bluuebunny/crossref_metadata_2025_split huggingface dataset:
Administration of an AAV vector coding for a P2X7-blocking nanobody-based biologic ameliorates colitis in mice
Authors: Abad Catalina , Demeules Mélanie , Guillou Charlotte , Gondé Henri , Zoubairi Rachid , Tan Yossan-Var , Pinto-Espinoza Carolina , Schäfer Waldemar , Mann Anna Marei , Vouret-Craviari Valérie , Koch-Nolte Friedrich , Adriouch Sahil 
Published: January 2024

Abstract
Background
The pro-inflammatory ATP-gated P2X7 receptor is widely expressed by immune and non-immune cells. Nanobodies targeting P2X7, with potentiating or antagonistic effects, have been developed. Adeno-associated virus (AAV)-mediated gene transfer represents an efficient approach to achieve long-term in vivo expression of selected nanobody-based biologics. This approach (AAVnano) was used to validate the relevance of P2X7 as a target in dextran sodium sulfate (DSS)-induced colitis in mice.

Results
Mice received an intramuscular injection of AAV vectors coding for potentiating (14D5-dimHLE) or antagonistic (13A7-Fc) nanobody-based biologics targeting P2X7. Long-term modulation of P2X7 activity was evaluated ex vivo from blood samples. Colitis was induced with DSS in mice injected with AAV vectors coding for nanobody-based biologics. Severity of colitis, colon histopathology and expression of chemokines and cytokines were determined to evaluate the impact of P2X7 modulation. A single injection of an AAV vector coding for 13A7-Fc or 14D5-dimHLE efficiently modulated P2X7 function in vivo from day 15 up to day 120 post-injection in a dose-dependent manner. An AAV vector coding for 13A7-Fc significantly ameliorated DSS-induced colitis and significantly reduced immune cell infiltration and expression of chemokines and proinflammatory cytokines in colonic tissue.

Conclusions
We have demonstrated the validity of AAVnano methodology to modulate P2X7 functions in vivo. Applying this methodological approach to a DSS-induced colitis model, we have shown that P2X7 blockade reduces inflammation and disease severity. Hence, this study confirms the importance of P2X7 as a pharmacological target and suggests the use of nanobody-based biologics as potential therapeutics in inflammatory bowel disease.

Graphical Abstract
Predictive value of HTS grade in patients with intrahepatic cholangiocarcinoma undergoing radical resection: a multicenter study from China
Authors: Huang Guan , Zhang Haofeng , Yang Zhenwei , Li Qingshan , Yuan Hao , Chen Pengyu , Xie Chenxi , Meng Bo , Zhang Xianzhou , Chen Kunlun , Yu Haibo 
Published: January 2024

Abstract
Background
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumor with a poor prognosis. This study aimed to investigate whether Hemoglobin, Albumin, Lymphocytes, and Platelets (HALP) score and Tumor Burden Score (TBS) serves as independent influencing factors following radical resection in patients with ICC. Furthermore, we sought to evaluate the predictive capacity of the combined HALP and TBS grade, referred to as HTS grade, and to develop a prognostic prediction model.

Methods
Clinical data for ICC patients who underwent radical resection were retrospectively analyzed. Univariate and multivariate Cox regression analyses were first used to find influencing factors of prognosis for ICC. Receiver operating characteristic (ROC) curves were then used to find the optimal cut-off values for HALP score and TBS and to compare the predictive ability of HALP, TBS, and HTS grade using the area under these curves (AUC). Nomogram prediction models were constructed and validated based on the results of the multivariate analysis.

Results
Among 423 patients, 234 (55.3%) were male and 202 (47.8) were aged ≥ 60 years. The cut-off value of HALP was found to be 37.1 and for TBS to be 6.3. Our univariate results showed that HALP, TBS, and HTS grade were prognostic factors of ICC patients (all P < 0.05), and ROC results showed that HTS had the best predictive value. The Kaplan–Meier curve showed that the prognosis of ICC patients was worse with increasing HTS grade. Additionally, multivariate regression analysis showed that HTS grade, carbohydrate antigen 19–9 (CA19-9), tumor differentiation, and vascular invasion were independent influencing factors for Overall survival (OS) and that HTS grade, CA19-9, CEA, vascular invasion and lymph node invasion were independent influencing factors for recurrence-free survival (RFS) (all P < 0.05). In the first, second, and third years of the training group, the AUCs for OS were 0.867, 0.902, and 0.881, and the AUCs for RFS were 0.849, 0.841, and 0.899, respectively. In the first, second, and third years of the validation group, the AUCs for OS were 0.727, 0.771, and 0.763, and the AUCs for RFS were 0.733, 0.746, and 0.801, respectively. Through the examination of calibration curves and using decision curve analysis (DCA), nomograms based on HTS grade showed excellent predictive performance.

