bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel CTBP1 variant in a Chinese pediatric patient with a phenotype distinct from hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome
Authors: Zhang Qiang , Liu Yusi , Liu Xuan , Zhao Yue , Zhang Jihong
Published: January 2024

Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome (HADDTS) is an exceptionally rare disorder resulting from a heterozygous variant in the C-terminal binding protein 1 (CTBP1) gene. To date, a mere two variants (14 patients) have been documented on a global scale. The aim of this study was to identify a causative CTBP1 variant in a Chinese patient, and to determine the potential pathogenicity of the identified variant. Here, Whole-exome sequencing (WES) was conducted on the proband to pinpoint the candidate variant. Following this, Sanger sequencing was employed to validate the identified candidate variant and examine its co-segregation within the available family members. Employing both in silico prediction and three-dimensional protein modeling, we conducted an analysis to assess the potential functional implications of the variant on the encoded protein. Our investigation led to the identification of a novel heterozygous variant in the CTBP1 gene, namely, c.371 C>T (p.Ser124Phe), in a Chinese patient. This case represents the first confirmed instance of such a variant in a Chinese patient. When comparing the patient’s clinical symptoms with those reported in the literature, notable distinctions were observed between her primary symptoms and those associated with HADDTS. She showed other signs such as microcephaly, coarse facial features, single transverse palmar crease, visible beard, myopia, coarse toenail and skeletal anomalies. This study enriching the spectrum of genetic variants observed in different ethnic populations and expanding the phenotypic profile associated with this gene. These findings are expected to contribute to the enhancement of future variant-based screening and genetic diagnosis, while also providing further insights into the pathogenic mechanisms underlying CTBP1-related conditions.
Disentangling specific and unspecific components of innate immune memory in a copepod–tapeworm system
Authors: Ng Tze Hann , Harrison Mark C. , Scharsack Jörn P. , Kurtz Joachim
Published: January 2024

Evidence that the innate immune system can respond with forms of memory upon reinfection has been accumulating over the past few years. These phenomena of “immune priming” in invertebrates, and “trained immunity” in vertebrates, are contrary to previous belief that immune memory and specificity are restricted to the adaptive immune system. However, while trained immunity is usually a response with rather low specificity, immune priming has shown highly specific responses in certain species. To date, it is largely unknown how specificity in innate immune memory can be achieved in response to different parasite types. Here, we revisited a system where an exceptionally high degree of innate immune specificity had been demonstrated for the first time, consisting of the copepod Macrocyclops albidus and its natural parasite, the tapeworm Schistocephalus solidus. Using homologous (same family) vs. heterologous (different family) priming-challenge experiments, we first confirm that copepods exposed to the same parasite family benefit from reduced secondary infections. We further focused on exposed-but-not-infected copepods in primary exposure to employ a transcriptomic approach, distinguishing between immunity that was either specific or unspecific regarding the discrimination between tapeworm types. A weighted gene co−expression network (WGCN) revealed differences between specific and unspecific immunity; while both involved histone modification regulation, specific immunity involved gene-splicing factors, whereas unspecific immunity was primarily involved in metabolic shift. We found a functional enrichment in spliceosome in specific immunity, whereas oxidative phosphorylation and carbon metabolism were enriched in unspecific immunity. Our findings allow discrimination of specific and unspecific components of an innate immune memory, based on gene expression networks, and deepen our understanding of basic aspects of immune systems.
Identification and characterization of CLEC11A and its derived immune signature in gastric cancer
Authors: Zheng Qing , Gong Zhenqi , Li Baizhi , Cheng Runzi , Luo Weican , Huang Cong , Wang Huaiming
Published: January 2024

Introduction

C-type lectin domain family 11 member A (CLEC11A) was characterized as a growth factor that mainly regulates hematopoietic function and differentiation of bone cells. However, the involvement of CLEC11A in gastric cancer (GC) is not well understood.

Methods

Transcriptomic data and clinical information pertaining to GC were obtained and analyzed from publicly available databases. The relationships between CLEC11A and prognoses, genetic alterations, tumor microenvironment (TME), and therapeutic responses in GC patients were analyzed by bioinformatics methods. A CLEC11A-derived immune signature was developed and validated, and its mutational landscapes, immunological characteristics as well as drug sensitivities were explored. A nomogram was established by combining CLEC11A-derived immune signature and clinical factors. The expression and carcinogenic effects of CLEC11A in GC were verified by qRT−PCR, cell migration, invasion, cell cycle analysis, and in vivo model analysis. Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), M2 macrophages, and T cells in tumor samples extracted from mice were analyzed utilizing flow cytometry analysis.

Results

CLEC11A was over-expressed in GC, and the elevated CLEC11A expression indicated an unfavorable prognosis in GC patients. CLEC11A was involved in genomic alterations and associated with the TME in GC. Moreover, elevated CLEC11A was found to reduce the benefit of immunotherapy according to immunophenoscore (IPS) and the tumor immune dysfunction, exclusion (TIDE). After validation, the CLEC11A-derived immune signature demonstrated a consistent ability to predict the survival outcomes in GC patients. A nomogram that quantifies survival probability was constructed to improve the accuracy of prognosis prediction in GC patients. Using shRNA to suppress the expression of CLEC11A led to significant inhibitions of cell cycle progression, migration, and invasion, as well as a marked reduction of in vivo tumor growth. Moreover, the flow cytometry assay showed that the knock-down of CLEC11A increased the infiltration of cytotoxic CD8+ T cells and helper CD4+ T into tumors while decreasing the percentage of M2 macrophages, MDSCs, and Tregs.

