Cardiovascular Toxicity of Androgen Deprivation Therapy.

PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) is the standard of care for the treatment of advanced prostate cancer (PC). ADT, particularly with GnRH agonists, leads to increased risk of cardiovascular disease, including myocardial infarction, hypertension, and stroke. This review discusses the options of ADT, the mechanism of ADT-associated cardiovascular side effects, and potential benefit by using GnRH antagonists. RECENT FINDINGS: GnRH antagonists have relatively less cardiovascular adverse effects compared to GnRH agonists. We highlight on a recently published phase III clinical trial on the oral GnRH antagonist, relugolix, and its comparative benefit to traditional GnRH agonist regarding development of cardiovascular disease. Recent data reinforces that GnRH antagonists have a more favorable cardiovascular outcomes compared to GnRH agonists yet maintain a similar efficacy profile. From the data we reviewed, GnRH antagonists may be the preferred method of ADT for PC, but further data with primary cardiovascular outcomes are warranted.

Catechols and 3-hydroxypyridones as inhibitors of the DNA repair complex ERCC1-XPF.

Catechol-based inhibitors of ERCC1-XPF endonuclease activity were identified from a high-throughput screen. Exploration of the structure-activity relationships within this series yielded compound 13, which displayed an ERCC1-XPF IC50 of 0.6 µM, high selectivity against FEN-1 and DNase I and activity in nucleotide excision repair, cisplatin enhancement and γH2AX assays in A375 melanoma cells. Screening of fragments as potential alternatives to the catechol group revealed that 3-hydroxypyridones are able to inhibit ERCC1-XPF with high ligand efficiency, and elaboration of the hit gave compounds 36 and 37 which showed promising ERCC1-XPF IC50 values of <10 µM.

Biportal Endoscopic Spine Surgery for Lumbar Laminectomy and Diskectomy: Postoperative Outcomes and Surgical Learning Curve, a Single US Surgeon's Experience.

INTRODUCTION: Biportal endoscopic spine surgery (BESS) has gained traction for lumbar laminectomy and diskectomy. To justify the transition to BESS, outcomes and the surgical learning curve should be known. This study evaluates rates of complications with BESS and how these rates change with increased surgeon experience. METHODS: A single surgeon's consecutive patients who underwent BESS were evaluated. Patients older than 18 years who underwent BESS for lumbar laminectomy and diskectomy were included. Patients with previous spine surgery, multiple levels, or BESS for fusion were excluded. Demographics, length of surgery, intraoperative complications, postoperative complications, and revision surgery were recorded. The learning phase group and mastery phase group were based on a cumulative summation analysis based on surgical time. RESULTS: A total of 63 patients, with 31 and 32 patients in the learning and mastery group, respectively, were included. Surgical time decreased from 87 to 52 minutes in the mastery phase. Conversion to open decreased from 3 to 0 cases (P = 0.1803), intraoperative complications decreased from 3 to 0 (P = 0.1803), postoperative complications decreased from 7 to 2 (P = 0.017), and rates of revision surgery decreased from 4 to 1 (P = 0.4233). CONCLUSION: This study suggests a learning curve of 31 cases for adequate performance of BESS for lumbar laminectomy and diskectomy.

Radiographic Fusion Outcomes for Trinity Cellular Based Allograft versus Local Bone in Posterolateral Lumbar Fusion.

