bluuebunny/crossref_metadata_2025 huggingface dataset:
Progress in 1,3-propanediol biosynthesis
Authors: Li Boran , Gao Wenyan , Pan Yuanyuan , Yao Yongpeng , Liu Gang
Published: November 2024

1,3-Propanediol (1,3-PDO) is one of the important organic chemical materials and is widely used in polyester synthesis, and it also shows great potential in medicine, cosmetics, resins, and biodegradable plastics. So far, 1,3-PDO mainly comes from chemical synthesis. However, the by-products and the side effects during chemical synthesis of 1,3-PDO bring about serious damage to the environment. In recent years, the biosynthetic pathway of 1,3-PDO has been elucidated in microorganisms. Under the action of glycerol dehydratase (GDHt) and propanediol oxidoreductase (PDOR), glycerol can be catalyzed to form 1,3-PDO through the reduction pathway. Compared to the chemical synthesis, the biosynthesis of 1,3-PDO is environmentally friendly but would face the problem of low production. To improve the yield, the native 1,3-PDO producing strains have been modified by genetic engineering, and the biosynthetic pathway has been reconstructed in the model microorganism, Escherichia coli. In this review, we summarize the research progress of the 1,3-PDO biosynthesis in microorganisms, and hopefully, it will provide reference for the renewable production of 1,3-PDO in industry.
Inflammation and immune response in the development of periodontal disease: a narrative review
Authors: López-Valverde Nansi , Quispe-López Norberto , Blanco Rueda José Antonio
Published: November 2024

We present this critical review with the aim of highlighting the current status of periodontal diseases, focusing on the relevance of host modulating agents and immune pathways, in addition to new complementary therapeutic approaches for the treatment of these pathologies. Periodontal diseases are prevalent pathologies worldwide and the main cause of edentulism in the adult population. Their pathogenesis seems to be based on a dysbiosis of the oral microbiota that interacts with the host’s immune defenses and is responsible for the inflammatory/immune response, which would be modified by a number of conditions such as individual susceptibility, environmental and sociodemographic factors, certain systemic pathologies and the individual’s genetic condition, among others. Numerous studies have reported on the complex web of inflammatory mediators in periodontal disease and their role in tissue destruction as well as in homeostatic imbalance. Precisely, the role of epigenetics as a modifier of the host genetic condition has captured research attention in recent years. Therefore, this mini-review first discusses an updated etiological hypothesis of periodontal disease and the roles of certain cytokines in the immune response. In addition, the latest therapeutic trends with new developments and future perspectives are summarized.
ZIKV prM hijacks PIM1 kinase for phosphorylation to prevent ubiquitin−mediated degradation and facilitate viral replication
Authors: Ren Yingying , Liu Yishuo , Pang Rui , Xu Gang , Lei Yining , Kwok Hang Fai , Wu Yingliang , Cao Zhijian
Published: November 2024

Introduction

Viral infection usually stimulates a variety of host cell factors to modulate the life cycle of the virus. PIM1, a serine/threonine protein kinase widely involved in cell proliferation, survival, differentiation and apoptosis, was recently reported to be upregulated by Zika virus (ZIKV) infection. However, how ZIKV-PIM1 interactions affect the viral life cycle are not fully understood.

Methods and results

Here, we demonstrated that ZIKV replication was suppressed by the PIM1 kinase inhibitor SGI-1776 in both wt and Ifnar1-/- murine peritoneal macrophages, indicating that PIM1 functions independently of type I IFN signaling. Co-immunoprecipitation and GST pull-down assays revealed that the ZIKV structural protein precursor membrane (prM) interacted with PIM1. Moreover, we found that prM protein stability was enhanced by PIM1, which was attributed to its kinase activity. Mechanistically, we revealed that prM can undergo ubiquitin‒mediated proteolysis and the E3 ubiquitin ligase AMFR can target prM for degradation. Importantly, PIM1 catalyzed phosphorylation of prM at Ser101 and Thr107, and this phosphorylation prevented the proteasome-dependent degradation of prM by impairing its association with AMFR. Therefore, the S101/T107-D phosphorylation mimic mutant of prM was more resistant to PIM1-induced increases in cellular abundance.

Discussion

These findings revealed PIM1 as a critical host factor that is advantageous to ZIKV and revealed that targeting the PIM1‒prM axis is a conducive strategy for controlling ZIKV infection.
HI-TAM, a hybrid intelligence framework for training and adoption of generative design assistants
Authors: Mao Yaoli , Rafner Janet , Wang Yi , Sherson Jacob
Published: November 2024

