020 May 21.

Department of Psychiatry and Psychology, Mayo Clinic Health System, Southwest Minnesota Region and Mayo Clinic College of Medicine and Science, Mankato, MN, USA.

Substance use disorder is a significant health concern. Hospitalists manage patient with various forms of substance use disorder on a daily basis. In this review, we have tried to synthesize evidence together to give a brief, yet succinct, review of commonly encounters disorders; alcohol intoxication and withdrawal, opioid intoxication and withdrawal, cocaine intoxication and methamphetamine intoxication. We describe clinical features, diagnosis and management, which would serve as a great resource for hospitalist when managing these complicated patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/20009666.2020.1742495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425622PMC
May 2020

Unexpected BP Sensitivity to Angiotensin II in a Patient With Coronavirus Disease 2019, ARDS, and Septic Shock.

Chest 2020 08 23;158(2):e55-e58. Epub 2020 Apr 23.

Department of Intensive Care, Mayo Clinic Health System, Mankato, MN. Electronic address:

We report the case of an 88-year-old man with coronavirus disease 2019 (COVID-19) who presented with ARDS and septic shock. The patient had exquisite BP sensitivity to low-dose angiotensin II (Ang-2), allowing for rapid liberation from high-dose vasopressors. We hypothesize that sensitivity to Ang-2 might be related to biological effect of severe acute respiratory syndrome coronavirus 2 infection. The case is suggestive of a potential role for synthetic Ang-2 for patients with COVID-19 and septic shock. Further studies are needed to confirm our observed clinical efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2020.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194656PMC
August 2020

Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting.

Leukemia 2021 01 16;35(1):189-200. Epub 2020 Apr 16.

Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, 91010, USA.

Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T-cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex vivo and in vivo. In support of Dara's immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-0810-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572537PMC
January 2021

Repurposing leflunomide for relapsed/refractory multiple myeloma: a phase 1 study.

Leuk Lymphoma 2020 07 8;61(7):1669-1677. Epub 2020 Apr 8.

Department of Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.

The inexpensive, well-tolerated, immunomodulatory agent leflunomide, used extensively for the treatment of rheumatoid arthritis, has been shown to produce significant activity against multiple myeloma (MM) in pre-clinical studies. We conducted a phase 1 study (clinicaltrials.gov: NCT02509052) of single agent leflunomide in patients with relapsed/refractory MM (≥3 prior therapies). At dose levels 1 and 2 (20 and 40 mg), no dose-limiting toxicities (DLTs) were observed. At dose level 3 (60 mg), one patient experienced elevated alanine aminotransferase; an additional three patients were enrolled at this dose level without further DLTs. Overall, toxicities were infrequent and manageable. Nine out of 11 patients achieved stable disease (SD), two subjects experiencing SD for nearly one year or longer. The tolerable safety profile of leflunomide, combined with a potential disease stabilization, is motivating future studies of leflunomide, in combination with other MM drugs, or as an approach to delay progression of smoldering MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1742900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384948PMC
July 2020

Graft-Versus-Host Disease in Multiple Myeloma Patients Treated With Daratumumab After Allogeneic Transplantation.

Clin Lymphoma Myeloma Leuk 2020 06 27;20(6):407-414. Epub 2020 Jan 27.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) represents an adoptive immunotherapy strategy for eliciting a graft-versus-myeloma, the effect for high-risk or relapsed multiple myeloma (MM). Allo-HCT recipients are at risk for graft-versus-host disease (GVHD) as well as associated increases in morbidity and mortality. Daratumumab, an anti-CD38 human immunoglobulin G1 kappa humanized monoclonal antibody, is used for treatment of MM. Daratumumab also affects CD38 nonmyeloma cells, including T cells, which mediate GVHD. The use of daratumumab after allo-HCT has not been well described, and its potential impact on GVHD is unknown.

Patients And Methods: In a multicenter retrospective study, we evaluated incidence of GVHD in 34 patients with relapsed MM treated with daratumumab after allo-HCT.

