bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreased but persistent epigenetic age acceleration is associated with changes in T-cell subsets after initiation of highly active antiretroviral therapy in persons living with HIV
Authors: Sehl Mary E. , Breen Elizabeth Crabb , Shih Roger , Li Fengxue , Zhang Joshua , Langfelder Peter , Horvath Steve , Bream Jay H. , Duggal Priya , Martinson Jeremy , Wolinsky Steven M. , Martinez-Maza Otoniel , Ramirez Christina M. , Jamieson Beth D.
Published: May 2024

Introduction

Persons living with HIV (PLWH) experience the early onset of age-related illnesses, even in the setting of successful human immunodeficiency virus (HIV) suppression with highly active antiretroviral therapy (HAART). HIV infection is associated with accelerated epigenetic aging as measured using DNA methylation (DNAm)-based estimates of biological age and of telomere length (TL).

Methods

DNAm levels (Infinium MethylationEPIC BeadChip) from peripheral blood mononuclear cells from 200 PLWH and 199 HIV-seronegative (SN) participants matched on chronologic age, hepatitis C virus, and time intervals were used to calculate epigenetic age acceleration, expressed as age-adjusted acceleration residuals from 4 epigenetic clocks [Horvath’s pan-tissue age acceleration residual (AAR), extrinsic epigenetic age acceleration (EEAA), phenotypic epigenetic age acceleration (PEAA), and grim epigenetic age acceleration (GEAA)] plus age-adjusted DNAm-based TL (aaDNAmTL). Epigenetic age acceleration was compared for PLWH and SN participants at two visits: up to 1.5 years prior and 2–3 years after HAART (or equivalent visits). Flow cytometry was performed in PLWH and SN participants at both visits to evaluate T-cell subsets.

Results

Epigenetic age acceleration in PLWH decreased after the initiation of HAART but remained greater post-HAART than that in age-matched SN participants, with differences in medians of 6.6, 9.1, and 7.7 years for AAR, EEAA, and PEAA, respectively, and 0.39 units of aaDNAmTL shortening (all p < 0.001). Cumulative HIV viral load after HAART initiation was associated with some epigenetic acceleration (EEAA, PEAA, and aaDNAmTL), but even PLWH with undetectable HIV post-HAART showed persistent epigenetic age acceleration compared to SN participants (p < 0.001). AAR, EEAA, and aaDNAmTL showed significant associations with total, naïve, and senescent CD8 T-cell counts; the total CD4 T-cell counts were associated with AAR, EEAA, and PEAA (p = 0.04 to <0.001). In an epigenome-wide analysis using weighted gene co-methylation network analyses, 11 modules demonstrated significant DNAm differences pre- to post-HAART initiation. Of these, nine were previously identified as significantly different from pre- to post-HIV infection but in the opposite direction.

Discussion

In this large longitudinal study, we demonstrated that, although the magnitude of the difference decreases with HAART is associated with the cumulative viral load, PLWH are persistently epigenetically older than age-matched SN participants even after the successful initiation of HAART, and these changes are associated with changes in T-cell subsets.
Characteristics and analysis of static strain response on typical asphalt pavement using fiber Bragg grating sensing technology
Authors: Liu Hongfu , Chen Bo , Cao Zhonglu , Pan Qinxue , Huang Tuo , Lv Songtao , Qian Guoping
Published: May 2024

To study the real internal strain response of asphalt pavement and provide crucial data for optimizing pavement design. By burying the fiber grating sensors on site, the strain tests of four asphalt pavement structures under different working conditions were carried out, and the results showed that the static strain time curve is viscoelastic and conforms well to the Bugers model, and the fitting coefficient of determination is 0.98. The strain response of the asphalt surface courses of the four pavement structures under static load shows a double hump variation with the transverse position, with peaks occurring directly beneath the wheel load center. The transverse strain fluctuated between tension and compression, mirroring changes in the lateral position. While longitudinal strains, always tensile, were symmetrically aligned with the centerline of the longitudinal sensors, this pattern differed notably from that of the transverse sensors. In the base layers, the strain profile typically presented a single peak, located at the wheel gap, underscoring a critical area of stress concentration. Numerically, the peak strain of asphalt surface course is larger than that of base course. The most unfavorable loading position of the base course occurs at the wheel gap of the lower base course. The most adverse loading position of the surface course appears at the wheel load at the bottom of the upper or middle course. The research results can provide data support for improving the design method of asphalt pavement.
Orphan response regulator NnaR is critical for nitrate and nitrite assimilation in Mycobacterium abscessus
Authors: Simcox Breven S. , Rohde Kyle H.
Published: May 2024

