Annals of medicine
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Altered epigenetic map is frequently observed in cancer and recent investigations have demonstrated a pertinent role of epigenetic modifications in the response to many anticancer drugs including the DNA damaging agents. Topoisomerase I (Top I) is a well-known nuclear enzyme that is critical for DNA function and cell survival and its inhibition causes DNA strand breaks and cell cycle arrest. Inhibitors of human Top I have proven to be a prosperous chemotherapeutic treatment for a vast number of cancer patients. While the treatment is efficacious in many cases, resistance and altered cellular response remain major therapeutic issues. ⋯ The field of epigenetic research is steadily growing. With its assistance, we could gain better understanding on how drug response and resistance work. Epigenetics can evolve as possible biomarkers and predictors of response to many medications including Top I inhibitors, and could have significant clinical implications that necessitate deeper attention.HIGHLIGHTSEpigenetic alterations, including DNA methylation and histone modifications, play a pertinent role in the response to several anticancer treatments, including DNA damaging agents like Top I inhibitors.Although camptothecin derivatives are used clinically as Top I inhibitors for management of cancer, certain types of cancer have inherent and or acquired resistance that limit the curative potential of them.Epigenetic modifications like DNA hypomethylation can either increase or decrease sensitivity to Top I inhibitors by different mechanisms.The combination of Top I inhibitors with the inhibitors of histone modifying enzymes can result in enhanced cytotoxic effects and sensitization of resistant cells to Top I inhibitors.MicroRNAs were found to directly influence the expression of Top I and other proteins in cancer cells resulting in positive or negative alteration of the response to Top I inhibitors.lncRNAs and their genetic polymorphisms have been found to be associated with Top I function and the response to its inhibitors.Clinical trials of epigenetic drugs in combination with Top I inhibitors are plentiful and some of them showed potentially promising outcomes.
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Tirofiban is a small non-peptide ligand-mimetic Glycoprotein (GP) IIb/IIIa inhibitor which can reversibly bind to the arginine-glycine-aspartic acid (RGD) recognition site of GP IIb/IIIa to prevent platelet aggregation. It reduces the incidence of thrombotic cardiovascular events in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). ⋯ This side effect caused by tirofiban is especially concerning given how frequently it is used in the practice of contemporary cardiovascular care. The present review provides an overview of the pathophysiology, clinical presentation, management, and risk factors associated with tirofiban-induced thrombocytopenia.
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Meta Analysis
Extracorporeal carbon dioxide removal for patients with acute respiratory failure: a systematic review and meta-analysis.
Acute respiratory failure (ARF) is a common clinical critical syndrome with substantial mortality. Extracorporeal carbon dioxide removal (ECCO2R) has been proposed for the treatment of ARF. However, whether ECCO2R could provide a survival advantage for patients with ARF is still controversial. ⋯ Our findings from both RCTs and observational studies did not confirm a significant beneficial effect of ECCO2R therapy on mortality. A shorter length of ICU stay in the ECCO2R group was only obtained in observational studies, and ECCO2R was associated with a longer length of hospital stay. ECCO2R was associated with lower intubation rate and tracheotomy rate, and shorter mechanical ventilation days in ARF patients with COPD. And an improvement in pH, PaO2, respiratory rate and PaCO2 was observed in the ECCO2R group. However, outcomes largely relied on data from observational studies targeted patients with ARF secondary to COPD, thus further larger high-quality RCTs are desirable to strengthen the evidence on the efficacy and benefits of ECCO2R for patients with ARF.Key messagesECCO2R therapy did not confirm a significant beneficial effect on mortality.ECCO2R was associated with lower intubation and tracheotomy rate, and shorter mechanical ventilation days in patients with ARF secondary to COPD.An improvement in pH, PaO2, respiratory rate, and PaCO2 was observed in ECCO2R group in patients with COPD exacerbations.Evidence for the future application of ECCO2R therapy for patients with ARF. The protocol of this meta-analysis was registered on PROSPERO (CRD42022295174).
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Disturbed circadian rhythms have been a risk factor for type 2 diabetes mellitus (T2DM). Melatonin is the major chronobiotic hormone regulating both circadian rhythm and glucose homeostasis. The rs10830963 (G allele) of the melatonin receptor 1B (MTNR1B) gene has the strongest genetic associations with T2DM according to several genome-wide association studies. ⋯ The rs10830963 G risk allele is associated with delayed melatonin secretion onset in dim-light and prolonged duration of peak melatonin. This delayed melatonin secretion may help human ancestors adapt to famine or food shortages during long nights and early mornings and avoid nocturnal hypoglycemia but confers susceptibility to T2DM due to adequate energy intake in modern society. We provide new insight into the role of MTNR1B variants in T2DM via disturbed circadian rhythms from the perspective of the "thrifty gene" hypothesis; these data indicate a novel target for the prevention and treatment of susceptible populations with the thrifty genotype.
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Dry eye disease (DED) is a multifactorial disorder characterized by loss of tear film homeostasis with an estimated worldwide prevalence of 5% to 50%. In DED, dysfunction of the ocular structures that create and regulate the tear film components-including the lacrimal glands, meibomian glands, cornea, and conjunctiva-causes a qualitative and/or quantitative tear deficiency with resultant tear film instability and hyperosmolarity. This initiates a vicious cycle of ocular surface inflammation and damage that may ultimately impair the quality of life and vision of affected patients. ⋯ Key messagesSuccessful management of dry eye disease often requires the use of various pharmacologic and/or nonpharmacologic therapies, as well as environmental and lifestyle modifications, to mitigate the underlying etiologies and restore tear film homeostasis. Primary care clinicians play an essential role in dry eye disease management by establishing a diagnosis, educating patients about the disorder, and providing referrals to eye care specialists for initiation of specialized treatment and long-term follow-up. Primary care clinicians and clinical specialists should consider prescribing medications with fewer ocular surface effects whenever possible in patients at risk for or with existing dry eye disease.