bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrating proteomics and explainable artificial intelligence: a comprehensive analysis of protein biomarkers for endometrial cancer diagnosis and prognosis
Authors: Yasar Seyma , Yagin Fatma Hilal , Melekoglu Rauf , Ardigò Luca Paolo
Published: June 2024

Endometrial cancer, which is the most common gynaecological cancer in women after breast, colorectal and lung cancer, can be diagnosed at an early stage. The first aim of this study is to classify age, tumor grade, myometrial invasion and tumor size, which play an important role in the diagnosis and prognosis of endometrial cancer, with machine learning methods combined with explainable artificial intelligence. 20 endometrial cancer patients proteomic data obtained from tumor biopsies taken from different regions of EC tissue were used. The data obtained were then classified according to age, tumor size, tumor grade and myometrial invasion. Then, by using three different machine learning methods, explainable artificial intelligence was applied to the model that best classifies these groups and possible protein biomarkers that can be used in endometrial prognosis were evaluated. The optimal model for age classification was XGBoost with AUC (98.8%), for tumor grade classification was XGBoost with AUC (98.6%), for myometrial invasion classification was LightGBM with AUC (95.1%), and finally for tumor size classification was XGBoost with AUC (94.8%). By combining the optimal models and the SHAP approach, possible protein biomarkers and their expressions were obtained for classification. Finally, EWRS1 protein was found to be common in three groups (age, myometrial invasion, tumor size). This article’s findings indicate that models have been developed that can accurately classify factors including age, tumor grade, and myometrial invasion all of which are critical for determining the prognosis of endometrial cancer as well as potential protein biomarkers associated with these factors. Furthermore, we were able to provide an analysis of how the quantities of the proteins suggested as biomarkers varied throughout the classes by combining the SHAP values with these ideal models.
Update on the mechanism of microglia involvement in post-stroke cognitive impairment
Authors: Zeng Tianxiang , Liu Jun , Zhang Wenjun , Yu Yanyan , Ye Xinyun , Huang Qianliang , Li Peng , Jiang Qiuhua
Published: June 2024

Post-stroke cognitive impairment (PSCI) is a clinical syndrome characterized by cognitive deficits that manifest following a stroke and persist for up to 6 months post-event. This condition is grave, severely compromising patient quality of life and longevity, while also imposing substantial economic burdens on societies worldwide. Despite significant advancements in identifying risk factors for PSCI, research into its underlying mechanisms and therapeutic interventions remains inadequate. Microglia, the brain’s primary immune effector cells, are pivotal in maintaining, nurturing, defending, and repairing neuronal function, a process intrinsically linked to PSCI’s progression. Thus, investigating microglial activation and mechanisms in PSCI is crucial. This paper aims to foster new preventive and therapeutic approaches for PSCI by elucidating the roles, mechanisms, and characteristics of microglia in the condition.
Molecular mechanisms and therapeutic possibilities of short-chain fatty acids in posttraumatic stress disorder patients: a mini-review
Authors: Petakh Pavlo , Duve Khrystyna , Oksenych Valentyn , Behzadi Payam , Kamyshnyi Oleksandr
Published: June 2024

This mini-review explores the role of short-chain fatty acids (SCFAs) in posttraumatic stress disorder (PTSD). Highlighting the microbiota-gut-brain axis, this study investigated the bidirectional communication between the gut microbiome and mental health. SCFAs, byproducts of gut microbial fermentation, have been examined for their potential impact on PTSD, with a focus on molecular mechanisms and therapeutic interventions. This review discusses changes in SCFA levels and bacterial profiles in individuals with PTSD, emphasizing the need for further research. Promising outcomes from clinical trials using probiotics and fermented formulations suggest potential avenues for PTSD management. Future directions involve establishing comprehensive human cohorts, integrating multiomics data, and employing advanced computational methods, with the goal of deepening our understanding of the role of SCFAs in PTSD and exploring microbiota-targeted interventions.
Dietary supplementation with plant extracts for amelioration of persistent myofascial discomfort in the cervical and back regions: a randomized double-blind controlled study
Authors: Pérez-Piñero Silvia , Muñoz-Carrillo Juan Carlos , Echepare-Taberna Jon , Luque-Rubia Antonio J. , Millán Rivero Jose Eduardo , Muñoz-Cámara Macarena , Díaz Silvente María Josefa , Valero Merlos Eloina , Ávila-Gandía Vicente , Caturla Nuria , Navarro Pau , Cabrera María , López-Román Francisco Javier
Published: June 2024

Background

Back pain is a common health problem that affects both workers and older people, reducing their quality of life. The primary objective was to assess the effect of dietary supplementation with plant extracts of rosemary, ashwagandha, and sesame consumed for 12 weeks on the intensity of back pain.

Methods

A single-center randomized double-blind study with three parallel arms depending on the product consumed. The duration of treatment was 12 weeks. The investigational product, Berelief®, contained a blend of three polyphenolic standardized extracts: rosemary (Rosmarinus officinalis L.), ashwagandha (Withania somnifera L.), and sesame (Sesamum indicum L.) seed. Two doses were tested: low dose (400 mg) and high dose (800 mg). There were 42 subjects in the placebo group, 39 in the low dose and 42 in the high dose groups. Study variables included back pain intensity [VAS score, Patient-Reported Outcomes Measurement Information System (PROMIS-29), and Cornell Musculoskeletal Discomfort Questionnaire; functionality Roland-Morris Disability (RMD) questionnaire]; quality of life (QoL) [36-item Short Form Survey (SF-36), the Beck Depression Inventory-II (BDI-II), the State–Trait Anxiety Inventory (STAI), and the Perceived Stress Scale (PSS)]; sleep quality [accelerometer and Pittsburgh Sleep Quality Index (PSQI)].

