Rutinosides-derived from Sarocladium strictum 6-O-α-rhamnosyl-ß-glucosidase show enhanced anti-tumoral activity in pancreatic cancer cells.

BACKGROUND: Low targeting efficacy and high toxicity continue to be challenges in Oncology. A promising strategy is the glycosylation of chemotherapeutic agents to improve their pharmacodynamics and anti-tumoral activity. Herein, we provide evidence of a novel approach using diglycosidases from fungi of the Hypocreales order to obtain novel rutinose-conjugates therapeutic agents with enhanced anti-tumoral capacity. RESULTS: Screening for diglycosidase activity in twenty-eight strains of the genetically related genera Acremonium and Sarocladium identified 6-O-α-rhamnosyl-ß-glucosidase (αRßG) of Sarocladium strictum DMic 093557 as candidate enzyme for our studies. Biochemically characterization shows that αRßG has the ability to transglycosylate bulky OH-acceptors, including bioactive compounds. Interestingly, rutinoside-derivatives of phloroglucinol (PR) resorcinol (RR) and 4-methylumbelliferone (4MUR) displayed higher growth inhibitory activity on pancreatic cancer cells than the respective aglycones without significant affecting normal pancreatic epithelial cells. PR exhibited the highest efficacy with an IC50 of 0.89 mM, followed by RR with an IC50 of 1.67 mM, and 4MUR with an IC50 of 2.4 mM, whereas the respective aglycones displayed higher IC50 values: 4.69 mM for phloroglucinol, 5.90 mM for resorcinol, and 4.8 mM for 4-methylumbelliferone. Further, glycoconjugates significantly sensitized pancreatic cancer cells to the standard of care chemotherapy agent gemcitabine. CONCLUSIONS: αRßG from S. strictum transglycosylate-based approach to synthesize rutinosides represents a suitable option to enhance the anti-proliferative effect of bioactive compounds. This finding opens up new possibilities for developing more effective therapies for pancreatic cancer and other solid malignancies.

How we perceive the width of grasped objects: Insights into the central processes that govern proprioceptive judgements.

Low-level proprioceptive judgements involve a single frame of reference, whereas high-level proprioceptive judgements are made across different frames of reference. The present study systematically compared low-level (grasp → $\rightarrow$ grasp) and high-level (vision → $\rightarrow$ grasp, grasp → $\rightarrow$ vision) proprioceptive tasks, and quantified the consistency of grasp → $\rightarrow$ vision and possible reciprocal nature of related high-level proprioceptive tasks. Experiment 1 (n = 30) compared performance across vision → $\rightarrow$ grasp, a grasp → $\rightarrow$ vision and a grasp → $\rightarrow$ grasp tasks. Experiment 2 (n = 30) compared performance on the grasp → $\rightarrow$ vision task between hands and over time. Participants were accurate (mean absolute error 0.27 cm [0.20 to 0.34]; mean [95% CI]) and precise ( R 2 $R^2$ = 0.95 [0.93 to 0.96]) for grasp → $\rightarrow$ grasp judgements, with a strong correlation between outcomes (r = -0.85 [-0.93 to -0.70]). Accuracy and precision decreased in the two high-level tasks ( R 2 $R^2$ = 0.86 and 0.89; mean absolute error = 1.34 and 1.41 cm), with most participants overestimating perceived width for the vision → $\rightarrow$ grasp task and underestimating it for grasp → $\rightarrow$ vision task. There was minimal correlation between accuracy and precision for these two tasks. Converging evidence indicated performance was largely reciprocal (inverse) between the vision → $\rightarrow$ grasp and grasp → $\rightarrow$ vision tasks. Performance on the grasp → $\rightarrow$ vision task was consistent between dominant and non-dominant hands, and across repeated sessions a day or week apart. Overall, there are fundamental differences between low- and high-level proprioceptive judgements that reflect fundamental differences in the cortical processes that underpin these perceptions. Moreover, the central transformations that govern high-level proprioceptive judgements of grasp are personalised, stable and reciprocal for reciprocal tasks. KEY POINTS: Low-level proprioceptive judgements involve a single frame of reference (e.g. indicating the width of a grasped object by selecting from a series of objects of different width), whereas high-level proprioceptive judgements are made across different frames of reference (e.g. indicating the width of a grasped object by selecting from a series of visible lines of different length). We highlight fundamental differences in the precision and accuracy of low- and high-level proprioceptive judgements. We provide converging evidence that the neural transformations between frames of reference that govern high-level proprioceptive judgements of grasp are personalised, stable and reciprocal for reciprocal tasks. This stability is likely key to precise judgements and accurate predictions in high-level proprioception.

