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Human Reproduction Update Jun 2020Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.
BACKGROUND
Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.
OBJECTIVE AND RATIONALE
We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to such treatments.
SEARCH METHODS
We performed a systematic Pubmed search covering articles published since 1958 about the use of progestins, estro-progestins and selective progesterone receptor modulators, to treat endometriosis and its related symptoms. Two reviewers screened the titles and abstracts to select articles for full-text assessment.
OUTCOMES
Progesterone receptor signalling leads to down-regulation of estrogen receptors and restrains local estradiol production through interference with aromatase and 17 beta-hydroxysteroid dehydrogenase type 1. Progestins inhibit cell proliferation, inflammation, neovascularisation and neurogenesis in endometriosis. However, progesterone receptor expression is reduced and disrupted in endometriotic lesions, with predominance of the less active isoform (PRA) over the full-length, active isoform (PRB), due to epigenetic abnormalities affecting the PGR gene transcription. Oxidative stress is another mechanism involved in progesterone resistance in endometriosis. Among the molecular targets of progesterone in the normal endometrium that resist progestin action in endometriotic cells are the nuclear transcription factor FOXO1, matrix metalloproteinases, the transmembrane gap junction protein connexin 43 and paracrine regulators of estradiol metabolism. Compared to other phenotypes, deep endometriosis appears to be more resistant to size regression upon medical treatments. Individual genetic characteristics can affect the bioavailability and pharmacodynamics of hormonal drugs used to treat endometriosis and, hence, explain part of the variability in the therapeutic response.
WIDER IMPLICATIONS
Medical treatment of endometriosis needs urgent innovation, which should start by deeper understanding of the disease core features and diverse phenotypes and idiosyncrasies, while moving from pure hormonal treatments to drug combinations or novel molecules capable of restoring the various homeostatic mechanisms disrupted by endometriotic lesions.
Topics: Endometriosis; Endometrium; Female; Fertility Agents, Female; Humans; Ligands; Peritoneal Diseases; Progesterone; Progestins; Receptors, Progesterone; Treatment Outcome; Uterine Diseases
PubMed: 32412587
DOI: 10.1093/humupd/dmaa009 -
Technology in Cancer Research &... 2021The purpose of this meta-analysis was to study the prognostic effects of androgen receptor splicing variant 7 (AR-V7) on metastatic castration-resistant prostate cancer... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The purpose of this meta-analysis was to study the prognostic effects of androgen receptor splicing variant 7 (AR-V7) on metastatic castration-resistant prostate cancer (mCRPC) under different treatment options (chemotherapy, hormone therapy).
METHODS
We conducted a systematic search of PubMed, EMBASE and Cochrane databases for clinical studies up to June 4, 2021, and used prostate-specific antigen (PSA) progression free-survival (PSA-PFS), radiologic PFS (r-PFS), overall survival (OS) and PSA response rate (PSA RR) as the main endpoints. Subgroup analyses were conducted based on the source of the specimens. STATA v.15 software was used for data analysis.
RESULTS
Twenty-one studies were included in this meta-analysis, with a total of 1578 samples. In the abiraterone (AA)/enzalutamide (E) treatment group, AR-V7 positive patients had worse PSA-PFS (hazard ratio [HR] = 3.40; 95% confidence interval [95%CI] 2.56-4.51; < 0.05) and worse r-PFS (HR = 2.69; 95%CI 1.70-4.24; < 0.05) and OS (HR = 3.02; 95%CI 1.73-5.30; < 0.05). Multivariate Cox regression results showed that AR-V7 positive status was an independent risk factor for OS in the AA/E treatment group. In the taxane treatment group, AR-V7-positive and negative patients had similar PSA-PFS (HR = 0.87; 95%CI 0.46-1.63; = 0.657), r-PFS (HR = 1.01; 95%CI 0.53-1.96; = 0.965) and OS (HR = 1.50; 95%CI 0.89-2.52; = 0.127). For AR-V7-positive patients, the difference in OS between taxane and AA/E treatment was not statistically significant (HR = 1.03; 95%CI 0.52-2.06; = 0.930). However, multivariate Cox regression results suggested that for AR-V7-positive patients, taxane therapy was a protective factor for OS (HR = 0.35; 95%CI 0.20-0.60; < 0.05).
CONCLUSION
The expression of AR-V7 indicates a poor prognosis and is an independent risk factor for OS in AA/E-treated mCRPC patients. However, AR-V7 positive status does not play the same role in taxane-treated patients. In addition, compared to AA/E, taxane treatment is a protective factor for OS in AR-V7-positive patients. AR-V7 may thus be an effective biomarker for treatment prognosis in patients with mCRPC.
Topics: Alternative Splicing; Biomarkers, Tumor; Humans; Male; Prognosis; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; RNA Isoforms; Receptors, Androgen
PubMed: 34313171
DOI: 10.1177/15330338211035260 -
Journal of Pharmacy & Pharmaceutical... 2022This narrative review explores the currently published studies that have evaluated tenapanor for the treatment of hyperphosphatemia in end-stage kidney disease (ESKD)...
