scholarly journals CYP51 as drug targets for fungi and protozoan parasites: past, present and future

Parasitology ◽  
2018 ◽  
Vol 145 (14) ◽  
pp. 1820-1836 ◽  
Author(s):  
Galina I. Lepesheva ◽  
Laura Friggeri ◽  
Michael R. Waterman
Keyword(s):  
Cell Growth ◽  
Drug Targets ◽  
Mortality Rates ◽  
Phenotypic Screening ◽  
Protozoan Parasites ◽  
First Line ◽  
Fungal Cell ◽  
History Of ◽  
Actual Target ◽  
Human Infections

AbstractThe efficiency of treatment of human infections with the unicellular eukaryotic pathogens such as fungi and protozoa remains deeply unsatisfactory. For example, the mortality rates from nosocomial fungemia in critically ill, immunosuppressed or post-cancer patients often exceed 50%. A set of six systemic clinical azoles [sterol 14α-demethylase (CYP51) inhibitors] represents the first-line antifungal treatment. All these drugs were discovered empirically, by monitoring their effects on fungal cell growth, though it had been proven that they kill fungal cells by blocking the biosynthesis of ergosterol in fungi at the stage of 14α-demethylation of the sterol nucleus. This review briefs the history of antifungal azoles, outlines the situation with the current clinical azole-based drugs, describes the attempts of their repurposing for treatment of human infections with the protozoan parasites that, similar to fungi, also produce endogenous sterols, and discusses the most recently acquired knowledge on the CYP51 structure/function and inhibition. It is our belief that this information should be helpful in shifting from the traditional phenotypic screening to the actual target-driven drug discovery paradigm, which will rationalize and substantially accelerate the development of new, more efficient and pathogen-oriented CYP51 inhibitors.

scholarly journals Polymeric Nanocarriers: A Transformation in Doxorubicin Therapies

Materials ◽  
2021 ◽  
Vol 14 (9) ◽  
pp. 2135
Author(s):  
Kamila Butowska ◽  
Anna Woziwodzka ◽  
Agnieszka Borowik ◽  
Jacek Piosik
Keyword(s):  
Drug Delivery ◽  
Wide Spectrum ◽  
Stimuli Responsive ◽  
First Line ◽  
Medical Expenses ◽  
Polymeric Nanocarriers ◽  
Essential Properties ◽  
Life Threatening ◽  
History Of ◽  
Cancerous Cells

Doxorubicin, a member of the anthracycline family, is a common anticancer agent often used as a first line treatment for the wide spectrum of cancers. Doxorubicin-based chemotherapy, although effective, is associated with serious side effects, such as irreversible cardiotoxicity or nephrotoxicity. Those often life-threatening adverse risks, responsible for the elongation of the patients’ recuperation period and increasing medical expenses, have prompted the need for creating novel and safer drug delivery systems. Among many proposed concepts, polymeric nanocarriers are shown to be a promising approach, allowing for controlled and selective drug delivery, simultaneously enhancing its activity towards cancerous cells and reducing toxic effects on healthy tissues. This article is a chronological examination of the history of the work progress on polymeric nanostructures, designed as efficient doxorubicin nanocarriers, with the emphasis on the main achievements of 2010–2020. Numerous publications have been reviewed to provide an essential summation of the nanopolymer types and their essential properties, mechanisms towards efficient drug delivery, as well as active targeting stimuli-responsive strategies that are currently utilized in the doxorubicin transportation field.