Conclusions
Our nomograms based on HTS grade had excellent predictive effects and may thus be able to help clinicians provide individualized clinical decision for ICC patients.
Taming microglia: the promise of engineered microglia in treating neurological diseases
Authors: Luo Echo Yongqi , Sugimura Rio Ryohichi 
Published: January 2024

AbstractMicroglia, the CNS-resident immune cells, are implicated in many neurological diseases. Nearly one in six of the world’s population suffers from neurological disorders, encompassing neurodegenerative and neuroautoimmune diseases, most with dysregulated neuroinflammation involved. Activated microglia become phagocytotic and secret various immune molecules, which are mediators of the brain immune microenvironment. Given their ability to penetrate through the blood–brain barrier in the neuroinflammatory context and their close interaction with neurons and other glial cells, microglia are potential therapeutic delivery vehicles and modulators of neuronal activity. Re-engineering microglia to treat neurological diseases is, thus, increasingly gaining attention. By altering gene expression, re-programmed microglia can be utilized to deliver therapeutics to targeted sites and control neuroinflammation in various neuroinflammatory diseases. This review addresses the current development in microglial engineering, including genetic targeting and therapeutic modulation. Furthermore, we discuss limitations to the genetic engineering techniques and models used to test the functionality of re-engineered microglia, including cell culture and animal models. Finally, we will discuss future directions for the application of engineered microglia in treating neurological diseases.
Graphical Abstract
Anterior cervical discectomy and fusion with a zero-profile VA spacer device: a clinical and radiological study with two-year follow-up
Authors: Zhao Hai-Hong , Xu Hao-Wei , Wang Shan-Jin , Hu Tao , Wu De-Sheng 
Published: January 2024

Abstract
Study design
A retrospective study.

Objective
The aim of this study was to compare clinical and radiological outcomes of the anterior cervical discectomy and fusion (ACDF) with a novel zero-profile variable-angle (Zero-P VA) spacer and a traditional poly-ether-ether-ketone (PEEK) cage and plate system in cases pertaining to cervical radiculopathy/myelopathy.

Summary of background data
There are two conventional types of ACDF procedures aimed at treating symptomatic cervical spondylosis. The first one involves an uninstrumented “stand-alone” approach utilizing bone graft/cage, while the second incorporates bone graft/cage in conjunction with a front plate positioned before the vertebral bodies. Both procedures have their own inherent advantages and disadvantages. The Zero-P VA spacer, however, represents a unique synthesis by amalgamating the advantages of both traditionally typical procedures. Notably, this spacer can potentially circumvent the issue related to prevertebral soft-tissue disturbance and reduce the occurrence of dysphagia.

Methods
Using our surgical database, the authors systematically conducted a retrospective analysis encompassing all patients who underwent single-level ACDF between January 2018 and January 2019, with a minimum two-year follow-up. Patients either received a Zero-P VA implant or PEEK cage coupled with plating. The Japanese Orthopedic Association (JOA) score and Visual Analogue Scale (VAS) for arm and neck pain were documented. Dysphagia was evaluated using the Eating Assessment Tool-10 (ETA-10). Additional parameters such as cervical alignment, fusion rate and the incidence of postoperative complications were assessed.

Results
According to the outcomes of the statistical analysis, there was no substantial disparity that emerged in the advancements observed in the JOA and VAS metrics between the two study cohorts. Noteworthy, however, the ETA-10 scores were statistically significantly reduced in the Zero-P VA group compared to the cage and plating group (p < 0.05). At the final follow-up, there were no statistically significant differences in the height of the operated segment, Cobb angle of the fused segment, C2–C7 Cobb angle and fusion rate between the two groups (p > 0.05). However, postoperative complications were slightly lower in patients with the Zero-P VA group (7.69%) as compared to the cage and plating group (16.67%).