The Hybrid Intelligence Technology Acceptance Model (HI-TAM) presented in this paper offers a novel framework for training and adopting generative design (GD) assistants, facilitating co-creation between human experts and AI systems. Despite the promising outcomes of GD, such as augmented human cognition and highly creative design products, challenges remain in the perception, adoption, and sustained collaboration with AI, especially in creative design industries where personalized and specialized assistance is crucial for individual style and expression. In this two-study paper, we present a holistic hybrid intelligence (HI) approach for individual experts to train and personalize their GD assistants on-the-fly. Culminating in the HI-TAM, our contribution to human-AI interaction is 4-fold including (i) domain-specific suitability of the HI approach for real-world application design, (ii) a programmable common language that facilitates the clear communication of expert design goals to the generative algorithm, (iii) a human-centered continual training loop that seamlessly integrates AI training into the expert's workflow, (iv) a hybrid intelligence narrative that encourages the psychological willingness to invest time and effort in training a virtual assistant. This approach facilitates individuals' direct communication of design objectives to AI and fosters a psychologically safe environment for adopting, training, and improving AI systems without the fear of job-replacement. To demonstrate the suitability of HI-TAM, in Study 1 we surveyed 41 architectural professionals to identify the most preferred workflow scenario for an HI approach. In Study 2, we used mixed methods to empirically evaluate this approach with 8 architectural professionals, who individually co-created floor plan layouts of office buildings with a GD assistant through the lens of HI-TAM. Our results suggest that the HI-TAM enables professionals, even non-technical ones, to adopt and trust AI-enhanced co-creative tools.
Untangling the impact of live baitfish restrictions on recreational fishing participation in the United States
Authors: DeRooy Victoria , Hansen Amanda
Published: November 2024

In recent decades, many jurisdictions have established regulations governing the use of live baitfish in recreational fishing. Live baitfish can originate from either aquaculture farms or wild harvest. Live bait regulations are usually motivated by conservation concerns, such as the role that live baitfish play in the spread of invasive species and aquatic diseases. One barrier that may prevent policy regulation of live baitfish is the fear among policymakers that limiting the use of live baitfish could impact the general public’s interest in fishing. However, conservation policy is hindered by the fact that there is very little research on this concern. In this study, we conduct a before-after control-intervention (BACI) analysis to test whether live baitfish regulations in the United States are followed by changes in recreational fishing. Using data from the 1960s to the present day, we analyze four states that have implemented live baitfish restrictions: Maine, New York, Vermont and Colorado. We find that live baitfish restrictions do not cause a decline in the public’s participation in fishing. Our results can empower policymakers to craft evidence-based regulations on the use of live baitfish for conservation purposes while remaining confident that such policies are not likely to cause any unintended consequences on the recreational fishing community.
Design-related bias in studies investigating diagnostic tests for venous thromboembolic diseases: a systematic review and meta-analysis
Authors: Boschetti Laura , Nilius Henning , Ten Cate Hugo , Wuillemin Walter A. , Faes Livia , Bossuyt Patrick M. , Bachmann Lucas M. , Nagler Michael
Published: November 2024

Background

Early detection and diagnosis of venous thromboembolism are vital for effective treatment. To what extent methodological shortcomings exist in studies of diagnostic tests and whether this affects published test performance is unknown.

Objectives

We aimed to assess the methodological quality of studies evaluating diagnostic tests for venous thromboembolic diseases and quantify the direction and impact of design characteristics on diagnostic performance.

Methods

We conducted a literature search using Medline and Embase databases for systematic reviews summarizing diagnostic accuracy studies for five target disorders associated with venous thromboembolism. The following data were extracted for each primary study: methodological characteristics, the risk of bias scored by the QUADAS QUADAS-2 instrument, and numbers of true-positives, true-negatives, false-positives, and false-negatives. In a meta-analysis, we compared diagnostic accuracy measures from studies unlikely to be biased with those likely to be biased.

Results

Eighty-five systematic reviews comprising 1’818 primary studies were included. Adequate quality assessment tools were used in 43 systematic reviews only (51%). The risk of bias was estimated to be low for all items in 23% of the primary studies. A high or unclear risk of bias in particular domains of the QUADAS/QUADAS-2 tool was associated with marked differences in the reported sensitivity and specificity.

Conclusions

Significant limitations in the methodological quality of studies assessing diagnostic tests for venous thromboembolic disorders exist, and studies at risk of bias are unlikely to report valid estimates of test performance. Established guidelines for evaluation of diagnostic tests should be more systematically adopted.

Systematic Review Registration

PROSPERO (CRD 42021264912).
Establishing and evaluating trustworthy AI: overview and research challenges
Authors: Kowald Dominik , Scher Sebastian , Pammer-Schindler Viktoria , Müllner Peter , Waxnegger Kerstin , Demelius Lea , Fessl Angela , Toller Maximilian , Mendoza Estrada Inti Gabriel , Šimić Ilija , Sabol Vedran , Trügler Andreas , Veas Eduardo , Kern Roman , Nad Tomislav , Kopeinik Simone
Published: November 2024

Artificial intelligence (AI) technologies (re-)shape modern life, driving innovation in a wide range of sectors. However, some AI systems have yielded unexpected or undesirable outcomes or have been used in questionable manners. As a result, there has been a surge in public and academic discussions about aspects that AI systems must fulfill to be considered trustworthy. In this paper, we synthesize existing conceptualizations of trustworthy AI along six requirements: (1) human agency and oversight, (2) fairness and non-discrimination, (3) transparency and explainability, (4) robustness and accuracy, (5) privacy and security, and (6) accountability. For each one, we provide a definition, describe how it can be established and evaluated, and discuss requirement-specific research challenges. Finally, we conclude this analysis by identifying overarching research challenges across the requirements with respect to (1) interdisciplinary research, (2) conceptual clarity, (3) context-dependency, (4) dynamics in evolving systems, and (5) investigations in real-world contexts. Thus, this paper synthesizes and consolidates a wide-ranging and active discussion currently taking place in various academic sub-communities and public forums. It aims to serve as a reference for a broad audience and as a basis for future research directions.
Differing perspectives on artificial intelligence in mental healthcare among patients: a cross-sectional survey study
Authors: Reading Turchioe Meghan , Desai Pooja , Harkins Sarah , Kim Jessica , Kumar Shiveen , Zhang Yiye , Joly Rochelle , Pathak Jyotishman , Hermann Alison , Benda Natalie
Published: November 2024

