[THE VALUE OF MUSCLE BIOPSY IN PATIENTS WITHOUT WEAKNESS, HIGH CREATINE KINASE OR MYOPATHY ON ELECTROMYOGRAPHY].

INTRODUCTION: Muscle biopsy is an important diagnostic procedure for the evaluation of neuromuscular disorders, commonly employed when patients present with muscle weakness, high creatine-kinase or electromyography which suggest myopathy. The diagnostic value of this procedure when these are normal is unclear. AIMS: To characterize the pathology in muscle biopsies of patients without clinical, laboratory or electromyographic suggestion for myopathy. METHODS: Retrospective chart and pathology review of consecutive patients who were evaluated by muscle biopsy at Sheba Medical Center. RESULTS: Of 109 patients, 12 (11%) had no indication for myopathy prior to biopsy. Pathology was identified in 2/3 of cases. Inflammation was detected in 5 cases (42%), with a perivascular infiltrate in four, and endomysial in one. A mild myopathy was present in 3/5 of these cases. Type-2 muscle fiber atrophy as the primary or only pathology was seen in 2 cases (17%) and mild neurogenic changes in one (8%). A history of systemic disease, additional laboratory tests or imaging suggestive for inflammation were predictive for inflammatory pathology in 4/5 of cases (P = 0.006). CONCLUSIONS: Perivascular inflammation without significant muscle fiber damage is common and meaningful in patients with inflammatory conditions in spite of normal evaluation for myopathy. DISCUSSION: Muscle disease is characterized by damage to muscle fibers, connective tissue or vessels. In the absence of fiber damage, muscle strength, creatine-kinase and electromyography may remain normal. These tests therefore do not rule-out perivascular inflammation and mild myopathy. Muscle biopsy is effective for the detection of inflammation in patients with inflammatory conditions in spite of normal strength creatine-kinase and electromyography.

Functional binding of PD1 ligands predicts response to anti-PD1 treatment in patients with cancer.

Accurate predictive biomarkers of response to immune checkpoint inhibitors (ICIs) are required for better stratifying patients with cancer to ICI treatments. Here, we present a new concept for a bioassay to predict the response to anti-PD1 therapies, which is based on measuring the binding functionality of PDL1 and PDL2 to their receptor, PD1. In detail, we developed a cell-based reporting system, called the immuno-checkpoint artificial reporter with overexpression of PD1 (IcAR-PD1) and evaluated the functionality of PDL1 and PDL2 binding in tumor cell lines, patient-derived xenografts, and fixed-tissue tumor samples obtained from patients with cancer. In a retrospective clinical study, we found that the functionality of PDL1 and PDL2 predicts response to anti-PD1 and that the functionality of PDL1 binding is a more effective predictor than PDL1 protein expression alone. Our findings suggest that assessing the functionality of ligand binding is superior to staining of protein expression for predicting response to ICIs.

Treatment of Diabetic Neuropathy with A Novel PAR1-Targeting Molecule.

Diabetic peripheral neuropathy (DPN) is a disabling common complication of diabetes mellitus (DM). Thrombin, a coagulation factor, is increased in DM and affects nerve function via its G-protein coupled protease activated receptor 1 (PAR1). METHODS: A novel PAR1 modulator (PARIN5) was designed based on the thrombin PAR1 recognition site. Coagulation, motor and sensory function and small fiber loss were evaluated by employing the murine streptozotocin diabetes model. RESULTS: PARIN5 showed a safe coagulation profile and showed no significant effect on weight or glucose levels. Diabetic mice spent shorter time on the rotarod (p <0.001), and had hypoalgesia (p <0.05), slow conduction velocity (p <0.0001) and reduced skin innervation (p <0.0001). Treatment with PARIN5 significantly improved rotarod performance (p <0.05), normalized hypoalgesia (p <0.05), attenuated slowing of nerve conduction velocity (p <0.05) and improved skin innervation (p <0.0001). CONCLUSION: PARIN5 is a novel pharmacological approach for prevention of DPN development, via PAR1 pathway modulation.