bluuebunny/crossref_metadata_2025 huggingface dataset:
Aqueous Zinc Ion Battery with Potassium Selective Hyper Cross-Linked Dibenzo-18-Crown-6-Ether Membrane
Authors: Bavdane Priyanka P. , Bhatt Bhavana , Nikumbe Devendra Y. , Dave Vidhiben , Sreenath Sooraj , Babujohn Nisar Ahamed , Nagarale Rajaram K.
Published: October 2023

Nonselective ion transport across the separator in zinc-iodine flow batteries (ZIFBs) alters concentration gradients, precipitates insoluble iodine, and generates uneven zinc nucleation on the anode surface. Here, we report the synthesis of a K+ ion-selective hyper-cross-linked dibenzo-18-crown-6-ether-containing polymer (HCP) that allows transfer of the K+ ion while avoiding the crossover of electroactive species. The sulfonated HCP was blended with SPEEK in compositions of 5, 10, and 15%, designated as SHCP1, SHCP2, and SHCP3, respectively. The blending of SHCP results in increases in ion exchange capacity (IEC), water uptake, ionic conductivity, and K+ ion selectivity. The best membrane, SHCP3, showed 7.6 times higher K+ ion selectivity than the neat SPEEK membrane. The galvanostatic charging/discharging over 200 cycles at 20 mA cm−2 current density showed 96% CE, 88% VE, and 84% EE for the SHCP3 membrane. It delivered 37.5 Ah l−1 capacity at 20 mA cm−2 current density, whereas Nafion-117 delivered 22 Ah l−1 capacity. The OCV of the cell with SHCP3 membranes remains at 1 V over 20 h. The results suggest that K+ ion selectivity is significantly helping in mitigating dendrite formation and enhancing the stability of the ZIFB battery, thus increasing its potential use.
Controlling Factors of Organic-Rich Lacustrine Shale in the Jurassic Dongyuemiao Member of Sichuan Basin, SW China
Authors: Zhou Yadong , Jiang Chan , Hu Dongfeng , Wei Zhihong , Wei Xiangfeng , Wang Daojun , Hao Jingyu , Jiang Yuqiang , Gu Yifan
Published: October 2023

Organic-rich continental shale, widespread in the Sichuan Basin during the deposition of the Jurassic Dongyuemiao Member (J1d), is considered the next shale hydrocarbon exploration target in southern China. To identify a shale gas sweetspot and reduce exploration risk, it is of great significance to determine the organic matter (OM) enrichment mechanism of J1d shale. In this study, based on sedimentological characteristics and organic matter content, high-resolution major and trace elements were systematically analyzed to demonstrate terrigenous influx, paleoredox, paleosalinity, paleoproductivity, and paleoclimate. The 1st section interval of the J1d 1st submember is dominated by shallow lake subfacies, while the other intervals have the characteristic of semideep to deep lake subfacies. The 1st submember interval of J1d lacustrine shale is characterized by the warmest-humid paleoclimate, strongest weathering degree, highest terrigenous input, moderate paleoproductivity, and paleoredox condition. Within the Dongyuemiao 1st submember, the 4th section interval has the highest paleoproductivity and the most oxygen-deficient condition in bottom water. During the deposition period of the 2nd submember, the sedimentary environment turned to a cold-dry paleoclimate, weak weathering degree, low terrigenous input, low paleosalinity, and high paleoproductivity. Under the background of semideep and deep lake, the terrigenous OM input plays the most critical role in controlling OM enrichment. Moreover, the high primary productivity of lake surface water and the suboxic condition of lake bottom water contribute to the formation of relatively higher TOC lacustrine shale interval in the 4th section of 1st submember.
Yangjing Capsule Increases Testosterone Production through SET/PI3K/Akt Pathway in Leydig Cell
Authors: Xing Dong , Liu Yuanyuan , Sun Dalin , Wang Dandan , Jin Yihan , Cai Bin , Jin Baofang
Published: October 2023

