On a sugar high: Role of O-GlcNAcylation in cancer.

Recent advances in the understanding of the molecular mechanisms underlying cancer progression have led to the development of novel therapeutic targeting strategies. Aberrant glycosylation patterns and their implication in cancer have gained increasing attention as potential targets due to the critical role of glycosylation in regulating tumor-specific pathways that contribute to cancer cell survival, proliferation, and progression. A special type of glycosylation that has been gaining momentum in cancer research is the modification of nuclear, cytoplasmic, and mitochondrial proteins, termed O-GlcNAcylation. This protein modification is catalyzed by an enzyme called O-GlcNAc transferase (OGT), which uses the final product of the Hexosamine Biosynthetic Pathway (HBP) to connect altered nutrient availability to changes in cellular signaling that contribute to multiple aspects of tumor progression. Both O-GlcNAc and its enzyme OGT are highly elevated in cancer and fulfill the crucial role in regulating many hallmarks of cancer. In this review, we present and discuss the latest findings elucidating the involvement of OGT and O-GlcNAc in cancer.

Beyond the cuff: a consideration of factors that affect sexual function after benign hysterectomy.

PURPOSE OF REVIEW: Hysterectomy is the most common gynecologic surgical procedure performed on women in the United States. While there are data supporting that hysterectomy for benign indication often does not reduce sexual function and may in fact improve sexual function as fibroids and endometriosis are resected, it remains unclear if there are factors within the perioperative period that affect sexual function in the years following surgery. To date, there is no consensus on what factors can optimize patients' sexual function after hysterectomy. RECENT FINDINGS: We present the current literature that assesses factors which may contribute to sexual function after hysterectomy. Preoperative demographic factors, including increasing age, pelvic pain, and preoperative sexual dysfunction, play a large role in postoperative sexual function. Perioperatively, there is a growing amount of data suggesting that premenopausal salpingo-oophorectomy at the time of hysterectomy may increase the risk of sexual dysfunction after hysterectomy, and no conclusive evidence that subtotal hysterectomy improves sexual function. The route of hysterectomy and technique of cuff closure can impact sexual function after hysterectomy due to the risk of shortening the vaginal length. SUMMARY: There is a lack of high-quality evidence that can provide a consensus on factors to optimize sexual function after hysterectomy. A growing area of research in the excision of endometriosis procedures is the consideration of nerve-sparing surgery. Considering the many variables that exist when counseling a patient on benign hysterectomy and its effects on sexual function, it is critical to understand the current research that exists with regards to these factors.

A Caenorhabditis elegans model of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology.

Inborn errors of purine metabolism are rare syndromes with an array of complex phenotypes in humans. One such disorder, adenylosuccinate lyase deficiency (ASLD), is caused by a decrease in the activity of the bi-functional purine biosynthetic enzyme adenylosuccinate lyase (ADSL). Mutations in human ADSL cause epilepsy, muscle ataxia, and autistic-like symptoms. Although the genetic basis of ASLD is known, the molecular mechanisms driving phenotypic outcome are not. Here, we characterize neuromuscular and reproductive phenotypes associated with a deficiency of adsl-1 in Caenorhabditis elegans. We demonstrate that adsl-1 function contributes to regulation of spontaneous locomotion, that adsl-1 functions acutely for proper mobility, and that aspects of adsl-1-related dysfunction are reversible. Using pharmacological supplementation, we correlate phenotypes with distinct metabolic perturbations. The neuromuscular defect correlates with accumulation of a purine biosynthetic intermediate whereas reproductive deficiencies can be ameliorated by purine supplementation, indicating differing molecular mechanisms behind the phenotypes. Because purine metabolism is highly conserved in metazoans, we suggest that similar separable metabolic perturbations result in the varied symptoms in the human disorder and that a dual-approach therapeutic strategy may be beneficial.

Growing pains: strategies for improving ergonomics in minimally invasive gynecologic surgery.

