bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of 10 KM run on foot morphology and bilateral symmetry in male recreational runners
Authors: Mo Shiwei , Lu Feifei , Li Chuhao , Zhao Huan
Published: August 2024

Foot morphology and arch integrity do not remain constant during a running bout. Previous studies have reported inconsistent changes in foot sizes and arch parameters and this discrepancy may be related to the variation in their test duration, e.g., 15-min treadmill run vs. 30 KM trial. Hence, this study sought to evaluate the change in foot morphology, arch integrity and bilateral symmetry after a 10 KM run among 19 male recreational runners. Before and after the run, a portable foot scanner was used to capture the 3-dimensional foot images and measure foot dimensions in both weight-bearing and non-weight-bearing conditions. Foot arch integrity was quantified by arch height ratio, arch height index, and arch stiffness index (ASI). Bilateral symmetry was evaluated by calculating the symmetry index. Increased foot length (p = 0.007; ηp2 = 0.18) and decreased ball girth (p = 0.038; ηp2 = 0.11) were demonstrated following the run with absolute differences of less than 2 mm. Navicular height, dorsum height, arch height ratio and arch height index significantly decreased after the run (p < 0.001; ηp2 ≥0.30) whereas ASI increased (p < 0.001, ηp2 = 0.33) and navicular height drop reduced (p < 0.001, ηp2 = 0.37). Significances of symmetry index were only demonstrated for navicular height (p = 0.019, effect size = 0.37) and arch height ratio (p = 0.019, effect size = 0.42). A few changes in foot morphology were detected but a reduction in foot arch height was demonstrated, which may give shoe manufacturers insights into shoe design. Male recreational runners were recommended to choose shoes with arch support for maintaining foot arch function during a 10 KM run.
DDS-type near-infrared light absorber enables deeper lesion treatment in laser photothermal therapy while avoiding damage to surrounding organs
Authors: Takahashi Masataka , Fujishiro Jun , Nomura Shinsuke , Harada Manabu , Hinoki Akinari , Arake Masashi , Ozeki Eiichi , Hara Isao , Satoh Ayano , Tainaka Takahisa , Uchida Hiro-o , Morimoto Yuji
Published: August 2024

The efficacy of drug delivery system (DDS)-type near-infrared (NIR) absorbing agents in enhancing laser photothermal therapy is widely acknowledged. Despite the acknowledged efficacy, the therapeutic advantages of photothermal therapy using DDS-type NIR-absorbing agents over simple photothermal therapy without such agents have not been fully elucidated. This study was designed to investigate two primary objectives: firstly, the ability of DDS-type NIR-absorbing agents to induce cell death at greater depths within tumors, and secondly, their capacity to minimize collateral damage to adjacent healthy organs. To investigate these objectives, we employed a combination of indocyanine green lactosome—a DDS-type NIR-absorbing agent—and a precision-controlled laser hyperthermia system. An orthotopic neuroblastoma tumor model was used to closely simulate clinical conditions. The findings revealed that photothermal therapy using the DDS-type NIR-absorbing agent not only facilitates deeper penetration of cell death within tumors but also significantly mitigates thermal damage to surrounding healthy tissues, when compared to simple phototherapy without the agent. Furthermore, the combined treatment significantly prolonged the survival periods of the animals involved. This study is the first to analyze these therapeutic efficacies using quantitative data from an orthotopic tumor animal model and substantiated the potential of DDS-type NIR-absorbing agents to deepen the therapeutic impact of photothermal therapy while safeguarding vital organs, thereby enhancing overall treatment outcomes.
ST8SIA6-AS1, a novel lncRNA star in liver cancer
Authors: Qiu Cheng , Fan Haoran , Tao Siyu , Deng Ziqing , Luo Hongliang , Liu Fangteng
Published: August 2024

Liver cancer is one of the most lethal gastrointestinal malignancies. Emerging evidence has underscored the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis, with ST8SIA6-AS1 identified as a novel oncogenic lncRNA contributing to liver cancer progression. ST8SIA6-AS1 is consistently upregulated in hepatic cancer tissues and is strongly associated with unfavorable prognosis. Moreover, it demonstrates high diagnostic efficacy in detecting HCC. ST8SIA6-AS1 is involved in various cellular processes including proliferation, migration, and invasion, primarily through its function as a competing endogenous RNA (ceRNA), thereby facilitating hepatocarcinogenesis and disease advancement. This review provides a detailed examination of the molecular functions and regulatory mechanisms of ST8SIA6-AS1 in hepatocellular carcinoma (HCC) and highlights its potential as a promising biomarker for liver cancer, aiming to propel the development of innovative therapeutic strategies for HCC management.
Regulation of biological processes by ubiquitin ligases: a focus on the Pagano Lab’s contribution
Authors: Kaldis Philipp , Porter Lisa A.
Published: August 2024