Mycobacterium abscessus (Mab) is an opportunistic pathogen afflicting individuals with underlying lung disease such as Cystic Fibrosis (CF) or immunodeficiencies. Current treatment strategies for Mab infections are limited by its inherent antibiotic resistance and limited drug access to Mab in its in vivo niches resulting in poor cure rates of 30-50%. Mab’s ability to survive within macrophages, granulomas and the mucus laden airways of the CF lung requires adaptation via transcriptional remodeling to counteract stresses like hypoxia, increased levels of nitrate, nitrite, and reactive nitrogen intermediates. Mycobacterium tuberculosis (Mtb) is known to coordinate hypoxic adaptation via induction of respiratory nitrate assimilation through the nitrate reductase narGHJI. Mab, on the other hand, does not encode a respiratory nitrate reductase. In addition, our recent study of the transcriptional responses of Mab to hypoxia revealed marked down-regulation of a locus containing putative nitrate assimilation genes, including the orphan response regulator nnaR (nitrate/nitrite assimilation regulator). These putative nitrate assimilation genes, narK3 (nitrate/nitrite transporter), nirBD (nitrite reductase), nnaR, and sirB (ferrochelatase) are arranged contiguously while nasN (assimilatory nitrate reductase identified in this work) is encoded in a different locus. Absence of a respiratory nitrate reductase in Mab and down-regulation of nitrogen metabolism genes in hypoxia suggest interplay between hypoxia adaptation and nitrate assimilation are distinct from what was previously documented in Mtb. The mechanisms used by Mab to fine-tune the transcriptional regulation of nitrogen metabolism in the context of stresses e.g. hypoxia, particularly the role of NnaR, remain poorly understood. To evaluate the role of NnaR in nitrate metabolism we constructed a Mab nnaR knockout strain (MabΔnnaR) and complement (MabΔnnaR+C) to investigate transcriptional regulation and phenotypes. qRT-PCR revealed NnaR is necessary for regulating nitrate and nitrite reductases along with a putative nitrate transporter. Loss of NnaR compromised the ability of Mab to assimilate nitrate or nitrite as sole nitrogen sources highlighting its necessity. This work provides the first insights into the role of Mab NnaR setting a foundation for future work investigating NnaR’s contribution to pathogenesis.
Geological characteristics of early cretaceous volcanic rocks and analysis of metallogenic potential of uranium mineralization in Moganshan basin, northern Zhejiang province, China
Authors: Wang Xiaolong , Zhang Wengao , Cheng Shenghong , Wang Bo , Tang Yifei , Li Wei
Published: May 2024

The Moganshan Volcanic Basin is located in the northeastern section of the Ganhang volcanic-tectonic-uranium polymetallic metallogenic belt. To explore the uranium mineralization potential of these volcanic rocks, petrographic, elemental geochemical, zircon U-Pb chronology, and Sr-Nd-Pb isotope analyses were performed on the volcanic rocks in the Moganshan Basin. The results showed that the volcanic rocks within the Moganshan Basin were formed at 130.8 ± 2.0 Ma; In addition, they are Si-rich (SiO2 content of 72.98%–77.32%), alkali-rich (Na2O+ K2O, with ALK values of =7.15–9.74), and potassium-rich (K2O/Na2O content of 1.41–4.34), with light rare earth elements (Rb, Th Nd, Zr, and Hf). Further more, the volcanic rocks within the Moganshan Basin are deficient in Ba, Ta, Nb, and Sr, with a negative europium anomaly (δEu of 0.10–0.17), high ISr (0.71028–0.71160), low εNd(t) values (−6.43–5.77), and other characteristics. The geological characteristics of the volcanic rocks in the Moganshan Basin are the same as those of the volcanic rocks in eastern China, and the formation age is Early Cretaceous. The formation environment is intra-land extensional and tensional. The rock-forming material primarily originates from the upper crust and has a higher average uranium content than that in the Ganhang volcanic belt. Additionally, it is speculated that the Moganshan Volcanic Basin has good potential for uranium mineralization.
Type 2 diabetes mellitus related sarcopenia: a type of muscle loss distinct from sarcopenia and disuse muscle atrophy
Authors: Liu Zhenchao , Guo Yunliang , Zheng Chongwen
Published: May 2024

Muscle loss is a significant health concern, particularly with the increasing trend of population aging, and sarcopenia has emerged as a common pathological process of muscle loss in the elderly. Currently, there has been significant progress in the research on sarcopenia, including in-depth analysis of the mechanisms underlying sarcopenia caused by aging and the development of corresponding diagnostic criteria, forming a relatively complete system. However, as research on sarcopenia progresses, the concept of secondary sarcopenia has also been proposed. Due to the incomplete understanding of muscle loss caused by chronic diseases, there are various limitations in epidemiological, basic, and clinical research. As a result, a comprehensive concept and diagnostic system have not yet been established, which greatly hinders the prevention and treatment of the disease. This review focuses on Type 2 Diabetes Mellitus (T2DM)-related sarcopenia, comparing its similarities and differences with sarcopenia and disuse muscle atrophy. The review show significant differences between the three muscle-related issues in terms of pathological changes, epidemiology and clinical manifestations, etiology, and preventive and therapeutic strategies. Unlike sarcopenia, T2DM-related sarcopenia is characterized by a reduction in type I fibers, and it differs from disuse muscle atrophy as well. The mechanism involving insulin resistance, inflammatory status, and oxidative stress remains unclear. Therefore, future research should further explore the etiology, disease progression, and prognosis of T2DM-related sarcopenia, and develop targeted diagnostic criteria and effective preventive and therapeutic strategies to better address the muscle-related issues faced by T2DM patients and improve their quality of life and overall health.
Research on the cost allocation method of deep sea wind power considering carbon trading and green certificate trading
Authors: Xue Guiyuan , Niu Wenjuan , Chen Chen , Wu Yin , Zhu Xiaojun
Published: May 2024