PURPOSE OF REVIEW: To evaluate factors contributing to the development of work-related musculoskeletal disorders (WMSDs) and review strategies for mitigating ergonomic strain in minimally invasive gynecologic surgery. RECENT FINDINGS: Factors associated with increased ergonomic strain and the development of WMSDs include increasing patient body mass index (BMI), smaller surgeon hand size, noninclusive design of instruments and energy devices and improper positioning of surgical equipment. Each type of minimally invasive surgery (laparoscopic, robotic, vaginal) confers its own ergonomic risk to the surgeon. Recommendations have been published regarding optimal ergonomic surgeon and equipment positioning. Intraoperative breaks and stretching are effective in reducing surgeon discomfort. Formal training in ergonomics has not yet been widely implemented, but educational interventions have been effective in reducing surgeon discomfort and can improve surgeon recognition of suboptimal ergonomics. SUMMARY: Considering the serious downstream effects of WMSDs on surgeons, it is imperative to implement strategies for WMSD prevention. Optimal positioning of the surgeons and operative equipment should be routine. Intraoperative breaks and stretching should be incorporated during procedures and between every case. Formal education in ergonomics should be provided to surgeons and trainees. Additionally, more inclusive instrument design by industry partners should be prioritized.

Non-extirpative Treatments for Uterine Myomas: Measuring Success.

OBJECTIVE: To analyze outcomes of nonextirpative treatments for uterine myomas compared with myomectomy. DATA SOURCES: A systematic search of the following databases from inception to January 2020 was performed: Ovid Medline, Embase, PubMed, and Cochrane Controlled Register of Trials. METHODS OF STUDY SELECTION: Two authors reviewed titles and abstracts for relevance, and full articles were obtained and evaluated for inclusion. Studies were included if they compared nonextirpative interventions for uterine myomas to myomectomy and reported at least one outcome of interest. TABULATION, INTEGRATION, AND RESULTS: Of the 2010 articles identified and reviewed, 125 full text articles were reviewed, and 22 were ultimately included in the analysis. Nonextirpative treatments reviewed included uterine artery embolization (UAE; 16 studies, n = 9555 subjects), focused ultrasound (FUS; 4 studies, n = 1516), laparoscopic radiofrequency ablation (RFA; 3 studies, n = 49). UAE, FUS, and laparoscopic RFA groups were compared with patients undergoing myomectomy (n = 34 872, n = 20 677, n = 47 respectively). In comparison with myomectomy, UAE had similar quality of life scores, symptom severity scores, sexual function scores, ovarian function, and miscarriage rates following intervention. There was lower likelihood of conceiving after UAE and a higher rate of reintervention after UAE compared with myomectomy. FUS had similar postprocedure sexual function scores and reintervention rates compared with myomectomy. Laparoscopic RFA had similar quality of life scores, symptom severity scores, sexual function scores, reintervention rates, and pregnancy rates after the procedure compared with myomectomy. CONCLUSION: Nonextirpative treatments for uterine myomas have similar outcomes to myomectomy in multiple domains, with most available evidence comparing UAE with myomectomy.

Fructose promotes liver cancer via microbial acetate-induced O-GlcNAcylation.

High dietary fructose consumption is linked to multiple disease states, including cancer. Zhou and colleagues recently reported a novel mechanism where high dietary fructose levels increase acetate production by the gut microbiome increasing post-translational modification O-GlcNAcylation in liver cells, which contributes to disease progression in mouse models of hepatocellular carcinoma.

Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells.

Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeline to identify novel brain-penetrant ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, and excretion (ADME) property predictions. We identified compounds AD-5584 and AD-8007 that were validated for specific binding affinity to ACSS2. Treatment of BCBM cells with AD-5584 and AD-8007 leads to a significant reduction in colony formation, lipid storage, acetyl-CoA levels and cell survival in vitro. In an ex vivo brain-tumor slice model, treatment with AD-8007 and AD-5584 reduced pre-formed tumors and synergized with irradiation in blocking BCBM tumor growth. Treatment with AD-8007 reduced tumor burden and extended survival in vivo. This study identifies selective brain-penetrant ACSS2 inhibitors with efficacy towards breast cancer brain metastasis.

