A phase 2 trial of hydroxychloroquine in individuals at risk for rheumatoid arthritis.

Background: Individuals with serum elevations of anti-cyclic citrullinated peptide (anti-CCP) antibodies are at increased risk for future rheumatoid arthritis (RA). No pharmacologic interventions have been approved for the prevention of RA in such 'at-risk' individuals. However, hydroxychloroquine (HCQ) is used without supporting clinical trial evidence.

Revealing polymerisation defects and formation mechanisms in aldol condensation for conjugated polymers via high-resolution molecular imaging.

Aldol condensation is a crucial synthetic reaction in organic chemistry, particularly valued for fabricating conjugated polymers without the use of metals or toxic organostannanes. However, due to the lack of reliable and precise analytical methods, no direct evidence of the microstructure and sequence of synthesised polymers has been obtained, limiting control over their structure and performance. Here, by combining electrospray deposition and scanning tunnelling microscopy (ESD-STM), we analyse sub-monomer resolution images of four different n-type polymers produced via aldol condensation, revealing unexpected defects in both the sequence of (co)monomers and their coupling.

Differences in Dynamics of Specific Antinuclear Antibodies and Their Susceptibility to B Cell-Targeting Treatment in Patients With Systemic Lupus Erythematosus.

Objective: The presence of antinuclear antibodies (ANAs) is characteristic for systemic lupus erythematosus (SLE). Antibody dynamics over time are thought to reflect the cellular source of ANAs and their therapeutic targetability. Anti-double-stranded DNA (anti-dsDNA) is the most prevalent and well-studied of all ANAs, and fluctuations in anti-dsDNA serum levels are associated with disease activity.

Soluble CD13 is a potential mediator of neutrophil-induced thrombogenic inflammation in SARS-CoV-2 infection.

The soluble variant of the ectopeptidase CD13 (sCD13), released from the cell surface by matrix metalloproteinase 14 (MMP14), is a potent pro-inflammatory mediator, displaying chemotactic, angiogenic, and arthritogenic properties through bradykinin receptor B1 (B1R). We revealed a link between sCD13 and amplified neutrophil-mediated inflammatory responses in SARS-CoV-2 infection. sCD13 was markedly elevated in patients with COVID-19 and correlated with disease severity and variants, ethnicity, inflammation markers, and neutrophil extracellular trap formation (NETosis).

Pharmacist-led sulfonylurea deprescribing in older adults.

Background: Sulfonylureas are a high-risk medication in the elderly due to risk of hypoglycemia. Given the continued use of these low-cost medications in elderly patients over recent decades and guideline recommendations for individualized glycosylated hemoglobin (A1c) goals in the elderly, opportunities exist to reduce use in patients with well-controlled diabetes. Hypoglycemia is a costly and potentially deadly adverse effect of inappropriate treatment with sulfonylureas in older adults.

CD6 in Human Disease.

CD6 is a cell surface protein expressed by T cells, a subset of NK cells, a small population of B cells, and thymocytes. CD6 has multiple and complex functions due to its distinct functional epitopes that mediate interactions with several ligands including CD166 (ALCAM) and CD318 (CDCP1). An additional molecule, CD44, is being investigated as a potential new ligand of CD6.

Outcomes of Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated With R-GemOx: A Multicenter Cohort Study.

Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is a commonly used chemoimmunotherapy regimen for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but there are limited real-world data. In a multicenter retrospective study from a cohort of eight US academic centers (LEO CReWE), we evaluated 183 patients with R/R DLBCL and high-grade B cell lymphoma treated with R-GemOx, including subgroups treated without intent for consolidation with autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T cell therapy (n = 100), those utilizing R-GemOx as a bridge to ASCT or CAR T (n = 83), and those aged 70 and older (n = 71). Overall response rates (ORRs) for all patients treated with R-GemOx were 45% with a complete response (CR) rate of 29%.

Ligands of CD6: roles in the pathogenesis and treatment of cancer.

Cluster of Differentiation 6 (CD6), an established marker of T cells, has multiple and complex functions in regulation of T cell activation and proliferation, and in adhesion of T cells to antigen-presenting cells and epithelial cells in various organs and tissues. Early studies on CD6 demonstrated its role in mediating cell-cell interactions through its first ligand to be identified, CD166/ALCAM. The observation of CD6-dependent functions of T cells that could not be explained by interactions with CD166/ALCAM led to discovery of a second ligand, CD318/CDCP1.

Pathways for non-manufacturers to drive generic drug repurposing for cancer in the U.S.

Repurposing generic drugs as new treatments for life-threatening diseases such as cancer is an exciting yet largely overlooked opportunity due to a lack of market-driven incentives. Nonprofit organizations and other non-manufacturers have been ramping up efforts to repurpose widely available generic drugs and rapidly expand affordable treatment options for patients. However, these non-manufacturers find it difficult to obtain regulatory approval in the U.

Stakeholder perspectives on the sustainability of the United States biosimilars market.