A Brief History of Psoriasis Management in Canada

2020 ◽  
Vol 24 (3) ◽  
pp. 273-277
Author(s):  
Khalad Maliyar ◽  
Patrick Fleming ◽  
Boluwaji Ogunyemi ◽  
Charles Lynde
Keyword(s):  
20Th Century ◽  
Coal Tar ◽  
Historical Review ◽  
Chronic Inflammatory Disease ◽  
Biologic Therapies ◽  
First Line ◽  
Revolutionary Change ◽  
Clinical Presentations ◽  
History Of ◽  
The 19Th Century

Psoriasis is a chronic, inflammatory disease with a varying degree of clinical presentations. Managing psoriasis has always been arduous due to its chronicity and its propensity to relapse. Prior to the development of targeted biologic therapies, there were few effective treatments for psoriasis. Ancient psoriasis therapies included pinetar, plant extracts, psychotherapy, arsenic, and ammoniated mercury. In the 19th century, chrysarobin was developed. Then, in the early half of the 20th century, anthralin and coal tar were in widespread use. In the latter half of the 20th century, treatments were limited to topical first-line therapies, systemic drugs, and phototherapy. However, as the treatment of psoriasis has undergone a revolutionary change with the development of novel biologic therapies, patients with moderate to severe psoriasis have been able to avail therapies with high efficacy and durability along with an acceptable safety profile. This article is a brief historical review of the management of psoriasis prior to the inception of biologics and with the development of novel biologic therapies.

scholarly journals Predictors of virological failure among people living with HIV receiving first line antiretroviral treatment in Myanmar: retrospective cohort analysis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Anita Mesic ◽  
Alexander Spina ◽  
Htay Thet Mar ◽  
Phone Thit ◽  
Tom Decroo ◽  
...  
Keyword(s):  
Viral Load ◽  
Virological Failure ◽  
Antiretroviral Treatment ◽  
People Living With Hiv ◽  
First Line ◽  
Hiv Viral Load ◽  
Loss To Follow Up ◽  
History Of ◽  
Living With Hiv

Abstract Background Progress toward the global target for 95% virological suppression among those on antiretroviral treatment (ART) is still suboptimal. We describe the viral load (VL) cascade, the incidence of virological failure and associated risk factors among people living with HIV receiving first-line ART in an HIV cohort in Myanmar treated by the Médecins Sans Frontières in collaboration with the Ministry of Health and Sports Myanmar. Methods We conducted a retrospective cohort study, including adult patients with at least one HIV viral load test result and having received of at least 6 months’ standard first-line ART. The incidence rate of virological failure (HIV viral load ≥ 1000 copies/mL) was calculated. Multivariable Cox’s regression was performed to identify risk factors for virological failure. Results We included 25,260 patients with a median age of 33.1 years (interquartile range, IQR 28.0–39.1) and a median observation time of 5.4 years (IQR 3.7–7.9). Virological failure was documented in 3,579 (14.2%) participants, resulting in an overall incidence rate for failure of 2.5 per 100 person-years of follow-up. Among those who had a follow-up viral load result, 1,258 (57.1%) had confirmed virological failure, of which 836 (66.5%) were switched to second-line treatment. An increased hazard for failure was associated with age ≤ 19 years (adjusted hazard ratio, aHR 1.51; 95% confidence intervals, CI 1.20–1.89; p < 0.001), baseline tuberculosis (aHR 1.39; 95% CI 1.14–1.49; p < 0.001), a history of low-level viremia (aHR 1.60; 95% CI 1.42–1.81; p < 0.001), or a history of loss-to-follow-up (aHR 1.24; 95% CI 1.41–1.52; p = 0.041) and being on the same regimen (aHR 1.37; 95% CI 1.07–1.76; p < 0.001). Cumulative appointment delay was not significantly associated with failure after controlling for covariates. Conclusions VL monitoring is an important tool to improve programme outcomes, however limited coverage of VL testing and acting on test results hampers its full potential. In our cohort children and adolescents, PLHIV with history of loss-to-follow-up or those with low-viremia are at the highest risk of virological failure and might require more frequent virological monitoring than is currently recommended.

scholarly journals 72. Improving Antibiotic Prescribing in Interventional Radiology Using Clinical Decision Support Tools to Assess Penicillin Allergies

