bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-infiltrating immune cells based TMEscore and related gene signature is associated with the survival of CRC patients and response to fluoropyrimidine-based chemotherapy
Authors: Guo Xian-Wen , Li Si-Qi , Lei Rong-E , Ding Zhen , Hu Bang-li , Lin Rong 
Published: August 2022

BackgroundTumor-infiltrating immune cells (TIICs) are associated with chemotherapy response. This study aimed to explore the prognostic value of a TIIC-related tumor microenvironment score (TMEscore) in patients with colorectal cancer (CRC) who underwent chemotherapy and construct a TMEscore-related gene signature to determine its predictive value.MethodsGene profiles of patients who underwent fluoropyrimidine-based chemotherapy were collected, and their TIIC fractions were calculated and clustered. Differentially expressed genes (DEGs) between clusters were used to calculate the TMEscore. The association between the TMEscore, chemotherapy response, and survival rate was analyzed. Machine learning methods were used to identify key TMEscore-related genes, and a gene signature was constructed to verify the predictive value.ResultsTwo clusters based on the TIIC fraction were identified, and the TMEscore was calculated based on the DEGs of the two clusters. The TMEscore was higher in patients who responded to chemotherapy than in those who did not, and was associated with the survival rate of patients who underwent chemotherapy. Three machine learning methods, support vector machine (SVM), decision tree (DT), and Extreme Gradient Boosting (XGBoost), identified three TMEscore-related genes (ADH1C, SLC26A2, and NANS) associated with the response to chemotherapy. A TMEscore-related gene signature was constructed, and three external cohorts validated that the gene signature could predict the response to chemotherapy. Five datasets and clinical samples showed that the expression of the three TMEscore-related genes was increased in tumor tissues compared to those in control tissues.ConclusionsThe TIIC-based TMEscore was associated with the survival of CRC patients who underwent fluoropyrimidine-based chemotherapy, and predicted the response to chemotherapy. The TMEscore-related gene signature had a better predictive value for response to chemotherapy than for survival.
Patient selection, inter-fraction plan robustness and reduction of toxicity risk with deep inspiration breath hold in intensity-modulated radiotherapy of locally advanced non-small cell lung cancer
Authors: Fjellanger Kristine , Rossi Linda , Heijmen Ben J. M. , Pettersen Helge Egil Seime , Sandvik Inger Marie , Breedveld Sebastiaan , Sulen Turid Husevåg , Hysing Liv Bolstad 
Published: August 2022

BackgroundState-of-the-art radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC) is performed with intensity-modulation during free breathing (FB). Previous studies have found encouraging geometric reproducibility and patient compliance of deep inspiration breath hold (DIBH) radiotherapy for LA-NSCLC patients. However, dosimetric comparisons of DIBH with FB are sparse, and DIBH is not routinely used for this patient group. The objective of this simulation study was therefore to compare DIBH and FB in a prospective cohort of LA-NSCLC patients treated with intensity-modulated radiotherapy (IMRT).MethodsFor 38 LA-NSCLC patients, 4DCTs and DIBH CTs were acquired for treatment planning and during the first and third week of radiotherapy treatment. Using automated planning, one FB and one DIBH IMRT plan were generated for each patient. FB and DIBH was compared in terms of dosimetric parameters and NTCP. The treatment plans were recalculated on the repeat CTs to evaluate robustness. Correlations between ΔNTCPs and patient characteristics that could potentially predict the benefit of DIBH were explored.ResultsDIBH reduced the median Dmean to the lungs and heart by 1.4 Gy and 1.1 Gy, respectively. This translated into reductions in NTCP for radiation pneumonitis grade ≥2 from 20.3% to 18.3%, and for 2-year mortality from 51.4% to 50.3%. The organ at risk sparing with DIBH remained significant in week 1 and week 3 of treatment, and the robustness of the target coverage was similar for FB and DIBH. While the risk of radiation pneumonitis was consistently reduced with DIBH regardless of patient characteristics, the ability to reduce the risk of 2-year mortality was evident among patients with upper and left lower lobe tumors but not right lower lobe tumors.ConclusionCompared to FB, DIBH allowed for smaller target volumes and similar target coverage. DIBH reduced the lung and heart dose, as well as the risk of radiation pneumonitis and 2-year mortality, for 92% and 74% of LA-NSCLC patients, respectively. However, the advantages varied considerably between patients, and the ability to reduce the risk of 2-year mortality was dependent on tumor location. Evaluation of repeat CTs showed similar robustness of the dose distributions with each technique.
Characterization of genetic predisposition to molecular subtypes of breast cancer in Brazilian patients
Authors: Paixão Daniele , Torrezan Giovana Tardin , Santiago Karina Miranda , Formiga Maria Nirvana , Ahuno Samuel Terkper , Dias-Neto Emmanuel , Tojal da Silva Israel , Foulkes William D. , Polak Paz , Carraro Dirce Maria 
Published: August 2022

