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PurposeNALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.MethodsPatients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).ResultsA total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups.ConclusionN+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Silver nanoparticles (AgNPs) have increasingly gained attention owing to their distinctive physicochemical and biological properties. The objective of the investigation was to biologically synthesize AgNPs using plant extracts from Barleria albostellata. The synthesized AgNPs, obtained from B. albostellata (leaves and stems), were characterized through various techniques including UV-visible spectroscopy, scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), energy-dispersive X-ray analysis, Fourier transform infrared (FTIR) spectral analysis, and nanoparticle tracking analysis (NTA). The antibacterial efficacy of the synthesized AgNPs was evaluated utilizing the disk diffusion method. The cytotoxicity effects of the synthesized AgNPs were determined using the MTT assay (3-[(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide]) in cervical cancer (HeLa), embryonic kidney (HEK293), and breast adenocarcinoma (MCF-7) cell lines. The results indicate that B. albostellata extracts could serve as eco-friendly biofactories for the synthesis of AgNPs. UV-vis spectroscopy of the leaf and stem extracts revealed absorption peaks within the range of 400–450 nm, thereby confirming the synthesis of AgNPs. Elemental Ag was highest in the methanol leaf extracts (16.87 ± 0.89%) and lowest in the powdered stem extracts (7.13 ± 1.44%). Synthesized AgNPs were predominantly spherical in shape. HRTEM revealed that synthesized AgNPs from the methanolic stem extracts (34.32 ± 16.99 nm) were larger in size, while those from the powdered stem extracts were smaller (16.57 ± 5.55 nm). AgNPs synthesized from both the leaf and stem extracts exhibited zeta potential values between −8.8 and −32.1 mV, with hydrodynamics diameters ranging from 34.3 to 111.3 nm. FTIR spectroscopy confirmed the presence of various functional groups on the AgNPs. AgNPs synthesized from the leaf and stem extracts displayed significant antibacterial activity and were sensitive to Gram-negative and Gram-positive bacteria. AgNPs exhibited significant antibacterial activity (diameter of the zone of inhibition) against Pseudomonas aeruginosa (21.67 ± 2.87 mm) in the leaf methanolic extract. Synthesized AgNPs exhibited selective in vitro cytotoxicity against HEK293, HeLa, and MCF-7 cell lines. The IC50 values of the AgNPs synthesized from the various extracts were all above 9 µg/mL. Significant cytotoxic levels (IC50 16.11 and 27.23 µg/mL) were observed for the MCF-7 cell line upon exposure to the methanolic leaf and stem AgNPs. This study recommends the use of medicinal plant extracts in producing economically effective AgNPs, due to their efficient capping. Overall, AgNPs synthesized from B. albostellata extracts comprised novel antibacterial and anticancer agents, and warrant further investigation. Bio-synthesized AgNPs show great potential in the area of nanotechnology and may be used as an affordable, eco-friendly alternative for the delivery of conventional therapeutics. [ABSTRACT FROM AUTHOR]

In this narrative review, we assess the pathophysiology of severe adverse events that presented after vaccination with DNA and mRNA vaccines against COVID‐19. The focus is on the perspective of an undersulfated and degraded glycocalyx, considering its impact on immunomodulation, inflammatory responses, coagulation and oxidative stress. The paper explores various factors that lead to glutathione and inorganic sulfate depletion and their subsequent effect on glycocalyx sulfation and other metabolites, including hormones. Components of COVID‐19 vaccines, such as DNA and mRNA material, spike protein antigen and lipid nanoparticles, are involved in possible cytotoxic effects. The common thread connecting these adverse events is endotheliopathy or glycocalyx degradation, caused by depleted glutathione and inorganic sulfate levels, shear stress from circulating nanoparticles, aggregation and formation of protein coronas; leading to imbalanced immune responses and chronic release of pro‐inflammatory cytokines, ultimately resulting in oxidative stress and systemic inflammatory response syndrome. By understanding the underlying pathophysiology of severe adverse events, better treatment options can be explored. [ABSTRACT FROM AUTHOR]

