bluuebunny/crossref_metadata_2025 huggingface dataset:
High expression of SIGLEC7 may promote M2-type macrophage polarization leading to adverse prognosis in glioma patients
Authors: An Wenhao , Ren Changyuan , Yuan Lei , Qiu Zhiqiang , Wang Peishen , Cheng Yanwen , He Zi , Han Xinye , Li Shouwei , An Yihua
Published: August 2024

Introduction

Gliomas are the most common primary intracranial tumors, known for their high invasiveness and destructiveness. Sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC7) is present in various immune cells, especially macrophages, and significantly affects immune homeostasis and cancer cell response. However, research on the role and prognostic impact of SIGLEC7 in glioma patients is currently limited.

Methods

We utilized transcriptomic data from 702 glioma patients in The Cancer Genome Atlas (TCGA) and 693 glioma patients in the Chinese Glioma Genome Atlas (CGGA), along with clinical samples we collected, to comprehensively investigate the impact of SIGLEC7 on glioma expression patterns, biological functions, and prognostic value. We focused on its role in glioma-related immune responses and immune cell infiltration and analyzed its expression at the single-cell level. Finally, we validated the role of SIGLEC7 in gliomas through tissue and cell experiments.

Results

SIGLEC7 expression was significantly increased in glioma patients with malignant characteristics. Survival analysis indicated that glioma patients with high SIGLEC7 expression had significantly lower survival rates. Gene function analysis revealed that SIGLEC7 is primarily involved in immune and inflammatory responses and is strongly negatively correlated with tumor-associated immune regulation. Additionally, the expression of most immune checkpoints was positively correlated with SIGLEC7, and immune cell infiltration analysis clearly demonstrated a significant positive correlation between SIGLEC7 expression and M2 macrophage infiltration levels. Single-cell analysis, along with tissue and cell experiments, confirmed that SIGLEC7 enhances macrophage polarization towards the M2 phenotype, thereby promoting glioma invasiveness through the immunosuppressive effects of M2 macrophages. Cox regression analysis and the establishment of survival prediction models indicated that high SIGLEC7 expression is an unfavorable prognostic factor for glioma patients.

Discussion

High SIGLEC7 expression predicts poor prognosis in glioma patients and is closely associated with M2 macrophages in the tumor environment. In the future, SIGLEC7 may become a promising target for glioma immunotherapy.
Prognostic and clinicopathological value of systemic immune-inflammation index in patients with osteosarcoma: a meta-analysis
Authors: Wang Xiaoyan , Wu Zhong , Zhang Zongxin , Jiang Ziwei
Published: August 2024

Background

The efficiency of systemic immune-inflammation index (SII) in predicting prognosis of osteosarcoma (OSA) patients has been extensively analyzed, but no consistent findings are obtained. Therefore, this meta-analysis focused on identifying the precise prognostic value of SII for OSA.

Methods

We comprehensively searched electronic databases of PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) from inception to 24 February, 2024. Meanwhile, the efficiency of SII in predicting prognosis of OSA was evaluated by calculating pooled hazard ratios (HRs) as well as 95% confidence intervals (CIs). Additionally, the correlation of SII with the OSA clinicopathological characteristics was analyzed based on pooled odds ratios (ORs) and 95%CIs.

Results

Six studies with 1015 cases were enrolled into this work. According to the combined data, the higher SII was markedly related to poor overall survival (OS) (HR=2.01, 95%CI=1.30-3.09, p=0.002) and Enneking stage III (OR=2.21, 95%CI=1.11-4.39, p=0.024) of patients with OSA. Nonetheless, SII was not significantly related to gender, age, pathological fracture, tumor size, tumor location, tumor differentiation, and metastasis in patients with OSA.

Conclusions

In summary, the higher SII is markedly related to poor OS and advanced Enneking stage in OSA patients.

Systematic review registration

https://inplasy.com/inplasy-2024-7-0107/,

identifier INPLASY202470107.
The role of metabolic reprogramming in immune escape of triple-negative breast cancer
Authors: Bao Ruochen , Qu Hongtao , Li Baifeng , Cheng Kai , Miao Yandong , Wang Jiangtao
Published: August 2024

Triple-negative breast cancer (TNBC) has become a thorny problem in the treatment of breast cancer because of its high invasiveness, metastasis and recurrence. Although immunotherapy has made important progress in TNBC, immune escape caused by many factors, especially metabolic reprogramming, is still the bottleneck of TNBC immunotherapy. Regrettably, the mechanisms responsible for immune escape remain poorly understood. Exploring the mechanism of TNBC immune escape at the metabolic level provides a target and direction for follow-up targeting or immunotherapy. In this review, we focus on the mechanism that TNBC affects immune cells and interstitial cells through hypoxia, glucose metabolism, lipid metabolism and amino acid metabolism, and changes tumor metabolism and tumor microenvironment. This will help to find new targets and strategies for TNBC immunotherapy.
Formononetin inhibits IgE by huPlasma/PBMCs and mast cells/basophil activation via JAK/STAT/PI3-Akt pathways
Authors: Musa Ibrahim , Wang Zhen-Zhen , Yang Nan , Li Xiu-Min
Published: August 2024

Rationale

Food allergy is a prevalent disease in the U.S., affecting nearly 30 million people. The primary management strategy for this condition is food avoidance, as limited treatment options are available. The elevation of pathologic IgE and over-reactive mast cells/basophils is a central factor in food allergy anaphylaxis. This study aims to comprehensively evaluate the potential therapeutic mechanisms of a small molecule compound called formononetin in regulating IgE and mast cell activation.