INTRODUCTION: Cellular-based autograft (CBA) is being used in posterolateral lumbar arthrodesis as a fusion supplementation alternative. OBJECTIVE: To assess radiographic fusion in patients undergoing posterolateral lumbar fusion with unilateral Trinity CBA compared with contralateral local bone autograft as an internal control. METHODS: A single surgeon's practice database was interrogated for consecutive patients undergoing primary posterolateral lumbar fusion with Trinity from 2018 to 2021. Patients had Trinity applied unilaterally, with local bone autograft applied contralaterally. Fusion was assessed postoperatively by using CT after 9 months. Demographics and patient-reported outcome measures were collected preoperatively and up to 12 months postoperatively. RESULTS: Thirty-nine patients were included. There were 81 attempted fusion levels. Overall fusion rate, defined as bony bridging on at least one side of a given level for all levels fused, was 85.2% of patients. No statistically significant difference was observed in fusion rates between CBA versus local bone (79.0% versus 76.54% of levels attempted, respectively, P = 0.3527). Oswestry Disability Index improved by 3 months (P = 0.0152) and was maintained. Two patients required revision for symptomatic nonunion. CONCLUSIONS: Similar radiographic fusion rates were achieved with Trinity and local bone. Trinity is a viable alternative to local bone in posterolateral lumbar fusion.

The Effect of Marijuana on Postoperative Spine Patients' Emergency Department Visits, Readmission Rates, and Opioid Consumption.

OBJECTIVE: To compare postoperative opioid consumption with patients who tested negative for tetrahydrocannabinol (THC) preoperatively with those who were THC-positive and patients who were positive for THC and any other drug and to compare 90-day rates of postoperative emergency department (ED) visits and 90-day readmission rates, using morphine milligram equivalents (MMEs), for those three patient populations. METHODS: Three patient groups were confirmed with preoperative urine drug screens. Chart reviews were conducted to determine whether there was an ED visit or hospital readmission 90 days from the index procedure. MMEs were calculated for all patients. RESULTS: There were a total of 252 patients in the THC-negative control group, 54 in the THC-positive group, and 47 in the THC-and-opioid-positive group. The 90-day ED visit and 90-day readmission rates were not statistically significant among the groups. Both the multidrug and THC-only-positive patients showed a higher 90-day MME compared with the control patients. DISCUSSION: Our study demonstrates that THC used may increase opioid consumption. The THC patients to be cautious toward are the multidrug user. Although not statistically significant, multidrug patients were noted for a trend toward increased ED visits and readmissions.

Anterior Cervical Discectomy and Fusions Supplemented With Cellular or Noncellular Allografts Have Similar Radiographic Fusion and Clinical Outcomes.

STUDY DESIGN: A retrospective, single-center study. OBJECTIVE: The aim of this study was to assess radiographic fusion after anterior cervical discectomy and fusion (ACDF) supplemented with either demineralized bone matrix or ViviGen in a polyetheretherketone biomechanical interbody cage. SUMMARY OF BACKGROUND DATA: Cellular and noncellular allografts are utilized as adjuncts in attempts to improve fusion after ACDF. The purpose of this study was to assess radiographic fusion and clinical outcomes after ACDF supplemented with cellular or noncellular allografts. MATERIALS AND METHODS: A single surgeon's clinical practice database was interrogated for consecutive patients who underwent a primary ACDF using cellular or noncellular allograft from 2017 to 2019. These subjects were matched by age, sex, body mass index, smoking status, and levels operated. Patient demographic and preoperative and postoperative patient-reported outcome measures (PROMs) including Visual Analog Scale Pain, Neck Disability Index, EuroQol-5 Dimension (EQ-5D), Patient-Reported Outcomes Measurement Information System (PROMIS), and Eating Assessment Tool 10 were collected preoperatively and at 3, 6, and 12 months postoperatively. Radiographic evidence of fusion was determined by <2 mm motion between spinous processes on flexion and extension radiographs and assessing bony bridging at 3, 6, and 12 months postoperatively. RESULTS: There were 68 total patients, with 34 patients in each group, and 69 and 67 operative levels in the cellular and noncellular allograft groups, respectively. There was no difference in age, sex, body mass index, or smoking status between groups ( P >0.05). There was no difference in number of 1-level, 2-level, 3-level, or 4-level ACDFs between cellular and noncellular groups ( P >0.05). At 3, 6, and 12 months postoperatively, there was no difference in the percent of operated levels with <2 mm motion between spinous processes, complete bony bridging, or both <2 mm motion and complete bony bridging in the cellular and noncellular groups ( P >0.05). There was no difference in the number of patients fused at all operated levels at 3, 6, or 12 months postoperatively ( P >0.05). No patient required revision ACDF for symptomatic pseudarthrosis. There was no significant difference in PROMs between the cellular and noncellular groups at 12 months postoperatively except for improved EQ-5D and PROMIS-physical in the cellular compared with noncellular group ( P =0.03). CONCLUSIONS: Similar radiographic fusion rates were achieved with cellular and noncellular allografts at all operated levels with similar PROMs in the cellular and noncellular groups at 3, 6, and 12 months postoperatively. Thus, ACDFs supplemented with cellular allograft demonstrate adequate radiographic fusion rates when compared with noncellular allografts with similar patient outcomes. LEVEL OF EVIDENCE: Level III.