Conclusion

Collectively, our findings revealed that CLEC11A could be a prognostic and immunological biomarker in GC, and CLEC11A-derived immune signature might serve as a new option for clinicians to predict outcomes and formulate personalized treatment plans for GC patients.
Radiofrequency ablation plays double role in immunosuppression and activation of PBMCs in recurrent hepatocellular carcinoma
Authors: Zhao Yang , Yang Tongwang , Ouyang Yabo , Rao Wei , Liu Kai , Zheng Jiasheng , Lv Fudong , Shi Ying , Wang Feng , Liu Dongjie , Qiao Luxin , Xia Zhenying , Zhang Yushi , Chen Dexi , Wang Wenjing
Published: January 2024

Background

Radiofrequency ablation (RFA) is the primary curative treatment for hepatocellular carcinoma (HCC) patients who are not eligible for surgery. However, the effects of RFA on the global tumor immune response remain unclear.

Method

In this study, we examined the phenotypic and functional changes in peripheral blood mononuclear cells (PBMCs) from recurrent HCC patients who had undergone two RFA treatments using mass cytometry and high-throughput mRNA assays.

Results

We observed significant increase in monocytes and decrease in T cell subpopulations three days after the first RFA treatment and three days after the second RFA treatment. The down-regulation of GZMB, GZMH, GZMK, and CD8A, which are involved in the cytotoxic function of T cells, was observed following RFA. Furthermore, the population of CD8 effector and memory T cells (CD8 Teff and CD8 Tem) significantly decreased after RFA. The expression of CD5 and CD161 in various T cell subpopulations also showed significant reductions. Additionally, elevated secretion of VEGF was observed in monocytes, B cells, regulatory T cells (Tregs), and CD4 naive T cells.

Conclusion

In recurrent HCC patients, serum components derived from radiofrequency therapy can enhance the antigen-presenting capacity of monocytes. However, they also inhibit the anti-cancer immune response by reducing the population of CD8 effector and memory T cells and suppressing the activation of T cells, as well as down-regulating the expression of CD161 and CD5 in various T cell subpopulations. These tumor-derived components also contribute to an immunosuppressive microenvironment by promoting the secretion of VEGF in monocytes, Tregs, B cells, and CD4 naive T cells.
Single-cell RNA sequencing reveals the dynamics and heterogeneity of lymph node immune cells during acute and chronic viral infections
Authors: Jin Yubei , He Yudan , Liu Bing , Zhang Xiaohui , Song Caimei , Wu Yunchen , Hu Wenjing , Yan Yiwen , Chen Nuo , Ding Yingying , Ou Yuanyuan , Wu Yixiu , Zhang Mingxia , Xing Shaojun
Published: January 2024

Introduction

The host immune response determines the differential outcome of acute or chronic viral infections. The comprehensive comparison of lymphoid tissue immune cells at the single-cell level between acute and chronic viral infections is largely insufficient.

Methods

To explore the landscape of immune responses to acute and chronic viral infections, single-cell RNA sequencing(scRNA-seq), scTCR-seq and scBCR-seq were utilized to evaluate the longitudinal dynamics and heterogeneity of lymph node CD45+ immune cells in mouse models of acute (LCMV Armstrong) and chronic (LCMV clone 13) viral infections.

Results

In contrast with acute viral infection, chronic viral infection distinctly induced more robust NK cells and plasma cells at the early stage (Day 4 post-infection) and acute stage (Day 8 post-infection), respectively. Moreover, chronic viral infection exerted decreased but aberrantly activated plasmacytoid dendritic cells (pDCs) at the acute phase. Simultaneously, there were significantly increased IgA+ plasma cells (MALT B cells) but differential usage of B-cell receptors in chronic infection. In terms of T-cell responses, Gzma-high effector-like CD8+ T cells were significantly induced at the early stage in chronic infection, which showed temporally reversed gene expression throughout viral infection and the differential usage of the most dominant TCR clonotype. Chronic infection also induced more robust CD4+ T cell responses, including follicular helper T cells (Tfh) and regulatory T cells (Treg). In addition, chronic infection compromised the TCR diversity in both CD8+ and CD4+ T cells.

Discussion

In conclusion, gene expression and TCR/BCR immune repertoire profiling at the single-cell level in this study provide new insights into the dynamic and differential immune responses to acute and chronic viral infections.
Composition and concentration of suspended matter in the Zhongsha Great Atoll, South China Sea, before and during the summer monsoon
Authors: Yan Wenwen , Du Jun , Gu Dongqi , Wang Yongzhi , Xu Guoqiang , Wang Guanxun , Sun Yonggen , Li Ping , Chen Wei
Published: January 2024

