Explore the vast range of titles available.

Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID‐19 infection via proposed anti‐cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID‐19 infection. We validated the AI‐predicted biochemical inhibitory effects of baricitinib on human numb‐associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID‐19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS‐CoV‐2 viral load, inflammatory markers, and IL‐6 levels. Collectively, these data support further evaluation of the anti‐cytokine and anti‐viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID‐19 patients. Synopsis This study provides biochemical and cellular evidence confirming artificial intelligence (AI)‐predictions focused on anti‐cytokine signaling and potential anti‐viral effects for baricitinib, along with a case series, supporting its potential utility in hospitalized COVID‐19 patients. Baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor used to treat rheumatoid arthritis, was hypothesised using AI to be useful in COVID‐19. Baricitinib‐mediated inhibition of numb associated kinases utilized by SARS‐CoV‐2 for its propagation, led to reduced viral infectivity in primary liver spheroids. Baricitinib reduces levels of cytokines implicated in COVID‐19 and inhibits their signaling. In patients with bilateral COVID‐19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS‐CoV‐2 viral load, inflammatory markers, and IL‐6 levels. Graphical Abstract This study provides biochemical and cellular evidence confirming artificial intelligence (AI)‐predictions focused on anti‐cytokine signaling and potential anti‐viral effects for baricitinib, along with a case series, supporting its potential utility in hospitalized COVID‐19 patients.

Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.

During the current pandemic, the vast majority of COVID-19 patients experienced mild symptoms, but some had a potentially fatal aberrant hyperinflammatory immune reaction characterized by high levels of IL-6 and other cytokines. Modulation of this immune reaction has proven to be the only method of reducing mortality in severe and critical COVID-19. The anti-inflammatory drug baricitinib (Olumiant) has recently been strongly recommended by the WHO for use in COVID-19 patients because it reduces the risk of progressive disease and death. It is a Janus Kinase (JAK) 1/2 inhibitor approved for rheumatoid arthritis which was suggested in early 2020 as a treatment for COVID-19. In this review the AI-assisted identification of baricitinib, its antiviral and anti-inflammatory properties, and efficacy in clinical trials are discussed and compared with those of other immune modulators including glucocorticoids, IL-6 and IL-1 receptor blockers and other JAK inhibitors. Baricitinib inhibits both virus infection and cytokine signalling and is not only important for COVID-19 management but is “non-immunological”, and so should remain effective if new SARS-CoV-2 variants escape immune control. The repurposing of baricitinib is an example of how advanced artificial intelligence (AI) can quickly identify new drug candidates that have clinical benefit in previously unsuspected therapeutic areas.

Background Glioblastoma recurrence after treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. It has been demonstrated that anti-VEGF/VEGFR therapies control the invasive phenotype and that relapse occurs through the increased activity of CXCR4. We therefore hypothesized that combining bevacizumab or sunitinib with the novel CXCR4 antagonist, PRX177561, would have superior antitumor activity. Methods The effects of bevacizumab, sunitinib, and PRX177561 were tested alone or in combination in subcutaneous xenografts of U87MG, U251, and T98G cells as well as on intracranial xenografts of luciferase tagged U87MG cells injected in CD1-nu/nu mice. Animals were randomized to receive vehicle, bevacizumab (4 mg/kg iv every 4 days), sunitinib (40 mg/kg po qd), or PRX177561 (50 mg/kg po qd). Results The in vivo experiments demonstrated that bevacizumab and sunitinib increase the in vivo expression of CXCR4, SDF-1α, and TGFβ1. In addition, we demonstrate that the co-administration of the novel brain-penetrating CXCR4 antagonist, PRX177561, with bevacizumab or sunitinib inhibited tumor growth and reduced the inflammation. The combination of PRX177561 with bevacizumab resulted in a synergistic reduction of tumor growth with an increase of disease-free survival (DSF) and overall survival (OS), whereas the combination of PRX177561 with sunitinib showed a mild additive effect. Conclusions The CXC4 antagonist PRX177561 may be a valid therapeutic complement to anti-angiogenic therapy, particularly when used in combination with VEGF/VEGFR inhibitors. Therefore, this compound deserves to be considered for future clinical evaluation.

