The Disabled Anesthesiologist.

A significant number of anesthesiologists will experience a disabling illness or injury during their careers. In addition to ethical obligations to patients, physicians have ethical obligations to their colleagues: both to recognize and intervene when disabilities have the potential of interfering with patient care and to try, whenever it is possible and safe, to support colleagues with disabilities in pursuing a successful career. Encouraging and accommodating physicians with disabilities in their practice of medicine benefits patients, by including physicians who may better understand the challenges of the disabled, and also the profession, by promoting acceptance of diversity in practice.

Dopamine D1-Like Receptor-Mediated Insurmountable Blockade of the Reinforcing Effects of Cocaine in Rats.

Previous studies indicated differing effects of dopamine D1-like and D2-like receptor (D1R and D2R, respectively) agonists on cocaine self-administration. Leftward shifts by D2R agonists in the cocaine self-administration dose-effect function contrast with decreases by D1R agonists in maximal cocaine self-administration without rightward or leftward displacement. Whether the effects of the D1R agonists are due to actions at D1Rs has not been determined possibly due to the difficulty in separating the blockade by a D1R antagonist of the effects of the D1R agonists and those of cocaine. In the present study, pretreatment with the D1R agonists R(+)-SKF-81297 (0.1-1.0 mg/kg) and ({plus minus})-SKF-82958 (0.032-0.32 mg/kg) dose-dependently decreased maximal cocaine self-administration at doses below those affecting food-reinforced responding. In contrast, pretreatment with the D2R agonists R(-)-NPA (0.001-0.01 mg/kg) and (-)-quinpirole (0.01-0.1 mg/kg) dose-dependently left shifted the cocaine self-administration dose-effect function. The decreases by D1R agonists in maximal cocaine self-administration were dose-dependently antagonized by the D1R antagonist SCH-39166 at doses that alone had no effects on cocaine self-administration. Doses of SCH-39166 that blocked the effects of the D1R agonists on cocaine self-administration were like those that shifted self-administration of D1R agonists to the right but had no effects on self-administration of D2R agonists. Self-administration of the D2R agonists was dose-dependently shifted to the right by the preferential D2R antagonist, L-741,626, but not by SCH-39166. These results demonstrate that the decreases by the D1R agonists in cocaine self-administration are selectively D1R-mediated, and support findings suggesting fundamentally distinct roles of the D1Rs and D2Rs in cocaine reinforcement. Significance Statement Dopamine D1-like (D1R) agonists decrease maximal cocaine self-administration, whereas D2-like (D2R) agonists shift the cocaine self-administration dose-effect function leftward with mechanisms for those different effects unclear. The present study demonstrates blockade by the selective D1R antagonist SCH-39166 of decreases in maximal cocaine self-administration at doses that blocked other D1R-mediated effects but not effects of cocaine, suggesting fundamentally distinct roles of the dopamine D1-like and D2-like receptors in cocaine reinforcement and development of D1R agonists as potential treatments for cocaine-use disorder.

Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.

BACKGROUND: The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS). METHODS AND FINDINGS: In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation. CONCLUSIONS: Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS. TRIAL REGISTRATION: Clintrials.gov ID:NCT04322149.

Long-term Tolerance to Islet Transplantation via Targeted Reduction of beta cell-specific T cells.

Type 1 diabetes (T1D) results from insulin insufficiency due to the loss or dysfunction of pancreatic beta cells following T cell-mediated autoimmune attack. Currently the only long-term therapy is daily exogenous insulin replacement. The ideal curative approach is the durable restoration of functional islets via transplantation. To date the limiting factors impeding realization of this goal is the lack of a cost effective and limitless source of high-quality islets suitable for transplantation and the ability to provide long-term islet graft acceptance without prolonged need for deleterious immunosuppression. Ongoing clinical trials are testing islets derived from human induced pluripotent stem cells (iPSC); however, long-term acceptance of islet graft will require a effective therapeutic strategy to prevent engrafted islet destruction by pre-existing islet-antigen specific T cells. Here we demonstrate in the NOD mouse model for T1D that autologous islet graft acceptance can be achieved by the targeted elimination of (re)-activated islet-reactive CD4 + and CD8 + T effector (Teff) cells in the initial post-transplantation period by using a short-acting, combination therapy that results in the elimination of islet-reactive Teff cells by exacerbation of their natural DNA damage response (DDR) to drive apoptosis while at the same time maintaining endogenous Treg cells. Article Highlights: Activated beta-cell reactive CD4 + and CD8 + T effector cells undergo a profound DNA-damage response which is targetable by small molecule inhibitors of the p53 and cell cycle pathways that lead to apoptosis. The use of a combination of MDM2 and WEE1 inhibitors, which termed "p53 potentiation with checkpoint abrogation" (PPCA), conferred significant therapeutic efficacy in treating mouse models of new onset T1D. Specific targeting of these T effector cells by PPCA results in a loss of inflammatory T cell subsets, notably proliferation CD4 + Th0 and Th1 subsets and CD8 + T effector memory cells, as determined by single cell RNA-seq studies with the preservation of T regulatory cells. When autologous islet grafts are given to established diabetic NOD mice, a single course of PPCA results in long-term islet graft acceptance, restoration of normoglycemia and loss of beta cell specific CD4 + and CD8 + T cells. PPCA shows promise as a potential means of estimating islet graft tolerance in T1D recipients of islet graft transplantation.