Suspended matter in seawater carries abundant nutrients and carbon, playing a significant role in carbon cycle and ecosystem in many oceanic settings such as atolls. The Zhongsha Great Atoll (hereafter ZGA), located in the deep South China Sea, sustains a both regionally and globally important ecosystem. Characteristic of the suspended matter in this area, however, remains poorly investigated. Using a data set encompassing temperature, salinity, depth, and suspended matter concentration (hereafter SMC) of seawater collected respectively in May 2019 (spring-summer monsoon transition period) and June 2020 (summer monsoon outbreak period) in the ZGA, the main components and spatial distribution of suspended matter together with their influencing factors were comprehensively analyzed. Our results show that the components of suspended matter vary widely in space and include more than 20 types of materials such as planktonic remains and biogenic siliceous debris. During the transit between spring and summer monsoons, the SMC in seawater was generally low, with an average value of approximately 3.26 mg L-1, which decreased from the surface to the middle layer and then increased to deep waters; Horizontally, the SMC in the west was generally higher than that in the east likely because the wind-driven current transport significant amounts of particles from the east to the west. During the 2020 summer monsoon outbreak, average SMC in this area was 6.27 mg L-1, higher than that during the 2019 spring-summer monsoon transit. Moreover, significantly higher SMC in the 1-100 m layer and lower SMC in the 150 m layer were observed in the west. Owing to the impact of mesoscale eddies, low SMC in the surface layer and high concentrations in the bottom layer can occur in parts of the ZGA, leading to the deepening of the west-high and east-low distribution layers of SMC during the 2020 summer monsoon outbreak. Notably, we for the first time have observed an anomalously high SMC in the 1–100 m layer of the northwest area during the 2020 summer monsoon outbreak. This anomaly is higher than any previously reported values in the South China Sea and can be attributed to the multiple monsoon impacts. Sources of suspended matter, topography, currents, and wind field were identified as the main factors influencing the spatial distribution of SMC in this area. Our findings provide a basic context for understanding the sources and dynamics of suspended material in atolls.
Assessment of the potential effect of thermal effluents on CO2 absorption in coastal waters
Authors: Ko Young Ho , Kim Tae-Wook
Published: January 2024

In recent decades, the cooling water discharge (CWD) from thermoelectric power plants into coastal waters has increased. The higher temperatures at the discharge outlets can elevate the seawater partial pressure of carbon dioxide (pCO2), potentially resulting in increased carbon dioxide (CO2) emissions or reduced CO2 absorption. Using a comprehensive global power plant database, we evaluated the impact of CWD on surface water CO2. Our assessment suggests that CWD from coastal power plants has the potential to contribute to a decline in oceanic CO2 uptake by 0.09–0.69 Tg C yr−1 (equivalent to 0.3–2.5 Tg CO2 yr−1). This estimation considered solely the influence of air–sea CO2 exchange, excluding the impact of air–sea heat exchange following cooling water discharge. Therefore, our estimate of 0.09–0.69 Tg C yr−1 is likely an upper theoretical limit. While our estimate appears minor in relation to global estimates of the oceanic CO2 flux, this impact of CWD should be addressed on a national scale. For precise quantification of the impact of CWD on local air–sea CO2 flux, accurate information on environmental factors such as wind speeds, mixed layer depth, and background carbonate chemistry is essential.
Deep convolutional network-based chest radiographs screening model for pneumoconiosis
Authors: Li Xiao , Xu Ming , Yan Ziye , Xia Fanbo , Li Shuqiang , Zhang Yanlin , Xing Zhenzhen , Guan Li
Published: January 2024

Background

Pneumoconiosis is the most important occupational disease all over the world, with high prevalence and mortality. At present, the monitoring of workers exposed to dust and the diagnosis of pneumoconiosis rely on manual interpretation of chest radiographs, which is subjective and low efficiency. With the development of artificial intelligence technology, a more objective and efficient computer aided system for pneumoconiosis diagnosis can be realized. Therefore, the present study reported a novel deep learning (DL) artificial intelligence (AI) system for detecting pneumoconiosis in digital frontal chest radiographs, based on which we aimed to provide references for radiologists.

Methods

We annotated 49,872 chest radiographs from patients with pneumoconiosis and workers exposed to dust using a self-developed tool. Next, we used the labeled images to train a convolutional neural network (CNN) algorithm developed for pneumoconiosis screening. Finally, the performance of the trained pneumoconiosis screening model was validated using a validation set containing 495 chest radiographs.

Results

Approximately, 51% (25,435/49,872) of the chest radiographs were labeled as normal. Pneumoconiosis was detected in 49% (24,437/49,872) of the labeled radiographs, among which category-1, category-2, and category-3 pneumoconiosis accounted for 53.1% (12,967/24,437), 20.4% (4,987/24,437), and 26.5% (6,483/24,437) of the patients, respectively. The CNN DL algorithm was trained using these data. The validation set of 495 digital radiography chest radiographs included 261 cases of pneumoconiosis and 234 cases of non-pneumoconiosis. As a result, the accuracy of the AI system for pneumoconiosis identification was 95%, the area under the curve was 94.7%, and the sensitivity was 100%.

Conclusion

DL algorithm based on CNN helped screen pneumoconiosis in the chest radiographs with high performance; thus, it could be suitable for diagnosing pneumoconiosis automatically and improve the efficiency of radiologists.
A study on the improvement in the ability of endoscopists to diagnose gastric neoplasms using an artificial intelligence system
Authors: Zhang Bojiang , Zhang Wei , Yao Hongjuan , Qiao Jinggui , Zhang Haimiao , Song Ying
Published: January 2024

Background

Artificial intelligence-assisted gastroscopy (AIAG) based on deep learning has been validated in various scenarios, but there is a lack of studies regarding diagnosing neoplasms under white light endoscopy. This study explored the potential role of AIAG systems in enhancing the ability of endoscopists to diagnose gastric tumor lesions under white light.

Methods

A total of 251 patients with complete pathological information regarding electronic gastroscopy, biopsy, or ESD surgery in Xi’an Gaoxin Hospital were retrospectively collected and comprised 64 patients with neoplasm lesions (excluding advanced cancer) and 187 patients with non-neoplasm lesions. The diagnosis competence of endoscopists with intermediate experience and experts was compared for gastric neoplasms with or without the assistance of AIAG, which was developed based on ResNet-50.

