bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implementation status of pharmacological studies in the development of orphan drugs
Authors: Yokoshiki Saki , Arato Teruyo 
Published: January 2024

Abstract
Background
The nonclinical as well as clinical development of orphan drugs is difficult, owing to unknown pathophysiology and the absence of animal models. Both, the U.S. Food and Drug Administration (FDA) Guidance and European Medicines Agency (EMA) Guidelines, for orphan drug development describe non-clinical studies, but lack specific information, such as animal species and study design. Against this background, this study aimed to elucidate efficient methods for evaluating nonclinical efficacy based on a review report of orphan drugs approved in Japan.

Results
A total of 184 orphan drugs, including 84 anticancer and 100 non-anticancer drugs, approved in Japan from January 2010 to December 2019 were investigated. Some anticancer drugs progressed to clinical development without distinct efficacy data in nonclinical studies. Patient-derived cells have been used for some drugs due to a lack of established cell lines. Cells used for non-clinical studies were devised for drugs indicated for cancers resistant to prior therapies, tumours with specific amino acid mutations in the target molecules, and solid tumours with specific biomarkers. For some non-anticancer drugs, similar disease animal models and normal animals were used for evaluation, since animal models did not exist. Biomarkers have been used specifically for evaluation in normal animals and as endpoints in some clinical trials.

Conclusions
It was possible to evaluate drug efficacy by flexibly designing nonclinical studies according to disease characteristics for potentials orphan drugs. These approaches, which are not described in detail in the EMA Guideline or FDA Guidance, may thus lead to approval.
Neurexin-1-dependent circuit activity is required for the maintenance of photoreceptor subtype identity in Drosophila
Authors: Lim-Kian-Siang Gabrielle , Izawa-Ishiguro Arianna R. , Rao Yong 
Published: January 2024

AbstractIn the human and Drosophila color vision system, each photoreceptor neuron (cone cell in humans and R7/R8 photoreceptor cell in Drosophila) makes a stochastic decision to express a single photopigment of the same family with the exclusion of the others. While recent studies have begun to reveal the mechanisms that specify the generation of cone subtypes during development in mammals, nothing is known about how the mosaic of mutually exclusive cone subtypes is maintained in the mammalian retina. In Drosophila, recent work has led to the identification of several intrinsic factors that maintain the identity of R8 photoreceptor subtypes in adults. Whether and how extrinsic mechanisms are involved, however, remain unknown. In this study, we present evidence that supports that the Drosophila transsynaptic adhesion molecule Neurexin 1 (Dnrx-1) is required non-cell autonomously in R8p subtypes for the maintenance of R8y subtype identity. Silencing the activity of R8p subtypes caused a phenotype identical to that in dnrx-1 mutants. These results support a novel role for Nrx-1-dependent circuit activity in mediating the communication between R8 photoreceptor subtypes for maintaining the subtype identity in the retina.
RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via hijacking YY1 binding
Authors: Lin Ying , Wu Yun , Zhang Qiangzu , Tu Xunwei , Chen Sufang , Pan Junfan , Xu Nengluan , Lin Ming , She Peiwei , Niu Gang , Chen Yusheng , Li Hongru 
Published: January 2024

Abstract
Background
Ceramide metabolism is crucial in the progress of brain metastasis (BM). However, it remains unexplored whether targeting ceramide metabolism may arrest BM.

Methods
RNA sequencing was applied to screen different genes in primary and metastatic foci and whole-exome sequencing (WES) to seek crucial abnormal pathway in BM + and BM-patients. Cellular arrays were applied to analyze the permeability of blood–brain barrier (BBB) and the activation or inhibition of pathway. Database and Co-Immunoprecipitation (Co-IP) assay were adopted to verify the protein–protein interaction. Xenograft and zebrafish model were further employed to verify the cellular results.

Results
RNA sequencing and WES reported the involvement of RPTOR and ceramide metabolism in BM progress. RPTOR was significantly upregulated in BM foci and increased the permeability of BBB, while RPTOR deficiency attenuated the cell invasiveness and protected extracellular matrix. Exogenous RPTOR boosted the SPHK2/S1P/STAT3 cascades by binding YY1, in which YY1 bound to the regions of SPHK2 promoter (at -353 ~ -365 nt), further promoting the expression of SPHK2. The latter was rescued by YY1 RNAi. Xenograft and zebrafish model showed that RPTOR blockade suppressed BM of non-small cell lung cancer (NSCLC) and impaired the SPHK2/S1P/STAT3 pathway.

