Unmet needs in the treatment of rheumatoid arthritis. An observational study and a real-life experience from a single university center

Objectives

To estimate the size of unmet needs in the treatment of early Rheumatoid Arthritis (eRA), using all the conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or biological DMARDs (bDMARDs) in a long-term observational study.

A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers

Cancer cells subvert the natural balance between cellular life and death, achieving immortality through pathologic enforcement of survival pathways and blockade of cell death mechanisms. Pro-apoptotic BCL-2 family proteins are frequently disarmed in relapsed and refractory cancer through genetic deletion or interaction-based neutralization by overexpressed antiapoptotic proteins, resulting in resistance to chemotherapy and radiation treatments. New pharmacologic strategies are urgently needed to overcome these formidable apoptotic blockades. We harnessed the natural killing activity of BCL-2-interacting mediator of cell death (BIM), which contains one of the most potent BH3 death domains of the BCL-2 protein family, to restore BH3-dependent cell death in resistant hematologic cancers. A hydrocarbon-stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity, blocked inhibitory antiapoptotic interactions, directly triggered proapoptotic activity, and induced dose-responsive and BH3 sequence-specific cell death of hematologic cancer cells. The therapeutic potential of stapled BIM BH3 was highlighted by the selective activation of cell death in the aberrant lymphoid infiltrates of mice reconstituted with BIM-deficient bone marrow and in a human AML xenograft model. Thus, we found that broad and multimodal targeting of the BCL-2 family pathway can overcome pathologic barriers to cell death.     

Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor

Cancer regression by gene-modified T cells bearing a chimeric antigen receptor (CAR) exodomain of mouse origin can be limited by the induction of transgene immunogenicity resulting in poor persistence and function in vivo. The development of functionally-active CAR of human origin can address this issue. Here, we constructed and evaluated fully human anti-mesothelin CARs comprised of a human mesothelin-specific single-chain antibody variable fragment (P4 scFv) coupled to T cell signaling domains. Primary human T cells expressing P4 CAR specifically produced proinflammatory cytokines, degranulated and exerted potent cytolytic functions when cultured with mesothelin-expressing tumors in vitro. P4 CAR T cells also mediated bystander killing of mesothelin-negative cancer cells during coculture. CAR reactivity was not abrogated by soluble tumor-secreted or recombinant mesothelin protein even at supraphysiological levels. Importantly, adoptive transfer of P4 CAR-expressing T cells mediated the regression of large, established tumor in the presence of soluble mesothelin in a xenogenic model of human ovarian cancer. Thus, primary human T cells expressing fully human anti-mesothelin CAR efficiently kill mesothelin-expressing tumors in vitro and in vivo and have the potential to overcome the issue of transgene immunogenicity that may limit CAR T cell trials that utilize scFvs of mouse origin.     

Corneal collagen crosslinking for keratoconus or corneal ectasia without epithelial debridement

Purpose

Corneal collagen crosslinking (CXL) is a relatively new technique to reduce the progression of keratoconus. The technique can be performed with or without complete debridement of the corneal epithelium. We describe a novel intermediate technique involving mechanical disruption of the epithelium, and evaluate its safety and efficacy.

Methods

The case notes of 128 eyes with progressive keratoconus or iatrogenic corneal ectasia who had undergone CXL using the epithelial disruption technique were retrospectively reviewed. Thin corneas were treated with hypotonic riboflavin. All others were treated with an isotonic solution. Note was made of preoperative and postoperative parameters, including uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), refraction, endothelial cell count, and corneal tomography. Occurrence of procedure-related complications was recorded. Statistical analyses were performed using the paired sample t-test and Wilcoxon signed-rank test, with a level of P<0.05 being accepted as statistically significant.

Results

At 12 months, 41.8% of patients treated with isotonic riboflavin had improved UCVA and 29.7% had improved BSCVA. Only 13.4% lost lines of UCVA and 14.9% lost BSCVA. Of the patients treated with hypotonic riboflavin, at 12 months, 75% demonstrated stability of BSCVA and 25% had stable Kmax. In addition, 25% showed improved visual acuity at 12 months, and 58.3% showed regression of their Kmax. Our rate of short-term complications was comparable to studies using complete epithelial removal.

Conclusions

CXL with epithelial disruption is a safe and effective treatment for keratoconus or iatrogenic corneal ectasia, and may be better tolerated by patients than the epithelium-off technique.     

Novel Assessment (BlueDop) Device for Detection of Lower Limb Arterial Disease: A Prospective Comparative Study

According to National Institute of Clinical Excellence guidelines, the ankle‐brachial pressure index coupled with a full clinical evaluation has been the mainstay of detecting peripheral arterial disease on its suspicion. However, this technique is not free of its own limitations in calcified arteries, ulcerative and diabetic patients. We introduce a new, novel, and effective assessment device (BlueDop) with a minimal learning curve that could overcome such barriers and serve as a valid replacement in perihospital settings.