Methods

In this study, we determined the inhibitory effect of formononetin on the production of human IgE from peripheral blood mononuclear cells of food-allergic patients using ELISA. We also measured formononetin’s effect on preventing mast cell degranulation in RBL-2H3 and KU812 cells using beta-hexosaminidase assay. To identify potential targets of formononetin in IgE-mediated diseases, mast cell disorders, and food allergies, we utilized computational modeling to analyze mechanistic targets of formononetin from various databases, including SEA, Swiss Target Prediction, PubChem, Gene Cards, and Mala Cards. We generated a KEGG pathway, Gene Ontology, and Compound Target Pathway Disease Network using these targets. Finally, we used qRT-PCR to measure the gene expression of selected targets in KU812 and U266 cell lines.

Results

Formononetin significantly decreased IgE production in IgE-producing human myeloma cells and PBMCs from food-allergic patients in a dose-dependent manner without cytotoxicity. Formononetin decreased beta-hexosaminidase release in RBL-2H3 cells and KU812 cells. Formononetin regulates 25 targets in food allergy, 51 in IgE diseases, and 19 in mast cell diseases. KEGG pathway and gene ontology analysis of targets showed that formononetin regulated disease pathways, primary immunodeficiency, Epstein-Barr Virus, and pathways in cancer. The biological processes regulated by formononetin include B cell proliferation, differentiation, immune response, and activation processes. Compound target pathway disease network identified NFKB1, NFKBIA, STAT1, STAT3, CCND1, TP53, TYK2, and CASP8 as the top targets regulated at a high degree by formononetin. TP53, STAT3, PTPRC, IL2, and CD19 were identified as the proteins mostly targeted by formononetin. qPCR validated genes of Formononetin molecular targets of IgE regulation in U266 cells and KU812 cells. In U266 cells, formononetin was found to significantly increase the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. In basophils KU812 cells, formononetin significantly increased the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK, TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R.

Conclusion

These findings comprehensively present formononetin’s mechanisms in regulating IgE production in plasma cells and degranulation in mast cells.
IL-2 and TCR stimulation induce expression and secretion of IL-32β by human T cells
Authors: Sanna Franziska Christine , Benešová Iva , Pervan Philip , Krenz Adriana , Wurzel Alexander , Lohmayer Robert , Mühlbauer Jasmin , Wöllner Amélie , Köhl Nina , Menevse Ayse Nur , Stamova Slava , Volpin Valentina , Beckhove Philipp , Xydia Maria
Published: August 2024

IL-32 expression is important for pathogen clearance but detrimental in chronic inflammation, autoimmunity, and cancer. T cells are major IL-32 producers in these diseases and key mediators of pathogen and tumor elimination but also autoimmune destruction. However, their contribution to IL-32 biology during immune responses is hardly understood due to several isoforms with divergent inflammatory properties. Here, we identified IL-32β as the predominant isoform in various T cell subsets of healthy individuals and breast cancer patients with the highest levels detected in intratumoral regulatory T cells. We show that IL-32β is induced by IL-2 but IL-32β release requires T Cell Receptor rather than IL2R stimulation. Using inhibitors of protein secretion pathways and serial (ultra)centrifugation of T cell supernatants, we demonstrate that T cells actively secrete IL-32β unconventionally, as a free protein and, to a minor degree, through exosomes. Thus, our data identify activated T cells as major IL-32β secretors in health and cancer.
Megalobrama amblycephala IL-22 attenuates Aeromonas hydrophila induced inflammation, apoptosis and tissue injury by regulating the ROS/NLRP3 inflammasome axis
Authors: Wang Zhensheng , Zhai Wenya , Liu Hong
Published: August 2024

Mammalian interleukin-22 (IL-22) attenuates organismal injury by inhibiting reactive oxygen species (ROS) and impeding the NLRP3 inflammasome activation. However, the role of fish IL-22 in this process remains unclear. We characterized MaIL-22, an IL-22 homolog in blunt snout bream (Megalobrama amblycephala). Despite its low sequence identity, it shares conserved structures and close evolutionary relationships with other teleost IL-22s. Furthermore, Aeromonas hydrophila (A. hydrophila) infection leads to tissue injury in M. amblycephala immune organs and concomitantly altered Mail-22 mRNA expression, suggesting that MaIL-22 was involved in the antimicrobial immune response. To explore MaIL-22’s biological functions, we produced recombinant MaIL-22 (rMaIL-22) protein and demonstrated it significantly enhanced the survival of M. amblycephala post-A. hydrophila infection. To unravel its protective mechanisms, we explored the ROS/NLRP3 inflammasome axis and its downstream signaling responses. The results showed that rMaIL-22 treatment significantly elevated antioxidant enzyme (T-SOD, CAT and GSH-PX) activities to inhibit MDA activity and scavenge ROS in visceral tissues. Meanwhile, rMaIL-22 impeded the activation of NLRP3 inflammasome by suppressing NLRP3 protein and mRNA expression. This indicated that rMaIL-22 contributed to inhibit A. hydrophila-induced activation of the ROS/NLRP3 inflammasome axis. Consistent with these findings, rMaIL-22 treatment attenuated the expression of proinflammatory cytokines (il-1β, tnf-α and il-6) and proapoptotic genes (caspase-3 and caspase-8) while promoting antiapoptotic genes (bcl-2b and mcl-1a) expression, ultimately mitigating tissue injury in visceral tissues. In conclusion, our research underscores MaIL-22’s key role in microbial immune regulation, offering insights for developing IL-22-targeted therapies and breeding programs.
Azithromycin targets the CD27 pathway to modulate CD27hi T-lymphocyte expansion and type-1 effector phenotype
Authors: Ansari Abdul Wahid , Jayakumar Manju Nidagodu , Ahmad Fareed , Venkatachalam Thenmozhi , Salameh Laila , Unnikannan Hema , Raheed Thesni , Mohammed Abdul Khader , Mahboub Bassam , Al-Ramadi Basel K. , Hamid Qutayba , Steinhoff Martin , Hamoudi Rifat
Published: August 2024