Background. Our previous works revealed Yangjing capsule (YC) could inhibit cell apoptosis and promote testosterone production in Leydig cells. SET protein has been reported to be important in regulating testosterone synthesis and apoptosis. The purpose of this study was to investigate whether the steroidogenic and antiapoptotic effects of YC are mediated in part by the SET/PI3K/Akt pathway in Leydig cells. Methods. MLTC-1 cells were treated with YC-medicated serum. si-RNA was used to knockdown SET expression in MLTC-1 cells. The elderly BALB/c mice were treated with different doses of YC extract. Flow cytometry and TUNEL staining were used to assess apoptosis in MLTC-1 cells and mouse testes. HE staining was conducted to detect the morphological changes in mouse testes. Testosterone levels in cell culture medium and serum were measured by ELISA kit. Quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression levels of key molecules. Results. YC-medicated serum could significantly increase the expression of SET and StAR, P450scc, HSD17B, and testosterone production in MLTC-1 cells. YC-medicated serum could increase Akt phosphorylation and Bcl-2/Bax ratio to suppress apoptosis in MLTC-1 cells. SET knockdown significantly inhibited YC-medicated serum-induced steroidogenic and antiapoptotic effects in MLTC-1 cells. In vivo experiments revealed the YC extract could enhance SET expression, trigger Akt phosphorylation, and suppress apoptosis in mouse testis to raise serum testosterone levels. Conclusions. A possible mechanism of promoting testosterone production induced by YC in Leydig cell was by triggering SET/PI3K/Akt pathway.
A Factor Marginal Effect Analysis Approach and Its Application in E‐Commerce Search System
Authors: Wang Yingshuai , Sachurengui Sachurengui , Zhang Dezheng , Aziguli Wulamu  , Bao Hashen
Published: October 2023

Feature explanation plays an increasingly essential role in the e‐commerce search platform. Most of the existing studies focus on modeling the user’s interests to estimate the click‐through rate (CTR). A good e‐commerce system not only needs precise ranking to inspire users’ shopping desire but also needs feature explanation to meet the demands of shop owners. The e‐commerce traffic health of merchants is very important. How to effectively achieve shop owners’ multiple goals still remains as an open problem. In industrial search systems, merchants’ key demands mainly include two aspects. On the one hand, merchants want to know rule analysis of online traffic distribution, so as to help them understand the logistics of online traffic. On the other hand, they need relevant online traffic participation tools, which instruct them to participate. To address these issues, we propose a factor marginal effect analysis approach (FMEA) based on game theory, which can compute the contribution of one‐dimensional features to the enhancement of online traffic. First, we use machine learning to model the business target. Then, we improve the SHAP value algorithm, which can provide clear business insights. Finally, we calculate the marginal effect of each feature on the business outcome. In this way, we provide a traffic analysis guidance method and address merchants’ participation challenges. In fact, the FMEA has been deployed in a real‐world Large‐Internet‐Company’s App search systems and successfully serves online e‐commerce service to over hundreds of millions of consumers. Our approach can guide operational decisions effectively and bring +10.05% revenue for the flow index, +7.54% for the user feedback index, and +2.46% for the service index.
The BRD4–NUT Fusion Alone Drives Malignant Transformation of NUT Carcinoma
Authors: Durall R. Taylor , Huang Julianna , Wojenski Luke , Huang Yeying , Gokhale Prafulla C. , Leeper Brittaney A. , Nash Joshua O. , Ballester Pedro L. , Davidson Scott , Shlien Adam , Sotirakis Emmanuel , Bertaux Fabien , Dubus Vincent , Luo Jia , Wu Catherine J. , Keskin Derin B. , Eagen Kyle P. , Shapiro Geoffrey I. , French Christopher A.
Published: October 2023

NUT carcinoma (NC) is an aggressive squamous carcinoma defined by the BRD4–NUT fusion oncoprotein. Routinely effective systemic treatments are unavailable for most NC patients. The lack of an adequate animal model precludes identifying and leveraging cell-extrinsic factors therapeutically in NC. Here, we created a genetically engineered mouse model (GEMM) of NC that forms a Brd4::NUTM1 fusion gene upon tamoxifen induction of Sox2-driven Cre. The model displayed complete disease penetrance, with tumors arising from the squamous epithelium weeks after induction and all mice succumbing to the disease shortly thereafter. Closely resembling human NC (hNC), GEMM tumors (mNC) were poorly differentiated squamous carcinomas with high expression of MYC that metastasized to solid organs and regional lymph nodes. Two GEMM-derived cell lines were developed whose transcriptomic and epigenetic landscapes harbored key features of primary GEMM tumors. Importantly, GEMM tumor and cell line transcriptomes co-classified with those of human NC. BRD4–NUT also blocked differentiation and maintained the growth of mNC as in hNC. Mechanistically, GEMM primary tumors and cell lines formed large histone H3K27ac-enriched domains, termed megadomains, that were invariably associated with the expression of key NC-defining proto-oncogenes, Myc and Trp63. Small-molecule BET bromodomain inhibition (BETi) of mNC induced differentiation and growth arrest and prolonged survival of NC GEMMs, as it does in hNC models. Overall, tumor formation in the NC GEMM is definitive evidence that BRD4–NUT alone can potently drive the malignant transformation of squamous progenitor cells into NC.