Results

The improvement in back pain recorded by the visual analogue scale (VAS) at the study visits after the beginning of treatment, as well as on a weekly basis recorded in the diary card was significantly higher in the intervention group than in the placebo group (p < 0.044 dose-low; p < 0.005 dose-high). Significant differences in pain intensity of the PROMIS-29 (p = 0.002) and upper back pain in the Cornell questionnaire (p = 0.011) in favour of the investigational product were found. Furthermore, benefits in improving health-related quality of life, mood and sleep quality were also detected.

Conclusion

Dietary supplementation for 12 weeks of a blend of polyphenolic standardized extracts of rosemary, ashwagandha, and sesame was effective in reducing the intensity of pain in subjects with chronic myofascial cervical and back pain.
Immune-related adverse events and their effects on survival outcomes in patients with non-small cell lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis
Authors: Liang Yuxiang , Xu Haidi , Liu Futao , Li Lei , Lin ChenXi , Zhang Yaozhong , Wang Na , Wang Lei
Published: June 2024

Background

The use of immune checkpoint inhibitors (ICIs) has become the standard of care for non-small cell lung cancer. The purpose of this study was to systematically review the literature to determine whether the occurrence of immune-related adverse events (irAEs) following the use of ICIs predicts different clinical outcomes in non-small cell lung cancer (NSCLC).

Methods

Relevant studies from the time of database creation to July 20, 2023, were systematically searched to explore the differences in clinical outcomes in patients with advanced NSCLC with or without irAEs. The outcome indicators included the occurrence of irAEs, progression-free survival (PFS), and overall survival (OS).

Results

25 studies met the inclusion criteria. Of these studies, 22 reported the effect on OS, and 19 reported the effect on PFS. The results showed that for patients with NSCLC, the occurrence of irAEs after receiving immunotherapy showed a statistically significant benefit over the absence of irAEs for OS (HR=0.55,95% CI=0.46–0.65) and PFS (HR=0.55 95% CI=0.48–0.64), but severe irAEs (grades 3–5) were associated with worse OS (HR=1.05, 95% CI=0.87–1.27). Compared with gastrointestinal, lung, and hepatitis, irAEs of the skin and endocrine system tend to predict better OS and PFS.

Conclusion

The occurrence of irAEs, especially mild and early irAEs, indicates better OS and PFS in patients with NSCLC treated with ICIs, irrespective of patient characteristics, type of ICIs, and irAEs. However, Grade 3 or higher toxicities resulted in worse OS.

Systematic review registration

https://www.crd.york.ac.uk/prospero/, identifier CRD42023409444.
Simultaneous integrated boost on pathologic lymph nodes safely improves clinical outcomes compared to sequential boost in locally advanced cervical cancer: a multicenter retrospective study
Authors: Guigo Marin , Dauda Mohammed Sali , Lequesne Justine , Blache Alice , Pereira Renata , Le Gall Ioana , Pernin Victor Emmanuel , Gaichies Léopold , Clarisse Bénédicte , Grellard Jean-Michel , Joly Florence , Meyer Emmanuel , Balosso Jacques
Published: June 2024

Background

Objective

This multicenter study aimed to retrospectively evaluate the impact of high boost simultaneous integrated boost (SIB) to pathologic lymph nodes compared to Sequential boost (Seq) in patients with locally advanced cervical cancer (LACC).

Materials and methods

97 patients with pelvic and/or para-aortic (PAo) node-positive LACC treated by definitive chemoradiation were included. Two groups were analyzed: Sequential boost group and simultaneous integrated boost (SIB) group. Endpoints were Distant Recurrence Free Survival (DRFS), Recurrence Free Survival (RFS), Overall Survival (OS), locoregional pelvic and PAo control and toxicities.

Results

3-years DRFS in SIB and Seq groups was 65% and 31% respectively (log-rank p < 0.001). 3-years RFS was 58% and 26% respectively (log-rank p = 0.009). DRFS prognostic factors in multivariable analysis were SIB, PAo involvement and maximum pelvic node diameter ≥ 2cm. Adenocarcinoma histology and absence of brachytherapy tended to be prognostic factors. SIB provided the best pelvic control at first imaging with 97%. There was no significant difference in terms of toxicities between groups.

Conclusions

Nodal SIB seems to be unavoidable in the treatment of node-positive LACC. It provides the best DRFS, RFS and pelvic control without additional toxicity, with a shortened treatment duration.
Anxiety and depression in patients with non-site-specific cancer symptoms: data from a rapid diagnostic clinic
Authors: Monroy-Iglesias Maria J. , Russell Beth , Martin Sabine , Fox Louis , Moss Charlotte , Bruno Flaminia , Millwaters Juliet , Steward Lindsay , Murtagh Colette , Cargaleiro Carlos , Bater Darren , Lavelle Grace , Simpson Anna , Onih Jemima , Haire Anna , Reeder Clare , Jones Geraint , Smith Sue , Santaolalla Aida , Van Hemelrijck Mieke , Dolly Saoirse
Published: June 2024

Background

Rapid diagnostic clinics (RDCs) provide a streamlined holistic pathway for patients presenting with non-site specific (NSS) symptoms concerning of malignancy. The current study aimed to: 1) assess the prevalence of anxiety and depression, and 2) identify a combination of patient characteristics and symptoms associated with severe anxiety and depression at Guy’s and St Thomas’ Foundation Trust (GSTT) RDC in Southeast London. Additionally, we compared standard statistical methods with machine learning algorithms for predicting severe anxiety and depression.

