bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating usability of and satisfaction with mHealth app in rural and remote areas—Germany GIZ collaboration in Bosnia-Herzegovina to optimize type 1 diabetes care
Authors: Ali Sherazi Bushra , Läer Stephanie , Hasanbegovic Snijezana , Obarcanin Emina
Published: June 2024

Background

Type 1 diabetes mellitus (T1DM) management in children and adolescents requires intensive supervision and monitoring to prevent acute and late diabetes complications and to improve quality of life. Digital health interventions, in particular diabetes mobile health apps (mHealth apps) can facilitate specialized T1DM care in this population. This study evaluated the initial usability of and satisfaction with the m-Health intervention Diabetes: M app, and the ease of use of various app features in supporting T1DM care in rural and remote areas of Bosnia-Herzegovina with limited access to specialized diabetes care.

Methods

This cross-sectional study, performed in February–March 2023, evaluated T1DM pediatric patients who used the Diabetes: M app in a 3-month mHealth-based T1DM management program, along with their parents and healthcare providers (HCPs). All participants completed self-administered online questionnaires at the end of the 3-month period. Data were analyzed by descriptive statistics.

Results

The study population included 50 T1DM patients (children/parents and adolescents) and nine HCPs. The mean ± SD age of the T1DM patients was 14 ± 4.54 years, with 26 (52%) being female. The mean ± SD age of the HCPs was 43.4 ± 7.76 years; all (100%) were women, with a mean ± SD professional experience of 17.8 ± 8.81 years. The app was reported usable in the domains of ease-of-use and satisfaction by the T1DM children/parents (5.82/7.0), T1DM adolescents/young adults (5.68/7.0), and HCPs (5.22/7.0). Various app features, as well as the overall app experience, were rated positively by the participants.

Conclusion

The results strongly support the usability of mHealth-based interventions in T1DM care, especially in overcoming care shortage and improving diabetes management and communications between HCPs and patients. Further studies are needed to compare the effectiveness of apps used to support T1DM management with routine care.
Targeting mitochondria for ovarian aging: new insights into mechanisms and therapeutic potential
Authors: Wang Zi-Han , Wang Zhen-Jing , Liu Huai-Chao , Wang Chen-Yu , Wang Yu-Qi , Yue Yang , Zhao Chen , Wang Guoyun , Wan Ji-Peng
Published: June 2024

Ovarian aging is a complex process characterized by a decline in oocyte quantity and quality, directly impacting fertility and overall well-being. Recent researches have identified mitochondria as pivotal players in the aging of ovaries, influencing various hallmarks and pathways governing this intricate process. In this review, we discuss the multifaceted role of mitochondria in determining ovarian fate, and outline the pivotal mechanisms through which mitochondria contribute to ovarian aging. Specifically, we emphasize the potential of targeting mitochondrial dysfunction through innovative therapeutic approaches, including antioxidants, metabolic improvement, biogenesis promotion, mitophagy enhancement, mitochondrial transfer, and traditional Chinese medicine. These strategies hold promise as effective means to mitigate age-related fertility decline and preserve ovarian health. Drawing insights from advanced researches in the field, this review provides a deeper understanding of the intricate interplay between mitochondrial function and ovarian aging, offering valuable perspectives for the development of novel therapeutic interventions aimed at preserving fertility and enhancing overall reproductive health.
A novel insertional allele of the CG18135 gene is associated with severe mutant phenotypes in Drosophila melanogaster
Authors: Ratiu Attila Cristian , Ionascu Adrian , Ecovoiu Alexandru Al.
Published: June 2024

Drosophila melanogaster has been at the forefront of genetic studies and biochemical modeling for over a century. Yet, the functions of many genes are still unknown, mainly because no phenotypic data are available. Herein, we present the first evidence data regarding the particular molecular and other quantifiable phenotypes, such as viability and anatomical anomalies, induced by a novel P{lacW} insertional mutant allele of the CG18135 gene. So far, the CG18135 functions have only been theorized based on electronic annotation and presumptive associations inferred upon high-throughput proteomics or RNA sequencing experiments. The descendants of individuals harboring the CG18135P{lacW}CG18135 allele were scored in order to assess mutant embryonic, larval, and pupal viability versus Canton Special (CantonS). Our results revealed that the homozygous CG18135P{lacW}CG18135/CG18135P{lacW}CG18135 genotype determines significant lethality both at the inception of the larval stage and during pupal development. The very few imago escapers that either breach or fully exit the puparium exhibit specific eye depigmentation, wing abnormal unfolding, strong locomotor impairment with apparent spasmodic leg movements, and their maximum lifespan is shorter than 2 days. Using the quantitative real-time PCR (qRT-PCR) method, we found that CG18135 is upregulated in male flies, but an unexpected gene upregulation was also detected in heterozygous mutants compared to wild-type flies, probably because of regulatory perturbations induced by the P{lacW} transposon. Our work provides the first phenotypic evidence for the essential role of CG18135, a scenario in accordance with the putative role of this gene in carbohydrate-binding processes.
The HHV-6B U20 glycoprotein binds ULBP1, masking it from recognition by NKG2D and interfering with natural killer cell activation
Authors: Weaver Grant C. , Schneider Christine L. , Becerra-Artiles Aniuska , Clayton Kiera L. , Hudson Amy W. , Stern Lawrence J.
Published: June 2024

Introduction

Human Herpesvirus 6B (HHV-6B) impedes host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells. Downregulation of MHC-I disengages inhibitory receptors on natural killer (NK) cells, resulting in activation and killing of the target cell if NK cell activating receptors such as NKG2D have engaged stress ligands upregulated on the target cells. Previous work has shown that HHV-6B downregulates three MHC-like stress ligands MICB, ULBP1, and ULBP3, which are recognized by NKG2D. The U20 glycoprotein of the related virus HHV-6A has been implicated in the downregulation of ULBP1, but the precise mechanism remains undetermined.