Climate change imposes tighter limits on carbon emissions, which require the development of more green electricity. Deep sea wind power has the advantages of high wind energy density, high power generation utilization hours, no land occupation, and near to power load centers for easy on-site consumption, which lead to a broad market prospect. In the foreseeable future, deep sea wind power will usher in large-scale construction and development. The initial investment and construction cost of deep sea wind power is high, subsidies are gradually decreasing, and there is a lack of full life cycle economic analysis combined with various market policies, resulting in a lack of guidance for its investment and construction. In order to promote the development of deep sea wind power, relevant cost recovery mechanisms must be found. This paper proposes a system cost allocation method based on the comparative difference method and load similarity with consideration of the transformation and operation costs of thermal power, demand-side response, and energy storage; a cost allocation method based on carbon trading and green certificate trading income is proposed; and a time sequence optimization operation simulation model is established to maximize the deep sea wind power income. A case study is proposed for a 300 MW deep sea wind farm, the results show that the cost allocation method and cost allocation model proposed in this paper have a significant effect on wind power cost recovery, and the effectiveness of the proposed method and model is verified.
Absence of causative genetic association between Helicobacter pylori infection and glaucoma: a bidirectional two-sample mendelian randomization study
Authors: Zhang Yan , Huang Yihong , Wu Yuyu , Zhang Jinying , Chen Wanzhu , Xu Danfeng , Guo Maosheng
Published: May 2024

Background: While clinical research has indicated a potential link between Helicobacter pylori infection and the onset of glaucoma, the causality of this association remains uncertain due to the susceptibility of observational studies to confounding factors and reverse causation.

Methods: A comprehensive two-sample bidirectional Mendelian randomization (MR) analysis was conducted to assess the causal connection between H. pylori infection and glaucoma. Glaucoma was categorized into primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), and pseudo-exfoliation glaucoma (PEG). Various methods, including inverse variance weighted, MR-Egger regression, weighted median, and mode-based estimator, were employed for effect estimation and pleiotropy testing. To enhance result robustness, a sensitivity analysis was performed by excluding proxy single nucleotide polymorphisms.

Results: Genetic predisposition for H. pylori infection has no causal effect on glaucoma: (OR 1.00; 95% CI 0.95–1.06, p = 0.980), (OR 0.97; 95% CI 0.86–1.09, p = 0.550), and (OR 0.99; 95% CI 0.90–1.08, p = 0.766) with POAG, NTG, and PEG, respectively. An inverse MR showed no causal effect of POAG, NTG, and PEG on H. pylori infection (OR 1.01; 95% CI 0.97–1.05, p = 0.693), (OR 1.00; 95% CI 0.98–1.03, p = 0.804), and (OR 0.99; 95% CI 0.96–1.01, p = 0.363), respectively. Heterogeneity (p > 0.05) and pleiotropy (p > 0.05) analysis confirmed the robustness of MR results.

Conclusion: These results indicated that there was no genetic evidence for a causal link between H. pylori and glaucoma, suggesting that the eradication or prevention of H. pylori infection might not benefit glaucoma and vice versa.
Oral curcumin ameliorates acute murine campylobacteriosis
Authors: Heimesaat Markus M. , Mousavi Soraya , Lobo de Sá Fábia Daniela , Peh Elisa , Schulzke Jörg-Dieter , Bücker Roland , Kittler Sophie , Bereswill Stefan
Published: May 2024

Introduction

Human infections with the food-borne enteropathogen Campylobacter jejuni are responsible for increasing incidences of acute campylobacteriosis cases worldwide. Since antibiotic treatment is usually not indicated and the severity of the enteritis directly correlates with the risk of developing serious autoimmune disease later-on, novel antibiotics-independent intervention strategies with non-toxic compounds to ameliorate and even prevent campylobacteriosis are utmost wanted. Given its known pleiotropic health-promoting properties, curcumin constitutes such a promising candidate molecule. In our actual preclinical placebo-controlled intervention trial, we tested the anti-microbial and anti-inflammatory effects of oral curcumin pretreatment during acute experimental campylobacteriosis.

Methods

Therefore, secondary abiotic IL-10-/- mice were challenged with synthetic curcumin via the drinking water starting a week prior oral C. jejuni infection. To assess anti-pathogenic, clinical, immune-modulatory, and functional effects of curcumin prophylaxis, gastrointestinal C. jejuni bacteria were cultured, clinical signs and colonic histopathological changes quantitated, pro-inflammatory immune cell responses determined by in situ immunohistochemistry and intestinal, extra-intestinal and systemic pro-inflammatory mediator measurements, and finally, intestinal epithelial barrier function tested by electrophysiological resistance analysis of colonic ex vivo biopsies in the Ussing chamber.

Results and discussion

Whereas placebo counterparts were suffering from severe enterocolitis characterized by wasting symptoms and bloody diarrhea on day 6 post-infection, curcumin pretreated mice, however, were clinically far less compromised and displayed less severe microscopic inflammatory sequelae such as histopathological changes and epithelial cell apoptosis in the colon. In addition, curcumin pretreatment could mitigate pro-inflammatory innate and adaptive immune responses in the intestinal tract and importantly, rescue colonic epithelial barrier integrity upon C. jejuni infection. Remarkably, the disease-mitigating effects of exogenous curcumin was also observed in organs beyond the infected intestines and strikingly, even systemically given basal hepatic, renal, and serum concentrations of pro-inflammatory mediators measured in curcumin pretreated mice on day 6 post-infection. In conclusion, the anti-Campylobacter and disease-mitigating including anti-inflammatory effects upon oral curcumin application observed here highlight the polyphenolic compound as a promising antibiotics-independent option for the prevention from severe acute campylobacteriosis and its potential post-infectious complications.
Pan-cancer analysis predict that FAT1 is a therapeutic target and immunotherapy biomarker for multiple cancer types including non-small cell lung cancer
Authors: Ding Chen , Huang Hua , Wu Di , Chen Chen , Hua Yu , Liu Jinghao , Li Yongwen , Liu Hongyu , Chen Jun
Published: May 2024

