mdpi-ai/citelens huggingface dataset:
The Landscape of Iron Metabolism-Related and Methylated Genes in the Prognosis Prediction of Clear Cell Renal Cell Carcinoma
Field: ONCOLOGY

Background: Clear cell renal cell carcinoma (ccRCC) is characteristics of resistance to chemotherapy and radiotherapy. The prognosis of ccRCC was dismay with immense diversity. Iron metabolism disturbance is a common phenomenon in ccRCC. The purpose of our study is to identify and validate the candidate prognostic gene signature of iron metabolism and methylation closely related to the poor prognosis of ccRCC through comprehensive bioinformatics analysis in The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Methods: The prognostic iron metabolism-related genes were screened according to the overlapping differentially expressed genes (DEGs) from the TCGA database. We built a prognostic model using risk score method to predict OS, each ccRCC patient's risk score was calculated, and the resulting score can divide these patients into two categories according to the cut-point risk score. The prognostic significance of the hub genes was further evaluated with the Kaplan-Meier (KM) survival and Receiver Operating Characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analysis was implemented to evaluate the impact of each variable on OS. Furthermore, the prediction power of the 25 gene signatures has been validated using an independent ccRCC cohort from the GEO database. The Gene Set Enrichment Analysis (GSEA) identified the characteristics of hub related oncogenes. Finally, we utilize Weighted Gene Co-expression Network Analysis (WGCNA) to investigate the co-expression network based on these DEGs. Results: In this study, we identified and validated 25 iron metabolism-related and methylated genes as the prognostic signatures, which differentiated ccRCC patients into high and low risk subgroups. The KM analysis showed that the survival rate of the high-risk patients was significantly lower than that of the low-risk patients. The risk score calculated with 25 gene signatures could largely predict OS and DFS for 1, 3, and 5 years in patients with ccRCC. Conclusions: Taken together, we identified the key iron metabolism-related and methylated genes for ccRCC through a comprehensive bioinformatics analysis. This study provides a reliable and robust gene signature for the prognostic predictor of ccRCC patients and maybe provides a promising treatment strategy for this lethal disease.
Implicit Standardization in a Minority Language Community: Real-Time Syntactic Change among Hasidic Yiddish Writers
Field: AI

The recent turn to “big data” from social media corpora has enabled sociolinguists to investigate patterns of language variation and change at unprecedented scales. However, research in this paradigm has been slow to address variable phenomena in minority languages, where data scarcity and the absence of computational tools (e.g., taggers, parsers) often present significant barriers to entry. This article analyzes socio-syntactic variation in one minority language variety, Hasidic Yiddish, focusing on a variable for which tokens can be identified in raw text using purely morphological criteria. In non-finite particle verbs, the overt tense marker tsu (cf. English to, German zu) is variably realized either between the preverbal particle and verb (e.g., oyf-tsu-es-n up-to-eat-INF ‘to eat up’; the conservative variant) or before both elements (tsu oyf-es-n to up-eat-INF; the innovative variant). Nearly 38,000 tokens of non-finite particle verbs were extracted from the popular Hasidic Yiddish discussion forum Kave Shtiebel (the ‘coffee room’; kaveshtiebel.com). A mixed-effects regression analysis reveals that despite a forum-wide favoring effect for the innovative variant, users favor the conservative variant the longer their accounts remain open and active. This process of rapid implicit standardization is supported by ethnographic evidence highlighting the spread of language norms among Hasidic writers on the internet, most of whom did not have the opportunity to express themselves in written Yiddish prior to the advent of social media.
A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors
Field: ONCOLOGY

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80–220 mg/day; Arm C) with 60–80 mg/m2/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.
Appropriate arrangement of cancer treatment after COVID-19 epidemic peaks in China
Field: ONCOLOGY

