Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected CD4+ T cells. We engineered an anti-PD-1 chimeric ...antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including lymph node CD4+ follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of CD8+ memory T cells. These data indicate anti-PD-1 CAR T cells depleted PD-1+ T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.
Introduction: Although transfemoral aortic valve replacement (TAVR) is a safe treatment for elderly patients with severe aortic valve stenosis, postoperative microembolism has been described. In this ...secondary endpoint analysis of the POST-TAVR trial, we aimed to investigate whether changes in neuron-specific enolase (NSE)—a biomarker of neuronal damage—are associated with changes in memory function or postoperative delirium (POD). Materials and Methods: This was a prospective single-center study enrolling patients undergoing elective TAVR. Serum NSE was measured before and 24 h after TAVR. POD was diagnosed using CAM-ICU testing. Memory function was assessed before TAVR and before hospital discharge using the “Consortium to Establish a Registry for Alzheimer’s Disease” (CERAD) word list and the digit span task (DST) implemented in “∆elta-App”. Results: Subjects’ median age was 82 years (25th to 75th percentile: 77.5–85.0), 42.6% of subjects were women. CERAD scores significantly increased from pre- to post-TAVR, with p < 0.001. POD occurred in 4.4% (6/135) of subjects at median 2 days after TAVR. After TAVR, NSE increased from a median of 1.85 ng/mL (1.30–2.53) to 2.37 ng/mL (1.69–3.07), p < 0.001. The median increase in NSE was 40.4% (13.1–138.0) in patients with POD versus 17.3% (3.3–43.4) in those without POD (p = 0.17). Conclusions: Memory function improved after TAVR, likely due to learning effects, with no association to change in NSE. Patients with POD appear to have significantly higher postoperative levels of NSE compared to patients without POD after TAVR. This finding suggests that neuronal damage, as indicated by NSE elevation, may not significantly impair assessed memory function after TAVR.
Purpose
The volume of arthroscopic hip surgery has increased dramatically in recent years with iliopsoas tendinitis (IPT) being one of the most common complications of this procedure. The purpose of ...this study is to investigate the prevalence of post-operative IPT in patients who undergo arthroscopic hip surgery with capsular closure using absorbable versus non-absorbable suture.
Methods
This is a single center, single surgeon, retrospective analysis performed between August 2007 and May 2023 comparing two cohorts who underwent hip arthroscopy. Patients were divided into those who underwent surgery with capsular closure using absorbable (Vicryl
®
, Johnson and Johnson, New Brunswick, NJ) suture and those who underwent capsular closure with non-absorbable suture (Suturetape, Arthrex, Naples FL). All patients who underwent primary or revision hip arthroscopy and were at least 2 months post-operation were initially included in the study.
Results
Between August 2007 and May 2023 a total of 1513 hip arthroscopy surgeries were performed. Within this cohort, 1421 hips underwent hip arthroscopy with non-absorbable suture and 64 hips underwent surgery with absorbable suture. There was no significant difference between the proportion of IPT in the non-absorbable cohort (2.3%) versus the absorbable cohort (1.6%) (
P
= 0.669).
Conclusion
Capsular closure with Absorbable sutures was non-inferior to capsular closure with non-absorbable sutures with respect to the proportion of post-operative IPT following hip arthroscopy for FAI. Additionally, the proportion of post-operative IPT was found to be significantly higher in patients undergoing revision versus primary hip arthroscopy, regardless of capsular closure suture type.
Level of evidence
IV.
Macrotermitinae termites have domesticated fungi of the genus
as food for their colony, analogously to human farmers growing crops. Termites propagate the fungus by continuously blending foraged and ...predigested plant material with fungal mycelium and spores (fungus comb) within designated subterranean chambers. To test the hypothesis that the obligate fungal symbiont emits specific volatiles (odor) to orchestrate its life cycle and symbiotic relations, we determined the typical volatile emission of fungus comb biomass and
nodules, revealing α-pinene, camphene, and d-limonene as the most abundant terpenes. Genome mining of
followed by gene expression studies and phylogenetic analysis of putative enzymes related to secondary metabolite production encoded by the genomes uncovered a conserved and specific biosynthetic repertoire across strains. Finally, we proved by heterologous expression and
enzymatic assays that a highly expressed gene sequence encodes a rare bifunctional mono-/sesquiterpene cyclase able to produce the abundant comb volatiles camphene and d-limonene.
The symbiosis between macrotermitinae termites and
is obligate for both partners and is one of the most important contributors to biomass conversion in the Old World tropic's ecosystems. To date, research efforts have dominantly focused on acquiring a better understanding of the degradative capabilities of
to sustain the obligate nutritional symbiosis, but our knowledge of the small-molecule repertoire of the fungal cultivar mediating interspecies and interkingdom interactions has remained fragmented. Our omics-driven chemical, genomic, and phylogenetic study provides new insights into the volatilome and biosynthetic capabilities of the evolutionarily conserved fungal genus
, which allows matching metabolites to genes and enzymes and, thus, opens a new source of unique and rare enzymatic transformations.
Abstract
Human immunodeficiency virus (HIV) infection is associated with impaired natural killer (NK) cell activity, which is only incompletely restored under antiretroviral therapy. Analyzing the ...bioenergetics profiles of oxygen consumption, we observed that several parameters were significantly reduced in HIV+ NK cells, indicating a mitochondrial defect. Accordingly, we found HIV+ CD56bright NK cells to display a decreased mitochondrial membrane potential and mitochondrial mass. Both parameters were positively correlated with interferon gamma (IFN-γ) production of NK cells. Finally, we demonstrated that stimulation of HIV+ NK cells with MitoTEMPO, a mitochondria-targeting antioxidant, significantly improved IFN-γ production. We identified mitochondrial dysfunction as a mechanism that contributes to impaired NK cell function.
