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The microbiome is a complex host factor and key determinant of the outcome of antibody-based and cellular immunotherapy. Its postbiotics are a blend of soluble commensal byproducts that are released into the host environment and have been associated with the regulation of immune homeostasis, particularly through impacts on epigenetics and cell signaling. In this study, we show that the postbiotic pentanoate is metabolized to citrate within the TCA cycle via both the acetyl- and succinyl-CoA entry points, a feature uniquely enabled by the chemical structure of the C5 aliphatic chain. We identified ATP-citrate lyase as the crucial factor that redirects pentanoate-derived citrate from the succinyl-CoA route to the nucleus, thereby linking metabolic output and histone acetylation. This epigenetic-metabolic crosstalk mitigated T cell exhaustion and promoted naive-like differentiation in pentanoate-programmed chimeric antigen receptor (CAR) T cells. The predictive and therapeutic potential of pentanoate was corroborated in two independent patient cohorts and three syngeneic models of CAR T adoptive therapy. Our data demonstrate that postbiotics are integrated into mitochondrial metabolism and subsequently incorporated as epigenetic imprints. This bridge between microbial and mammalian interspecies communication can ultimately impact T cell differentiation and efficacy.

We report a rhenium diimine photosensitizer equipped with a peripheral disulfide unit on one of the bipyridine ligands, [Re(CO) 3 (bpy)( S-S bpy 4,4 )] + ( 1 + , bpy = 2,2'-bipyridine, S-S bpy 4,4 = [1,2]dithiino[3,4- c :6,5- c ']dipyridine), showing anti-Kasha luminescence. Steady-state and ultrafast time-resolved spectroscopies complemented by nonadiabatic dynamics simulations are used to disclose its excited-state dynamics. The calculations show that after intersystem crossing the complex evolves to two different triplet minima: a ( S-S bpy 4,4 )-ligand-centered excited state ( 3 LC) lying at lower energy and a metal-to-(bpy)-ligand charge transfer ( 3 MLCT) state at higher energy, with relative yields of 90% and 10%, respectively. The 3 LC state involves local excitation of the disulfide group into the antibonding σ* orbital, leading to significant elongation of the S-S bond. Intriguingly, it is the higher-lying 3 MLCT state, which is assigned to display luminescence with a lifetime of 270 ns: a signature of anti-Kasha behavior. This assignment is consistent with an energy barrier ≥ 0.6 eV or negligible electronic coupling, preventing reaction toward the 3 LC state after the population is trapped in the 3 MLCT state. This study represents a striking example on how elusive excited-state dynamics of transition-metal photosensitizers can be deciphered by synergistic experiments and state-of-the-art calculations. Disulfide functionalization lays the foundation of a new design strategy toward harnessing excess energy in a system for possible bimolecular electron or energy transfer reactivity.

Background: Chronic primary pelvic pain syndrome in men (CPPPSm) can be associated with urogenital pain, urinary symptoms, sexual dysfunction, and emotional disturbance. Its clinical heterogeneity and incompletely understood pathogenesis make it more difficult to treat. This article is intended to familiarize the reader with basic aspects of the manifestations, pathophysiology, diagnostic evaluation, differential diagnosis, and treatment of this condition., Methods: This article is based on relevant publications retrieved by a selective search of the literature, including the current guidelines of the European Association of Urology. The features of this disease pertaining to urology, psychosomatic medicine, and pain medicine are illuminated from an interdisciplinary perspective., Results: Chronic pelvic pain appears to arise through a complex interaction of inflammatory, infectious, neurological, musculoskeletal, and psychosomatic factors. A comprehensive diagnostic work-up should be carried out to evaluate and exclude the numerous differential diagnoses. Treatment strategies are based on the clinical phenotype. Randomized controlled trials have shown that significant relief can be achieved with a variety of drugs and non-pharmacological treatments, selected according to the manifestations of the condition in the individual case. Attention must be paid to treatment-specific adverse effects., Conclusion: The management of patients with CPPPSm should consist of a comprehensive differential diagnostic evaluation and an individually oriented treatment strategy.