Methods

We set out to investigate the role of HHV-6B U20 in modulating NK cell activity. We used HHV-6B U20 expressed as a recombinant protein or transduced into target cells, as well as HHV-6B infection, to investigate binding interactions with NK cell ligands and receptors and to assess effects on NK cell activation. Small-angle X-ray scattering was used to align molecular models derived from machine-learning approaches.

Results

We demonstrate that U20 binds directly to ULBP1 with sub-micromolar affinity. Transduction of U20 decreases NKG2D binding to ULBP1 at the cell surface but does not decrease ULBP1 protein levels, either at the cell surface or in toto. HHV-6B infection and soluble U20 have the same effect. Transduction of U20 blocks NK cell activation in response to cell-surface ULBP1. Structural modeling of the U20 – ULBP1 complex indicates some similarities to the m152-RAE1γ complex.
Improving cancer immunotherapy in prostate cancer by modulating T cell function through targeting the galectin-1
Authors: Wang Hsiao-Chi , Xia Roger , Chang Wen-Hsin , Hsu Ssu-Wei , Wu Chun-Te , Chen Ching-Hsien , Shih Tsung-Chieh
Published: June 2024

Our study aimed to elucidate the role of Galectin-1 (Gal-1) role in the immunosuppressive tumor microenvironment (TME) of prostate cancer (PCa). Our previous findings demonstrated a correlation between elevated Gal-1 expression and advanced PCa stages. In this study, we also observed that Gal-1 is expressed around the tumor stroma and its expression level is associated with PCa progression. We identified that Gal-1 could be secreted by PCa cells, and secreted Gal-1 has the potential to induce T cell apoptosis. Gal-1 knockdown or inhibition of Gal-1 function by LLS30 suppresses T cell apoptosis resulting in increased intratumoral T cell infiltration. Importantly, LLS30 treatment significantly improved the antitumor efficacy of anti-PD-1 in vivo. Mechanistically, LLS30 binds to the carbohydrate recognition domain (CRD) of Gal-1, disrupting its binding to CD45 leading to the suppression of T cell apoptosis. In addition, RNA-seq analysis revealed a novel mechanism of action for LLS30, linking its tumor-intrinsic oncogenic effects to anti-tumor immunity. These findings suggested that tumor-derived Gal-1 contributes to the immunosuppressive TME in PCa by inducing apoptosis in effector T cells. Targeting Gal-1 with LLS30 may offer a strategy to enhance anti-tumor immunity and improve immunotherapy.
Systemic inflammation biomarkers during angioedema attacks in hereditary angioedema
Authors: Gil-Serrano Johana , Labrador-Horrillo Moisés , Galvan-Blasco Paula , Sala-Cunill Anna , Bigas Patricia , Pereira-González Javier , Luengo Olga , Cardona Victoria , Guilarte Mar
Published: June 2024

Background

Hereditary angioedema (HAE) is a rare disease characterized by localized and self-limited angioedema (AE) attacks. A local increase of bradykinin (BK) mediates AE attacks in HAE, however the role of inflammation in HAE has been poorly explored We aim to analyze the role of inflammatory mediators in HAE patients during AE attacks.

Methods

Patients with a confirmed HAE diagnosis due to C1 inhibitor deficiency (HAE-C1INH) or patients F12 gene mutations (HAE-FXII) attending to our outpatient clinic between November-2019 and May-2022 were included. Demographic and clinical characteristics were analyzed. Blood samples were collected both during symptom-free periods (baseline) and during HAE attacks, and acute phase reactants (APR), such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-Dimer and white blood cells were measured.

Results

Seventy-eight patients were enrolled in the study, with a predominant representation of women (76%, n=59), and a mean age of 47.8 years (range 6–88). Among them, 67% (n=52) of patients had HAE-C1INH (46 classified as type 1 and 6 as type 2) while 33% (n=26) had HAE-FXII. During attack-free periods, the majority of patients exhibited normal levels of SAA, ESR, D-dimer, ACE and WCC. However, in a subset of patients (16% for SAA, 18% for ESR, and 14.5% for D-dimer), elevations were noted at baseline. Importantly, during HAE attacks, significant increases were observed in SAA in 88% of patients (p< 0.0001 vs. baseline), in ESR in 65% (p= 0.003 vs. baseline) and D-dimer in 71% (p=0.001 vs. baseline) of the patients. A comparison between baseline and acute attack levels in 17 patients revealed significant differences in SAA AA (p<0. 0001), ESR (p<0.0001) and D-dimer (p= 0.004). No significant differences were observed in CRP (p=0.7), ACE (p=0.67) and WCC (p=0.54). These findings remained consistent regardless of HAE type, disease activity or location of angioedema.