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation.

Background and Objective: Prostate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. Methods: A novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Results: unveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. Conclusion: The lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.

The Metabolism and Disposition of Brepocitinib in Humans and Characterization of the Formation Mechanism of an Aminopyridine Metabolite.

Brepocitinib is an oral once-daily Janus kinase 1 and Tyrosine kinase 2 selective inhibitor currently in development for the treatment of several autoimmune disorders. Mass balance and metabolic profiles were determined using accelerator mass spectrometry in six healthy male participants following a single oral 60 mg dose of 14C-brepocitinib (~300 nCi). The average mass balance recovery was 96.7% {plus minus} 6.3% with the majority of dose (88.0% {plus minus} 8.0%) recovered in urine and 8.7% {plus minus} 2.1% of the dose in recovered in feces. Absorption of brepocitinib was rapid, with maximal plasma concentrations of total radioactivity and brepocitinib achieved within 0.5 hours after dosing. Circulating radioactivity consisted primarily of brepocitinib (47.8%) and metabolite M1 (37.1%) derived from hydroxylation at the C5' position of the pyrazole ring. Fractional contributions to metabolism via cytochrome P450 (CYP) enzymes were determined to be 0.77 for CYP3A4/5 and 0.14 for CYP1A2 based on phenotyping studies in HLM. However, additional clinical studies are required to understand the potential contribution of CYP1A1. Approximately 83% of the dose was eliminated as N-methylpyrazolyl oxidative metabolites, with 52.1% of the dose excreted as M1 alone. Notably, M1 was not observed as a circulating metabolite in earlier metabolic profiling of human plasma from a multiple ascending study with unlabeled brepocitinib. Mechanistic studies revealed M1 was highly unstable in human plasma and phosphate buffer, undergoing chemical oxidation leading to loss of the 5-hydroxy-1-methylpyrazole moiety and formation of aminopyrimidine cleavage product M2. Time dependent inhibition and trapping studies with M1 yielded insights into the mechanism of this unusual and unexpected instability. Significance Statement This work describes the mass balance and metabolic profile of brepocitinib in human, a JAK1/TYK2 inhibitor being developed for treatment of autoimmune diseases.

Specific Birth Defects Following Antiseizure Medications Used By Pregnant Women With Epilepsy.

Background and Objectives: Previous research has been limited in the comprehensive study of associations between the use of individual antiseizure medications (ASMs) in pregnancy and specific groups of birth defects, and systematic reviews and meta-analyses on the topic are limited by pooled samples and study designs. This study investigated birth defects related to ASM use in pregnancy in children born to women with epilepsy in Sweden over 20 years. Methods: We used data from Swedish national registers to follow a cohort of 17,996 children born to women diagnosed with epilepsy any time before conception in Sweden from 1996 to 2016, following them through 2017. We examined maternal-reported use of the 4 most commonly reported ASMs: lamotrigine (n = 2,148, 11.9%), carbamazepine (n = 1,940, 10.8%), valproic acid (n = 1,043, 5.80%), and levetiracetam (n = 587, 3.26%). We identified birth defects using diagnoses recorded at the time of discharge from the hospital and inpatient and outpatient diagnoses recorded in the first year of life. Models were estimated in a stepped fashion: unadjusted, adjusted for covariates, among a subcohort born to women diagnosed 10 years before conception (n = 14,586), and restricted to monotherapy. Results: Valproic acid use in pregnancy had the strongest and most widespread associations with birth defects in children, with carbamazepine also having links to several birth defects, including respiratory system and genital organ defects. Lamotrigine use in pregnancy was associated with cleft lip/palate and chromosomal abnormalities. Levetiracetam was most often used with other ASMs and preliminarily associated with many birth defects. Discussion: Our findings support avoidance of valproic acid use in pregnancy whenever possible. Lamotrigine and carbamazepine may be safer alternatives. However, these medications were also associated with certain birth defects, including some not reported previously. We are among the first to examine the possible effects of levetiracetam use in pregnancy, though more research is needed to investigate this further.