Alloreactive memory CD4 T cells promote transplant rejection by engaging DCs to induce innate inflammation and CD8 T cell priming.

Alloreactive memory T cells have been implicated as central drivers of transplant rejection. Perplexingly, innate cytokines, such as IL-6, IL-1ß, and IL-12, are also associated with rejection of organ transplants. However, the pathways of innate immune activation in allogeneic transplantation are unclear. While the role of microbial and cell death products has been previously described, we identified alloreactive memory CD4 T cells as the primary triggers of innate inflammation. Memory CD4 T cells engaged MHC II-mismatched dendritic cells (DCs), leading to the production of innate inflammatory cytokines. This innate inflammation was independent of several pattern recognition receptors and was primarily driven by TNF superfamily ligands expressed by alloreactive memory CD4 T cells. Blocking of CD40L and TNFα resulted in dampened inflammation, and mice genetically deficient in these molecules exhibited prolonged survival of cardiac allografts. Furthermore, myeloid cell and CD8 T cell infiltration into cardiac transplants was compromised in both CD40L- and TNFα-deficient recipients. Strikingly, we found that priming of naive alloreactive CD8 T cells was dependent on licensing of DCs by memory CD4 T cells. This study unravels the key mechanisms by which alloreactive memory CD4 T cells contribute to destructive pathology and transplant rejection.

Effects of Dual Inhibition at Dopamine Transporter and σ Receptors in the Discriminative-Stimulus Effects of Cocaine in Male Rats.

Previous studies demonstrated that sigma receptor (σR) antagonists alone fail to alter cocaine self-administration despite blocking various other effects of cocaine. However, σR antagonists when combined with dopamine transporter (DAT) inhibitors substantially decrease cocaine self-administration. To better understand the effects of this combination, the present study examined the effects of σR antagonist and DAT inhibitor combinations in male rats discriminating cocaine (10 mg/kg, i.p.) from saline injections. The DAT inhibitors alone [(-)-2-ß-carbomethoxy-3-ß-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate monohydrate (WIN 35,428) and methylphenidate] at low (0.1-mg/kg) doses that were minimally active failed to shift the dose-effect function for discriminative-stimulus effects of cocaine to the left more than 2-fold. At 0.32 mg/kg the DAT inhibitors alone shifted the cocaine dose-effect function leftward 24- or 6.6-fold, respectively. The σR antagonists (BD1008, BD1047, and BD1063) failed to fully substitute for cocaine, although BD1008 and BD1047 substituted partially. At 10 mg/kg, BD1008, BD1047, or BD1063 alone shifted the cocaine dose-effect function leftward less than 6.0-fold. In combination with 0.1 mg/kg WIN 35,428, the 10 mg/kg doses of σR antagonists shifted the cocaine dose-effect function from 12.3- to 36.7-fold leftward, and with 0.32 mg/kg WIN 35,428 from 14.3- to 440-fold leftward. In combination with 0.1 mg/kg methylphenidate, those σR antagonist doses shifted the cocaine dose-effect function from 5.5- to 55.0-fold leftward, and with 0.32 mg/kg methylphenidate from 10.5- to 48.1-fold leftward. The present results suggest that dual DAT/σR inhibition produces agonist-like subjective effects that may promote decreases in self-administration obtained in previous studies. SIGNIFICANCE STATEMENT: There is currently no approved medication for treating stimulant abuse, although dopamine uptake inhibitors in combination with sigma receptor (σR) antagonists decrease cocaine self-administration in laboratory animals. The present study assessed how this combination alters the discriminative-stimulus effects of cocaine in male rats. Results suggest that concurrent dopamine uptake inhibition and σR antagonism together may promote decreases in self-administration, possibly by mimicking the subjective effects extant when subjects cease continued cocaine self-administration.

Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

KLF5 inhibition initiates epithelial-mesenchymal transition in non-transformed human squamous epithelial cells.

The transcriptional regulator Krüppel-like factor 5 (KLF5) is highly expressed in squamous epithelial cells of the esophagus. Increased KLF5 activity induces tumorigenesis and promotes metastasis in several cancers, although this function appears to be context-dependent. Here, we demonstrate that acute KLF5 inhibition, both genetically and with the potent KLF5 inhibitor ML264, causes non-transformed human primary esophageal squamous epithelial cells to enter the epithelial to mesenchymal transition (EMT). Moreover, chronic KLF5 inhibition with ML264 leads to the development of cells with a mesenchymal phenotype characterized by the expression of mesenchymal markers and functionally by reduced cell growth and increased migration and cellular invasion. This EMT resulting from chronic KLF5 inhibition is not driven by ß-Catenin or TGF-ß signaling. Pharmacologically, ML264 inhibits KLF5 by promoting proteasomal-mediated degradation. Taken together, we demonstrate that reduced KLF5 activity reprograms epithelial cells towards a mesenchymal phenotype and enhances their migratory and invasive potential. These findings have potential implications not only for esophageal cancers but also for normal processes such as esophageal tissue repair following injury.

Holmium laser enucleation of the prostate for a case of transition zone prostate cancer.

Standard treatment approaches for localized prostate cancer remain limited to active surveillance, radiotherapy, and radical prostatectomy. We present a case of transition zone prostate cancer that was treated with holmium laser enucleation of the prostate, a procedure that is normally reserved for the management of benign prostatic hyperplasia.

Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.

INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R. RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFß1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFß1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.

Application of Natural Language Processing in Electronic Health Record Data Extraction for Navigating Prostate Cancer Care: A Narrative Review.

Introduction: Natural language processing (NLP)-based data extraction from electronic health records (EHRs) holds significant potential to simplify clinical management and aid research. This review aims to evaluate the current landscape of NLP-based data extraction in prostate cancer (PCa) management. Materials and Methods: We conducted a literature search of PubMed and Google Scholar databases using the keywords: "Natural Language Processing," "Prostate Cancer," "data extraction," and "EHR" with variations of each. No language or time limits were imposed. All results were collected in a standardized manner, including country of origin, sample size, algorithm, objective of outcome, and model performance. The precision, recall, and the F1 score of studies were collected as a metric of model performance. Results: Of the 14 studies included in the review, 2 articles focused on documenting digital rectal examinations, 1 on identifying and quantifying pain secondary to PCa, 8 on extracting staging/grading information from clinical reports, with an emphasis on TNM-classification, risk stratification, and identifying metastasis, 2 articles focused on patient-centered post-treatment outcomes such as incontinence, erectile, and bowel dysfunction, and 1 on loneliness/social isolation following PCa diagnosis. All models showed moderate to high data annotation/extraction accuracy compared with the gold standard method of manual data extraction by chart review. Despite their potential, NLPs face challenges in handling ambiguous, institution-specific language and context nuances, leading to occasional inaccuracies in clinical data interpretation. Conclusion: NLP-based data extraction has effectively extracted various outcomes from PCa patients' EHRs. It holds the potential for automating outcome monitoring and data collection, resulting in time and labor savings.

Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats.

Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.

Multimorbidity in Rheumatoid Arthritis: Literature Review and Future Directions.

PURPOSE OF REVIEW: To offer a narrative review of literature and an update on rheumatoid arthritis (RA) multimorbidity research over the past five years as well as future directions. RECENT FINDINGS: Patients with RA experience higher prevalence of multimorbidity (31-86% vs 18-71% in non-RA) and faster accumulation of comorbidities. Patients with multimorbidity have worse outcomes compared to non-RA multimorbid patients and RA without multimorbidity including mortality, cardiac events, and hospitalizations. Comorbid disease clusters often included: cardiopulmonary, cardiometabolic, and depression and pain-related conditions. High-frequency comorbidities included interstitial lung disease, asthma, chronic obstructive pulmonary disease, cardiovascular disease, fibromyalgia, osteoarthritis, and osteoporosis, thyroid disorders, hypertension, and cancer. Furthermore, patients with RA and multimorbidity are paradoxically at increased risk of high RA disease activity but experience a lower likelihood of biologic use and more biologic failures. RA patients experience higher prevalence of multimorbidity and worse outcomes versus non-RA and RA without multimorbidity. Findings call for further studies.

Prior viral infection primes cross-reactive CD8+ T cells that respond to mouse heart allografts.