Unlocking the Healing Potential: Cannabinoids in Spine Surgery for Pain Relief and Recovery.

¼ Cannabinoids, such as D9-tetrahydrocannabinol and cannabidiol, interact with endocannabinoid receptors in the central nervous system and immune system, potentially offering pain relief. The entourage effect, resulting from the interaction of multiple cannabis components, may enhance therapeutic impact and efficacy, making them promising candidates for exploring pain relief in spine operations, known to be among the most painful operative procedures.¼ The use of cannabinoids in pain management requires careful consideration of safety, including their cognitive and psychomotor effects, potential cardiovascular risks, risk of dependence, mental health implications, and drug interactions.¼ Few studies have analyzed cannabinoid use in relation to spine surgery, with variable results reported, indicating possible effects on reoperation rates, mortality, complications, postoperative opioid use, and length of hospital stay.¼ Current knowledge gaps exist in the understanding of cannabinoid effects on spine surgery, including the exploration of different administration routes, timing, dosage, and specific outcomes. In addition, mechanistic explanations for the observed results are lacking.¼ Ethical considerations related to informed consent, medical expertise, societal impact, and legal compliance must also be thoroughly addressed when considering the utilization of cannabinoids in spinal pathologies and back pain treatment.

Gangrene of the Foot After Coronary Artery Bypass Graft Surgery.

Coronary artery bypass grafting (CABG) is the most common surgery performed by cardiothoracic surgeons worldwide. Risks of CABG include neurological outcomes, deep vein thrombosis, renal or gastrointestinal injury, and death. Perioperatively, some patients may need intra-aortic balloon pump (IABP) use to help assist with cardiac function. In this case, a 75-year-old man presented with multivessel myocardial infarction requiring IABP for cardiac assistance prior to undergoing CABG. Eighteen days after his CABG, his toes turned black at home. A CT angiogram showed aortic atherosclerosis, right tibioperoneal trunk stenosis, mild atherosclerotic right proximal anterior tibial artery stenosis, and multifocal occlusive lesions in the right and left infrapopliteal vessels. Vascular surgery performed balloon angioplasty of the right anterior tibial artery and podiatry performed a transmetatarsal amputation of the dry gangrene. The aim of this case report is to present a rare complication of CABG with peri-operative IABP use and to highlight the need for prompt diagnosis and treatment of dry gangrene.

The medicinal chemistry of mitochondrial dysfunction: a critical overview of efforts to modulate mitochondrial health.

Mitochondria are subcellular organelles that perform a variety of critical biological functions, including ATP production and acting as hubs of immune and apoptotic signalling. Mitochondrial dysfunction has been extensively linked to the pathology of multiple neurodegenerative disorders, resulting in significant investment from the drug discovery community. Despite extensive efforts, there remains no disease modifying therapies for neurodegenerative disorders. This manuscript aims to review the compounds historically used to modulate the mitochondrial network through the lens of modern medicinal chemistry, and to offer a perspective on the evidence that relevant exposure was achieved in a representative model and that exposure was likely to result in target binding and engagement of pharmacology. We hope this manuscript will aid the community in identifying those targets and mechanisms which have been convincingly (in)validated with high quality chemical matter, and those for which an opportunity exists to explore in greater depth.

