bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive genomic and transcriptomic profiling of pulmonary nodules in synchronous multiple primary lung cancer.
Authors: Liu Xingsheng , Zhang Yi , Han Li , Li Zhenzhen
Published: June 2024

e20022

Background: Synchronous Multiple Primary Lung Cancer (sMPLC) exhibits distinct histopathological characteristics among pulmonary nodules. However, a comprehensive understanding of the somatic mutation landscape and transcriptome heterogeneity is lacking. Therefore, our study aims to meticulously investigate genomic distinctions among multiple pulmonary nodules within individual patients. Methods: We performed targeted sequencing on tumor specimens and conducted bulk RNA transcriptome analysis on 53 multiple nodules originating from 26 lung cancer patients. The multiple nodules from the same patient was determined as major nodule and minor nodule. Additionally, the tumor tissues underwent histopathological evaluation through H&E staining, complemented by a comprehensive series of immunohistochemistry (IHC) analyses to detect protein expression. The detected protein markers encompassed PD-L1, Ki67, and others. Results: For the 53 nodule samples from 26 MPLCs patients, EGFR was the mostly mutated genes, and the TP53 mutation frequency demonstrated notably different between major and minor nodules. Furthermore, pathway enrichment analysis based on the differentially expressed genes (DEGs) between major and minor nodules revealed the significantly active cell cycle and p53 pathways in the major nodules. Additionally, both major and minor nodules demonstrated mostly similar immune microenvironment and PD-L1 protein expression, and a significantly higher expression of Ki67. A noteworthy suppression was observed in the immune microenvironment in nodules, revealed by the expression of macrophage, neutrophils, and NK cells. Furthermore, minor nodules exhibited a modestly elevated expression of macrophages compared to major nodules. Additionally, among the significantly up-regulated cell cycle related genes in the major nodules when compared with minor nodules, CCNE1 mRNA expression demonstrated significant correlation with poor prognosis in the lung cancer. Conclusions: This study validated molecular distinctions between samples from major and minor nodules in patients with sMPLC at both genomic and transcriptomic levels. The major nodules exhibited heightened activity in tumor cell proliferation pathways and demonstrated malignancy-related biological characteristics, which correlated with pathological assessment results.
Accurate identification of lung cancer in the early phase by serum exosomal miR-1271-5p.
Authors: Zhang Jinmin , Wang Lian , Zhang Haijun
Published: June 2024

e20029

Background: Exosomal miRNAs are associated with the proliferation, migration, and invasion of lung cancer cells. We aim to investigate the clinical significance of serum exosomal miR-1271-5p in early-stage lung cancer (ESLC) mainly characterized by pulmonary nodules to push forward the prevention and treatment of lung cancer. Methods: The serum exosome (sEVs) miR-1271-5p was obtained from a total of 134 subjects from the patients with ESLC and the benign nodule (BLN) and healthy controls, and the expression level of miR-1271-5p were detected by RT-qPCR. Through analysis the clinical feature and CT (Computed Tomography) imaging finding of the subjects confirmed by pathology, independent risk factors for ESLC were obtained according to univariate and multivariate logistic regression analysis. R software was incorporated to build a mathematical prediction model of nomogram, and the clinical significance of sEVs-miR-1271-5p in the prediction and diagnosis of ESLC was verified by ROC curve. Results: The relative expression of sEVs-miR-1271-5p was lower in the patients with ESLC than the patients with BLN and healthy controls. The AUC value of the ESLC predicted by sEVs-miR-1271-5p was 0.9845 (95%CI: 0.9649-1.000, P < 0.0001). The results of multi-factor logistic regression analysis showed that gender (OR = 0.213, p = 0.046), nodule diameter (OR = 0.794, p = 0.031), lobulation (OR = 0.013, p < 0.0001), and sEVs-miR-1271-5p (OR = 0.014, p = 0.037) were independent risk factors for ESLC. Based on these independent risk factors, a prediction model for ESLC was established, with an AUC value of 0.8810 (95% CI: 0.8076-0.9553, P < 0.0001), the sensitivity, specificity, positive and negative predictive value and accuracy of the model were 85%, 80.43%, 79.07%, 86.05% and 82.56% respectively. Conclusions: Serum exosomal miR-1271-5p may break through the early diagnosis of lung cancer and provide important therapeutic targets.
Optimization of fusion detection in non-small cell lung cancer by amplicon-based RNA sequencing.
Authors: Feng Qin , Wang Yue , Lin Dongmei , Zhang Junling , Huang Mengli , Zhang Ding , Zheng Yating , Huang Depei , Ma Jing , Xiong Lei
Published: June 2024