PURPOSE
This narrative review explores the currently published studies that have evaluated tenapanor for the treatment of hyperphosphatemia in end-stage kidney disease (ESKD) patients on hemodialysis. This medication's new phosphate lowering mechanism of action reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux by inhibition of the sodium/hydrogen exporter isoform 3 (NHE3). Tenapanor additionally prevents active transcellular phosphate absorption compensation by decreasing the expression of sodium phosphorus 2b transport protein (NaPi2b).
METHODS
A comprehensive search of the literature was conducted using PubMed and ClinicalTrials.gov search engines. The search term "tenapanor hyperphosphatemia" was used for study retrieval. Results were limited to studies published in the English language and excluded review articles. Human, animal, and in vitro studies were included. No date range was specified.
RESULTS
A total of 11 primary studies were identified and included in this review, the largest human study of which enrolled 236 patients. Each study is presented in table format along with measured end points.
CONCLUSIONS
Tenapanor is the first drug in its class that lowers hyperphosphatemia in ESKD patients through a novel mechanism of action involving paracellular inactive transport. Although more studies are needed, early results indicate that tenapanor may have a place in managing hyperphosphatemia in ESKD patients both as monotherapy and as an adjunct to existing phosphate binder therapy.
Topics: Animals; Biological Transport, Active; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Humans; Hyperphosphatemia; Intestinal Absorption; Isoquinolines; Kidney Failure, Chronic; Phosphates; Rats; Sodium-Hydrogen Exchanger 3; Sulfonamides
PubMed: 35041802
DOI: 10.18433/jpps32284 -
Toxins Nov 2020Snakebite envenoming (SBE) is a public health issue in developing countries. The estimated annual global incidence of snakebites is about 5.4 million snakebites per...
Snakebite envenoming (SBE) is a public health issue in developing countries. The estimated annual global incidence of snakebites is about 5.4 million snakebites per year, resulting from 1.8 to 2.7 million cases of SBE and from 81,000 to 138,000 deaths with 400,000 survivors suffering permanent physical and psychological disabilities. There are more than 3000 species of snakes around the world: 600 are venomous and over 200 are considered to be medically important because of their clinical effects. The severity of SBE depends on several factors among which bite localization, snake's size, condition of glands and teeth, bite angle and bite duration, the microflora of the snake's mouth and victim's skin, age of the victim, weight, health status, and victim's activity after a bite. Snake venoms are mixtures of protein families, and each of these families contains many different toxins or toxin isoforms. Based on their effects, snake venoms can be classified as hemotoxic, neurotoxic, or cytotoxic and they can all act together involving multiple tissues and organs. When the bite is fatal, the mechanism of death is primarily related to the paralysis of respiratory muscles, which causes asphyxia and hypoxic-ischemic encephalopathy, but also anaphylactic shock, hemorrhagic shock, cardiomyopathy, acute tubular necrosis (ATN). The purpose of this literature review is to evaluate epidemiological and post-mortem examination findings in fatal SBEs in order to better understand the pathophysiological mechanisms, thus helping pathologists in defining the correct diagnosis.
Topics: Adolescent; Adult; Aged; Animals; Autopsy; Cause of Death; Child; Child, Preschool; Female; Forensic Pathology; Humans; Male; Middle Aged; Reproducibility of Results; Snake Bites; Snake Venoms; Snakes; Young Adult
PubMed: 33153179
DOI: 10.3390/toxins12110699 -
Cytokine Jan 2021COVID-19, as a newly-emerged viral infection has now spread all over the world after originating in Wuhan, China. Pneumonia is the hallmark of the disease, with dyspnea...
BACKGROUND
COVID-19, as a newly-emerged viral infection has now spread all over the world after originating in Wuhan, China. Pneumonia is the hallmark of the disease, with dyspnea in half of the patients and acute respiratory distress syndrome (ARDS) in up to one -third of the cases. Pulmonary edema, neutrophilic infiltration, and inflammatory cytokine release are the pathologic signs of this disease. The anti-inflammatory effect of the photobiomodulation (PBM) has been confirmed in many previous studies. Therefore, this review study was conducted to evaluate the direct effect of PBM on the acute lung inflammation or ARDS and also accelerating the regeneration of the damaged tissues. The indirect effects of PBM on modulation of the immune system, increasing the blood flow and oxygenation in other tissues were also considered.
METHODOLOGY
The databases of PubMed, Cochrane library, and Google Scholar were searched to find the relevant studies. Keywords included the PBM and related terms, lung inflammation, and COVID-19 -related signs. Studies were categorized with respect to the target tissue, laser parameters, and their results.