Introduction

Artificial intelligence (AI) is being developed for mental healthcare, but patients' perspectives on its use are unknown. This study examined differences in attitudes towards AI being used in mental healthcare by history of mental illness, current mental health status, demographic characteristics, and social determinants of health.

Methods

We conducted a cross-sectional survey of an online sample of 500 adults asking about general perspectives, comfort with AI, specific concerns, explainability and transparency, responsibility and trust, and the importance of relevant bioethical constructs.

Results

Multiple vulnerable subgroups perceive potential harms related to AI being used in mental healthcare, place importance on upholding bioethical constructs, and would blame or reduce trust in multiple parties, including mental healthcare professionals, if harm or conflicting assessments resulted from AI.

Discussion

Future research examining strategies for ethical AI implementation and supporting clinician AI literacy is critical for optimal patient and clinician interactions with AI in mental healthcare.
Prompt engineering as a new 21st century skill
Authors: Federiakin Denis , Molerov Dimitri , Zlatkin-Troitschanskaia Olga , Maur Andreas
Published: November 2024

Artificial Intelligence (AI) promises to revolutionize nearly every aspect of human learning. However, users have observed that the efficacy of AI assistants hinges crucially on the quality of the prompts supplied to them. A slight alteration in wording can make the difference between an assistant misinterpreting an instruction and exceeding expectations. The skill of precisely communicating the essence of a problem to an AI assistant is as crucial as the assistant itself. This paper aims to introduce Prompt Engineering (PE) as an emerging skill essential for personal and professional learning and development in the 21st century. We define PE as the skill of articulating a problem, its context, and the constraints of the desired solution to an AI assistant, ensuring a swift and accurate response. We show that no existing related frameworks on 21st skills and others cover PE to the extent that allows for its valid assessment and targeted promotion in school and university education. Thus, we propose a conceptual framework for this skill set including (1) comprehension of the basic prompt structure, (2) prompt literacy, (3) the method of prompting, and (4) critical online reasoning. We also discuss the implications and challenges for the assessment framework of this skill set and highlight current PE-related recommendations for researchers and educators.
Serum 25-hydroxy vitamin D level is associated with elastography-detected liver fibrosis in patients with type 2 diabetes mellitus in China
Authors: Huang Nan , Su Xianghui , Yu Ting , Wu Xiaodong , Lu Bing , Sun Weixia , Yao Liqin , Wang Maoyun , Wang Yao , Wu Wenxuan , Liu Yingzhao , Yang Ting , Gao Ruidong , Miao Congqing , Li Ling
Published: November 2024

Objective

In this cross-sectional study including patients with type 2 diabetes mellitus (T2DM) we aimed to explore the relationship between serum 25-hydroxy vitamin (25(OH)D) level and liver steatosis and fibrosis in the Chinese population.

Methods

Patients visiting 16 clinical centers with T2DM were recruited. Their liver steatosis and fibrosis status were then assessed using elastography. Factors associated with steatosis and fibrosis were explored using regression analysis. Correlations between serum 25(OH)D levels and other patient characteristics were analyzed using linear regression.

Results

In total, 1,513 patients with T2DM were included in the study. The prevalence of steatosis and fibrosis was 69.7%, and 34.6%, separately. A lower level of 25(OH)D was detected in patients with liver steatosis compared to those without, although it was not an independent predictor of this condition. However, 25(OH)D level was independently associated with liver fibrosis even when adjusted for age, sex, body mass index, hemoglobin A1c, insulin, and homeostatic model assessment of insulin resistance (OR = 0.964 [0.935-0.993], P = 0.015). When patients were separated into subgroups by sex, a correlation between 25(OH)D and fibrosis was identified in the male group (OR = 0.969 [0.940-0.998], P = 0.038).

Conclusions

In conclusion, this multi-center, cross-sectional study in patients with T2DM showed that serum 25-hydroxy vitamin D level was strongly associated with liver fibrosis and this relationship was more pronounced in male patients.

Clinical trial registration

https://clinicaltrials.gov/ct2/show/, identifier NCT05597709.
Endometrial expression of ERRβ and ERRγ: prognostic significance and clinical correlations in severe endometriosis
Authors: Wang Zhenna , Guo Sang , Xie Yi , Tong Yao , Qi Wei , Wang Zhenhong
Published: November 2024

Background

Endometriosis (EMs) results in approximately 50% of reproductive-age women facing infertility. Currently, no precise model is available to predict successful postoperative pregnancy.