e20042

Background: In non-small cell lung cancer (NSCLC), more and more driver fusions are suitable for targeted therapy. Sequential or parallel DNA and RNA sequencing is an option, but it is costly and requires sufficiently high quality biopsy material. The purpose of this study was to confirm the consistency of fusion genes detected by DNA-based NGS and RNA-based NGS in the same sample, and to validate the performance of FFPE samples for RNA-based NGS. Methods: In this study, we evaluated the benefits of capture-based DNA sequencing and amplicon-based RNA sequencing in identifying gene fusion and exon-skipping events in 98 NSCLC patients. All cases were FFPE samples stored for 1-5 years. In addition, we investigated the limiting performance of RNA-based NGS for RNA initiation. Results: In the cases of positive DNA sequencing fusion samples, the fusion consistency detection rate of RNA sequencing was 95% (38/40). Two cases were not detected by RNA-based NGS, one was a five-year FFPE sample and the other was due to a probe not covered problem. In patients with negative DNA fusion genes, RNA sequencing could detect 12.07% more fusion-positive cases involving ALK (n = 1), ROS (n = 3), MET 14 exon skipping (n = 1), RET (n = 1), and BRAF (n = 1). Moreover, the FFPE samples stored for 3-5 years inevitably degrade the RNA, but could still be used for RNA-based sequencing. Among 66 FFPE samples stored for 3-5 years, the detection rate of fusion consistency between DNA sequencing fusion samples and RNA sequencing was 96.77%(30/31). In patients with negative DNA fusion genes, RNA sequencing was able to detect 14.29% (5/35) more fusion-positive cases. The performance verification of the other 8 samples with different RNA input amounts found that 87.5% (7/8) of the samples could meet the quality control of RNA sequencing and accurately detect fusion mutations as low as 1 ng. Conclusions: Molecular profiling based on mixed DNA and RNA sequencing improves the effectiveness of detection of fusion-driven NSCLC. The method was feasible on small tissue samples as well as FFPE samples stored for 3-5 years, and could greatly reduce the complexity and cost of molecular examination.
Histopathological features of SMARCA4-deficient thoracic malignancies: Data from resource-limited setting.
Authors: Karapetyan Nune , Zohrabyan Davit , Khachatryan Parandzem , Safaryan Liana , Harutyunyan Lilit , Avagyan Armen , Galumyan Aramayis , Voskanyan Gevorg , Geghamyan Gor , Mkhitaryan Sergo , Arustamyan Mikayel , Ghayamyan Meri , Karamyan Sona , Khachatryan Mariam , Arzumanyan Armen , Hovhannisyan Mariam , Bardakhchyan Samvel , Mkhitaryan Armen
Published: June 2024

e20045

Background: SMARCA4 deficient tumors are rare malignancies that develop due to inactivating mutation in switch/sucrose-nonfermenting chromatin remodeling complexes (SWI/SNF). This is an aggressive type of non-small cell lung cancer (NSCLC) with a poor prognosis and mediocre treatment response. The trials and observational research on SMARCA4 deficient thoracic malignancies are lacking, especially in limited resource settings. This study aims to analyze pathological and immunohistochemical (IHC) profiles of patients with SMARCA4 deficient thoracic malignancies in Armenia. Methods: The current research utilizes a retrospective cohort single-center study design. The study setting was the only pathology center in Armenia that runs an IHC panel for SMARCA4/BRG1 protein evaluation. For data collection purposes, a census sampling has been done and all the pathology reports of SMARCA4 deficient thoracic malignancies were reviewed. The study timeframe was from 24 February 2021 up to 11 December 2023. Descriptive statistics through portions were done to analyze the data. Results: In total, 19 patients with SMARCA4 deficient thoracic malignancies were diagnosed. The male-to-female ratio was 15:1 and the median age was 63 years (range: 50-73 years). Of those cases, 21% (n = 4) were excluded from the current analysis as histopathological examination of those tissue samples was not performed. The diagnosis was based on an IHC evaluation to obtain a second opinion. The tissue histopathological architecture was represented: 60% (n = 9) solid, 6.67% (n = 1) trabecular, and 6.67% (n = 1) papillary. Of those samples, 66.7% (n = 10) had hyperchromatic/polymorphic nuclei and 33.3% (n = 5) pleomorphic nuclei. Similarly, the evaluated sample cells have 53.3% (n = 8) eosinophilic, 13.3% (n = 2) clear, and 13.3% (n = 2) scant cytoplasm. All 19 cases were included in the descriptive analysis of the IHC profile as examinations were performed for all the subjects. The IHC profile of the cohort is presented in the table. Ki67 was checked in 47.4% (n = 9) of cases with 70-75% median expression. In general, the most frequently examined markers were TTF1, p40, Chromogranin, and AE1/3. Conclusions: In conclusion, the study shed light on SMARCA4 thoracic tumors spread in Armenia. Considering the rarity of the disease, further research is required to investigate the actual prevalence of SMARCA4 deficient thoracic tumors and treatment approaches in Armenia. [Table: see text]
Cutaneous adverse event profile of epidermal growth factor receptor tyrosine kinase inhibitors in patients with non-small cell lung cancer: A meta-analysis of phase 3 randomized controlled trials.
Authors: Zhou Susu , Alerasool Parissa , Kishi Noriko , Rohs Nicholas Cole
Published: June 2024

e20049

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the frontline treatment of choice for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, EGFR-TKIs are associated with unique and dramatic dermatologic side effects that negatively impact patients’ quality of life, potentially resulting in poor adherence, including dose reductions or premature treatment cessation. Thus, it is crucial for the oncologists to be familiar with the array of dermatologic manifestations caused by these drugs for effective patient management. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for phase 3 randomized controlled trials (RCTs) comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with NSCLC. We calculated the odds ratio (OR) of all- and high-grade 10 dermatologic adverse events (dAEs). We conducted a meta-analysis using a random-effects model to compare the risk of dAEs in patients receiving EGFR-TKIs versus placebo/chemotherapy. Subgroup analysis based on control arm (placebo or chemotherapy) and individual EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib of osimertinib) were conducted. Results: 35 RCTs comprising 16,151 patients were included. In addition to all- and high-grade rash (all-grade: 12.21, 95% CI: 9.00-16.56; high-grade: OR 7.83, 95% CI: 5.11-12.00), EGFR-TKIs were associated with a significantly increased risk of all-grade acne (OR 12.24, 95% CI: 3.11-48.2), dermatitis acneiform (OR 8.46, 95% CI: 4.03-17.8), dry skin (OR 6.15, 95% CI: 4.02-9.40), palmar-plantar erythrodysesthesia syndrome (OR 11.14, 95% CI:3.00-41.4), paronychia (OR 31.97, 95% CI: 17.9-57.1), pruritus (OR 2.86, 95% CI: 2.17-3.77), skin exfoliation (OR 7.62, 95% CI: 2.55-22.8), and skin fissures (OR 11.59, 95% CI:4.86-27.6). The increased risk of EGFR-TKI-related dAEs was more prominent when compared with chemotherapy than placebo. In subgroup analyses of individual EGFR-TKIs, the risk of high-grade rash was significantly increased in patients treated with erlotinib or gefitinib but not in those treated with other EGFR-TKIs. Conclusions: This is the most comprehensive meta-analysis summarizing currently available evidence on cutaneous toxicity profile of EGFR-TKIs. These findings provide physicians with a better understanding for prompt recognition and management of these dAEs, to avoid unnecessary dose modifications and/or termination, and to prevent impairments in patients' quality of life.
Understanding the safety and toxicity profile of durvalumab for Black patients with lung cancer.
Authors: Gundroo Hafsa M , Chandora Kapil , Jack Deborah Anthony , Arnett Benson , Jain Sanjay R.
Published: June 2024