Results

For the 251 patients with difficult clinical diagnoses included in the study, compared with endoscopists with intermediate experience, AIAG’s diagnostic competence was much higher, with a sensitivity of 79.69% (79.69% vs. 72.50%, p = 0.012) and a specificity of 73.26% (73.26% vs. 52.62%, p < 0.001). With the help of AIAG, the endoscopists with intermediate experience (<8 years) demonstrated a relatively higher specificity (59.79% vs. 52.62%, p < 0.001). Experts (≥8 years) had similar results with or without AI assistance (with AI vs. without AI; sensitivities, 70.31% vs. 67.81%, p = 0.358; specificities, 83.85% vs. 85.88%, p = 0.116).

Conclusion

With the assistance of artificial intelligence (AI) systems, the ability of endoscopists with intermediate experience to diagnose gastric neoplasms is significantly improved, but AI systems have little effect on experts.
Isolation and in vitro assessment of chicken gut microbes for probiotic potential
Authors: Shahbaz Fatima , Muccee Fatima , Shahab Aansa , Safi Sher Zaman , Alomar Suliman Yousef , Qadeer Abdul
Published: January 2024

Poultry production occupies an important place in the economy of any country. High broiler production in recent years has badly affected its profitability due to bad feed quality, excessive use of chemotherapeutic agents, emergence of diverse pathogens, and the deficiencies in management practices during rearing cycle. Microbiological improvement of the meat quality using potential probiotics can be beneficial for broiler farming. Present study was initiated to isolate chicken gastrointestinal tract (GIT) bacteria with probiotic potential. To isolate probiotics from chicken gut, alimentary canal of chickens of known sizes and ages was suspended in ringers soln. Under shaking conditions for overnight followed by serial dilutions of ringers soln. Bacterial isolates were analyzed via growth curve analysis, biochemical testing using RapID™ NF Plus Panel kit, molecular characterization, antimicrobial activity assay, antibiotic sensitivity assay, GIT adherence assay, bile salt and gastric acid resistant assay, and cholesterol assimilation assay. Four bacteria isolated in present study were identified as Limosilactobacillus antri strain PUPro1, Lactobacillus delbrueckii strain PUPro2, Lacticaseibacillus casei strain PUPro3, and Ligilactobacillus salivarius strain PUPro4. L. delbrueckii strain PUPro2 grew extremely fast. All isolates exhibited exceptional resistance to increasing concentrations of NaCl and bile salts with value of p >0.5. L. delbrueckii strain PUPro2 adhered to chicken ileum epithelial cells and demonstrated the highest viable counts of 320 colony forming units (CFUs). Antagonistic action was found in all isolates against P. aeruginosa, B. subtilis, B. proteus, and S. aureus, with value of p >0.5. Antibiotic susceptibility testing showed sensitivity to all the antibiotics used. Cholesterol assimilation was detected in all bacteria, with values ranging from 216.12 to 192.2 mg/dL. All isolates exhibited γ-hemolysis. In future, these bacteria might be tested for their impact on broilers meat quality and growth and can be recommended for their use as supplements for broilers diet with positive impact on poultry production.
Fish oil supplementation, physical activity and risk of incident Parkinson’s disease: results of longitudinal analysis from the UK Biobank
Authors: Lin Fabin , Shi Yisen , Zheng Jiayi , Li Yueping , Chen Xuanjie , Zou Xinyang , Hong Yi , Chen Ke , Zeng Yuqi , Ye Qinyong , Chen Xiaochun , Chen Xinyan , Wang Yingqing , Cai Guoen
Published: January 2024

Objective

Evidence on the individual and combined relationship of physical activity (PA) and fish oil supplement use on the incidence of Parkinson’s disease (PD) risk remains lacking.

Materials and methods

This UK population-based prospective cohort study, involving 385,275 UK Biobank participants, collected PA and fish oil supplement data via touchscreen questionnaires. Using Cox proportional hazards models and restricted cubic splines to examined the associations between use of fish oil supplements, PA and PD risk.

Results

During a median 12.52-year follow-up, 2,131 participants incident PD. Analysis showed that fish oil supplement users had a lower PD risk [hazard ratio (HR), 0.89; 95% confidence interval (CI), 0.82–0.98]. The adjusted HRs for the PD incidence were 0.96 (95% CI, 0.95–0.98) for total PA; 0.93 (95% CI, 0.90–0.96) for moderate PA; 0.95 (95% CI, 0.91–0.99) for vigorous PA and 0.93 (95% CI, 0.89–0.98) for walking activity. Significant interactions were found between fish oil supplement use and total PA (P for interaction = 0.011), moderate PA (P for interaction = 0.015), and walking activity (P for interaction = 0.029) in relation to PD incidence.

Conclusion

Both fish oil supplement use and PA were associated with a reduced risk of PD, and the effect of PA in reducing the risk of PD was more pronounced when fish oil supplement was used.
Guillain–Barré syndrome post-SARS-CoV-2 vaccine: a systematic review and data analysis on its clinical, laboratory, electrophysiological, and radiological features
Authors: Hadhiah Kawther , Alhashim Ali , Al-Dandan Hassan A. , Alhassan Eman , Alqarni Abdulaziz M. , Memish Abdullah Adil A. , Alabdali Majed
Published: January 2024

Introduction

Guillain–Barré syndrome (GBS) is a rare disease that affects almost 0.8–1.9 cases per 100,000 people worldwide every year. This is the most prevalent cause of subacute flaccid paralyzing illness today. It is a subacute inflammatory demyelinating polyradiculoneuropathy; the typical scenario involves ascending symmetrical flaccid paralysis, but in some circumstances, sensory, autonomic, and cranial neuropathy may also be involved. Several vaccines have been found to have complications since the previous century. Numerous case reports of GBS in the literature have been reported following COVID-19 vaccines in recent times.