Macrolide antibiotic azithromycin is widely used in clinical practice to treat respiratory tract infections and inflammatory diseases. However, its mechanism of action is not fully understood. Given the involvement of the CD27 pathway in the pathophysiology of various T-lymphocyte-mediated inflammatory, autoimmune, and lymphoproliferative diseases, we examined the impact of AZM on CD27 regulation and potential consequences on CD4+ and CD8+ T-cell phenotypes. Using cellular immunology approaches on healthy donors’ peripheral blood mononuclear cells, we demonstrate AZM-mediated downregulation of surface CD27 expression as well as its extracellular release as soluble CD27. Notably, AZM-exposed CD27high (hi) cells were defective in their ability to expand compared to CD27intermediate (Int) and CD27low (lo) subsets. The defective CD27hi subset expansion was found to be associated with impaired cell proliferation and cell division. At the molecular level, the CD27hi subset exhibited lower mTOR activity than other subsets. Functionally, AZM treatment resulted in marked depletion of helper CD4+ (Th1) and cytotoxic CD8+ T-lymphocyte (Tc1)-associated CXCR3+CD27hi effector cells and inhibition of inflammatory cytokine IFN-γ production. These findings provide mechanistic insights on immunomodulatory features of AZM on T-lymphocyte by altering the CD27 pathway. From a clinical perspective, this study also sheds light on potential clinical benefits observed in patients on prophylactic AZM regimens against various respiratory diseases and opens avenues for future adjunct therapy against Th1- and Tc1-dominated inflammatory and autoimmune diseases.
Lymphatic system regulation of anti-cancer immunity and metastasis
Authors: Lei Pin-Ji , Fraser Cameron , Jones Dennis , Ubellacker Jessalyn M. , Padera Timothy P.
Published: August 2024

Cancer dissemination to lymph nodes (LN) is associated with a worse prognosis, increased incidence of distant metastases and reduced response to therapy. The LN microenvironment puts selective pressure on cancer cells, creating cells that can survive in LN as well as providing survival advantages for distant metastatic spread. Additionally, the presence of cancer cells leads to an immunosuppressive LN microenvironment, favoring the evasion of anti-cancer immune surveillance. However, recent studies have also characterized previously unrecognized roles for tumor-draining lymph nodes (TDLNs) in cancer immunotherapy response, including acting as a reservoir for pre-exhausted CD8+ T cells and stem-like CD8+ T cells. In this review, we will discuss the spread of cancer cells through the lymphatic system, the roles of TDLNs in metastasis and anti-cancer immune responses, and the therapeutic opportunities and challenges in targeting LN metastasis.
Circulating inflammatory cytokines and sarcopenia-related traits: a mendelian randomization analysis
Authors: Sun Aochuan , Liu Saiya , Yin Fen , Li Zhuangzhuang , Liu Zhengtang
Published: August 2024

Objective

To explore the causal relationships between 91 circulating inflammatory cytokines and sarcopenia-related traits (low hand grip strength, appendicular lean mass, and usual walking pace) by Mendelian randomized analysis.

Methods

Independent genetic variations of inflammatory cytokines and sarcopenia-related traits were selected as instrumental variables from publicly available genome-wide association studies (GWAS). The MR analysis was primarily conducted using the inverse variance-weighted (IVW) method. Sensitivity analyses included Steiger filtering and MR PRESSO, with additional assessments for heterogeneity and pleiotropy.

Results

The IVW method indicated a causal relationship between Vascular Endothelial Growth Factor A (VEGF-A) and low hand grip strength (OR = 1.05654, 95% CI: 1.02453 to 1.08956, P = 0.00046). Additionally, Tumor Necrosis Factor-beta (TNF-β) was found to have a causal relationship with appendicular lean mass (ALM) (β = 0.04255, 95% CI: 0.02838 to 0.05672, P = 3.96E-09). There was no evidence suggesting a significant causal relationship between inflammatory cytokines and usual walking pace.

Conclusion

Our research substantiated the causal association between inflammatory cytokines, such as VEGF-A and TNF-β, and sarcopenia. This finding may provide new avenues for future clinical treatments.
Pulmonary thromboembolism: a case report and misdiagnosis analysis of a 63-year-old female patient
Authors: Deng Yingli , Lai Jing , He Qingmin
Published: August 2024

This paper presents a case of a 63-year-old female patient who was initially misdiagnosed with mycoplasma pneumonia due to symptoms such as chest pain, hemoptysis, and fever, but was later confirmed to have pulmonary thromboembolism (PTE) through further examination. This case highlights the similarities between PTE and pneumonia in terms of symptoms, as well as the complexity of PTE diagnosis. The article provides a detailed description of the patient’s medical history, symptoms, examination process, and treatment outcomes. Furthermore, it discusses the possible reasons for the misdiagnosis, including insufficient awareness of PTE among physicians, lack of in-depth investigation into the causes of abnormally elevated D-dimer levels, the non-specific clinical manifestations of PTE, and the concerns of the patient’s family regarding pulmonary artery CTA examination. Additionally, the article emphasizes the importance of clinicians in improving their ability to differentiate and diagnose PTE, rationally utilizing clinical examination methods, and ensuring timely diagnosis and treatment of PTE.
Prevalence of undetected chronic kidney disease in high-risk middle-aged patients in primary care: a cross-sectional study
Authors: Siebenhofer Andrea , Loder Christine , Avian Alexander , Platzer Elisabeth , Zipp Carolin , Mauric Astrid , Spary-Kainz Ulrike , Berghold Andrea , Rosenkranz Alexander R.
Published: August 2024

Introduction

The global health burden of chronic kidney disease (CKD) results from both the disease itself and the numerous health problems associated with it. The aim of this study was to estimate the prevalence of previously undetected CKD in middle-aged patients with risk factors for CKD. Identified patients were included in the Styrian nephrology awareness program “kidney.care 2.0” and data on their demographics, risk factors and kidney function were described.