Methods

This study involved 81 patients with severe EMs (stages III and IV) and 38 controls with benign gynecological conditions, matched by age and BMI, diagnosis at Fujian Maternity and Child Health Hospital from January 2018 to December 2019. Relative expression levels of ERRβ and ERRγ mRNA in ectopic and ectopic endometrial tissues were measured using fluorescence quantitative PCR. Serum levels of ERRβ, ERRγ, and fertility-related hormones (AMH, FSH, LH, CA125) were assessed. Correlations were analyzed, and the predictive value of ERRγ for postoperative pregnancy was evaluated using a nomogram based on LASSO and multivariate logistic regression. Internal validation using bootstrapping techniques assessed the nomograms performance, including calibration and DCA.

Results

ERRβ and ERRγ mRNA levels from ectopic tissues were significantly reduced in patients with severe EMs compared to controls. High serum CA125 correlated with increased ERRγ mRNA expression in ectopic tissues. ERRγ mRNA expression in ectopic endometrial tissues was negatively correlated with age, BMI, and FSH levels, and positively with AMH and LH/FSH ratio. ERRγ mRNA and FSH were significant predictors of postoperative pregnancy, with the nomogram model showing a Brier score of 0.175 and a consistency statistic of 0.811.

Conclusions

ERRβ and ERRγ are downregulated in ectopic tissues from severe EMs. Elevated ERRγ mRNA expression and lower FSH levels are predictive factors for successful postoperative pregnancy.
Study on sealing performance of main gate valve of marine nuclear power plant based on fluid-solid-thermal coupling method
Authors: Yuqing Chen , Hang Yu , Shengwei Fu , Ang Li
Published: November 2024

Introduction

The main gate valve is a critical component of the coolant system in marine nuclear power plants, yet its integrity is often compromised by leakage, particularly during transient operations. This study employs a fluid-solid-thermal coupling method to numerically investigate the sealing performance of the main gate valve under rapid coolant temperature drops.

Methods

The analysis reveals that thermal shock-induced uneven stress and deformation significantly reduce contact pressure on the sealing surface, leading to leakage.

Results and Discussion

Notably, only when the bolt preload reaches the material yield limit can the valve maintain a seal during operation. Furthermore, the study demonstrates that a faster rate of coolant temperature drop exacerbates the leakage. These findings offer valuable insights for optimizing the operation of marine nuclear power plants and enhancing the structural integrity of the main gate valve.
Method for calculating a water surface profile at the watershed scale with little observed data based on ASTER GDEM: a case study in the Naoli River, northeast China
Authors: Tian Lin , Wei Yinying , Wang Sheng , Zhang Guorong , Zhao Chuangjia , Huang Xin , Huang Weiyu
Published: November 2024

The calculation of a river water surface profile is a very important problem in the field of hydraulic engineering. With the development of research on surface and groundwater coupled simulation, the river water surface profile has become an indispensable boundary condition for simulating the inter-relationship between surface water and groundwater. River channel large-section data are the basic prerequisites for building most hydrodynamic models, and obtaining field data can consume considerable effort and material resources. We extracted river sections using ArcGIS based on the ASTER GDEM data and interpolated the corresponding water levels of different guarantee flow rates in Baoqing and Caizuizi stations. We analyzed the variation of upstream water levels under different Manning coefficients n, and the bed resistance of the Naoli River was determined to be 0.025. In order to ensure the rationality of the model and the reliability of the operation results, three indexes (non-scouring velocity, the shear stress of the riverbed, and the water surface slope) were used to analyze and test the rationality of the simulation results. Ultimately, the calculation of the water surface profile from the Baoqing hydrologic station to the Caizuizi hydrologic station in the Naoli River was achieved using the MIKE 11 hydrodynamics model under the guarantee flow rates of 20%, 50%, 75%, and 95%. Calculating the water surface profile can provide hydrological boundary conditions for surface and groundwater conversion and the combined simulation. Furthermore, the present study can provide a feasible method for calculating a river water surface profile in areas that lack measured section data.
PARP inhibitors in testicular germ cell tumors: what we know and what we are looking for
Authors: Parola Sara , Oing Christoph , Rescigno Pasquale , Feliciano Salvatore , Carlino Francesca , Pompella Luca , Marretta Antonella Lucia , De Santo Irene , Viggiani Martina , Muratore Margherita , Facchini Bianca Arianna , Orefice Jessica , Cioli Eleonora , Sparano Francesca , Mallardo Domenico , De Giorgi Ugo , Palmieri Giovannella , Ascierto Paolo Antonio , Ottaviano Margaret
Published: November 2024

