The outbreak of Covid-19 worldwide has presented an unprecedented challenge for the equity-in-education agenda, especially in developing countries of the Global South (e.g., the English-speaking ...Caribbean). This article examines the impact school closures have had in Jamaica and Barbados, and highlights the emerging disparities the global pandemic has had on education. The central organizing questions are as follows: Who was affected by school closures in Barbados and Jamaica? How did the Ministries of Education (MOEs) support curriculum and instruction during the pandemic? What challenges does Covid-19 present for MOEs? What are the implications for education after Covid-19? School closure data suggest a gender disparity, with more males than females out of school due to Covid-19 from preprimary to secondary school in Barbados and Jamaica. MOEs in the region responded to school closures primarily by increasing access to technology to facilitate remote learning. Some of the challenges with continuing education for students during Covid-19 were due to a lack of infrastructure and amenities to support remote learning. Implications for education post-Covid-19 are considered.
Distant metastases are detrimental for cancer patients, but the increasingly early detection of tumors offers a chance for metastasis prevention. Importantly, cancers do not metastasize randomly: ...depending on the type of cancer, metastatic progenitor cells have a predilection for well-defined organs. This has been theorized by Stephen Paget, who proposed the “seed-and-soil hypothesis”, according to which metastatic colonization occurs only when the needs of a given metastatic progenitor cell (the seed) match with the resources provided by a given organ (the soil). Here, we propose to explore the seed-and-soil hypothesis in the context of cancer metabolism, thus hypothesizing that metastatic progenitor cells must be capable of detecting the availability of metabolic resources in order to home in a secondary organ. If true, it would imply the existence of metabolic sensors. Using human triple-negative MDA-MB-231 breast cancer cells and two independent brain-seeking variants as models, we report that cyclooxygenase 7b (Cox7b), a structural component of Complex IV of the mitochondrial electron transport chain, belongs to a probably larger family of proteins responsible for breast cancer brain tropism in mice. For metastasis prevention therapy, this proof-of-principle study opens a quest for the identification of therapeutically targetable metabolic sensors that drive cancer organotropism.
Essentials
AFSTYLA exhibits ≈50% underestimation in activity when the one‐stage (OS) assay is utilized.
A field study compared the performance of AFSTYLA with Advate in factor VIII activity assays.
...AFSTYLA activity can be monitored with both the chromogenic substrate and the OS assay.
The consistent OS underestimation allows for a conversion factor to be applied to OS results.
Summary
Introduction
AFSTYLA (antihemophilic factor recombinant single chain) is a novel B‐domain truncated recombinant factor VIII (rFVIII). For AFSTYLA, an approximate 50% discrepancy was observed between results of the one‐stage (OS) and chromogenic substrate (ChS) FVIII activity assays. An investigation was undertaken to test whether there is a linear relationship between ChS and OS assay results that would allow reliable clinical interpretation of results independent of the assay method used.
Aims
To provide confidence in future clinical monitoring, this field study investigated the performance of AFSTYLA and a full‐length rFVIII (Advate®) in FVIII activity assays routinely performed in clinical laboratories.
Methods
The comparison of AFSTYLA and Advate was performed in an international, multicenter and blinded field study of simulated post‐infusion samples. The study documented the extent of variability between methods and laboratories and characterized the relationship between the ChS and OS assays.
Results
Results from 23 laboratories demonstrate that intra and interlaboratory variability in OS assays were similar for both products. When comparing within the OS assay format, there was a similar and reagent‐correlated variability in response to different activators for both AFSTYLA and Advate. The OS underestimation was highly predictable and consistent across the complete range of FVIII plasma concentrations.
Conclusion
Post‐infusion plasma AFSTYLA levels can be monitored in patients by the OS and ChS assays. The consistent and predictable difference between the two assay formats provides clinicians with adequate guidance on how to interpret the results of the OS assay using a single conversion factor.
Essentials
rVIII‐SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains.
Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe ...hemophilia A.
Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00.
rVIII‐SingleChain showed excellent hemostatic efficacy and a favorable safety profile.
Summary
Background
rVIII‐SingleChain is a novel B‐domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor.
Objectives
This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII‐SingleChain in previously treated pediatric patients < 12 years of age with severe hemophilia A.
Patients/Methods
Patients could be assigned to prophylaxis or on‐demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on‐demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of ‘excellent’ or ‘good’ on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events.
Results
The study enrolled 84 patients (0 to < 6 years, n = 35; ≥ 6 to < 12 years, n = 49); 81 were assigned to prophylaxis and three to an on‐demand regimen. Patients accumulated a total of 5239 exposure days (EDs), with 65 participants reaching > 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor.
Conclusions
rVIII‐SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy and a favorable safety profile in a clinical study in children < 12 years of age with severe hemophilia A.
Background
rVIII‐SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B‐domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding ...affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full‐length rFVIII.
Aim
To investigate the pharmacokinetics of rVIII‐SingleChain and compare them against those of full‐length rFVIII.
Methods
This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4‐day washout period, all patients received a single infusion of 50 IU kg−1 octocog alfa (Advate®); after a ≥4‐day postinfusion washout period, they received a single infusion of 50 IU kg−1 rVIII‐SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products.