Methods

Patients seen at GSTT RDC between June 2019 and January 2023 completed the General Anxiety Disorder Questionnaire (GAD-7) and Patient Health Questionnaire (PHQ-8) questionnaires, at baseline. We used logistic regression (LR) and 2 machine learning (ML) algorithms (random forest (RF), support vector machine (SVM)) to predict risk of severe anxiety and severe depression. The models were constructed using a set of sociodemographic and clinical variables.

Results

A total of 1734 patients completed GAD-7 and PHQ-8 questionnaires. Of these, the mean age was 59 years (Standard Deviation: 15.5), and 61.5% (n:1067) were female. Prevalence of severe anxiety (GAD-7 score ≥15) was 13.8% and severe depression (PHQ-8 score≥20) was 9.3%. LR showed that a combination of previous mental health condition (PMH, Adjusted Odds Rario (AOR) 3.28; 95% confidence interval (CI) 2.36–4.56), symptom duration >6 months (AOR 2.20; 95%CI 1.28–3.77), weight loss (AOR 1.88; 95% CI 1.36–2.61), progressive pain (AOR 1.71; 95%CI 1.26–2.32), and fatigue (AOR 1.36; 95%CI 1.01–1.84), was positively associated with severe anxiety. Likewise, a combination PMH condition (AOR 3.95; 95%CI 2.17–5.75), fatigue (AOR 2.11; 95%CI 1.47–3.01), symptom duration >6 months (AOR 1.98; 95%CI 1.06–3.68), weight loss (AOR 1.66; 95%CI 1.13–2.44), and progressive pain (AOR 1.50; 95%CI 1.04–2.16), was positively associated with severe depression. LR and SVM had highest accuracy levels for severe anxiety (LR: 86%, SVM: 85%) and severe depression (SVM: 89%, LR: 86%).

Conclusion

High prevalence of severe anxiety and severe depression was found. PMH, fatigue, weight loss, progressive pain, and symptoms >6 months emerged as combined risk factors for both these psychological comorbidities. RDCs offer an opportunity to alleviate distress in patients with concerning symptoms by expediting diagnostic evaluations.
A 23-year bibliometric analysis of the development of global research on hereditary renal carcinoma
Authors: Lan Xiaopeng , Feng Mei , Lv Ji , Zhang Luchen , Hu Pengcheng , Wang Yizhen , Zhang Yanhui , Wang Shen , Liu Chunzhao , Liu Chunlei
Published: June 2024

Objectives

Medical research continues to be extensively devoted to investigating the pathogenesis and treatment approaches of hereditary renal cancer. By aspect including researchers, institutions, countries, journals, and keywords, we conduct a bibliometric analysis of the literature pertaining to hereditary renal cancer over the last 23 years.

Methods

From the Web of Science Core Collection, we conducted a search for publications published between January 1, 2000 and November 28, 2023. Reviews and original articles were included.

Results

A cumulative count of 2,194 publications met the specified criteria for inclusion. The studies of the included articles involved a collective of 2,402 institutions representing 80 countries. Notably, the United States exhibited the highest number of published documents, constituting approximately 45.49% of the total. The preeminent institution in this discipline is the National Cancer Institute (NCI), which maintains a publication volume of 8.98%. In addition to being the most prolific author (125 publications), Linehan WM’s works received the highest number of citations (11,985). In a comprehensive count, 803 journals have published related articles. In the top 10 most recent occurrences were the terms “hereditary leiomyomatosis” and “fumarate hydratase.”

Conclusion

This is the first bibliometric analysis of the literature on hereditary renal cancer. This article offers a thorough examination of the present status of investigations concerning hereditary renal cancer during the previous 23 years.
Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis
Authors: Yao Tao , Lin Yun-Lu , Wu Yu-Qing , Qian Xin-Ge , Wang Zhe-Ning , Qian Sang , Jiang Ting , Liu Jing-Chen , Fang Luo-Xiang , Zhen Cheng , Wu Chun-Hui
Published: June 2024

Background

Breast cancer (BC) exhibits a high incidence rate, imposing a substantial burden on healthcare systems. Novel drug targets are urgently needed for BC. Mendelian randomization (MR) has gained widespread application for identifying fresh therapeutic targets. Our endeavor was to pinpoint circulatory proteins causally linked to BC risk and proffer potential treatment targets for BC.

Methods

Through amalgamating protein quantitative trait loci from 2,004 circulating proteins and comprehensive genome-wide association study data from the Breast Cancer Association Consortium, we conducted MR analyses. Employing Steiger filtering, bidirectional MR, Bayesian colocalization, phenotype scanning, and replication analyses, we further solidified MR study outcomes. Additionally, protein-protein interaction (PPI) network was harnessed to unveil latent associations between proteins and prevailing breast cancer medications. The phenome-wide MR (Phe-MR) was employed to assess potential side effects and indications for the druggable proteins of BC. Finally, we further affirmed the drugability of potential drug targets through mRNA expression analysis and molecular docking.