Testicular germ cell tumors (TGCTs), the most common malignancies affecting young men, are characterized by high sensitivity to cisplatin-based chemotherapy, which leads to high cure rates even in metastatic disease. However, approximately 30% of patients with metastatic TGCTs relapse after first-line treatment and those who can be defined as platinum-refractory patients face a very dismal prognosis with only limited chemotherapy-based treatment options and an overall survival of few months. Hence, to understand the mechanisms underlying cisplatin resistance is crucial for developing new treatment strategies. This narrative review explores the potential role of PARP inhibitors (PARPis) in overcoming cisplatin resistance in TGCTs, starting from the rationale of their ability to induce DNA damage in cells with homologous recombination repair (HRR). Thus far, PARPis have failed to show meaningful clinical activity in platinum-refractory TGCT patients, either alone or in combination with chemotherapy. However, few responses to PARPis in TGCTs have been detected in patients with BRCA1/2, ATM or CHEK2 mutations, reinforcing the idea that patients should be optimally selected for tailored treatments in the era of personalized medicine. Future preclinical and clinical research is needed to further investigate the molecular mechanisms of cisplatin resistance and to identify novel therapeutic strategies in resistant/refractory TGCTs patients.
Stakeholder analysis towards unpacking communities of practice for transdisciplinary research and action in climate change and health in Africa
Authors: Atela Joanes , Bolo Emily , Agevi Humphrey , Muindi Kanyiva , Thiam Sokhna , Gordon Ezekiel , Wanjiru Irungu Ann , Gitau Hellen
Published: November 2024

Health and climate drivers and solutions in Africa co-exist within the same social context. Primary healthcare systems are increasingly becoming impacted by climate change. Health and climate change communities still work in isolation in addition to limited multidisciplinary and integrated research on health and climate change to inform programming, and policy and unlock climate finance. Holistic and transdisciplinary approaches that make use of resources and inputs from different sectors are key to guaranteeing effective responses to the health impacts of climate change. This paper aims to understand the landscape of climate and health (C&H) research, policy capacity building, and stakeholders hence identifying models of collaboration that could be scaled up to strengthen transdisciplinary C&H research and action. A mixed method approach was used in this study that involved the combination of consultative webinars (n = 411) online surveys (n = 198), Focused Group Discussions (n = 123), and Key informant interviews (n = 25) used on targeted stakeholders. In addition, a scoping review of policy academic documents, and databases was done. It was evident that engaging partners from diverse sectors is crucial for the broad range of perspectives, interests, skills, levels of knowledge, and resources. Stakeholder engagement in C&H initiatives is increasing and yet unevenly distributed in Africa due to funding patterns and other structural patterns. Existing C&H research predominantly focuses on climate impacts on diseases, particularly vector-borne and infectious illnesses. While crucial, this disease-centric approach limits the provision of integrated solutions for complex African socio-economic contexts. In addition, Dedicated C&H capacity-building efforts are emerging, but they mainly focus on research and policy, overlooking critical areas like leadership, investment skills, and impact assessment. Health governance and climate change should be addressed through a holistic approach that is transdisciplinary and multisectoral and through the transborder framework. The approach will need innovative thinking in socio-economies, policies, ecologies, and geographies with emphasis centered on the most vulnerable groups.
Entry into the lytic cycle exposes EBV-infected cells to NK cell killing via upregulation of the MICB ligand for NKG2D and activation of the CD56bright and NKG2A+KIR+CD56dim subsets
Authors: Desimio Maria Giovanna , Covino Daniela Angela , Cancrini Caterina , Doria Margherita
Published: November 2024

The Epstein–Barr virus (EBV) is usually acquired during infancy as an asymptomatic infection and persists throughout life in a latent state under the control of the host immune system. However, EBV is associated with various malignant diseases that preferentially develop in immunodeficient individuals. Accumulating evidence suggests an important role for NK cells, though the mechanisms by which EBV evades or triggers NK cell responses are poorly understood. Here, we generated EBV-immortalized lymphoblastoid cell lines stably expressing an inducible form of the BZLF1 early lytic viral protein (LCL-Z) to challenge primary NK cells with EBV+ targets in either the latent or lytic phase of infection. We show that entry into the lytic phase results in drastic downregulation of HLA-E but not HLA-A, -B, and -C molecules and in increased expression of ligands for the activating NKG2D receptor, with MICB being upregulated at the cell membrane and released in a soluble form while ULBP2 and ULBP4 accumulate intracellularly. Furthermore, LCL-Z cells are killed by NK cells in an NKG2D-dependent manner and to a much higher extent during the lytic phase, but HLA-class I molecules constrain killing throughout the viral life cycle; unexpectedly, the antibody-mediated block of the inhibitory NKG2A receptor results in reduced lysis of lytic LCL-Z cells that are nearly devoid of the cognate HLA-E ligand. Accordingly, we show that NKG2A+ NK cell subsets, specifically CD56bright and NKG2A+KIR+CD56dim cells, are those that preferentially respond against cells with lytic EBV replication. Overall, these results shed light on NK/EBV+ cell interactions providing new information for improving NK cell-based immunotherapies to treat EBV-induced diseases.
A novel anti-HER2 monoclonal antibody IAH0968 in HER2-positive heavily pretreated solid tumors: results from a phase Ia/Ib first-in-human, open-label, single center study
Authors: Song Na , Teng Yuee , Shi Jing , Teng Zan , Jin Bo , Qu Jinglei , Zhang Lingyun , Yu Ping , Zhao Lei , Wang Jin , Li Aodi , Tong Linlin , Jiang Shujie , Liu Yang , Yin Liusong , Jiang Xiaoling , Xu Tie , Cui Jian , Qu Xiujuan , Liu Yunpeng
Published: November 2024

Background

IAH0968 is an afucosylated anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody which improved the activity of antibody-dependent cellular cytotoxicity (ADCC) and superior anti-tumor efficacy.