Purpose COVID-19 is causing a lot of problems in health services around the world, especially in medical institutions receiving cancer patients. On March 12, China’s National Health Commission announced that the peak of the COVID-19 epidemic has passed in China. Thus, a proper arrangement of medication, surgery and radiotherapy for patients with cancer is of vital importance after the epidemic peak. Methods A range of measures have been implemented in our center. Specific patients take priority for chemotherapy treatment. The amount of semi-elective and elective surgeries could be gradually increased beyond urgent and emergency surgery. The hypofractionated radiotherapy is recommended in the right circumstances. Results On March 13, our center announced that more than 5000 visits of chemotherapy and radiotherapy are arranged in our outpatient clinics and none of our patients and staffs have been diagnosed with COVID-19 as of March 28, 2020. Conclusion The rational arrangement we make now may be helpful to the future restoration of cancer treatments in other countries.
Form-Focused Instruction in the Heritage Language Classroom: Toward Research-Informed Heritage Language Pedagogy
Field: EDUCATION

In the context of adult second language teaching, heritage language speakers have been recognized as a special group of language learners, whose experience with their home language, as well as their motivations for (re)learning it, differ drastically from those of an average learner of a second language. Current heritage language pedagogical approaches focus primarily on the development of communicative (or functional) abilities of the heritage learners and on critical exploration of bilingual practices and identities. However, structural accuracy remains a persistent issue for heritage speakers, who do not always reach higher levels of proficiency in their heritage language (as measured by standard language proficiency tests). In this paper, we use the example of heritage Russian instruction in American college classrooms to argue for the critical role of form-focused instruction in teaching a heritage language, and in particular in bringing heritage learners to greater proficiency. The argument for the importance of form-focused instruction is based on the results of extensive linguistic research combined with insights from the currently available pedagogically oriented research. We formulate and discuss instructional methods that help educators (1) develop heritage learners’ attention to grammatical form, (2) foster heritage learners’ understanding of grammatical concepts, and (3) increase the learners’ metalinguistic awareness. Given consistent parallels across different heritage languages, the methodologies developed for Russian learners can apply to other heritage language classrooms as well, with adjustments based on the sociolinguistic context of particular heritage languages.
Improving Daily Peak Flow Forecasts Using Hybrid Fourier-Series Autoregressive Integrated Moving Average and Recurrent Artificial Neural Network Models
Field: AI

In multi-purpose reservoirs, to achieve optimal operation, sophisticated models are required to forecast reservoir inflow in both short- and long-horizon times with an acceptable accuracy, particularly for peak flows. In this study, an auto-regressive hybrid model is proposed for long-horizon forecasting of daily reservoir inflow. The model is examined for a one-year horizon forecasting of high-oscillated daily flow time series. First, a Fourier-Series Filtered Autoregressive Integrated Moving Average (FSF-ARIMA) model is applied to forecast linear behavior of daily flow time series. Second, a Recurrent Artificial Neural Network (RANN) model is utilized to forecast FSF-ARIMA model’s residuals. The hybrid model follows the detail of observed flow time variation and forecasted peak flow more accurately than previous models. The proposed model enhances the ability to forecast reservoir inflow, especially in peak flows, compared to previous linear and nonlinear auto-regressive models. The hybrid model has a potential to decrease maximum and average forecasting error by 81% and 80%, respectively. The results of this investigation are useful for stakeholders and water resources managers to schedule optimum operation of multi-purpose reservoirs in controlling floods and generating hydropower.
Quantitative Analysis of Differential Expression of HOX Genes in Multiple Cancers
Field: ONCOLOGY

Transcription factors encoded by Homeobox (HOX) genes play numerous key functions during early embryonic development and differentiation. Multiple reports have shown that mis-regulation of HOX gene expression plays key roles in the development of cancers. Their expression levels in cancers tend to differ based on tissue and tumor type. Here, we performed a comprehensive analysis comparing HOX gene expression in different cancer types, obtained from The Cancer Genome Atlas (TCGA), with matched healthy tissues, obtained from Genotype-Tissue Expression (GTEx). We identified and quantified differential expression patterns that confirmed previously identified expression changes and highlighted new differential expression signatures. We discovered differential expression patterns that are in line with patient survival data. This comprehensive and quantitative analysis provides a global picture of HOX genes’ differential expression patterns in different cancer types.
Progression of Cognitive-Affective States During Learning in Kindergarteners: Bringing Together Physiological, Observational and Performance Data
Field: EDUCATION