e20051

Background: Constituting 12.2% of all new cancer diagnosis in 2023,Lung cancer continues to be among the most common cancers in the US. According to statistics 1 in 16 black males and1 in 20 black females are likely to develop lung cancer in their lifetime.The results of the PACIFIC trial changed the paradigm of management in non-resectable NonSmall Cell Ca and made Durvalumab the standard of care. The toxicity profile of the drug were extensively studied in the study however, only 2% (n-14) of the study population was Black. More studies are required to understand the tolerability and toxicity profile of the drug in the Black population. Methods: This is a retrospective study. Study population consisted of 55 self-identified African Americans diagnosed with stage 3 Non-small Cell Ca who received Durvalumab for consolidation therapy after chemo radiation at a large safety net hospital between 2018-2023.Their charts were reviewed to study: 1. The development of any grade- known adverse side effects of the drug. 2. The tolerability of the drug- assessed as the lack of severe toxicities resulting in discontinuation of the drug. 3. Appearance of any peculiar adverse effects not previously known. 4. Adverse side effects warranting the use of more healthcare resources, like ED visits and hospital admissions for adverse effects. The results were then compared to the results of the PACIFIC trial. Results: 52.7% (n=29) developed known adverse effects of the drug-any grade.20 % (n=11) developed severe adverse effects leading to discontinuation of therapy.32.7%(n=18) were able to tolerate completion of therapy in-spite of adverse effects. 16.3% ( n=9) required ED visits/ hospital visit due to immunotherapy adverse effects. ADRs leading to discontinuation of therapy-pneumonitis -9%, Debilitating Chest Pain-1.8%, Hyperglycemia- 1.8%, severe fatigue-1.8%, atrial fibrillation-1.8%, Autoimmune hepatitis -1.8% and Pan uveitis -1.8%. Other adverse effects are listed in the table. Conclusions: Based on our results, AA are more likely to develop any grade adverse effects than was estimated in the PACIFIC trial, however, the percentage of the AA population discontinuing therapy due to severe adverse effect was lower. While the occurrence of most common adverse effects including Pneumonitis was comparable to the PACIFIC trial, thyroid dysfunction – both hypo and hyperthyroidism was about 3 times more in the AA population. All the thyroid dysfunctions noted were G1 and G2, and did not require discontinuation of therapy. We therefore, recommend providers to be more watchful for signs and symptoms suggestive of thyroid dysfunction when treating AA patients with Durvalumab. [Table: see text]
Shannon index analysis in TCR sequencing for patients with lung adenocarcinoma: The clinical implications.
Authors: Jiang Bo , Lin Yangui , Hui Hongliang , Li Huaming , Zhang Yiqian , Zhou Shuxiong , Zhang Xiaoni , Li Hui , Huang Zhijuan , Liu Yuanyuan , Dong Linfeng
Published: June 2024

e20053

Background: Immune repertoire (IR) is the collection of functionally diverse T and B cells in an individual's circulatory repertoire at a particular time. The CDR3 is the main variation region of the CDR of T cell receptors (TCRs), which directly determines the antigen specificity of the receptor. The purpose of this study was to investigate the differences in TCRs between tumor patients and healthy people by using NGS sequencing of the CDR3 region of the human TRB. Shannon indices and Simpson indices were used to evaluate the TCR richness and evenness. Methods: From 2018 to 2022, a total of 537 cases of lung adenocarcinoma and 85 cases of healthy individual PBMC in China were collected. We identified 59 V and 14 J genes in the TRB CDR3 region by amplicon sequencing, and analyzed the differences between Shannon_index and simpson index. Results: TCR diversity were significantly higher in healthy people compared to lung adenocarcinoma patients as determined by Shannon index analysis ( P = 0.006), and the uniformity of TCRs in the latter group was lower (Simpson index 0.997 and 0.992 for controls and cases, respectively). For different age groups of lung cancer patients (age 20-44, n = 66; age 45-59, n = 205; age 60-74, n = 221; age 75-90, n = 45), the overall abundance and uniformity of T cells in lung cancer patients decreased with the increase of age (Shannon index: 7.91, 7.63, 7.38, 6.99, respectively. Simpson Index: 0.996, 0.994, 0.991, 0.986 respectively). The downward trend in the Shannon index between healthy individuals and lung adenocarcinoma patients exhibit a high correlation (spearman r = 1, P < 0.01), indicating that age rather than cancer may be the main factor in immune decline in patients with lung adenocarcinoma. In terms of gender, the abundance and uniformity of T cell types in male patients were lower than that in female patients (male: Shannon index = 7.36, Simpson index = 0.991; Female: Shannon index = 7.61, Simpson index = 0.994), suggesting higher levels of immunity in the female patients. Conclusions: The Shannon index (immune diversity) in TCR sequencing was significantly different between lung adenocarcinoma patients and healthy individuals. In patients with lung adenocarcinoma, immunity declines more due to aging than the cancer itself. TCR diversity was lower in male lung adenocarcinoma patients than in female patients. In conclusion, Shannon index (immune diversity) in TCR sequencing can be used as a predictor of lung adenocarcinoma.
Predicting pathological response to neoadjuvant immunotherapy plus chemotherapy in resectable non-small cell lung cancer through liquid biopsy.
Authors: Lei Siyu , Xu Haiyan , Yang Yaning , Tian Linyan , Wang Yan
Published: June 2024