FAT1, a substantial transmembrane protein, plays a pivotal role in cellular adhesion and cell signaling. Numerous studies have documented frequent alterations in FAT1 across various cancer types, with its aberrant expression being linked to unfavorable survival rates and tumor progression. In the present investigation, we employed bioinformatic analyses, as well as in vitro and in vivo experiments to elucidate the functional significance of FAT1 in pan-cancer, with a primary focus on lung cancer. Our findings unveiled FAT1 overexpression in diverse cancer types, including lung cancer, concomitant with its association with an unfavorable prognosis. Furthermore, FAT1 is intricately involved in immune-related pathways and demonstrates a strong correlation with the expression of immune checkpoint genes. The suppression of FAT1 in lung cancer cells results in reduced cell proliferation, migration, and invasion. These collective findings suggest that FAT1 has potential utility both as a biomarker and as a therapeutic target for lung cancer.
Determining diagnostic delays in Romanian multiple myeloma patients using the Aarhus statement
Authors: Irimia Ruxandra , Badelita Sorina , Barbu Sinziana , Cirlan Ioana Loredana , Zidaru Larisa , Coriu Daniel
Published: May 2024

Introduction

Multiple Myeloma (MM) is classified as one of the most challenging cancers to diagnose, and the hematological malignancy is associated with prolonged diagnostic delays. Although major steps have been made in the improvement of MM patient diagnosis and care, Romanian patients still face long diagnostic delays. Thus far, there have been no studies evaluating the factors associated with diagnostic errors in Romanian MM patients.

Methods

Using the Aarhus statement, we prospectively determined the diagnostic intervals for 103 patients diagnosed with MM at Fundeni Clinical Institute, between January 2022 and March 2023.

Results

Our data revealed that the main diagnostic delays are experienced during the “patient interval.” Patients spend a median of 162 days from the first symptom onset until the first doctor appointment. Bone pain is the most frequently reported symptom by patients (78.64%), but it leads to a medical-seeking behavior in only half of the reporting patients and results in a median delay of 191 days. The changes in routine lab tests are considered most worrisome for patients, leading to a medical appointment after a median of only 25 days. The median primary care interval was 70 days, with patients having an average of 3.7 medical visits until MM suspicion was first raised. The secondary care interval did not contribute to the diagnostic delays.

Discussion

Overall, the median diagnostic path for MM patients in Romania was more than 6 months, leading to a higher number of emergency presentations and myeloma-related end-organ damage.
Estuarine mangrove niches select cultivable heterotrophic diazotrophs with diverse metabolic potentials—a prospective cross-dialog for functional diazotrophy
Authors: Mondal Sumana , Biswas Biswajit , Chowdhury Rajojit , Sengupta Rudranil , Mandal Anup , Kotal Hemendra Nath , Giri Chayan Kumar , Ghosh Anjali , Saha Subhajit , Begam Mst Momtaj , Mukherjee Chandan , Das Ipsita , Basak Sandip Kumar , Mitra Ghosh Mahashweta , Ray Krishna
Published: May 2024

Introduction

Biological nitrogen fixation (BNF), an unparalleled metabolic novelty among living microorganisms on earth, globally contributes ~88-101 Tg N year−1 to natural ecosystems, ~56% sourced from symbiotic BNF while ~22-45% derived from free-living nitrogen fixers (FLNF). The success of symbiotic BNF is largely dependent on its interaction with host-plant, however ubiquitous environmental heterotrophic FLNFs face many limitations in their immediate ecological niches to sustain unhindered BNF. The autotrophic FLNFs like cyanobacteria and oceanic heterotrophic diazotrophs have been well studied about their contrivances acclimated/adapted by these organisms to outwit the environmental constraints for functional diazotrophy. However, FLNF heterotrophs face more adversity in executing BNF under stressful estuarine/marine/aquatic habitats.

Methods

In this study a large-scale cultivation-dependent investigation was accomplished with 190 NCBI accessioned and 45 non-accessioned heterotrophic FLNF cultivable bacterial isolates (total 235) from halophilic estuarine intertidal mangrove niches of Indian Sundarbans, a Ramsar site and UNESCO proclaimed World Heritage Site. Assuming ~1% culturability of the microbial community, the respective niches were also studied for representing actual bacterial diversity via cultivation-independent next-generation sequencing of V3-V4 rRNA regions.

Results

Both the studies revealed a higher abundance of culturable Gammaproteobacteria followed by Firmicutes, the majority of 235 FLNFs studied belonging to these two classes. The FLNFs displayed comparable selection potential in media for free nitrogen fixers and iron-oxidizing bacteria, linking diazotrophy with iron oxidation, siderophore production, phosphorus solubilization, phosphorus uptake and accumulation as well as denitrification.