Conclusion
RPTOR is a key driver gene in the brain metastasis of lung cancer, which signifies that RPTOR blockade may serve as a promising therapeutic candidate for clinical application.
A novel PDPN antagonist peptide CY12-RP2 inhibits melanoma growth via Wnt/β-catenin and modulates the immune cells
Authors: Feng Chunyan , Yu Albert , Wang Zhongfu , Wang Kun , Chen Jiawei , Wu Yaojiong , Deng Ting , Chen Huaqing , Hou Yibo , Ma Shaohua , Dai Xiaoyong , Huang Laiqiang 
Published: January 2024

Abstract
Background
Podoplanin (PDPN) is a highly conserved, mucin-type protein specific to the lymphatic system. Overexpression of PDPN is associated with the progression of various solid tumors, and plays an important roles in the tumor microenvironment by regulating the immune system. However, the role of PDPN-mediated signal activation in the progression of melanoma is still unknown.

Methods
PDPN expression was first analyzed in 112 human melanoma tissue microarrays and melanoma cell lines. Functional experiments including proliferation, clone formation, migration, and metastasis were utilized to identify the suppressive effects of PDPN. The Ph.D.TM-12 Phage Display Peptide Library was used to obtain a PDPN antagonist peptide, named CY12-RP2. The immunofluorescence, SPR assay, and flow cytometry were used to identify the binding specificity of CY12-RP2 with PDPN in melanoma cells. Functional and mechanistic assays in vivo and in vitro were performed for discriminating the antitumor and immune activation effects of CY12-RP2.

Results
PDPN was overexpressed in melanoma tissue and cells, and inhibited melanoma cells proliferation, migration, and metastasis by blocking the EMT and Wnt/β-catenin pathway. PDPN antagonistic peptide, CY12-RP2, could specifically bind with PDPN, suppressing melanoma various functions inducing apoptosis in both melanoma cells and 3D spheroids. CY12-RP2 also enhanced the anti-tumor capacity of PBMC, and inhibited melanoma cells growth both in xenografts and allogeneic mice model. Moreover, CY12-RP2 could inhibit melanoma lung metastasis, and abrogated the immunosuppressive effects of PDPN by increasing the proportion of CD3 + CD4 + T cells, CD3 + CD8 + T cells, CD49b + Granzyme B + NK cells, and CD11b + CD86 + M1-like macrophages and the levels of IL-1β, TNF-α, and IFN-γ.

Conclusions
This study has demonstrated the important role of PDPN in the progression of melanoma and formation of immunosuppressive environment, and provided a potential approach of treating melanoma using the novel CY12-RP2 peptide.

Graphical Abstract
In melanoma, PDPN is overexpressed in the cancer cells, and promotes melanoma cells growth and metastasis through activating the Wnt/β-catenin pathway. Treatment with the PDPN antagonistic peptide CY12-RP2 could not only inhibit the melanoma growth and metastasis both in vitro and in vivo through Wnt/β-catenin pathway blockade, but also abrogate the immunosuppressive effects of PDPN through modulating immune cells.
Loratidine is associated with improved prognosis and exerts antineoplastic effects via apoptotic and pyroptotic crosstalk in lung cancer
Authors: Liu Xiwen , Zhong Ran , Huang Jiaxing , Chen Zisheng , Xu Haoxiang , Lin Lixuan , Cai Qi , He Miao , Lao Shen , Deng Hongsheng , Li Caichen , Li Jianfu , Zheng Yongmei , Liu Xiaoyan , Zeng Riqi , He Jianxing , Liang Wenhua 
Published: January 2024

Abstract
Background
Tumor-associated inflammation suggests that anti-inflammatory medication could be beneficial in cancer therapy. Loratadine, an antihistamine, has demonstrated improved survival in certain cancers. However, the anticancer mechanisms of loratadine in lung cancer remain unclear.

Objective
This study investigates the anticancer mechanisms of loratadine in lung cancer.

Methods
A retrospective cohort of 4,522 lung cancer patients from 2006 to 2018 was analyzed to identify noncancer drug exposures associated with prognosis. Cellular experiments, animal models, and RNA-seq data analysis were employed to validate the findings and explore the antitumor effects of loratadine.

Results
This retrospective study revealed a positive association between loratadine administration and ameliorated survival outcomes in lung cancer patients, exhibiting dose dependency. Rigorous in vitro and in vivo assays demonstrated that apoptosis induction and epithelial-mesenchymal transition (EMT) reduction were stimulated by moderate loratadine concentrations, whereas pyroptosis was triggered by elevated dosages. Intriguingly, loratadine was found to augment PPARγ levels, which acted as a gasdermin D transcription promoter and caspase-8 activation enhancer. Consequently, loratadine might incite a sophisticated interplay between apoptosis and pyroptosis, facilitated by the pivotal role of caspase-8.