Biologic therapies play a critical role in modern medical practice but also present challenges for payers, patients, and other stakeholders because of their high cost. Biosimilars can mitigate the cost pressures of reference biologic therapy because they are typically priced at least 25% lower, providing a means to administer cutting-edge biologic therapy while also managing cost of care. In fact, the US health care system has saved an estimated $23.

Real-world total cost of care by line of therapy in relapsed/refractory diffuse large B-cell lymphoma.

Aims: There are multiple recently approved treatments and a lack of clear standard-of-care therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). While total cost of care (TCC) by the number of lines of therapy (LoTs) has been evaluated, more recent cost estimates using real-world data are needed. This analysis assessed real-world TCC of R/R DLBCL therapies by LoT using the IQVIA PharMetrics Plus database (1 January 2015-31 December 2021), in US patients aged ≥18 years treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or an R-CHOP-like regimen as first-line therapy.

Siponimod Attenuates Neuronal Cell Death Triggered by Neuroinflammation via NFκB and Mitochondrial Pathways.

Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS), consisting of heterogeneous clinical courses varying from relapsing-remitting MS (RRMS), in which disability is linked to bouts of inflammation, to progressive disease such as primary progressive MS (PPMS) and secondary progressive MS (SPMS), in which neurological disability is thought to be linked to neurodegeneration. As a result, successful therapeutics for progressive MS likely need to have both anti-inflammatory and direct neuroprotective properties. The modulation of sphingosine-1-phosphate (S1P) receptors has been implicated in neuroprotection in preclinical animal models.

Activation of cytotoxic lymphocytes through CD6 enhances killing of cancer cells.

Immune checkpoint inhibitors (ICIs) have demonstrated efficacy and improved survival in a growing number of cancers. Despite their success, ICIs are associated with immune-related adverse events that can interfere with their use. Therefore, safer approaches are needed.

Challenges and promise of targeting miRNA in rheumatic diseases: a computational approach to identify miRNA association with cell types, cytokines, and disease mechanisms.

MicroRNAs (miRNAs) are small non-coding RNAs that alter the expression of target genes at the post-transcriptional level, influencing diverse outcomes in metabolism, cell differentiation, proliferation, cell survival, and cell death. Dysregulated miRNA expression is implicated in various rheumatic conditions, including ankylosing spondylitis (AS), gout, juvenile idiopathic arthritis (JIA), osteoarthritis (OA), psoriatic arthritis, rheumatoid arthritis (RA), Sjogren's syndrome, systemic lupus erythematosus (SLE) and systemic sclerosis. For this review, we used an open-source programming language- PowerShell, to scan the massive number of existing primary research publications on PubMed on miRNAs in these nine diseases to identify and count unique co-occurrences of individual miRNAs and the disease name.

New molecular targets in the treatment of rheumatoid arthritis.

Purpose Of Review: This review will discuss selected emerging molecular targets and associated potential therapeutic agents for rheumatoid arthritis (RA)-directed treatment.

Recent Findings: Agents in active development for RA treatment include those targeted to CD40 and CD40 ligand, programmed death protein 1 (PD-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Several other molecules with a strong theoretical role in RA pathogenesis and/or demonstrated efficacy in other autoimmune diseases are also being evaluated as potential drug targets in preclinical or translational studies in RA.

Skin barrier function for regulatory skin absorption tests and effects on testosterone and sucrose absorption.

In vitro absorption through human skin is a critical component in the safety assessment of chemicals, crop protection products, consumer healthcare products and cosmetics. A barrier integrity assay is used to identify skin samples which are potentially damaged. A retrospective analysis of 9978 electrical resistance (ER) measurements generated in a single laboratory (DTL) over a 15-year period was performed.

Herbal compound cepharanthine attenuates inflammatory arthritis by blocking macrophage M1 polarization.

Objective: Cepharanthine (CEP) is a drug candidate for tumor, viral infection, and some inflammatory diseases, but its effect on rheumatoid arthritis (RA) and the underlying mechanism are incompletely understood.

Methods: CEP was administered intraperitoneally to a collagen-induced arthritis (CIA) model. Joints went radiological and histological examination and serum cytokines were examined with cytometry-based analysis.

A CD6-targeted antibody-drug conjugate as a potential therapy for T cell-mediated disorders.

The selective targeting of pathogenic T cells is a holy grail in the development of new therapeutics for T cell-mediated disorders, including many autoimmune diseases and graft versus host disease. We describe the development of a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating an inactive form of monomethyl auristatin E (MMAE), a potent mitotic toxin, onto a mAb against CD6, an established T cell surface marker. Even though CD6 is present on all T cells, only the activated (pathogenic) T cells vigorously divide and thus are susceptible to the antimitotic MMAE-mediated killing via the CD6-ADC.

Activation of Cytotoxic Lymphocytes Through CD6 Enhances Killing of Cancer Cells.

Immune checkpoint inhibitors (ICIs) have demonstrated efficacy and improved survival in a growing number of cancers. Despite their success, ICIs are associated with immune-related adverse events that can interfere with their use. Therefore, safer approaches are needed.