Discussion

This observation validated the hypothesis that under extreme estuarine mangrove niches, diazotrophs are naturally selected as a specialized multidimensional entity, to expedite BNF and survive. Earlier metagenome data from mangrove niches demonstrated a microbial metabolic coupling among C, N, P, S, and Fe cycling in mangrove sediments, as an adaptive trait, evident with the co-abundant respective functional genes, which corroborates our findings in cultivation mode for multiple interrelated metabolic potential facilitating BNF in a challenging intertidal mangrove environment.
Association between gut microbiota and common overlapping gastrointestinal disorders: a bidirectional two-sample Mendelian randomization study
Authors: Huang Yuhan , Kang Zhen , He Yuhan , Qiu Yi , Song Yuhui , Liu Weiai
Published: May 2024

Background

The main functional gastrointestinal disorders (FGIDs) include functional dyspepsia (FD) and irritable bowel syndrome (IBS), which often present overlapping symptoms with gastroesophageal reflux disease (GERD), posing a challenge for clinical diagnosis and treatment. The gut microbiota is closely associated with FGIDs and GERD, although the causal relationship has not been fully elucidated. Therefore, we aimed to investigate the potential causal relationship using bidirectional two-sample Mendelian randomization (MR) analysis.

Materials and methods

The genetic data of the 211 gut microbiota were obtained from the MiBioGen consortium (N = 14,306, from phylum to genus level) and species level of gut microbiota were acquired from the Dutch Microbiome Project (N = 7,738). For FD and IBS, we utilized the FinnGen consortium, whereas, for GERD data analysis, we obtained the IEU OpenGWAS project. The inverse-variance weighted (IVW) method was used as the primary method to calculate causal effect values. Sensitivity analyses were also performed to confirm the robustness of the primary findings of the MR analyses. Moreover, a reverse MR analysis was conducted to assess the likelihood of reverse causality.

Results

Combining the results of the preliminary and sensitivity analyses, we identified that 8 gut microbial taxa were associated with FD. Genus Lachnospiraceae NK4A136 group (p = 3.63 × 10−3) and genus Terrisporobacter (p = 1.13 × 10−3) were strongly associated with FD. At the same time, we found that 8 gut microbial taxa were associated with IBS. Family Prevotellaceae (p = 2.44 × 10−3) and species Clostridium leptum (p = 7.68 × 10−3) display a robust correlation with IBS. In addition, 5 gut microbial taxa were associated with GERD using the IVW approach. In the reverse MR analysis, 2 gut microbial taxa were found to be associated with FD, 5 gut microbial taxa were found to be associated with IBS, and 21 gut microbial taxa were found to be associated with GERD.

Conclusion

The study reveals the potential causal effects of specific microbial taxa on FD, IBS, and GERD and may offer novel insights into the diagnosis and treatment of these conditions.
Study of hub nodes of transcription factor-target gene regulatory network and immune mechanism for type 2 diabetes based on chip analysis of GEO database
Authors: Xu Guangyu , Zhao Yuehan , Bai Yu , Lin Yan
Published: May 2024

Identification of novel therapeutic targets for type 2 diabetes is a key area of contemporary research. In this study, we screened differentially expressed genes in type 2 diabetes through the GEO database and sought to identify the key virulence factors for type 2 diabetes through a transcription factor regulatory network. Our findings may help identify new therapeutic targets for type 2 diabetes. Data pertaining to the humoral (whole blood) gene expression profile of diabetic patients were obtained from the NCBI’s GEO Datasets database and gene sets with differential expression were identified. Subsequently, the TRED transcriptional regulatory element database was integrated to build a gene regulatory network for type 2 diabetes. Functional analysis (GO-Analysis) and Pathway-analysis of differentially expressed genes were performed using the DAVID database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Finally, gene-disease correlation analysis was performed using the DAVID online annotation tool. A total of 236 pathogenic genes, four transcription factors related to the pathogenic genes, and 261 corresponding target genes were identified. A transcription factor-target gene regulatory network for type 2 diabetes was constructed. Most of the key factors of the transcription factor-target gene regulatory network for type 2 diabetes were found closely related to the immune metabolic system and the functions of cell proliferation and transformation.
The role of digestive system diseases in cerebrovascular disease: a comprehensive Mendelian randomization study
Authors: Qin Hao , Suo Shihuan , Yang Fan , Hao Pengfei , Zhang Xianfeng
Published: May 2024

Background

Cerebrovascular disease, among the most prevalent neurological disorders, poses a substantial threat to human health with its elevated mortality and disability rates, placing considerable strain on healthcare systems. Although several studies in recent years have suggested a potential association between digestive system diseases and cerebrovascular diseases, the findings remain inconsistent.

Methods

Genome-wide association study (GWAS) summary data for 12 digestive diseases and cerebrovascular diseases were used to conduct Mendelian randomization (MR) analysis. In this investigation, we endeavored to elucidate the causal relationship between digestive system diseases and cerebrovascular diseases. Employing a comprehensive approach, including two-sample MR (TSMR), multivariate MR (MVMR), and two-step MR analysis, we leveraged summary statistics data obtained from published GWAS. The primary analysis method employed was inverse variance weighted (IVW), with MR-Egger and weighted median (WM) as secondary methods. Sensitivity analysis included heterogeneity testing, horizontal multivariate testing, MR-PRESSO, and a “leave-one-out” method. Additionally, the F-statistic was utilized to assess the strength of instrumental variables, ensuring robust results.