Selective loss of inhibitory interneurons (INs) that promotes a shift toward an excitatory predominance may have a critical impact on the generation of epileptic activity. While research on mesial temporal lobe epilepsy (MTLE) has mostly focused on hippocampal changes, including IN loss, the subiculum as the major output region of the hippocampal formation has received less attention. The subiculum has been shown to occupy a key position in the epileptic network, but data on cellular alterations are controversial. Using the intrahippocampal kainate (KA) mouse model for MTLE, which recapitulates main features of human MTLE such as unilateral hippocampal sclerosis and granule cell dispersion, we identified cell loss in the subiculum and quantified changes in specific IN subpopulations along its dorso-ventral axis. We performed intrahippocampal recordings, FluoroJade C-staining for degenerating neurons shortly after status epilepticus (SE), fluorescence in situ hybridization for glutamic acid decarboxylase ( Gad) 67 mRNA and immunohistochemistry for neuronal nuclei (NeuN), parvalbumin (PV), calretinin (CR) and neuropeptide Y (NPY) at 21 days after KA. We observed remarkable cell loss in the ipsilateral subiculum shortly after SE, reflected in lowered density of NeuN+ cells in the chronic stage when epileptic activity occurred in the subiculum concomitantly with the hippocampus. In addition, we show a position-dependent reduction of Gad67 -expressing INs by ∼50% (along the dorso-ventral as well as transverse axis of the subiculum). This particularly affected the PV- and to a lesser extent CR-expressing INs. The density of NPY-positive neurons was increased, but the double-labeling for Gad67 mRNA expression revealed that an upregulation or de novo expression of NPY in non-GABAergic cells with a concomitant reduction of NPY-positive INs underlies this observation. Our data suggest a position- and cell type-specific vulnerability of subicular INs in MTLE, which might contribute to hyperexcitability of the subiculum, reflected in epileptic activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Franz, Barheier, Wilms, Tulke, Haas and Häussler.)

Due to the large number of men affected and a variable clinical presentation, the widespread disease "benign prostatic syndrome" requires individual treatment options tailored to the patient's specific clinical characteristics and wishes. If surgical treatment is indicated, there is a wide range of invasive procedures available. For a long time, transurethral resection of the prostate and simple prostatectomy were considered the gold standard, but these procedures are associated with increased morbidity and limitations in sexual function. Therefore, there is now an increasing call for minimally invasive treatment options that will provide effective and safe treatment in the outpatient setting. Over the past years, a variety of technologies and procedures have been developed and tested, but only a few of them have found their way into clinical practice, mostly due to insufficient functional results. For instance, transurethral needle ablation, transurethral microwave thermotherapy, intraprostatic botulinum toxin A or PRX302 injections as well as prostatic stents are no longer recommended. In contrast, the European Association of Urology is currently recommending UroLift, Aquablation and prostatic artery embolisation, which achieve significant long-term improvements in functional parameters while providing a good safety profile and preserved sexual function. Promising data are also available for the temporarily implanted nitinol device (iTIND), Rezūm, intraprostatic injection of fexapotide triflutate and transperineal laser ablation of the prostate, but the efficacy and safety of these procedures need to be confirmed in further studies., Competing Interests: J. Franz erklärt, dass keine Interessenskonflikte bestehen. C. Gratzke erhielt Honorare für Beratertätigkeiten von Astellas, Ipsen, Janssen, Steba, Bayer, Olympus, Medi-Tate, MSD, Astra-Zeneca und Roche. Ihm wurden Teilnahmegebühren für Kongresse erstattet von Astellas, Olympus und Recordati. Ihm wurden Erstattungen für Reise- und Übernachtungskosten zuteil von Procept, Olympus, Medi-Tate, MSD, Astra-Zeneca, Roche, GSK und Recordati. Für die Vorbereitung von wissenschaftlichen Fortbildungsveranstaltungen, bei denen ein Bezug zum Thema besteht, wurde er honoriert von Astellas, Amgen, Ipsen, Janssen, Bayer, Takeda und Medac. Für die Durchführung von klinischen Auftragsstudien erhielt er Gelder von Astellas Pharma, Neotract, Medi-Tate und Recordati. Gelder für ein von ihm initiiertes Forschungsvorhaben bekam er von Recordati und Medi-Tate. A. Miernik erhält Forschungsmittel durch das Bundesministerium für Bildung und Forschung (BMBF), Berlin (D). Unterstützung für seine Reisetätigkeit erfährt er durch die Europäische Gesellschaft für Urologie, Arnhem (NL), sowie durch die Deutsche Gesellschaft für Urologie, Düsseldorf (D). Des Weiteren leistete A. Miernik Beratungen für: KLS Martin, Tuttlingen (D), Avatera medical, Jena (D), LISA Laser Products GmbH, Katlenburg-Lindau (D), Schoelly fiberoptics GmbH, Denzlingen (D), Dornier MedTech Europe GmbH (D), Medi-Tate Ltd. (IL) und b.braun New ventures GmbH, Freiburg (D). Für die Firmen RichardWolf GmbH (D) und Boston Scientific (USA) war A. Miernik als Referent tätig. Des Weiteren übte er gutachterliche Tätigkeit für die Ludwig Boltzmann Gesellschaft (A) aus. A. Miernik ist beteiligt an zahlreichen Patenten und Erfindungen im Bereich der Medizintechnik., (Thieme. All rights reserved.)