Significance:

The development of an immunocompetent model of NUT carcinoma that closely mimics the human disease provides a valuable global resource for mechanistic and preclinical studies to improve treatment of this incurable disease.
Racial Disparities in Accessing Care along the Continuum of Cancer Genetic Service Delivery
Authors: Wagner Ingrid M. , Xuan Ziming , Lu Haibo , Wang Catharine
Published: October 2023

Background:

Public health calls to ensure equity in genomics and precision medicine necessitate a closer examination of how these efforts might differentially affect access to genetic services across demographic subgroups. This study set out to examine racial/ethnic disparities along the cancer genetic service delivery continuum.

Methods:

Retrospective data are drawn from 15 clinical sites across 6 U.S. States. Individuals who screened at-risk for hereditary cancer were: (i) referred/scheduled to see a genetic counselor (referral workflow), or (ii) offered genetic testing at the point-of-care (POC testing workflow). Logistic regression analyses evaluated the associations between race/ethnicity and several outcomes including appointment scheduling, genetic counseling, and genetic testing, controlling for demographics, clinical factors, and county-level covariates.

Results:

A total of 14,527 patients were identified at-risk. Genetic testing uptake was significantly higher at POC sites than referral sites (34% POC vs. 11% referral, P < 0.001). Race/ethnicity was significantly associated with testing uptake among all sites, with non-Hispanic Blacks having lower odds of testing compared with non-Hispanic Whites [aOR = 0.84; 95% confidence interval (CI), 0.71–1.00; P = 0.049]. Moreover, this disparity was observed at referral sites, but not POC sites. Among patients scheduled, non-Hispanic Blacks had lower odds of counseling (aOR = 0.28; 95% CI, 0.17–0.47; P < 0.001).

Conclusions:

Findings suggest that factors influencing genetic counseling show rates may be driving disparities in genetic testing.

Impact:

Strategies to reduce barriers to seeing a genetic counselor, including modifications to clinical workflow, may help mitigate racial/ethnic disparities in genetic testing.
Lenvatinib, Toripalimab plus FOLFOX Chemotherapy in Hepatocellular Carcinoma Patients with Extrahepatic Metastasis: A Biomolecular Exploratory, Phase II Trial (LTSC)
Authors: He MinKe , Huang YeXing , Du ZeFeng , Lai ZhiCheng , Ouyang Hanyue , Shen JingXian , Wen DongSheng , Li QiJiong , Zhang YaoJun , Wei Wei , Chen MinShan , Xu Li , Kan Anna , Shi Ming
Published: October 2023

Purpose:

To investigate the efficacy, safety, and biomarkers of systemic chemotherapy with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) in combination with lenvatinib and toripalimab as the first-line treatment for advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis.

Patients and Methods:

In this biomolecular exploratory, phase II trial, eligible patients underwent the triple combination therapy of lenvatinib, toripalimab, plus FOLFOX chemotherapy. Primary endpoint was progression-free survival (PFS) rate at 6 months by RECIST v1.1. Single-nucleus RNA sequencing (snRNA-seq) of tumor biopsy samples was performed for exploratory biomarker analyses.

Results:

Between November 19, 2019, and July 4, 2021, 30 patients were enrolled. The primary endpoint was a 6-month PFS rate of 66.7%, with a median PFS of 9.73 months [95% confidence interval (CI), 2.89–16.58]. The median overall survival (OS) was 14.63 months (95% CI, 11.77–17.50), with an objective response rate of 43.3%. Twenty-four (80.0%) patients exhibited high-risk features, among whom the median OS and PFS were 13.7 months (95% CI, 9.24–18.16) and 8.3 months (95% CI, 3.02–13.58), respectively. The most common adverse events were neutropenia, and increased aspartate aminotransferase and alanine aminotransferase levels. Exploratory analyses of snRNA-seq profiles suggested that patients with higher abundance of tumor-infiltrating immune cells were more likely to benefit from this combination. In addition, two subtypes of hepatocytes (AKR1C2+ and CFHR4+ malignant hepatocytes) were associated with reduced clinical benefits.