Introduction: Significant evidence suggests a connection between transplant rejection and the presence of high levels of pre-existing memory T cells. Viral infection can elicit viral-specific memory T cells that cross-react with allo-MHC capable of driving allograft rejection in mice. Despite these advances, and despite their critical role in transplant rejection, a systematic study of allo-reactive memory T cells, their specificities, and the role of cross-reactivity with viral antigens has not been performed. Methods: Here, we established a model to identify, isolate, and characterize cross-reactive T cells using Nur77 reporter mice (C57BL/6 background), which transiently express GFP exclusively upon TCR engagement. We infected Nur77 mice with lymphocytic choriomeningitis virus (LCMV-Armstrong) to generate a robust memory compartment, where quiescent LCMV-specific memory CD8+ T cells could be readily tracked with MHC tetramer staining. Then, we transplanted LCMV immune mice with allogeneic hearts and monitored expression of GFP within MHC-tetramer defined viral-specific T cells as an indicator of their ability to cross-react with alloantigens. Results: Strikingly, prior LCMV infection significantly increased the kinetics and magnitude of rejection as well as CD8+ T cell recruitment into allogeneic, but not syngeneic, transplanted hearts, relative to non-infected controls. Interestingly, as early as day 1 after allogeneic heart transplant an average of ~8% of MHC-tetramer+ CD8+ T cells expressed GFP, in contrast to syngeneic heart transplants, where the frequency of viral-specific CD8+ T cells that were GFP+ was <1%. These data show that a significant percentage of viral-specific memory CD8+ T cells expressed T cell receptors that also recognized alloantigens in vivo. Notably, the frequency of cross-reactive CD8+ T cells differed depending upon the viral epitope. Further, TCR sequences derived from cross-reactive T cells harbored distinctive motifs that may provide insight into cross-reactivity and allo-specificity. Discussion: In sum, we have established a mouse model to track viral-specific, allo-specific, and cross-reactive T cells; revealing that prior infection elicits substantial numbers of viral-specific T cells that cross-react to alloantigen, respond very early after transplant, and may promote rapid rejection.

Integration of Patient-Derived Organoids and Organ-on-Chip Systems: Investigating Colorectal Cancer Invasion within the Mechanical and GABAergic Tumor Microenvironment.

Three-dimensional (3D) in vitro models are essential in cancer research, but they often neglect physical forces. In our study, we combined patient-derived tumor organoids with a microfluidic organ-on-chip system to investigate colorectal cancer (CRC) invasion in the tumor microenvironment (TME). This allowed us to create patient-specific tumor models and assess the impact of physical forces on cancer biology. Our findings showed that the organoid-on-chip models more closely resembled patient tumors at the transcriptional level, surpassing organoids alone. Using 'omics' methods and live-cell imaging, we observed heightened responsiveness of KRAS mutant tumors to TME mechanical forces. These tumors also utilized the γ-aminobutyric acid (GABA) neurotransmitter as an energy source, increasing their invasiveness. This bioengineered model holds promise for advancing our understanding of cancer progression and improving CRC treatments.

Synthesis and anti-cancer potential of potent peripheral MAOA inhibitors designed to limit blood:brain penetration.

Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi's) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of decreasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH2 or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N-methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications.

Neutrophils in Cancer and Potential Therapeutic Strategies Using Neutrophil-Derived Exosomes.

Neutrophils are the most abundant immune cells and make up about 70% of white blood cells in human blood and play a critical role as the first line of defense in the innate immune response. They also help regulate the inflammatory environment to promote tissue repair. However, in cancer, neutrophils can be manipulated by tumors to either promote or hinder tumor growth depending on the cytokine pool. Studies have shown that tumor-bearing mice have increased levels of neutrophils in peripheral circulation and that neutrophil-derived exosomes can deliver various cargos, including lncRNA and miRNA, which contribute to tumor growth and degradation of extracellular matrix. Exosomes derived from immune cells generally possess anti-tumor activities and induce tumor-cell apoptosis by delivering cytotoxic proteins, ROS generation, H2O2 or activation of Fas-mediated apoptosis in target cells. Engineered exosome-like nanovesicles have been developed to deliver chemotherapeutic drugs precisely to tumor cells. However, tumor-derived exosomes can aggravate cancer-associated thrombosis through the formation of neutrophil extracellular traps. Despite the advancements in neutrophil-related research, a detailed understanding of tumor-neutrophil crosstalk is still lacking and remains a major barrier in developing neutrophil-based or targeted therapy. This review will focus on the communication pathways between tumors and neutrophils, and the role of neutrophil-derived exosomes (NDEs) in tumor growth. Additionally, potential strategies to manipulate NDEs for therapeutic purposes will be discussed.