Conclusion
Loratadine use is linked to enhanced survival in lung cancer patients, potentially due to its role in modulating the interplay between apoptosis and pyroptosis via caspase-8.
Analysis and applications of respiratory surface EMG: report of a round table meeting
Authors: Jonkman A. H. , Warnaar R. S. P. , Baccinelli W. , Carbon N. M. , D’Cruz R. F. , Doorduin J. , van Doorn J. L. M. , Elshof J. , Estrada-Petrocelli L. , Graßhoff J. , Heunks L. M. A. , Koopman A. A. , Langer D. , Moore C. M. , Nunez Silveira J. M. , Petersen E. , Poddighe D. , Ramsay M. , Rodrigues A. , Roesthuis L. H. , Rossel A. , Torres A. , Duiverman M. L. , Oppersma E. 
Published: January 2024

AbstractSurface electromyography (sEMG) can be used to measure the electrical activity of the respiratory muscles. The possible applications of sEMG span from patients suffering from acute respiratory failure to patients receiving chronic home mechanical ventilation, to evaluate muscle function, titrate ventilatory support and guide treatment. However, sEMG is mainly used as a monitoring tool for research and its use in clinical practice is still limited—in part due to a lack of standardization and transparent reporting. During this round table meeting, recommendations on data acquisition, processing, interpretation, and potential clinical applications of respiratory sEMG were discussed. This paper informs the clinical researcher interested in respiratory muscle monitoring about the current state of the art on sEMG, knowledge gaps and potential future applications for patients with respiratory failure.
Remote ischemic conditioning reduces adverse events in patients with acute ischemic stroke complicating acute myocardial infarction: a randomized controlled trial
Authors: Li Sijie , Xing Xiurong , Wang Lanjing , Xu Jiali , Ren Changhong , Li Yalin , Wang Jing , Liu Zhi , Zhao Heng , Zhao Wenbo , Ji Xunming 
Published: January 2024

Abstract
Background
Acute ischemic stroke (AIS) complicating an acute myocardial infarction (AMI) is not uncommon, but can severely worsen the clinical prognosis. This study aimed to investigate whether remote ischemic conditioning (RIC) could provide clinical benefits to patients with AIS complicating AMI.

Methods
Subjects with AIS complicating AMI were recruited in this double-blind, randomized, controlled trial; assigned to the RIC and sham groups; and respectively underwent twice daily RIC and sham RIC for 2 weeks. All subjects received standard medical therapy. The primary endpoint was the rate of major adverse cardiac and cerebrovascular events (MACCEs) within 3 months after enrollment. MACCEs comprise of death from all causes, unstable anginas, AMI, acute ischemic strokes, and transient ischemic attacks.

Results
Eighty subjects were randomly assigned; 37 patients in the RIC group and 40 patients in the sham-RIC group completed the 3-month follow-up and were included in the final analysis. Both RIC and sham RIC procedures were well tolerated. At 3-month follow-up, 11 subjects (29.7%) in the RIC group experienced MACCEs compared to 21 (52.5%) in the sham group (hazard ratio [HR], 0.396; 95% confidence interval, 0.187–0.838; adjusted p < 0.05). Six subjects (16.2%) in the RIC group had died at the 3-month follow up, significantly lower than the 15 (37.5%) deaths in the sham group (adjusted HR 0.333; 95% CI 0.126–0.881; p = 0.027). Seventeen subjects (45.9%) in the RIC group and 6 subjects (15.0%) in the sham group achieved functional independence (mRS score ≤ 2) at 3-month follow-up (adjusted OR 12.75; 95% CI 2.104–77.21; p = 0.006).

Conclusions
Among patients with acute ischemic stroke complicating acute myocardial infarction, treatment with remote ischemic conditioning decreased the major adverse cardiac and cerebrovascular events and improved functional outcomes at 90 days.
Trial registration: URL: www.clinicaltrials.gov. Unique identifier: NCT03868007. Registered 8 March 2019.
Addition of polygenic risk score to a risk calculator for prediction of breast cancer in US Black women
Authors: Zirpoli Gary R. , Pfeiffer Ruth M. , Bertrand Kimberly A. , Huo Dezheng , Lunetta Kathryn L. , Palmer Julie R. 
Published: January 2024

Abstract
Background
Previous work in European ancestry populations has shown that adding a polygenic risk score (PRS) to breast cancer risk prediction models based on epidemiologic factors results in better discriminatory performance as measured by the AUC (area under the curve). Following publication of the first PRS to perform well in women of African ancestry (AA-PRS), we conducted an external validation of the AA-PRS and then evaluated the addition of the AA-PRS to a risk calculator for incident breast cancer in Black women based on epidemiologic factors (BWHS model).