Conclusion

The systemic increase in APR observed during HAE attacks suggests that inflammation extends beyond the localized edematous area. This finding underscores the potential involvement of inflammatory pathways in HAE and highlights the need for further investigation into their role in the pathophysiology of HAE.
Aspergillus fumigatus binding IgA and IgG1 are increased in bronchoalveolar lavage fluid of horses with neutrophilic asthma
Authors: Jentsch Maria-Christin , Keilhaue Aline , Wagner Bettina , Rhyner Claudio , Lübke Sabrina , Karagulyan Mariam , Arnold Corinna , Lohmann Katharina L. , Schnabel Christiane L.
Published: June 2024

Introduction

Equine asthma (EA) is a common lower airway disease in horses, but whether its pathogenesis is allergic is ambiguous. Extrinsic stimuli like hay dust induce acute exacerbation of clinical signs and sustained local neutrophilic inflammation in susceptible horses. Aspergillus fumigatus is an EA stimulus, but it is unclear if it merely acts as an IgE-provoking allergen. We aimed to comprehensively analyze immunoglobulin (Ig) isotypes in EA, elucidating their binding to different A. fumigatus antigens, and their quantities systemically in serum and locally in bronchoalveolar lavage fluid (BALF).

Methods

Serum and BALF from healthy horses (HE, n = 18) and horses with mild-moderate asthma (MEA, n = 20) or severe asthma (SEA, n = 24) were compared. Ig isotype (IgG1, IgG3/5, IgG4/7, IgG6, IgA, and IgE) binding to nine antigens (A. fumigatus lysate, and recombinant Asp f 1, Asp f 7, Asp f 8, dipeptidyl-peptidase 5, class II aldolase/adducin domain protein, glucoamylase, beta-hexosaminidase, and peptide hydrolase) was compared by enzyme-linked immunosorbent assays. Total Ig isotype contents were determined by bead-based assays.

Results

MEA and SEA differed from HE but hardly from each other. Compared to HE, asthmatic horses showed increased anti-A. fumigatus binding of IgG (BALF and serum) and IgA (BALF). Serum and BALF IgE binding and total IgE contents were similar between HE and EA. Single antigens, as well as A. fumigatus lysate, yielded similar Ig binding patterns. Serum and BALF IgG1 binding to all antigens was increased in SEA and to several antigens in MEA. Serum IgG4/7 binding to two antigens was increased in SEA. BALF IgA binding to all antigens was increased in SEA and MEA. Total BALF IgG1 and IgG4/7 contents were increased in SEA, and serum IgG4/7 content was increased in MEA compared to HE. Yet, total isotype contents differentiated EA and HE less clearly than antigen-binding Ig.

Discussion

A. fumigatus immunogenicity was confirmed without identification of single dominant antigens here. A. fumigatus provoked elevated BALF IgG1 and IgA binding, and these isotypes appear relevant for neutrophilic EA, which does not support allergy. BALF Ig isotype differentiation beyond IgE is crucial for a comprehensive analysis of immune responses to fungi in EA pathogenesis.
The Brazilian Santos basin underwater soundscape monitoring project (PMPAS-BS)
Authors: Lima José Antonio Moreira , Soares Filho William , Xavier Fabio C. , Paula Thiago Pires de , Spengler Angela , Almeida Fernando Gonçalves de , Pereira Diogo Peregrino Correa , Rego Valéria Souza , Galotta Cátia , Corrêa Junior Carlos , Bazyl Alexandre
Published: June 2024

This paper describes the Santos Basin Underwater Soundscape Monitoring Project (PMPAS-BS), a Brazilian ocean soundscape monitoring initiative. The main objective of the project is to quantify and assess hydroacoustic noise of anthropogenic origin in a large sedimentary basin extending from 23° S to 28° S on the southeastern Brazilian continental margin of the South Atlantic Ocean. Noise associated with oil and gas (O&G) exploration and production activities is the primary target, but this oceanic region also has busy shipping lanes for commercial, military, and fishing vessels. The two main hubs of Brazil’s export and import of goods by sea are located in this region: Santos and Rio de Janeiro ports. The project has three measurement components: mobile monitoring based on gliders and drifting acoustic profilers, fixed shallow-water monitoring based on acoustic measurements at coastal stations near shipping lanes associated with exploration and production activities in the Santos Basin, and fixed oceanic monitoring based on deep-water mooring lines equipped with passive autonomous acoustic recorders near production units, shipping lanes, and areas with lower intensity of O&G activities (pristine or reference sites). Numerical modeling of anthropogenic underwater acoustic noise has also been included as a fourth project component. The PMPAS-BS covers an area of more than 251,000 km2 and uses several instruments with different methods and sensors for acoustic measurements. Its results provide current sound levels over a very large region of the western South Atlantic, both in areas more and less affected by anthropogenic activities.
Disseminated Acanthamoeba castellanii infection in a patient with AIDS: a case report and literature review
Authors: Jiang Qunqun , Zhang Zhongwei , Cai Yuxiang , Chen Liangjun , Deng Liping , Xiong Yong
Published: June 2024

Background

Acanthamoeba castellanii infection is a rare condition primarily occurring in immunocompromised patients with extremely high mortality. Currently, there is no standard treatment for this condition, and successful treatment reports are scarce.

Case presentation

We present a case of Acanthamoeba castellanii infection in a 63-year-old female patient with AIDS, who was admitted to our hospital with symptoms of fever, skin ulcers, subcutaneous nodules, and food regurgitation from the nose while eating. After initial empirical treatment failed, a biopsy of the subcutaneous nodule was performed, and metagenomic next-generation sequencing (mNGS) technology was used to detect pathogenic microorganisms in both the biopsy specimen and blood samples. The results revealed Acanthamoeba castellanii infection. Additionally, histopathological examination of the biopsy specimen and cytological examination of the secretions from the ulcer surface also confirmed this pathogenic infection. The patient’s symptoms significantly improved upon discharge after adjusting the treatment regimen to a combination of anti-amebic therapy.