Methods

To determine the maximum tolerated dose (MTD) with dose-limiting toxicity (DLT), a single institution, phase Ia/Ib study was undertaken, using 3 + 3 design. The primary endpoints were safety, tolerability and preliminary clinical activity. Eighteen patients were evaluable for safety and fifteen patients were suitable for efficacy analysis. Dose escalations were 6 mg/kg (N = 2), 10 mg/kg (N = 7), 15 mg/kg (N = 5), and tolerable up to 20 mg/kg (N = 4).

Results

Only one DLT was found at dosage 10 mg/kg, and no MTD was reached. The most common Grade 3 treatment-related adverse events (TRAEs) were hypokalemia (5.6%), supraventricular tachycardia (5.6%), interval extension of QTC (5.6%), and infusion reaction (5.6%). Grade 4 TRAE was arrhythmia (5.6%). No serious TRAE or Grade 5 was reported. 22.2% of patients had a TRAE leading to dose adjustment and 16.7% of patients had a TRAE resulting in discontinuation of IAH0968. After a median follow-up of 9.7 months (range, 3.7 - 22.0), the objective response rate (ORR) was 13.3% (2/15), the disease control rate (DCR) was 53.3% (8/15), and median progression-free survival (mPFS) was 4.2 months (95% CI: 1.4 - 7.7), and the median duration of disease control (DDC) was 6.3 months (95% CI: 2.9–not reached), with 4/15 responses ongoing.

Conclusions

In HER2-positive heavily pretreated metastatic patients, IAH0968 demonstrated promising clinical activity with durable responses and tolerable safety profiles.

Clinical trial registration

ClinicalTrials.gov, identifier NCT04934514.
Comparison of lenvatinib plus pembrolizumab versus first-line systemic chemotherapy for advanced intrahepatic cholangiocarcinoma: a real-world retrospective study
Authors: Yang Zhenyun , Wu Weijie , Hu Zhiwen , Fu Yizhen , Hu Zili , Pan Yangxun , Wang Juncheng , Chen Jinbin , Zhou Zhongguo , Zhang Yaojun , Chen Minshan , Hu Dandan
Published: November 2024

Background

Systemic chemotherapy (SC) stands the only first-line treatment for advanced intrahepatic cholangiocarcinoma (iCCA) for the past few decades. Immune checkpoint inhibitors (ICIs) have been proved to provide additional benefit in disease control. However, oncological outcome of iCCA remains poor and awaits further improvement with new treatment modalities. Promising results have been observed in lenvatinib plus pembrolizumab (Len-P) as a second-line therapy in iCCA. This study aimed to explore the safety and efficacy of Len-P as a first-line therapy for iCCA patients in real-world clinical practice.

Methods

We retrospectively enrolled 133 patients with advanced iCCA who received Len-P or SC between May 2019 and May 2023. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were compared between the two groups.

Results

There were 72 patients and 61 patients in the Len-P and SC groups, respectively. The median OS for the Len-P and SC groups was 16.3 and 17.8 months, respectively. The median PFS for the Len-P and SC groups was 8.9 and 11.4 months, respectively. There was no significant difference in ORR and DCR between the Len-P and SC groups (ORR: 22.2% vs. 23%; P=0.92; DCR: 69.4% vs. 77%; P=0.58). Additionally, the overall incidence of AEs was lower in the Len-P group than SC group. Low inflammation-based scores were indicative of favorable outcomes in patients undergoing Len-P therapy.

Conclusion

This study demonstrated that Len-P is promising for the treatment of advanced ICC, with highly improved safety. It emerges as a viable treatment alternative for advanced iCCA. Inflammation-based scores show potential utility in identifying individuals likely to benefit from Len-P therapy.
Breaking barriers: advancing cellular therapies in autoimmune disease management
Authors: Fu Yanhong , Feng Chunjing , Qin Shan , Xing Zhiyao , Liu Chong , Liu Zichuan , Yu Hongjian
Published: November 2024

Autoimmune diseases occur due to a dysregulation within the immune system, leading to an aberrant assault on the organism’s own tissues. The pathogenesis of these conditions is multifactorial, encompassing intricate interplays among genetic predispositions, environmental determinants, and hormonal fluctuations. The spectrum of autoimmune diseases is broad, impacting a multitude of organ systems, with notable examples such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), psoriasis, and vitiligo. Despite substantial progress in therapeutic interventions over recent years, a definitive cure for autoimmune diseases has yet to be realized, with existing modalities largely providing palliative care. Cellular therapy is considered the fourth pillar in the management of oncological disorders subsequent to surgical resection, radiotherapy, and chemotherapy. Cellular therapies have shown potential in augmenting immune competence and eliminating of targeted neoplastic cells in a spectrum of cancers. As targeting specific molecules on the surface of autoreactive B and T cells, such as CD19, BCMA, CD20, and CTLA-4, cellular therapies are emerging as promising approaches for the treatment of autoimmune diseases. This review delineates the advancements in the application of cellular therapies applied recently for autoimmune diseases and proposes considerations for the advancement of novel therapeutic strategies.
Effect of fish-heavy metals contamination on the generation of reactive oxygen species and its implications on human health: a review
Authors: Wang Yuxia , Noman Anwar , Zhang Chao , AL-Bukhaiti Wedad Q. , Abed Sherif M.
Published: November 2024