e20073

Background: Neoadjuvant immunotherapy (ICI) plus chemotherapy (CT) provides a significant benefit compared to CT alone in resectable non-small cell lung cancer (NSCLC). However, further research is needed to identify the populations benefitting from this combined strategy. Methods: Patients (pts) diagnosed with stage II-III resectable NSCLC who opted for neoadjuvant ICI plus CT were enrolled. Plasma samples were collected before treatment initiation (T1) and before surgery (T2). A next-generation sequencing (NGS) platform spanning 769 cancer-related genes was utilized to detect circulating tumor DNA (ctDNA). The ctDNA concentration was presented as haploid genome equivalents (hGE) per mL of plasma. Additionally, low-pass whole-methylome sequencing was employed to explore three features of cell-free DNA, including methylated fragment ratio (MFR), fragment size index (FSI), and chromosomal aneuploidy of featured fragments (CAFF). Clinical and pathological data was obtained from medical records. Results: Out of 24 pts enrolled, 18 pts were evaluable on both platforms. The major pathological response (MPR) rate was 70.8% (17/24), and the pathological complete response (pCR) rate was 37.5% (9/24). Squamous cell carcinoma (SCC) showed a higher MPR rate than adenocarcinoma (P = 0.014). Pts with clinical T stage 2 showed a trend toward a higher MPR rate than those with T stage 3/4 (P = 0.069). No single molecular biomarker was found to be independently associated with MPR or pCR at T1. A linear discriminant model was constructed based on clinical T stage, MFR, and hGE at T1, which predicted both MPR and pCR with an accuracy of 83.3% (n = 18). In pts with SCC (n = 15), the accuracy of this model in predicting MPR and pCR was 80.0% and 86.7%, respectively. Moreover, the CAFF score at T2 was significantly higher in non-MPR pts than in MPR pts (P = 0.003). The dynamic change of CAFF score [calculation: (T2-T1) / T1] was also significantly related to MPR (P = 0.006). Conclusions: Baseline cfDNA features and clinical parameters effectively predicted pathological response of neoadjuvant ICI plus CT in resectable NSCLC, which could potentially serve as a tool for identifying patients that would benefit most from the combined approach.
Prognostic impact of clinical stage on non-surgical patients with pleural mesothelioma.
Authors: Knapp Brendan , Cittolin Santos Giordano Fabricio , Wu Ningying , Flanagan Mary Ellen , Baral Maun , Gao Feng , Rohatgi Anjali , Ward Jeffrey , Govindan Ramaswamy , Morgensztern Daniel
Published: June 2024

e20096

Background: Most patients with pleural mesothelioma (PM) are not surgical candidates and receive systemic therapy. Clinical stage is usually not reported in mesothelioma clinical trials. We evaluated the prognostic impact of clinical stage in mesothelioma using a large database with the hypothesis that M1 patients will have worse OS compared to M0 patients. Methods: The Surveillance, Epidemiology and End Results (SEER) Program was used to identify adult patients with PM diagnosed between 2004 and 2020, who received chemotherapy and did not undergo surgery. Patients with unknown stage were excluded. Staging was subdivided into I, II-III and IV for better accuracy. Age, sex, and stage were included in multivariable analyses (MVAs) using a Cox proportional hazard regression model. Unadjusted OS was estimated by the Kaplan-Meier method and compared using log-rank tests. Results: Among the 10,422 patients, 2,644 (25.4%) met the inclusion criteria. Histology classification was not available for 1,120 patients (42.4%), which were reported as malignant mesothelioma. Most patients were male (78.3%) and older than 70 years (54.5%). There were 970 patients (36.7%) with stage I, 893 (33.8%) with stage II-III and 781 (29.5%) with stage IV. The median OS for all patients was 11 months, with 1-year, 3-year and 5-year OS of 43.9%, 10.3% and 4.3% respectively. The median OS for stages I, II-III, and IV was 13 months, 11 months, and 9 months respectively, with 1-year OS of 50.5%, 42.8% and 36.9% respectively and 5-year OS for stages I, II-III, and IV of 5.3%, 3.0% and 4.9% respectively. The median and 1-year OS were 12 months and 46.8% respectively for M0 and 9 months and 36.9% respectively for M1 (p < 0.001). For patient with M0, the median OS for N0, N1 and N2 was 12 months, 11 months, and 11 months, respectively. In MVA, worse OS was observed in patients with age 71 or older compared to < 60 (HR 1.24, 1.09-1.4), and in male patients compared to females (HR 1.27, 1.15.-1.4). Stage IV was associated with worse OS when compared to stage II-III (HR 1.11, 1.001-1.23, p = 0.04) and stage I (HR 1.34, 1.21-1.49, p < 0.001) while stage II-III was associated with worse OS compared to stage I (HR 1.21, 1.1-1.33, p = 0.0001). Conclusions: Clinical stage is a significant predictor for outcomes in patients with unresected pleural mesothelioma treated with chemotherapy, has been underreported, and should be included in clinical trials for a better evaluation of novel treatment strategies.
3-CMC, 4-CMC, and 4-BMC Human Metabolic Profiling: New Major Pathways to Document Consumption of Methcathinone Analogues?
Authors: Berardinelli Diletta , Taoussi Omayema , Daziani Gloria , Tavoletta Francesco , Ricci Giovanna , Tronconi Livio P. , Adamowicz Piotr , Busardò Francesco P. , Carlier Jeremy
Published: June 2024