Objective

This study aimed to conduct a comprehensive examination of GBS cases that have been reported after COVID-19 vaccines; to analyze the descriptive statistical analysis of data gathered regarding clinical, laboratory, electrophysiological, and radiological characteristics; to discuss, based on the available evidence, whether the disease has a preference for a particular vaccine type; and to speculate on the potential pathogenesis.

Methodology

This review has been carried out by recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Result

Reviewing 60 case reports illustrated that most of them are from the USA (18.1%) and the majority of affected individuals were males (60%). The results favored the association between vector-based SARS-CoV-2 vaccine, particularly AstraZeneca vaccine, and the GBS. The mean of symptoms onset is 11.4 days. The results of diagnostic tests such as LP are consistent mostly with albumin-cytological dissociation (81.81%), where brain and spine MRI was unremarkable in 59.52%. Regarding electrodiagnostic tests, AIDP is the most common variant (61.81%). The management was not consistent among the case reports. However, IVIG is the most frequent way of treating these patients (68.33%). The functional outcome was documented in 47 patients; 65% improved with medical management.

Conclusion

This study aimed to conduct a systematic review of reported cases of GBS following COVID-19 vaccines and descriptive statistical analysis of collected data on clinical, laboratory, electrophysiological, and radiological features, to discuss, based on available results, whether the disease has a predilection to a specific vaccine type and to speculate the potential pathogenesis.
Methods to extract and analyze fluid from human pluripotent stem cell-derived choroid plexus organoids
Authors: Chew Leon H. , Mercier Eloi , Rogalski Jason C. , Pippard Sara , Knock Erin
Published: January 2024

The choroid plexus (ChP) is a highly vascularized tissue lining the ventricular space of the brain. The ChP generates cerebrospinal fluid (CSF) and forms a protective barrier in the central nervous system (CNS). Recently, a three-dimensional human pluripotent stem cell (hPSC)-derived ChP organoid model has been developed. This model generates cystic structures that are filled with a fluid resembling CSF and are surrounded by an epithelial layer expressing ependymal choroid plexus-specific markers. Here we describe a method to generate these choroid plexus organoids using a commercial kit and methods to extract the CSF-like fluid for use in downstream analysis.
Human iPSC-derived neurons reveal NMDAR-independent dysfunction following HIV-associated insults
Authors: Starr Alexander , Nickoloff-Bybel Emily , Abedalthaqafi Razan , Albloushi Naela , Jordan-Sciutto Kelly L.
Published: January 2024

The central nervous system encounters a number of challenges following HIV infection, leading to increased risk for a collection of neurocognitive symptoms clinically classified as HIV-associated neurocognitive disorders (HAND). Studies attempting to identify causal mechanisms and potential therapeutic interventions have historically relied on primary rodent neurons, but a number of recent reports take advantage of iPSC-derived neurons in order to study these mechanisms in a readily reproducible, human model. We found that iPSC-derived neurons differentiated via an inducible neurogenin-2 transcription factor were resistant to gross toxicity from a number of HIV-associated insults previously reported to be toxic in rodent models, including HIV-infected myeloid cell supernatants and the integrase inhibitor antiretroviral drug, elvitegravir. Further examination of these cultures revealed robust resistance to NMDA receptor-mediated toxicity. We then performed a comparative analysis of iPSC neurons exposed to integrase inhibitors and activated microglial supernatants to study sub-cytotoxic alterations in micro electrode array (MEA)-measured neuronal activity and gene expression, identifying extracellular matrix interaction/morphogenesis as the most consistently altered pathways across HIV-associated insults. These findings illustrate that HIV-associated insults dysregulate human neuronal activity and organization even in the absence of gross NMDA-mediated neurotoxicity, which has important implications on the effects of these insults in neurodevelopment and on the interpretation of primary vs. iPSC in vitro neuronal studies.
Curcuma longa extract reduces serum inflammatory markers and postprandial hyperglycemia in healthy but borderline participants with overweight and glycemia in the normal/prediabetes range: a randomized, double-blind, and placebo-controlled trial
Authors: Uchio Ryusei , Okuda-Hanafusa Chinatsu , Sakaguchi Haruka , Saji Ryosuke , Muroyama Koutarou , Murosaki Shinji , Yamamoto Yoshihiro , Hirose Yoshitaka
Published: January 2024

The spice turmeric, which has the Latin name Curcuma longa (C. longa), has various physiological effects. This study evaluated the effects of a hot water mixture with supercritical carbon dioxide C. longa extracts, CLE, and the potential active components of C. longa, turmeronols A and B and bisacurone on inflammation and glucose metabolism. First, we investigated the effect of CLE and the potential active components of C. longa on lipopolysaccharide-induced inflammation in RAW264.7 macrophages. We found a significant decrease in the production of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and nitric oxide with CLE, turmeronol A, and bisacurone, Significant inhibition of each of these substances was also observed, except for TNF-α with turmeronol B. The second part of our work was a 12-week randomized, double-blind, placebo-controlled study in healthy but borderline adults aged 40 to 69 years with overweight and normal/prediabetes glycemia. We compared blood inflammatory and glycometabolic markers in the CLE (n = 55) and placebo groups (n = 55). We found significantly lower serum high-sensitivity C-reactive protein and hemoglobin A1c levels in the CLE group. This group also showed significant improvements in postprandial hyperglycemia and insulin sensitivity indices. Our findings indicate that CLE may reduce low-grade inflammation and thus improve insulin sensitivity and postprandial hyperglycemia.