Conclusions:

FOLFOX chemotherapy in combination with lenvatinib and toripalimab showed promising antitumor activity with manageable toxicities in advanced HCC with extrahepatic metastasis. AKR1C2+ and CFHR4+ hepatocyte subtypes may be predictive biomarkers of resistance to the combination therapy.
A Phase I Expansion Cohort Study Evaluating the Safety and Efficacy of the CHK1 Inhibitor LY2880070 with Low-dose Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma
Authors: Huffman Brandon M. , Feng Hanrong , Parmar Kalindi , Wang Junning , Kapner Kevin S. , Kochupurakkal Bose , Martignetti David B. , Sadatrezaei Golbahar , Abrams Thomas A. , Biller Leah H. , Giannakis Marios , Ng Kimmie , Patel Anuj K. , Perez Kimberly J. , Singh Harshabad , Rubinson Douglas A. , Schlechter Benjamin L. , Andrews Elizabeth , Hannigan Alison M. , Dunwell Stanley , Getchell Zoe , Raghavan Srivatsan , Wolpin Brian M. , Fortier Caroline , D'Andrea Alan D. , Aguirre Andrew J. , Shapiro Geoffrey I. , Cleary James M.
Published: October 2023

Purpose:

Combining gemcitabine with CHK1 inhibition has shown promise in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we report the findings from a phase I expansion cohort study (NCT02632448) investigating low-dose gemcitabine combined with the CHK1 inhibitor LY2880070 in patients with previously treated advanced PDAC.

Patients and Methods:

Patients with metastatic PDAC were treated with gemcitabine intravenously at 100 mg/m2 on days 1, 8, and 15, and LY2880070 50 mg orally twice daily on days 2–6, 9–13, and 16–20 of each 21-day cycle. Pretreatment tumor biopsies were obtained from each patient for correlative studies and generation of organoid cultures for drug sensitivity testing and biomarker analyses.

Results:

Eleven patients with PDAC were enrolled in the expansion cohort between August 27, 2020 and July 30, 2021. Four patients (36%) experienced drug-related grade 3 adverse events. No objective radiologic responses were observed, and all patients discontinued the trial by 3.2 months. In contrast to the lack of efficacy observed in patients, organoid cultures derived from biopsies procured from two patients demonstrated strong sensitivity to the gemcitabine/LY2880070 combination and showed treatment-induced upregulation of replication stress and DNA damage biomarkers, including pKAP1, pRPA32, and γH2AX, as well as induction of replication fork instability.

Conclusions:

No evidence of clinical activity was observed for combined low-dose gemcitabine and LY2880070 in this treatment-refractory PDAC cohort. However, the gemcitabine/LY2880070 combination showed in vitro efficacy, suggesting that drug sensitivity for this combination in organoid cultures may not predict clinical benefit in patients.
TABLE 4 from The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC
Authors: Weidhaas Joanne B. , Hu Chen , Komaki Ritsuko , Masters Gregory A. , Blumenschein George R. , Chang Joe Y. , Lu Bo , Dicker Adam P. , Bogart Jeffrey A. , Garces Yolanda I. , Narayan Samir , Robinson Clifford G. , Kavadi Vivek S. , Greenberger Joel S. , Koprowski Christopher D. , Welsh James , Gore Elizabeth M. , MacRae Robert M. , Paulus Rebecca , Bradley Jeffrey D.
Published: October 2023

Worst treatment-related toxicity logistic regression model of KRAS and cetuximab interaction
Supplementary Data Table 4 from The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC
Authors: Weidhaas Joanne B. , Hu Chen , Komaki Ritsuko , Masters Gregory A. , Blumenschein George R. , Chang Joe Y. , Lu Bo , Dicker Adam P. , Bogart Jeffrey A. , Garces Yolanda I. , Narayan Samir , Robinson Clifford G. , Kavadi Vivek S. , Greenberger Joel S. , Koprowski Christopher D. , Welsh James , Gore Elizabeth M. , MacRae Robert M. , Paulus Rebecca , Bradley Jeffrey D.
Published: October 2023