Results

In the TSMR analysis, this study found a significant causal relationship between genetically predicted gastroesophageal reflux disease (GERD) and any stroke (AS), any ischemic stroke (AIS), large-artery atherosclerotic stroke (LAS), intracranial aneurysm (IA), and subarachnoid hemorrhage (SAH). In MVMR analysis, this study found that even after adjusting for systolic blood pressure (SBP), body mass index (BMI) and type 2 diabetes (T2D), the causal relationship remains exist. In the two-step MR mediation analysis, it was found that BMI, SBP and T2D play mediating role in the causal relationship between GERD and cerebrovascular diseases.

Conclusion

This study indicates a clear positive causal relationship between GERD and cerebrovascular diseases, and this causal association remains significant even after adjusting for BMI, SBP and T2D. The mediation MR analysis suggests that BMI, SBP and T2D may mediate the causal relationship between GERD and the risk of cerebrovascular diseases.
Bidirectional communication of the gut-brain axis: new findings in Parkinson’s disease and inflammatory bowel disease
Authors: Wanyi Zhang , Jiao Yan , Wen Huang , Bin Xu , Xuefei Wang , Lan Jiang , Liuyin Zhou
Published: May 2024

Parkinson’s disease (PD) and inflammatory bowel disease (IBD) are the two chronic inflammatory diseases that are increasingly affecting millions of people worldwide, posing a major challenge to public health. PD and IBD show similarities in epidemiology, genetics, immune response, and gut microbiota. Here, we review the pathophysiology of these two diseases, including genetic factors, immune system imbalance, changes in gut microbial composition, and the effects of microbial metabolites (especially short-chain fatty acids). We elaborate on the gut–brain axis, focusing on role of gut microbiota in the pathogenesis of PD and IBD. In addition, we discuss several therapeutic strategies, including drug therapy, fecal microbiota transplantation, and probiotic supplementation, and their potential benefits in regulating intestinal microecology and relieving disease symptoms. Our analysis will provide a new understanding and scientific basis for the development of more effective therapeutic strategies for these diseases.
Application value of MRI-guided wire localization to the non-palpable breast lesions only shown in Breast MRI
Authors: Ma Jiaqi , Hou Leina , Liang Xiufen , Yan Bin , Dai Qiang , Wang Yunmei , Gao Hongbian , Zhu Jiang , Song Canxu , Yuan Quan
Published: May 2024

Introduction

Magnetic resonance imaging (MRI)-guided wire localization can be applied to assist to remove suspected breast lesions accurately. This study aimed to evaluate the clinical application value of this technique in Chinese women.

Methods

A total of 126 patients (131 lesions) who had underwent such technique in our hospital from April 2017 to June 2023 were enrolled. 1.5T MRI system and a wire localization device were used. Image characteristics, clinical features and postoperative pathology were collected and analyzed.

Results

All of 126 patients (131 lesions) were successfully localized by MRI and excised for biopsy. There were 39 malignant lesions (29.77%) and 92 benign lesions (70.23%). There was no significant correlation between the morphology of DCE-MRI and the ratio of malignant lesions (P=0.763), while there was a statistical correlation between the BPE, TIC curve and the malignancy rate (P<0.05). All the lesions were assessed according to BI-RADS category of MRI (C4A=77, C4B=40, C4C=12, C5=2). The malignancy rates were as follows: 16.88% for 4A lesions (13/77), 37.50% for 4B lesions (15/40), 75.00% for 4C lesions (9/12) and 100% for 5 lesions (2/2). There was a significant correlation between the BI-RADS category and the incidence of benign-to-malignant lesions (P<0.001).

Conclusion

MRI-guided wire localization can assist to remove suspected breast lesions early, safely and accurately. This technique makes up for the deficiency of X-ray and ultrasound, improves the accuracy of diagnosis and resection therapy in intraductal carcinoma and early invasive carcinoma, and helps to improve the the prognosis of breast cancer.
Novel prognostic biomarkers in nasopharyngeal carcinoma unveiled by mega-data bioinformatics analysis
Authors: Tan Yishuai , Zhou Jiao , Liu Kai , Liu Ruowu , Zhou Jing , Wu Zhenru , Li Linke , Zeng Jiaqi , Feng Xuxian , Dong Biao , Du Jintao
Published: May 2024

Nasopharyngeal carcinoma (NPC) is commonly diagnosed at an advanced stage with a high incidence rate in Southeast Asia and Southeast China. However, the limited availability of NPC patient survival data in public databases has resulted in less rigorous studies examining the prediction of NPC survival through construction of Kaplan-Meier curves. These studies have primarily relied on small samples of NPC patients with progression-free survival (PFS) information or data from head and neck squamous cell carcinoma (HNSCC) studies almost without NPC patients. Thus, we coanalyzed RNA expression profiles in eleven datasets (46 normal (control) vs 160 tumor (NPC)) downloaded from the Gene Expression Omnibus (GEO) database and survival data provided by Jun Ma from Sun Yat-sen University. Then, differential analysis, gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and network analysis were performed using STRING database. After that, 2142 upregulated differentially expressed genes (DEGs) and 3857 downregulated DEGs were screened. Twenty-five of them were identified as hub genes, which were enriched in several pathways (cilium movement, extracellular matrix structural constituent, homologous recombination and cell cycle). Utilizing the comprehensive dataset we amassed from GEO database, we conducted a survival analysis of DEGs and subsequently constructed survival models. Seven DEGs (RASGRP2, MOCOS, TTC9, ARHGAP4, DPM3, CD37, and CD72) were identified and closely related to the survival prognosis of NPC. Finally, qRT-PCR, WB and IHC were performed to confirm the elevated expression of RASGRP2 and the decreased expression of TTC9, CD37, DPM3 and ARHGAP4, consistent with the DEG analysis. Conclusively, our findings provide insights into the novel prognostic biomarkers of NPC by mega-data bioinformatics analysis, which suggests that they may serve special targets in the treatment of NPC.
Stereotactic central/core ablative radiation therapy: results of a phase I study of a novel strategy to treat bulky tumor
Authors: Yang Jun , Lu Qiuxia , Qi Weihua , Kolb Ryann D. , Wang Lei , Li Yuan , Li Sida , Lin Yihui , Liu Jiayi , Mourad Waleed , MirkhaghaniHaghighi Farzaneh , Slavisa Tubin , Wu Xiaodong , You Wei-Ciang , Yang Eddy , Hanlon Alex , Zhu Alan , Yan Weisi
Published: May 2024