Results

Through comprehensive analysis, we identified five potential drug targets, comprising four (TLR1, A4GALT, SNUPN, and CTSF) for BC and one (TLR1) for BC_estrogen receptor positive. None of these five potential drug targets displayed reverse causation. Bayesian colocalization suggested that these five latent drug targets shared variability with breast cancer. All drug targets were replicated within the deCODE cohort. TLR1 exhibited PPI with current breast cancer therapeutic targets. Furthermore, Phe-MR unveiled certain adverse effects solely for TLR1 and SNUPN.

Conclusion

Our study uncovers five prospective drug targets for BC and its subtypes, warranting further clinical exploration.
Development of liquid biopsy in detection and screening of pancreatic cancer
Authors: Chen Xiangcheng , Hu Xinyi , Liu Tiancai
Published: June 2024

Pancreatic cancer is a highly lethal malignant tumor, which has the characteristics of occult onset, low early diagnosis rate, rapid development and poor prognosis. The reason for the high mortality is partly that pancreatic cancer is usually found in the late stage and missed the best opportunity for surgical resection. As a promising detection technology, liquid biopsy has the advantages of non-invasive, real-time and repeatable. In recent years, the continuous development of liquid biopsy has provided a new way for the detection and screening of pancreatic cancer. The update of biomarkers and detection tools has promoted the development of liquid biopsy. Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA) and extracellular vesicles (EVs) provide many biomarkers for liquid biopsy of pancreatic cancer, and screening tools around them have also been developed. This review aims to report the application of liquid biopsy technology in the detection of pancreatic cancer patients, mainly introduces the biomarkers and some newly developed tools and platforms. We have also considered whether liquid biopsy technology can replace traditional tissue biopsy and the challenges it faces.
Comparison of invasive blood pressure monitoring vs. non-invasive blood pressure monitoring in critically ill children receiving vasoactive agents—a prospective observational study
Authors: Shah Sachin , Kaul Amita , Nagarkar Rohini , Thorat Amol
Published: June 2024

Objective

The primary aim of this study was to compare non-invasive blood pressure (NIBP) measurement using the automated oscillometric method with invasive blood pressure (IBP) measurement using peripheral arterial line insertion in critically ill children receiving vasoactive agents.

Design

Single-centre, prospective cohort study.

Setting

Tertiary care 15 bedded Pediatric ICU in Urban Indian city.

Subjects

All critically ill children between the ages of 1 month to 16 years with shock on vasoactive medications and with IBP monitoring.

Results

Forty children with 1,072 paired BP measurements were incorporated in the final analysis. Among all normotensive children (Total number of paired measurements = 623) receiving vasoactive agents, Bland–Altman analysis revealed an acceptable agreement between Invasive mean blood pressure (MBP) and non-invasive MBP with a bias of −2.10 mmHg (SD 11.35). The 95% limits of agreement were from −24.34 to 20.14 mmHg. In children with hypotension (Total number of paired measurements = 449), Bland–Altman analysis showed disagreement between Invasive MBP and non-invasive MBP i.e., a bias of −8.44 mmHg (SD 9.62). The 95% limits of agreement were from −27.29 to 10.41 mmHg.

Conclusion

A limited agreement exists between invasive blood pressure (IBP) and non-invasive blood pressure (NIBP) measurements in critically ill children requiring vasoactive agents. This discrepancy can lead to either an underestimation or an overestimation of blood pressure. While NIBP can serve as a screening tool for hemodynamically stable children, those who are hemodynamically unstable and necessitate the initiation of vasoactive agents should undergo IBP monitoring.
Advancements in surgical education: exploring animal and simulation models in fetal and neonatal surgery training
Authors: Davidson Emily L. , Penniston Kristina L. , Farhat Walid A.
Published: June 2024

Introduction

Surgical education is undergoing a transformation, moving away from traditional models towards more modern approaches that integrate experiential and didactic methods. This shift is particularly pertinent in the realm of fetal and neonatal surgery, where specialized training is crucial. Historical training methods, such as cadaveric dissection, have been prevalent for centuries, but newer innovations, including animal and non-animal simulation models, are gaining prominence. This manuscript aims to explore the use of both animal and non-animal models in surgical education, with a specific focus on fetal and neonatal surgery.

Animal models

The use of animal models in surgical training has a long history, dating back to Halsted's introduction in 1889. These models, often utilizing large animals like swine and dogs, offer valuable insights into fetal and neonatal surgeries. They allow for the study of long-term outcomes and the simulation of various diseases and anomalies, providing essential training experiences not readily available in human surgeries. However, there are notable limitations, including anatomical and physiological differences from humans, ethical considerations, and substantial infrastructure and maintenance costs.

Simulation models

Simulation-based training offers several benefits, including standardized and safe learning environments without risks to real patients. Bench models, using synthetic materials or non-living animal tissue, provide cost-effective options for skills development. Virtual reality and 3-D printing technologies further enhance simulation experiences, allowing for the replication of complex clinical scenarios and patient-specific anatomies. While these models offer significant advantages, they lack the complexity of biological systems found in animal models.

