bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute cannabinoids impair association learning via selectively enhancing synaptic transmission in striatonigral neurons
Authors: Wu Meilin , Di Yuanyuan , Diao Zhijun , Yan Chuanting , Cheng Qiangqiang , Huang Huan , Liu Yingxun , Wei Chunling , Zheng Qiaohua , Fan Juan , Han Jing , Liu Zhiqiang , Tian Yingfang , Duan Haijun , Ren Wei , Sun Zongpeng 
Published: May 2022

Abstract
Background
Cannabinoids and their derivatives attract strong interest due to the tremendous potential of their psychoactive effects for treating psychiatric disorders and symptoms. However, their clinical application is restricted by various side-effects such as impaired coordination, anxiety, and learning and memory disability. Adverse impact on dorsal striatum-dependent learning is an important side-effect of cannabinoids. As one of the most important forms of learning mediated by the dorsal striatum, reinforcement learning is characterized by an initial association learning phase, followed by habit learning. While the effects of cannabinoids on habit learning have been well-studied, little is known about how cannabinoids influence the initial phase of reinforcement learning.

Results
We found that acute activation of cannabinoid receptor type 1 (CB1R) by the synthetic cannabinoid HU210 induced dose-dependent impairment of association learning, which could be alleviated by intra-dorsomedial striatum (DMS) injection of CB1R antagonist. Moreover, acute exposure to HU210 elicited enhanced synaptic transmission in striatonigral “direct” pathway medium spiny neurons (MSNs) but not indirect pathway neurons in DMS. Intriguingly, enhancement of synaptic transmission that is also observed after learning was abolished by HU210, indicating cannabinoid system might disrupt reinforcement learning by confounding synaptic plasticity normally required for learning. Remarkably, the impaired response-reinforcer learning was also induced by selectively enhancing the D1-MSN (MSN that selectively expresses the dopamine receptor type 1) activity by virally expressing excitatory hM3Dq DREADD (designer receptor exclusively activated by a designer drug), which could be rescued by specifically silencing the D1-MSN activity via hM4Di DREADD.

Conclusion
Our findings demonstrate dose-dependent deleterious effects of cannabinoids on association learning by disrupting plasticity change required for learning associated with the striatal direct pathway, which furthers our understanding of the side-effects of cannabinoids and the underlying mechanisms.
Sustained correction of hippocampal neurogenic and cognitive deficits after a brief treatment by Nutlin-3 in a mouse model of fragile X syndrome
Authors: Javadi Sahar , Li Yue , Sheng Jie , Zhao Lucy , Fu Yao , Wang Daifeng , Zhao Xinyu 
Published: May 2022

Abstract
Background
Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic forms of autism, is caused by a loss of fragile X messenger ribonucleoprotein 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice, and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects.

Methods
We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying the persistent effects of Nutlin-3, we analyzed the proliferation and differentiation of neural stem/progenitor cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice.

Results
We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6 months of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to the extracellular matrix, secreted factors, and cell membrane proteins in the FMR1-deficient hippocampus.

Conclusions
Our data indicates that transient Nutlin-3 treatment in young adults leads to long-lasting neurogenic and behavioral changes likely through modulating adult neurogenic niche that impact adult neural stem cells. Our results demonstrate that cognitive impairments in FXS may be prevented by an early intervention through Nutlin-3 treatment.
Activation of the chemokine receptor 3 pathway leads to a better response to immune checkpoint inhibitors in patients with metastatic urothelial carcinoma
Authors: Feng Wenqin , Lin Anqi , Sun Le , Wei Ting , Ying Haoxuan , Zhang Jian , Luo Peng , Zhu Weiliang 
Published: May 2022

AbstractImmune checkpoint inhibitors (ICIs) have made important breakthrough in anti-tumor therapy, however, no single biomarker can accurately predict their efficacy. Studies have found that tumor microenvironment is a key factor for determining the response to ICI therapy. Cytokine receptor 3 (C-X-C Motif Chemokine Receptor 3, CXCR3) pathway has been reported to play an important role in the migration, activation, and response of immune cells. We analyzed survival data, genomics, and clinical data from patients with metastatic urothelial carcinoma (mUC) who received ICI treatment to explore the relationship between CXCR3 pathway activation and the effectiveness of ICIs. The Cancer Genome Atlas Bladder Urothelial Carcinoma cohort and six other cohorts receiving ICI treatment were used for mechanism exploration and validation. In the ICI cohort, we performed univariate and multivariate COX analyses and discovered that patients in the CXCR3-high group were more sensitive to ICI treatment. A Kaplan–Meier analysis demonstrated that patients in the high CXCR3-high group had a better prognosis than those in the CXCR3-low group (P = 0.0001, Hazard Ratio = 0.56; 95% CI 0.42−0.75). CIBERSORT analysis found that mUC patients in the CXCR3-high group had higher levels of activated CD8+ T cells, M1 macrophages, and activated NK cells and less regulatory T cell (Treg) infiltration. Immunogenicity analysis showed the CXCR3-high group had higher tumor neoantigen burden (TNB). Our study suggests that CXCR3 pathway activation may be a novel predictive biomarker for the effectiveness of immunotherapy in mUC patients.
CDK4/6 inhibitors sensitize gammaherpesvirus-infected tumor cells to T-cell killing by enhancing expression of immune surface molecules
Authors: Wu Yiquan , Shrestha Prabha , Heape Natalie M. , Yarchoan Robert 
Published: May 2022