Methods

Cross-sectional analysis of baseline data derived from the “kidney.care 2.0” study of 40–65 year old patients with at least one risk factor for CKD (hypertension, diabetes, cardiovascular disease, obesity or family history of end-stage kidney disease). Participants were considered to have previously undetected CKD if their estimated glomular filtration rate (eGFR) was less than 60 ml/min/1.73 m2 and/or albumin creatinine ratio (ACR) ≥ 30 mg/g. We calculated the prevalence of previously undetected CKD and performed multivariate analyses.

Results

A total of 749 participants were included in this analysis. The prevalence of previously undetected CKD in an at-risk population was estimated at 20.1% (95%CI: 17.1–23.6). Multivariable analysis showed age (OR 1.06, 95%CI: 1.02–1.09), diabetes mellitus (OR 1.65, 95%CI: 1.12–2.30) and obesity (OR: 1.55, 95%CI: 1.04–2.30) to be independent predictors of CKD. The majority of patients with previously undetected CKD had category A2-A3 albuminuria (121 out of 150). Most patients with previously undetected eGFR < 60 ml/min/1.73 m2 were in stage G3 (36 out of 39 patients).

Discussion

Pragmatic, targeted, risk-based screening for CKD in primary care successfully identified a significant number of middle-aged patients with previously undetected CKD and addressed the problem of these patients being overlooked for future optimized care. The intervention may slow progression to kidney failure and prevent related cardiovascular events.
Correlation between ZJU index and hepatic steatosis and liver fibrosis in American adults with NAFLD
Authors: Luo Shuang , Weng Xiaolu , Xu Jing , Lin Hao
Published: August 2024

Background

ZJU index, a novel calculation combining blood glucose, body mass index (BMI), lipids and liver functions, is closely related with non-alcoholic fatty liver disease (NAFLD). However, the correlation between ZJU index and hepatic steatosis and liver fibrosis has not been reported in the studies. This study aims to examine the correlation between these variables.

Methods

Data from the 2017–2020 NHANES were collected for a cross-sectional study, to explore the linear relationship between ZJU, liver stiffness measurements (LSM) and controlled attenuation parameters (CAP) with multivariate linear regression models. Restricted cubic spline (RCS) regression and threshold effect analyses were utilized to describe the nonlinear relationship. The correlation in subgroups was analyzed based on race, gender, drinking, age, BMI, diabetes and moderate activities.

Results

In this population-based study, a total of 2,122 adults aged 18–80 years old with NAFLD were included. According to the multivariate linear regression analysis, ZJU had a significant positive correlation with liver fibrosis (LSM, β = 0.182, 95%CI = 0.154–0.211, p < 0.001) and hepatic steatosis (CAP, β = 2.35, 95%CI = 2.14–2.56, p < 0.001), which was stronger in males. According to the RCS analysis, an inverted L-shaped relationship between ZJU and CAP (inflection point at 60.56) and a J-shaped relationship between ZJU index and LSM (inflection point at 51.27) were observed.

Conclusion

ZJU had a positive correlation with CAP and LSM in American adults with NAFLD. The findings suggest that ZJU may be a valuable biomarker for assessing the severity of liver fibrosis and hepatic steatosis in individuals with NAFLD.
Imaging findings of inflammatory myofibroblastic tumor of sigmoid colon: literature review and case report
Authors: Hu Xianwen , Zhao Wei , Yu Ronghua , Wang Pan
Published: August 2024

Inflammatory myofibroblastic tumor (IMT) is an intermediate tumor composed of differentiated myofibroblastic spindle cells with inflammatory cell infiltration. It can occur in all parts of the body, with the lungs being the most common, while the tissues outside the lungs, including the sigmoid colon, are rare. Herein, we present a case of a 10-year-old girl with sigmoid IMT who presented to our hospital with abdominal pain. An abdominal computed tomography (CT) revealed a well-defined, slightly low-density mass in her lower abdomen that was not clearly demarcated from the sigmoid colon. The mass showed significant uneven enhancement on contrast-enhanced CT and increased fluorine-18 fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography (PET). Moreover, a systematic review of the published literature on sigmoid IMT was conducted and its clinical and radiographic features were summarized to increase the understanding of this rare disease.
TetR-like regulator BP1026B_II1561 controls aromatic amino acid biosynthesis and intracellular pathogenesis in Burkholderia pseudomallei
Authors: McMillan Ian A. , Norris Michael H. , Heacock-Kang Yun , Zarzycki-Siek Jan , Sun Zhenxin , Hartney Brooke A. , Filipowska Liliana K. , Islam M. Nurul , Crick Dean C. , Borlee Bradley R. , Hoang Tung T.
Published: August 2024