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S54-S54
Author(s):  
Vidya Atluri ◽  
Paula Marsland ◽  
Luke M Johnson ◽  
Rupali Jain ◽  
Paul Pottinger ◽  
...  
Keyword(s):  
Interventional Radiology ◽  
Decision Support ◽  
Clinical Decision Support ◽  
Clinical Decision ◽  
Prophylactic Antibiotics ◽  
Decision Support Tools ◽  
First Line ◽  
Support Tools ◽  
History Of ◽  
Clinical Decision Support Tools

Abstract Background Patients labeled with penicillin allergies often receive alternative antibiotics, leading to increased cost, higher risk of adverse events, and decreased efficacy of procedural prophylaxis. However, most of those patients can tolerate a cephalosporin. University of Washington Medical Center – Montlake (UWMC-ML) Interventional Radiology (IR) frequently administer a pre-procedure prophylactic cephalosporin. We worked with the clinicians in IR to develop tools to allow them to better assess penicillin allergies, make the most appropriate antibiotic choice, and update the patient’s allergy documentation. Methods We identified all patients who underwent procedures in IR between 2017–2019. Chart review was done to determine the procedures performed, patient demographic information, allergies, allergy documentation, and prophylactic antibiotics received. In May 2020 we implemented new Clinical Decision Support tools, including an online assessment app (https://tinyurl.com/IRPCNAllAssess) and handouts to guide antibiotic decision making to clinicians in IR. Results From 2017 to 2019, 381 patients underwent 958 procedures in IR. Of those, 379 patients underwent 496 procedures for which the recommended first line choice for antibiotic prophylaxis is a cephalosporin. Of patients who received pre-procedure prophylactic antibiotics for those procedures, 15.9% [n=11] of patients with penicillin allergies received the first line antibiotic, compared to 89.9% [n=319] of patients without a reported penicillin allergy. Since implementation, the online app has been used to evaluate 9 patients, of whom 8 had penicillin allergies. All 8 patients safely received the first line antibiotic (3 were delabeled, 4 reported a history of mild reactions, and 1 reported a history of an immediate IgE mediated response to penicillin but safely received cefazolin). Conclusion IR evaluates hundreds of patients who may receive prophylactic antibiotics each year. By providing tools to assess penicillin allergies, we were able to improve both their prescribing and de-label patients which will provide a much broader impact on their care than on just their current procedure. Our free tool can be accessed at the website above, and we will demonstrate in person. Disclosures All Authors: No reported disclosures

BRCA mutations and their clinical relevance in unselected pancreatic cancer population.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16240-e16240
Author(s):  
Viola Barucca ◽  
Andrea Petricca Mancuso ◽  
Salvatore De Marco ◽  
Daniela Iacono ◽  
Carmelilia De Bernardo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Family History ◽  
Disease Progression ◽  
Personal History ◽  
First Line ◽  
Brca Mutations ◽  
Cancer Family ◽  
Cancer Family History ◽  
Brca 2 ◽  
History Of

