bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequence of androgen receptor-targeted vaccination with androgen deprivation therapy affects anti-prostate tumor efficacy
Authors: Muralidhar Anusha , Gamat-Huber Melissa , Vakkalanka Sita , McNeel Douglas G 
Published: May 2024

RationaleAndrogen deprivation therapy (ADT) is the primary treatment for recurrent and metastatic prostate cancer. In addition to direct antitumor effects, ADT has immunomodulatory effects such as promoting T-cell infiltration and enhancing antigen processing/presentation. Previous studies in our laboratory have demonstrated that ADT also leads to increased expression of the androgen receptor (AR) and increased recognition of prostate tumor cells by AR-specific CD8+T cells. We have also demonstrated that ADT combined with a DNA vaccine encoding the AR significantly slowed tumor growth and improved the survival of prostate tumor-bearing mice. The current study aimed to investigate the impact of the timing and sequencing of ADT with vaccination on the tumor immune microenvironment in murine prostate cancer models to further increase the antitumor efficacy of vaccines.MethodsMale FVB mice implanted with Myc-CaP tumor cells, or male C57BL/6 mice implanted with TRAMP-C1 prostate tumor cells, were treated with a DNA vaccine encoding AR (pTVG-AR) and ADT. The sequence of administration was evaluated for its effect on tumor growth, and tumor-infiltrating immune populations were characterized.ResultsVaccination prior to ADT (pTVG-AR → ADT) significantly enhanced antitumor responses and survival. This was associated with increased tumor infiltration by CD4+ and CD8+ T cells, including AR-specific CD8+T cells. Depletion of CD8+T cells prior to ADT significantly worsened overall survival. Following ADT treatment, however, Gr1+ myeloid-derived suppressor cells (MDSCs) increased, and this was associated with fewer infiltrating T cells and reduced tumor growth. Inhibiting Gr1+MDSCs recruitment, either by using a CXCR2 antagonist or by cycling androgen deprivation with testosterone replacement, improved antitumor responses and overall survival.ConclusionVaccination prior to ADT significantly improved antitumor responses, mediated in part by increased infiltration of CD8+T cells following ADT. Targeting MDSC recruitment following ADT further enhanced antitumor responses. These findings suggest logical directions for future clinical trials to improve the efficacy of prostate cancer vaccines.
Developing a membrane-proximal CD33-targeting CAR T cell
Authors: Freeman Ruby , Shahid Sanam , Khan Abdul G , Mathew Serena C , Souness Sydney , Burns Erin R , Um Jasmine S , Tanaka Kento , Cai Winson , Yoo Sarah , Dunbar Andrew , Park Young , McAvoy Devin , Hosszu Kinga K , Levine Ross L , Boelens Jaap Jan , Lorenz Ivo C , Brentjens Renier J , Daniyan Anthony F 
Published: May 2024

BackgroundCD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.MethodsWe developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.ResultsWe found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy.ConclusionsShowing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models.
Comparison of in-shoe plantar pressure between Korean combat boots and running shoes
Authors: Yoon Young Sik , An D H , Lee Y J , Lee D Y , Kyung M G 
Published: May 2024

IntroductionCombat boots are special shoes designed for soldiers to wear during activities in rough terrain, such as long marches or military training. Combat boots have been known to cause high plantar pressure and increase the injury rate of the lower extremities. Therefore, this study aimed to compare the difference in in-shoe plantar pressure between Korean combat boots and running shoes. We hypothesised that the newest Korean combat boots would have comparable plantar pressure distribution with running shoes.MethodsWe prospectively recruited 30 asymptomatic male participants, who are candidates for military services, from the local area. Two types of shoes (the newly developed Korean combat boots and running shoes) were examined. Pedobarographic measurements were collected using the pedar-X in-shoe pressure measurement system. Peak pressure (PP), pressure time integral (PTI), contact area and contact time were analysed.ResultsBoth PP and PTI at the region of central and lateral forefeet (FF) were significantly higher in combat boots. The contact area of combat boots was significantly lower at the region of the hallux, second–fifth toes, medial FF, central FF and midfoot. Contact time at the region of central FF and medial heel was significantly higher in combat boots.ConclusionsUnderstanding the plantar pressure distribution of combat boots can be helpful for developing combat boots and preventing injury. Based on the results of our study, the next-generation Korean combat boots should be developed to increase contact area and distribute impulse under the head of the metatarsal bone.
Role of aortic valve replacement in moderate aortic stenosis: a 10-year outcomes study
Authors: Hariri Essa H , Badwan Osamah , Kassab Joseph , Layoun Habib , Skoza Warren , Burton Robert , Harb Serge C , Puri Rishi , Reed Grant W , Krishnaswamy Amar , Svensson Lars G , Kapadia Samir 
Published: May 2024