It has been shown that combining data from multiple sources, such as observations, self-reports, and performance with physiological markers offers better insights into cognitive-affective states during the learning process. Through a study with 12 kindergarteners, we explore the role of utilizing insights from multiple data sources, as a potential arsenal to supplement and complement existing assessments methods in understanding cognitive-affective states across two main pedagogical approaches—constructionist and instructionist—as children explored learning a chosen Science, Technology, Engineering and Mathematics (STEM) concept. We present the trends that emerged across pedagogies from different data sources and illustrate the potential value of additional data channels through case illustrations. We also offer several recommendations for such studies, particularly when collecting physiological data, and summarize key challenges that provide potential avenues for future work.
A Novel Combination Treatment with Honokiol and Rapamycin Effectively Restricts c-Met-Induced Growth of Renal Cancer Cells, and also Inhibits the Expression of Tumor Cell PD-L1 Involved in Immune Escape
Field: ONCOLOGY

The mTOR inhibitor Rapamycin has tumor inhibitory properties; and it is also used as an immunosuppressive agent after organ transplantation. However, prolonged Rapamycin treatment re-activates Akt and can promote cancer growth. Honokiol is a natural compound with both anti-tumorigenic and anti-inflammatory properties. Here, we assessed the anti-tumor effects of Rapamycin and Honokiol combination in renal cell carcinoma (RCC). Receptor tyrosine kinase c-Met-mediated signaling plays a major role in RCC growth. We observed that compared with Rapamycin alone, Rapamycin + Honokiol combination can effectively down-regulate c-Met-induced Akt phosphorylation in renal cancer cells; and it markedly inhibited Ras activation and cell proliferation and promoted G1 phase cell cycle arrest. The combination treatment significantly induced ROS generation and cancer cell apoptosis even when c-Met is activated. Importantly, Honokiol, but not Rapamycin, decreased c-Met-induced expression of the co-inhibitory molecule PD-L1, implied in the immune escape of renal cancer cells. In mouse renal cancer cells and Balb/c splenocytes co-culture assay, Rapamycin + Honokiol markedly potentiated immune-cell-mediated killing of cancer cells, possibly through the down-regulation of PD-L1. Together, Honokiol can effectively overcome the limitation of Rapamycin treatment alone; and the combination treatment can markedly restrict the growth of RCC, with particular importance to post-transplantation renal cancer.
Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas
Field: ONCOLOGY

Purpose: The aim of this study was to investigate DNA methylation alterations in non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinomas (HCCs). Methods: Genome-wide DNA methylation analysis was performed using the Infinium Human Methylation 450 K BeadChip, and levels of mRNA expression were analyzed by quantitative reverse transcription-PCR. Results: Compared to 36 samples of normal control liver tissue (C), DNA methylation alterations were observed on 19,281 probes in 22 samples of cancerous tissue (T) obtained from patients showing histological features compatible with NASH in their non-cancerous liver tissue (N). Among those probes, 1396 were located within CpG islands or their shores and shelves, designed around the transcription start sites of 726 genes. In representative genes, such as DCAF4L2, CKLF, TRIM4, PRC1, UBE2C and TUBA1B, both DNA hypomethylation and mRNA overexpression were observed in T samples relative to C samples, and the levels of DNA methylation and mRNA expression were inversely correlated with each other. DNA hypomethylation occurred even in N samples at the precancerous NASH stage, and this was inherited by or further strengthened in T samples. DNA hypomethylation of DCAF4L2, CKLF and UBE2C was observed in both NASH-related and viral hepatitis-related HCCs, whereas that of TRIM4, PRC1 and TUBA1B occurred in a NASH-related HCC-specific manner. DNA hypomethylation and/or mRNA overexpression of these genes was frequently associated with the necroinflammatory grade of NASH and was correlated with poorer tumor differentiation. Conclusion: DNA methylation alterations may occur under the necroinflammatory conditions characteristic of NASH and participate in NASH-related hepatocarcinogenesis through aberrant expression of tumor-related genes.
Risk Factor Analysis of Acute Kidney Injury After Microwave Ablation of Hepatocellular Carcinoma: A Retrospective Study
Field: ONCOLOGY