Purpose

Bulky tumor remains as a challenge to surgery, chemotherapy and conventional radiation therapy. Hence, in efforts to overcome this challenge, we designed a novel therapeutic paradigm via strategy of Stereotactic Central/Core Ablative Radiation Therapy (SCART).), which is based on the principles of SBRT (stereotactic body radiation therapy and spatially fractionated radiation therapy (SFRT). We intend to safely deliver an ablative dose to the core of the tumor and with a low dose at tumor edge. The purpose of the phase 1 study was to determine dose-limiting toxicities (DLT)s and the Maximum Tolerated Dose (MTD) of SCART.

Methods and materials

We defined a SCART-plan volume inside the tumor, which is proportional to the dimension of tumor. VMAT/Cyberknife technique was adopted. In the current clinical trial; Patients with biopsy proven recurrent or metastatic bulky cancers were enrolled. The five dose levels were 15 Gy X1, 15Gy X3, 18GyX3, 21GyX3 and 24GyX3, while keeping the whole tumor GTV’s border dose at 5Gy each fraction. There was no restriction on concurrent systemic chemotherapy agents.

Results

21 patients were enrolled and underwent SCART. All 21 patients have eligible data for study follow-up. Radiotherapy was well tolerated with all treatment completed as scheduled. The dose was escalated for two patients to 24GyX3. No grade 3 or higher toxicity was observed in any of the enrolled patients. The average age of patients was 66 years (range: 14–85) and 13 (62%) patients were male. The median SCART dose was 18Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.3 months (range: 1 - 25.6). The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.5% (SD: 40.89, p-value:0.009).

Conclusion

SCART was safely escalated to 24 GyX 3 fractions, which is the maximum Tolerated Dose (MTD) for SCART. This regimen will be used in future phase II trials.
Immunotherapy and stereotactic body radiotherapy for older patients with non-metastatic renal cancer unfit for surgery or decline nephrectomy: practical proposal by the International Geriatric Radiotherapy Group
Authors: Nguyen Nam P. , Chirila Monica-Emilia , Page Brandi R. , Vinh-Hung Vincent , Gorobets Olena , Mohammadianpanah Mohammad , Giap Huan , Arenas Meritxell , Bonet Marta , Lara Pedro Carlos , Kim Lyndon , Dutheil Fabien , Lehrman David , Montes Luis Zegarra , Tlili Ghassen , Dahbi Zineb , Loganadane Gokoulakrichenane , Blanco Sergio Calleja , Bose Satya , Natoli Elena , Li Eric , Mallum Abba , Morganti Alessio G.
Published: May 2024

The standard of care for non-metastatic renal cancer is surgical resection followed by adjuvant therapy for those at high risk for recurrences. However, for older patients, surgery may not be an option due to the high risk of complications which may result in death. In the past renal cancer was considered to be radio-resistant, and required a higher dose of radiation leading to excessive complications secondary to damage of the normal organs surrounding the cancer. Advances in radiotherapy technique such as stereotactic body radiotherapy (SBRT) has led to the delivery of a tumoricidal dose of radiation with minimal damage to the normal tissue. Excellent local control and survival have been reported for selective patients with small tumors following SBRT. However, for patients with poor prognostic factors such as large tumor size and aggressive histology, there was a higher rate of loco-regional recurrences and distant metastases. Those tumors frequently carry program death ligand 1 (PD-L1) which makes them an ideal target for immunotherapy with check point inhibitors (CPI). Given the synergy between radiotherapy and immunotherapy, we propose an algorithm combining CPI and SBRT for older patients with non-metastatic renal cancer who are not candidates for surgical resection or decline nephrectomy.
Ovarian carcinosarcoma is highly aggressive compared to other ovarian cancer histotypes
Authors: McFarlane Iona , Porter Joanna M. , Brownsell Elizabeth , Ghaoui Nidal , Connolly Kathryn C. , Herrington C. Simon , Hollis Robert L.
Published: May 2024

Background

Ovarian carcinosarcoma (OCS) is an unusual ovarian cancer type characterized by distinct carcinomatous and sarcomatous components. OCS has been excluded from many of the pan-histotype studies of ovarian carcinoma, limiting our understanding of its behavior.