Radiofrequency Ablation for Treatment of Leiomyomas: Review of the Manufacturer and User Facility Device Experience (MAUDE) Database.

Radiofrequency ablation (RFA) is a relatively novel, increasingly popular treatment option for leiomyomas. We studied medical device-related reports of leiomyoma RFA devices to determine whether there are emerging device-related issues. The Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database was queried from 2012 through November 2022. Sixty unique reports, including adverse events and device malfunctions, were analyzed for both laparoscopic and transcervical RFA devices. Forty-three injury reports were reviewed. The most common adverse event was infection. Of the injury cases, 34.9% required additional surgical intervention. Although the details of each event are limited, these reports highlight the importance of postmarket surveillance of new technologies and the necessity of improving the current system of implementation and monitoring.

Discovery of novel brain permeable human ACSS2 inhibitors for blocking breast cancer brain metastatic growth.

Breast-cancer brain metastasis (BCBM) poses a significant clinical challenge, resulting in an end-stage diagnosis and hindered by limited therapeutic options. The blood-brain barrier (BBB) acts as an anatomical and physiological hurdle for therapeutic compounds, restricting the effective delivery of therapies to the brain. In order to grow and survive in a nutrient-poor environment, tumors in the brain must adapt to their metabolic needs, becoming highly dependent on acetate. These tumors rely on the conversion of acetate to acetyl-CoA by the enzyme Acetyl-CoA synthetase 2 (ACSS2), a key metabolic enzyme involved in regulating fatty acid synthesis and protein acetylation in tumor cells. ACSS2 has emerged as a crucial enzyme required for the growth of tumors in the brain. Here, we utilized a computational pipeline, combining pharmacophore-based shape screen methodology with ADME property predictions to identify novel brain-permeable ACSS2 inhibitors. From a small molecule library, this approach identified 30 potential ACSS2 binders, from which two candidates, AD-5584 and AD-8007, were validated for their binding affinity, predicted metabolic stability, and, notably, their ability to traverse the BBB. We show that treatment of BCBM cells, MDA-MB-231BR, with AD-5584 and AD-8007 leads to a significant reduction in lipid storage, reduction in colony formation, and increase in cell death in vitro . Utilizing an ex vivo orthotopic brain-slice tumor model, we show that treatment with AD-8007 and AD-5584 significantly reduces tumor size and synergizes with radiation in blocking BCBM tumor growth ex vivo. Importantly, we show that following intraperitoneal injections with AD-5584 and AD-8007, we can detect these compounds in the brain, confirming their BBB permeability. Thus, we have identified and validated novel ACSS2 inhibitor candidates for further drug development and optimization as agents for treating patients with breast cancer brain metastasis.

Endoscopic endonasal resection of a primary intraosseous clival myxoma: illustrative case.

BACKGROUND: An intraosseous myxoma is a rare, benign mesenchymal tumor that penetrates the bone. The occurrence of an intraosseous myxoma in the clivus is a unique presentation of the disease. OBSERVATIONS: The authors discuss the case of a 15-year-old male with a new diagnosis of a primary clival intraosseous myxoma presenting with cranial nerve VI palsy. This is the third documented case of this pathology occurring in the clivus. This patient was successfully treated with endoscopic endonasal resection of the tumor. LESSONS: Primary clival intraosseous myxomas are extremely rare, but nonetheless it is important to add it to the differential diagnosis of clival masses. This mass has a high risk of recurrence, and prior literature suggests gross total resection may improve chances of progression-free survival. However, further larger studies are needed to provide guidelines regarding proper management of this pathology.