Facility- and patient-level factors associated with implementation of contact precautions in hospitalized VA patients with positive CRE cultures.

Decreasing the time to contact precautions (CP) is critical to carbapenem-resistant Enterobacterales (CRE) prevention. Identifying factors associated with delayed CP can decrease the spread from patients with CRE. In this study, a shorter length of stay was associated with being placed in CP within 3 days.

Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors.

This study identified tumorigenic processes most dependent on murine HSP72 in the MMTV-PyMT mammary tumor model, which give rise to spontaneous mammary tumors that exhibit HSP72-dependent metastasis to the lung. RNA-seq expression profiling of Hspa1a/Hspa1b (Hsp72) WT and Hsp72-/- primary mammary tumors discovered significantly lower expression of genes encoding components of the extracellular matrix (ECM) in Hsp72 knockout mammary tumors compared to WT controls. In vitro studies found that genetic or chemical inhibition of HSP72 activity in cultured collagen-expressing human or murine cells also reduces mRNA and protein levels of COL1A1 and several other ECM-encoding genes. In search of a possible mechanistic basis for this relationship, we found HSP72 to support the activation of the TGF-ß - SMAD3 signaling pathway and evidence of SMAD3 and HSP72 co-precipitation, suggesting potential complex formation. Human COL1A1 mRNA expression was found to have prognostic value for HER2+ breast tumors over other breast cancer subtypes, suggesting a possible human disease context where targeting HSP72 may have a therapeutic rationale. Analysis of human HER2+ breast tumor gene expression data using a gene set comprising ECM- and protein folding-related genes as an input to the statistical learning algorithm, Galgo, found a subset of these genes that can collectively stratify patients by relapse-free survival, further suggesting a potential interplay between the ECM and protein-folding genes may contribute to tumor progression.

Lateral Flow Assay Biotesting by Utilizing Plasmonic Nanoparticles Made of Inexpensive Metals─Replacing Colloidal Gold.

Nanoparticles (NPs) can be conjugated with diverse biomolecules and employed in biosensing to detect target analytes in biological samples. This proven concept was primarily used during the COVID-19 pandemic with gold-NP-based lateral flow assays (LFAs). Considering the gold price and its worldwide depletion, here we show that novel plasmonic NPs based on inexpensive metals, titanium nitride (TiN) and copper covered with a gold shell (Cu@Au), perform comparable to or even better than gold nanoparticles. After conjugation, these novel nanoparticles provided high figures of merit for LFA testing, such as high signals and specificity and robust naked-eye signal recognition. Since the main cost of Au NPs in commercial testing kits is the colloidal synthesis, our development with the Cu@Au and the laser-ablation-fabricated TiN NPs is exciting, offering potentially inexpensive plasmonic nanomaterials for various bioapplications. Moreover, our machine learning study showed that biodetection with TiN is more accurate than that with Au.

Somatic Mutations in Surgically Treated Colorectal Liver Metastases: An Overview.

