Lumbar Fusions in Patients with Sickle Cell Disease: A Propensity-Matched Analysis of Postoperative Complications.

OBJECTIVE: The present study compares postoperative outcomes between patients with and without sickle cell disease (SCD) undergoing one- to three-level lumbar spinal fusion for degenerative pathologies. METHODS: Patients who underwent one- to three-level lumbar spinal fusion for degenerative pathologies from 2010-2021 were identified using the PearlDiver database. Patients were separated into 1) SCD and 2) non-SCD groups and were propensity-matched 1:1 for age, sex, Elixhauser Comorbidity Index (ECI), surgical approach, and various comorbidities. Complications were separately analyzed by single- and multi-level procedures using chi-squared and Mann-Whitney U testing. RESULTS: Propensity-score matching identified 1,934 SCD and non-SCD patients who underwent single-level fusion and 2,094 SCD and non-SCD patients who underwent multi-level fusion. Across single-level fusions, those with SCD had a significantly higher risk of neurovascular compromise (p < 0.001), venous thromboembolism (p = 0.004), pneumonia (p = 0.032), urinary tract infections (UTI) (p = 0.001), and greater postoperative opioid usage out to twelve months (p = 0.018). Across multi-level fusions, SCD carried higher risk for neurovascular compromise (p < 0.001), pneumonia (p = 0.010), and UTI (p < 0.001). All SCD patients had significantly higher opioid use at one month (p = 0.001) and at six months (p = 0.009) postoperatively. CONCLUSIONS: Patients with SCD undergoing lumbar spinal fusion demonstrate higher risks for coagulopathic, ischemic, and infectious-related complications, as well as long-term postoperative opioid use. Awareness of the unique complication profile in SCD patients may help guide surgeons in refining perioperative management strategies to optimize outcomes in patients with SCD.

Top 25 Most Cited Articles on Intraoperative Computer Tomography-Guided Navigation in Spine Surgery.

BACKGROUND: In recent years, the use of intraoperative computer tomography-guided (CT-guided) navigation has gained significant popularity among health care providers who perform minimally invasive spine surgery. This review aims to identify and analyze trends in the literature related to the widespread adoption of CT-guided navigation in spine surgery, emphasizing the shift from conventional fluoroscopy-based techniques to CT-guided navigation. METHODS: Articles pertaining to this study were identified via a database review and were hierarchically organized based on the number of citations. An "advanced document search" was performed on September 28th, 2022, utilizing Boolean search operator terms. The 25 most referenced articles were combined into a primary list after sorting results in descending order based on the total number of citations. RESULTS: The "Top 25" list for intraoperative CT-guided navigation in spine surgery cumulatively received a total of 2742 citations, with an average of 12 new citations annually. The number of citations ranged from 246 for the most cited article to 60 for the 25th most cited article. The most cited article was a paper by Siewerdsen et al., with 246 total citations, averaging 15 new citations per year. CONCLUSIONS: Intraoperative CT-guided navigation is 1 of many technological advances that is used to increase surgical accuracy, and it has become an increasingly popular alternative to conventional fluoroscopy-based techniques. Given the increasing adoption of intraoperative CT-guided navigation in spine surgery, this review provides impactful evidence for its utility in spine surgery.

A DNA unwinding equilibrium serves as a checkpoint for CRISPR-Cas12a target discrimination.

CRISPR-associated proteins such as Cas9 and Cas12a are programable RNA-guided nucleases that have emerged as powerful tools for genome manipulation and molecular diagnostics. However, these enzymes are prone to cleaving off-target sequences that contain mismatches between the RNA guide and DNA protospacer. In comparison to Cas9, Cas12a has demonstrated distinct sensitivity to protospacer-adjacent-motif (PAM) distal mismatches, and the molecular basis of Cas12a's enhanced target discrimination is of great interest. In this study, we investigated the mechanism of Cas12a target recognition using a combination of site-directed spin labeling, fluorescent spectroscopy, and enzyme kinetics. With a fully matched RNA guide, the data revealed an inherent equilibrium between a DNA unwound state and a DNA-paired duplex-like state. Experiments with off-target RNA guides and pre-nicked DNA substrates identified the PAM-distal DNA unwinding equilibrium as a mismatch sensing checkpoint prior to the first step of DNA cleavage. The finding sheds light on the distinct targeting mechanism of Cas12a and may better inform CRISPR based biotechnology developments.

A DNA Unwinding Equilibrium Serves as a Checkpoint for CRISPR-Cas12a Target Discrimination.

CRISPR-associated proteins such as Cas9 and Cas12a are programable RNA-guided nucleases that have emerged as powerful tools for genome manipulation and molecular diagnostics. However, these enzymes are prone to cleaving off-target sequences that contain mismatches between the RNA guide and DNA protospacer. In comparison to Cas9, Cas12a has demonstrated distinct sensitivity to protospacer-adjacent-motif (PAM) distal mismatches, and the molecular basis of Cas12a's enhanced target discrimination is of great interest. In this study, we investigated the mechanism of Cas12a target recognition using a combination of site-directed spin labeling, fluorescent spectroscopy, and enzyme kinetics. With a fully matched RNA guide, the data revealed an inherent equilibrium between a DNA unwound state and a DNA-paired duplex-like state. Experiments with off-target RNA guides and pre-nicked DNA substrates identified the PAM-distal DNA unwinding equilibrium as a mismatch sensing checkpoint prior to the first step of DNA cleavage. The data sheds light on the distinct targeting mechanism of Cas12a and may better inform CRISPR based biotechnology developments.

Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors.