Results: Overall response to daratumumab (partial response or better) was 41% (95% confidence interval, 24-59). Five patients (15%) developed acute GVHD after daratumumab therapy; no chronic GVHD events were observed after daratumumab therapy. One of these 5 patients had a history of chronic GVHD and developed a flare of acute GVHD during daratumumab therapy. The remaining 4 patients did not have a history of GVHD before daratumumab.

Conclusion: The incidence of GVHD after daratumumab was low and did not result in increased exacerbation of GVHD in patients with a history of GVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.01.010DOI Listing
June 2020

Antimicrobial Efficacy of Methylated Lac Dye, an Anthraquinone Derivative.

Indian J Microbiol 2017 Dec 24;57(4):470-476. Epub 2017 Oct 24.

ICAR-Research Complex for Eastern Region, Research Station, Ranchi, India.

A natural red dye which is produced by the tiny insects while feeding on host trees is popularly known as lac dye. Lac dye is a mixture of at least five closely related pure compounds all being anthraquinone derivatives designated as laccaic acid A, B, C, D and E. Anthraquinones isolated from different natural sources and reported to have potent antimicrobial activity. The lac dye, which is also a mixture of anthraquinone derivatives, is expected to exhibit antifungal and antibacterial activity. Lac dye cannot be used as antibacterial and antifungal agent due to its low water solubility and high polarity. Therefore, it is modified into its methyl derivative to enhance its bio-efficacy. Methylated lac dye is characterized with the help of TLC, UV-Vis spectroscopy and FT-IR, NMR analysis. An in vitro spore germination assay was carried out to evaluate the antifungal efficacy of methylated lac dye against some phytopathogenic fungi which commonly caused a various foliar diseases in crop plants viz., , , , and sp. Among the tested fungi, sp. showed highest sensitivity, which showed 100% inhibition at 750 and 1000 µg/ml as compared to control. However, an obligate parasite also showed varied sensitivity but at 1000 µg/ml showed 100% spore germination as compared to control. Methylated lac dye also showed strong antibacterial properties against at very low concentration (40 and 50 µg/ml). Hence, lac dye may serve as potent antifungal and antibacterial agent in plant disease management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12088-017-0682-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671437PMC
December 2017

An uncommon cause of chest pain - penetrating atherosclerotic aortic ulcer.

J Community Hosp Intern Med Perspect 2016 6;6(3):31506. Epub 2016 Jul 6.

Department of Internal Medicine, The Brooklyn Hospital Center, Academic Affiliate of the Icahn School of Medicine at Mount Sinai, Clinical Affiliate of the Mount Sinai Hospital, Brooklyn, NY, USA.

Chest pain is a very common symptom and can be of cardiac or non-cardiac origin. It accounts for approximately 5.5 million annual emergency room visits in the United States, according to 2011 CDC data. Penetrating atherosclerotic aortic ulcer (PAU), an uncommon condition, is also a potential cause of chest pain. We here report the case of a 65-year-old woman who presented with atypical chest and back pain. The pain persisted for 4 weeks necessitating two emergency room visits. Initial tests were non-significant including cardiac troponins, an electrocardiogram (EKG), and a chest X-ray on her first visit. Upon her second visit, she underwent a computed tomography angiogram of chest with contrast which revealed a PAU with an intramural hematoma in descending aorta. The PAU was finally diagnosed with an exclusion of other chest pain causes. She was treated non-surgically with a blood pressure control strategy and pain management. After a 2-month period of smoking cessation and following the achievement of a controlled blood pressure, she felt well without chest pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942518PMC
http://dx.doi.org/10.3402/jchimp.v6.31506DOI Listing
July 2016

Metal toxicity at the synapse: presynaptic, postsynaptic, and long-term effects.

J Toxicol 2012 12;2012:132671. Epub 2012 Jan 12.

Weill Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144, Doha, Qatar.