Conclusion

In conclusion, both animal and non-animal simulation models play crucial roles in enhancing surgical education, particularly in fetal and neonatal surgery. While advancements in non-animal technologies are important for ethical reasons, the continued necessity of animal models in certain areas should be acknowledged. By responsibly integrating these models into training programs, surgical education can be further enriched while upholding ethical standards and ensuring optimal patient outcomes.
Untargeted metabonomics and TLR4/ NF-κB signaling pathway analysis reveals potential mechanism of action of Dendrobium huoshanense polysaccharide in nonalcoholic fatty liver disease
Authors: Deng Guang-hui , Zhao Chen-chen , Cai Xiao , Zhang Xiao-qian , Ma Meng-zhen , Lv Jia-hui , Jiang Wen-li , Peng Dai-yin , Wang Yan-yan , Xing Li-hua , Yu Nian-jun
Published: June 2024

Nonalcoholic fatty liver disease (NAFLD) is marked by hepatic steatosis accompanied by an inflammatory response. At present, there are no approved therapeutic agents for NAFLD. Dendrobium Huoshanense polysaccharide (DHP), an active ingredient extracted from the stems of Dendrobium Huoshanense, and exerts a protective effect against liver injury. However, the therapeutic effects and mechanisms of action DHP against NAFLD remain unclear. DHP was extracted, characterized, and administered to mice in which NAFLD had been induced with a high-fat and high-fructose drinking (HFHF) diet. Our results showed that DHP used in this research exhibits the characteristic polysaccharide peak with a molecular weight of 179.935 kDa and is composed primarily of Man and Glc in a molar ratio of 68.97:31.03. DHP treatment greatly ameliorated NAFLD by significantly reducing lipid accumulation and the levels of liver function markers in HFHF-induced NAFLD mice, as evidenced by decreased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and total triglyceride (TG). Furthermore, DHP administration reduced hepatic steatosis, as shown by H&E and Oil red O staining. DHP also inhibited the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway expression, thereby reducing levels of hepatic proinflammatory cytokines. Besides, untargeted metabolomics further indicated that 49 metabolites were affected by DHP. These metabolites are strongly associated the metabolism of glycine, serine, threonine, nicotinate and nicotinamide, and arachidonic acid. In conclusion, DHP has a therapeutic effect against NAFLD, whose underlying mechanism may involve the modulation of TLR4/NF-κB, reduction of inflammation, and regulation of the metabolism of glycine, serine, threonine, nicotinate and nicotinamide metabolism, and arachidonic acid metabolism.
Translational PK/PD and the first-in-human dose selection of a PD1/IL15: an engineered recombinant targeted cytokine for cancer immunotherapy
Authors: Yadav Rajbharan , Schubbert Suzanne , Holder Patrick G. , Chiang Eugene Y. , Kiabi Nargess , Bogaert Liz , Leung Irene , Rashid Rumana , Avery Kendra N. , Bonzon Christine , Desjarlais John R. , Sanjabi Shomyseh , Sharma Amy , Lepherd Michelle , Shelton Amy , Chan Pam , Liu Yanqiu , Joslyn Louis , Hosseini Iraj , Stefanich Eric G. , Kamath Amrita V. , Bernett Matthew J. , Shivva Vittal
Published: June 2024

Introduction

Interleukin 15 (IL-15) is a potential anticancer agent and numerous engineered IL-15 agonists are currently under clinical investigation. Selective targeting of IL-15 to specific lymphocytes may enhance therapeutic effects while helping to minimize toxicities.

Methods

We designed and built a heterodimeric targeted cytokine (TaCk) that consists of an anti-programmed cell death 1 receptor antibody (anti-PD-1) and an engineered IL-15. This “PD1/IL15” selectively delivers IL-15 signaling to lymphocytes expressing PD-1. We then investigated the pharmacokinetic (PK) and pharmacodynamic (PD) effects of PD1/IL15 TaCk on immune cell subsets in cynomolgus monkeys after single and repeat intravenous dose administrations. We used these results to determine the first-in-human (FIH) dose and dosing frequency for early clinical trials.

Results

The PD1/IL15 TaCk exhibited a nonlinear multiphasic PK profile, while the untargeted isotype control TaCk, containing an anti-respiratory syncytial virus antibody (RSV/IL15), showed linear and dose proportional PK. The PD1/IL15 TaCk also displayed a considerably prolonged PK (half-life range ∼1.0–4.1 days) compared to wild-type IL-15 (half-life ∼1.1 h), which led to an enhanced cell expansion PD response. The PD was dose-dependent, durable, and selective for PD-1+ lymphocytes. Notably, the dose- and time-dependent PK was attributed to dynamic TMDD resulting from test article-induced lymphocyte expansion upon repeat administration. The recommended first-in-human (FIH) dose of PD1/IL15 TaCk is 0.003 mg/kg, determined based on a minimum anticipated biological effect level (MABEL) approach utilizing a combination of in vitro and preclinical in vivo data.

Conclusion

This work provides insight into the complex PK/PD relationship of PD1/IL15 TaCk in monkeys and informs the recommended starting dose and dosing frequency selection to support clinical evaluation of this novel targeted cytokine.
Helicobacter pylori antibiotic resistance profile in Chinese children with upper gastrointestinal symptoms and a literature review for developing personalized eradicating strategies
Authors: Zhou Danli , Wang Wuyu , Gu Lan , Han Meiling , Hao Wujuan , Huang Junfeng , Lin Qiong , Wang Yan
Published: June 2024

Background:H. pylori (Helicobacter pylori) infections typically occur in early childhood. Although the prevalence of H. pylori in children is lower than that in adults, the eradication rate of this infection in children is relatively low because of resistance. In this study, we analyzed personalized treatment strategies to achieve treatment goals based on H. pylori resistance characteristics. This retrospective single-center study was conducted between January 2019 and December 2022 and enrolled 1,587 children who presented with upper gastrointestinal symptoms and underwent endoscopy. H. pylori culturing and antimicrobial susceptibility testing were performed.