Protein homeostasis depends on many fundamental processes including mRNA synthesis, translation, post-translational modifications, and proteolysis. In the late 70s and early 80s the discovery that the small 76 amino acid protein ubiquitin could be attached to target proteins via a multi-stage process involving ubiquitin-activating enzymes, ubiquitin conjugating enzymes, and ubiquitin ligases, revealed an exciting new post-translational mechanism to regulate protein degradation. This cellular system was uncovered using biochemical methods by Avram Hershko, who would later won the Nobel prize for this discovery; however, the biological functions of ubiquitin ligases remained unknown for many years. It was initially described that ubiquitin modifies proteins at one or more lysine residues and once a long ubiquitin chain was assembled, proteins were degraded by the proteasome. Now we know that proteins can be mono-, multimono-, homotypic poly-, or heterotypic poly-ubiquitylated, each of which confers a specific signal that goes beyond protein degradation regulating additional key cellular functions such as signal transduction, protein localization, recognition of damaged proteins, etc.
Structural analogs of 2-(4-fluorophenyl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine for targeting Candida albicans non-essential stress kinase Yck2 through protein-ligand binding and dynamics analysis
Authors: Hassan Ahmed M. , Khateb Aiah M. , Turkistani Safaa A. , Alhamdan Meshari M. , Garout Raed M. , Dwivedi Vivek Dhar , Azhar Esam I.
Published: August 2024

The rise in drug-resistant fungal infections poses a significant public health concern, necessitating the development of new antifungal therapies. We aimed to address this challenge by targeting a yeast casein kinase of Candida albicans for antifungal drug development. The compound library contained 589 chemical structures similar to the previously identified kinase inhibitor GW461484A. Through virtual screening, four compounds with the PubChem IDs 102583821, 12982634, 102487860, and 86260205 were selected based on their binding energies. Hydrophobic bonds and van der Waals interactions stabilised the docked complexes. Comprehensive interaction studies and a 200-nanosecond molecular dynamics simulation suggested that these molecules can maintain stable interactions with the target, as evidenced by satisfactory RMSD and RMSF values. The Rg-RMSD-based Free Energy Landscape of these complexes indicated thermodynamic stability due to the presence of conformers with global minima. These promising findings highlight the potential for developing novel antifungal therapies targeting Yck2 in C. albicans. Further experimental validation is required to assess the efficacy of these compounds as antifungal agents. This research provides a significant step towards combating antifungal resistance and opens up a new avenue for drug discovery.
Mini-Review: Immunogenic epitopes in apolipoprotein B-100 for atheroprotective immunization
Authors: Gerdes Norbert , Klingenberg Roland
Published: August 2024

Here, we provide a concise overview of recent developments in the identification of immunogenic epitopes in human apolipoprotein B-100 for immunization against atherosclerotic cardiovascular disease. Major steps forward toward a clinical application of vaccines include the design of humanized mouse models, tetramer-based identification of antigen-specific T cells, and novel analysis tools, such as single-cell RNA sequencing and cytometry by time of flight, to assess temporal and spatial changes in immune cells in atherosclerotic cardiovascular disease.
Longitudinal mixed-methods analysis of tertiary students’ dropout considerations
Authors: Lykkegaard Eva , Qvortrup Ane
Published: August 2024

The paper presents a longitudinal mixed methods study investigating tertiary humanity students’ dropout considerations, utilizing Tinto’s institutional departure model as theoretical background. The research question is: How do students’ dropout considerations take form and evolve throughout tertiary education? Methodically we have collected half-yearly register and survey data from 2,781 tertiary humanities students matriculating in 2017–2019. Additionally, we have conducted half-yearly interviews with 14 focus students that had high dropout considerations in the first survey round. Quantitative analysis of all humanity students and qualitative analysis of three case students are presented and discussed. The complementary analysis provides an in-depth understanding of the complex interplay between individual characteristics and institutional factors in shaping different students’ dropout considerations and decisions in tertiary education. We find that there is a stable share of students with low, medium, and high dropout considerations throughout time. However, although we find stable shares, we identify primary movements from high dropout considerations towards dropout, and from low dropout considerations towards completion, we also find considerable secondary movement (i.e., from low dropout considerations towards dropout). As is also confirmed in the qualitative analyses, there are significant fluctuations in some students’ dropout considerations. Dropout considerations are thus malleable and do not necessarily accumulate linearly over time to dropout. Individual students’ dropout considerations change repeatedly in interaction with their experiences, their expectations for the future as well as with current challenges in meeting academic and personal requirements. Challenges are often about a lack of alignment between expectations and experiences and how well students and the study programs’ norms and values match. We find students who seek to improve this match through personal transformations and others who try to change their study program. In both regards successfully improving the match seems to be a profitable strategy to prevent dropout.
Meta-analysis and systematic review: burosumab as a promising treatment for children with X-linked hypophosphatemia
Authors: Wang Kangning , Zhang Runze , Chen Ziyi , Bai Yi , He Qing
Published: August 2024

Objective

The aim of this study was to evaluate the effectiveness of burosumab therapy in children with X-Linked Hypophosphatemia (XLH).