Synthetic cathinones represent one of the largest and most abused new psychoactive substance classes, and have been involved in numerous intoxications and fatalities worldwide. Methcathinone analogues like 3-methylmethcathinone (3-MMC), 3-chloromethcathinone (3-CMC), and 4-CMC currently constitute most of synthetic cathinone seizures in Europe. Documenting their consumption in clinical/forensic casework is therefore essential to tackle this trend. Targeting metabolite markers is a go-to to document consumption in analytical toxicology, and metabolite profiling is crucial to support investigations. We sought to identify 3-CMC, 4-CMC, and 4-bromomethcathinone (4-BMC) human metabolites. The substances were incubated with human hepatocytes; incubates were screened by liquid chromatography-high-resolution tandem mass spectrometry and data were mined with Compound Discoverer (Themo Scientific). 3-CMC-positive blood, urine, and oral fluid and 4-CMC-positive urine and saliva from clinical/forensic casework were analyzed. Analyses were supported by metabolite predictions with GLORYx freeware. Twelve, ten, and ten metabolites were identified for 3-CMC, 4-CMC, and 4-BMC, respectively, with similar transformations occurring for the three cathinones. Major reactions included ketoreduction and N-demethylation. Surprisingly, predominant metabolites were produced by combination of N-demethylation and ω-carboxylation (main metabolite in 3-CMC-positive urine), and combination of β-ketoreduction, oxidative deamination, and O-glucuronidation (main metabolite in 4-CMC-positive urine). These latter metabolites were detected in negative-ionization mode only and their non-conjugated form was not detected after glucuronide hydrolysis; this metabolic pathway was never reported for any methcathinone analogue susceptible to undergo the same transformations. These results support the need for comprehensive screening strategies in metabolite identification studies, to avoid overlooking significant metabolites and major markers of consumption.

Graphical Abstract
Cenicriviroc Suppresses and Reverses Steatohepatitis by Regulating Macrophage Infiltration and M2 Polarization in Mice
Authors: Chen Guanliang , Yu Yanwen , Zhu Yuqin , Nagashimada Mayumi , Wang Yajiao , Nagata Naoto , Xu Liang
Published: June 2024

The inhibition of hepatic macrophage and Kupfer cell recruitment and activation is a potential strategy for treating insulin resistance and nonalcoholic steatohepatitis (NASH). Cenicriviroc (CVC), a dual C-C chemokine receptor 2 (CCR2) and CCR5 antagonist, has shown antifibrotic activity in murine models of NASH and has been evaluated in clinical trials on patients with NASH. This study investigated the effects of CVC on macrophage infiltration and polarization in a lipotoxic model of NASH. C57BL/6 mice were fed a high-cholesterol, high-fat (CL) diet or a CL diet containing 0.015% CVC (CL + CVC) for 12 weeks. Macrophage recruitment and activation were assayed by immunohistochemistry and flow cytometry. CVC supplementation attenuated excessive hepatic lipid accumulation and peroxidation and alleviated glucose intolerance and hyperinsulinemia in the mice that were fed the CL diet. Flow cytometry analysis revealed that compared with the CL group, mice fed the CL + CVC diet had fewer M1-like macrophages, more M2-like macrophages, and fewer T cell counts, indicating that CVC caused an M2-dominant shift of macrophages in the liver. Similarly, CVC decreased lipopolysaccharide-stimulated M1-like macrophage activation, whereas it increased interleukin-4-induced M2-type macrophage polarization in vitro. In addition, CVC attenuated hepatic fibrosis by repressing hepatic stellate cell activation. Lastly, CVC reversed insulin resistance as well as steatosis, inflammation, and fibrosis of the liver in mice with pre-existing NASH. In conclusion, CVC prevented and reversed hepatic steatosis, insulin resistance, inflammation, and fibrogenesis in the liver of NASH mice via M2 macrophage polarization.
Ethnic Disparities in the Risk Factors, Morbidity, and Mortality of Cardiovascular Disease in People With Diabetes
Authors: Nair Lekshmi , Asuzu Peace , Dagogo-Jack Sam
Published: June 2024

Cardiovascular disease (CVD) is the leading cause of death in people with diabetes. Compared with European Americans, African Americans have more favorable lipid profiles, as indicated by higher high-density lipoprotein cholesterol, lower triglycerides, and less dense low-density lipoprotein particles. The less atherogenic lipid profile translates to lower incidence and prevalence of CVD in African Americans with diabetes, despite higher rates of hypertension and obesity. However, African Americans with CVD experience worse clinical outcomes, including higher mortality, compared with European Americans. This mini-review summarizes the epidemiology, pathophysiology, mechanisms, and management of CVD in people with diabetes, focusing on possible factors underlying the “African American CVD paradox” (lower CVD incidence/prevalence but worse outcomes). Although the reasons for the disparities in CVD outcomes remain to be fully elucidated, we present a critical appraisal of the roles of suboptimal control of risk factors, inequities in care delivery, several biological factors, and psychosocial stress. We identify gaps in current knowledge and propose areas for future investigation.
In Vitro Investigation of Insulin Dynamics During 4 Hours of Simulated Cardiopulmonary Bypass
Authors: Schweizer Thilo , Nossen Caroline M. , Galova Barbara , Schild Christof , Huber Markus , Bally Lia , Vogt Andreas , Siepe Matthias , Nagler Michael , Fischer Kady , Guensch Dominik P.
Published: June 2024