Conclusion

Immunocompromised patients presenting with unexplained fever and skin or sinus lesions should be evaluated for Acanthamoeba castellanii infection. Multi-drug combination therapy is required for this organism infection, and a standard treatment protocol still needs further research. Metagenomic next-generation sequencing is a valuable tool for early diagnosis of unknown pathogen infections.
Functional evaluation of pure natural edible Ferment: protective function on ulcerative colitis
Authors: Chen Yanjun , Ye Shengzhi , Shi Jiaolong , Wang Hao , Deng Guangxu , Wang Guangxian , Wang Shijie , Yuan Qingbin , Yang Lunan , Mou Tingyu
Published: June 2024

Purpose

To investigate the therapeutic efficiency of a novel drink termed “Ferment” in cases of ulcerative colitis (UC) and its influence on the gut microbiota.

Method

In this study, we developed a complex of mixed fruit juice and lactic acid bacteria referred to as Ferment. Ferment was fed to mice for 35 days, before inducing UC with Dextran Sulfate Sodium Salt. We subsequently investigated the gut microbiome composition using 16S rRNA sequencing.

Result

After Ferment treatment, mouse body weight increased, and animals displayed less diarrhea, reduced frequency of bloody stools, and reduced inflammation in the colon. Beneficial bacteria belonging to Ileibacterium, Akkermansia, and Prevotellacea were enriched in the gut after Ferment treatment, while detrimental organisms including Erysipelatoclostridium, Dubosiella, and Alistipes were reduced.

Conclusion

These data place Ferment as a promising dietary candidate for enhancing immunity and protecting against UC.
Bioenergetic myths of energy transduction in eukaryotic cells
Authors: Brown Guy C.
Published: June 2024

The study of energy transduction in eukaryotic cells has been divided between Bioenergetics and Physiology, reflecting and contributing to a variety of Bioenergetic myths considered here: 1) ATP production = energy production, 2) energy transduction is confined to mitochondria (plus glycolysis and chloroplasts), 3) mitochondria only produce heat when required, 4) glycolysis is inefficient compared to mitochondria, and 5) mitochondria are the main source of reactive oxygen species (ROS) in cells. These myths constitute a ‘mitocentric’ view of the cell that is wrong or unbalanced. In reality, mitochondria are the main site of energy dissipation and heat production in cells, and this is an essential function of mitochondria in mammals. Energy transduction and ROS production occur throughout the cell, particularly the cytosol and plasma membrane, and all cell membranes act as two-dimensional energy conduits. Glycolysis is efficient, and produces less heat per ATP than mitochondria, which might explain its increased use in muscle and cancer cells.
Residual and bidirectional LSTM for epileptic seizure detection
Authors: Zhao Wei , Wang Wen-Feng , Patnaik Lalit Mohan , Zhang Bao-Can , Weng Su-Jun , Xiao Shi-Xiao , Wei De-Zhi , Zhou Hai-Feng
Published: June 2024

Electroencephalogram (EEG) plays a pivotal role in the detection and analysis of epileptic seizures, which affects over 70 million people in the world. Nonetheless, the visual interpretation of EEG signals for epilepsy detection is laborious and time-consuming. To tackle this open challenge, we introduce a straightforward yet efficient hybrid deep learning approach, named ResBiLSTM, for detecting epileptic seizures using EEG signals. Firstly, a one-dimensional residual neural network (ResNet) is tailored to adeptly extract the local spatial features of EEG signals. Subsequently, the acquired features are input into a bidirectional long short-term memory (BiLSTM) layer to model temporal dependencies. These output features are further processed through two fully connected layers to achieve the final epileptic seizure detection. The performance of ResBiLSTM is assessed on the epileptic seizure datasets provided by the University of Bonn and Temple University Hospital (TUH). The ResBiLSTM model achieves epileptic seizure detection accuracy rates of 98.88–100% in binary and ternary classifications on the Bonn dataset. Experimental outcomes for seizure recognition across seven epilepsy seizure types on the TUH seizure corpus (TUSZ) dataset indicate that the ResBiLSTM model attains a classification accuracy of 95.03% and a weighted F1 score of 95.03% with 10-fold cross-validation. These findings illustrate that ResBiLSTM outperforms several recent deep learning state-of-the-art approaches.
A new framework for understanding stress and disease: the developmental model of stress as applied to multiple sclerosis
Authors: Fauver Michelle , Clark Eva M. , Schwartz Carolyn E.
Published: June 2024