RESULTS
Seventeen related papers were included in this review. All of them were in animal models. They showed that the PBM could significantly decrease the pulmonary edema, neutrophil influx, and generation of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), intracellular adhesion molecule (ICAM), reactive oxygen species (ROS), isoform of nitric oxide synthase (iNOS), and macrophage inflammatory protein 2 (MIP-2)).
CONCLUSION
Our findings revealed that the PBM could be helpful in reducing the lung inflammation and promoting the regeneration of the damaged tissue. PBM can increase the oxygenation indirectly in order to rehabilitate the affected organs. Thus, the infra-red lasers or light-emitting diodes (LEDs) are recommended in this regard.
Topics: COVID-19; Cytokines; Humans; Low-Level Light Therapy; Lung; Macrophages; Neutrophils; Pneumonia; PubMed; Pulmonary Edema; Reactive Oxygen Species; Respiratory Distress Syndrome
PubMed: 33128927
DOI: 10.1016/j.cyto.2020.155312 -
Acta Obstetricia Et Gynecologica... Sep 2019Progestogens are widely used for the conservative treatment of endometrial hyperplasia and early endometrial cancer. Nevertheless, they do not achieve the regression in...
INTRODUCTION
Progestogens are widely used for the conservative treatment of endometrial hyperplasia and early endometrial cancer. Nevertheless, they do not achieve the regression in all cases. Although several immunohistochemical markers have been assessed to predict the response to treatment, their usefulness is still unclear. We aimed to analyze the usefulness of each immunohistochemical marker studied in predicting the response to progestogens in endometrial hyperplasia and early endometrial cancer.
MATERIAL AND METHODS
Electronic databases were searched for relevant articles from January 2000 to June 2018. All studies assessing the association of immunohistochemical markers with the outcome of the progestogen-based therapy in endometrial hyperplasia and early endometrial cancer were included. The expression of immunohistochemical markers in pretreatment phase and changes of expression during the follow-up were evaluated in relation to response to therapy and relapse.
RESULTS
Twenty-seven studies with 1360 women were included in the systematic review; 43 immunohistochemical markers were assessed. The most studied predictive markers in the pretreatment phase were progesterone and estrogen receptors, although with conflicting results; their isoforms, and in particular progesterone receptor B, appeared more promising. Further studies are needed to confirm the usefulness of mismatch repair proteins, Dusp6, GRP78 and PTEN combined with other molecules such as phospho-AKT or phospho-mTOR. In the follow-up phase, Nrf2 and survivin showed the stronger evidence; a role may also be played by Bcl2 and Ki67. Further studies are necessary for Fas, NCoR, AKR1C1, HE4, PAX2 and SPAG9.
CONCLUSIONS
Several immunohistochemical markers might be helpful in predicting the response to conservative treatment of endometrial hyperplasia and early endometrial cancer on pretreatment and follow-up specimens. Further studies are needed to confirm their usefulness and possibly integrate them in a predictive immunohistochemical panel.
Topics: Biomarkers, Tumor; Conservative Treatment; Endometrial Hyperplasia; Endometrial Neoplasms; Endoplasmic Reticulum Chaperone BiP; Female; Humans; Immunohistochemistry; Predictive Value of Tests; Progestins
PubMed: 30793281
DOI: 10.1111/aogs.13587 -
Drugs Nov 2021Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A (AGAL/GLA) gene. The lysosomal accumulation of the...
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A (AGAL/GLA) gene. The lysosomal accumulation of the substrates globotriaosylceramide (Gb) and globotriaosylsphingosine (lyso-Gb) results in progressive renal failure, cardiomyopathy associated with cardiac arrhythmia, and recurrent strokes, significantly limiting life expectancy in affected patients. Current treatment options for FD include recombinant enzyme-replacement therapies (ERTs) with intravenous agalsidase-α (0.2 mg/kg body weight) or agalsidase-β (1 mg/kg body weight) every 2 weeks, facilitating cellular Gb clearance and an overall improvement of disease burden. However, ERT can lead to infusion-associated reactions, as well as the formation of neutralizing anti-drug antibodies (ADAs) in ERT-treated males, leading to an attenuation of therapy efficacy and thus disease progression. In this narrative review, we provide a brief overview of the clinical picture of FD and diagnostic confirmation. The focus is on the biochemical and clinical significance of neutralizing ADAs as a humoral response to ERT. In addition, we provide an overview of different methods for ADA measurement and characterization, as well as potential therapeutic approaches to prevent or eliminate ADAs in affected patients, which is representative for other ERT-treated lysosomal storage diseases.
Topics: Antibodies, Neutralizing; Antibody Formation; Enzyme Replacement Therapy; Fabry Disease; Humans; Injection Site Reaction; Isoenzymes; Lysosomal Storage Diseases; Male; Recombinant Proteins; Risk Factors; Trihexosylceramides; alpha-Galactosidase
PubMed: 34748189
DOI: 10.1007/s40265-021-01621-y