BACKGROUND:

Hyperglycemia is common in patients undergoing cardiovascular surgery with cardiopulmonary bypass. We hypothesize that intraoperative hyperglycemia may be, at least partially, attributable to insulin loss due to adhesion on artificial surfaces and/or degradation by hemolysis. Thus, our primary aim was to investigate the loss of insulin in 2 different isolated extracorporeal circulation circuits (ECCs), that is, a conventional ECC (cECC) with a roller pump, and a mini-ECC (MiECC) system with a centrifugal pump. The secondary aim was to assess and compare the relationship between changes in insulin concentration and the degree of hemolysis in our 2 ECC models.

METHODS:

Six cECC and 6 MiECC systems were primed with red packed blood cells and thawed fresh-frozen plasma (1:1). Four additional experiments were performed in cECC using only thawed fresh-frozen plasma. Human insulin (Actrapid) was added, targeting a plasma insulin concentration of 400 mU/L. Insulin concentration and hemolysis index were measured at baseline and hourly thereafter. The end points were the change in insulin level after 4 hours compared to baseline and hemolysis index after 4 hours. The insulin concentration and hemolysis index were analyzed by means of a saturated linear mixed-effect regression model with a random offset for each experiment to account for the repeated measure design of the study, resulting in mean estimates and 95% confidence intervals (CIs) of the primary end points as well as of pairwise contrasts with respect to ECC type.

RESULTS:

Insulin concentration decreased by 63% (95% CI, 48%–77%) in the MiECC and 92% (95% CI, 77%–106%) in the cECC system that contained red blood cells. Insulin loss was significantly higher in the cECC system compared to the MiECC (P = .022). In the cECC with only plasma, insulin did not significantly decrease (−4%; 95% CI, −21% to 14%). Hemolysis index in MiECC increased from 68 (95% CI, 46–91) to 76 (95% CI, 54–98) after 4 hours, in cECC from 81 (95% CI, 59–103) to 121 (95% CI, 99–143). Hemolysis index and percent change of insulin showed an excellent relationship (r = −0.99, P < .01).

CONCLUSIONS:

Our data showed that insulin levels substantially decreased during 4 hours of simulated cardiopulmonary bypass only in the ECC that contained hemoglobin. The decrease was more pronounced in the cECC, which also exhibited a greater degree of hemolysis. Our results suggest that insulin degradation by hemolysis products may be a stronger contributor to insulin loss than adhesion of insulin molecules to circuit surfaces.
Distinct Neural Mechanisms Between Anesthesia Induction and Emergence: A Narrative Review
Authors: Zhang Donghang , Wei Yiyong
Published: June 2024

Anesthesia induction and emergence are critical periods for perioperative safety in the clinic. Traditionally, the emergence from general anesthesia has been recognized as a simple inverse process of induction resulting from the elimination of general anesthetics from the central nervous system. However, accumulated evidence has indicated that anesthesia induction and emergence are not mirror-image processes because of the occurrence of hysteresis/neural inertia in both animals and humans. An increasing number of studies have highlighted the critical role of orexinergic neurons and their involved circuits in the selective regulation of emergence but not the induction of general anesthesia. Moreover, additional brain regions have also been implicated in distinct neural mechanisms for anesthesia induction and emergence, which extends the concept that anesthetic induction and emergence are not antiparallel processes. Here, we reviewed the current literature and summarized the evidence regarding the differential mechanism of neural modulation in anesthesia induction and emergence, which will facilitate the understanding of the underlying neural mechanism for emergence from general anesthesia.
The Pressure Reactivity Index as a Measure for Cerebrovascular Autoregulation: Validation in a Porcine Cranial Window Model
Authors: Klein Samuel P. , Decraene Brecht , De Sloovere Veerle , Kempen Bavo , Meyfroidt Geert , Depreitere Bart
Published: June 2024

BACKGROUND AND OBJECTIVES:

Pressure reactivity index (PRx) has been proposed as a metric associated with cerebrovascular autoregulatory (CA) function and has been thoroughly investigated in clinical research. In this study, PRx is validated in a porcine cranial window model, developed to visualize pial arteriolar autoregulation and its limits.

METHODS:

We measured arterial blood pressure, intracranial pressure, pial arteriolar diameter, and red blood cell (RBC) velocity in a closed cranial window piglet model during gradual balloon catheter–induced arterial hypotension (n = 10) or hypertension (n = 10). CA limits were derived through piecewise linear regression of calculated RBC flux vs cerebral perfusion pressure (CPP), leading for each arteriole to 1 lower limit of autoregulation (LLA) and 2 upper limits of autoregulation (ULA1 and ULA2). Autoregulation limits were compared with PRx thresholds, and receiver operating curve analysis was performed with and without CPP binning. A linear mixed effects model of PRx was performed.

RESULTS:

Receiver operating curve analysis indicated an area under the curve (AUC) for LLA prediction by a PRx of 0.65 (95% CI: 0.64-0.67) and 0.77 (95% CI: 0.69-0.86) without and with CPP binning, respectively. The AUC for ULA1 prediction by PRx was 0.69 (95% CI: 0.68-0.69) without and 0.75 (95% CI: 0.68-0.82) with binning. The AUC for ULA2 prediction was 0.55 (95% CI: 0.55-0.58) without and 0.63 (95% CI 0.53-0.72) with binning. The sensitivity and specificity of binned PRx were 65%/90% for LLA, 69%/71% for ULA1, and 59%/74% for ULA2, showing wide interindividual variability. In the linear mixed effects model, pial arteriolar diameter changes were significantly associated with PRx changes (P = .002), whereas RBC velocity (P = .28) and RBC flux (P = .24) were not.