This paper proposes a new model of stress that integrates earlier models and adds insights from developmental psychology. Previous models describe the behavioral and physical effects of stress events, but have not explained the translation of experiences into stress itself. The Developmental Model of Stress shows how psychosocial developmental challenges in childhood create persistent negative beliefs and behaviors that increase threat perception and maladaptive stress responses. These developmental challenges produce early psychological and physiological predispositions for increased stress responses over time. Ongoing stress leads to dysregulation of physical stress-response systems (allostatic load), which is associated with multiple diseases. High allostatic load provides the necessary preconditions for the diathesis-stress model, which says the addition of an acute stressor to a weakened or predisposed system can lead to disease development. The paper also documents the evolving measurement of stress to better understand the stress-disease relationship, helping to resolve conflicting results between studies. The Developmental Model of Stress was combined with clinician insight and patient reports to build an integrative framework for understanding the role of stress in the development and progression of multiple sclerosis (MS). It includes the first mapping of maladaptive beliefs and behaviors arising from developmental challenges that are common to people with MS. An initial comparison shows these may be distinct from those of people with other chronic diseases. These beliefs and behaviors form the predisposing factors and contribute to the triggering factors, which are the acute stressors triggering disease onset. These often took two forms, a prolonged incident experienced as feeling trapped or stuck, and threat of a breach in a relationship. The reinforcing factors add the stress of a chronic disease with a poor prognosis and seemingly random symptom fluctuation, still managed with the same beliefs and behaviors developed in childhood, increasing physiological dysregulation and symptom severity. A pilot study is described in which these three categories of stress factors in MS were explicitly addressed. This study noted clinically important improvements in physical and mental well-being, providing preliminary support for the Developmental Model. Future research might expand on the pilot using a more robust sample and design.
Case report: Phosphoinositide 3-kinase inhibitor with fulvestrant in a patient with ER+/HER2- metastatic breast carcinoma induced fatal arrhythmias: a preventable event?
Authors: Zhang Li , Zheng Yanlei , Chen Gao , Zhao Fang , Li Shi
Published: June 2024

Phosphoinositide 3-kinase (PI3K) inhibitors have shown synergistic anticancer effects with endocrine therapy against ER+/PIK3CA-mutated breast cancer. PI3K inhibitors for cancer therapy are becoming more common. There is an increasing need to understand their cardiac adverse events. In this report, we describe the features of near-fatal mixed arrhythmias in a patient who was undergoing a phase Ib clinical study of PI3Kα inhibitor with fulvestrant. Subsequently, the patient survived by cardiopulmonary resuscitation and therefore did not die. This case highlights that PI3K inhibitors can induce QT/QTc prolongation and predispose patients to TdP. The combination of QT/QTc prolongation in combination with prolonged cardiac repolarization, such as an AV block during treatment with PI3Kα inhibitor, may aggravate the occurrence of TdP. It is likely to be a safer strategy to adjust the standard of discontinuing drugs and continuing drugs (QTc interval was <500 and <60 ms at baseline) or choose other types of alternative treatment options. This report provided some ideas for clinicians to identify early and prevent the occurrence of fatal arrhythmias during anticancer treatment.
Partial response to trastuzumab deruxtecan (DS8201) following progression in HER2-amplified breast cancer with pulmonary metastases managed with disitamab vedotin (RC48): a comprehensive case report and literature review
Authors: Lan Yanfang , Zhao Jiahui , Zhao Fangrui , Li Juanjuan , Li Xiangpan
Published: June 2024

Breast cancer remains one of the predominant malignancies worldwide. In the context of inoperable advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, systemic management primarily relies on HER2-targeting monoclonal antibodies. With the successful development of anti-HER2 antibody-drug conjugates (ADCs), these agents have been increasingly integrated into therapeutic regimens for metastatic breast cancer. Here, we present the case of a 42-year-old female patient with HER2-positive pulmonary metastatic breast cancer who underwent an extensive treatment protocol. This protocol included chemotherapy, radiation therapy, hormonal therapy, surgical intervention on the breast, and anti-HER2 therapies. The anti-HER2 therapies involved both singular and dual targeting strategies using trastuzumab and the ADC disitamab vedotin (RC48) over an 8-year period. After experiencing disease progression following HER2-targeted therapy with RC48, the patient achieved noticeable partial remission through a therapeutic regimen that combined trastuzumab deruxtecan (DS8201) and tislelizumab. The data suggest a promising role for DS8201 in managing advanced stages of HER2-amplified metastatic breast cancer, especially in cases that demonstrate progression after initial HER2-directed therapies using ADCs. Furthermore, its combination with anti-PD-1 agents enhances therapeutic efficacy by augmenting the anti-tumoral immune response.
Molecular pathways and targeted therapies in head and neck cancers pathogenesis
Authors: Constantin Marian , Chifiriuc Mariana Carmen , Bleotu Coralia , Vrancianu Corneliu Ovidiu , Cristian Roxana-Elena , Bertesteanu Serban Vifor , Grigore Raluca , Bertesteanu Gloria
Published: June 2024

The substantial heterogeneity exhibited by head and neck cancer (HNC), encompassing diverse cellular origins, anatomical locations, and etiological contributors, combined with the prevalent late-stage diagnosis, poses significant challenges for clinical management. Genomic sequencing endeavors have revealed extensive alterations in key signaling pathways that regulate cellular proliferation and survival. Initiatives to engineer therapies targeting these dysregulated pathways are underway, with several candidate molecules progressing to clinical evaluation phases, including FDA approval for agents like the EGFR-targeting monoclonal antibody cetuximab for K-RAS wild-type, EGFR-mutant HNSCC treatment. Non-coding RNAs (ncRNAs), owing to their enhanced stability in biological fluids and their important roles in intracellular and intercellular signaling within HNC contexts, are now recognized as potent biomarkers for disease management, catalyzing further refined diagnostic and therapeutic strategies, edging closer to the personalized medicine desideratum. Enhanced comprehension of the genomic and immunological landscapes characteristic of HNC is anticipated to facilitate a more rigorous assessment of targeted therapies benefits and limitations, optimize their clinical deployment, and foster innovative advancements in treatment approaches. This review presents an update on the molecular mechanisms and mutational spectrum of HNC driving the oncogenesis of head and neck malignancies and explores their implications for advancing diagnostic methodologies and precision therapeutics.
Gastrointestinal stromal tumor with small cell carcinoma infiltration: a case report
Authors: Zhou Yitong , Song Liyuan , Lyu Li , Li Shengjie , Wang Qimin
Published: June 2024