Materials and methods

We systematically reviewed literature from PubMed, Web of Science, The Cochrane Library, and Embase up until January 2024, using EndNote Web for study organization. The Newcastle–Ottawa scale guided quality assessment, while Revman software was used for data analysis and visualization. Study selection, quality evaluation, and data aggregation were independently performed by three researchers.

Results

The meta-analysis encompassed ten studies, including eight cohort studies that examined burosumab’s impact pre- and post-administration, and two randomized controlled trials comparing burosumab to standard therapy. The evidence from this review suggests burosumab’s superiority in managing XLH in pediatric populations, particularly in improving key biochemical markers including 1,25-dihydroxyvitamin D (1,25-(OH)2D), phosphorus, and alkaline phosphatase (ALP), alongside improvements in the renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), and significant skeletal improvements as indicated by the rickets severity score (RSS) and the 6-minute walk test (6MWT). However, the long-term safety and effects, including height and quality of life (QOL) data, remains to be elucidated.

Conclusions

Burosumab has shown significant therapeutic effectiveness in treating children with XLH, highlighting its potential as a key treatment option.
Impact of sleeve gastrectomy on the periodontal status of patients with and without type 2 diabetes: a 1-year prospective real-world study
Authors: Bi Xiaocheng , Zhao Peikai , Liu Teng , Zhu Tao , Li Yuxuan , Xiong Sisi , Liu Shaozhuang , Hu Xiaole , Huang Xin
Published: August 2024

Background

Periodontitis is a chronic inflammatory disease potentially associated with obesity and type 2 diabetes (T2D). Sleeve gastrectomy (SG) has shown substantial effect on weight loss and treatment of T2D. However, there is no direct evidence comparing the impact of SG on the periodontal status of patients with and without T2D.

Objectives

To determine the impact of SG on the periodontal status of patients with and without T2D in a real-world setting.

Methods

In a prospective and two-armed cohort design, participants who were scheduled for SG at an affiliated hospital between April 2022 and December 2022 were approached for eligibility. After a clinical evaluation and oral examination, those with periodontitis were included and further divided into the DM group (diabetic) and the Control group (non-diabetic) with a 1-year follow-up after surgery. The primary outcome was the periodontal status of patients at 12 months after SG. The secondary outcomes included weight loss, diabetes remission, and alterations in inflammatory markers for up to 1 year after SG.

Results

Fifty-seven and 49 patients were included in the DM and the Control group, respectively. Before surgery, patients in the DM group had further worsened periodontal condition compared with those in the Control group. Accompanied by weight loss and glucose reduction, patients in both groups demonstrated significant decreases in plaque index (PLI) and bleeding index (BI) with no alterations in probing depth or clinical attachment loss for up to 1 year after SG. Even patients in the DM group achieved less TWL% (32.79 ± 6.20% vs. 37.95 ± 8.34, P<0.01), their periodontal condition had more substantial improvement with no significant difference in PLI and BI between groups at 1 year after SG. We also observed a significant reduction in the levels of high sensitive C-reactive protein and interleukin-6 in both groups at 1 year after SG.

Conclusion

Both patients with and without T2D demonstrated improved periodontal status for up to 1 year after SG. Patients with T2D achieved less weight loss but a more substantial improvement in periodontal condition. The significant reduction in inflammatory biomarkers contributed to the improvement of periodontal status after SG.
Genetic association of lipids and lipid-lowering drug target genes with Endometrial carcinoma: a drug target Mendelian randomization study
Authors: Yang Zhehan , Chen Junpan , Wen Minghao , Lei Jiayuan , Zeng Ming , Li Sichen , Long Yao , Zhou Zhiyi , Wang Chunyan
Published: August 2024

Background

Aberrant lipid metabolism is intricately linked to the development of endometrial cancer, and statin lipid-lowering medications are regarded as promising adjunctive therapies for future management of this malignancy. This study employed Mendelian randomization (MR) to explore the causal association between lipid traits and endometrial cancer while assessing the potential impact of drug targets on lower lipids on endometrial cancer.

Method

Two-sample Mendelian randomization was employed to probe the causal association between lipid traits and endometrial carcinoma. Drug-target Mendelian randomization was also utilized to identify potential drug-target genes for managing endometrial carcinoma. In instances where lipid-mediated effects through particular drug targets were notable, the impacts of these drug targets on endometrial carcinoma risk factors were investigated to bolster the findings.

Result

No causal association between genetically predicted lipid traits (LDL-C, TG, TC, and HDL-C) and EC was found in two-sample Mendelian randomization. In drug target Mendelian randomization, genetic modeling of apolipoprotein B (APOB) (OR [95%CI]=0.31, [0.16-0.60]; p=4.73e-04) and cholesteryl ester transfer protein (CETP) (OR [95%CI]=1.83, [1.38-2.43]; p=2.91e-05) genetic mimicry was associated with non-endometrioid carcinoma.