The airway epithelial glycocalyx plays an important role in preventing severe acute respiratory syndrome coronavirus 2 entry into the epithelial cells, while the endothelial glycocalyx contributes to vascular permeability and tone, as well as modulating immune, inflammatory, and coagulation responses. With ample evidence in the scientific literature that coronavirus disease 2019 (COVID-19) is related to epithelial and endothelial dysfunction, preserving the glycocalyx should be the main focus of any COVID-19 treatment protocol. The most studied functional unit of the glycocalyx is the glycosaminoglycan heparan sulfate, where the degree and position of the sulfate groups determine the biological activity. N-acetylcysteine (NAC) and other sulfur donors contribute to the inorganic sulfate pool, the rate-limiting molecule in sulfation. NAC is not only a precursor to glutathione but also converts to hydrogen sulfide, inorganic sulfate, taurine, Coenzyme A, and albumin. By optimising inorganic sulfate availability, and therefore sulfation, it is proposed that COVID-19 can be prevented or at least most of the symptoms attenuated. A comprehensive COVID-19 treatment protocol is needed to preserve the glycocalyx in both the prevention and treatment of COVID-19. The use of NAC at a dosage of 600 mg bid for the prevention of COVID-19 is proposed, but a higher dosage of NAC (1200 mg bid) should be administered upon the first onset of symptoms. In the severe to critically ill, it is advised that IV NAC should be administered immediately upon hospital admission, and in the late stage of the disease, IV sodium thiosulfate should be considered. Doxycycline as a protease inhibitor will prevent shedding and further degradation of the glycocalyx.

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The use of rivers for recreational and domestic practices makes it imperative to scrutinize the water quality circulating within surrounding communities. The complexity of biological, physical and chemical constituents in water is constantly evolving. This study evaluated various microbial and physico-chemical parameters in a polluted river system over a 12-month period. Apart from an increase in chemical pollutants, elevated levels of E. coli, total (TC) and faecal (FC) coliforms, and Shigella species could be attributed to faecal contamination entering the catchment. Canonical correspondence analysis revealed a strong relationship between FC, TC and temperature whereas moderate interactions was seen between total dissolved solids, electrical conductivity, TC and FC populations. Furthermore, close relationships between the bacterial and phage communities were also observed. The complex interactions of these physico-chemical and microbial indicators could be due to anthropogenic activities, changing climatic conditions and the excreta of infected and non-infected individuals entering the river. Assessing the complexity of aquatic ecosystems can aid in the development of novel, customizable, inexpensive water purification tools.

Aim: The OPTIM1SE study observed long‐term real‐world outcomes of cetuximab‐based infusional 5‐fluorouracil (5‐FU) regimens for first‐line treatment of metastatic colorectal cancer (mCRC) across Asia‐Pacific and Middle East regions, aiming to characterize their use, effectiveness, and safety in routine practice. Methods: OPTIM1SE was a prospective, open‐label, observational study. Patients with untreated KRAS wild‐type mCRC and distant metastases were treated per locally approved labels and monitored for 3 years via electronic medical records. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression‐free survival (PFS), and overall survival (OS). Results: From November 19, 2013, to June 30, 2016, 520 patients were enrolled in 51 sites. Patients were mostly male (61.2%), with a mean age of 58.5 (±12.0) years; 420 patients received leucovorin, 5‐FU, and irinotecan–based regimens and 94 received leucovorin, 5‐FU, and oxaliplatin. The most common primary tumor site was the rectum (38.8%), with liver metastases (65.0%). ORR was 45.4% (95% CI, 41.1%–49.7%), including 26 patients (5.0%) with a complete response. Median PFS was 9.9 months (95% CI, 8.2–11.0); median OS (mOS) was 30.8 months (95% CI, 27.9–33.6). Higher mOS was associated with tumors of left compared with right‐sided origin (hazard ratio, 0.69 [95% CI, 0.49–0.99]); higher ORR was also associated with liver metastases compared with all other metastases (55.4% vs. 40.2%). Adverse events were consistent with the known safety profile of cetuximab. Conclusion: Cetuximab‐based 5‐FU regimens were effective first‐line treatments for mCRC in routine practice, particularly in patients with left‐sided disease and liver metastases only. [ABSTRACT FROM AUTHOR]