Colorectal cancer is the second most common cause of cancer death in the United States, and up to half of patients develop colorectal liver metastases (CRLMs). Notably, somatic genetic mutations, such as mutations in RAS, BRAF, mismatch repair (MMR) genes, TP53, and SMAD4, have been shown to play a prognostic role in patients with CRLM. This review summarizes and appraises the current literature regarding the most relevant somatic mutations in surgically treated CRLM by not only reviewing representative studies, but also providing recommendations for areas of future research. In addition, advancements in genetic testing and an increasing emphasis on precision medicine have led to a more nuanced understanding of these mutations; thus, more granular data for each mutation are reviewed when available. Importantly, such knowledge can pave the way for precision medicine with the ultimate goal of improving patient outcomes.

Resumen ejecutivo del documento de consenso sobre el manejo de la anemia perioperatoria en España / Executive summary of the consensus document on the management of perioperative anemia in Spain

La anemia perioperatoria constituye un factor independiente de riesgo de morbimortalidad posoperatoria. Sin embargo, persisten barreras conceptuales, logísticas y administrativas que dificultan la implementación generalizada de protocolos para su manejo. El coordinador del proyecto convocó a un grupo multidisciplinar de ocho profesionales para elaborar un documento de consenso sobre el manejo de la anemia perioperatoria, con base a en serie puntos claves (PCs) relativos a su prevalencia, consecuencias, diagnóstico y tratamiento. Estos PCs fueron evaluados utilizando una escala Likert de 5 puntos, desde «totalmente en desacuerdo [1]» a «totalmente de acuerdo [5]». Cada PC se consideró consensuado si recibía una puntuación de 4 o 5 por al menos siete participantes (> 75%). A partir de los 36 PCs consensuados, se construyeron algoritmos diagnóstico-terapéuticos que pueden facilitar la implementación de programas de identificación precoz y manejo adecuado de la anemia perioperatoria, adaptados a las características de las instituciones hospitalarias de nuestro país.(AU)

Perioperative anemia is an independent risk factor for postoperative morbidity and mortality. However, conceptual, logistical and administrative barriers persist that hinder the widespread implementation of protocols for their management. The project coordinator convened a multidisciplinary group of 9 experienced professionals to develop perioperative anemia management algorithms, based on a series of key points (KPs) related to its prevalence, consequences, diagnosis and treatment. These KPs were assessed using a 5-point Likert scale, from “strongly disagree [1]” to “strongly agree [5]”. For each KP, consensus was reached when receiving a score of 4 or 5 from at least 7 participants (>75%). Based on the 36 KPs agreed upon, diagnostic-therapeutic algorithms were developed that we believe can facilitate the implementation of programs for early identification and adequate management of perioperative anemia, adapted to the characteristics of the different institutions in our country.(AU)

Design of the Dutch multicentre study on opportunistic screening of geriatric patients for atrial fibrillation using a smartphone PPG app: the Dutch-GERAF study.

BACKGROUND: Screening of high-risk patients is advocated to achieve early detection and treatment of clinical atrial fibrillation (AF). The Dutch-GERAF study will address two major issues. Firstly, the effectiveness and feasibility of an opportunistic screening strategy for clinical AF will be assessed in frail older patients and, secondly, observational data will be gathered regarding the efficacy and safety of oral anticoagulation (OAC). METHODS: This is a multicentre study on opportunistic screening of geriatric patients for clinical AF using a smartphone photoplethysmography (PPG) application. Inclusion criteria are age ≥ 65 years and the ability to perform at least three PPG recordings within 6 months. Exclusion criteria are the presence of a cardiac implantable device, advanced dementia or a severe tremor. The PPG application records patients' pulse at their fingertip and determines the likelihood of clinical AF. If clinical AF is suspected after a positive PPG recording, a confirmatory electrocardiogram is performed. Patients undergo a comprehensive geriatric assessment and a frailty index is calculated. Risk scores for major bleeding (MB) are applied. Standard laboratory testing and additional laboratory analyses are performed to determine the ABC-bleeding risk score. Follow-up data will be collected at 6 months, 12 months and 3 years on the incidence of AF, MB, hospitalisation, stroke, progression of cognitive disorders and mortality. DISCUSSION: The Dutch-GERAF study will focus on frail older patients, who are underrepresented in randomised clinical trials. It will provide insight into the effectiveness of screening for clinical AF and the efficacy and safety of OAC in this high-risk population. TRIAL REGISTRATION: NCT05337202.