Burkholderia pseudomallei (Bp) causes the tropical disease melioidosis that afflicts an estimated 165,000 people each year. Bp is a facultative intracellular pathogen that transits through distinct intracellular stages including attachment to host cells, invasion through the endocytic pathway, escape from the endosome, replication in the cytoplasm, generation of protrusions towards neighboring cells, and host cell fusion allowing Bp infection to spread without exiting the intracellular environment. We have identified a TetR-like transcriptional regulator, BP1026B_II1561, that is up-regulated during the late stages of infection as Bp protrudes toward neighboring cells. We have characterized BP1026B_II1561 and determined that it has a role in pathogenesis. A deletional mutant of BP1026B_II1561 is attenuated in RAW264.7 macrophage and BALB/c mouse models of infection. Using RNA-seq, we found that BP1026B_II1561 controls secondary metabolite biosynthesis, fatty acid degradation, and propanoate metabolism. In addition, we identified that BP1026B_II1561 directly controls expression of an outer membrane porin and genes in the shikimate biosynthetic pathway using ChIP-seq. Transposon mutants of genes within the BP1026B_II1561 regulon show defects during intracellular replication in RAW264.7 cells confirming the role of this transcriptional regulator and the pathways it controls in pathogenesis. BP1026B_II1561 also up-regulates the majority of the enzymes in shikimate and tryptophan biosynthetic pathways, suggesting their importance for Bp physiology. To investigate this, we tested fluorinated analogs of anthranilate and tryptophan, intermediates and products of the shikimate and tryptophan biosynthetic pathways, respectively, and showed inhibition of Bp growth at nanomolar concentrations. The expression of these pathways by BP1026b_II1561 and during intracellular infection combined with the inhibition of Bp growth by fluorotryptophan/anthranilate highlights these pathways as potential targets for therapeutic intervention against melioidosis. In the present study, we have identified BP1026B_II1561 as a critical transcriptional regulator for Bp pathogenesis and partially characterized its role during host cell infection.
Computational insights into the mechanisms underlying structural destabilization and recovery in trafficking-deficient hERG mutants
Authors: AlRawashdeh Sara , Mosa Farag E. S. , Barakat Khaled H.
Published: August 2024

Cardiovascular diseases are a major global health concern, responsible for a significant number of deaths each year, often linked to cardiac arrhythmias resulting from dysfunction in ion channels. Hereditary Long QT Syndrome (LQTS) is a condition characterized by a prolonged QT interval on ECG, increasing the risk of sudden cardiac death. The most common type of LQTS, LQT2, is caused by mutations in the hERG gene, affecting a potassium ion channel. The majority of these mutations disrupt the channel’s trafficking to the cell membrane, leading to intracellular retention. Specific high-affinity hERG blockers (e.g., E-4031) can rescue this mutant phenotype, but the exact mechanism is unknown. This study used accelerated molecular dynamics simulations to investigate how these mutations affect the hERG channel’s structure, folding, endoplasmic reticulum (ER) retention, and trafficking. We reveal that these mutations induce structural changes in the channel, narrowing its central pore and altering the conformation of the intracellular domains. These changes expose internalization signals that contribute to ER retention and degradation of the mutant hERG channels. Moreover, the study found that the trafficking rescue drug E-4031 can inhibit these structural changes, potentially rescuing the mutant channels. This research offers valuable insights into the structural issues responsible for the degradation of rescuable transmembrane trafficking mutants. Understanding the defective trafficking structure of the hERG channel could help identify binding sites for small molecules capable of restoring proper folding and facilitating channel trafficking. This knowledge has the potential to lead to mechanism-based therapies that address the condition at the cellular level, which may prove more effective than treating clinical symptoms, ultimately offering hope for individuals with hereditary Long QT Syndrome.
Isoflurane conditioning improves functional outcomes after peripheral nerve injury in a sciatic cut repair murine model
Authors: Xu Yameng , Yan Ying , Zipfel Gregory J. , MacEwan Matthew , Ray Wilson Z. , Athiraman Umeshkumar
Published: August 2024

Introduction

Anesthetic conditioning has been shown to provide neuroprotection in several neurological disorders. Whether anesthetic conditioning provides protection against peripheral nerve injuries remains unknown. The aim of our current study is to investigate the impact of isoflurane conditioning on the functional outcomes after peripheral nerve injury (PNI) in a rodent sciatic nerve injury model.

Methods

Adult male Lewis rats underwent sciatic nerve cut and repair and exposed to none (Group 1, sham), single isoflurane exposure (Group 2), three-time isoflurane exposure (Group 3), and six-time isoflurane exposure (Group 4). Isoflurane conditioning was established by administration of 2% isoflurane for 1 hour, beginning 1-hour post sciatic nerve cut and repair. Groups 3 and 4 were exposed to isoflurane for 1 hour, 3 and 6 consecutive days respectively. Functional outcomes assessed included compound muscle action potential (CMAP), evoked muscle force (tetanic and specific tetanic force), wet muscle mass, and axonal counting.

Results

We observed an increase in axons, myelin width and a decrease in G-ratio in the isoflurane conditioning groups (3- and 6-days). This correlated with a significant improvement in tetanic and specific tetanic forces, observed in both groups 3 and 4.

Discussion

Isoflurane conditioning (3- and 6-day groups) resulted in improvement in functional outcomes at 12 weeks post peripheral nerve injury and repair in a murine model. Future experiments should be focused on identifying the therapeutic window of isoflurane conditioning and exploring the underlying molecular mechanisms responsible for isoflurane conditioning induced neuroprotection in PNI.
Targeting transcription factor pu.1 for improving neurologic outcomes after spinal cord injury
Authors: Shi Yi , Zheng Meige , Luo Yang , Li Jianjian , Ouyang Fangru , Zhao Yuanzhe , Wang Jingwen , Ma Zhida , Meng Congpeng , Bi Yihui , Cheng Li , Jing Juehua
Published: August 2024

Background

After spinal cord injury (SCI), lipid metabolism dysregulation at the lesion site exacerbates secondary damage. The transcription factor pu.1 has been implicated as a negative regulator of multiple lipid metabolism-related genes and pathways. However, its role in post-SCI lipid metabolism remains unclear.