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive system. They usually occur in the gastrointestinal tract. However, we discovered a rare phenomenon in which small cell carcinoma infiltrated the GIST of a patient. The patient came to the hospital and presented with chest tightness and shortness of breath for 2 months and a dry cough for half a month. As the ancillary tests were refined, it was discovered that he also had a lesion in the pelvic cavity. After pathological examination of the core needle biopsy (CNB) samples from the pelvic cavity lesion, the patient was diagnosed with GIST with small cell carcinoma infiltration. The patient is currently receiving a chemotherapy regimen of etoposide combined with cisplatin.
CT radiomics to differentiate neuroendocrine neoplasm from adenocarcinoma in patients with a peripheral solid pulmonary nodule: a multicenter study
Authors: Liu Xiaoyu , Li Hongjian , Wang Shengping , Yang Shan , Zhang Guobin , Xu Yonghua , Yang Hanfeng , Shan Fei
Published: June 2024

Purpose

To construct and validate a computed tomography (CT) radiomics model for differentiating lung neuroendocrine neoplasm (LNEN) from lung adenocarcinoma (LADC) manifesting as a peripheral solid nodule (PSN) to aid in early clinical decision-making.

Methods

A total of 445 patients with pathologically confirmed LNEN and LADC from June 2016 to July 2023 were retrospectively included from five medical centers. Those patients were split into the training set (n = 316; 158 LNEN) and external test set (n = 129; 43 LNEN), the former including the cross-validation (CV) training set and CV test set using ten-fold CV. The support vector machine (SVM) classifier was used to develop the semantic, radiomics and merged models. The diagnostic performances were evaluated by the area under the receiver operating characteristic curve (AUC) and compared by Delong test. Preoperative neuron-specific enolase (NSE) levels were collected as a clinical predictor.

Results

In the training set, the AUCs of the radiomics model (0.878 [95% CI: 0.836, 0.915]) and merged model (0.884 [95% CI: 0.844, 0.919]) significantly outperformed the semantic model (0.718 [95% CI: 0.663, 0.769], p both<.001). In the external test set, the AUCs of the radiomics model (0.787 [95% CI: 0.696, 0.871]), merged model (0.807 [95%CI: 0.720, 0.889]) and semantic model (0.729 [95% CI: 0.631, 0.811]) did not exhibit statistical differences. The radiomics model outperformed NSE in sensitivity in the training set (85.3% vs 20.0%; p <.001) and external test set (88.9% vs 40.7%; p = .002).

Conclusion

The CT radiomics model could non-invasively, effectively and sensitively predict LNEN and LADC presenting as a PSN to assist in treatment strategy selection.
Combined aqupla, paclitaxel liposome, and docetaxel treatment: survival and biomarker outcomes in recurrent ovarian cancer patients
Authors: Yang Jie , Zhang Mengyu , Zhang Yilei , Zhu Lanfen , Wang Qiming
Published: June 2024

As one lethal malignancy in women’s reproductive systems, ovarian cancer (OC) is frequently detected at an advanced phase during diagnosis. when the disease has spread widely. The absence of obvious symptoms and powerful screening tools in the early stages makes treatment difficult and the prognosis poor. Despite the clinical remission that can be achieved in some patients after initial treatment, the recurrence rate is conspicuous, posing a considerable challenge in treating recurrent OC (ROC). In the retrospective analysis, we compared the effects of two treatment regimens, aqupla combined with paclitaxel liposome (NP group) versus aqupla combined with docetaxel (ND group), on survival and biomarkers in patients with ROC. The study included 121 OC patients, and clinical data were collected through an electronic medical record system, outpatient review records, and a follow-up record system. The results revealed a notably higher overall remission rate in the ND group than the NP group, but revealed no notable inter-group discrepancy in toxicities, implying that the aqupla combined with docetaxel regimen may be more effective in platinum-sensitive ROC patients. Additionally, post-treatment CA125 levels were lower in patients in the ND group, suggesting that the regimen may be more effective in reducing tumour load. Survival analysis further revealed that treatment regimen, FIGO stage, number of recurrent lesions, and pretreatment CA125 level were independent prognostic factors affecting patients’ 5-year OS and PFS. Overall for ROC patients, especially platinum-sensitive patients, the aqupla in combination with docetaxel regimen provided an improved survival benefit with a comparable safety profile, highlighting the importance of individualised treatment strategies.
Open optimism as an “embodied-health” ethic for the information era
Authors: Naidoo Meshandren
Published: June 2024