Conclusion

The results of our MR study revealed no causal association between genetically predicted lipid traits (LDL-C, TG, TC, and HDL-C) and EC. Among the six lipid-lowering drug targets, we observed a significant association between lower predicted APOB levels and higher CETP levels with an increased risk of endometrioid carcinoma. These findings provide novel insights into the importance of lipid regulation in individuals with endometrial carcinoma, warranting further clinical validation and mechanistic investigations.
Optimal revenue sharing model of a wind–solar-storage hybrid energy plant under the green power trading market
Authors: Zeng Zhuo , Gao Xiang , Fang Baling , Zhang Tao , Zhu Ying
Published: August 2024

In the current model, the unclear and unreasonable method of revenue sharing among wind-solar-storage hybrid energy plants may a lso hinder the effective measurement of energy storage power station costs. This lack of clarity discourages energy storage from effectively collaborating with renewable energy stations for greenpower trading and spot trading.Therefore, this study proposes an optimal revenue sharing model of wind-solar-storage hybrid energy plant under medium and long-term green power trading market to facilitate the coordinated operation and equitable revenue allocation. Firstly, a method for decomposing transaction volume of green power is introduced by considering the uncertainty of spot market prices and physical delivery characteristics of green power trading. Then, a coordinated scheduling strategy of hybrid renewable energy plant is proposed to maximize revenues generated from both the green power and spot markets. Consequently, a cost-benefit contribution index system is developed to quantify the contribution of energy storage in the wind-solar-storage hybrid power plant. The revenue sharing model based on the minimum cost-remaining savings (MCRS) method can significantly increase overall revenue for renewable energy plants by reducing deviation penalties. It also enhances the operating revenue of energy storage power stations by considering the contributions of both energy storage and renewable energy plant in the green power market. The superiority of the proposed cooperation revenue sharing m odel for profitability enhancement of energy storage is v alidated through comparative case studies.
A landscape analysis of clinical trials and infant clinical trials in Kenya, Ethiopia, and Nigeria
Authors: Amboka Patrick , Kurui Daniel , Wamukoya Marylene , Sindi Julius Kirimi , Vicente-Crespo Marta
Published: August 2024

Introduction

Global inequality in clinical research capacity and service delivery can be indicated simply by the proportion of clinical trials that a country or region has registered in clinical trial registry databases. The proportion of clinical trials registered in Africa is very low at 0.02%, even though the region accounts for approximately 15% of the world's population. Despite the economic challenges in most African countries, they have shown potential for growth and change in recent years.

Methods

We conducted desk reviews on the interventional clinical trials done in Kenya, Ethiopia, and Nigeria between 2015 to May 2023. The search was done in clinical trials repositories, and journal repositories. The search focused on intervention clinical trials. Data was extracted by screening through the publications and clinical trial platforms. The data extracted from the publications included the type of clinical trial, clinical trial phase, diseases, etc. The data extracted from the reports included: challenges in conducting clinical trials, capacity-building efforts, and the impact of the clinical trial.

Results

The number of clinical trial studies identified in Kenya was 113 (28 were on infant clinical trials). The study identified 97 clinical trials in Nigeria, of which 11 studies were on infant clinical trials. In Ethiopia, there were 28 clinical trials and only five were on infant clinical trials. The landscape review also expanded to capacity and gaps in clinical trials in the three countries. The largest proportion of clinical trials carried out in Kenya was on injury, occupational disease, and poisoning, 30.5% (n = 18) and the smallest proportion was on kidney disease, neonatal disease, obstetrics, and gynecology. Most Infant clinical trials were carried out in the area of infections and infestations 33.3% (n = 7). Most of the challenges faced by clinical trials in the three countries include a lack of infrastructure, a lack of human resources, and a lack of financial resources.

Implications

There is a need to map clinical trials done by African researchers based in Africa to exclude the trials done by non-African researchers based in Africa. Opportunities for clinical trials should be supported and challenges addressed.
Asymmetric scapuloperoneal phenotype of MATR3-related distal myopathy: case series
Authors: Murtazina Aysylu , Subbotin Dmitrii , Kuchina Anna , Gilvanova Olga , Degterev Daniil , Shchagina Olga , Cherevatova Tatiana , Bulakh Maria , Sherstyukova Darya , Ryzhkova Oksana , Kurushina Olga , Skoblov Mikhail , Borovikov Artem , Kutsev Sergey
Published: August 2024

Recent research has sparked a discussion on the spectrum of diseases linked to the MATR3 gene associated with amyotrophic lateral sclerosis and distal myopathy with vocal cord and pharyngeal weakness (VCPDM). To date, fewer than 50 cases of VCPDM have been reported in the literature. We aim to build upon the work of previous researchers by gathering additional information about VCPDM. In this study, we present six patients from four unrelated families affected by VCPDM. Our observations include patients exhibiting both the typical phenotype associated with MATR3-related distal myopathy and rare symptomatic manifestations of the disease. Notably, two cases presented with an asymmetric scapuloperoneal phenotype, leading in one case to an initial misdiagnosis of facioscapulohumeral muscular dystrophy.
Stem-like CD8+ T cells in cancer
Authors: Steiner Chelsea , Denlinger Nathan , Huang Xiaopei , Yang Yiping
Published: August 2024