Methods

We performed a multi-cohort cross-sectional study of characteristics and outcomes in ovarian cancer patients from Scotland (n=2082) and the Surveillance, Epidemiology and End Results Program (SEER, n=44946) diagnosed with OCS or one of the other major histotypes: high grade serous (HGSOC), endometrioid (EnOC), clear cell (CCOC), mucinous (MOC) or low grade serous ovarian carcinoma (LGSOC). Differences in overall survival were quantified using Cox regression models to calculate hazard ratios (HR).

Results

Across both cohorts, OCS patients were significantly older at diagnosis compared to all other histotypes (median age at diagnosis 69 and 67 in Scottish and SEER cohorts) and demonstrated the shortest survival time upon univariable analysis. Within the Scottish cohort, 59.3% and 16.9% of OCS patients presented with FIGO stage III and IV disease, respectively; this was significantly higher than in EnOC, CCOC or MOC (P<0.0001 for all), but lower than in HGSOC (P=0.004). Multivariable analysis accounting for other prognostic factors identified OCS as independently associated with significantly shorter survival time compared to HGSOC, EnOC, LGSOC and MOC in both the Scottish (multivariable HR vs OCS: HGSOC 0.45, EnOC 0.39, LGSOC 0.26, MOC 0.43) and SEER cohorts (multivariable HR vs OCS: HGSOC 0.59, EnOC 0.34, LGSOC 0.30, MOC 0.81). Within the SEER cohort, OCS also demonstrated shorter survival compared to CCOC (multivariable HR 0.63, 95% CI 0.58-0.68), but this was not replicated within the Scottish cohort (multivariable HR for CCOC: 1.05, 95% CI 0.74-1.51). Within early-stage disease specifically (FIGO I-II or SEER localized stage), OCS was associated with the poorest survival of all histotypes across both cohorts. In the context of late-stage disease (FIGO III-IV or SEER distant stage), OCS, MOC and CCOC represented the histotypes with poorest survival.

Conclusion

OCS is a unique ovarian cancer type that affects older women and is associated with exceptionally poor outcome, even when diagnosed at earlier stage. New therapeutic options are urgently required to improve outcomes.
Transcriptome analysis reveals molecular targets of erythrocyte invasion phenotype diversity in natural Plasmodium falciparum isolates from Cameroon
Authors: Ngoh Ines A. , Mane Karim , Manneh Jarra , Bojang Fatoumata , Jawara Aminata S. , Akenji Theresia N. , Anong Damian N. , D’Alessandro Umberto , Amambua-Ngwa Alfred
Published: May 2024

Further understanding of the molecular mediators of alternative RBC invasion phenotypes in endemic malaria parasites will support malaria blood-stage vaccine or drug development. This study investigated the prevalence of sialic acid (SA)-dependent and SA-independent RBC invasion pathways in endemic Plasmodium falciparum parasites from Cameroon and compared the schizont stage transcriptomes in these two groups to uncover the wider repertoire of transcriptional variation associated with the use of alternative RBC invasion pathway phenotypes. A two-color flow cytometry-based invasion-inhibition assay against RBCs treated with neuraminidase, trypsin, and chymotrypsin and deep RNA sequencing of schizont stages harvested in the first ex vivo replication cycle in culture were employed in this investigation. RBC invasion phenotypes were determined for 63 isolates from asymptomatic children with uncomplicated malaria. Approximately 80% of the isolates invaded neuraminidase-treated but not chymotrypsin-treated RBCs, representing SA-independent pathways of RBC invasion. The schizont transcriptome profiles of 16 isolates with invasion phenotypes revealed a total of 5,136 gene transcripts, with 85% of isolates predicted at schizont stages. Two distinct transcriptome profile clusters belonging to SA-dependent and SA-independent parasites were obtained by data reduction with principal component analysis. Differential analysis of gene expression between the two clusters implicated, in addition to the well-characterized adhesins, the upregulation of genes encoding proteins mediating merozoite organelle discharges as well as several conserved, virulent, merozoite-associated, and exported proteins. The latter majority have been shown to have structural and physiological relevance to RBC surface remodeling and immune evasion in malaria and thus have potential as anti-invasion targets.
Testing the reported long-term advantages of protein-fortified human milk in very low birth weight neonates
Authors: Biasini Augusto , Neri Erica , Stella Marcello , Malaigia Laura , Mariani Elisa , Rizzo Vittoria , Agostini Francesca
Published: May 2024

Preterm infants are at-risk for extrauterine growth restriction and downward percentile-crossing between birth and discharge. Increased energy and protein intake through fortification of human milk during the first weeks of life has been associated with improved short-term growth and better developmental outcomes. The aim of this study was to evaluate whether these benefits persist up to children school age. The study was designed as an observational study. During hospitalization, 22 very low birth weight preterm infants were fed with increasing protein fortification of human milk (protein supplemented group, PSG). As a control group (CG), 11 preterm infants were fed with standard nutrition regimen. At children school age (9–11 years), we assessed anthropometric data (weight, height, BMI), global health (renal function), and specific psychological outcomes (Child Behavior Checklist 6–18). A global homogeneity between CG and PSG groups emerged: we found no significant differences in weight, height, and BMI, nor in internalizing symptom outcomes (all ps > 0.05). However, mothers reported significantly higher externalizing symptoms for the PSG infants compared to CG infants. Therefore, neonatal enteral protein supplementation in very low birth weight preterm infants leads to no positive nor adverse consequences in long-term assessment, suggesting that benefits are restricted to the neonatal term and first years of age.