IntroductionBRCA1 and BRCA2 germline pathogenic variants (GPVs) account for most of the 5-10% of breast cancer (BC) that is attributable to inherited genetic variants. BRCA1 GPVs are associated with the triple negative subtype, whereas BRCA2 GPVs are likely to result in higher grade, estrogen-receptor positive BCs. The contribution of other genes of high and moderate risk for BC has not been well defined and risk estimates to specific BC subtypes is lacking, especially for an admixed population like Brazilian.ObjectiveThe aim of this study is to evaluate the value of a multigene panel in detecting germline mutations in cancer-predisposing genes for Brazilian BC patients and its relation with molecular subtypes and the predominant molecular ancestry.Patients and methodsA total of 321 unrelated BC patients who fulfilled NCCN criteria for BRCA1/2 testing between 2016-2018 were investigated with a 94-genes panel. Molecular subtypes were retrieved from medical records and ancestry-specific variants were obtained from off-target reads obtained from the sequencing data.ResultsWe detected 83 GPVs in 81 patients (positivity rate of 25.2%). Among GPVs, 47% (39/83) were identified in high-risk BC genes (BRCA1/2, PALB2 and TP53) and 18% (15/83) in moderate-penetrance genes (ATM, CHEK2 and RAD51C). The remainder of the GPVs (35% - 29/83), were identified in lower-risk genes. As for the molecular subtypes, triple negative BC had a mutation frequency of 31.6% (25/79), with predominance in BRCA1 (12.6%; 10/79). Among the luminal subtypes, except Luminal B HER2-positive, 18.7% (29/155) had GPV with BRCA1/2 genes contributing 7.1% (11/155) and non-BRCA1/2 genes, 12.9% (20/155). For Luminal B HER2-positive subtype, 40% (16/40) had GPVs, with a predominance of ATM gene (15% - 6/40) and BRCA2 with only 2.5% (1/40). Finally, HER2-enriched subtype presented a mutation rate of 30.8% (4/13) with contribution of BRCA2 of 7.5% (1/13) and non-BRCA1/2 of 23% (3/13). Variants of uncertain significance (VUS) were identified in 77.6% (249/321) of the patients and the number of VUS was increased in patients with Asian and Native American ancestry.ConclusionThe multigene panel contributed to identify GPVs in genes other than BRCA1/2, increasing the positivity of the genetic test from 9.6% (BRCA1/2) to 25.2% and, considering only the most clinically relevant BC predisposing genes, to 16.2%. These results indicate that women with clinical criteria for hereditary BC may benefit from a multigene panel testing, as it allows identifying GPVs in genes that directly impact the clinical management of these patients and family members.
Immune function in newborns with in-utero exposure to anti-TNFα therapy
Authors: Weiss Batia , Ben-Horin Shomron , Lev Atar , Broide Efrat , Yavzori Miri , Lahat Adi , Kopylov Uri , Picard Orit , Eliakim Rami , Ron Yulia , Avni-Biron Irit , Yerushalmy-Feler Anat , Assa Amit , Somech Raz , Bar-Gil Shitrit Ariella 
Published: August 2022