Stem-like CD8+ T cells (TSL) are a subset of immune cells with superior persistence and antitumor immunity. They are TCF1+ PD-1+ and important for the expansion of tumor specific CD8+ T cells in response to checkpoint blockade immunotherapy. In acute infections, naïve CD8+ T cells differentiate into effector and memory CD8+ T cells; in cancer and chronic infections, persistent antigen stimulation can lead to T cell exhaustion. Recent studies have highlighted the dichotomy between late dysfunctional (or exhausted) T cells (TLD) that are TCF1– PD-1+ and self-renewing TCF1+ PD-1+ TSL from which they derive. TCF1+ TSL cells are considered to have stem cell-like properties akin to memory T cell populations and can give rise to cytotoxic effector and transitory T cell phenotypes (TTE) which mediate tumor control. In this review, we will discuss recent advances made in research on the formation and expansion of TSL, as well as distinct niches required for their differentiation and maintenance in the setting of cancer. We will also discuss potential strategies to generate these cells, with clinical implications for stemness enhancement in vaccine design, immune checkpoint blockade (ICB), and adoptive T cell therapies.
Design and validation of novel flow cytometry panels to analyze a comprehensive range of peripheral immune cells in mice
Authors: Barco-Tejada Ainara , López-Esteban Rocio , Mulero Francisca , Pion Marjorie , Correa-Rocha Rafael , Desco Manuel , Cussó Lorena
Published: August 2024

The use of flow cytometry in mice is constrained by several factors, including the limited availability of mouse-specific antibodies and the need to work with small volumes of peripheral blood. This is particularly challenging for longitudinal studies, as serial blood samples should not exceed 10% of the total blood volume in mice. To address this, we have developed two novel flow cytometry panels designed to extensively analyze immune cell populations in mice during longitudinal studies, using only 50 µL of peripheral blood per panel. Additionally, a third panel has been designed to conduct a more detailed analysis of cytotoxic and inhibitory markers at the end point. These panels have been validated on a lipopolysaccharide (LPS)-induced lung inflammation model. Two experiments were conducted to 1) validate the panels’ sensitivity to immune challenges (n=12) and 2) to assess intrinsic variability of measurements (n=5). In both experiments, we collected 50 µL of peripheral blood for each cytometry panel from the maxillary venous sinus. All antibodies were titrated to identify the optimal concentration that maximized the signal from the positive population while minimizing the signal from the negative population. Samples were processed within 1 hour of collection using a MACSQuant Analyzer 16 cytometer. Our results demonstrate that these immunological panels are sensitive enough to detect changes in peripheral blood after LPS induction. Moreover, our findings help determine the sample size needed based on the immune population variability. In conclusion, the panels we have designed enable a comprehensive analysis of the murine immune system with a low blood volume requirement, enabling the measure of both absolute values and relative percentages effectively. This approach provides a robust platform for longitudinal studies in mice and can be used to uncover significant insights into immune responses.
Transcriptomic response of lumpfish (Cyclopterus lumpus) head kidney to viral mimic, with a focus on the interferon regulatory factor family
Authors: Emam Mohamed , Kumar Surendra , Eslamloo Khalil , Caballero-Solares Albert , Hall Jennifer R. , Xue Xi , Paradis Hélène , Gendron Robert L. , Santander Javier , Rise Matthew L.
Published: August 2024

The economic importance of lumpfish (Cyclopterus lumpus) is increasing, but several aspects of its immune responses are not well understood. To discover genes and mechanisms involved in the lumpfish antiviral response, fish were intraperitoneally injected with either the viral mimic polyinosinic:polycytidylic acid [poly(I:C)] or phosphate-buffered saline (PBS; vehicle control), and head kidneys were sampled 24 hours post-injection (hpi) for transcriptomic analyses. RNA sequencing (RNA-Seq) (adjusted p-value <0.05) identified 4,499 upregulated and 3,952 downregulated transcripts in the poly(I:C)-injected fish compared to the PBS-injected fish. Eighteen genes identified as differentially expressed by RNA-Seq were included in a qPCR study that confirmed the upregulation of genes encoding proteins with antiviral immune response functions (e.g., rsad2) and the downregulation of genes (e.g., jarid2b) with potential cellular process functions. In addition, transcript expression levels of 12 members of the interferon regulatory factor (IRF) family [seven of which were identified as poly(I:C)-responsive in this RNA-Seq study] were analyzed using qPCR. Levels of irf1a, irf1b, irf2, irf3, irf4b, irf7, irf8, irf9, and irf10 were significantly higher and levels of irf4a and irf5 were significantly lower in the poly(I:C)-injected fish compared to the PBS-injected fish. This research and associated new genomic resources enhance our understanding of the genes and molecular mechanisms underlying the lumpfish response to viral mimic stimulation and help identify possible therapeutic targets and biomarkers for viral infections in this species.
Sacituzumab govitecan in triple-negative breast cancer: from bench to bedside, and back
Authors: Rossi Valentina , Turati Alessandra , Rosato Antonio , Carpanese Debora
Published: August 2024

Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors.
The role of trained immunity in sepsis
Authors: Wang Wenjuan , Ma Lisi , Liu Bin , Ouyang Liangliang
Published: August 2024

Sepsis is defined as a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection, characterized by a systemic inflammatory response to infection. The use of antibiotics, fluid resuscitation, and organ support therapy has limited prognostic benefit in patients with sepsis, and its incidence is not diminishing, which is attracting increased attention in medicine. Sepsis remains one of the most debilitating and expensive illnesses. One of the main reasons of septic mortality is now understood to be disruption of immune homeostasis. Immunotherapy is revolutionizing the treatment of illnesses in which dysregulated immune responses play a significant role. This “trained immunity”, which is a potent defense against infection regardless of the type of bacteria, fungus, or virus, is attributed to the discovery that the innate immune cells possess immune memory via metabolic and epigenetic reprogramming. Here we reviewed the immunotherapy of innate immune cells in sepsis, the features of trained immunity, and the relationship between trained immunity and sepsis.
Pain in non-communicative older adults beyond dementia: a narrative review
Authors: Tagliafico Luca , Maizza Giada , Ottaviani Silvia , Muzyka Mariya , Rovere Federica Della , Nencioni Alessio , Monacelli Fiammetta
Published: August 2024

Aging is associated with an increased risk of developing pain, especially in the presence of concurrent chronic clinical conditions. Similarly, multimorbidity can affect the perception and ability of older adults to appropriately respond to and communicate pain, and there is a clinical heterogeneity in the processing of painful sensations in different neurological conditions. The present narrative review is aimed at assessing the prevalent diseases associated with poor communication and pain in older adults, together with the available diagnostic instruments for the clinical assessment of pain in such a vulnerable population. Dementia was the most described pathology identified in the current literature associated with poor communication in older adults affected by pain, along with Parkinson’s disease and stroke. Notably, a common pattern of pain behaviors in these neurological disorders also emerged, indicating potential similarities in the clinical presentation and appropriate diagnostic workout. At the same time, there are many differences in the way patients express their pain according to their main neurological pathology. In addition to this, although a plethora of observation-based tools for pain in patients with dementia have been developed, there is no gold standard, and the clinical utility of such measurements is still largely unaddressed. Meanwhile, there is substantially no standardized observation-based tool for pain in non-communicative patients with Parkinson’s disease, and only a few for stroke. Overall, the present narrative review provides an update on the prevalent diseases beyond dementia associated with a communicative disability and a painful condition in older adults.
Association between lactate to hematocrit ratio and 30-day all-cause mortality in patients with sepsis: a retrospective analysis of the Medical Information Mart for Intensive Care IV database
Authors: Duan Wentao , Yang Feng , Ling Hua , Li Qiong , Dai Xingui
Published: August 2024

Background

The lactate to hematocrit ratio (LHR) has not been assessed for predicting all-cause death in sepsis patients. This study aims to evaluate the relationship between LHR and 30-day all-cause mortality in sepsis patients.

Methods

This retrospective study used the data from Medical information mart for intensive care IV (MIMIC-IV, version 2.0). Our study focused on adult sepsis patients who were initially hospitalized in the Intensive care unit (ICU). The prognostic significance of admission LHR for 30-day all-cause mortality was evaluated using a multivariate Cox regression model, ROC curve analysis, Kaplan–Meier curves, and subgroup analyses.

Results

A total of 3,829 sepsis patients participated in this study. Among the cohort, 8.5% of individuals died within of 30 days (p < 0.001). The area under the curve (AUC) for LHR was 74.50% (95% CI: 71.6–77.50%), higher than arterial blood lactate (AUC = 71.30%), hematocrit (AUC = 64.80%), and shows no significant disadvantage compared to qSOFA, SOFA, and SAPS II. We further evaluated combining LHR with qSOFA score to predict mortality in sepsis patients, which shows more clinical significance. ROC curve analysis showed that 6.538 was the optimal cutoff value for survival and non-survival groups. With LHR ≥6.538 vs. LHR <6.538 (p < 0.001). Subgroup analysis showed significant interactions between LHR, age, sex, and simultaneous acute respiratory failure (p = 0.001–0.005).