ObjectivePatients with moderate aortic stenosis (AS) exhibit high morbidity and mortality. Limited evidence exists on the role of aortic valve replacement (AVR) in this patient population. To investigate the benefit of AVR in moderate AS on survival and left ventricular function.MethodsIn a retrospective cohort study, patients with moderate AS between 2008 and 2016 were selected from the Cleveland Clinic echocardiography database and followed until 2018. Patients were classified as receiving AVR or managed medically (clinical surveillance). All-cause and cardiovascular mortality were assessed by survival analyses. Temporal haemodynamic and structural changes were assessed with longitudinal analyses using linear mixed effects models.ResultsWe included 1421 patients (mean age, 75.3±5.4 years and 39.9% women) followed over a median duration of 6 years. Patients in the AVR group had lower risk of all-cause (adjusted HR (aHR)=0.51, 95% CI: 0.34 to 0.77; p=0.001) and cardiovascular mortality (aHR=0.50, 95% CI: 0.31 to 0.80; p=0.004) compared with those in the clinical surveillance group irrespective of sex, receipt of other open-heart surgeries and underlying malignancy. These findings were seen only in those with preserved left ventricular ejection fraction (LVEF) ≥50%. Further, patients in the AVR group had a significant trend towards an increase in LVEF and a decrease in right ventricular systolic pressure compared with those in the clinical surveillance group.ConclusionsIn patients with moderate AS, AVR was associated with favourable clinical outcomes and left ventricular remodelling.
Acute pain management after vaginal delivery with perineal tears or episiotomy
Authors: Luxey Xavier , Lemoine Adrien , Dewinter Geertrui , Joshi Girish P , Le Ray Camille , Raeder Johan , Van de Velde Marc , Bonnet Marie-Pierre 
Published: May 2024

BackgroundA vaginal delivery may be associated with acute postpartum pain, particularly after perineal trauma. However, pain management in this setting remains poorly explored.ObjectiveThe aim of this systematic review was to evaluate the literature and to develop recommendations for pain management after a vaginal delivery with perineal trauma.Evidence reviewMEDLINE, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) and systematic reviews assessing pain after a vaginal delivery with perineal tears or episiotomy until March 2023. Cochrane Covidence quality assessment generic tool and the RoB Vis 2 tool were used to grade the quality of evidence.FindingsOverall, 79 studies (69 RCTs and 10 systematic reviews and meta-analyses) of good quality of evidence were included. Acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line treatment. Epidural morphine (≤2 mg) is recommended among women with labor epidural analgesia and severe perineal tears, with adequate respiratory monitoring. Local anesthetic infiltration, topical local anesthetic, ointment application, and pudendal nerve block are not recommended due to insufficient or lack of evidence. Ice or chemical cold packs are recommended for postpartum pain first-line treatment due to their simplicity of use. Transcutaneous nerve stimulation and acupuncture are recommended as adjuvants. When a perineal suture is indicated, a continuous suture compared with an interrupted suture for the repair of episiotomy or second-degree perineal tears is recommended for the outcome of pain. For women with first-degree or second-degree perineal tears, no suturing or glue compared with suturing is recommended for the outcome of pain.ConclusionsPostpartum pain management after a vaginal delivery with perineal trauma should include acetaminophen, NSAIDs, and ice or chemical cold packs. Epidural morphine should be reserved for severe perineal tears. A surgical repair technique should depend on perineal tear severity.
Shutdown dose rate experiment at JET during DTE2
Authors: Fonnesu N. , Loreti S. , Villari R. , Flammini D. , Mariano G. , Batistoni P. , Colangeli A. , Moro F. , Previti A. , Klix A. ,   JET Contributors
Published: May 2024