Glioblastoma is the most frequent and the most lethal primary brain tumor among adults. Standard of care is the association of radiotherapy with concomitant or adjuvant temozolomide. However, to date, recurrence is inevitable. The CXCL12/CXCR4 pathway is upregulated in the glioblastoma tumor microenvironment regulating tumor cell proliferation, local invasion, angiogenesis, and the efficacy of radio-chemotherapy. In this study, we evaluated the effects of the novel CXCR4 antagonist, PRX177561, in preclinical models of glioblastoma. CXCR4 expression and PRX177561 effects were assessed on a panel of 12 human glioblastoma cells lines and 5 patient-derived glioblastoma stem cell cultures. Next, the effect of PRX177561 was tested in vivo, using subcutaneous injection of U87MG, U251, and T98G cells as well as orthotopic intrabrain inoculation of luciferase-transfected U87MG cells. Here we found that PRX177561 impairs the proliferation of human glioblastoma cell lines, increases apoptosis, and reduces CXCR4 expression and cell migration in response to stromal cell–derived factor 1alpha in vitro. PRX177561 reduced the expression of stem cell markers and increased that of E-cadherin and glial fibrillary acidic protein in U87MG cells consistent with a reduction in cancer stem cells. In vivo, PRX177561 reduced the weight and increased the time to progression of glioblastoma subcutaneous tumors while increasing disease-free survival and overall survival of mice bearing orthotopic tumors. Our findings suggest that targeting stromal cell–derived factor 1 alpha/CXCR4 axis by PRX177561 might represent a novel therapeutic approach against glioblastoma and support further investigation of this compound in more complex preclinical settings in order to determine its therapeutic potential.

With escalating global regulatory pressure for countries to adhere to emission laws, repurposing existing natural gas pipelines for hydrogen-based commodities stands to be an economical solution. However, the effects of hydrogen embrittlement must be thoroughly considered for this application to avoid the unexpected catastrophic failure of these pipelines. The literature proposes several physicochemical embrittlement models. This paper reports one aspect of hydrogen embrittlement that remains to be quantified: the recovery of ductility (embrittlement) of mild steel specimens subjected to artificially accelerated hydrogen absorption via electrochemical charging as a function of time. The effects of charging duration and particularly the delay period between charging and mechanical tensile testing were investigated. Unsurprisingly, longer charging time shows a greater loss of elongation; however, a more extensive recovery of ductility correlated with longer charging time in the first few days after charging. The data also show that while the uncharged mild steel met all minimum required values for strength and elongation for the specified grade, there was a substantial variability in the elongation to failure. The same trends in variability of elongation translated to the hydrogen-charged specimens. Due to this extensive variability, failure to meet the elongation specification of the grade is reported based on the worst-case scenario obtained for a given set of samples for each exposure condition. These results have practical implications for the monitoring and testing of infrastructure exposed to hydrogen, particularly as this relates to industry planned operational shutdown schedules.

The voltage-sensitive sodium channel confers electrical excitability on neurons, a fundamental property required for higher processes including cognition. The ion-conducting α-subunit of the channel is regulated by two known auxiliary subunits, β1 and β2. We have identified rat and human forms of an additional subunit, β3. It is most closely related to β1 and is the product of a separate gene localized to human chromosome 11q23.3. When expressed in Xenopus oocytes, β3 inactivates sodium channel opening more slowly than β1 does. Structural modeling has identified an amino acid residue in the putative α-subunit binding site of β3 that may play a role in this difference. The expression of β3 within the central nervous system differs significantly from β1. Our results strongly suggest that β3 performs a distinct neurophysiological function.