Fluoroquinolone resistance in urinary tract infections: Epidemiology, mechanisms of action and management strategies.

Background: Fluoroquinolone resistance is an issue of concern amongst physicians worldwide. In urology, fluoroquinolones are often used in the treatment of acute pyelonephritis and prostatitis, as well as infections caused by multidrug-resistant pathogens. Aims: We aim to highlight the importance of antimicrobial stewardship and the need for ongoing biomedical research to discover novel agents in our losing battle against resistant pathogens. Materials and methods: In this review, we survey the literature and summarise fluoroquinolone resistance as it pertains to pyelonephritis and prostatitis, as well as alternative treatment strategies and prevention of multidrug resistance. Results: The rise of fluoroquinolone resistance in bacteria has reduced the available treatment options, often necessitating hospital admission for intravenous antibiotics, which places an additional burden on both patients and the healthcare system. Many countries such as Australia have attempted to limit fluoroquinolone resistance by imposing strict prescribing criteria, though these efforts have not been entirely successful. Solutions to overcome resistance include prevention, combination therapy and the development of novel antimicrobial agents. Conclusions: Prevention of the proliferation of resistant organisms by antimicrobial stewardship is paramount, and urologists are obliged to be aware of responsible prescribing practices such as referring to local guidelines when prescribing. By reserving fluoroquinolones for infections in which they are truly indicated and by prescribing based on both patient and local environmental factors, we can preserve this effective resource for future use.

New Approaches to Targeting Epigenetic Regulation in Bladder Cancer.

Epigenetics is a growing field and in bladder cancer, it is of particular interest in advanced or metastatic disease. As opposed to genetic mutations in which the nucleotide sequence itself is altered, epigenetic alterations refer to changes to the genome that do not involve nucleotides. This is of great interest in cancer research because epigenetic alterations are reversible, making them a promising target for pharmacological agents. While chemoimmunotherapy is the mainstay for metastatic disease, there are few alternatives for patients who have progressed on first- or second-line treatment. By targeting reversible epigenetic alterations, novel epigenetic therapies are important potential treatment options for these patients. A search of clinical registries was performed in order to identify and collate epigenetic therapies currently in human trials. A literature search was also performed to identify therapies that are currently in preclinical stages, whether this be in vivo or in vitro models. Twenty-five clinical trials were identified that investigated the use of epigenetic inhibitors in patients with bladder cancer, often in combination with another agent, such as platinum-based chemotherapy or pembrolizumab. The main classes of epigenetic inhibitors studied include DNA-methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, and histone methyltransferase (HMT) inhibitors. At present, no phase 3 clinical trials have been registered. Few trials have published results, though DNMT inhibitors have shown the most promise thus far. Many patients with advanced or metastatic bladder cancer have limited treatment options, particularly when first- or second-line chemoimmunotherapy fails. Epigenetic alterations, which are common in bladder cancer, are potential targets for drug therapies, and these epigenetic agents are already in use for many cancers. While they have shown promise in pre-clinical trials for bladder cancer, more research is needed to assess their benefit in clinical settings.

Long-term Health-related Quality of Life in Patients on Active Surveillance for Prostate Cancer: A Systematic Review.

CONTEXT: Active surveillance (AS) represents the preferred treatment option in patients with low-risk prostate cancer. Optimised patient selection has enabled more patients to be managed with AS for a longer time. Thus, there is growing interest in its effect on long-term quality of life compared with interventional management. OBJECTIVE: To perform a systematic review evaluating the long-term patient-reported outcomes regarding mental health, and sexual and urinary function in patients on AS. EVIDENCE ACQUISITION: We performed a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. We included series assessing validated patient-reported outcomes of health-related quality of life, and sexual and urinary function in AS patients followed up for at least 5 yr. EVIDENCE SYNTHESIS: Our search yielded 1854 citations, including 19 papers involving 3643 patients on AS, 14 651 patients receiving surgery or radiotherapy, and 2478 controls without prostate cancer. In ten studies, major differences were observed in sexual and urinary symptoms between groups, such as better sexual function and fewer irritative urinary symptoms in patients on AS, though overall functional outcomes were comparable. In all studies, health-related quality of life for patients on AS was better than, or similar to, that for patients who had undergone surgery or radiotherapy and comparable with that for individuals without cancer. CONCLUSIONS: We observed differences in specific functional outcomes between patients on AS and surgery or radiotherapy, ≥5 yr after treatment. Patients on AS reported good quality of life, similar to that in individuals without prostate cancer. AS should continue to be a recommended management strategy for appropriately selected patients. PATIENT SUMMARY: Active surveillance is an accepted pathway for patients with low-risk localised prostate cancer. Previous literature has shown that it did not negatively affect short-term quality of life. This review finds that long-term quality of life for these patients is similar to that for people without prostate cancer.