Methods

We employed a mouse model of complete T10 crush SCI. Non-targeted metabolomics and bioinformatics analysis were utilized to investigate lipid metabolism at the lesion site after SCI. Polarized light imaging was used to evaluate the presence of cholesterol crystals. DB1976, a specific inhibitor of pu.1, was administered to examine its impact on local lipid metabolism after SCI. Immunofluorescence staining was performed to assess pu.1 expression and distribution, and to evaluate lipid droplet formation, astrocytic/fibrotic scar development, inflammatory cell infiltration, and tight junctions within the vasculature.

Results

Non-targeted metabolomics and bioinformatics analyses revealed significant alterations in lipid metabolism components after SCI. Moreover, immunofluorescence staining and polarized light imaging demonstrated substantial BODIPY+ lipid droplet accumulation and persistent cholesterol crystal formation at the lesion site after SCI. Increased pu.1 expression was predominantly observed within macrophages/microglia at the lesion site after SCI. DB1976 treatment significantly mitigated lipid droplet accumulation and cholesterol crystal formation, reduced CD68+ macrophage/microglial infiltration, and attenuated fibrotic scar formation. Moreover, DB1976 treatment promoted the expression of claudin-5 and zonula occludens-1 between vascular endothelial cells and enhanced GFAP+ glial connectivity after SCI.

Conclusion

Our study reveals a significant correlation between lipid metabolism disturbance post-SCI and transcription factor pu.1 upregulation, specifically in macrophages/microglia at the lesion site. Thus, targeted pu.1 modulation has the potential to yield promising results by substantially diminishing the deposition of lipid metabolism byproducts at the lesion site and fostering a milieu conducive to SCI repair.
Determinants of severe acute malnutrition among under-five children in Ethiopia: analysis using data from the 2016 Ethiopia Demographic and Health Survey
Authors: Areba Abriham Shiferaw , Abame Desta Erkalo , Tirore Lire Lemma , Bubamo Bisrat Feleke
Published: August 2024

Objective

Malnutrition is a silent killer that is under-reported, under-addressed, and, as a result, emphasized. This study aimed to identify the determinants of severe acute malnutrition (SAM) among under-five children in Ethiopia.

Methods

Cross-sectional data from the 2016 Ethiopian Demographic and Health Survey (EDHS) were used. A total of 6,170 under-five children were included in the current analysis. The data were cleaned and analyzed using STATA 14. An adjusted odds ratio (AOR) and their 95% confidence intervals (CIs) were calculated to determine the association between factors and outcomes. A p-value of less than 0.05 was considered significant in multivariable logistic regression.

Results

A multivariable logistic regression revealed that under-five children with the age of children in months 6–11 (AOR = 1.52, 95% CI: 1.25, 1.86), 12–23 (AOR = 1.98, 95% CI: 1.65, 2.37), and 24–59 months (AOR = 1.71, 95% CI: 1.40, 2.08), birth order between fourth and fifth (AOR = 1.24, 95% CI: 1.01, 1.54), having fever (AOR = 1.31, 95% CI: 1.09, 1.58), anemic children (AOR = 1.21, 95% CI: 1.07, 1.36), age of mothers in years 25–34 (AOR = 0.60, 95% CI: 0.51, 0.72) and 35–49 (AOR = 0.49, 95% CI: 0.39, 0.63), antenatal care (ANC) visits (AOR = 0.83, 95% CI: 0.71, 0.92), rural residence (AOR = 2.98, 95% CI: 2.54, 3.49), and solid fuels users (AOR = 2.46, 95% CI: 1.86, 3.26) were significant predictors.

Conclusion

Older age of children, those with higher birth order, those having fever, anemic children, those living in rural areas, and solid fuel users were more likely to suffer from SAM, while older mothers and those having ANC visits had reduced SAM as significant predictors.
Preliminary study on DCE-MRI radiomics analysis for differentiation of HER2-low and HER2-zero breast cancer
Authors: Yin Liang , Zhang Yun , Wei Xi , Shaibu Zakari , Xiang Lingling , Wu Ting , Zhang Qing , Qin Rong , Shan Xiuhong
Published: August 2024

Purpose

This study aims to evaluate the utility of radiomic features from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in distinguishing HER2-low from HER2-zero breast cancer.

Patients and methods

We retrospectively analyzed 118 MRI cases, including 78 HER2-low and 40 HER2-zero patients confirmed by immunohistochemistry or fluorescence in situ hybridization. From each DCE-MRI case, 960 radiomic features were extracted. These features were screened and reduced using intraclass correlation coefficient, Mann-Whitney U test, and least absolute shrinkage to establish rad-scores. Logistic regression (LR) assessed the model’s effectiveness in distinguishing HER2-low from HER2-zero. A clinicopathological MRI characteristic model was constructed using univariate and multivariate analysis, and a nomogram was developed combining rad-scores with significant MRI characteristics. Model performance was evaluated using the receiver operating characteristic (ROC) curve, and clinical benefit was assessed with decision curve analysis.