Pretreatment Characteristics by KRAS Analysis Inclusion Status
Supplementary Data Table 3 from The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC
Authors: Weidhaas Joanne B. , Hu Chen , Komaki Ritsuko , Masters Gregory A. , Blumenschein George R. , Chang Joe Y. , Lu Bo , Dicker Adam P. , Bogart Jeffrey A. , Garces Yolanda I. , Narayan Samir , Robinson Clifford G. , Kavadi Vivek S. , Greenberger Joel S. , Koprowski Christopher D. , Welsh James , Gore Elizabeth M. , MacRae Robert M. , Paulus Rebecca , Bradley Jeffrey D.
Published: October 2023

KRAS Analysis Inclusion Status
Supplementary Data Table 2 from The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC
Authors: Weidhaas Joanne B. , Hu Chen , Komaki Ritsuko , Masters Gregory A. , Blumenschein George R. , Chang Joe Y. , Lu Bo , Dicker Adam P. , Bogart Jeffrey A. , Garces Yolanda I. , Narayan Samir , Robinson Clifford G. , Kavadi Vivek S. , Greenberger Joel S. , Koprowski Christopher D. , Welsh James , Gore Elizabeth M. , MacRae Robert M. , Paulus Rebecca , Bradley Jeffrey D.
Published: October 2023

Representativeness of Study Participants
Supplementary Data Table 16 from The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC
Authors: Weidhaas Joanne B. , Hu Chen , Komaki Ritsuko , Masters Gregory A. , Blumenschein George R. , Chang Joe Y. , Lu Bo , Dicker Adam P. , Bogart Jeffrey A. , Garces Yolanda I. , Narayan Samir , Robinson Clifford G. , Kavadi Vivek S. , Greenberger Joel S. , Koprowski Christopher D. , Welsh James , Gore Elizabeth M. , MacRae Robert M. , Paulus Rebecca , Bradley Jeffrey D.
Published: October 2023

Overall Survival Squamous Cell Variant Patients Only
Supplementary Data Table 11 from The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC
Authors: Weidhaas Joanne B. , Hu Chen , Komaki Ritsuko , Masters Gregory A. , Blumenschein George R. , Chang Joe Y. , Lu Bo , Dicker Adam P. , Bogart Jeffrey A. , Garces Yolanda I. , Narayan Samir , Robinson Clifford G. , Kavadi Vivek S. , Greenberger Joel S. , Koprowski Christopher D. , Welsh James , Gore Elizabeth M. , MacRae Robert M. , Paulus Rebecca , Bradley Jeffrey D.
Published: October 2023

Local Failure within KRAS Variant Patients by As-Treated Cetuximab
FIGURE 1 from The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC
Authors: Weidhaas Joanne B. , Hu Chen , Komaki Ritsuko , Masters Gregory A. , Blumenschein George R. , Chang Joe Y. , Lu Bo , Dicker Adam P. , Bogart Jeffrey A. , Garces Yolanda I. , Narayan Samir , Robinson Clifford G. , Kavadi Vivek S. , Greenberger Joel S. , Koprowski Christopher D. , Welsh James , Gore Elizabeth M. , MacRae Robert M. , Paulus Rebecca , Bradley Jeffrey D.
Published: October 2023

OS by KRAS and treatment arm. A, OS in non-variant patients by radiation level; B, OS in non-variant patients by cetuximab; C, OS in KRAS-variant patients by radiation level; D, OS within KRAS-variant patients by cetuximab. Radiation level P values stratified by cetuximab; cetuximab P values stratified by radiation level.
Extracorporeal Blood Purification with CytoSorb in 359 Critically Ill Patients
Authors: Pieri Marina , Bonizzoni Matteo A. , Belletti Alessandro , Calabrò Maria G. , Fominskiy Evgeny , Nardelli Pasquale , Ortalda Alessandro , Scandroglio Anna M.
Published: October 2023