Efforts to target glucose metabolism in cancer have been limited by the poor potency and specificity of existing anti-glycolytic agents and a poor understanding of the glucose dependence of cancer subtypes in vivo. Here, we present an extensively characterized series of potent, orally bioavailable inhibitors of the class I glucose transporters (GLUTs). The representative compound KL-11743 specifically blocks glucose metabolism, triggering an acute collapse in NADH pools and a striking accumulation of aspartate, indicating a dramatic shift toward oxidative phosphorylation in the mitochondria. Disrupting mitochondrial metabolism via chemical inhibition of electron transport, deletion of the malate-aspartate shuttle component GOT1, or endogenous mutations in tricarboxylic acid cycle enzymes, causes synthetic lethality with KL-11743. Patient-derived xenograft models of succinate dehydrogenase A (SDHA)-deficient cancers are specifically sensitive to KL-11743, providing direct evidence that TCA cycle-mutant tumors are vulnerable to GLUT inhibitors in vivo.

Discovery and Optimization of Glucose Uptake Inhibitors.

Aerobic glycolysis, originally identified by Warburg as a hallmark of cancer, has recently been implicated in immune cell activation and growth. Glucose, the starting material for glycolysis, is transported through the cellular membrane by a family of glucose transporters (GLUTs). Therefore, targeting glucose transporters to regulate aerobic glycolysis is an attractive approach to identify potential therapeutic agents for cancers and autoimmune diseases. Herein, we describe the discovery and optimization of a class of potent, orally bioavailable inhibitors of glucose transporters, targeting both GLUT1 and GLUT3.

4-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators.

4-(1-Phenyl-1H-pyrazol-4-yl)quinoline (1) was identified by screening the Lundbeck compound collection, and characterized as having mGlu4 receptor positive allosteric modulator properties. Compound 1 is selective over other mGlu receptors and a panel of GPCRs, ion channels and enzymes, but has suboptimal lipophilicity and high plasma and brain non-specific binding. In view of the challenges at the hit-to-lead stage previously reported in the development of mGlu4 receptor positive allosteric modulators (PAMs), a thorough structure-mGlu4 PAM activity relationship study was conducted to interrogate the chemical tractability of this chemotype. The central pyrazole ring tolerates the addition of one or two methyl groups. The C-7 position of the quinoline ring provides a site tolerant to hydrophilic substituents, enabling the design of diverse analogs with good in vitro mGlu4 PAM potency and efficacy, as well as improved microsomal turnover in vitro, compared to 1. In spite of the excellent ligand efficiency of 1 (LE=0.43), optimization of in vitro potency for this series reached a plateau around EC(50)=200 nM.

Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators.

There is an increasing amount of evidence to support that activation of the metabotropic glutamate receptor 4 (mGlu4 receptor), either with an orthosteric agonist or a positive allosteric modulator (PAM), provides impactful interventions in diseases such as Parkinson's disease, anxiety, and pain. mGlu4 PAMs may have several advantages over mGlu4 agonists for a number of reasons. As part of our efforts in identifying therapeutics for central nervous system (CNS) diseases such as Parkinson's disease, we have been focusing on metabotropic glutamate receptors. Herein we report our studies with a series of tricyclic thiazolopyrazoles as mGlu4 PAMs.

Identification of 3-sulfonylindazole derivatives as potent and selective 5-HT(6) antagonists.

As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT(6) antagonists. The synthesis and detailed SAR of this class of compounds are reported.

5-Piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists.

As part of our efforts to develop agents for CNS diseases, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for cognitive enhancement. Herein we report the identification of a novel series of 5-piperazinyl-3-sulfonylindazoles as potent and selective 5-HT(6) antagonists. The synthesis, SAR, and pharmacokinetic and pharmacological activities of some of the compounds including 3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-indazole (WAY-255315 or SAM-315) will be described.

Identification of a novel series of 3-piperidinyl-5-sulfonylindazoles as potent 5-HT6 ligands.

Cognitive dysfunction is a characteristic of various forms of dementia such as Alzheimer's disease (AD) and a core feature of schizophrenia. As part of our continuing efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor-one of the emerging therapeutic targets in this area. Herein, we report the identification of a novel series of 3-piperidinyl-5-sulfonylindazole derivatives as potent 5-HT(6) antagonists. The synthesis and SAR of this class of compounds are reported.

1-Sulfonylindazoles as potent and selective 5-HT6 ligands.

As part of our continuing efforts to identify therapeutics for CNS diseases, such as schizophrenia and Alzheimer's disease (AD), we have been focused on the 5-HT(6) receptor in an attempt to identify ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of 1-sulfonylindazole derivatives as potent and selective 5-HT(6) antagonists. The synthesis and SAR of this class of compounds are reported. Several potent compounds in both binding and cyclase functional assays also display good selectivity, microsomal stability, solubility, and brain penetration as well as low cytochrome P450 inhibition. One compound exemplified in this series showed 24% oral bioavailability and in vivo efficacy in a NOR cognition model at 10mg/kg following an oral administration in rats.

Identification of a series of benzoxazoles as potent 5-HT6 ligands.

As part of our continuing efforts to identify therapeutics for CNS diseases such as schizophrenia and Alzheimer's disease (AD), we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of benzoxazole derivatives as potent 5-HT(6) ligands. The synthesis and detailed SAR of this class of compounds are reported. The compounds have been shown to be full antagonists in a cyclic AMP functional assay.

A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands.

A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands is reported.

Rearrangement of 3,3-disubstituted indolenines and synthesis of 2,3-substituted indoles.

Synthesis of 2,3-substituted indoles from phenylhydrazine and alpha-branched aldehydes via rearrangement of 3,3-disubstituted indolenine intermediates is reported. [reaction: see text]