Clinical trial registration:https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000051492, UMIN-CTR, UMIN000045106.
Safety of bevacizumab and olaparib as frontline maintenance therapy in advanced ovarian cancer: expert review for clinical practice
Authors: Romero Ignacio , Guerra Eva , Madariaga Ainhoa , Manso Luis
Published: January 2024

Olaparib, a poly(ADP-ribose) polymerase inhibitor, in combination with the antiangiogenic agent bevacizumab, is approved as maintenance therapy for patients with newly diagnosed stage III or IV epithelial ovarian cancer who have homologous recombination deficient tumors with a deleterious or suspected deleterious BRCA mutation and/or genomic instability based on the long-lasting survival benefit observed in the PAOLA-1 trial. Despite treatment with olaparib and bevacizumab showing an acceptable safety profile, the rate of discontinuations due to adverse events was relatively high, and toxicity related to this regimen may restrict its clinical use. Proper management of olaparib/bevacizumab-related adverse events is important for the improvement of quality of life and maximization of the efficacy of maintenance therapy. Here, we summarize the safety results of the PAOLA-1 study, focusing on treatment discontinuation reasons and adverse event profiles. We sought to shed light on toxicity monitoring and prevention, providing concise recommendations for the clinical management of the most relevant side effects.
Nomogram for predicting the surgical difficulty of laparoscopic total mesorectal excision and exploring the technical advantages of robotic surgery
Authors: Guo Fangliang , Xia Cong , Wang Zongheng , Wang Ruiqi , Gao Jianfeng , Meng Yue , Pan Jiahao , Zhang Qianshi , Ren Shuangyi
Published: January 2024

Background

Total mesorectal excision (TME), represents a key technique in radical surgery for rectal cancer. This study aimed to construct a preoperative nomogram for predicting the surgical difficulty of laparoscopic total mesorectal excision (L-TME) and to investigate whether there were potential benefits of robotic TME (R-TME) for patients with technically challenging rectal cancer.

Methods

Consecutive mid­low rectal cancer patients receiving total mesorectal excision were included. A preoperative nomogram to predict the surgical difficulty of L-TME was established and validated. Patients with technically challenging rectal cancer were screened by calculating the prediction score of the nomogram. Then patients with technically challenging rectal cancer who underwent different types of surgery, R-TME or L-TME, were analyzed for comparison.

Results

A total of 533 consecutive patients with mid­low rectal cancer who underwent TME at a single tertiary medical center between January 2018 and January 2021 were retrospectively enrolled. Multivariable analysis demonstrated that mesorectal fat area, intertuberous distance, tumor size, and tumor height were independent risk factors for surgical difficulty. Subsequently, these variables were used to construct the nomogram model to predict the surgical difficulty of L-TME. The area under the receiver operating characteristic curve of the nomogram was 0.827 (95% CI 0.745 - 0.909) and 0.809 (95% CI 0.674- 0.944) in the training and validation cohort, respectively. For patients with technically challenging rectal cancer, R-TME was associated with a lower diverting ileostomy rate (p = 0.003), less estimated blood loss (p < 0.043), shorter procedure time (p = 0.009) and shorter postoperative hospital stay (p = 0.037).

Conclusion

In this study, we established a preoperative nomogram to predict the surgical difficulty of L-TME. Furthermore, this study also indicated that R-TME has potential technical advantages for patients with technically challenging rectal cancer.
Robotic stereotactic radiosurgery for intracranial meningiomas in elderly patients: assessment of treatment efficacy and safety
Authors: Früh Anton , Bodnar Bohdan , Nachbar Marcel , Gradhand Julia , Kalinauskaite Goda , Rubarth Kerstin , Truckenmueller Peter , Kaul David , Zips Daniel , Vajkoczy Peter , Senger Carolin , Acker Güliz
Published: January 2024

Purpose

Stereotactic radiosurgery (SRS) has been increasingly used to treat intracranial pathologies in elderly patients. The treatment efficiency of SRS has been demonstrated in meningiomas, with excellent local control. We aimed to analyze the safety of robotic SRS in elderly patients with meningiomas.

Methods

We searched for patients with suspected WHO °I meningioma ≥ 60 years old, who underwent CyberKnife (CK) SRS from January 2011 to December 2021. Tumor localization was categorized using the “CLASS” algorithmic scale. Tumor response was evaluated using the Response Assessment in Neuro-Oncology (RANO) criteria for meningiomas. Adverse effects were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and a cox regression was performed to investigate possible predictors.