Results: Culture-positive results for H. pylori were obtained in 535 children. The resistance rates to clarithromycin (CLA), metronidazole (MET), and levofloxacin (LEV) were 39.8%, 78.1%, and 20.2%, respectively. None of the isolates were resistant to tetracycline (TET), amoxicillin (AMO), or furazolidone (FZD). Double resistance rates to CLA + MET, CLA + LEV, and MET + LEV were 19.1%, 3.0%, and 5.8%, respectively. Notably, triple-resistant to CLA + MET + LEV was 9.7%. Based on susceptibility tests, individualized triple therapy [proton pump inhibitor (PPI) +AMO + CLA/MET] was selected for 380 children with H. pylori sensitive to MET and/or CLA. In 155 children resistant to CLA and MET, bismuth-based quadruple therapy was recommended; for unable to receive bismuth, concomitant therapy was recommended for 14 children (<8 years of age); triple therapy with TET was recommended for 141 children (>8 years of age), with 43 children (>14 years of age) requiring FZD rather than TET.

Conclusion: Resistance to H. pylori in Chinese children was relatively poor. Personalized therapy regimens should be based on susceptibility tests and avoided factors associated with treatment failure.
Effects of exercise dose based on the ACSM recommendations on patients with post-stroke cognitive impairment: a systematic review and meta-analyses
Authors: Zhao Xuejiao , Li Juan , Xue Chao , Li Yujie , Lu Ting
Published: June 2024

Purpose

This review aimed to assess the impact of different exercise dosages on cognitive function in individuals with post-stroke cognitive impairment (PSCI).

Methods

Four electronic databases—Embase, PubMed, Web of Science, and Cochrane Library—were systematically searched from inception to 01 January 2024, focusing on the impact of exercise therapy on cognitive function in individuals with PSCI. Only randomized controlled trials meeting the criteria were included. The exercise therapy dose and adherence were evaluated following the American College of Sports Medicine (ACSM) guidelines, categorized into a high compliance group with ACSM recommendations and a low or uncertain compliance group. A random-effects model compared the effect of ACSM compliance on cognitive function in individuals with PSCI, with the effect size represented by the standardized mean difference (SMD) and a 95% confidence interval (CI).

Results

In total, 18 studies meeting the criteria were included, with data from 1,742 participants. The findings suggested a beneficial effect of exercise on cognitive function in individuals with PSCI [SMD = 0.42, 95% CI (0.20, 0.65)]. Ten studies were categorized as the “high adherence group” and eight in the “low or uncertain adherence group” based on the ACSM recommendations. The subgroup analysis revealed that the SMD of the high compliance group was 0.46 (95% CI: 0.10, 0.82) (p = 0.01), while the SMD of the low or uncertain compliance group was 0.38 (95% CI: 0.07, 0.70) (p = 0.02).

Conclusion

Our study indicates the beneficial impact of exercise for patients with PSCI over no exercise. Furthermore, high adherence to the exercise dose recommended by ACSM guidelines demonstrated a more substantial improvement in cognitive function than low or uncertain adherence in patients with PSCI.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42023487915.
Predicting potential and quality distribution of Anisodus tanguticus (Maxim.) Pascher under different climatic conditions in the Qinghai–Tibet plateau
Authors: Chen Chen , Wang Bo , Li Jianan , Xiao Yuanming , Chen Kaiyang , Liu Na , Zhou Guoying
Published: June 2024

Anisodus tanguticus (Maxim.) Pascher, a distinctive medicinal plant native to the Qinghai-Tibet Plateau, China, has garnered attention due to increasing market demand. This study explores the impact of environmental factors on the distribution and levels of active compounds namely anisodamine, anisodine, and atropine within A. tanguticus. Our goal was to identify suitable cultivation areas for this plant. This study employs the maximum entropy model to simulate the suitable area of A. tanguticus under current conditions and three climate change scenarios during the 2050s and 2070s. The finding revealed that altitude, precipitation in the warmest season (Bio 18), the average annual temperature (Bio 1) exerted significant influences on the distribution of A. tanguticus. Among the environmental factors considered, temperature difference between day and night (Bio 2) had the most substantial impact on the distribution of anisodamine, temperature seasonal variation variance (Bio 4) predominantly influenced anisodine distribution, and Bio 1 had the greatest effected on the distribution of atropine. The suitable areas primarily exist in the eastern Qinghai-Tibet Plateau in China, encompassing a total area of 30.78 × 104 km2. Under the climate scenarios for the future, the suitable areas exhibit increasing trends of approximately 30.2%, 30.3%, and 39.8% by the 2050s, and 25.1%, 48.8%, and 60.1% by the 2070s. This research would provide theoretical suggestions for the protection, and cultivation management of A. tanguticus resources to face the challenge of global climate change.
A tree peony RING-H2 finger protein, PsATL33, plays an essential role in cold-induced bud dormancy release by regulating gibberellin content
Authors: Mao Yanxiang , Yuan Yanping , Gao Yeshen , Zeng Lingling , Fan Siyu , Luo Jianrang , Sun Daoyang
Published: June 2024