CONCLUSION:

We conclude that PRx is predominantly determined by pial arteriolar diameter changes and moderately predicts CA limits. Performance to detect the CA limits varied highly on an individual level. Active therapeutic strategies based on PRx and the associated correlation metrics should incorporate these limitations.
Reversine enhances the conversion of dedifferentiated fat cells into mature cardiomyocytes
Authors: Dharmadjati Budi Baktijasa , Sargowo Djanggan , . Aulanni’am , Pikir Budi Susetyo , Oktaviono Yudi Her , Sativa Oryza , Arjani Kandita , Nugraha Ricardo Adrian
Published: June 2024

Background There is an essential need for cardiomyocyte regeneration among patients with heart failure. Transplantation of dedifferentiated fat (DFAT) cells may lead to an improvement of cardiomyocyte regeneration among heart failure patients. We believe that DFAT cells are promising candidate cell sources for cardiac regeneration. However, the pathway underlying how DFAT cells of the adipose lineage differentiate into mature cardiomyocytes isn’t fully understood. Methods We conducted an experimental laboratory study on isolated DFAT cells from adipose tissue of healthy adults. Then, we treated cells with different concentrations of reversine (10, 20 and 40 nM), and performed RNA extraction and cDNA synthesis. Next, we used a ceiling culture method based on the buoyancy properties of mature lipid-filled adipocytes. Stemness expression (Octamer-binding transcription factor 4 [Oct4], brachyury, Fetal liver kinase 1 [Flk-1]) was quantified by reverse transcription-quantitative (RT-q)PCR, while cardiomyocyte expression (Transcription factor GATA-4 [GATA4] and cardiac troponin T [cTnT]) was quantified by immunocytochemistry. Results ANOVA with Tukey’s post-hoc found that 10 nM reversine increased greater Flk-1 expression compared to the control group (MD: 5.037 + 0.998; p < 0.001), but there were no significant changes among Oct4 (MD: 0.013 + 1.244; p = 0.99) and brachyury expression (MD: 0.157 + 0.084; p = 0.252). Kruskal-Wallis revealed that the expression of GATA4 (1.65 [0.41-1.98] to 0.015 [0.007-0.034]; p =0.017) reduced significantly from day 7 until day 21 and cTnT (5.07 [6.62-8.91] to 8.22 [6.81-9.40]; p= 0.001) increased significantly from day 7 until day 21. Conclusions Reversine could increase the expression of Flk-1, but it was unable to stimulate the expression of Oct4 and brachyury related to cell stemness. An optimal concentration of 10 nM reversine may have the greatest effect on enhancing the differentiation of DFAT cells into mature cardiomyocytes, as indicated by higher cTnT expression between cells.
Whole body vibration and rider comfort determination of an electric two-wheeler test rig
Authors: Krishna Keerthan , Hegde Sriharsha , G T Mahesha , Shenoy B Satish
Published: June 2024

Background Two-wheeled vehicles are the major mode of transportation in India. Such vehicles are exposed to excessive vibration on the road when compared to four-wheeled vehicles. However, the research on the reduction of whole body vibration in the case of two-wheelers is not explored in detail. The present study predicts rider comfort in the case of an electric two-wheeler as per ISO 2631-1, by obtaining the finding the weighted acceleration at the strategic locations of vibration at the test rig. Methods An electric two-wheeler test rig is used in the study. The values of acceleration from the test rig in running conditions are obtained by using NI LabVIEW 2019. The drive cycle of the electric vehicle (EV) test rig is controlled by Sync sols’ EV lab software. Obtaining the weighted root mean square (RMS) acceleration from running the test setup, it is compared with the ISO 2631-1 standard to obtain the rider comfort. Results Loading area, traction motor, base mount, and suspension were found to be the strategic points of vibration. Frequency weighted RMS acceleration of 0.3 to 0.4 m/s2 obtained at these points are prone to cause discomfort for the rider. Vehicle speed, road profile, and duration of exposure were found to be important parameters affecting the rider’s comfort. A maximum of 4.6 m/s2 amplitude was observed. The loading area, which corresponds to a rider’s seat in actual vehicle, is important and reduction of these vibrations make the ride comfortable for the rider. Suspension and base mount of the test rig are found to be uncomfortable observing the weighted RMS acceleration. Conclusions A suitable damping technique design is very much essential in reducing these vibrations and improve the rider comfort, as many more non-deterministic vibrations are prone to cause dis-comfort in case of actual on road riding conditions.
Explicit training through neurodevelopmental therapy improves tone and postural control in hemiplegic stroke-A Systematic review protocol
Authors: Raghuveer Raghumahanti , Hullumani V Sharath , Bansal Kshitija , Agarwal Parul Raj
Published: June 2024