Long-Term Second Malignancies in Prostate Cancer Patients Treated With Low-Dose-Rate Brachytherapy and Radical Prostatectomy.

PURPOSE: Second malignancy is a rare but potentially lethal event after prostate brachytherapy, but data remain scarce on its long-term risk. The objective of this study is to estimate the number of pelvic second malignancies following brachytherapy compared to radical prostatectomy (RP). MATERIALS AND METHODS: We retrospectively reviewed patients treated with low-dose 125I brachytherapy and RP in British Columbia from 1999 to 2010. Kaplan-Meier estimates for pelvic (bladder and rectum), invasive pelvic, any second malignancy, and death from any second malignancy were assessed. Cox multivariable analyses were performed adjusting for initial treatment type, age, post-RP adjuvant/salvage external beam radiation therapy status, and smoking history. RESULTS: Two thousand three hundred seventy-eight brachytherapy and 9089 RP patients were included. Median age was 66 years (interquartile range [IQR] 61-71) and 63 years (IQR 58-67), respectively. Median follow-up time to event or censured was 14 years (IQR 11.5-17.3). The Kaplan-Meier estimates for pelvic second malignancy at 15 and 20 years were 6.4% and 9.8%, respectively, after brachytherapy, and 3.2% and 4.2% after RP. Time to any second malignancy and time to death from any second malignancy were not significantly different (P > .05). On Cox multivariable analysis, brachytherapy, compared to surgery, was an independent factor for pelvic (hazard ratio [HR] 1.81 [95% CI 1.45-2.26], P < .001) and invasive pelvic second malignancy (HR 2.13 [95% CI 1.61-2.83], P < .001). Increased age and smoking were also associated with higher estimates of events (P < .001). CONCLUSIONS: After adjustment for age, post-RP adjuvant/salvage external beam radiation therapy status, and smoking status, numerically higher long-term HRs of pelvic and invasive pelvic second malignancy in patients treated with brachytherapy compared to RP were noted.

Associating protein sequence positions with the modulation of quantitative phenotypes.

Although protein sequences encode the information for folding and function, understanding their link is not an easy task. Unluckily, the prediction of how specific amino acids contribute to these features is still considerably impaired. Here, we developed a simple algorithm that finds positions in a protein sequence with potential to modulate the studied quantitative phenotypes. From a few hundred protein sequences, we perform multiple sequence alignments, obtain the per-position pairwise differences for both the sequence and the observed phenotypes, and calculate the correlation between these last two quantities. We tested our methodology with four cases: archaeal Adenylate Kinases and the organisms optimal growth temperatures, microbial rhodopsins and their maximal absorption wavelengths, mammalian myoglobins and their muscular concentration, and inhibition of HIV protease clinical isolates by two different molecules. We found from 3 to 10 positions tightly associated with those phenotypes, depending on the studied case. We showed that these correlations appear using individual positions but an improvement is achieved when the most correlated positions are jointly analyzed. Noteworthy, we performed phenotype predictions using a simple linear model that links per-position divergences and differences in the observed phenotypes. Predictions are comparable to the state-of-art methodologies which, in most of the cases, are far more complex. All of the calculations are obtained at a very low information cost since the only input needed is a multiple sequence alignment of protein sequences with their associated quantitative phenotypes. The diversity of the explored systems makes our work a valuable tool to find sequence determinants of biological activity modulation and to predict various functional features for uncharacterized members of a protein family.

Multimodal Treatment of Pleural Mesothelioma with Cytoreductive Surgery and Hyperthermic Intrathoracic Chemotherapy: Impact of Additive Chemotherapy.

