Clinical Outcomes of Upper Extremity Nerve Transfers in Neuralgic Amyotrophy.

SUMMARY: Neuralgic amyotrophy (NA) is a disease affecting peripheral nerves. Treatment has historically been conservative, as the natural course of the disease was thought to be self-limiting. Recent work has demonstrated that as many as two-thirds of people with NA have persistent pain, fatigue, or weakness. At the authors' center, supercharged end-to-side (SETS) nerve transfers are commonly performed in patients with NA to optimize motor recovery while allowing for native axonal regrowth. The authors describe the technique and clinical outcomes of patients with NA affecting the anterior interosseous nerve (AIN) who were treated with SETS nerve transfer from extensor carpi radialis brevis to AIN. Ten patients (90% male; mean age, 51.3 ± 9.7 years) underwent extensor carpi radialis brevis-to-AIN transfer at a mean period of 6.4 ± 1.4 months after onset of symptoms. Mean postoperative follow-up duration was 14.8 ± 3.2 months. Before surgery, all patients demonstrated clinically significant weakness in the flexor pollicis longus (FPL), flexor digitorum profundus muscle to the index finger (FDP2), or both. FPL strength improved from a median Medical Research Council (MRC) grade of 1.5 to 4 ( P = 0.011) and FDP2 strength improved from a median MRC grade of 1 to 5 ( P = 0.016). A postoperative MRC grade of 4 or greater was achieved in nine of 10 (90%) FPL and 10 of 10 (100%) FDP muscles. This is the first report of SETS nerve transfer for the treatment of NA. The outcomes of this work suggest that SETS nerve transfers may be an option to optimize motor outcomes in patients with NA. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover.

Chromosome instability (CIN), or progressive changes in chromosome numbers, is an enabling feature of many cancers; however, the mechanisms giving rise to CIN remain poorly understood. To expand our mechanistic understanding of the molecular determinants of CIN in humans, we employed a cross-species approach to identify 164 human candidates to screen. Using quantitative imaging microscopy (QuantIM), we show that silencing 148 genes resulted in significant changes in CIN-associated phenotypes in two distinct cellular contexts. Ten genes were prioritized for validation based on cancer patient datasets revealing frequent gene copy number losses and associations with worse patient outcomes. QuantIM determined silencing of each gene-induced CIN, identifying novel roles for each as chromosome stability genes. SKP1 was selected for in-depth analyses as it forms part of SCF (SKP1, CUL1, FBox) complex, an E3 ubiquitin ligase that targets proteins for proteolytic degradation. Remarkably, SKP1 silencing induced increases in replication stress, DNA double strand breaks and chromothriptic events that were ascribed to aberrant increases in Cyclin E1 levels arising from reduced SKP1 expression. Collectively, these data reveal a high degree of evolutionary conservation between human and budding yeast CIN genes and further identify aberrant mechanisms associated with increases in chromothriptic events.

Diminished Condensin Gene Expression Drives Chromosome Instability That May Contribute to Colorectal Cancer Pathogenesis.

Chromosome instability (CIN), or constantly evolving chromosome complements, is a form of genome instability implicated in the development and progression of many cancer types, however, the molecular determinants of CIN remain poorly understood. Condensin is a protein complex involved in chromosome compaction, and recent studies in model organisms show that aberrant compaction adversely impacts mitotic fidelity. To systematically assess the clinical and fundamental impacts that reduced condensin gene expression have in cancer, we first assessed gene copy number alterations of all eight condensin genes. Using patient derived datasets, we show that shallow/deep deletions occur frequently in 12 common cancer types. Furthermore, we show that reduced expression of each gene is associated with worse overall survival in colorectal cancer patients. To determine the overall impact that reduced condensin gene expression has on CIN, a comprehensive siRNA-based screen was performed in two karyotypically stable cell lines. Following gene silencing, quantitative imaging microscopy identified increases in CIN-associated phenotypes, including changes in nuclear areas, micronucleus formation, and chromosome numbers. Although silencing corresponded with increases in CIN phenotypes, the most pronounced phenotypes were observed following SMC2 and SMC4 silencing. Collectively, our clinical and fundamental findings suggest reduced condensin expression and function may be a significant, yet, underappreciated driver of colorectal cancer.