With an increasing number of novel therapeutic options for lower urinary tract symptoms (LUTS), the spectrum of potential treatment pathways resulting from different combinations of treatment decisions is expanding and evolving. Treatment decisions are frequently made with little or no evidence from randomized controlled trials (RCTs) and thus require evidence from other data sources. Clinical routine data reflect real-world treatment pathways. However, evidence for LUTS from routine data means that heterogeneous pathways need to be simultaneously analyzed for compiling evidence in the absence of RCTs. Statistical multi-state model approaches can provide a powerful framework for achieving this goal. More extensive statistical and methodological efforts in the area of similarity of small data are needed to enable the valid pooling of pathways towards joining evidence. PATIENT SUMMARY: Treatment decisions should rely primarily on evidence from clinical trials. When treatment for which there is limited trial evidence needs to be provided, analysis of results from routine clinical practice can represent valuable complementary evidence, but this requires integration of data from heterogeneous treatment pathways., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Although several studies have compared different morcellators and enucleation techniques for the management of benign prostatic hyperplasia (BPH), there is sparse literature on morcellation, so further experimental and clinical research is required for its optimization., Objective: To critically appraise the contemporary literature on prostate morcellation and to evaluate the safety and efficiency of currently available morcellators for endoscopic enucleation of the prostate (EEP) in the context of BPH., Evidence Acquisition: A comprehensive review of the English and French literature relevant to prostate morcellation was performed using the PubMed-MEDLINE, Cochrane Library, Web of Science, and Wiley Online Library database from 1998 to 2020 using PICOS (patient population, intervention, comparison, outcome, and study design) criteria., Evidence Synthesis: We retrieved 26 studies involving 5652 patients treated with a morcellator that were eligible for data extraction and analysis. The mean patient age was 67.4 (range 61.4-72.8) yr. The weighted mean efficiency of Piranha, VersaCut, and DrillCut morcellators was 5.29, 3.95, and 5.3 g/min, respectively. Several approaches, such as en bloc, two-lobe, inverse, and improved techniques, may increase morcellation efficiency and safety. The lowest weighted mean rate of bladder wall injury was 1.24% for Piranha, followed by 1.98% for DrillCut, and 5.23% for VersaCut, while the VersaCut morcellator had the lowest weighted mean rate of device malfunction at 0.74%, compared to 2.07% for Piranha and 7.86% for DrillCut., Conclusions: All three morcellators are efficient and safe for prostatic morcellation after EEP. Further development of devices and techniques may improve the efficiency and safety profile of morcellation. To increase safety, surgeon expertise, technical equipment, and patient characteristics should be considered. Therefore, interdisciplinary exchange of knowledge and further technological innovations are strongly encouraged., Patient Summary: We reviewed the safety and efficacy of devices called morcellators. These devices cut tissue into small pieces that are easier to remove from the body, and are used during laser surgery for benign enlargement of the prostate. Three morcellators are currently available on the market and are comparable in safety and efficacy., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)