Results

We identified 82 patients with 102 CK-treated lesions that matched the criteria for the first SRS. The median age was 70 [IQR 64-75] years, and 24.3% of the patients were aged > 75 years. Multiple lesions (up to six) were treated in 14.1% of the SRS-sessions. A previous surgery was performed in 57.3% of lesions, with a median time interval of 41 [IQR 10 – 58] months between the initial surgical procedure and the SRS treatment. In 47.9% of cases, CLASS 3 meningiomas at high-risk locations were irradiated. Single fraction radiosurgery was applied to 62.5% of the lesions, while in the remaining cases multi-session SRS with three to five fractions was used. During the median follow-up period of 15.9 months, lesion size progression was observed in 3 cases. Karnofsky Performance Status (KPS) declined by ≥ 20 points in four patients. Adverse effects occurred in 13 patients, while only four patients had CTCAE ≥2 toxicities. Hereby only one of these toxicities was persistent. The occurrence of complications was independent of age, planned target volume (PTV), high-risk localization, and surgery before SRS.

Conclusion

The data indicates that SRS is a safe, efficient, and convenient treatment modality for elderly patients with meningioma, even at high-risk locations
Diffuse infantile hepatic hemangioma successfully treated with propranolol orally: a case report and literature review
Authors: Li Zengyan , Wu Zhiming , Dong Youhong , Yuan Xiaojun , Zhang Dongdong
Published: January 2024

Background

Infantile hepatic hemangioma (IHH) is a common vascular, fast-growing hepatic tumor that is usually accompanied by multiple cutaneous hemangiomas. Diffuse IHH (DIHH) is a rare type of IHH that exhibits many tumors with nearly complete hepatic parenchymal replacement. At present, there is no specific standardized treatment plan for DIHH. Herein, we present the case of a 2-month-old girl with DIHH and without cutaneous hemangioma who achieved complete remission after undergoing propranolol monotherapy.

Case presentation

The infant with low birth weight was presented to the pediatric department with a 2-month history of persistent vomiting and feeding difficulty. Ultrasonography and abdominal magnetic resonance imaging revealed hepatomegaly and diffused intrahepatic lesions. A computed tomography-guided percutaneous liver biopsy was performed, and the pathological examination suggested the diagnosis was DIHH. The patient exhibited remarkably response to an increasing dose of oral propranolol, from 0.5 mg/kg to 2 mg/kg every day. The intrahepatic lesions were almost completely regressed after one year of treatment and no distinct adverse reaction was observed.

Conclusion

DIHH can induce life-threatening complications that require prompt interventions. Propranolol monotherapy can be an effective and safe first-line treatment strategy for DIHH.
Aluminium phthalocyanine-mediated photodynamic therapy induces ATM-related DNA damage response and apoptosis in human oesophageal cancer cells
Authors: Didamson Onyisi Christiana , Chandran Rahul , Abrahamse Heidi
Published: January 2024

Introduction

Photodynamic therapy (PDT) is a light-based technique used in the treatment of malignant and non-malignant tissue. Aluminium-phthalocyanine chloride tetra sulfonate (AlPcS4Cl)-mediated PDT has been well investigated on several cancer types, including oesophageal cancer. However, the effects of (AlPcS4Cl)-mediated PDT on DNA damage response and the mechanism of cell death in oesophageal cancer needs further investigation.

Methods

Here, we examined the in vitro effects of AlPcS4Cl-mediated PDT on cell cycle, DNA damage response, oxidative stress, and intrinsic apoptotic cell death pathway in HKESC-1 oesophageal cancer cells. The HKESC-1 cells were exposed to PDT using a semiconductor laser diode (673.2 nm, 5 J/cm2 fluency). Cell viability and cytotoxicity were determined by the ATP cell viability assay and the lactate dehydrogenase (LDH) release assay, respectively. Cell cycle and DNA damage response (DDR) analyses were conducted using the Muse™ cell cycle kit and the Muse® multi-color DNA damage kit, respectively. The mode of cell death was identified using the Annexin V-FITC/PI detection assay and Muse® Autophagy LC3 antibody-based kit. The intrinsic apoptotic pathway was investigated by measuring the cellular reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm) function, cytochrome c levels and the activity of caspase 3/7 enzymes.

Results

The results show that AlPcS4Cl-based PDT reduced cell viability, induced cytotoxicity, cell cycle arrest at the G0/G1 phase, and DNA double-strand break (DSB) through the upregulation of the ataxia telangiectasia mutated (ATM), a DNA damage sensor. In addition, the findings showed that AlPcS4Cl-based PDT induced cell death via apoptosis, which is observed through increased ROS production, reduced ΔΨm, increased cytochrome c release, and activation of caspase 3/7 enzyme. Finally, no autophagy was observed in the AlPcS4Cl-mediated PDT-treated cells.

Conclusion

Our findings showed that apoptotic cell death is the main cell death mechanism triggered by AlPcS4Cl-mediated PDT in oesophageal cancer cells.
Mechanisms underlying the therapeutic effects of cinobufagin in treating melanoma based on network pharmacology, single-cell RNA sequencing data, molecular docking, and molecular dynamics simulation
Authors: Yang Jiansheng , Cheng Chunchao , Wu Zhuolin
Published: January 2024