Introduction: Critically ill patients with inflammatory dysregulation and organ disfunction may benefit from blood purification, although the use of this technique has not been described in large case series. We evaluated clinical outcomes and survival in high-risk intensive care unit (ICU) patients who underwent extracorporeal blood purification. Methods: 359 consecutive ICU patients treated with CytoSorb were included. Results: Main admission diagnoses were 120 (34%) refractory cardiac arrest under mechanical chest compression; 101 (28%) profound cardiogenic shock; 81 (23%) post-cardiotomy cardiogenic shock; and 37 (10%) respiratory failure. Fifteen patients (4%) were positive for SARS-CoV-2 infection. We observed 49% 30-day mortality, 57% ICU mortality, and 62% hospital mortality, all lower than the 71% mortality predicted by SAPS II and 68% predicted by SOFA score. Parameters of shock and organ failure, above all vasoactive inotropic score, reduced during CytoSorb treatment. Multivariable analysis identified SAPS II, lactate dehydrogenase, ICU stay duration, vasoactive inotropic score, lactates, intra-aortic counterpulsation on top of VA-ECMO, and total bilirubin as predictors of mortality. No CytoSorb-related complications occurred. Conclusion: CytoSorb treatment was effective in reducing laboratory parameters of shock and vasoactive inotropic score with possible survival implications in a large population of critically ill patients.
Steroid-Responsive Encephalopathy Associated with Thyroiditis (SREAT): A Case Report of Saving a Young Female Life
Authors: Senosy Abdelrahman Mahmoud
Published: October 2023

Hashimoto’s encephalopathy (HE), a rare autoimmune disorder associated with thyroiditis, is a condition with no definitive cause. Symptoms include altered mental status, seizures, and cognitive impairment. When diagnostic criteria are met, steroids are the cornerstone of treatment with a reported good response. This report presents a 26-year-old female with HE who presented with persistent status epilepticus and altered mental status, complicated by aspiration pneumonia and laryngeal edema, and had been managed successfully. After exclusion of the common causes of acute altered mental status and seizures, early workup for treatable rare causes such as HE can help rapid recovery and avoid complications. However, proper management of complications such as lower respiratory tract infection, if happened, is necessary for good outcome.
Obesity Paradox in Lung Diseases: What Explains It?
Authors: Yao Surui , Zeng Lei , Wang Fengyuan , Chen Kejie
Published: October 2023

Background: Obesity is a globally increasing health problem that impacts multiple organ systems and a potentially modifiable risk factor for many diseases. Obesity has a significant impact on lung function and is strongly linked to the pathophysiology that contributes to lung diseases. On the other hand, reports have emerged that obesity is associated with a better prognosis than for normal weight individuals in some lung diseases, including pneumonia, acute lung injury/acute respiratory distress syndrome, chronic obstructive pulmonary disease, and lung cancer. The lesser mortality and better prognosis in patients with obesity is known as obesity paradox. While obesity paradox is both recognized and disputed in epidemiological studies, recent research has suggested possible mechanisms. Summary: In this review, we attempted to explain and summarize these factors and mechanisms, including immune response, pulmonary fibrosis, lung function, microbiota, fat and muscle reserves, which are significantly altered by obesity and may contribute to the obesity paradox in lung diseases. We also discuss contrary literature that attributes the “obesity paradox” to confounding. Key Messages: The review will illustrate the possible role of obesity in the prognosis or course of lung diseases, leading to a better understanding of the obesity paradox and provide hints for further basic and clinical research in lung diseases.
Advances in Imaging Modalities for Pediatric Brain and Spinal Cord Tumors
Authors: Huisman Thierry A.G.M. , Patel Rajan , Kralik Stephen , Desai Nilesh K. , Meoded Avner , Chen Karen , Weiner Howard L. , Curry Daniel J. , Lequin Maarten , Kranendonk Mariette , Orman Gunes , Jallo George
Published: October 2023