Metal neurotoxicity is a global health concern. This paper summarizes the evidence for metal interactions with synaptic transmission and synaptic plasticity. Presynaptically metal ions modulate neurotransmitter release through their interaction with synaptic vesicles, ion channels, and the metabolism of neurotransmitters (NT). Many metals (e.g., Pb(2+), Cd(2+), and Hg(+)) also interact with intracellular signaling pathways. Postsynaptically, processes associated with the binding of NT to their receptors, activation of channels, and degradation of NT are altered by metals. Zn(2+), Pb(2+), Cu(2+), Cd(2+), Ni(2+), Co(2+), Li(3+), Hg(+), and methylmercury modulate NMDA, AMPA/kainate, and/or GABA receptors activity. Al(3+), Pb(2+), Cd(2+), and As(2)O(3) also impair synaptic plasticity by targeting molecules such as CaM, PKC, and NOS as well as the transcription machinery involved in the maintenance of synaptic plasticity. The multiple effects of metals might occur simultaneously and are based on the specific metal species, metal concentrations, and the types of neurons involved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2012/132671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263637PMC
August 2012

Effect of hydroxyurea on procyclic Trypanosoma brucei: an unconventional mechanism for achieving synchronous growth.

Eukaryot Cell 2008 Feb 14;7(2):425-8. Epub 2007 Dec 14.

Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

Procyclic Trypanosoma brucei cells were synchronized with 0.2 mM hydroxyurea. The cells did not arrest at the G(1)/S boundary but proceeded through one round of replication and arrested near the end of S phase. The mitochondrial genome (kinetoplast DNA network) replicated, forming two progeny networks, but the repair of minicircle gaps was inhibited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/EC.00369-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2238168PMC
February 2008

DNA topoisomerases in life and death: implications in kinetoplastid protozoa.

Curr Mol Med 2004 Sep;4(6):711-22

Chembiotek Research International, Biology Research Lab, BIPL Complex, Block EP-GP, Salt Lake, Kolkata 700 091, India.

Current biomedical research has its focus on the search for newer intervention strategies to control public health impact of parasitic diseases. The dramatic advances of molecular and cellular biology in recent times have provided opportunities for discovering and evaluating molecular targets for drug designing, which now form a rational basis for the development of improved anti parasitic therapy. DNA topoisomerases, the "cellular magicians" involved in nearly all biological processes governing DNA, have emerged as one such biological target. Over the last two decades, interest in topoisomerases has expanded beyond the realm of the basic science laboratory into the clinical arena. This review aims at providing a comprehensive insight into the biology of DNA topoisomerases and also focus on its evolution as a drug target in the unicellular kinetoplastids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1566524043360302DOI Listing
September 2004

Dihydrobetulinic acid induces apoptosis in Leishmania donovani by targeting DNA topoisomerase I and II: implications in antileishmanial therapy.

Mol Med 2003 Jan-Feb;9(1-2):26-36

Division of Molecular Parasitology, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India.

Leishmaniasis is the second-most dreaded parasitic disease in the modern world, behind malaria. The lack of effective vaccines demand improved chemotherapy along with the development of lead compounds and newer targets. We report here that the pentacyclic triterpenoid, dihydrobetulinic acid (DHBA), is a novel lead compound for antileishmanial therapy. It acts by targeting DNA topoisomerases. DNA topoisomerase I and II activity was studied using relaxation and decatenation assays. Mechanistic studies were based on the decreased mobility of enzyme-bound DNA compared with free DNA and the differential mobility of nicked and supercoiled monomers in 1% agarose gel. Pulsed field gradient gel electrophoresis, confocal microscopy, and transmission electron microscopy were performed to assess cytotoxicity of the compound and ultrastructural damage of the parasite. Apoptosis was studied by the isolation of DNA from DHBA-treated parasites and subsequent electrophoresis in 1% agarose gel. DHBA inhibits growth of Leishmania donovani promastigotes and amastigotes with an IC50 of 2.6 and 4.1 microM respectively. The compound is a dual inhibitor of DNA topoisomerases that fails to induce DNA cleavage and acts by preventing the formation of enzyme-DNA binary complex, ultimately inducing apoptosis. Treatment of infected golden hamsters with the compound markedly reduces (> 92%) parasitic burden, both in spleen and liver. Interestingly, the 17-decarboxylated analogue, dihydrolupeol, does not inhibit DNA topoisomerase I and II, has no effect on parasitic growth, and also fails to induce apoptosis. DHBA is a potent antileishmanial agent that induces apoptosis by primarily targeting DNA topoisomerases. Therefore it is a strong candidate for use in designing new antileishmanial drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1430381PMC
September 2003

Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: identification of the inhibitory step, the major functional group responsible and development of more potent derivatives.