Conclusion

LHR is an independent predictor of all-cause mortality in sepsis patients after admission, with superior predictive ability compared to blood lactate or hematocrit alone.
Genomic and transcriptomic analyses of Phytophthora cinnamomi reveal complex genome architecture, expansion of pathogenicity factors, and host-dependent gene expression profiles
Authors: Shands Aidan C. , Xu Guangyuan , Belisle Rodger J. , Seifbarghi Shirin , Jackson Natasha , Bombarely Aureliano , Cano Liliana M. , Manosalva Patricia M.
Published: August 2024

Phytophthora cinnamomi is a hemibiotrophic oomycete causing Phytophthora root rot in over 5,000 plant species, threatening natural ecosystems, forestry, and agriculture. Genomic studies of P. cinnamomi are limited compared to other Phytophthora spp. despite the importance of this destructive and highly invasive pathogen. The genome of two genetically and phenotypically distinct P. cinnamomi isolates collected from avocado orchards in California were sequenced using PacBio and Illumina sequencing. Genome sizes were estimated by flow cytometry and assembled de novo to 140–141 Mb genomes with 21,111–21,402 gene models. Genome analyses revealed that both isolates exhibited complex heterozygous genomes fitting the two-speed genome model. The more virulent isolate encodes a larger secretome and more RXLR effectors when compared to the less virulent isolate. Transcriptome analysis after P. cinnamomi infection in Arabidopsis thaliana, Nicotiana benthamiana, and Persea americana de Mill (avocado) showed that this pathogen deploys common gene repertoires in all hosts and host-specific subsets, especially among effectors. Overall, our results suggested that clonal P. cinnamomi isolates employ similar strategies as other Phytophthora spp. to increase phenotypic diversity (e.g., polyploidization, gene duplications, and a bipartite genome architecture) to cope with environmental changes. Our study also provides insights into common and host-specific P. cinnamomi infection strategies and may serve as a method for narrowing and selecting key candidate effectors for functional studies to determine their contributions to plant resistance or susceptibility.
Investigating the causal relationship between gut microbiota and gastroenteropancreatic neuroendocrine neoplasms: a bidirectional Mendelian randomization study
Authors: Zhang Chun-yu , Jiang Shi-jing , Cao Jing-jing , Xu Yan , Wang Xiao-yu , Li Rui , Miao Zhi-wei
Published: August 2024

Background

The interaction between the intestinal flora and gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) remains poorly understood, despite the known effect of the gut microbiota on gastrointestinal adenocarcinomas. Hence, the present research aimed to determine the potential causal correlation between the intestinal flora and GEP-NENs by conducting a bidirectional Mendelian randomization (MR) analysis.

Methods

Two-sample MR analysis was conducted using the summary statistics of the gut microbiota from the MiBioGen consortium and those of GEP-NENs from the FinnGen research project. The inverse-variance weighted approach was utilized as the primary analytical method. To enhance the robustness of our findings, multiple sensitivity tests were performed, including Cochran’s Q test for evaluating heterogeneity, the MR-Egger intercept test to detect horizontal pleiotropy, and the MR-PRESSO test to identify outliers and assess pleiotropy bias. Additionally, a leave-one-out analysis was performed to validate the consistency of our findings. The MR-Steiger test was also utilized to determine the causal direction in the correlation between the gut microbiota and GEP-NENs. Finally, a reverse MR analysis was performed to assess reverse causality between the intestinal flora and GEP-NENs.

Results

We identified 42 taxa of the gut microbiota that were potentially causally associated with GEP-NENs; of these taxa, 7, 8, 11, and 16 taxa were causally associated with pancreatic NENs, colorectal NENs, small intestinal NENs, and gastric NENs, respectively. After adjusting for false discovery rate (FDR) correction, we found significant causal links of Euryarchaeota with small intestinal NENs and Family XIII UCG-001 with gastric NENs. The sensitivity analyses confirmed the stability of these correlations. In the reverse MR analysis, colorectal NENs and small intestinal NENs were found to be associated with variations in 8 and 6 different taxa of the gut microbiota, respectively. After adjusting for FDR correction, no significant causal links were detected between GEP-NENs and the intestinal flora.

Conclusion

The present study reveals a potential causal association between certain taxa of the intestinal flora and GEP-NENs, thus providing new perspectives regarding the role of the intestinal flora in the development of these tumors. These insights could provide innovative approaches to screen and prevent these diseases.
Enhanced enrichment of extracellular vesicles for laboratory and clinical research from drop-sized blood samples
Authors: Guerrero-Alba Alexa , Bansal Sandhya , Sankpal Aryan N. , Mitra Geetanjali , Rahman Mohammad , Ravichandran Ranjithkumar , Poulson Christin , Fleming Timothy P. , Smith Michael A. , Bremner Ross M. , Mohanakumar T. , Sankpal Narendra V.
Published: August 2024