e16240 Background: Germline pathogenetic mutations in BRCA1/2 genes are described in pancreatic cancer patients (PCP) in about 5–9% of cases. The purpose of this study was to determine their relevance in an unselected consecutive cohort of PCP describing family and clinical history. Methods: Patients (pts) were recruited at a single cancer center from September 2019 to October 2020. Participants provided blood for DNA analysis; cancer family history and treatment records were reviewed; DNA was analyzed by Next Generation Sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1/2 Results: 69 pts were included, 61 (88,4%) with locally advanced and metastatic pancreatic cancer received first line chemotherapy and 38 (62%) were full eligible for BRCA analysis; 8 out of 69 pts were BRCA screened even if in adjuvant setting, 10 patients are still under evaluation. Out of the 38 first line screened PCP germline BRCA mutations were found in 9 (19%): 4 pts (8,7%) with pathogenetic BRCA-2 variants (subgroup 1 – S1) and 5 pts (10,8%) with variants of unknown significances (VUSs), i.e. c.5339T>C and c.5096G>A in BRCA1 (subgroup 2 – S2). Samples from 29 pts were established as BRCA wild-type (subgroup 3 – S3). Pathogenetic BRCA-2 variants were observed in 2 male and 2 female (median age, 61.5 years, range 48-69), 3 out 4 without family history of breast, ovarian and pancreatic cancer, one patient (pt) had ovarian cancer family history. All pts had a negative personal history of others cancers. All S1 pts received FOLFIRINOX regimen achieving one complete response, 2 partials responses and 1 disease progression with RECIST criteria. The S2 included 2 male and 3 female (median age, 61 years, range 45-70) 2 with family history of pancreatic cancer, no pt had personal history of others cancers; 2 pts had stable disease and 3 disease progression receiving platinum-based regimen (4 pts) and gemcitabine/nabpaclitaxel (1 pt), respectively. Platinum responders were observed only in the well known pathogenetic BRCA-2 variants group with twice a median progression-free survival (PFS, months -ms-) as compared to the one observed in VUSs group. (>6 C.I. 95% 2- >12 ms; vs 3 ms, 95% C.I. 3-12 ms). S3 included 9 male and 20 female, (median age, 66 years, range 42-78); 5 pts had family history of pancreatic or breast cancer, 5 pts had a personal history of other cancers (breast and thyroid). In this group,16 pts received a platinum based regimen and 12 pts have been treated without platinum based regimen. Conclusions: Our results suggest that: 1) BRCA pathogenetic mutations rate (8,7%) is in line with literature data and seems not to be related with family or personal history, and to be associated with a better outcome; 2) No BRCA mutations were detected in patients over 70 years. 3) VUSs subgroup do not seem to benefit from platinum-regimen.

scholarly journals CHRONIC ANAL FISSURE

2011 ◽  
Vol 18 (04) ◽  
pp. 562-565
Author(s):  
ABID HUSSAIN ◽  
KISHWAR NAHEED
Keyword(s):  
Anal Fissure ◽  
Chronic Anal Fissure ◽  
Medical Center ◽  
Anal Verge ◽  
Symptomatic Relief ◽  
First Line ◽  
Detailed History ◽  
History Of ◽  
First Line Treatment

Objective: To determine the role of chemical syphincterotomy as non surgical management of chronic anal fissure. Study Design: Descriptive. Setting: This study was conducted at Margalla teaching Hospital and United Medical center .Rawalpndi. Period: 1½ years. Patients & Methods: This study included 70 patients of either sex. A personal bio data and detailed history of dietary and bowel habits were registered. Topical 0.2% GTN (Gylciryltrinitrate) was applied to anal verge 2 times per day for the period of two months and its effects were noted. Result: 58 patients (83%) got symptomatic relief and 12 patients (17%) did not get improvement. Conclusions: Chemical syphincterotomy heals majority of the fissure . Topical 0.2% GNT ointment is widely used as a first line treatment in U.K . It is generally accepted as an effective treatment for chronic fissure .

scholarly journals DGAT1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity

2020 ◽  
Author(s):  
Daniel J. Wilcock ◽  
Andrew P. Badrock ◽  
Rhys Owen ◽  
Melissa Guerin ◽  
Andrew D. Southam ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Cell Growth ◽  
Cancer Cells ◽  
Melanoma Cell ◽  
Drug Targets ◽  
Lipid Peroxides ◽  
Acid Oxidation ◽  
Growth Factor Signaling ◽  
Bona Fide

ABSTRACTDysregulated cellular metabolism is a hallmark of cancer. As yet, few druggable oncoproteins directly responsible for this hallmark have been identified. Increased fatty acid acquisition allows cancer cells to meet their membrane biogenesis, ATP, and signaling needs. Excess fatty acids suppress growth factor signaling and cause oxidative stress in non-transformed cells, but surprisingly not in cancer cells. Molecules underlying this cancer adaptation may provide new drug targets. Here, we identify Diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, as a frequently up-regulated oncoprotein allowing cancer cells to tolerate excess fatty acids. DGAT1 over-expression alone induced melanoma in zebrafish melanocytes, and co-operated with oncogenic BRAF or NRAS for more rapid melanoma formation. Mechanistically, DGAT1 stimulated melanoma cell growth through sustaining mTOR kinase–S6 kinase signaling and suppressed cell death by tempering fatty acid oxidation, thereby preventing accumulation of reactive oxygen species including lipid peroxides.SIGNIFICANCEWe show that DGAT1 is a bona fide oncoprotein capable of inducing melanoma formation and co-operating with other known drivers of melanoma. DGAT1 facilitates enhanced fatty acid acquisition by melanoma cells through suppressing lipototoxicity. DGAT1 is also critical for maintaining S6K activity required for melanoma cell growth.