Conclusion
The clinical outcomes observed with the Zero-P VA spacer used for single-level ACDF were found to be satisfactory. The performance of this device is comparable or even superior to the traditional cage and plating method in preventing postoperative dysphagia and mitigating potential complications associated with the use of a plate.
PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer
Authors: Xu Liang , Xiang Wanying , Yang Jiezhen , Gao Jing , Wang Xinyue , Meng Li , Ye Kaihong , Zhao Xiao Hong , Zhang Xu Dong , Jin Lei , Ye Yan 
Published: January 2024

Abstract
Background
Prohibitin 2 (PHB2) exhibits opposite functions of promoting or inhibiting tumour across various cancer types. In this study, we aim to investigate its functions and underlying mechanisms in the context of gastric cancer (GC).

Methods
PHB2 protein expression levels in GC and normal tissues were examined using western blot and immunohistochemistry. PHB2 expression level associations with patient outcomes were examined through Kaplan–Meier plotter analysis utilizing GEO datasets (GSE14210 and GSE29272). The biological role of PHB2 and its subsequent regulatory mechanisms were elucidated in vitro and in vivo. GC cell viability and proliferation were assessed using MTT cell viability analysis, clonogenic assays, and BrdU incorporation assays, while the growth of GC xenografted tumours was measured via IHC staining of Ki67. The interaction among PHB2 and SHIP2, as well as between SHIP2 and NEDD4, was identified through co-immunoprecipitation, GST pull-down assays, and deletion-mapping experiments. SHIP2 ubiquitination and degradation were assessed using cycloheximide treatment, plasmid transfection and co-immunoprecipitation, followed by western blot analysis.

Results
Our analysis revealed a substantial increase in PHB2 expression in GC tissues compared to adjacent normal tissues. Notably, higher PHB2 levels correlated with poorer patient outcomes, suggesting its clinical relevance. Functionally, silencing PHB2 in GC cells significantly reduced cell proliferation and retarded GC tumour growth, whereas overexpression of PHB2 further enhanced GC cell proliferation. Mechanistically, PHB2 physically interacted with Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) in the cytoplasm of GC cells, thus leading to SHIP2 degradation via its novel E3 ligase NEDD4. It subsequently activated the PI3K/Akt signaling pathway and thus promoted GC cell proliferation.

Conclusions
Our findings highlight the importance of PHB2 upregulation in driving GC progression and its association with adverse patient outcomes. Understanding the functional impact of PHB2 on GC growth contributes valuable insights into the molecular underpinnings of GC and may pave the way for the development of targeted therapies to improve patient outcomes.
Effects of finerenone and glucagon-like peptide 1 receptor agonists on cardiovascular and renal outcomes in type 2 diabetes mellitus: a systematic review and meta-analysis
Authors: Gu Xia , Jiang Shimin , Yang Yue , Li Wenge 
Published: January 2024

Abstract
Objective
To assess the effects of finerenone and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), and the relative cardiovascular benefits in patients with or without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs.

Methods
We searched PubMed, the Cochrane Library, and Embase from January 1, 2000, to December 30, 2022, to identify randomized controlled trials. The primary outcomes were the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (MACE); hospitalization for heart failure (HHF); and a composite of renal outcomes. The results were reported as hazard ratios (HRs) with 95% confidence intervals (CIs).

Results
In total, we identified 11 trials and 73,927 participants, 13,847 (18.7%) in finerenone trials and 60,080 (81.3%) in GLP1-RA trials. Finerenone reduced the risk of MACE by 13% (HR, 0.87; 95% CI, 0.79–0.95; P = 0.003), while GLP1-RA reduced the risk in a similar magnitude by 13% (HR, 0.87; 95% CI, 0.83–0.92; P < 0.001). For both drug classes, the effect on lowering the risk of MACE was restricted to approximately 14% in patients with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.82–0.90; P < 0.001), whereas no effect was observed in patients without established atherosclerotic cardiovascular disease (HR, 0.93; 95% CI, 0.85–1.02; P = 0.12). GLP1-RA reduced myocardial infarction, stroke and cardiovascular death more than finerenone (which appeared to have no effect). Only finerenone was beneficial for reducing the risk of HHF (HR, 0.78; 95% CI, 0.66–0.92; P = 0.003). Both finerenone (HR, 0.84; 95% CI, 0.77–0.92; P < 0.001) and GLP1-RA (HR, 0.81; 95% CI, 0.76–0.86; P < 0.001) reduced the risk of kidney disease progression, including macroalbuminuria, and finerenone was superior to GLP1-RA in delaying deterioration of kidney function.