Results
rVIII‐SingleChain had a longer mean half‐life (t1/2) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h−1 kg−1), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUCinf (2090 vs. 1550 IU?h dL−1) than octocog alfa, respectively. The mean AUCinf after rVIII‐SingleChain infusion was ~35% larger than after octocog alfa. A similar pattern was observed for AUC0‐last. No serious adverse events or inhibitors were reported.
Conclusions
rVIII‐SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t1/2, larger AUC and reduced CL of rVIII‐SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment.
Purpose
Although ovarian tissue transportation has been validated for up to 24 h, there is no standard protocol to date. We aimed to elucidate how existing media currently used for ovarian tissue ...transportation affect ovarian tissue metabolism and cell viability.
Methods
Cow ovarian fragments were immersed in 0.9% NaCl solution, IVF medium, Leibovitz 15 medium (L-15), or PBS for 1, 4, or 24 h at 4 °C. Media were analyzed for pH, lactate dehydrogenase (LDH) activity, and glucose, pyruvate, and lactate concentrations, while apoptosis was assessed by TUNEL assays in fixed fragments. Viability rates were assessed by flow cytometry (FACS).
Results
There were lower pH levels in NaCl at all time points compared with other media. LDH activity increased with time and was lowest in NaCl at 1 and 4 h. There was no significant difference in glucose levels, but a significant pyruvate decrease in L-15 and a significant lactate increase in all media. TUNEL showed apoptosis rates ranging from 0 to 5%. FACS showed a mean of 4% necrotic cells and 15–19% apoptotic cells after 1 h of incubation, but less than 1% necrotic cells and 2–6% apoptotic cells after 24 h in all media.
Conclusion
Our results indicate marked metabolic activity in ovarian tissue at 4 °C and suggest that cells use internal sources of energy, which may influence transplantation outcomes. This highlights the importance of better understanding whole tissue dynamics to develop a standard protocol for ovarian tissue transportation.
Graphical abstract
Metastasis is of dismal prognosis for cancer patients, but recent evidence in mouse models of cancer shows that metastasis prevention is a reachable clinical objective. These experiments indicate ...that altered mitochondrial activities are associated with the metastatic phenotype. Mitochondrial transfer from metastatic to non-metastatic cells can indeed transfer the metastatic phenotype, and metastatic progenitor cells differ from other cancer cells by a higher sublethal production of mitochondrial reactive oxygen species (ROS). Moreover, mitochondria-targeted antioxidants can prevent metastatic dissemination in mouse models of cancer. Comparatively, general antioxidants have unpredictable effects on cancer metastasis, most probably because they affect several cell types, several subcellular ROS production sites and, often, several endogenous oxidant species. Thus, targeting antioxidants to mitochondria could improve their antimetastatic activities, as previously exemplified with mitochondria-targeted mitoTEMPO and mitoQ that can prevent metastatic dissemination in cancer-bearing mice. Our objective in this study was to identify whether catechins, which are known to be potent antioxidants, can inhibit cancer cell migration
and metastatic take
. Comparative analysis of the response to epigallocatechin-3-gallate, (+)-catechin and (+)-catechin:lysine complexes revealed that, whereas all compounds had similar general antioxidant properties, (+)-catechin:lysine 1:2, but not epigallocatechin-3-gallate, can prevent metastatic take of melanoma cells to the lungs of mice. (+)-Catechin:lysine 1:2 possesses two net positive charges provided by lysines at physiological pH, which could provide high affinity for the negatively charged mitochondrial matrix. While this study reveals that (+)-catechin:lysine 1:2 has interesting antimetastatic effects, future experiments are needed to formally demonstrate the stability of the complex, its effective tropism for mitochondria and whether or not its activity can be globally attributed to its antioxidant activity at this precise subcellular location.
Anthracyclines Doxorubicin, Epirubicin, Daunorubicin and Idarubicin are used to treat a variety of tumor types in the clinics, either alone or, most often, in combination therapies. While their ...cardiotoxicity is well known, the emergence of chemoresistance is also a major issue accounting for treatment discontinuation. Resistance to anthracyclines is associated to the acquisition of multidrug resistance conferred by overexpression of permeability glycoprotein-1 or other efflux pumps, by altered DNA repair, changes in topoisomerase II activity, cancer stemness and metabolic adaptations. This review further details the metabolic aspects of resistance to anthracyclines, emphasizing the contributions of glycolysis, the pentose phosphate pathway and nucleotide biosynthesis, glutathione, lipid metabolism and autophagy to the chemoresistant phenotype.
Surveillance of circulating microbial populations is critical for monitoring the performance of a molecular diagnostic test. In this study, we characterized 31 isolates of
(group B
GBS) from several ...geographic locations in the United States and Ireland that contain deletions in or adjacent to the region of the chromosome that encodes the hemolysin gene
, the region targeted by the Xpert GBS and GBS LB assays. PCR-negative, culture-positive isolates were recognized during verification studies of the Xpert GBS assay in 12 laboratories between 2012 and 2018. Whole-genome sequencing of 15 GBS isolates from 11 laboratories revealed four unique deletions of chromosomal DNA ranging from 181 bp to 49 kb. Prospective surveillance studies demonstrated that the prevalence of GBS isolates containing deletions in the convenience sample was <1% in three geographic locations but 7% in a fourth location. Among the 15 isolates with chromosomal deletions, multiple pulsed-field gel electrophoresis types were identified, one of which appears to be broadly dispersed across the United States.
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