Bud dormancy is crucial for woody perennial plants to resist low-temperature stress in winter. However, the molecular regulatory mechanisms underlying bud dormancy release are largely unclear. Here, a tree peony (Paeonia suffruticosa) transcript ARABIDOPSIS TOXICOS EN LEVADURA 33 (PsATL33), encoding a RING-H2 finger protein, was selected from previously generated RNA sequencing data of chilling-treated buds. The objective of this study is to investigate the role of PsATL33 in the regulation of cold-induced bud dormancy release. Subcellular localization assay revealed that PsATL33 was localized to the nucleus and plasma membrane. Reverse transcription–quantitative PCR analysis showed that PsATL33 was dramatically upregulated during cold-triggered bud dormancy release. Exogenous treatments with gibberellin (GA3) increased, but abscisic acid (ABA) inhibited the transcription of PsATL33. Ectopic transformation assay indicated that overexpression of PsATL33 in petunia promoted seed germination, plant growth, and axillary bud break. Silencing of PsATL33 in tree peony through virus-induced gene silencing assay delayed bud dormancy release. tobacco rattle virus (TRV)-PsATL33-infected buds exhibited reduced expression levels of dormancy break-related genes EARLY BUD-BREAK 1 (PsEBB1) and CARBOXYLESTERASE 15 (PsCXE15). Silencing of PsATL33 decreased the accumulation of bioactive GAs, GA1 and GA3, rather than ABA. Transcript levels of several genes involved in GA biosynthesis and signaling, including GA20-OXIDASE 1 (PsGA20ox1), GA3-OXIDASE 1 (PsGA3ox1), PsGA3ox3, GA2-OXIDASE 1 (PsGA2ox1), and GA-INSENSITIVE 1A (PsGAI1A), were changed by PsATL33 silencing. Taken together, our data suggest that PsATL33 functions as a positive regulator of cold-induced bud dormancy release by modulating GA production.
High-density linkage to physical mapping in a unique Tall × Dwarf coconut (Cocos nucifera L.) outbred F2 uncovers a major QTL for flowering time colocalized with the FLOWERING LOCUS T (FT)
Authors: Grattapaglia Dario , Alves Wellington Bruno dos Santos , Pacheco Cleso Antônio Patto
Published: June 2024

Introduction

The coconut tree crop (Cocos nucifera L.) provides vital resources for millions of people worldwide. Coconut germplasm is largely classified into ‘Tall’ (Typica) and ‘Dwarf’ (Nana) types. While Tall coconuts are outcrossing, stress tolerant, and late flowering, Dwarf coconuts are inbred and flower early with a high rate of bunch emission. Precocity determines the earlier production of a plantation and facilitates management and harvest.

Methods

A unique outbred F2 population was used, generated by intercrossing F1 hybrids between Brazilian Green Dwarf from Jiqui (BGDJ) and West African Tall (WAT) cultivars. Single-nucleotide polymorphism (SNP) markers fixed for alternative alleles in the two varieties, segregating in an F2 configuration, were used to build a high-density linkage map with ~3,000 SNPs, anchored to the existing chromosome-level genome assemblies, and a quantitative trait locus (QTL) mapping analysis was carried out.

Results

The linkage map established the chromosome numbering correspondence between the two reference genome versions and the relationship between recombination rate, physical distance, and gene density in the coconut genomes. Leveraging the strong segregation for precocity inherited from the Dwarf cultivar in the F2, a major effect QTL with incomplete dominance was mapped for flowering time. FLOWERING LOCUS T (FT) gene homologs of coconut previously described as putatively involved in flowering time by alternative splice variant analysis were colocalized within a ~200-kb window of the major effect QTL [logarithm of the odds (LOD) = 11.86].

Discussion

Our work provides strong phenotype-based evidence for the role of the FT locus as the putative underlying functional variant for the flowering time difference between Dwarf and Tall coconuts. Major effect QTLs were also detected for developmental traits of the palm, plausibly suggesting pleiotropism of the FT locus for other precocity traits. Haplotypes of the two SNPs flanking the flowering time QTL inherited from the Dwarf parent BGDJ caused a reduction in the time to flower of approximately 400 days. These SNPs could be used for high-throughput marker-assisted selection of early-flowering and higher-productivity recombinant lines, providing innovative genetic material to the coconut industry.
Genome-wide profiling of WRKY genes involved in flavonoid biosynthesis in Erigeron breviscapus
Authors: Song Wanling , Zhang Shuangyan , Li Qi , Xiang Guisheng , Zhao Yan , Wei Fan , Zhang Guanghui , Yang Shengchao , Hao Bing
Published: June 2024

The transcription factors of WRKY genes play essential roles in plant growth, stress responses, and metabolite biosynthesis. Erigeron breviscapus, a traditional Chinese herb, is abundant in flavonoids and has been used for centuries to treat cardiovascular and cerebrovascular diseases. However, the WRKY transcription factors that regulate flavonoid biosynthesis in E. breviscapus remain unknown. In this study, a total of 75 EbWRKY transcription factors were predicted through comprehensive genome-wide characterization of E. breviscapus and the chromosomal localization of each EbWRKY gene was investigated. RNA sequencing revealed transient responses of 74 predicted EbWRKY genes to exogenous abscisic acid (ABA), salicylic acid (SA), and gibberellin 3 (GA3) after 4 h of treatment. In contrast, the expression of key structural genes involved in flavonoid biosynthesis increased after 4 h in GA3 treatment. However, the content of flavonoid metabolites in leaves significantly increased at 12 h. The qRT-PCR results showed that the expression patterns of EbWRKY11, EbWRKY30, EbWRKY31, EbWRKY36, and EbWRKY44 transcription factors exhibited a high degree of similarity to the 11 structural genes involved in flavonoid biosynthesis. Protein-DNA interactions were performed between the key genes involved in scutellarin biosynthesis and candidate WRKYs. The result showed that F7GAT interacts with EbWRKY11, EbWRKY36, and EbWRKY44, while EbF6H has a self-activation function. This study provides comprehensive information on the regulatory control network of flavonoid accumulation mechanisms, offering valuable insights for breeding E. breviscapus varieties with enhanced scutellarin content.
Dynamics of self-control during choice and post-choice consumption quantity
Authors: Oh Ga-Eun , Mukhopadhyay Anirban
Published: June 2024