AbstractBackgroundThe two oncogenic human gammaherpesviruses, Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV), both downregulate immune surface molecules, such as MHC-I, ICAM-1, and B7-2, enabling them to evade T-cell and natural killer cell immunity. Both also either encode for human cyclin homologues or promote cellular cyclin activity, and this has been shown to be important for proliferation and survival of gammaherpesvirus-induced tumors. CDK4/6 inhibitors, which are approved for certain breast cancers, have been shown to enhance expression of MHC-I in cell lines and murine models of breast cancer, and this was attributed to activation of interferons by endogenous retrovirus elements. However, it was not known if this would occur in gammaherpesvirus-induced tumors in which interferons are already activated.MethodsMultiple KSHV/EBV-infected cell lines were treated with CDK4/6 inhibitors. The growth of viable cells and expression of surface markers was assessed. T cell activation stimulated by the treated cells was assayed by a T-cell activation bioassay. Both viral and host gene expression was surveyed using RT-qPCR.ResultsThree CDK4/6 inhibitors, abemaciclib, palbociclib, and ribociclib, inhibited cell growth in KSHV-induced primary effusion lymphoma (PEL) and EBV positive Burkitt’s lymphoma (BL) cell lines, and KSHV-infected human umbilical vein endothelial cells (HUVECs). Moreover, CDK4/6 inhibitors increased mRNA and surface expression of MHC-I in all three and prevented downregulation of MHC-I surface expression during lytic replication in KSHV-infected cells. CDK4/6 inhibitors also variably increased mRNA and surface expression of ICAM-1 and B7-2 in the tested lines. Abemaciclib also significantly enhanced T-cell activation induced by treated PEL and BL cells. Certain gammaherpesvirus genes as well as endogenous retrovirus (ERV) 3–1 genes were enhanced by CDK4/6 inhibitors in most PEL and BL lines and this enhancement was associated with expression of gamma interferon-induced genes including MHC-I.ConclusionsThese observations provide evidence that CDK4/6 inhibitors can induce expression of surface immune markers MHC-I, B7-2, and ICAM-1 in gammaherpesvirus-infected cell lines and induce virus-specific immunity. They can thus thwart virus-induced immune evasion. These effects, along with their direct effects on KSHV- or EBV-induced tumors, provide a rational for the clinical testing of these drugs in these tumors.
Recommendations for addressing the translational gap between experimental and clinical research on amyloid diseases
Authors: Solomon Miriam , Foderà Vito , Langkilde Annette Eva , Elliott Perry , Tagliavini Fabrizio , Forsyth Trevor , Klementieva Oxana , Bellotti Vittorio 
Published: May 2022

AbstractThis paper is a report of recommendations for addressing translational challenges in amyloid disease research. They were developed during and following an international online workshop organized by the LINXS Institute of Advanced Neutron and X-Ray Science in March 2021. Key suggestions include improving cross-cultural communication between basic science and clinical research, increasing the influence of scientific societies and journals (vis-à-vis funding agencies and pharmaceutical companies), improving the dissemination of negative results, and strengthening the ethos of science.
Plasma Torquetenovirus (TTV) microRNAs and severity of COVID-19
Authors: Stincarelli Maria Alfreda , Baj Andreina , Guidotti Bernardo , Spezia Pietro Giorgio , Novazzi Federica , Lucenteforte Ersilia , Tillati Silvia , Focosi Daniele , Maggi Fabrizio , Giannecchini Simone 
Published: May 2022

Abstract
Background
Torquetenovirus (TTV), a widespread anellovirus recognized as the main component of the healthy human virome, displays viremia that is highly susceptible to variations in immune competence. TTV possesses microRNA (miRNA)-coding sequences that might be involved in viral immune evasion. Among TTV-encoded miRNAs, miRNA t1a, t3b, and tth8 have been found in biological fluids. Here, the presence of TTV DNA and TTV miRNAs in the plasma of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected subjects was investigated to monitor the possible association with coronavirus disease 2019 (COVID-19) severity.