In the realm of biomedical advancement, extracellular vesicles (EVs) are revolutionizing our capacity to diagnose, monitor, and predict disease progression. However, the comprehensive exploration and clinical application of EVs face significant limitations due to the current isolation techniques. The size exclusion chromatography, commercial precipitation reagents, and ultracentrifugation are frequently employed, necessitating skilled operators and entailing challenges related to consistency, reproducibility, quality, and yields. Notably, the formidable challenge of extracellular vesicle isolation persists when dealing with clinical samples of limited availability. This study addresses these challenges by aiming to devise a rapid, user-friendly, and high-recovery EVs isolation technique tailored for blood samples. The NTI-EXO precipitation method demonstrated a 5-fold increase in the recovery of serum EVs compared to current methodologies. Importantly, we illustrate that a mere two drops of blood (∼100 µL) suffice for the recovery of enriched EVs. The integrity and quality of these isolated EVs were rigorously assessed for the size, purity, and contaminants. This method was validated through the successful isolation of EVs from organ transplant recipients to detect disease-specific exosomal markers, including LKB1, SARS-CoV-2 spike protein, and PD-L1. In conclusion, NTI-EXO method can be used for small clinical samples, thereby advancing discoveries in the EV-centric domain and propelling the frontiers of biomedical research and clinical applications.
Impact of repetitive negative thinking on subjective cognitive decline: insights into cognition and brain structure
Authors: Mulet-Pons Lídia , Solé-Padullés Cristina , Cabello-Toscano María , Abellaneda-Pérez Kilian , Perellón-Alfonso Ruben , Cattaneo Gabriele , Solana Sánchez Javier , Alviarez-Schulze Vanessa , Bargalló Nuria , Tormos-Muñoz Josep M. , Pascual-Leone Alvaro , Bartrés-Faz David , Vaqué-Alcázar Lídia
Published: August 2024

Introduction

Individuals with subjective cognitive decline (SCD) express concern about self-perceived cognitive decline despite no objective impairment and are at higher risk of developing Alzheimer’s disease. Despite documented links between SCD and repetitive negative thinking (RNT), the specific impact of RNT on brain integrity and cognition in exacerbating the SCD condition remains unclear. We aimed to investigate the influence of RNT on global cognition and brain integrity, and their interrelationships among healthy middle-aged and older adults experiencing SCD.

Methods

Out of 616 individuals with neuroimaging and neuropsychological data available, 89 (mean age = 56.18 years; 68.54% females) met SCD criteria. Eighty-nine non-SCD individuals matched by age, sex, and education were also selected and represented the control group (mean age = 56.09 years; 68.54% females). Global cognition was measured using the preclinical Alzheimer’s cognitive composite (PACC5), which includes dementia screening, episodic memory, processing speed, and category fluency tests. RNT was calculated through three questionnaires assessing intrusive thoughts, persistent worry, and rumination. We generated cortical thickness (CTh) maps and quantified the volume of white matter lesions (WML) in the whole brain, as grey and white matter integrity measures, respectively.

Results

SCD individuals exhibited higher RNT scores, and thinner right temporal cortex compared to controls. No differences were observed in PACC5 and WML burden between groups. Only the SCD group demonstrated positive associations in the CTh-PACC5, CTh-RNT, and WML-RNT relationships.

Discussion

In this cross-sectional study, RNT was exclusively associated with brain integrity in SCD. Even though our findings align with the broader importance of investigating treatable psychological factors in SCD, further research may reveal a modulatory effect of RNT on the relationship between cognition and brain integrity in SCD.
Transplantation of neural stem cells improves recovery of stroke-affected mice and induces cell-specific changes in GSDMD and MLKL expression
Authors: Lisjak Damir , Alić Ivan , Šimunić Iva , Mitrečić Dinko
Published: August 2024

Introduction

Stroke, the second leading cause of death and disability in Europe, is primarily caused by interrupted blood supply, leading to ischemia–reperfusion (IR) injury and subsequent neuronal death. Current treatment options are limited, highlighting the need for novel therapies. Neural stem cells (NSCs) have shown promise in treating various neurological disorders, including stroke. However, the underlying mechanisms of NSC-mediated recovery remain unclear.

Methods

Eighty C57Bl/6–Tyrc-Brd mice underwent ischemic stroke induction and were divided into four groups: sham, stroke-affected, stroke-affected with basal cell medium injection, and stroke-affected with NSCs transplantation. NSCs, isolated from mouse embryos, were stereotaxically transplanted into the stroke-affected brains. Magnetic resonance imaging (MRI) and neurological scoring were used to assess recovery. Immunohistochemical analysis and gene expression assays were performed to evaluate pyroptosis and necroptosis markers.

Results

NSC transplantation significantly improved neurological recovery compared to control groups. In addition, although not statistically significant, NSCs reduced stroke volume. Immunohistochemical analysis revealed upregulation of Gasdermin D (GSDMD) expression post-stroke, predominantly in microglia and astrocytes. However, NSC transplantation led to a reduction in GSDMD signal intensity in astrocytes, suggesting an effect of NSCs on GSDMD activity. Furthermore, NSCs downregulated Mixed Lineage Kinase Domain-Like Protein (Mlkl) expression, indicating a reduction in necroptosis. Immunohistochemistry demonstrated decreased phosphorylated MLKL (pMLKL) signal intensity in neurons while stayed the same in astrocytes following NSC transplantation, along with increased distribution in microglia.

Discussion

NSC transplantation holds therapeutic potential in stroke recovery by targeting pyroptosis and necroptosis pathways. These findings shed light on the mechanisms underlying NSC-mediated neuroprotection and support their further exploration as a promising therapy for stroke patients.