Observed choices between options representing a relative vice and a relative virtue have commonly been used as a measure of eating self-control in the literature. However, even though self-control operations may manifest across the post-choice consumption stage, either similarly or in different ways from the choice stage, most prior research has ignored consumption quantity of the chosen option. While the behavior of choosing a virtue instead of a vice does manifest self-control, we examine how this plays out in post-choice consumption. Specifically, we find that when processing resources are limited, after having chosen a virtue food, unrestrained eaters ironically consumed greater quantities and therefore more calories than restrained eaters (Study 1). This reflects more persistent self-control in the post-choice consumption stage among restrained eaters than unrestrained eaters, and occurs because choosing a virtue lowers accessibility of the self-control goal among unrestrained eaters relative to restrained eaters (Study 2), thereby increasing intake of the virtuous food. In contrast, subsequent to having chosen a vice, unrestrained eaters and restrained eaters did not show any such difference in intake (Study 1) or goal accessibility (Study 2). Together, these results reveal that persistence of self-control in the post-choice consumption stage depends on individuals’ dietary restraint and their initial exercise of self-control in the choice decision. The mere act of choosing a virtue satisfies unrestrained eaters’ self-control goal and leads to increased food intake, whereas the same act keeps the same goal activated among restrained eaters who reduce intake of the chosen virtue. Put differently, persistent self-control across choice and quantity decisions is observed only when those with a dietary goal show successful self-control enactment in the choice stage. We therefore highlight that the operation of self-control can be dynamic within a consumption episode, and thus, choice and post-choice quantity are both informative of self-control.
Impaired episodic verbal memory recall after 1 week and elevated forgetting in children after mild traumatic brain injury – results from a short-term longitudinal study
Authors: Lidzba Karen , Afridi Zainab , Romano Fabrizio , Wingeier Kevin , Bigi Sandra , Studer Martina
Published: June 2024

Objective

There is preliminary evidence that children after traumatic brain injury (TBI) have accelerated long-term forgetting (ALF), i.e., an adequate learning and memory performance in standardized memory tests, but an excessive rate of forgetting over delays of days or weeks. The main aim of this study was to investigate episodic memory performance, including delayed retrieval 1 week after learning, in children after mild TBI (mTBI).

Methods

This prospective study with two time-points (T1: 1 week after injury and T2: 3–6 months after injury), included data of 64 children after mTBI and 57 healthy control children aged between 8 and 16 years. We assessed episodic learning and memory using an auditory word learning test and compared executive functions (interference control, working memory, semantic fluency and flexibility) and divided attention between groups. We explored correlations between memory performance and executive functions. Furthermore, we examined predictive factors for delayed memory retrieval 1 week after learning as well as for forgetting over time.

Results

Compared to healthy controls, patients showed an impaired delayed recall and recognition performance 3–6 months after injury. Executive functions, but not divided attention, were reduced in children after mTBI. Furthermore, parents rated episodic memory as impaired 3–6 months after injury. Additionally, verbal learning and group, but not executive functions, were predictive for delayed recall performance at both time-points, whereas forgetting was predicted by group.

Discussion

Delayed recall and forgetting over time were significantly different between groups, both post-acutely and in the chronic phase after pediatric mTBI, even in a very mildly injured patient sample. Delayed memory performance should be included in clinical evaluations of episodic memory and further research is needed to understand the mechanisms of ALF.
Perceptions of parental involvement in youth handball players, the effects of sport participation stage and sports injury
Authors: Kovács Krisztina , Takács Johanna , Juhász István , Kovács Katalin
Published: June 2024

Introduction

Globally, from the age of 14, the dropout rate of young athletes is high in all sports games in Hungary. The reasons for dropping out are complex, however parental support is critical to succeed or continue, especially after failure or injury. The present study explored the main effects of sports injury and sport participation stage on parental involvement in sports.

Methods

1,174 parents and 690 athletes completed our questionnaire, which contains questions on young players’ sport participation, injury background and Parental Involvement in Sport Questionnaire.

Results

Parents’ self-perceived level of involvement differed from the parental involvement perceived by their children. The significant predictors were the person who completed, the parent/athlete, the athlete’s previous sports injury and the child’s current stage of sport participation. In Directive Behavior, the main effect of stages is only seen in parents whose child has been injured. In the sample of injured athletes, the rate of perceived parental Praise and Understanding tends to be lower in the specializing stage.

Discussion

Our findings suggest that these two behaviors could be part of the same parenting style, which requires further investigation. The results expand the existing knowledge of the complexity of parents’ involvement in children’s sports careers. These findings have implications beyond parental psychoeducation impacting the work of coaches, sports physicians and rehabilitation experts.