Analyzing the bioenergetics profiles of oxygen consumption together with mitochondrial membrane potential and mitochondrial mass in HIV+compared to HIV–natural killer (NK) cells, we identified mitochondrial dysfunction as a mechanism that might contribute to impaired NK cell function in HIV infection.
Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear ...energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I.
CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1–10.5 Gy (total doses 32.4–42.0 Gy RBE). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks.
Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores CP A5 n = 10, A6 n = 4, B8 n = 1, and B9 n = 1). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression.
CIRT of HCC yields excellent local control without dose-limiting toxicity.
To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials.
The study is registered at ClinicalTrials.gov (NCT01167374).
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•High-dose CIRT can safely spare non-tumorous liver without relevant toxicity.•CIRT for HCC yields excellent local control (100% in this study).•The promising results of Japanese and Chinese trials can be transferred to European centers and cohorts.•Intrahepatic progression outside of the CIRT target volume remains the main challenge.
A series of twelve novel diamminetetrakis(carboxylato)platinum(IV) and 18 novel bis(carboxylato)dichlorido(ethane‐1,2‐diamine)platinum(IV) complexes with mixed axial carboxylato ligands was ...synthesized and characterized by multinuclear 1H‐, 13C‐, 15N‐, and 195Pt‐NMR spectroscopy. Their cytotoxic potential was evaluated (by MTT assay) against three human cancer cell lines derived from ovarian teratocarcinoma (CH1/PA‐1), lung (A549), and colon carcinoma (SW480). In the cisplatin‐sensitive CH1/PA‐1 cancer cell line, diamminetetrakis(carboxylato)platinum(IV) complexes showed IC50 values in the low micromolar range, whereas, for the most lipophilic compounds of the bis(carboxylato)dichlorido(ethane‐1,2‐diamine)platinum(IV) series, IC50 values in the nanomolar range were found.
Hemodynamic improvement from biventricular pacing is well documented; however, its electrophysiologic effects have not been systematically studied. Sporadic case reports suggest a proarrhythmic ...effect of biventricular pacing resulting primarily in polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF).
The purpose of this study was to report a series of patients in whom implantation of a biventricular system resulted in VT/VF storm with predominance of monomorphic VT.
In a retrospective analysis of all biventricular implants over a 4-year period at a single medical center, we identified 5 of 145 patients (3.4%) who developed VT/VF after they were upgraded to a biventricular system. All patients were male, age 71 +/- 8 years, with ejection fraction of 0.25 +/- 0.1. Four of five patients had ischemic cardiomyopathy.
All patients developed incessant VT/VF within 1 week of implantation. Monomorphic VT of single morphology was noted in 3 of 5 patients, monomorphic VT of multiple morphologies in 1, and polymorphic VT/VF in 1. VT was managed by temporary discontinuation of biventricular pacing in all patients, amiodarone in 3 of 5, sotalol in 1, and beta-blocker in 1. During 11 +/- 7 months of follow-up, 4 of 5 patients remain alive and are arrhythmia-free.
Biventricular pacing may result in precipitation of VT/VF storm in a minority of patients with prior history of VT/VF. This may be the first case series reporting both monomorphic and polymorphic VT after an upgrade to a system with biventricular pacing capabilities. The arrhythmias can be managed by conventional therapy and may require temporary discontinuation of left ventricular pacing. This observation is relevant to patients receiving a biventricular pacemaker without an implantable cardioverter-defibrillator backup.
We investigated the pleiotropic effects of an angiotensin receptor-neprilysin inhibitor (ARNi) on collateral-dependent myocardial perfusion in a rat model of coronary arteriogenesis, and performed ...comprehensive analyses to uncover the underlying molecular mechanisms.
A rat model of coronary arteriogenesis was established by implanting an inflatable occluder on the left anterior descending coronary artery followed by a 7-day repetitive occlusion procedure (ROP). Coronary collateral perfusion was measured by using a myocardial particle infusion technique. The putative ARNi-induced pro-arteriogenic effects were further investigated and compared with an angiotensin-converting enzyme inhibitor (ACEi). Expression of the membrane receptors and key enzymes in the natriuretic peptide system (NPS), renin-angiotensin-aldosterone system (RAAS) and kallikrein-kinin system (KKS) were analyzed by quantitative polymerase chain reaction (qPCR) and immunoblot assay, respectively. Protein levels of pro-arteriogenic cytokines were measured by enzyme-linked immunosorbent assay, and mitochondrial DNA copy number was assessed by qPCR due to their roles in arteriogenesis. Furthermore, murine heart endothelial cells (MHEC5-T) were treated with a neprilysin inhibitor (NEPi) alone, or in combination with bradykinin receptor antagonists. MHEC5-T proliferation was analyzed by colorimetric assay.
The
study showed that ARNis markedly improved coronary collateral perfusion, regulated the gene expression of KKS, and increased the concentrations of relevant pro-arteriogenic cytokines. The
study demonstrated that NEPis significantly promoted MHEC5-T proliferation, which was diminished by bradykinin receptor antagonists.
ARNis improve coronary collateral perfusion and exert pro-arteriogenic effects
the bradykinin receptor signaling pathway.
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