Malignant melanoma is one of the most aggressive of cancers; if not treated early, it can metastasize rapidly. Therefore, drug therapy plays an important role in the treatment of melanoma. Cinobufagin, an active ingredient derived from Venenum bufonis, can inhibit the growth and development of melanoma. However, the mechanism underlying its therapeutic effects is unclear. The purpose of this study was to predict the potential targets of cinobufagin in melanoma. We gathered known and predicted targets for cinobufagin from four online databases. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were then performed. Gene expression data were downloaded from the GSE46517 dataset, and differential gene expression analysis and weighted gene correlation network analysis were performed to identify melanoma-related genes. Using input melanoma-related genes and drug targets in the STRING online database and applying molecular complex detection (MCODE) analysis, we identified key targets that may be the potential targets of cinobufagin in melanoma. Moreover, we assessed the distribution of the pharmacological targets of cinobufagin in melanoma key clusters using single-cell data from the GSE215120 dataset obtained from the Gene Expression Omnibus database. The crucial targets of cinobufagin in melanoma were identified from the intersection of key clusters with melanoma-related genes and drug targets. Receiver operating characteristic curve (ROC) analysis, survival analysis, molecular docking, and molecular dynamics simulation were performed to gain further insights. Our findings suggest that cinobufagin may affect melanoma by arresting the cell cycle by inhibiting three protein tyrosine/serine kinases (EGFR, ERBB2, and CDK2). However, our conclusions are not supported by relevant experimental data and require further study.
The dynamic equilibrium between the protective and toxic effects of matrine in the development of liver injury: a systematic review and meta-analysis
Authors: Feng Weiyi , Kao Te-chan , Jiang Jiajie , Zeng Xinyu , Chen Shuang , Zeng Jinhao , Chen Yu , Ma Xiao
Published: January 2024

Background: Matrine, an alkaloid derived from the dried roots of Sophora flavescens Aiton, has been utilized for the treatment of liver diseases, but its potential hepatotoxicity raises concerns. However, the precise condition and mechanism of action of matrine on the liver remain inconclusive. Therefore, the objective of this systematic review and meta-analysis is to comprehensively evaluate both the hepatoprotective and hepatotoxic effects of matrine and provide therapeutic guidance based on the findings.

Methods: The meta-analysis systematically searched relevant preclinical literature up to May 2023 from eight databases, including PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure, WanFang Med Online, China Science and Technology Journal Database, and China Biomedical Literature Service System. The CAMARADES system assessed the quality and bias of the evidence. Statistical analysis was conducted using STATA, which included the use of 3D maps and radar charts to display the effects of matrine dosage and frequency on hepatoprotection and hepatotoxicity.

Results: After a thorough screening, 24 studies involving 657 rodents were selected for inclusion. The results demonstrate that matrine has bidirectional effects on ALT and AST levels, and it also regulates SOD, MDA, serum TG, serum TC, IL-6, TNF-α, and CAT levels. Based on our comprehensive three-dimensional analysis, the optimal bidirectional effective dosage of matrine ranges from 10 to 69.1 mg/kg. However, at a dose of 20–30 mg/kg/d for 0.02–0.86 weeks, it demonstrated high liver protection and low toxicity. The molecular docking analysis revealed the interaction between MT and SERCA as well as SREBP-SCAP complexes. Matrine could alter Ca2+ homeostasis in liver injury via multiple pathways, including the SREBP1c/SCAP, Notch/RBP-J/HES1, IκK/NF-κB, and Cul3/Rbx1/Keap1/Nrf2.

Conclusion: Matrine has bidirectional effects on the liver at doses ranging from 10 to 69.1 mg/kg by influencing Ca2+ homeostasis in the cytoplasm, endoplasmic reticulum, Golgi apparatus, and mitochondria.

Systematic review registration:https://inplasy.com/, identifier INPLASY202340114
Understanding bovine embryo elongation: a transcriptomic study of trophoblastic vesicles
Authors: Degrelle Séverine A. , Liu Fulin , Laloe Denis , Richard Christophe , Le Bourhis Daniel , Rossignol Marie-Noëlle , Hue Isabelle
Published: January 2024

Background: During the process of elongation, the embryo increases in size within the uterus, while the extra-embryonic tissues (EETs) develop and differentiate in preparation for implantation. As it grows, the ovoid embryo transforms into a tubular form first and then a filamentous form. This process is directed by numerous genes and pathways, the expression of which may be altered in the case of developmental irregularities such as when the conceptus is shorter than expected or when the embryo develops after splitting. In bovines, efforts to understand the molecular basis of elongation have employed trophoblastic vesicles (TVs)—short tubular EET pieces that lack an embryo—which also elongate in vivo. To date, however, we lack molecular analyses of TVs at the ovoid or filamentous stages that might shed light on the expression changes involved.

Methods: Following in vivo development, we collected bovine conceptuses from the ovoid (D12) to filamentous stages (D18), sectioned them into small pieces with or without their embryonic disc (ED), and then, transferred them to a receptive bovine uterus to assess their elongation abilities. We also grew spherical blastocysts in vitro up to D8 and subjected them to the same treatment. Then, we assessed the differences in gene expression between different samples and fully elongating controls at different stages of elongation using a bovine array (10 K) and an extended qPCR array comprising 224 genes across 24 pathways.

Results:In vivo, TVs elongated more or less depending on the stage at which they had been created and the time spent in utero. Their daily elongation rates differed from control EET, with the rates of TVs sometimes resembling those of earlier-stage EET. Overall, the molecular signatures of TVs followed a similar developmental trajectory as intact EET from D12–D18. However, within each stage, TVs and intact EET displayed distinct expression dynamics, some of which were shared with other short epithelial models.

Conclusion: Differences between TVs and EET likely result from multiple factors, including a reduction in the length and signaling capabilities of TVs, delayed elongation from inadequate uterine signals, and modified crosstalk between the conceptus and the uterus. These findings confirm that close coordination between uterine, embryonic, and extra-embryonic tissues is required to orchestrate proper elongation and, based on the partial differentiation observed, raise questions about the presence/absence of certain developmental cues or even their asynchronies.