Methods
Detection of TTV DNA and miRNA t1a, t3b, and tth8 was investigated in plasma samples of 56 SARS-CoV-2-infected subjects with a spectrum of different COVID-19 outcomes. TTV DNA and TTV miRNAs were assessed with a universal single step real-time TaqMan PCR assay and miRNA quantitative RT-PCR miRNA assay, respectively.

Results
The TTV DNA prevalence was 59%, whereas at least one TTV miRNA was found in 94% of the patients tested. miRNA tth8 was detected in 91% of subjects, followed by miRNAs t3b (64%) and miRNAt1a (30%). Remarkably, although TTV DNA was unrelated to COVID-19 severity, miRNA tth8 was significantly associated with the degree of disease (adjusted incidence rate ratio (IRR) 2.04, 95% CI 1.14–3.63, for the subjects in the high severity group compared to those in the low severity group).

Conclusions
Our findings encourage further investigation to understand the potential role of TTV miRNAs in the different outcomes of COVID-19 at early and late stages.
Postoperative locoregional recurrence pattern and treatment management of stage pT4 sigmoid colon cancer: a retrospective cohort study
Authors: Lin Yaobin , Liu Shan , Hong Liang , Shao Lingdong , Wu Junxin 
Published: May 2022

Abstract
Background
This study aimed to explore the pattern of locoregional recurrence after surgery in patients with non-metastatic stage pT4 sigmoid colon cancer and the role of adjuvant radiotherapy on survival.

Methods
We retrospectively analyzed data from 208 patients who underwent surgery in our hospital. The patients were randomly divided into training and validation groups at a 1:1 ratio. Patients at high risk for locoregional recurrence were screened using Cox regression analysis. Based on the data of 2,886 patients in the Surveillance, Epidemiology, and End Results (SEER) database, the effect of adjuvant radiotherapy on overall survival (OS) and cancer-specific survival (CSS) was evaluated by Kaplan–Meier curves.

Results
Of the 208 patients, 57 (27.4%) presented with locoregional recurrences (14 anastomotic and 43 abdominal or pelvic lymph node recurrences). Multivariate analysis showed that serum CEA, differentiation, lymph node dissection number, and N stage were independent predictors of locoregional recurrence-free survival (all p < 0.05). A risk-stratification model was constructed, and a total score of ≥ 6.5 points was considered the high-risk group for locoregional recurrence. Both the training and validation sets presented that the model had a good predictive ability (area under the curve = 0.828 and 0.724, respectively). Analysis of SEER data revealed that adjuvant radiotherapy significantly prolonged OS and CSS in the high-risk population (all p < 0.05, vs. no radiotherapy).

Conclusions
Patients with a total risk score of 6.5 or more had a high likelihood of locoregional recurrence, and perhaps adjuvant radiotherapy could improve their survival.
Three-dimensional mapping study of pure transverse acetabular fractures
Authors: Li Junran , Zhai Jingxiu , Yin Yingchao , Tian Siyu , Wang Zhongzheng , Li Ligeng , Hou Zhiyong , Zhang Yingze 
Published: May 2022

AbstractBackgroundTo describe and analyze the morphological characteristics, location and frequency of pure transverse acetabular fracture lines through fracture mapping and quantitative measurements.MethodsTransverse fractures were retrospectively reviewed and analyzed. All computed tomography (CT) data were used for reconstruction and manual reduction. The reductive fracture fragments were graphically overlaid onto a three-dimensional (3D) right hemipelvis template. Then, the fracture lines were accurately depicted onto the surface of the 3D template. The fracture lines were overlapped onto the model to create the 3D fracture map and heatmap. All cases were subdivided into infratectal (62-B1.1), juxtatectal (62-B1.2), and transtectal (62-B1.3) types based on the AO Foundation/Orthopedic Trauma Association (AO/OTA) classification. Some anatomic parameters of the transverse fractures were also analyzed in these 3 groups.ResultsOur study included forty-nine transverse fractures from 32 male and 17 female patients (mean age, 42 years; range 21–74 years) and included 19 type 62-B1.1, 17 type 62-B1.2, and 13 type 62-B1.3 fractures. The average anterior rim fracture angle was 70.0° (± 11.6°), and the posterior rim fracture angle was 92.4° (± 28.5°). The anterior rim fracture angles in 40 cases (40/49, 81.6%) fell within a wide range between 63° and 80°. On the heatmap, the hot zones were located on the highest position of the cotyloid fossa and the narrowed region, and the cold zone was on the inferior third of the articular surface. For type 62-B1.3 fractures, the hot zone was located on the posterior of the acetabular dome. There were no significant differences in anterior rim fracture angle and anterior height among the three patterns (P = 0.071,P = 0.072). Post hoc tests of the posterior rim fracture angle and the posterior height revealed significant differences among fracture subtypes (P < 0.01). The posterior intra-articular fracture line was significantly longer than the anterior intra-articular fracture line in type 62-B1.1 and type 62-B1.2 fractures (P < 0.01).ConclusionThe fracture lines of transverse fractures through the anterior rim were concentrated on the narrowed zone, and the posterior fracture lines were diffusely distributed. The intra-articular fracture line distribution was focused on the superior and middle thirds of the joint surface. The recurrent fracture lines involving the weight-bearing dome mainly converged on the posterior region of the roof.
Hospital-onset sepsis and community-onset sepsis in critical care units in Japan: a retrospective cohort study based on a Japanese administrative claims database
Authors: Tonai Mayuko , Shiraishi Atsushi , Karumai Toshiyuki , Endo Akira , Kobayashi Hirotada , Fushimi Kiyohide , Hayashi Yoshiro 
Published: May 2022

