A chronic infection with Shigella flexneri 2a has been established in mice for the evaluation of compounds for therapeutic potential. Evidence of infection is indicated by prolonged symptomless excretion in the feces and by positive isolation of organisms from different segments of the intestinal tract and from mesenteric lymph nodes. Serum antibody titer reaches a maximum after 9 days of infection and remains at a low level until 32 days postinfection. In this model, five drugs used in human shigellosis were evaluated for efficacy. Ampicillin was found to be the most active followed by oxytetracycline and kanamycin. Neomycin and colistin were the least active in this system.

Melatonin is a pineal hormone, secreted at the subjective night. It is involved in the regulation of many physiological functions, including the sleep-wake cycle, gonadal activity, free radical scavenging, immunomodulation, neuro-protection, and cancer progression. Melatonin acts through cell surface receptors (MT1 and MT2) as well as nuclear receptors. Circadian dysfunction can alter the secretion of melatonin. Inappropriate melatonin level promotes the initiation of many pathologies including cancer. Ovarian cancer is a common form of gynecological disease. Several studies indicate the profound link between impaired melatonin secretion and the progression of ovarian cancer. Melatonin exerts oncostatic effects in multiple ways; it acts as a potent antioxidant, induces apoptosis, and regulates metabolism, and chronic inflammatory response in ovarian cancer cells. Moreover, melatonin improves the efficacy of the current treatment regimen of ovarian cancer and can be used as an adjuvant.

Melatonin is the primary hormone of the pineal gland that is secreted at night. It regulates many physiological functions, including the sleep-wake cycle, gonadal activity, free radical scavenging, immunomodulation, neuro-protection, and cancer progression. The precise functions of melatonin are mediated by guanosine triphosphate (GTP)-binding protein (G-protein) coupled melatonin receptor 1 (MT1) and MT2 receptors. However, nuclear receptors are also associated with melatonin activity. Circadian rhythm disruption, shift work, and light exposure at night hamper melatonin production. Impaired melatonin level promotes various pathophysiological changes, including cancer. In our modern society, breast cancer is a serious problem throughout the world. Several studies have been indicated the link between low levels of melatonin and breast cancer development. Melatonin has oncostatic properties in breast cancer cells. This indolamine advances apoptosis, which arrests the cell cycle and regulates metabolic activity. Moreover, melatonin increases the treatment efficacy of cancer and can be used as an adjuvant with chemotherapeutic agents.

Objectives: KEYNOTE-426 demonstrated statistically and clinically meaningful improvements in overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) in ccmRCC subjects treated with P+A versus (vs) sunitinib. This NMA synthesized RCT evidence to indirectly compare the relative treatment effects of P+A vs other therapies. Methods: A systematic literature review identified RCTs of approved or investigational 1L treatments of mRCC. Fixed-effect Bayesian NMA was conducted to determine the relative efficacy of treatments; OS, PFS [hazard ratios (HRs)] and ORR (odds ratio [OR]) were presented with 95% credible intervals (CrIs). Results: 18 RCTs (total ITT population: 10,547) that evaluated 17 interventions were identified (10 evaluable for OS, 14 for PFS, 13 for ORR). P+A showed statistically significant OS benefit over 7 out of 9 interventions evaluated [ranging from interferon-alpha (IFN-a) (HR=0.43, 0.29-0.64) through bevacizumab (B) + IFN-a, B + temsirolimus (B+T), sunitinib, placebo, pazopanib to atezolizumab + bevacizumab (A+B) [HR=0.65, 0.43-0.99]. OS benefit favored P+A vs avelumab + axitinib (A+A) [HR=0.68, 0.43-1.09] and vs nivolumab + ipilimumab (N+I) [HR=0.75, 0.51-1.09], but was not statistically significant. P+A showed statistically significant PFS benefit over 11 out of 13 interventions evaluated [ranging from placebo (HR=0.26, 0.16-0.42) through sorafenib, IFN-a, axitinib, tivozanib, B+T, B+ IFN-a, pazopanib, atezolizumab, sunitinib to A+B (HR=0.77, 0.60-0.99)]; PFS benefit favored P+A over N+I [HR=0.81, 0.64-1.03] but was not statistically significant, and P+A showed no difference compared to A+A [HR=1.00, 0.76-1.32]. P+A showed statistically significant ORR benefit over 11 out of 12 interventions evaluated [ranging from placebo (OR=25.22, 7.93-110.97) , sorafenib, IFN-a, axitinib, B+T, B+ IFN-a, atezolizumab, A+B, sunitinib, pazopanib to N+I (OR=1.95, 1.35-2.82)]; results favored A+A over P+A [OR=0.86, 0.58-1.27], but were not statistically significant. Conclusions: These analyses suggest that P+A provides significant OS, PFS and ORR benefits when indirectly compared to majority of 1L ccmRCC treatments.

A chronic infection with Shigella flexneri 2a has been established in mice for the evaluation of compounds for therapeutic potential. Evidence of infection is indicated by prolonged symptomless excretion in the feces and by positive isolation of organisms from different segments of the intestinal tract and from mesenteric lymph nodes. Serum antibody titer reaches a maximum after 9 days of infection and remains at a low level until 32 days postinfection. In this model, five drugs used in human shigellosis were evaluated for efficacy. Ampicillin was found to be the most active followed by oxytetracycline and kanamycin. Neomycin and colistin were the least active in this system.