Non-Invasive microRNA Profiling in Saliva can Serve as a Biomarker of Alcohol Exposure and Its Effects in Humans.

Alcohol Use Disorder (AUD) is one of the most prevalent mental disorders worldwide. Considering the widespread occurrence of AUD, a reliable, cheap, non-invasive biomarker of alcohol consumption is desired by healthcare providers, clinicians, researchers, public health and criminal justice officials. microRNAs could serve as such biomarkers. They are easily detectable in saliva, which can be sampled from individuals in a non-invasive manner. Moreover, microRNAs expression is dynamically regulated by environmental factors, including alcohol. Since excessive alcohol consumption is a hallmark of alcohol abuse, we have profiled microRNA expression in the saliva of chronic, heavy alcohol abusers using microRNA microarrays. We observed significant changes in salivary microRNA expression caused by excessive alcohol consumption. These changes fell into three categories: downregulated microRNAs, upregulated microRNAs, and microRNAs upregulated de novo. Analysis of these combinatorial changes in microRNA expression suggests dysregulation of specific biological pathways leading to impairment of the immune system and development of several types of epithelial cancer. Moreover, some of the altered microRNAs are also modulators of inflammation, suggesting their contribution to pro-inflammatory mechanisms of alcohol actions. Establishment of the cellular source of microRNAs in saliva corroborated these results. We determined that most of the microRNAs in saliva come from two types of cells: leukocytes involved in immune responses and inflammation, and buccal cells, involved in development of epithelial, oral cancers. In summary, we propose that microRNA profiling in saliva can be a useful, non-invasive biomarker allowing the monitoring of alcohol abuse, as well as alcohol-related inflammation and early detection of cancer.

Cysteine specific bioconjugation with benzyl isothiocyanates.

Protein labelling has a wide variety of applications in medicinal chemistry and chemical biology. In addition to covalent inhibition, specific labelling of biomolecules with fluorescent dyes is important in both target discovery, validation and diagnostics. Our research was conducted through the fragment-based development of a new benzyl-isothiocyanate-activated fluorescent dye based on the fluorescein scaffold. This molecule was evaluated against fluorescein isothiocyanate, a prevalent labelling agent. The reactivity and selectivity of phenyl- and benzyl isothiocyanate were compared at different pHs, and their activity was tested on several protein targets. Finally, the clinically approved antibody trastuzumab (and it's Fab fragment) were specifically labelled through reaction with free cysteines reductively liberated from their interchain disulfide bonds. The newly developed benzyl-fluorescein isothiocyanate and its optimized labelling protocol stands to be a valuable addition to the tool kit of chemical biology.

Enabling the controlled assembly of antibody conjugates with a loading of two modules without antibody engineering.

The generation of antibody conjugates with a loading of two modules is desirable for a host of reasons. Whilst certain antibody engineering approaches have been useful in the preparation of such constructs, a reliable method based on a native antibody scaffold without the use of enzymes or harsh oxidative conditions has hitherto not been achieved. The use of native antibodies has several advantages in terms of cost, practicality, accessibility, time and overall efficiency. Herein we present a novel, reliable method of furnishing antibody conjugates with a loading of two modules starting from a native antibody scaffold.

Next-generation disulfide stapling: reduction and functional re-bridging all in one.

Herein we present a significant step towards next-generation disulfide stapling reagents. A novel class of reagent has been designed to effect both disulfide reduction and functional re-bridging. The strategy has been applied to great success across various peptides and proteins. Moreover, application to a multi-disulfide system resulted in functional re-bridging without disulfide scrambling.

A mild TCEP-based para-azidobenzyl cleavage strategy to transform reversible cysteine thiol labelling reagents into irreversible conjugates.

It has recently emerged that the succinimide linkage of a maleimide thiol addition product is fragile, which is a major issue in fields where thiol functionalisation needs to be robust. Herein we deliver a strategy that generates selective cysteine thiol labelling reagents, which are stable to hydrolysis and thiol exchange.