Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Role of Centrosomal P4.1 Associated Protein (CPAP) in Tumor Suppression

In eukaryotic cells, centrosomes are membrane-less organelles that function as the primary microtubules organizing center with a crucial role in cell division. For accurate bipolar spindle assembly and genetic transmission between generations, fidelity in centriolar duplication is critical. Disruption in this process can cause genomic instability, which could then lead to conditions like aneuploidy, a common feature of various cancers. Among the numerous proteins associated with mammalian centrioles, the centrosomal P4.1 associated protein (CPAP) stands out for its essential role in regulating centriole duplication. Dysfunctions in CPAP have been linked to abnormalities in centriole length that can contribute to conditions ranging from ciliopathies, immune dysfunction, and cancer. Recent discoveries in our lab have shed light on CPAP\u27s involvement in endocytic vesicular transport and are investigating its implications in cancer control. Specifically, defective CPAP function in oral cancer cell lines has been associated with constitutive signaling through the epidermal growth factor receptor, heightened epithelial-mesenchymal transition (EMT), and enhanced spontaneous tumorigenic properties, suggesting a potential role for CPAP as a tumor suppressor protein. Building on these findings, my research aimed to investigate the impact of CPAP dysfunction on tumorigenesis, by utilizing a hypomorphic mouse model. We evaluated the EMT features of both, primary and immortalized, lung as well as tongue-derived fibroblasts from these mice. In addition, we have also assessed the CPAP-deficient mice for their susceptibility towards spontaneous and induced tumors. Through my investigation, we seek to deepen our understanding of CPAP\u27s role as a tumor suppressor and its broader implications for cellular health

The criticality of sensemaking in climate change education:closing the gap between information gathering and curriculum making in schools

Children and young people in England increasingly question both the relevance and impact of climate change education (British Science Association and the University of Plymouth, 2023) and this is further compounded by teachers reporting that they largely rely on ‘self-taught’ methods of professional development (Greer et al., 2023). Insights, on the implementation of climate change education (CEE) in England, from these recent reports imply that untrustworthy information sources gathered concerning CCE, particularly during ‘self-taught’ professional development, could influence the quality of the content taught in the classroom. Understanding information sources through a lens of trustworthiness, therefore, is a critical component in the curriculum making process undertaken by teachers (Puttick & Talks, 2021).Curriculum making in CCE is crucial because it starts with considering the needs of children and young people first, involves teachers considering their own curriculum content and choosing resources carefully (Wallace & Priestley, 2016). The question of which resources and information sources are selected is in turn constrained by the sheer quantity of information sources available (Puttick & Talks, 2021). This, along with the lack of diversity in the sources selected, poses challenges for teachers in discerning what and how information on climate change should be incorporated into curriculum making (Puttick & Talks, 2021). Given the urgency of CCE (Greer et al., 2023), there is a need to consider how teachers in England process complex information on climate change, with a consideration of the potential misconceptions that could arise and how teachers can be better supported to develop their expertise about CCE. While Puttick and Talks (2021) emphasise the importance of focusing on information gathering, the practice of curriculum making requires teachers to analyse information and engage in a process of sensemaking so that CCE is both meaningful and relevant to the children and young people being taught

Microbial Metabolism of Nitriles and Its Biotechnological Potential

925-947Biocatalysts display a remarkable capability to function under normal temperature and pressure with high specificity and are potentially very economical. Bioconversion of nitrile compounds to a number of economically important compounds is described. A wide variety of microorganisms having the ability to metabolize different nitriles and discovered during the last two decades are described. It is pointed out that the microbial degradation of nitriles proceeds through two distinct enzymatic pathways: nitrilase catalyzes the direct hydrolysis of nitriles to the corresponding carboxylic acids and ammonia, while nitrile hydratase catalyzes the hydration of nitriles to  the corresponding amides, followed by their conversion to the corresponding carboxylic acids plus ammonia by amidase. It is mentioned that the versatile biocatalytic nature and applications of these enzymes are being increasingly recognised for the selective hydrolysis of various types of nitriles for the production of several fine chemicals, pharmaceuticals and optically active nitriles, amides and carboxylic acids, which are not generally feasible by chemical routes. A commercial process involving the multi-kiloton scale synthesis of acrylamide using Rhodococcus rhodochrous J 1 nitrile hydratase is described, which is the best example of a fully developed industrial application of this biotechnology. Though, recent developments broadened the potential application of these versatile biocatalysts in chemical synthesis and bioremediation, further studies are required to fully harness their biotechnological potential

Transforming growth factor <img src='/image/spc_char/beta.gif' border=0> 2: A predictive marker for breast cancer

879-887Dual role of TGF- signaling in breast tumorigenesis as an inhibitor in early stages and promoter in advanced stages has been well established and known as TGF- switch. However, the biological mechanisms needs to be explored. Aim of the present study was to look for the usefulness of TGF-2 as a predictive marker for breast cancer and to offer a better predictability to identify patients likely to benefit from antiTGF- strategies. Circulatory as well as transcript levels of TGF-2 were estimated from 118 pretherapeutic breast cancer patients using ELISA and q-PCR with ddCt method. Multifactorial analysis was performed to correlate the results to clinico-pathological prognosticators and Kaplan-Meier survival analysis with a median follow-up of 49 months was also evaluated. Circulating TGF-2 was similar in control and breast cancer patients. TGF-2 was significantly upregulated in advanced tumors compared to early tumors. An inverse correlation was observed between TGF-2 protein and mRNA; nevertheless both exhibited significant correlations with clinico-pathological prognosticators. Higher expression of TGF-2 mRNA was connected to an early relapse in advanced stage than early stage patients. It is the first report to evaluate circulatory and transcript levels exhibiting TGF- switch and confirming the utility of TGF-2 as an important predictive marker for breast cancer

Integrating mental health into climate change education to inspire climate action while safeguarding mental health

Climate change is the greatest threat humanity faces, and puts at risk the mental health and wellbeing of children and young people. Climate change education must equip children and young people with the knowledge, skills and resilience to live in an uncertain future, sustainably take relevant climate action and work in climate careers. As attention on climate change education grows, this is a critical moment for the mental health community to ensure mental health and wellbeing considerations are embedded. Critically, appropriate integration of mental health can enable these very necessary goals of equipping children and young people to live and work in a future where climate change looms large. This paper explores why promoting good mental health and wellbeing and building psychological resilience can help achieve climate change education outcomes, and why not doing so risks harming children and young people’s mental health. It also explores how integrating discussions about emotions, mental health, and coping strategies within climate change education can be a route into wider discussions about mental health, to support children and young people in the context of rising mental health needs. Learning from an existing approach to promoting good mental health and wellbeing in schools (the ‘whole school approach’) provides the opportunity to explore one avenue through which such an integrated approach could be implemented in practice. Identifying appropriate mechanisms to integrate mental health into climate change education will require co-design and research with educators and young people, and addressing systemic barriers facing the schools sector