Introduction Hemiplegia is the common term used to describe a multitude of clinical problems associated with a stroke. Hemiplegic stroke accounts for 70-85% of all first strokes. Trunk stability is impaired due to hypertonia and weakness in hemiplegia. Impaired trunk control leads to gait and postural abnormalities which if left untreated causes permanent disability in hemiplegics. Objective To investigate the scope of research on the benefits of explicit training using Neurodevelopmental Therapy (NDT) for enhancing tone and postural control in subjects with hemiplegic stroke. Methods In order to adhere to established protocols of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, the systematic review will be carried out to find pertinent studies published up to the search date, and a thorough search strategy will be applied across popular electronic databases including PubMed/Medline, Scopus, and Cochrane Library. This systematic review methodology has been registered in PROSPERO for rigorous and transparent dissemination of study search, synthesis, and analysis. Discussion As the motor impairments due to abnormal tone and postural impairment in hemiplegic stroke substantially impact a stroke survivor’s quality of life, this study will provide a thorough and methodical approach to synthesize and report the merits and demerits on the effectiveness of NDT in enhancing tone and postural control, considering the potential variability in interventions and outcomes, and the methodological rigor of particular studies. The review also intends to provide significant insights for clinicians, researchers, and policymakers by critically analysing and summarizing the present state of research in this domain. This will facilitate evidence-based decision-making in rehabilitation techniques for patients with hemiplegic stroke. Systematic Review Registration number CRD42023476137
Zoom fatigue related to online learning among medical students in Thailand: Prevalence, predictors, and association with depression
Authors: Charoenporn Veevarin , Hanvivattanakul Sirashat , Jongmekwamsuk Kanathip , Lenavat Rinradee , Hanvivattanakul Korravit , Charernboon Thammanard
Published: June 2024

Background Amidst the COVID-19 pandemic, the learning pattern of medical students shifted from onsite to online. This transition may contribute to what has been called “Zoom fatigue.” This study aimed to evaluate the prevalence of Zoom fatigue related to online learning, identify associated factors of Zoom fatigue, and explore its correlation with depression among medical students during the COVID-19 pandemic. Methods This cross-sectional study was conducted among 1st to 6th-year Thai medical students. The online survey was administered using a demographic and health behavior questionnaire, the Patient Health Questionnaire-9 (PHQ-9), and the Thai version of the Zoom Exhaustion & Fatigue Scale (ZEF-T). Results Among the 386 participating students, 221 (57%) were female, with a mean age of 20.6 years. The prevalence of high Zoom fatigue was 9.6%. In the multivariable regression analysis, a lower academic year and a higher number of online learning sessions were significant predictors of Zoom fatigue (p < 0.001), while regular exercise emerged as a protective factor (p = 0.009). The prevalence of depressive disorder was 61.9%, and a significant correlation was found between having a depressive disorder and experiencing Zoom fatigue (p = 0.004). Conclusion Zoom fatigue among medical students was correlated with depression. Consequently, medical students experiencing Zoom fatigue should undergo further assessment for depression. It is crucial to closely monitor medical students in lower academic years with a high number of online sessions for signs of Zoom fatigue. Additionally, implementing strategies, such as reducing the frequency of online sessions and promoting regular exercise, may help alleviate the symptoms.
Current real world health data of telemedicine for heart failure with reduced ejection fraction: a systematic review and meta-analysis
Authors: William Yohanes , Tarigan Tinanda , Chen Jery , Ismail Muhamad Taufik , Hariawan Hariadi
Published: June 2024

Abstract* Background Telemedicine has improved adherence to heart failure (HF) treatment, however it has not yet been tailored specifically to address HF with reduced ejection fraction (HFrEF). Our objective is to undertake a comprehensive systematic review and meta-analysis of existing research studies that focus on telemedicine in HFrEF. Methods We conducted an extensive literature review encompassing trials which included outpatients with HFrEF who underwent telemedicine compared with usual care. We exclude any studies without ejection fraction data. Three bibliographic databases from PubMed, ScienceDirect, and Cochrane Library were utilized in our search from January 1999 to May 2023. The endpoints of interest included all-cause mortality, cardiovascular-related mortality, all-cause hospitalization, and HF-related hospitalization. The Cochrane risk-of-bias (RoB) and the risk of bias in non-randomized studies – of interventions (ROBINS-I) were used for non-randomized or observational studies. To quantitatively analyze the collective findings, a pooled odds ratio (OR) was computed for each outcome. Results Out of the initial pool of 4,947 articles, we narrowed down our analysis to 27 studies, Results showed that telemedicine significantly reduced all-cause mortality (OR: 0.65; 95% CI 0.54 – 0.78; p<0.00001), cardiovascular-related mortality (OR 0.68, 95% CI 0.58 – 0.80, p < 0.00001), and HF-related hospitalization based on number of events (OR 0.77, 95% CI 0.64 – 0.94, p = 0.009) as well as number of patients (OR 0.78, 95% CI 0.69 – 0.87, p < 0.0001). Conclusion Telemedicine was shown significantly beneficial in decreasing mortality and hospitalization in HFrEF patients. Future research should focus on standardizing effective telemedicine practices due to the existing variability in methods and clinical situation of the patients. PROSPERO: CRD42023471222 registerd on October 21, 2023
The genome sequence of the oak pinhole borer, Platypus cylindrus Fabricius, 1792
Authors: Barclay Maxwell V. L. , Vassiliades Danaë , Bayfield Farrell Will , Cristóvão Joana , Matsumoto Keita , Geiser Michael , Telfer Mark G. ,   Natural History Museum Genome Acquisition Lab,   University of Oxford and Wytham Woods Genome Acquisition Lab,   Darwin Tree of Life Barcoding collective,   Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team,   Wellcome Sanger Institute Scientific Operations: Sequencing Operations,   Wellcome Sanger Institute Tree of Life Core Informatics team,   Tree of Life Core Informatics collective,   Darwin Tree of Life Consortium
Published: June 2024

We present a genome assembly from an individual male Platypus cylindrus (the oak pinhole borer; Arthropoda; Insecta; Coleoptera; Curculionidae). The genome sequence is 147.5 megabases in span. Most of the assembly is scaffolded into 8 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 19.29 kilobases in length. Gene annotation of this assembly on Ensembl identified 13,468 protein coding genes.