This article forms part of a series on “openness,” “non-linearity,” and “embodied-health” in the post-physical, informational (virtual) era of society. This is vital given that the threats posed by advances in artificial intelligence call for a holistic, embodied approach. Typically, health is separated into different categories, for example, (psycho)mental health, biological/bodily health, genetic health, environmental health, or reproductive health. However, this separation only serves to undermine health; there can be no separation of health into subgroups (psychosomatics, for example). Embodied health contains no false divisions and relies on “optimism” as the key framing value. Optimism is only achieved through the mechanism/enabling condition of openness. Openness is vital to secure the embodied health for individuals and societies. Optimism demands that persons become active participants within their own lives and are not mere blank slates, painted in the colors of physical determinism (thus a move away from nihilism—which is the annihilation of freedom/autonomy/quality). To build an account of embodied health, the following themes/aims are analyzed, built, and validated: (1) a modern re-interpretation and validation of German idealism (the crux of many legal–ethical systems) and Freud; (2) ascertaining the bounded rationality and conceptual semantics of openness (which underlies thermodynamics, psychosocial relations, individual autonomy, ethics, and as being a central constitutional governmental value for many regulatory systems); (3) the link between openness and societal/individual embodied health, freedom, and autonomy; (4) securing the role of individualism/subjectivity in constituting openness; (5) the vital role of nonlinear dynamics in securing optimism and embodied health; (6) validation of arguments using the methodological scientific value of invariance (generalization value) by drawing evidence from (i) information and computer sciences, (ii) quantum theory, and (iii) bio-genetic evolutionary evidence; and (7) a validation and promotion of the inalienable role of theoretic philosophy in constituting embodied health, and how modern society denigrates embodied health, by misconstruing and undermining theoretics. Thus, this paper provides and defends an up-to-date non-physical account of embodied health by creating a psycho-physical–biological–computational–philosophical construction. Thus, this paper also brings invaluable coherence to legal and ethical debates on points of technicality from the empirical sciences, demonstrating that each field is saying the same thing.
Treatment of hypertension during pregnancy: a cohort of pregnancy episodes from the SIDIAP database, Catalonia, Spain
Authors: Gomez-Lumbreras Ainhoa , Vilaplana-Carnerero Carles , Lestón Vázquez Marta , Vedia Cristina , Morros Rosa , Giner-Soriano Maria
Published: June 2024

Introduction

Hypertension during pregnancy is one of the most frequent causes of maternal and fetal morbimortality. Perinatal and maternal death and disability rates have decreased by 30%, but hypertension during pregnancy has increased by approximately 10% in the last 30 years. This research aimed to describe the pharmacological treatment and pregnancy outcomes of pregnancies with hypertension.

Methods

We carried out an observational cohort study from the Information System for the Development of Research in Primary Care (SIDIAP) database. Pregnancy episodes with hypertension (ICD-10 codes for hypertension, I10–I15 and O10–O16) were identified. Antihypertensives were classified according to the ATC WHO classification: β-blocking agents (BBs), calcium channel blockers (CCBs), agents acting on the renin‐angiotensin system (RAS agents), diuretics, and antiadrenergic agents. Exposure was defined for hypertension in pregnancies with ≥2 prescriptions during the pregnancy episode. Descriptive statistics for diagnoses and treatments were calculated.

Results

In total, 4,839 pregnancies with hypertension diagnosis formed the study cohort. There were 1,944 (40.2%) pregnancies exposed to an antihypertensive medication. There were differences in mother’s age, BMI, and alcohol intake between pregnancies exposed to antihypertensive medications and those not exposed. BBs were the most used (n = 1,160 pregnancy episodes; 59.7%), followed by RAS agents (n = 825, 42.4%), and CCBs were the least used (n = 347, 17.8%).

Discussion

Pregnancies involving hypertension were exposed to antihypertensive medications, mostly BBs. We conduct a study focused on RAS agent use during pregnancy and its outcomes in the offspring.
Ezetimibe, Niemann-Pick C1 like 1 inhibitor, modulates hepatic phospholipid metabolism to alleviate fat accumulation
Authors: Yang Hyekyung , Suh Dong Ho , Jung Eun Sung , Lee Yoonjin , Liu Kwang-Hyeon , Do In-Gu , Lee Choong Hwan , Park Cheol-Young
Published: June 2024

Background

Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and animals. Here, we demonstrate the changes in hepatic metabolites and lipids and explain the underlying mechanism of ezetimibe in hepatic steatosis.

Methods

We fed Otsuka Long-Evans Tokushima Fatty (OLETF) rats a high-fat diet (60 kcal % fat) with or vehicle (control) or ezetimibe (10 mg kg-1) via stomach gavage for 12 weeks and performed comprehensive metabolomic and lipidomic profiling of liver tissue. We used rat liver tissues, HepG2 hepatoma cell lines, and siRNA to explore the underlying mechanism.

Results

In OLETF rats on a high-fat diet, ezetimibe showed improvements in metabolic parameters and reduction in hepatic fat accumulation. The comprehensive metabolomic and lipidomic profiling revealed significant changes in phospholipids, particularly phosphatidylcholines (PC), and alterations in the fatty acyl-chain composition in hepatic PCs. Further analyses involving gene expression and triglyceride assessments in rat liver tissues, HepG2 hepatoma cell lines, and siRNA experiments unveiled that ezetimibe’s mechanism involves the upregulation of key phospholipid biosynthesis genes, CTP:phosphocholine cytidylyltransferase alpha and phosphatidylethanolamine N-methyl-transferase, and the phospholipid remodeling gene lysophosphatidylcholine acyltransferase 3.