Background and aimAnti-TNFα is measurable in infants exposed in utero up to 12 months of age. Data about the exposure effect on the infant’s adaptive immunity are limited. We aimed to prospectively evaluate the distribution and function of T and B cells, in infants of females with inflammatory bowel disease, in utero exposed to anti-TNFα or azathioprine.MethodsA prospective multi-center study conducted 2014–2017. Anti-TNFα levels were measured in cord blood, and at 3 and 12 months. T-cell repertoire and function were analyzed at 3 and 12 months by flow-cytometry, expression of diverse T cell receptors (TCR) and T-cell receptor excision circles (TREC) quantification assay. Serum immunoglobulins and antibodies for inactivated vaccines were measured at 12 months. Baseline clinical data were retrieved, and 2-monthly telephonic interviews were performed regarding child infections and growth.Results24 pregnant females, age 30.6 (IQR 26.5–34.5) years were recruited, 20 with anti-TNFα (infliximab 8, adalimumab 12), and 4 with azathioprine treatment. Cord blood anti-TNFα was higher than maternal blood levels [4.3 (IQR 2.3–9.2) vs. 2.5 (IQR 1.3–9.7) mcg/ml], declining at 3 and 12 months. All infants had normal number of B-cells (n = 17), adequate levels of immunoglobulins (n = 14), and protecting antibody levels to Tetanus, Diphtheria, Hemophilus influenza-B and hepatitis B (n = 17). All had normal CD4+, CD8+ T-cells, and TREC numbers. TCR repertoire was polyclonal in 18/20 and slightly skewed in 2/20 infants. No serious infections requiring hospitalization were recorded.ConclusionWe found that T-cell and B-cell immunity is fully mature and immune function is normal in infants exposed in utero to anti-TNFα, as in those exposed to azathioprine. Untreated controls and large-scale studies are needed to confirm these results.
The correlation between probiotic use and outcomes of cancer patients treated with immune checkpoint inhibitors
Authors: Zhang Lilong , Jin Qi , Chai Dongqi , Kuang Tianrui , Li Chunlei , Guan Yongjun , Liu Li , Wang Weixing , Deng Wenhong 
Published: August 2022

Objective: Immune checkpoint inhibitors (ICIs) have recently demonstrated promising results in improving the prognosis of cancer patients. The goal of this meta-analysis was to determine the impact of probiotic use on the survival of cancer patients treated with ICIs.Methods: Before 3 March 2022, the eligible literature was searched using PubMed, EMBASE, Cochrane Library, Google Scholar, and Clinical trials.gov databases. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were the primary endpoints.Results: A total of 6 studies met the inclusion criteria, and 1,123 patients were included. Meta-analysis showed a trend for probiotic use to prolong PFS (HR: 0.585, 95% CI: 0.328–1.045, p = 0.070) and increase DCR (HR: 1.868, 95% CI: 0.890–3.922, p = 0.099), although it was of borderline statistical significance. We also found that probiotics significantly improved OS (HR: 0.526, 95% CI: 0.341–0.812, p = 0.004) and ORR (OR: 2.831, 95% CI: 1.578–5.076, p &lt; 0.001) in ICI-treated cancer patients. Besides, subgroup analysis showed that non-small cell lung cancer (NSCLC) patients treated with ICIs in combination with probiotics would achieve significantly longer PFS (HR: 0.532, 95% CI: 0.354–0.798, p = 0.002) and OS (HR: 0.528, 95% CI: 0.306–0.912, p = 0.022), as well as higher ORR (OR: 2.552, 95% CI: 1.279–5.091, p = 0.008) and DCR (OR: 2.439, 95% CI: 1.534–3.878, p &lt; 0.001). Sensitivity analysis showed that the above results are stable and reliable. The publication bias test confirmed that there was no publication bias in these results.Conclusion: Current evidence reveals that probiotics can improve the efficacy of ICI treatment in NSCLC patients.Systematic Review Registeration:https://www.crd.york.ac.uk/prospero/, identifier CRD42022316104.
Development and internal validation of simplified predictive scoring (ICU-SEPSA score) for mortality in patients with multidrug resistant infection
Authors: Sirichayanugul Taranee , Srisawat Chansinee , Thummakomut Chawin , Prawang Abhisit , Huynh Nina S , Saokaew Surasak , Phisalprapa Pochamana , Kanchanasurakit Sukrit 
Published: August 2022