Conclusions
Finerenone and GLP1-RA lead to a risk reduction in MACE to a similar degree in patients with established atherosclerotic cardiovascular disease. For both drug classes, the effect on lowering the risk of progression of kidney disease was also in a similar magnitude in patients with T2DM, whereas only finerenone had a significant protective effect against HHF. Treatment decisions for patients with T2DM should consider the clinical benefit profiles of each drug.
Is bladder outlet obstruction rat model to induce overactive bladder (OAB) has similarity to human OAB? Research on the events in smooth muscle, collagen, interstitial cell and telocyte distribution
Authors: Wishahi Mohamed , Hassan Sarah , Kamal Nabawya , Badawy Mohamed , Hafiz Ehab 
Published: January 2024

Abstract
Background
Cellular and cytoskeletal events of overactive bladder (OAB) have not been sufficiently explored in human bladder due to different limitations. Bladder outlet obstruction (BOO) had been induced in different animal models with different methods to induce (OAB). Similarity of the animal models of BOO to the human OAB is postulated but has not been confirmed. The interstitial cells of Cajal (ICCs), and telocytes (TCs) are an important players in smooth muscles conductivity, they had not been well investigated in the previous BOO models. Objectives are to investigate the morphological pattern of cellular, cytoskeleton and telocytes distribution in BOO rat model and to match the events in two time periods and compare it to the findings in real-world human OAB.

Methods
Female Sprague-Dawley rats (Rattus norvegicus) were randomly divided into: sham (n = 10), BOO 6 W (n = 10), BOO 8 W (n = 10). Operative procedure to Induce BOO was done under anesthesia with intraperitoneal Ketamine administration. The Effect of induction of BOO was evaluated after 6 and 8 weeks. The rats were anesthetized, and the urinary bladder was removed, while the rat was unconscious under anaesthesia it was transferred to the inhalation anaesthesia cage for euthanasia, rats were sacrificed under light anesthesia using isoflurane. Care of animals, surgical procedure, and euthanasia adhered to Guide for the Care and Use of Laboratory Animals, and AVMA Guidelines for the Euthanasia of Animals. The retrieved bladder was processed for examination with histopathology, immunohistochemistry (IHC), and transmission electron microscopy (EM).

Results
Histological examination of the bladder shows thinner urothelium, condensation of collagen between muscle bundles. IHC with c-kit shows the excess distribution of ICCs between smooth muscle bundles. EM shows frequent distribution of TCs that were situated between collagen fibers. Finings in BOO 6 W group and BOO 8 W group were comparable.

Conclusion
The animal model study demonstrated increased collagen/ smooth muscle ratio, high intensity of ICCs and presence of TCs. Findings show that a minimally invasive procedure to induce BOO in rats had resulted in an OAB that has morphological changes that were stable in 6 & 8 weeks. We demonstrated the distribution of TCs and ICCs in the rat animal model and defined them. The population of TCs in the BOO rat model is described for the first time, suggests that the TCs and ICCs may contribute to the pathophysiology of OAB. Similarity of animal model to human events OAB was demonstrated. These findings warrant further study to define the role of TCs in OAB.

Clinical trial registry
The study does not require a clinical trial registration; it is an experimental animal study in basic science and does not include human subjects.
Conversion surgery for initially unresectable locally advanced pancreatic ductal adenocarcinoma after chemotherapy followed by carbon-ion radiotherapy: a case report
Authors: Watanabe Yusuke , Tatsuguchi Takaaki , Date Kenjiro , Shinkawa Tomohiko , Kuga Hirotaka , Tamiya Sadafumi , Nishihara Kazuyoshi , Nakano Toru 
Published: January 2024

Abstract
Background
Recent advances in chemotherapy and chemoradiotherapy have enabled conversion surgery (CS) to be performed for selected patients with initially unresectable locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Many studies indicate CS might extend the survival of patients with initially unresectable LA PDAC. However, several clinical questions concerning CS remain, such as the optimal preoperative treatment. Carbon-ion radiotherapy (CIRT) is a unique radiotherapy that offers higher biological effectiveness than conventional radiotherapy. Here, we report a long-term survival case with initially unresectable LA PDAC who underwent CS after chemotherapy followed by CIRT.