Heavy metals (HMs) contamination significantly threatens plants, animals, aquatic ecosystems, and public health. HMs’ accumulation in aquatic environments has become a serious environmental issue due to their high stability, bioaccumulation, and biomagnification properties. These metals enter ecosystems through both natural sources and/or human activities. The toxicity of HMs poses a threat to the aquaculture sector’s sustainability by negatively affecting fish growth, reproduction, and overall physiology. Exposure to HMs in various forms can cause environmental damage, which may affect human health through direct poisoning symptoms or other adverse effects. One such effect is the increased production of reactive oxygen species (ROS), crucial metabolites that modulate the functions of pathogenic organisms and lead to oxidative stress. This, in turn, can contribute to the onset and exacerbation of numerous diseases that threaten human health. This review article examines the potential sources of HMs contamination in aquatic organisms, the impact of this contamination on the generation of ROS, and the implications for human health resulting from the consumption of contaminated aquatic products.
The CRISPR-Cas system in Lactiplantibacillus plantarum strains: identification and characterization using a genome mining approach
Authors: Rostampour Mohaddeseh , Panahi Bahman , Masoumi Jahandizi Reza
Published: November 2024

Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (CAS) genes make up bacteria’s adaptive immune system against bacteriophages. In this study, 675 sequences of Lactiplantibacillus plantarum isolates deposited in GenBank were analyzed in terms of diversity, occurrence, and evolution of the CRISPR-Cas system. This study investigated the presence, structural variations, phylogenetic relationships, and diversity of CRISPR-Cas systems in 675 L. plantarum strains. The analysis revealed that 143 strains harbor confirmed CRISPR-Cas systems, with subtype II-A being predominant. Moreover, targeting phages and plasmid diversity between the predicted systems were dissected. The results indicated that approximately 22% of the isolates with verified and complete CRISPR systems exhibited the coexistence of both subtypes II-A and I-E within their genomes. The results further showed that in subtype II-A, the length of the repeat sequence was 36 nucleotides, on average. In addition, the number of spacers in subtypes II-A and I-E varied between 1–24 and 3–16 spacers, respectively. The results also indicated that subtype II-A has nine protospacer adjacent motifs, which are 5′-CC-3′, 5′-GAA-3′, 5′-TGG-3′, 5′-CTT-3′, 5′-GGG-3′, 5′-CAT-3′, 5′-CTC-3′, 5′-CCT-3′, and 5′-CGG-3′. In addition, the identified systems displayed a potential for targeting Lactobacillus phages. The investigation of the relationship between the targeting of Lactobacillus phages by the antiphage system in L. plantarum species showed that subtype II-A had the highest diversity in targeting Lactobacillus phages than subtype I-E. In conclusion, current findings offer a perspective on the prevalence and evolution of the CRISPR-Cas system in L. plantarum, contributing novel insights to the expanding field of CRISPR-Cas systems within lactobacillus strains. This knowledge establishes a foundation for future applied studies focused on enhancing phage resistance in industrial fermentation, reducing contamination risks, and improving product quality. The identified targeting diversity may also foster advancements in phage therapy through the development of CRISPR-based antimicrobials.
A Bacillus subtilis strain with efficient algaecide of Microcystis aeruginosa and degradation of microcystins
Authors: Chen Yuanyuan , Xiong Fei , Zhu Ying , Zhai Dongdong , Liu Hongyan , Zhang Lin , Xia Ming
Published: November 2024

Global concerns over harmful cyanobacterial blooms brought on by eutrophication are now widespread. Aquatic ecological restoration techniques that use algicidal bacteria to control toxic algae show promise. A Bacillus subtilis S4 (S4) strain with strong Microcystis aeruginosa algicidal activity and the capacity to degrade microcystins (MCs) were successfully isolated and evaluated in this study. The dynamics of internal and extracellular MC concentration as well as the physiological response and morphological properties of M. aeruginosa were investigated in the M. aeruginosa/bacteria co-culture system. The findings demonstrated that when S4 density grew from 1 × 106 cells/ml to 1 × 108 cells/ml, the release of M. aeruginosa lysis and MCs was boosted; however, MCs dropped by approximately 90% within 18 h, regardless of bacterial density. Comparing the bacterial cell incubation system to the control and bacterial cell-free filtrate systems, the assessment of extracellular and intracellular MCs revealed a 95% reduction in MCs. The findings showed that 89% of MCs were decreased by bacterial cells, while 98% of M. aeruginosa cells were algaecided by bacterial metabolites. Sustainable eradication of M. aeruginosa and MCs has been accomplished by the combined efforts of the S4 strain and its metabolites. By secreting algicidal chemicals that are resistant to proteases, acid, base, and heat, the S4 strain indirectly acts as an algaecide. The S4 strain possesses a strong ability to break down MCs and a very effective and stable algaecide function, indicating that it can potentially treat eutrophic water with hazardous algae.
The bidirectional relationship between subjective visual function and domain-specific cognition in cognitively unimpaired older adults and adults with mild cognitive impairment
Authors: Dubois Abigail , Sergio Jordan , Mozdbar Sima , Price Ashley , Stradtman Megan , Thompson Louisa I. , Snyder Peter J. , Alber Jessica
Published: November 2024

Introduction

Subjective visual impairment (VI) is related to cognition in cognitively unimpaired (CU) older adults, mild cognitive impairment (MCI) patients, and Alzheimer’s disease (AD) patients. The utility of subjective VI as an indicator for domain-specific cognitive impairment is unknown.

