Targeting 14-3-3ε activates apoptotic signaling to prevent cutaneous squamous cell carcinoma.

More than a million cases of cutaneous squamous cell carcinoma are diagnosed in the USA each year, and its incidence is increasing. Most of these malignancies arise from premalignant lesions, providing an opportunity for intervention before malignant progression. We previously documented how cytoplasmic mislocalization of CDC25A in premalignant and malignant skin cancers confers resistance to apoptotic cell death via a mechanism that depends on its interaction with 14-3-3ε. From these data, we hypothesized that 14-3-3ε overexpression drives skin tumor development and progression, such that targeting 14-3-3ε may be a useful strategy for skin cancer treatment. Like CDC25A, 14-3-3ε was overexpressed and mislocalized to the cytoplasm of both benign and malignant human skin cancer. Skin-targeted deletion of the 14-3-3ε gene reduced skin tumor development by 75% and blocked malignant progression. 14-3-3ε suppressed apoptosis through activation of Akt, leading to inhibition of BCL2 associated agonist of cell death and upregulation of Survivin. Using virtual tetrapeptide libraries, we developed a novel peptide that specifically blocked 14-3-3ε heterodimerization and thereby prevented its interaction with CDC25A. The peptide reduced prosurvival signaling, killed skin cancer cells and reduced skin tumor growth in xenograft. Normal skin keratinocytes were unaffected by inhibition or deletion of 14-3-3ε. Thus, targeting of 14-3-3ε dimerization is a promising strategy for the treatment of premalignant skin lesions.

Direct targeting of the ventral intermediate nucleus of the thalamus in deep brain stimulation for essential tremor: a prospective study with comparison to a historical cohort.

OBJECTIVE: The ventral intermediate nucleus of the thalamus (VIM) is an effective target for deep brain stimulation (DBS) to control symptoms related to essential tremor. The VIM is typically targeted using indirect methods, although studies have reported visualization of the VIM on proton density-weighted MRI. This study compares the outcomes between patients who underwent VIM DBS with direct and indirect targeting. METHODS: Between August 2013 and December 2019, 230 patients underwent VIM DBS at the senior author's institution. Of these patients, 92 had direct targeting (direct visualization on proton density 3-T MRI). The remaining 138 patients had indirect targeting (relative to the third ventricle and anterior commissure-posterior commissure line). RESULTS: Coordinates of electrodes placed with direct targeting were significantly more lateral (p < 0.001) and anterior (p < 0.001) than those placed with indirect targeting. The optimal stimulation amplitude for devices measured in voltage was lower for those who underwent direct targeting than for those who underwent indirect targeting (p < 0.001). Patients undergoing direct targeting had a greater improvement only in their Quality of Life in Essential Tremor Questionnaire hobby score versus those undergoing indirect targeting (p = 0.04). The direct targeting group had substantially more symptomatic hemorrhages than the indirect targeting group (p = 0.04). All patients who experienced a postoperative hemorrhage after DBS recovered without intervention. CONCLUSIONS: Patients who underwent direct VIM targeting for DBS treatment of essential tremor had similar clinical outcomes to those who underwent indirect targeting. Direct VIM targeting is safe and effective.

Mean arterial pressure maintenance following spinal cord injury: Does meeting the target matter?

INTRODUCTION: Neurosurgical guidelines recommend maintaining mean arterial pressure (MAP) between 85 and 90 mm Hg following acute spinal cord injury (SCI). In our hospital, SCI patients receive orders for MAP targeting for 72 hours following admission, but it is unclear how often the patient's MAP meets the target and whether or not this affects outcome. We hypothesized that the proportion of MAP measurements ≥85 mm Hg would be associated with neurologic recovery. METHODS: Spinal cord injury patients with blunt mechanism of injury admitted between 2014 and 2019 were identified from the registry of a level 1 trauma center. Proportion of MAP values ≥85 mm Hg was calculated for each patient. Neurologic improvement, as measured by positive change in American Spinal Injury Association (ASIA) impairment scale by ≥1 level from admission to discharge was evaluated with respect to proportion of elevated MAP values. RESULTS: A total of 136 SCI patients were evaluated. Average proportion of elevated MAP values was 75%. Admission ASIA grades were as follows: A, 30 (22.1%); B, 20 (14.7%); C, 28 (20.6%); and D, 58 (42.6%). One hundred six patients (77.9%) required vasopressors to elevate MAP (ASIA A, 86.7%; B, 95.0%; C, 92.9%; D, 60.3%). Forty patients (29.4%) were observed to have improvement in ASIA grade by discharge (admission ASIA A, 15%; B, 33%; C, 40%; D, 13%). The proportion of elevated MAP values was higher for patients with neurologic improvement (0.81 ± 0.15 vs. 0.72 ± 0.25, p = 0.014). Multivariate modeling demonstrated a significant association between proportion of elevated MAP values and neurologic improvement (p = 0.028). An interaction revealed this association to be moderated by vasopressor dose (p = 0.032). CONCLUSION: The proportion of MAP measurements ≥85 mm Hg was determined to be an independent predictor of neurologic improvement. Increased vigilance regarding MAP maintenance above 85 mm Hg is warranted to optimize neurologic recovery following SCI. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

A Large Sporadic Intra-abdominal Desmoid-Type Fibromatosis in a Young Male: A Case Report.

Desmoid type fibromatosis (DTF) is a rare benign tumor of connective tissue origin. While these tumors are typically not malignant, they can exhibit aggressive growth patterns causing mass effect on surrounding organs. These tumors typically present in the extremities and abdominal wall, rarely occurring in the mesentery, and abdominal organs. Due to the rarity of this tumor and the variable size and origin, it is difficult to provide exact prognosis, recurrence, and treatment efficacy regarding desmoid tumors arising from the ileocolic mesentery. We present a case of a young male with a sporadic 31 × 25 × 12 cm DTF arising from the ileocolic mesentery that was complicated by mass effect on bowel and intra-abdominal organs requiring surgical intervention. On presentation, the patient exhibited weight gain and abdominal pressure. Abdominal distension without tenderness on palpation was noted on physical examination. The tumor biopsy confirmed the diagnosis of DTF. No evidence of familial adenomatous polyposis or Gardner syndrome was identified. The tumor was surgically excised and intimately associated with the bowel requiring ileocolonic resection with primary anastomosis. At 3-months follow up, surveillance MRI showed no residual or recurrent lesion. A multi-disciplinary approach to this patient's diagnosis and treatment allowed for an accurate diagnosis, efficient treatment, and follow up plan.