Methods
Data from the Black Women’s Health Study, an ongoing prospective cohort study of 59,000 US Black women followed by biennial questionnaire since 1995, were used to calculate AUCs and 95% confidence intervals (CIs) for discriminatory accuracy of the BWHS model, the AA-PRS alone, and a new model that combined them. Analyses were based on data from 922 women with invasive breast cancer and 1844 age-matched controls.

Results
AUCs were 0.577 (95% CI 0.556–0.598) for the BWHS model and 0.584 (95% CI 0.563–0.605) for the AA-PRS. For a model that combined estimates from the questionnaire-based BWHS model with the PRS, the AUC increased to 0.623 (95% CI 0.603–0.644).

Conclusions
This combined model represents a step forward for personalized breast cancer preventive care for US Black women, as its performance metrics are similar to those from models in other populations. Use of this new model may mitigate exacerbation of breast cancer disparities if and when it becomes feasible to include a PRS in routine health care decision-making.
Genetic effects of sequence-conserved enhancer-like elements on human complex traits
Authors: Zhu Xiang , Ma Shining , Wong Wing Hung 
Published: January 2024

Abstract
Background
The vast majority of findings from human genome-wide association studies (GWAS) map to non-coding sequences, complicating their mechanistic interpretations and clinical translations. Non-coding sequences that are evolutionarily conserved and biochemically active could offer clues to the mechanisms underpinning GWAS discoveries. However, genetic effects of such sequences have not been systematically examined across a wide range of human tissues and traits, hampering progress to fully understand regulatory causes of human complex traits.

Results
Here we develop a simple yet effective strategy to identify functional elements exhibiting high levels of human-mouse sequence conservation and enhancer-like biochemical activity, which scales well to 313 epigenomic datasets across 106 human tissues and cell types. Combined with 468 GWAS of European (EUR) and East Asian (EAS) ancestries, these elements show tissue-specific enrichments of heritability and causal variants for many traits, which are significantly stronger than enrichments based on enhancers without sequence conservation. These elements also help prioritize candidate genes that are functionally relevant to body mass index (BMI) and schizophrenia but were not reported in previous GWAS with large sample sizes.

Conclusions
Our findings provide a comprehensive assessment of how sequence-conserved enhancer-like elements affect complex traits in diverse tissues and demonstrate a generalizable strategy of integrating evolutionary and biochemical data to elucidate human disease genetics.
DTX2 promotes glioma development via regulation of HLTF
Authors: Li Ren , Chen Yang , Yang Biao , Li Ziao , Li Peize , Chen Yu , Li Jiayu , He Jianhang , Wu Yongqiang , Sun Yanqi , Wang Xiaogang , Guo Xiaolong , Zhang Wenju , Zhao Yuanli , Guo Geng 
Published: January 2024

Abstract
Background
Human Deltex 2 (DTX2) is a ubiquitin E3 ligase that functions as an oncogene and has been shown to participate in many human cancers. However, the role of DTX2 in glioma progression has remained obscure. In this study, we explore the mechanism underlying the function of DTX2 in glioma progression.

Methods
The associations between DTX2 expression and clinical characteristics of glioma were determined by bioinformatic analysis of data from The Cancer Genome Atlas and Human Protein Atlas. The expression of DTX2 in glioma tissues was detected using immunohistochemistry and western blotting. Lentivirus-mediated gene knockdown and overexpression were used to determine the effects of DTX2 and helicase-like transcription element (HLTF) on glioma cell proliferation and migration with CCK-8, cell colony formation, transwell, and wound healing assays; flow cytometry in vitro; and animal models in vivo. The interaction of the DTX2 and HLTF proteins was verified by immunoprecipitation assay and confocal microscopy.

Results
DTX2 was highly expressed in glioma samples, and this was correlated with worse overall survival. Silencing of DTX2 suppressed glioma cell viability, colony formation, and migration and induced cell apoptosis. In vitro ubiquitination assays confirmed that DTX2 could downregulate HLTF protein levels by increasing ubiquitination of the HLTF protein. We also observed that HLTF inhibited proliferation and migration of glioma cells. Subcutaneous xenografts with DTX2-overexpressing U87 cells showed significantly increased tumor volumes and weights.