Results

The radiomics model, clinical model, and nomogram successfully distinguished between HER2-low and HER2-zero. The radiomics model showed excellent performance, with area under the curve (AUC) values of 0.875 in the training set and 0.845 in the test set, outperforming the clinical model (AUC = 0.691 and 0.672, respectively). HER2 status correlated with increased rad-score and Time Intensity Curve (TIC). The nomogram outperformed both models, with AUC, sensitivity, and specificity values of 0.892, 79.6%, and 82.8% in the training set, and 0.886, 83.3%, and 90.9% in the test set.

Conclusions

The DCE-MRI-based nomogram shows promising potential in differentiating HER2-low from HER2-zero status in breast cancer patients.
Re-examining the role of hematopoietic stem cell transplantation in relapsed large B-cell lymphoma in the era of chimeric antigen receptor (CAR) T-cell therapy
Authors: Moyo Tamara K. , Vaidya Rakhee
Published: August 2024

Historically, salvage chemoimmunotherapy with consolidative autologous hematopoietic stem cell transplantation (ASCT) was the only potentially curative therapeutic option for patients with relapsed/refractory large B-cell lymphoma (LBCL). Treatment options were few and outcomes poor for patients whose lymphoma failed to respond to salvage chemotherapy/ASCT and for patients not eligible for ASCT. The approval of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory LBCL revolutionized the treatment landscape with unprecedented response rates and durability of responses. As a result, earlier intervention with CAR T-cell therapy has been explored, and the enthusiasm for CAR T-cell therapy has overshadowed ASCT. In this article, we will review the data available for ASCT and CAR T-cell therapy in relapsed LBCL and will examine the role for ASCT in relapsed/refractory LBCL in the era of CAR T-cell therapy.
To cut or not to cut – that is the question: a comparative analysis of long-term follow-up after complete and incomplete electroconization of the cervix due to high-grade squamous intraepithelial lesion
Authors: Suchońska Barbara E. , Gajewska Małgorzata E. , Blok Joanna M.
Published: August 2024

Introduction

Electroconization of the uterine cervix (LEEP/LLETZ) is an appropriate and sufficient procedure for high-grade squamous epithelial lesion – HSIL. Negative margins are considered fundamental for confirming the absence of residual disease. Further management after incomplete excision among women who have not completed their procreative plans is difficult because subsequent cervical procedures may cause issues with carrying a pregnancy to term. Since almost one-third of the untreated patients with HSIL will develop cervical carcinoma, it is essential to balance the desire to radicalize treatment with its obstetric consequences. We compared the further clinical course of the patients after complete and incomplete procedures to observe whether completeness of excision is necessary for a successful outcome. We aim to identify risk factors that influence persistent or recurrent HSIL.

Methods

The study has comprised 781 patients aged 18-85 – the research group was composed of 140 (17.93%) patients after incomplete conization and the control group of 641 (82.17%) patients after the complete one. Patients were scheduled for follow-up examinations every 6 months – including cytology, HPV typing, and colposcopy with tissue sampling. The Chi-square test or Fisher’s exact test was performed as a tool for group comparisons for variables on the qualitative scale. Univariable and multivariable logistic regression models have been used to determine factors associated with the risk of persistent or recurrent HSIL. To evaluate the discriminatory ability of the logistic regression models, the Area Under the Curve (AUC) was calculated.

Results

The statistical analysis results don’t indicate a statistical significance between the frequency of HSIL in groups. HPV infection has increased the risk of persistent/recurrent lesions by 38 times, constituting the most important factor.

Discussion

Close follow-up instead of inconsiderate repeat procedures should be taken under consideration among patients of reproductive age after incomplete conization of the cervix. HPV typing may be an essential method to predict recurrent cervical dysplasia. Promoting HPV typing and vaccination can reduce the number of invasive procedures and improve quality of life and obstetrics outcomes.
Understanding the impact of radiotherapy fractionation on overall survival in a large head and neck squamous cell carcinoma dataset: a comprehensive approach combining mechanistic and machine learning models
Authors: Shuryak Igor , Wang Eric , Brenner David J.
Published: August 2024

Introduction

Treating head and neck squamous cell carcinomas (HNSCC), especially human papillomavirus negative (HPV-) and locally advanced cases, remains difficult. Our previous analyses of radiotherapy-only HNSCC clinical trials data using mechanistically-motivated models of tumor repopulation and killing by radiotherapy predicted that hyperfractionation with twice-daily fractions, or hypofractionation involving increased doses/fraction and reduced treatment durations, both improve tumor control and reduce late normal tissue toxicity, compared with standard protocols using 35×2 Gy. Here we further investigated the validity of these conclusions by analyzing a large modern dataset on 3,346 HNSCC radiotherapy patients from the University Health Network in Toronto, Canada, where 42.5% of patients were also treated with chemotherapy.

Methods

We used a two-step approach that combines mechanistic modeling concepts with state-of-the-art machine learning, beginning with Random Survival Forests (RSF) for an exploratory analysis and followed by Causal Survival Forests (CSF) for a focused causal analysis. The mechanistic concept of biologically effective dose (BED) was implemented for the standard dose-independent (DI) tumor repopulation model, our alternative dose-dependent (DD) repopulation model, and a simple model with no repopulation (BEDsimp). These BED variants were included in the RSF model, along with age, stage, HPV status and other relevant variables, to predict patient overall survival (OS) and cause-specific mortality (deaths from the index cancer, other cancers or other causes).

Results

Model interpretation using Shapley Additive Explanations (SHAP) values and correlation matrices showed that high values of BEDDD or BEDDI, but not BEDsimp, were associated with decreased patient mortality. Targeted causal inference analyses were then performed using CSF to estimate the causal effect of each BED variant on OS. They revealed that high BEDDD (>61.8 Gy) or BEDDI (>57.6 Gy), but not BEDsimp, increased patient restricted mean survival time (RMST) by 0.5-1.0 years and increased survival probability (SP) by 5-15% several years after treatment. In addition to population-level averages, CSF generated individual-level causal effect estimates for each patient, facilitating personalized medicine.