Background: Mortality from multidrug-resistant (MDR) pathogens is an urgent healthcare crisis worldwide. At present we do not have any simplified screening tools to predict the risk of mortality associated with MDR infections. The aim of this study was to develop a screening tool to predict mortality in patients with multidrug-resistant organisms.Methods: A retrospective cohort study to evaluate mortality risks in patients with MDR infections was conducted at Phrae Hospital. Univariable and multivariable analyses were used to classify possible risk factors. The model performance was internally validated utilizing the mean of three measures of discrimination corrected by the optimism using a 1000-bootstrap procedure. The coefficients were transformed into item scores by dividing each coefficient with the lowest coefficient and then rounding to the most adjacent number. The area under the receiver operating characteristic curve (AuROC) was used to determine the performance of the model.Results: Between 1 October 2018 and 30 September 2020, a total of 504 patients with MDR infections were enrolled. The ICU-SEPSA score composed of eight clinical risk factors: 1) immunocompromised host, 2) chronic obstructive pulmonary disease, 3) urinary tract infection, 4) sepsis, 5) placement of endotracheal tube, 6) pneumonia, 7) septic shock, and 8) use of antibiotics within the past 3 months. The model showed good calibration (Hosmer-Lemeshow χ2 = 19.27; p-value = 0.50) and good discrimination after optimism correction (AuROC 84.6%, 95% confidence interval [Cl]: 81.0%–88.0%). The positive likelihood ratio of low risk (score ≤ 5) and high risk (score ≥ 8) were 2.07 (95% CI: 1.74–2.46) and 12.35 (95% CI: 4.90–31.13), respectively.Conclusion: A simplified predictive scoring tool wad developed to predict mortality in patients with MDR infections. Due to a single-study design of this study, external validation of the results before applying in other clinical practice settings is warranted.
The Chinese herb Styrax triggers pharmacokinetic herb-drug interactions via inhibiting intestinal CYP3A
Authors: Zhang Feng , Zhang Tiantian , Gong Jiahao , Fang Qinqin , Qi Shenglan , Li Mengting , Han Yan , Liu Wei , Ge Guangbo 
Published: August 2022

Human cytochrome P450 3A4 (hCYP3A4) is a predominant enzyme to trigger clinically relevant drug/herb-drug interactions (DDIs or HDIs). Although a number of herbal medicines have been found with strong anti-hCYP3A4 effects in vitro, the in vivo modulatory effects of herbal medicines on hCYP3A4 and their potential risks to trigger HDIs are rarely investigated. Herein, we demonstrate a case study to efficiently find the herbal medicine(s) with potent hCYP3A4 inhibition in vitro and to accurately assess the potential HDIs risk in vivo. Following screening over 100 herbal medicines, the Chinese herb Styrax was found with the most potent hCYP3A4 inhibition in HLMs. In vitro assays demonstrated that Styrax could potently inhibit mammalian CYP3A in liver and intestinal microsomes from both humans and rats. In vivo pharmacokinetic assays showed that Styrax (i.g., 100 mg/kg) significantly elevated the plasma exposure of two CYP3A-substrate drugs (midazolam and felodipine) when midazolam or felodipine was administered orally. By contrast, the plasma exposure of either midazolam or felodipine was hardly affected by Styrax (i.g.) when the victim drug was administered intravenously. Further investigations demonstrated that seven pentacyclic triterpenoid acids (PTAs) in Styrax were key substances responsible for CYP3A inhibition, while these PTAs could be exposed to intestinal tract at relatively high exposure levels but their exposure levels in rat plasma and liver were extremely low. These findings well explained why Styrax (i.g.) could elevate the plasma exposure of victim drugs only when these agents were orally administrated. Collectively, our findings demonstrate that Styrax can modulate the pharmacokinetic behavior of CYP3A-substrate drugs via inhibiting intestinal CYP3A, which is very helpful for the clinical pharmacologists to better assess the HDIs triggered by Styrax or Styrax-related herbal products.
The neuroprotective effects of melatonin against diabetic neuropathy: A systematic review of non-clinical studies
Authors: Hosseini Asieh , Samadi Mahedeh , Baeeri Maryam , Rahimifard Mahban , Haghi-Aminjan Hamed 
Published: August 2022

Backgrounds: Diabetes can cause diabetic neuropathy (DN), a nerve injury. High blood sugar (glucose) levels can harm nerves all over your body. The nerves in your legs and feet are the most commonly affected by DN. The purpose of this study was to conduct a review of melatonin’s potential neuroprotective properties against DN.Method: A full systematic search was conducted in several electronic databases (Scopus, PubMed, and Web of Science) up to March 2022 under the PRISMA guidelines. Forty-seven studies were screened using predefined inclusion and exclusion criteria. Finally, the current systematic review included nine publications that met the inclusion criteria.Result: According to in vivo findings, melatonin treatment reduces DN via inhibition of oxidative stress and inflammatory pathways. However, compared to the diabetes groups alone, melatonin treatment exhibited an anti-oxidant trend. According to other research, DN also significantly produces biochemical alterations in neuron cells/tissues. Additionally, histological alterations in neuron tissue following DN were detected.Conclusion: Nonetheless, in the majority of cases, these diabetes-induced biochemical and histological alterations were reversed when melatonin was administered. It is worth noting that the administration of melatonin ameliorates the neuropathy caused by diabetes. Melatonin exerts these neuroprotective effects via various anti-oxidant, anti-inflammatory, and other mechanisms.
Analysis of the absorbed constituents and mechanism of liquidambaris fructus extract on hepatocellular carcinoma
Authors: Wang Shuai , Yang Xin-Xin , Li Tian-Jiao , Zhao Lin , Bao Yong-Rui , Meng Xian-Sheng 
Published: August 2022