scholarly journals Trends in Use of Cardioprotective Medication in Peripheral Artery Disease: A Nationwide Study

2021 ◽  
Author(s):  
Sadaf Kamil ◽  
Thomas S. G. Sehested ◽  
Kim Houlind ◽  
Jens F. Lassen ◽  
Gunnar H. Gislason ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Angiotensin Converting Enzyme ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Mortality Rates ◽  
Converting Enzyme ◽  
Peripheral Artery ◽  
Nationwide Study ◽  
History Of ◽  
Artery Disease

Background Guideline‐based cardioprotective medical therapy is intended to reduce the burden of adverse cardiovascular and limb outcomes in patients with peripheral artery disease (PAD). However, contemporary data describing trends in use of medication remains limited. The present study, therefore, aims to investigate changes in use of cardioprotective medication in PAD. Methods and Results By using Danish national healthcare registries, we identified all patients with first‐time diagnosis of PAD (1997–2016) and classified them into two groups: (1) PAD+ that includes all patients with PAD with a history of cardiovascular disease, ie, myocardial infarction, atrial fibrillation, and stroke (n=162 627); and (2) PAD (n=87 935) that comprise patients without a history of cardiovascular disease. We determined the use of medication in the first 12 months after the incident diagnosis of PAD and estimated age standardized 1‐year mortality rates. Our results showed increase in use of cardioprotective medication throughout the study period in both groups. However, PAD+ had a higher use of medication (acetylsalicylic acid, 3.5%–48.4%; Clopidogrel, 0%–17.6%; vitamin K antagonists, 0.9%–7.8%; new oral anticoagulants, 0.0%–10.1%; Statins, 1.9%–58.1%; angiotensin‐converting enzyme inhibitors, 1.2%–20.6%), compared with PAD (acetylsalicylic acid, 2.9%–54.4%; Clopidogrel, 0%–11.9%; vitamin K antagonists, 0.9%–2.4%; new oral anticoagulants, 0.0%–3.4%; Statins, 1.5%–56.9%; angiotensin‐converting enzyme, 0.9%–17.2%), respectively. Furthermore, 1‐year mortality rates in PAD declined with increased use of medications during study. Conclusions In this nationwide study, use of cardioprotective medication increased considerably with time, but compared to patients with other atherosclerotic diseases, there remains an underuse of guideline‐based medical therapy in patients with PAD.

Armageddon and the Gulag, 1939–1945

2011 ◽  
Author(s):  
Steven A. Barnes
Keyword(s):  
Soviet Union ◽  
Mortality Rates ◽  
Postwar Period ◽  
Social Phenomenon ◽  
Soviet System ◽  
Total War ◽  
The Soviet Union ◽  
Initial Stage ◽  
Red Army ◽  
History Of

This chapter focuses on the Gulag during the Armageddon of the Great Patriotic War. It shows how the institutions, practices, and identities of the Gulag shifted in accord with the demands of total war. The war was an era of mass release on an unprecedented scale side by side with the highest mortality rates in the history of the Gulag system. After four years of brutal, exhausting warfare and a disastrous initial stage, the Soviet Union emerged from its Armageddon victorious. The early postwar period offered no indication that the Gulag would cease to be a mass social phenomenon within fifteen years. Rather, the Gulag remained a pillar in the reestablishment of the Soviet system, following the Red Army into liberated territories, so that every liberated district received its own corrective labor colony. By 1944, the camp and colony population began to grow again.

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