Abstract
Background
Hospital- and community-onset sepsis are significant sepsis subgroups. Japanese data comparing these subgroups are limited. This study aimed to describe the epidemiology of hospital- and community-onset sepsis in critical care units in Japan.

Methods
We performed a retrospective cohort study using the Japanese Diagnosis and Procedure Combination database. Adult patients admitted to critical care units with sepsis from April 2010 to March 2020 were included. Sepsis cases were identified based on ICD-10 codes for infectious diseases, procedure codes for blood culture tests, and medication codes for antimicrobials. Patients’ characteristics, in-hospital mortality, and resource utilization were assessed. The in-hospital mortality between groups was compared using the Poisson regression generalized linear mixed-effect model.

Results
Of 516,124 patients, 52,183 (10.1%) had hospital-onset sepsis and 463,940 (89.9%) had community-onset sepsis. Hospital-onset sepsis was characterized by younger age, infrequent emergency hospitalization, frequent surgery under general anesthesia, and frequent organ support upon critical care unit admission compared to community-onset sepsis. In-hospital mortality was higher for hospital-onset than for community-onset sepsis (35.5% versus 19.2%; unadjusted mean difference, 16.3% [95% confidence interval (CI) 15.9–16.7]; adjusted mean difference, 15.6% [95% CI 14.9–16.2]). Mean hospital length of stay was longer for hospital-onset than for community-onset sepsis (47 days versus 30 days; unadjusted mean difference, 17 days [95% CI 16–17]; adjusted mean difference, 13 days [95% CI 12–14]).

Conclusion
Patients with hospital-onset sepsis admitted to critical care units in Japan had a poorer prognosis and more resource utilization including organ support rate, number of days with critical care unit surcharge codes, and hospital length of stay than those with community-onset sepsis.
Repair of acute respiratory distress syndrome by stromal cell administration (REALIST): a structured study protocol for an open-label dose-escalation phase 1 trial followed by a randomised, triple-blind, allocation concealed, placebo-controlled phase 2 trial
Authors: Gorman Ellen , Shankar-Hari Manu , Hopkins Phil , Tunnicliffe William S. , Perkins Gavin D. , Silversides Jonathan , McGuigan Peter , Jackson Colette , Boyle Roisin , McFerran Jamie , McDowell Cliona , Campbell Christina , McFarland Margaret , Smythe Jon , Thompson Jacqui , Williams Barry , Curley Gerard , Laffey John G. , Clarke Mike , McAuley Daniel F. , O’Kane Cecilia 
Published: May 2022

Abstract
Background
Mesenchymal stromal cells (MSCs) may be of benefit in ARDS due to immunomodulatory and reparative properties. This trial investigates a novel CD362 enriched umbilical cord derived MSC product (REALIST ORBCEL-C), produced to Good Manufacturing Practice standards, in patients with moderate to severe ARDS due to COVID-19 and ARDS due to other causes.

Methods
Phase 1 is a multicentre open-label dose-escalation pilot trial. Patients will receive a single infusion of REALIST ORBCEL-C (100 × 106 cells, 200 × 106 cells or 400 × 106 cells) in a 3 + 3 design. Phase 2 is a multicentre randomised, triple blind, allocation concealed placebo-controlled trial. Two cohorts of patients, with ARDS due to COVID-19 or ARDS due to other causes, will be recruited and randomised 1:1 to receive either a single infusion of REALIST ORBCEL-C (400 × 106 cells or maximal tolerated dose in phase 1) or placebo. Planned recruitment to each cohort is 60 patients. The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is oxygenation index at day 7. The trial will be reported according to the Consolidated Standards for Reporting Trials (CONSORT 2010) statement.

Discussion
The development and manufacture of an advanced therapy medicinal product to Good Manufacturing Practice standards within NHS infrastructure are discussed, including challenges encountered during the early stages of trial set up. The rationale to include a separate cohort of patients with ARDS due to COVID-19 in phase 2 of the trial is outlined.

Trial registration
ClinicalTrials.gov NCT03042143. Registered on 3 February 2017. EudraCT Number 2017-000584-33