New approaches to targeting epigenetic regulation in prostate cancer.

PURPOSE OF REVIEW: Many clinical trials are currently underway to target the epigenome of castration-resistant prostate cancer. In this review, we summarize the major epigenetic alterations that occur during prostate cancer progression, describe their biological consequences, and highlight potential of therapies that target epigenetic regulators for use in patients. RECENT FINDINGS: Epigenetic alterations frequently occur in tumour suppressor genes, DNA repair genes, and genes that regulate cell proliferation and differentiation. Unlike genetic alterations, epigenetic changes are reversible, making them promising targets for cancer therapy. Epigenetic regulators can be divided into three broad groups: writers, readers, and erasers , each with specific drug targets that are being assessed in phase I and II clinical trials for prostate cancer. CBP/p300, and BRD4 are coregulators of the androgen receptor and inhibit androgen signalling, making bromodomain extra-terminal inhibitors and CBP/p300 inhibitors attractive targets in prostate cancer. Enhancer of zeste homolog 2, a histone methyltransferase, is also a potential target in castrate-resistant prostate cancer. An emerging direction is to combine epigenetic inhibitors with other compounds to enhance their efficacy. SUMMARY: Preclinical studies indicate that the epigenome is a potential target in prostate cancer, and clinical trials are testing multiple agents that target the epigenome in different ways. However, the process of translating these therapies into the clinic is ongoing and none have yet been approved for castrate-resistant prostate cancer.

Potential of Flavonoid-Inspired Phytomedicines against COVID-19.

Flavonoids are widely used as phytomedicines. Here, we report on flavonoid phytomedicines with potential for development into prophylactics or therapeutics against coronavirus disease 2019 (COVID-19). These flavonoid-based phytomedicines include: caflanone, Equivir, hesperetin, myricetin, and Linebacker. Our in silico studies show that these flavonoid-based molecules can bind with high affinity to the spike protein, helicase, and protease sites on the ACE2 receptor used by the severe acute respiratory syndrome coronavirus 2 to infect cells and cause COVID-19. Meanwhile, in vitro studies show potential of caflanone to inhibit virus entry factors including, ABL-2, cathepsin L, cytokines (IL-1ß, IL-6, IL-8, Mip-1α, TNF-α), and PI4Kiiiß as well as AXL-2, which facilitates mother-to-fetus transmission of coronavirus. The potential for the use of smart drug delivery technologies like nanoparticle drones loaded with these phytomedicines to overcome bioavailability limitations and improve therapeutic efficacy are discussed.

Effect of emulin on blood glucose in type 2 diabetics.

Emulin™ is a patented blend of chlorogenic acid, myricetin, and quercetin that has shown efficacy in reducing midday and post-oral glucose tolerance test (OGTT) area under the curve (AUC) glucose in streptozotocin-treated rats. The purpose of this study was to determine if similar effects would be evident in type 2 diabetic humans. Forty human subjects with confirmed type 2 diabetes (10 each in 4 groups: placebo/no medication, Emulin/no medication, placebo/metformin and Emulin/metformin) were evaluated. At the end of 1 week, fasting blood glucose, 2 h postprandial, actual peak glucose, and AUC (post-50 g OGTT) were determined. The placebo-only group had a large (5%-13%) increase in all parameters. The Emulin group and those on metformin performed similarly with reductions between 1% and 5%, with Emulin slightly outperforming the medication-alone group. The most significant reduction occurred in the Emulin/metformin group, with decreases in the parameters by up to 20%. These results suggest that Emulin, if consumed regularly, could not only have the acute effect of lowering the glycemic impact of foods, but chronically lower background blood glucose levels of type 2 diabetics.