AbstractThe EUROfusion activities on the technological exploitation of deuterium–tritium (DT) operation at JET (started within the work package JET3 and continued under PrIO) were established to maximize the scientific and technological return of DTE2 campaign occurred in the second part of 2021. In particular, the aim of the NEXP sub-project was to take advantage of the expected significant neutron production during DTE2 to validate the numerical tools used for neutron streaming and shutdown dose rate (SDR) calculation for ITER through the comparison between numerical predictions and measurements. In the frame of SDR activity, a dosimetry system to measure the dose rate and based on some ionization chambers (ICs) was installed in the torus hall and upgraded both hardware and software since 2015 by exploiting the previous DD and TT campaigns. Two spherical 1-L air-vented ICs had been installed in some ex-vessel positions close to the horizontal ports of the tokamak in octants 1 and 2 and a third IC, suitable for higher dose rates, was then added in octant 1. As for SDR calculation, numerical tools employed rely on MCNP code for radiation transport and in this regard the MCNP model has been updated to include the last detector installed in octant 1. The present work is dedicated to the analysis of dose rate measurements carried out during DTE2 in the inter-pulse periods and at the shutdown. Influence quantities and error sources are analyzed to calculate the dose rate from raw signal and experimental uncertainty. Some experimental points are chosen and employed for a preliminary comparison with numerical predictions obtained from three-dimensional simulations with Advanced D1S tool. The results are presented and discussed with the major objective to contribute to the optimization of the planned SDR code validation.
Holonomic swap and controlled-swap gates of neutral atoms via selective Rydberg pumping
Authors: Sun C. F. , Chen X. Y. , Mu W. L. , Wang G. C. , You J. B. , Shao X. Q. 
Published: May 2024

AbstractHolonomic quantum computing offers a promising paradigm for quantum computation due to its error resistance and the ability to perform universal quantum computations. Here, we propose a scheme for the rapid implementation of a holonomic swap gate in neutral atomic systems, based on the selective Rydberg pumping mechanism. By employing time-dependent soft control, we effectively mitigate the impact of off-resonant terms even at higher driving intensities compared to time-independent driving. This approach accelerates the synthesis of logic gates and passively reduces the decoherence effects. Furthermore, by introducing an additional atom and applying the appropriate driving field, our scheme can be directly extended to implement a three-qubit controlled-swap gate. This advancement makes it a valuable tool for quantum state preparation, quantum switches, and a variational quantum algorithm in neutral atom systems.
Fear learning activated anterior basolateral amygdala neurons modulate anxiety behaviors
Authors: Hammack Robert , Daws Lynette , Toney Glenn 
Published: May 2024

Traumatic events may result in development of neuropsychiatric disorders such as post-traumatic stress disorder (PTSD) with symptoms such as anxiety. While a clear connection between fear and anxiety is well established, the neuronal substrates mediating this relationship are understudied. In this study, we investigated the extent to which neurons in the anterior portion of the basolateral amygdala (aBLA), an area implicated in both fear and anxiety behavior, which are activated during fear learning, modulate anxiety-like behavior during testing in the elevated plus maze (EPM) or open field (OF). In TRAP2 transgenic mice, we permanently expressed the photoexcitatory effector channelrhodopsin or the photoinhibitory effector Jaws in aBLA neurons transcriptionally activated ( c-fos) during contextual fear learning (footshocks, fear-TRAP) or exploration of the conditioning chamber (no footshocks, context-TRAP). Three weeks later, we photoexcited or photoinhibited the fear and context-TRAPed mice during EPM or OF exploration. While photostimulation did not alter anxiety-like behavior during EPM or OF testing compared to dummy stimulation in context-TRAPed mice (n=6-10 mice/group, 8 groups), photoexcitation increased and photoinhibition decreased anxiety-like behaviors in fear-TRAPed mice (n=6-11 mice/group, 8 groups). Our results support a model in which fear learning-activated aBLA neurons are not only suffcient to exaggerate, but also contribute to, endogenous anxiety-like behaviors during exploration of novel environments. Thus, the fear learning-activated aBLA population may be a common substrate that couples fear learning to anxiety behaviors and therefore could play a vital role in development/maintenance of fear-related anxiety disorders. MH093320 (LCD & GMT). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Simulation of Conducted Responses in Microvascular Networks: Role of Current Rectification by Endothelial Cell Gap Junctions
Authors: Djurich Sara , Secomb Timothy 
Published: May 2024