Background: Neuroimaging has evolved from anatomical imaging toward a multi-modality comprehensive anatomical and functional imaging in the past decades, important functional data like perfusion-weighted imaging, permeability imaging, diffusion-weighted imaging (DWI), and diffusion tensor imaging (DTI), tractography, metabolic imaging, connectomics, event-related functional imaging, resting state functional imaging, and much more is now being offered. Summary: Precision diagnostics has proven to be essential for precision treatment. Many minimal invasive techniques have been developed, taking advantage of digital subtraction angiography and interventional neuroradiology. Furthermore, intraoperative CT and/or MRI and more recently MR-guided focused ultrasound have complemented the diagnostic and therapeutic armamentarium. Key Messages: In the current manuscript, we discuss standard imaging sequences including advanced techniques like DWI, DTI, susceptibility-weighted imaging, and 1H magnetic resonance spectroscopy, various perfusion weighted imaging approaches including arterial spin labeling, dynamic contrast enhanced imaging, and dynamic susceptibility contrast imaging. Pre-, intra, and postoperative surgical imaging including visualize imaging will be discussed. The value of connectomics will be presented for its value in neuro-oncology. Minimal invasive therapeutic possibilities of interventional neuroradiology and image-guided laser ablation and MR-guided high-intensity-focused ultrasound will be presented for treatment of pediatric brain and spinal cord tumors. Finally, a comprehensive review of spinal cord tumors and matching neuropathology has been included.
The Aging Ovary and the Tales Learned Since Fetal Development
Authors: Lopez Jesus , Hohensee Gabe , Liang Jing , Sela Meirav , Johnson Joshua , Kallen Amanda N.
Published: October 2023

Background: While the term “aging” implies a process typically associated with later life, the consequences of ovarian aging are evident by the time a woman reaches her forties, and sometimes earlier. This is due to a gradual decline in the quantity and quality of oocytes which occurs over a woman’s reproductive lifespan. Indeed, the reproductive potential of the ovary is established even before birth, as the proper formation and assembly of the ovarian germ cell population during fetal life determines the lifetime endowment of oocytes and follicles. In the ovary, sophisticated molecular processes have been identified that regulate the timing of ovarian aging and these are critical to ensuring follicular maintenance. Summary: The mechanisms thought to contribute to overall aging have been summarized under the term the “hallmarks of aging” and include such processes as DNA damage, mitochondrial dysfunction, telomere attrition, genomic instability, and stem cell exhaustion, among others. Similarly, in the ovary, molecular processes have been identified that regulate the timing of ovarian aging and these are critical to ensuring follicular maintenance. In this review, we outline critical processes involved in ovarian aging, highlight major achievements for treatment of ovarian aging, and discuss ongoing questions and areas of debate. Key Messages: Ovarian aging is recognized as what may be a complex process in which age, genetics, environment, and many other factors contribute to the size and depletion of the follicle pool. The putative hallmarks of reproductive aging outlined herein include a diversity of plausible processes contributing to the depletion of the ovarian reserve. More research is needed to clarify if and to what extent these putative regulators do in fact govern follicle and oocyte behavior, and how these signals might be integrated in order to control the overall pattern of ovarian aging.
The Good, the Bad, and the Serum Creatinine: Exploring the Effect of Muscle Mass and Nutrition
Authors: De Rosa Silvia , Greco Massimiliano , Rauseo Michela , Annetta Maria Giuseppina
Published: October 2023

Muscle wasting (sarcopenia) is one of the hallmarks of critical illness. Patients admitted to intensive care unit develop sarcopenia through increased protein catabolism, a decrease in protein syntheses, or both. Among the factors known to promote wasting are chronic inflammation and cytokine imbalance, insulin resistance, hypermetabolism, and malnutrition. Moreover, muscle wasting, known to develop in chronic kidney disease patients, is a harmful consequence of numerous complications associated with deteriorated renal function. Plenty of published data suggest that serum creatinine (SCr) reflects increased kidney damage and is also related to body weight. Based on the concept that urea and creatinine are nitrogenous end products of metabolism, the urea:creatinine ratio (UCR) could be applied but with limited clinical usability in case of kidney damage, hypovolemia, excessive, or protein intake, where UCR can be high and independent of catabolism. Recent data suggest that the sarcopenia index should be considered an alternative to serum creatinine. It is more reliable in estimating muscle mass than SCr. However, the optimal biomarker of catabolism is still an unresolved issue. The SCr is not a promising biomarker for renal function and muscle mass based on the influence of several factors. The present review highlights recent findings on the limits of SCr as a surrogate marker of renal function and the assessment modalities of nutritional status and muscle mass measurements.
Genetic Polymorphisms of rs9949644 in MAPK4 Are Associated with Clinical Response to Methotrexate in Patients with Psoriasis
Authors: Fan Zhijia , Huang Qiong , Zhang Zhenghua , Han Ling , Fang Xu , Yang Ke , Huang Guiqin , Zheng Zhizhong , Yawalkar Nikhil , Lin Yong , Wang Zhicheng , Yan Kexiang
Published: October 2023