Discussion

These findings are generally consistent with those of our previous mechanistic modeling, implying the potential benefits of altered radiotherapy fractionation schemes (e.g. 25×2.4 Gy, 20×2.75 Gy, 18×3.0 Gy) which increase BEDDD and BEDDI and counteract tumor repopulation more effectively than standard fractionation. Such regimens may represent potentially useful hypofractionated options for treating HNSCC.
Effects of dance sports exercise on vestibular function and balance of children with sensorineural hearing loss; a randomized quasi-experimental trial
Authors: Hu Fang , Qiu Xuan , Wu Xinbo , Wu Xilong , Li Han , Kim Sukwon
Published: August 2024

Background

Sensorineural hearing loss (SNHL) children have difficulty living and limited movement due to impaired vestibular function and reduced balance ability.

Objectives

The present study evaluated the effects of Latin dance training on the vestibular function and balance of SNHL children.

Methods

Thirty SNHL children with no difference in vestibular function and balance ability were randomly divided into two groups, the Latin dance training group (LTG, n = 15) and the control group (CONG, n = 15). Vestibular function, timed eyes-closed static (ECS) and functional reach test (FRT) were measured before and after the intervention, and a two-way repeated-measures analysis of variance was performed.

Results

After training, the vestibular function performance of LTG was higher than that of CONG (CONG: 16.425 ± 3.616 vs. LTG: 12.241 ± 2.610, p = 0.0411, ES = 1.3914), the left foot ECS performance of LTG was higher than that of CONG (CONG: 2.765 ± 0.872 vs. LTG: 4.688 ± 1.113, p = 0.0026, ES = 1.9857), the right foot ECS performance of LTG was higher than that of CONG (CONG: 3.113 ± 0.639 vs. LTG: 4.797 ± 1.071, p = 0.0137, ES = 2.01), the FRT performance of LTG was higher than that of CONG (CONG: 32.009 ± 6.134 vs. LTG: 43.797 ± 6.616, p = 0.0021, ES = 1.9135).

Conclusions

After Latin dance training, SNHL children improved vestibular function and balance. The static balance ability of the left foot has been improved significantly than right foot.
Timing of menarche and pubertal growth patterns using the QEPS growth model
Authors: Gårdstedt-Berghog Jenni , Niklasson Aimon , Sjöberg Agneta , Aronson A. Stefan , Pivodic Aldina , Nierop Andreas F. M. , Albertsson-Wikland Kerstin , Holmgren Anton
Published: August 2024

Objectives

To explore the timing of menarche, postmenarcheal growth, and to investigate the impact of various variables on menarcheal age and postmenarcheal and pubertal growth.

Study Design

This longitudinal community population-based study analyzed pubertal growth and menarcheal age in 793 healthy term-born Swedish girls, a subset of the GrowUp1990Gothenburg cohort. The timing of menarche and postmenarcheal growth was related to variables from the Quadratic-Exponential-Pubertal-Stop (QEPS) growth model, birth characteristics, and parental height. Multivariable models were constructed for clinical milestones; at birth, age 7 years, pubertal growth onset, and midpuberty.

Results

Menarche aligned with 71.6% (18.8) of the QEPS model's specific pubertal growth function, at a mean age of 13.0 (1.3) years, ranging from 8.2 to 17.2 years. Postmenarcheal growth averaged 8.0 (4.9) cm, varying widely from 0.2 to 31.1 cm, decreasing with later menarche. Significant factors associated with menarcheal age included height at 7 years, childhood body-mass index, parental height, and QEPS-derived pubertal growth variables. Multivariable models demonstrated increasing explanatory power for each milestone, explaining 1% of the variance in menarcheal age at birth, 8% at age 7 years, 44% at onset of pubertal growth, and 45% at midpuberty.

Conclusions

This study underscores the strong link between pubertal growth and age at menarche. Data available at start of puberty explain 44% of the variation in menarcheal age, apparent on average 3.2 years before menarche. In addition, the study shows a previously seldom noticed wide variation in postmenarcheal height gain from 0.2 to 31.1 cm.
Advancements in understanding cardiotoxicity of EGFR- TKIs in non-small cell lung cancer treatment and beyond
Authors: Li Xin , Lin Yongping , Lin Song , Huang Jiayi , Ruan Zhongbao
Published: August 2024

Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) are a class of oral targeted anticancer drugs that have been demonstrated to significantly inhibit tumor progression and improve clinical prognosis in patients diagnosed with EGFR-mutated tumors, particularly in those with non-small cell lung cancer. However, the sustained usage of EGFR-TKIs may cause potential cardiotoxicity, thus limiting their applicability. The primary objective of this review is to systematically analyze the evolving landscape of research pertaining to EGFR-TKI-induced cardiotoxicity and elucidate its underlying mechanisms, such as PI3K signaling pathway inhibition, ion channel blockade, oxidative stress, inflammatory responses, and apoptosis. Additionally, the review includes an exploration of risk assessment for cardiotoxicity induced by EGFR-TKIs, along with management and response strategies. Prospective research directions are outlined, emphasizing the need for more accurate predictors of cardiotoxicity and the development of innovative intervention strategies. In summation, this review consolidates recent research advances, illuminates the risks associated with EGFR-TKI-induced cardiac toxicity and presents crucial insights for refining clinical dosage protocols, optimizing patient management strategies, and unraveling the intricate mechanisms governing EGFR-TKI-induced cardiotoxicity.