Conclusions
We have identified DTX2/HLTF as a new axis in the development of glioma that could serve as a prognostic or therapeutic marker.

Graphical abstract
Dreaming during gastrointestinal endoscopy under propofol, ciprofol, or remimazolam anesthesia: study protocol for a parallel-design double-blind, single-center trial
Authors: Xia Le-Qiang , Zhou Rui , Deng Rui , Zhou Dan , Han Jia , Zhao Zhi-Fu , Gao San-Jie , Zhang Xian-Jie , Zhou Yu-Kai , Xiong Li-Ze 
Published: January 2024

AbstractBackgroundDreaming sometimes occurs during sedation. It has been reported that factors such as different anesthetics, depth of anesthesia, age, sex, and preoperative psychological state may affect dreams. Ciprofol and remimazolam are novel choices for painless endoscopy. Herein, we aimed to investigate dreaming during gastrointestinal endoscopy under propofol, ciprofol, and remimazolam anesthesia respectively.MethodsThis is a prospective, parallel-design double-blind, single-center clinical trial. Three hundred and sixty subjects undergoing elective painless gastroscopy, colonoscopy, or gastroenteroscopy will be enrolled. Eligible subjects will undergo propofol-, ciprofol-, or remimazolam-induced anesthesia to finish the examination. Interviews about the modified Brice questionnaire will be conducted in the recovery room. Incidence of dreaming is set as the primary outcome. Secondary outcomes include type of dreams, improvement of sleep quality, evaluation of patients, incidence of insufficient anesthesia, and intraoperative awareness. Safety outcomes are the incidences of hypotension and hypoxia during examination and adverse events during recovery.DiscussionThis study may observe different incidences of dreaming and diverse types of dreams, which might lead to different evaluations to the anesthesia procedure. Based on the coming results, anesthesiologists can make a better medication plan for patients who are going to undergo painless diagnosis and treatment.Trial registrationThis trial was registered at the Chinese Clinical Trial Registry on May 18, 2023 (registration number ChiCTR2300071565).
ERASURE: early autologous blood pleurodesis for postoperative air leaks—a randomized, controlled trial comparing prophylactic autologous blood pleurodesis versus standard watch and wait treatment for postoperative air leaks following thoracoscopic anatomic lung resections
Authors: Karampinis Ioannis , Ruckes Christian , Doerr Fabian , Bölükbas Servet , Ricciardi Sara , Cardillo Giuseppe , Galvez Carlos , Vidmar Bogdan , Stupnik Tomaz , Fang Vincent , Petersen Rene Horsleben , Roessner Eric Dominic 
Published: January 2024

Abstract
Background
The prolonged air leak is probably the most common complication following lung resections. Around 10–20% of the patients who undergo a lung resection will eventually develop a prolonged air leak. The definition of a prolonged air leak varies between an air leak, which is evident after the fifth, seventh or even tenth postoperative day to every air leak that prolongs the hospital stay. However, the postoperative hospital stay following a thoracoscopic lobectomy can be as short as 2 days, making the above definitions sound outdated. The treatment of these air leaks is also very versatile. One of the broadly accepted treatment options is the autologous blood pleurodesis or “blood patch”. The purpose of this trial is to investigate the impact of a prophylactic autologous blood pleurodesis on reducing the duration of the postoperative air leak and therefore prevent the air leak from becoming prolonged.

Methods
Patients undergoing an elective thoracoscopic anatomic lung resection for primary lung cancer or metastatic disease will be eligible for recruitment. Patients with an air leak of > 100 ml/min within 6 h prior to the morning round on the second postoperative day will be eligible for inclusion in the study and randomization. Patients will be randomized to either blood pleurodesis or watchful waiting. The primary endpoint is the time to drain removal measured in full days. The trial ends on the seventh postoperative day.

Discussion
The early autologous blood pleurodesis could lead to a faster cessation of the air leak and therefore to a faster removal of the drain. A faster removal of the drain would relieve the patient from all the well-known drain-associated complications (longer hospital stay, stronger postoperative pain, risk of drain-associated infection, etc.). From the economical point of view, faster drain removal would reduce the hospital costs as well as the costs associated with the care of a patient with a chest drain in an outpatient setting.

Trial registration
German Clinical Trials Register (DRKS) DRKS00030810. 27 December 2022