Neuronal activity in the brain stimulates local increases in blood flow. Such flow increases require dilation of feeding arterioles, which can be initiated by upstream conducted responses in the form of electrical currents transmitted along the endothelial lining of the vessels. One potential trigger for this response is hyperpolarization of capillary endothelial cells in active regions resulting from local elevation of extracellular K+ concentration. The conducted hyperpolarization causes arteriolar dilation. For this mechanism to be effective in delivering increased flow to a specific location, the conducted response must travel in the upstream direction only, without reentry into adjacent parallel flow pathways. Such specificity in the response to activation has been observed in skeletal muscle, and may result from partial rectification of current in gap junctions connecting adjacent endothelial cells. The goal of this work is to simulate the spread of hyperpolarizing currents along vessel walls in microvascular networks of the cerebral circulation, including the effects of rectification in gap junctions. A theoretical model was developed for the spread of electrical current in the endothelial cells of a network of microvessels in response to local K+- induced hyperpolarization. Transmembrane currents are represented in the model by a KIR-channel conductance, a non-voltage-dependent K+ conductance, and a background conductance. Currents along vessel walls are represented assuming asymmetric gap junction conductance between adjacent endothelial cells, with higher conductance for downstream currents (causing upstream hyperpolarization) than for upstream currents. The model was applied to a synthetic network of 45 segments, assuming 20 nS conductance for upstream propagation, while a range of values was used for downstream propagation. The model shows effective upstream propagation of conducted responses when the gap junction conductance for downstream propagation is 1 nS or less. This result was confirmed in a simulation of a reconstructed murine cerebral cortex network with 4881 segments. In conclusion, partial current rectification by endothelial gap junctions can result in preferential upstream propagation of conducted responses, consistent with experimental observations of local flow regulation. Supported by NIH grant U01 HL133362. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Increases of renal sodium transporters before and after the occurrence of the hypertension in spontaneously hypertensive rats
Authors: Xue Ying , Ren Zhiyun , Wang Ping , Liu Mingda , Wang Weiwan , Wang Xiaoyan 
Published: May 2024

Background: Adult spontaneously hypertensive rats (SHR) have increases of renal sodium transporters associated with hypertension. It remains to be determined whether the increases of renal sodium transporters are precede by occurrence of hypertension and reflected by urine exosomal sodium transporters that may serve as non-invasive biomarkers for the effcacy of anti-hypertensive drugs. Methods: 1. Male WKY rats and SHRs were aged of 4, 7 and 10 weeks respectively (n=5/group). 2. Additional 3 sets of 10-week-old rat (n=5/group) were administered by a 7-day intraperitoneal injections of furosemide (NKCC2 inhibitor, 5mg/kg), hydrochlorothiazide (NCC2 inhibitor, 30mg/kg) and amiloride (ENaC inhibitor, 10mg/kg) respectively. 3. The systolic blood pressure (SBP) was measured with a catheter in carotid artery of rats under anesthesia. Tail-cuff methods were used to monitor the drug responses. 4. All rats were rationally fed 0.4% NaCl agar-gelled diet for 7 days. 5. Exosomes were extracted with ultracentrifuge from the urines. Results: SHRs (4 weeks) exhibited similar SBP. The renal NKCC2, the major apical sodium transporters in thick ascending limb, was more than doubled in SHRs (215±14 % of WKY, student t-test, p<0.05, same as below) while the other sodium transporters were normal. However, SHRs had a higher SBP than WKY at ages of 7 (157±10 vs 125±14, mmHg) and 10 weeks (192±8 vs 128±12). There were no differences for the all age groups in heart rate, body weight, urine volume, urine Na+ and Cl− excretion, and serum Cr, K+, Na+, and Cl− concentration between rat strains. At 10-weeks old, renal (161±24) and urine exosomal (159±21, corrected by UCr, same as below) NKCC2 were higher in SHR than WKY. Frusemide normalized SBP on day 1 (day 0: 190±18 vs 138±13; day 1: 149±13 vs 128±16) in SHR; Renal (129±9) and urine-exosomal (137±12) NCC were higher in SHR than WKY. Hydrochlorothiazide normalized SBP in SHR on day 1 (day 0: 206±4 vs 140±9; day 1: 159±11 vs 144±11). Renal (α:134±16; β:137±25) and urine-exosomal (α:153±13; β:158±12) ENaCs were higher in SHR than WKY. Amiloride diminished the difference in SBP between rat strains on day 1 (day 0: 188±18 vs 138±11; day 1: 164±16 vs 147±7). Conclusions: The increase of renal NKCC2 precedes the elevation of SBP in SHRs. Urine exosomal NKCC2, NCC, ENaCs may reflect their renal levels and be indicative of the corresponding inhibitors on the hypertension model. Natural Science Foundation of China 81970605. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.