Cytoreductive surgery (CRS) combined with hyperthermic intrathoracic chemoperfusion (HITOC) is a promising treatment strategy for pleural mesothelioma (PM). The aim of this study was to evaluate the impacts of this multimodal approach in combination with systemic treatment on disease-free survival (DFS) and overall survival (OS). In this retrospective multicenter study, clinical data from patients after CRS and HITOC for PM at four high-volume thoracic surgery departments in Germany were analyzed. A total of 260 patients with MPM (220 epithelioid, 40 non-epithelioid) underwent CRS and HITOC as part of a multimodal treatment approach. HITOC was administered with cisplatin alone (58.5%) or cisplatin and doxorubicin (41.5%). In addition, 52.1% of patients received neoadjuvant and/or adjuvant chemotherapy. The median follow-up was 48 months (IQR = 38 to 58 months). In-hospital mortality was 3.5%. Both the resection status (macroscopic complete vs. incomplete resection) and histologic subtype (epithelioid vs. non-epithelioid) had significant impacts on DFS and OS. In addition, adjuvant chemotherapy (neoadjuvant/adjuvant) significantly increased DFS (p = 0.003). CRS and HITOC within a multimodal treatment approach had positive impacts on the survival of patients with epithelioid PM after macroscopic complete resection. The addition of chemotherapy significantly prolonged the time to tumor recurrence or progression.

NKp44/HLA-DP-dependent regulation of CD8 effector T cells by NK cells.

Although natural killer (NK) cells are recognized for their modulation of immune responses, the mechanisms by which human NK cells mediate immune regulation are unclear. Here, we report that expression of human leukocyte antigen (HLA)-DP, a ligand for the activating NK cell receptor NKp44, is significantly upregulated on CD8+ effector T cells, in particular in human cytomegalovirus (HCMV)+ individuals. HLA-DP+ CD8+ T cells expressing NKp44-binding HLA-DP antigens activate NKp44+ NK cells, while HLA-DP+ CD8+ T cells not expressing NKp44-binding HLA-DP antigens do not. In line with this, frequencies of HLA-DP+ CD8+ T cells are increased in individuals not encoding for NKp44-binding HLA-DP haplotypes, and contain hyper-expanded CD8+ T cell clones, compared to individuals expressing NKp44-binding HLA-DP molecules. These findings identify a molecular interaction facilitating the HLA-DP haplotype-specific editing of HLA-DP+ CD8+ T cell effector populations by NKp44+ NK cells and preventing the generation of hyper-expanded T cell clones, which have been suggested to have increased potential for autoimmunity.

IRX4204 Induces Senescence and Cell Death in HER2-positive Breast Cancer and Synergizes with Anti-HER2 Therapy.

PURPOSE: Rexinoids, agonists of nuclear retinoid X receptor (RXR), have been used for the treatment of cancers and are well-tolerated in both animals and humans. However, the usefulness of rexinoids in treatment of breast cancer remains unknown. This study examines the efficacy of IRX4204, a highly specific rexinoid, in breast cancer cell lines and preclinical models to identify a biomarker for response and potential mechanism of action. EXPERIMENTAL DESIGN: IRX4204 effects on breast cancer cell growth and viability were determined using cell lines, syngeneic mouse models and primary PDX tumors. In vitro assays of cell cycle, apoptosis, senescence, and lipid metabolism were used to uncover a potential mechanism of action. Standard anti-HER2 therapies were screened in combination with IRX4204 on a panel of breast cancer cell lines to determine drug synergy. RESULTS: IRX4204 significantly inhibits the growth of HER2-positive breast cancer cell lines, including trastuzumab and lapatinib resistant JIMT-1 and HCC1954. Treatment with IRX4204 reduced tumor growth rate in the MMTV-ErbB2 mouse and HER2-positive PDX model by 49% and 44% respectively. Mechanistic studies revealed IRX4204 modulates lipid metabolism and induces senescence of HER2-positive cells. In addition, IRX4204 demonstrates additivity and synergy with HER2 targeted monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates. CONCLUSIONS: These findings identify HER2 as a biomarker for IRX4204 treatment response and demonstrate a novel use of RXR agonists to synergize with current anti-HER2 therapies. Furthermore, our results suggest that RXR agonists can be useful for the treatment of anti-HER2 resistant and metastatic HER2-positive breast cancer.