Methods

We used the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25 item) and a neuropsychological battery to assess the relationship between subjective VI and domain-specific cognitive performance in CU older adults (N = 58) and MCI patients (N = 16).

Results

The CU group showed a positive relationship between subjective VI and visuospatial performance. CU older adults at high risk for AD demonstrated a unique relationship between subjective VI and attention, processing speed, and executive function. Peripheral vision was related to domain-specific performance in the patient group.

Discussion

Subjective VI complaints may indicate potential for domain-specific cognitive decline in visuospatial performance, executive function, processing speed, and attention in older adults.
Association between cardiometabolic index and biological aging in the US population: evidence from NHANES 2015–2020
Authors: Sun Miao , Bao Shuang
Published: November 2024

Purpose

It is crucial to identify biomarkers that influence the aging process and associated health risks, given the growing severity of the global population aging issue. The objectives of our research were to evaluate cardiac metabolic index (CMI) as a novel biomarker for identifying individuals at increased risk of accelerated biological aging and to assess its use in guiding preventive strategies for aging-related health risks.

Methods

The National Health and Nutrition Examination Survey (NHANES) provided cross-sectional data on participants with complete information on CMI, phenotypic age (PA), and other variables. Analyses of variance and weighted χ2 tests were conducted to assess differences between groups. The relationship between CMI and biological aging was investigated using a weighted multivariate logistic regression model, restricted cubic spline (RCS) regression analysis, subgroup analysis, and interaction testing.

Results

A positive correlation between CMI and biological aging was observed in 6,272 participants. RCS regression analysis confirmed the non-linear relationship, identifying significant inflection point at 1.10. In the crude or adjusted models, the OR (95% CI), for the highest group versus the reference were 3.608 (3.108, 4.188), 3.397 (2.920, 3.952), and 1.550 (1.299, 1.850), respectively, when categorizing CMI into different groups. Subgroup analyses and interaction tests indicate that the association between CMI and biological aging remained consistent across different subgroups. Gender, race, education level, marital status, poverty income ratio (PIR), drinking status and diabetes had an interaction with CMI in relation to biological aging.

Conclusion

An elevated CMI is linked to increased risk for biological aging. This relationship may inform more effective prevention and treatment strategies for biological aging in the future. CMI be integrated into routine health screenings or aging assessments by healthcare professionals.
Prognostic factors and surgical approaches in the analysis of primary central nervous system diffuse large B-cell lymphoma: a large population-based cohort study and external validation
Authors: Pan Zhibo , Huang Zhaoneng , Xing Zhenqiu , Yang Jianjing , Huang Shengwei , Zhang Yu
Published: November 2024

Introduction

This study aims to investigate prognostic indicators and assess surgical interventions’ impact on Primary central nervous system lymphoma-diffuse large B-cell lymphoma (PCNS-DLBCL) patients.

Methods

A comprehensive examination was performed on a group of 3,962 cases in the Surveillance, Epidemiology, and End Results (SEER) database, as well as 27 cases of PCNS-DLBCL from the First Affiliated Hospital of Wenzhou Medical University. The application of both univariate and multivariate Cox regression analyses facilitated the identification of significant risk factors associated with PCNS-DLBCL. Developing and verifying nomograms, the reliability of the nomogram was evaluated by C-index, ROC curve, calibration curve and decision curve analysis. Finally, by using Kaplan–Meier (KM) curves to assess the survival rates for PCNS-DLBCL patients.

Results

Age, gender, marital status, tumor location, HIV infection status, chemotherapy, and surgical scopes emerged as independent prognostic factors for overall survival (OS) in multivariate Cox regression analysis, whereas gender did not demonstrate significance as a factor for cancer-specific survival (CSS). The C-index, calibration curves, ROC curves, and DCA curves demonstrating strong reliability and practicality. KM analysis revealed significantly improved OS and CSS in patients who underwent surgical resection compared to those who received no surgery/biopsy, especially receiving subtotal resection (STR). In addition, among patients receiving chemotherapy, both STR and gross total resection (GTR) improved survival time compared to chemotherapy alone, particularly with STR. In the non-chemotherapy group, GTR potentially improved CSS, there was no notable disparity in OS between patients who underwent surgery and those who did not or received biopsy.

Conclusion

This study analyzed prognostic factors in PCNS-DLBCL patients, resulting in nomograms predicting 1-, 3-, and 5-year OS and CSS, which showed preferable performance. Combining different resection scopes with chemotherapy improved survival compared to chemotherapy alone, advocating for integrated treatment strategies. Surgery alone is not recommended based on our findings.