Background: Hepatocellular carcinoma (HCC) refers to one of the top 10 cancers in terms of morbidity and mortality globally, seriously influencing people’s lives. First recorded in Compendium of Materia Medica, liquidambaris fructus (LF) generates definite anti-liver tumor effect. However, its effective substances and mechanism remain to be elucidated.Methods: Serum pharmacochemistry and UPLC-QTOF-MS technologies were employed to explore the plasma of rats after intragastric administration of liquidambaris fructus extract (LFE) in order to find the active ingredients. Subsequently, DEN-induced rat liver cancer model was established with the purpose of investigating the anti-tumor activity of LFE from physiological, pathological and biochemical aspects. Finally, non-target metabonomics combined with q-PCR and Western blot methods were adopted for revealing the mechanism.Results: Totally 11 prototype blood transfused ingredients, including imperatorin and phellopterin were detected. LFE presents excellent impact on enhancing the quality of life, prolonging the life cycle, reducing inflammatory reaction, protecting hepatocytes, improving body immunity and killing liver tumor cells. Altogether 82 endogenous differential metabolites were found in metabonomics, suggesting that LFE can treat HCC by acting on key targets of PTEN/PI3K/Akt pathway and fatty acid metabolism. Further research also verified that LFE can upregulate the relative expression levels of PTEN, PDCD4, Caspase 9, Caspase 3, Bax and Bad as well as lower the relative expression levels of PI3K, AKT, VEGFA and Bcl-2.Conclusion: This study revealed the pharmacodynamic material basis of LFE in the treatment of HCC, and from the perspective of metabolomics proved that the effects of inhibiting the growth of tumor cells, promoting tumor cell apoptosis, reducing inflammatory reaction, protecting hepatocytes, improving the survival state of tumor rats, and prolonging the life cycle are related to its impact on PTEN/PI3K/Akt, fatty acid metabolism and other key signal pathways.
Food safety knowledge and risk perception among pregnant women: A cross-sectional study in Jordan during the COVID-19 pandemic
Authors: Almanasrah Safaa , Osaili Tareq M. , Al-Nabulsi Anas A. , Obeidat Nail A. , Sindiani Amer M. , Elsalem Lina , Alkhalidy Hana , Mohamad Maysm N. , Saleh Sheima T. , Al Daour Rameez , Al Dhaheri Ayesha S. , Cheikh Ismail Leila 
Published: August 2022

BackgroundPregnant women are at a higher risk of food poisoning compared to the general population. This can be detrimental to both the mother and the fetus. This study aimed to assess the level of knowledge and risk perception of basic food safety and handling among pregnant women in Jordan amid the COVID-19 pandemic.MethodsA descriptive cross-sectional quantitative study among pregnant women in Jordan was conducted using an online questionnaire between November 2020 and January 2021. The survey included socio-demographic data, food safety knowledge, and risk perception questions as well as COVID-19 related questions. A total score for food safety awareness out of 50 was derived for each participant based on the sum of scores from all domains. Student t-test and Analysis of Variance (ANOVA) were conducted using SPSS (Version 26) to compare the mean sum of correct responses of every section (knowledge score) by sociodemographic characteristics.ResultsA total of 325 participants completed the web-based survey. Most of the participants reported receiving food safety-related information during pregnancy (64.9%). The mean total score for the participants was 23.3 ± 4.6 out of 50 (score percentage 46.6%). Participants were mostly aware of foodborne diseases (82.7%) followed by cleaning and sanitation (51.2%), and personal hygiene (49.1%). The least amount of awareness was observed in the cross-contamination (35.0%), food consumption and safety (35.0%), and temperature control (32.8%) domains. Older participants and those with higher education had significantly higher mean scores (p &lt; 0.001). Most participants agreed that the pandemic had a positive impact on enhancing the measures taken to maintain food safety during the pandemic.ConclusionsThis study identified gaps in food safety-related knowledge. Educational programs for pregnant women need robust reinforcement within the community. Efficient educational approaches related to food safety should be provided by health care providers and local health authorities. While the COVID-19 pandemic persists, pregnant women must be well-educated about the virus and its prevention strategies to avoid being infected and ensure their baby's safety as well as their own.