Conclusion

This study demonstrate that ezetimibe improves metabolic parameters and reduces hepatic fat accumulation by influencing the composition and levels of phospholipids, specifically phosphatidylcholines, and by upregulating genes related to phospholipid biosynthesis and remodeling. These findings provide valuable insights into the molecular pathways through which ezetimibe mitigates hepatic fat accumulation, emphasizing the role of phospholipid metabolism.
Association of thrombocytopenia with immune checkpoint inhibitors: a large-scale pharmacovigilance analysis based on the data from FDA adverse event reporting system database
Authors: Liu Geliang , Zhang Shuxian , Mo Zhuang , Huang Tai , Yu Qi , Lu Xuechun , He Peifeng
Published: June 2024

Introduction: An increasing number of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been reported during clinical treatment. We aimed to explore the clinical characteristics of patients with ICIs-induced ITP under different therapeutic strategies based on the FAERS database and explore the potential biological mechanisms in combination with TCGA pan-cancer data.

Methods: Data from FAERS were collected for ICIs adverse reactions between January 2012 and December 2022. Disproportionality analysis identified ICIs-induced ITP in the FAERS database using the reporting odds ratio (ROR), proportional reporting ratio (PRP), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker algorithms (MGPS). The potential biological mechanisms underlying ITP induced by ICIs were examined using TCGA transcriptome data on cancers.

Results: In the FAERS, 345 ICIs-induced ITP reports were retrieved, wherein 290 (84.06%) and 55 (15.94%) were reported as monotherapy and combination therapy, respectively. The median age of the reported patients with ICIs-induced ITP was 69 years (IQR 60-76), of which 62 (18%) died and 47 (13.6%) had a life-threatening outcome. The majority of reported indications were lung, skin, and bladder cancers, and the median time to ITP after dosing was 42 days (IQR 17-135), with 64 patients (43.5%) experiencing ITP within 30 days of dosing and 88 patients experiencing ITP in less than 2 months (59.9%). The occurrence of ICIs-induced ITP may be associated with ICIs-induced dysregulation of the mTORC1 signaling pathway and megakaryocyte dysfunction.

Conclusion: There were significant reporting signals for ITP with nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab/ipilimumab, and pembrolizumab/ipilimumab. Patients treated with anti-PD-1 in combination with anti-CTLA-4 are more likely to have an increased risk of ICIs-induced ITP. Patients with melanoma are at a higher risk of developing ITP when treated with ICI and should be closely monitored for this risk within 60 days of treatment. The potential biological mechanism of ICIs-induced ITP may be related to the dysfunction of megakaryocyte autophagy through the overactivation of the mTOR-related signaling pathway. This study provides a comprehensive understanding of ICIs-induced ITP. Clinicians should pay attention to this potentially fatal adverse reaction.
Non-human primate studies for cardiomyocyte transplantation—ready for translation?
Authors: von Bibra Constantin , Hinkel Rabea
Published: June 2024

Non-human primates (NHP) are valuable models for late translational pre-clinical studies, often seen as a last step before clinical application. The unique similarity between NHPs and humans is often the subject of ethical concerns. However, it is precisely this analogy in anatomy, physiology, and the immune system that narrows the translational gap to other animal models in the cardiovascular field. Cell and gene therapy approaches are two dominant strategies investigated in the research field of cardiac regeneration. Focusing on the cell therapy approach, several xeno- and allogeneic cell transplantation studies with a translational motivation have been realized in macaque species. This is based on the pressing need for novel therapeutic options for heart failure patients. Stem cell-based remuscularization of the injured heart can be achieved via direct injection of cardiomyocytes (CMs) or patch application. Both CM delivery approaches are in the late preclinical stage, and the first clinical trials have started. However, are we already ready for the clinical area? The present review concentrates on CM transplantation studies conducted in NHPs, discusses the main sources and discoveries, and provides a perspective about human translation.
Staphylococcus arlettae mediated defense mechanisms and metabolite modulation against arsenic stress in Helianthus annuus
Authors: Qadir Muhammad , Hussain Anwar , Shah Mohib , Hamayun Muhammad , Iqbal Amjad , Irshad Muhammad , Ahmad Ayaz , Alrefaei Abdulwahed Fahad , Ali Sajid
Published: June 2024

Introduction

Arsenate, a metalloid, acting as an analog to phosphate, has a tendency to accumulate more readily in plant species, leading to adverse effects.

Methods

In the current study, sunflower seedlings were exposed to 25, 50 and 100 ppm of the arsenic.

Results

Likewise, a notable reduction (p<0.05) was observed in the relative growth rate (RGR) by 4-folds and net assimilation rate (NAR) by 75% of Helianthus annuus when subjected to arsenic (As) stress. Nevertheless, the presence of Staphylococcus arlettae, a plant growth-promoting rhizobacterium with As tolerance, yielded an escalation in the growth of H. annuus within As-contaminated media. S. arlettae facilitated the conversion of As into a form accessible to plants, thereby, increasing its uptake and subsequent accumulation in plant tissues. S. arlettae encouraged the enzymatic antioxidant systems (Superoxide dismutase (SOD), peroxidase (POD), ascorbate peroxidase (APX) and catalase (CAT)) and non-enzymatic antioxidants (flavonoids, phenolics, and glutathione) in H. annuus seedlings following substantial As accumulation. The strain also induced the host plant to produce osmolytes like proline and sugars, mitigating water loss and maintaining cellular osmotic balance under As-induced stress. S. arlettae rectified imbalances in lignin content, reduced high malonaldehyde (MDA) levels, and minimized electrolyte leakage, thus counteracting the toxic impacts of the metal.

Conclusion

The strain exhibited the capability to concurrently encourage plant growth and remediate Ascontaminated growth media through 2-folds rate of biotransformation and bio-mobilization.