Objectives:Acute kidney injury (AKI) is a recently observed side effect in patients after microwave ablation (MWA) of hepatocellular carcinoma (HCC) and is associated with negative outcomes. The aim of this study is to explore the risk factors of affecting the occurrence of AKI (stages 1b, 2, and 3), because they have a higher mortality rate than patients with AKI (stage 1a) and without AKI. Materials and methods:In this retrospective study, a total of 1,214 patients with HCC who were treated with MWA under ultrasound (US) guidance in our department between January 2005 and November 2017 were enrolled. We evaluated the influence of 20 risk factors. Univariate and multivariate analysis were used for statistical analysis. The possible risk factors of AKI after MWA for HCC were summarized. Results:AKI, AKI (stage 1a), and AKI (stages 1b, 2, and 3) after MWA were found in 34, 15, and 19 patients (2.80, 1.24, and 1.57%), respectively. Among 34 patients with AKI, 10 cases with AKI (stage 1a) and 6 cases with AKI (stages 1b, 2, and 3) recovered before their discharge without any treatment for AKI and 9 cases with AKI (stages 1b, 2, and 3) with further treatment. Four cases who had chronic renal failure before MWA of liver accepted renal dialysis. By univariate analysis, the number of antenna insertions (P= 0.027, OR = 3.3), MWA time >= 20 min (P= 0.029, OR = 4.3), creatinine (Cr)-pre above the upper limit of the reference value (P< 0.001, OR = 35.5), albumin (Alb)-pre (P= 0.030, OR = 0.9), and red blood cell (RBC)-pre (P< 0.001, OR = 0.3) were significant risk factors. By multivariate analysis, Cr-pre >= 110 mu mol/L (P< 0.001, OR = 31.4) and MWA time >= 20 min (P= 0.043 OR = 9.9) were the independent risk factors. Conclusion:AKI (stages 1b, 2, and 3) is a relatively serious complication after MWA for HCC, which is related to MWA time and Cr-pre. It requires attention by clinicians. So it is of great necessity to assess the Cr-pre level and reduce the MWA time to <20 min to minimize the risk of AKI after MWA for HCC.
Clustering and Recognition of Spatiotemporal Features Through Interpretable Embedding of Sequence to Sequence Recurrent Neural Networks
Field: AI

Encoder-decoder recurrent neural network models (RNN Seq2Seq) have achieved success in ubiquitous areas of computation and applications. They were shown to be effective in modeling data with both temporal and spatial dependencies for translation or prediction tasks. In this study, we propose an embedding approach to visualize and interpret the representation of data by these models. Furthermore, we show that the embedding is an effective method for unsupervised learning and can be utilized to estimate the optimality of model training. In particular, we demonstrate that embedding space projections of the decoder states of RNN Seq2Seq model trained on sequences prediction are organized in clusters capturing similarities and differences in the dynamics of these sequences. Such performance corresponds to an unsupervised clustering of any spatio-temporal features and can be employed for time-dependent problems such as temporal segmentation, clustering of dynamic activity, self-supervised classification, action recognition, failure prediction, etc. We test and demonstrate the application of the embedding methodology to time-sequences of 3D human body poses. We show that the methodology provides a high-quality unsupervised categorization of movements. The source code with examples is available in a Github repository1.
Baoyuan Jiedu Decoction Alleviates Cancer-Induced Myotube Atrophy by Regulating Mitochondrial Dynamics Through p38 MAPK/PGC-1α Signaling Pathway
Field: ONCOLOGY

