Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance.

The coexistence of brown adipocytes with low and high thermogenic activity is a fundamental feature of brown adipose tissue heterogeneity and plasticity. However, the mechanisms that govern thermogenic adipocyte heterogeneity and its significance in obesity and metabolic disease remain poorly understood. Here we show that in male mice, a population of transcription factor jun-B (JunB)-enriched (JunB+) adipocytes within the brown adipose tissue exhibits lower thermogenic capacity compared to high-thermogenic adipocytes. The JunB+ adipocyte population expands in obesity. Depletion of JunB in adipocytes increases the fraction of adipocytes exhibiting high thermogenic capacity, leading to enhanced basal and cold-induced energy expenditure and protection against diet-induced obesity and insulin resistance. Mechanistically, JunB antagonizes the stimulatory effects of PPARγ coactivator-1α on high-thermogenic adipocyte formation by directly binding to the promoter of oestrogen-related receptor alpha, a PPARγ coactivator-1α downstream effector. Taken together, our study uncovers that JunB shapes thermogenic adipocyte heterogeneity, serving a critical role in maintaining systemic metabolic health.

Microvascular clamp technique as a reversible simulation of parathyroid gland excision.

INTRODUCTION: This study demonstrates the effectiveness of a microvascular clamp to simulate parathyroid adenoma excision with respect to intraoperative parathyroid hormone (ioPTH) changes in vivo. METHODS: Cases in which microvascular clamps were employed intraoperatively in conjunction with intraoperative parathyroid hormone(ioPTH) assays were reviewed. ioPTH values were recorded throughout these procedures to assess the efficacy and reversibility of tissue ischemia using microvascular clamps. RESULTS: Application of a microvascular clamp across the vascular pedicle of a parathyroid adenoma resulted in a significant ioPTH drop in 95% of cases (N = 20). Removal of the clamp resulted in complete or partial rebound of ioPTH in 90% of cases (N = 20). CONCLUSION: The use of a microvascular clamp to temporarily occlude a parathyroid gland's vascular pedicle is an effective simulation of gland excision with respect to ioPTH changes. Rebound of ioPTH levels after clamp removal demonstrates that this technique is generally reversible. LEVEL OF EVIDENCE: 2b, Retrospective cohort study.

Adipose mTORC1 Suppresses Prostaglandin Signaling and Beige Adipogenesis via the CRTC2-COX-2 Pathway.

Beige adipocytes are present in white adipose tissue (WAT) and have thermogenic capacity to orchestrate substantial energy metabolism and counteract obesity. However, adipocyte-derived signals that act on progenitor cells to control beige adipogenesis remain poorly defined. Here, we show that adipose-specific depletion of Raptor, a key component of mTORC1, promoted beige adipogenesis through prostaglandins (PGs) synthesized by cyclooxygenase-2 (COX-2). Moreover, Raptor-deficient mice were resistant to diet-induced obesity and COX-2 downregulation. Mechanistically, mTORC1 suppressed COX-2 by phosphorylation of CREB-regulated transcription coactivator 2 (CRTC2) and subsequent dissociation of CREB to cox-2 promoter in adipocytes. PG treatment stimulated PKA and promoted differentiation of progenitor cells to beige adipocytes in culture. Ultimately, we show that pharmacological inhibition or suppression of COX-2 attenuated mTORC1 inhibition-induced thermogenic gene expression in inguinal WAT in vivo and in vitro. Our study identifies adipocyte-derived PGs as key regulators of white adipocyte browning, which occurs through mTORC1 and CRTC2.

Poorly differentiated thyroid carcinoma with sternal invasion. A case report and review of the literature.

INTRODUCTION: Surgical resection of poorly differentiated thyroid carcinoma with direct invasion of the sternum has not been previously reported. Only 4 cases of concomitant thyroidectomy and sternal resection and reconstruction for sternal metastases have been published. PRESENTATION OF CASE: A 66-year-old female with a poorly differentiated thyroid carcinoma and direct sternal invasion underwent total thyroidectomy and resection of the manubrium and both clavicular heads, and chest wall reconstruction with polypropylene mesh and bilateral myocutaneous pectoralis major muscle flaps. Postoperatively, the patient received radioactive iodine ablation. She developed a local recurrence, requiring additional ablation with radioactive iodine and external beam radiation therapy. Although there was no clinical or radiographic evidence of recurrent disease 5-years postoperatively, a possible local recurrence was discovered 4 months later. DISCUSSION: In previous case reports the sternal metastases were not in continuity with the thyroid tumor. In our patient, however, there was evidence of direct extension between the thyroid tumor and the sternal mass that were connected together with cords of tumor. CONCLUSION: In our patient with poorly differentiated thyroid carcinoma invading the sternum, total thyroidectomy and resection of the manubrium with sternal reconstruction, combined with adjuvant radioactive iodine ablation and external beam radiation therapy was associated with prolonged survival after 5 years despite a small local recurrence.

Safety of botulinum toxin for dysphagia in oculopharyngeal muscular dystrophy.

INTRODUCTION: Despite multiple studies reporting marked benefit of botulinum toxin (BTX) for treatment of cricopharyngeal dysphagia, little is known about its safety for this indication. We examined the safety of cricopharyngeal BTX for dysphagia in oculopharyngeal muscular dystrophy (OPMD). METHODS: We reviewed records of patients with OPMD who received cricopharyngeal BTX. RESULTS: Twenty-four patients underwent 66 procedures. Overall adverse event frequency was 44%. The most common adverse events were dysphonia (24%) and worsened dysphagia (14%). Logistic regression demonstrated that dose was a significant predictor of worsened dysphagia (P = 0.036) and of the composite event of dysphonia or worsened dysphagia (P = 0.009). There was a nonsignificant trend for dose as a predictor of dysphonia (P = 0.073). 59% of procedures were associated with symptomatic improvement. CONCLUSIONS: While BTX appears to be beneficial for treatment of dysphagia in OPMD, caution is warranted when injecting the cricopharyngeus muscle due to dose-related risk of dysphonia or worsened dysphagia.

A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma.

OBJECTIVES: The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy. MATERIALS AND METHODS: Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0-2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines. RESULTS: Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression. CONCLUSIONS: The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted.

Anaplastic carcinoma of the thyroid with chondroblastoma features mimicking papillary carcinoma: a case report.

BACKGROUND: An unusual case of anaplastic carcinoma of the thyroid arising from a metastatic focus of papillary carcinoma. CASE: The tumor affected a 69-year-old woman with a history of total thyroidectomy for papillary thyroid carcinoma 4 years previously. She presented with a rapidly enlarging neck mass that histologically simulated chondroblastoma. A small, embedded focus of residual follicular variant of papillary carcinoma was present. The patient died of disease 3 months later. CONCLUSION: This "chondroblastoma" variant of anaplastic thyroid carcinoma has not been reported to date.