Electrical stimulation of the cuneiform nucleus enhances the effects of rehabilitative training on locomotor recovery after incomplete spinal cord injury.

Most human spinal cord injuries are anatomically incomplete, leaving some fibers still connecting the brain with the sublesional spinal cord. Spared descending fibers of the brainstem motor control system can be activated by deep brain stimulation (DBS) of the cuneiform nucleus (CnF), a subnucleus of the mesencephalic locomotor region (MLR). The MLR is an evolutionarily highly conserved structure which initiates and controls locomotion in all vertebrates. Acute electrical stimulation experiments in female adult rats with incomplete spinal cord injury conducted in our lab showed that CnF-DBS was able to re-establish a high degree of locomotion five weeks after injury, even in animals with initially very severe functional deficits and white matter lesions up to 80-95%. Here, we analyzed whether CnF-DBS can be used to support medium-intensity locomotor training and long-term recovery in rats with large but incomplete spinal cord injuries. Rats underwent rehabilitative training sessions three times per week in an enriched environment, either with or without CnF-DBS supported hindlimb stepping. After 4 weeks, animals that trained under CnF-DBS showed a higher level of locomotor performance than rats that trained comparable distances under non-stimulated conditions. The MLR does not project to the spinal cord directly; one of its main output targets is the gigantocellular reticular nucleus in the medulla oblongata. Long-term electrical stimulation of spared reticulospinal fibers after incomplete spinal cord injury via the CnF could enhance reticulospinal anatomical rearrangement and in this way lead to persistent improvement of motor function. By analyzing the spared, BDA-labeled giganto-spinal fibers we found that their gray matter arborization density after discontinuation of CnF-DBS enhanced training was lower in the lumbar L2 and L5 spinal cord in stimulated as compared to unstimulated animals, suggesting improved pruning with stimulation-enhanced training. An on-going clinical study in chronic paraplegic patients investigates the effects of CnF-DBS on locomotor capacity.

Scenarios of future mpox outbreaks among men who have sex with men: a modelling study based on cross-sectional seroprevalence data from the Netherlands, 2022.

BackgroundFollowing the 2022-2023 mpox outbreak, crucial knowledge gaps exist regarding orthopoxvirus-specific immunity in risk groups and its impact on future outbreaks.AimWe combined cross-sectional seroprevalence studies in two cities in the Netherlands with mathematical modelling to evaluate scenarios of future mpox outbreaks among men who have sex with men (MSM).MethodsSerum samples were obtained from 1,065 MSM attending Centres for Sexual Health (CSH) in Rotterdam or Amsterdam following the peak of the Dutch mpox outbreak and the introduction of vaccination. For MSM visiting the Rotterdam CSH, sera were linked to epidemiological and vaccination data. An in-house developed ELISA was used to detect vaccinia virus (VACV)-specific IgG. These observations were combined with published data on serial interval and vaccine effectiveness to inform a stochastic transmission model that estimates the risk of future mpox outbreaks.ResultsThe seroprevalence of VACV-specific antibodies was 45.4% and 47.1% in Rotterdam and Amsterdam, respectively. Transmission modelling showed that the impact of risk group vaccination on the original outbreak was likely small. However, assuming different scenarios, the number of mpox cases in a future outbreak would be markedly reduced because of vaccination. Simultaneously, the current level of immunity alone may not prevent future outbreaks. Maintaining a short time-to-diagnosis is a key component of any strategy to prevent new outbreaks.ConclusionOur findings indicate a reduced likelihood of large future mpox outbreaks among MSM in the Netherlands under current conditions, but emphasise the importance of maintaining population immunity, diagnostic capacities and disease awareness.