Case presentation
The patient was a 72-year-old Japanese woman with unresectable LA pancreatic head cancer with tumor contact to the superior mesenteric artery (SMA). She underwent four courses of chemotherapy (gemcitabine plus nanoparticle albumin-bound paclitaxel). However, the lesion did not shrink and tumor contact with the SMA did not improve after chemotherapy. Because the probability of achieving curative resection was judged to be low, she underwent radical dose CIRT, and chemotherapy was continued. She complained of vomiting 2 months after CIRT. Although imaging studies showed no tumor growth or metastasis, a duodenal obstruction which was speculated to be an adverse effect of CIRT was observed. She could not eat solid food and a trans-nasal feeding tube was inserted. Therapeutic intervention was required to enable enteral nutrition. We proposed several treatment options. She chose resection with the expectation of an anti-tumor effect of chemotherapy and CIRT rather than course observation with tube feeding or bypass surgery. Therefore, subtotal-stomach-preserving pancreatoduodenectomy with portal vein resection was performed as CS. Pathological examination of the resected specimen revealed an R0 resection with a histological response of Evans grade IIA. Postoperatively, she recovered uneventfully. Adjuvant chemotherapy with tegafur/gimeracil/oteracil (S1) was administrated. At the time of this report, 5 years have passed since the initial consultation and she has experienced no tumor recurrence.

Conclusions
The present case suggests that multidisciplinary treatment consisting of a combination of recent chemotherapy and CIRT may be beneficial for unresectable LA PDAC. However, further studies are required to assess the true efficacy of this treatment strategy.
Cobdock: an accurate and practical machine learning-based consensus blind docking method
Authors: Ugurlu Sadettin Y. , McDonald David , Lei Huangshu , Jones Alan M. , Li Shu , Tong Henry Y. , Butler Mark S. , He Shan 
Published: January 2024

AbstractProbing the surface of proteins to predict the binding site and binding affinity for a given small molecule is a critical but challenging task in drug discovery. Blind docking addresses this issue by performing docking on binding regions randomly sampled from the entire protein surface. However, compared with local docking, blind docking is less accurate and reliable because the docking space is too largetly sampled. Cavity detection-guided blind docking methods improved the accuracy by using cavity detection (also known as binding site detection) tools to guide the docking procedure. However, it is worth noting that the performance of these methods heavily relies on the quality of the cavity detection tool. This constraint, namely the dependence on a single cavity detection tool, significantly impacts the overall performance of cavity detection-guided methods. To overcome this limitation, we proposed Consensus Blind Dock (CoBDock), a novel blind, parallel docking method that uses machine learning algorithms to integrate docking and cavity detection results to improve not only binding site identification but also pose prediction accuracy. Our experiments on several datasets, including PDBBind 2020, ADS, MTi, DUD-E, and CASF-2016, showed that CoBDock has better binding site and binding mode performance than other state-of-the-art cavity detector tools and blind docking methods.
Neural electric bass guitar synthesis framework enabling attack-sustain-representation-based technique control
Authors: Koguchi Junya , Morise Masanori 
Published: January 2024

AbstractMusical instrument sound synthesis (MISS) often utilizes a text-to-speech framework because of its similarity to speech in terms of generating sounds from symbols. Moreover, a plucked string instrument, such as electric bass guitar (EBG), shares acoustical similarities with speech. We propose an attack-sustain (AS) representation of the playing technique to take advantage of this similarity. The AS representation treats the attack segment as an unvoiced consonant and the sustain segment as a voiced vowel. In addition, we propose a MISS framework for an EBG that can control its playing techniques: (1) we constructed a EBG sound database containing a rich set of playing techniques, (2) we developed a dynamic time warping and timbre conversion to align the sounds and AS labels, (3) we extend an existing MISS framework to control playing techniques using AS representation as control symbols. The experimental evaluation suggests that our AS representation effectively controls the playing techniques and improves the naturalness of the synthetic sound.