Med Sci Monit 2002 Jul;8(7):BR254-65

Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, Kolkata, India.

Background: Betulinic acid, a naturally abundant, plant derived, pentacyclic triterpenoid possesses anti-HIV, anti-malarial and anti-inflammatory properties and has recently emerged as a potent anti-tumor compound. This study explores the mode of action of betulinic acid on eukaryotic topoisomerase I and identifies the major functional group responsible along with more potent derivatives.

Material/methods: Topoisomerase I relaxation activity was electrophoretically measured by the decreased mobility of the relaxed monomers followed by ethidium bromide staining. DNA cleavage was studied by electrophoretic separation of the nicked monomers from the relaxed and supercoiled monomers in presence of ethidium bromide. In-vivo DNA cleavage was studied in blasted mouse splenocytes by the SDS-K+ trapping of 3H-DNA-topoisomerase I-camptothecin ternary complex.

Results: Betulinic acid exerts its inhibitory effect by preventing topoisomerase I-DNA interaction as a result of which the 'cleavable complex' is not formed. In consequence, it also acts as an antagonist to camptothecin-mediated cleavage. A series of analogues modified at C-3, C-17 and C-20 positions of betulinic acid were subsequently assayed for inhibition of topoisomerase I catalytic activity. Replacement of the 17-carboxylic group reduces the inhibitory effect and decarboxylation leads to the complete loss of inhibitory effect.

Conclusions: This study is the first detail report of betulinic acid as a very potent inhibitior of eukaryotic topoisomerase I and highlights the necessity of the carboxylic functional group. Dihydro betulinic acid is the most potent (IC50=0.5 mM) pentacyclic triterpenoid to inhibit eukaryotic topoisomerase I till date and can be exploited as a strong candidate for anti-tumor drug designing.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2002

Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I.

Biochem J 2002 Sep;366(Pt 2):653-61

Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700 032, India.

Luteolin, a naturally occurring flavonoid, is abundant in our daily dietary intake. It exhibits a wide spectrum of pharmacological properties, but little is known about its biochemical targets other than the fact that it induces topoisomerase II-mediated apoptosis. In the present study, we show that luteolin completely inhibits the catalytic activity of eukaryotic DNA topoisomerase I at a concentration of 40 microM, with an IC50 of 5 microM. Preincubation of enzyme with luteolin before adding a DNA substrate increases the inhibition of the catalytic activity (IC50=0.66 microM). Treatment of DNA with luteolin before addition of topoisomerase I reduces this inhibitory effect. Subsequent fluorescence tests show that luteolin not only interacts directly with the enzyme but also with the substrate DNA, and intercalates at a very high concentration (>250 microM) without binding to the minor groove. Direct interaction between luteolin and DNA does not affect the assembly of the enzyme-DNA complex, as evident from the electrophoretic mobility-shift assays. Here we show that the inhibition of topoisomerase I by luteolin is due to the stabilization of topoisomerase-I DNA-cleavable complexes. Hence, luteolin is similar to camptothecin, a class I inhibitor, with respect to its ability to form the topoisomerase I-mediated 'cleavable complex'. But, unlike camptothecin, luteolin interacts with both free enzyme and substrate DNA. The inhibitory effect of luteolin is translated into concanavalin A-stimulated mouse splenocytes, with the compound inducing SDS-K+-precipitable DNA-topoisomerase complexes. This is the first report on luteolin as an inhibitor of the catalytic activity of topoisomerase I, and our results further support its therapeutic potential as a lead anti-cancer compound that poisons topoisomerases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BJ20020098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1222798PMC
September 2002