Cancer cachexia is a multifactorial syndrome characterized by continuous body wasting and loss of skeletal muscle. Impaired mitochondria function is closely associated with muscle atrophy in cancer cachexia. Our previous study confirmed the effectiveness of Baoyuan Jiedu decoction (BJD) in inhibiting cancer-induced muscle atrophy in an in vivo model. However, little is known about its mechanisms in regulating mitochondria dysfunction. In this study, we evaluated the therapeutic effect and action mechanisms of BJD against atrophy both in the Lewis-conditioned medium induced C2C12 myotube atrophy model and in a BALB/c mice xenograft model using mouse colon cancer C26 cells. The mitochondrial content was tested by 10-Non-ylacridine orange staining. Expressions of related proteins and mRNAs were detected by western blotting (WB) and qPCR, respectively. As a result, 18 major components were identified in BJD by ultra-high performance liquid chromatography-quadrupole (UHPLC-Q) Exactive analysis. As shown in the in vitro results, BJD treatment prevented prominent myotube atrophy and increased the myotube diameter of C2C12 cells. Besides, BJD treatment increased mitochondrial content and ATPase activity. Furthermore, the protein and mRNA expressions that were related to mitochondrial functions and generation such as cytochrome-c oxidase IV, Cytochrome C, nuclear respiratory factor 1, and mitochondrial transcription factor A were significantly increased in BJD treatment compared to the control group. The in vivo results showed that BJD treatment prevented body weight loss and improved the gastrocnemius index in cachexia mice. Moreover, the expressions of Atrogin-1 and muscle RING-finger protein-1 were decreased by BJD treatment. Mechanically, BJD increased the expression of peroxisome proliferator-activated receptor-gamma coactivator 1, and consistently, inhibited the expression of p38 MAPK and its phosphorylation both in vivo and in vitro. Taken together, this study identified that BJD effectively relieved cancer-induced myotube atrophy and provided a potential mechanism for BJD in regulating mitochondrial dynamics through p38 MAPK/PGC-1α signaling pathway.
Pembrolizumab-Induced Psoriasis in Metastatic Melanoma: Activity and Safety of Apremilast, a Case Report
Field: ONCOLOGY

Background: Immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 receptor (PD-1), and programmed death-1 receptor and its ligand (PD-L1) increased the survival of patients affected by metastatic malignant melanoma. Due to their mechanism of action, these drugs are associated with a unique toxicity profile. Indeed, immune-related adverse events (irAEs) present a wide clinical spectrum representing the Achilles’ heel of immunotherapy. Overall, cutaneous toxicities are among the most common irAEs. Immunomodulatory drugs are used for the management of irAEs and can theoretically lead to tumor escape. Case Presentation: We report the case of a 75-year-old man with metastatic melanoma receiving the anti-PD1 Pembrolizumab therapy. After 10 treatment cycles, the patient came to our clinic with itchy psoriatic manifestations widespread >30% of the body surface [12.3 Psoriasis Area and Severity Index (PASI) score] that negatively impacted on the patient’s quality of life and compliance with immunotherapy. Additionally, he had no positive personal history of psoriasis. Given the severity of the cutaneous manifestations, in a multidisciplinary approach, Apremilast (an oral small molecule PDE4 inhibitor) was started. Furthermore, Pembrolizumab was interrupted for 4 weeks until the improvement of skin lesions and the disappearance of itching. Immunosuppressive methylprednisolone therapy was initiated with a dose of 16 mg/die; then, this initial dose was progressively reduced until discontinuation. After 10 months, the patient had a good general clinical condition with psoriasis complete remission. Moreover, positron emission tomography (PET) and computed tomography (CT) scans showed complete response by immune Response Evaluation Criteria in Solid Tumors (iRECIST). Conclusion: To the best of our knowledge, this is the first report on the safety and efficacy of Apremilast for the treatment of immunotherapy-induced psoriasis in metastatic melanoma.