Background: The study aimed to investigate the relationship of MAPK4 genetic variants with the efficacy of methotrexate (MTX) in psoriasis patients. Methods: Patients treated with MTX were classified as responders or nonresponders if the Psoriasis Area and Severity Index (PASI) at week 12 was reduced to greater than 75% or lower than 75%, respectively. The genotypes of 14 MAPK4 single-nucleotide polymorphisms in 310 patients were analyzed. The expression levels of MAPK4 protein were detected by Western blot. Results: Only rs9949644 polymorphisms were associated with the efficacy after adjusting for the confounding factors. Patients with the rs9949644 AG or GG genotype had a better clinical response compared to patients with the AA genotype. Rs9949644 polymorphisms were significantly associated with the PASI improvement rate. Besides, the protein level of MAPK4, positively associated with the psoriasis severity, was higher in patients. There were no significant differences of MAPK4 protein levels among the three groups. While after treatment, MAPK4 levels in the AG or GG group showed a significantly down-regulated trend. Conclusion: By demonstrating the significant association of MAPK4 with the efficacy of MTX, this study indicates that MAPK4 may be involved in the psoriasis progression and act as a predictor of therapeutic response.
Iron Supplements Concomitant within Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Inhibitors in the Treatment of Chronic Kidney Disease Anemia
Authors: Wang Xue , Wei Cuiting , Zhao Delong , Sun Xuefeng , Zhu Fengge , Mei Yan , Ma Qian , Cai Guangyan , Chen Xiangmei , Li Ping
Published: October 2023

Background: Anemia is a common and important complication in patients with chronic kidney disease (CKD). Accordingly, the current treatment is based on erythropoiesis-stimulating agents (ESAs) and iron. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain inhibitors (HIF-PHIs) have been developed to treat renal anemia through a novel mechanism. HIF-PHIs increase erythropoietin at physiologic blood concentrations and also improve the supply of hematopoietic iron. Iron is the main component of hemoglobin, and ensuring efficient iron metabolism is essential in the treatment of anemia. Summary: HIF-PHIs may have advantages in improving iron utilization and mobilization compared to ESAs. Most HIF-PHI trials revealed a significant decline of hepcidin, increase in transferrin level and total iron binding capacity in patients. From a clinical point of view, improvements in iron metabolism should translate into reductions in iron supplementation. There are differences in the iron treatment regimentation currently used, so it is important to evaluate and timely iron supplementation across studies. Key Messages: This review summarizes the mechanism of HIF-PHIs on improved iron metabolism and the route of iron usage in the trials for dialysis-dependent CKD and non-dialysis CKD. And this review also makes an interpretation of the clinical practice guidelines in China and recommendation by Asia Pacific Society of Nephrology.
Microstructural Brain Development and Neurodevelopmental Outcome of Very Preterm Infants of Mothers with Gestational Diabetes Mellitus
Authors: Sappler Maria , Volleritsch Nina , Hammerl Marlene , Pellkofer Yasmin , Griesmaier Elke , Gizewski Elke Ruth , Kaser Susanne , Kiechl-Kohlendorfer Ursula , Neubauer Vera
Published: October 2023

Introduction: There are data linking gestational diabetes mellitus (GDM) with adverse neurodevelopmental outcome in the offspring. We investigated the effect of GDM on microstructural brain development and neurodevelopmental outcome of very preterm infants. Materials and Methods: Preterm infants <32 gestational weeks of mothers with GDM obtained cerebral magnetic resonance imaging (MRI) including diffusion-tensor imaging at term-equivalent age. For every infant, two gestational age-, sex-, and MRI scanner type-matched controls were included. Brain injury was assessed and fractional anisotropy (FA) and apparent diffusion coefficient (ADC) measured in 14 defined cerebral regions. Neurodevelopmental outcome was quantified at the corrected age of 24 months using the Bayley Scales of Infant Development. Results: We included 47 infants of mothers with GDM and 94 controls. There were no differences in neonatal morbidity between the groups, nor in any type of brain injury. The GDM group showed significantly higher FA values in the centrum semiovale, the posterior limb of the internal capsule and the pons bilaterally, in the corpus callosum and the right occipital white matter, as well as lower ADC values in the right centrum semiovale, the right occipital white matter and the corpus callosum. Neurodevelopmental outcome did not differ between the groups. Conclusion: We found no impairment of brain development in GDM-exposed infants compared to matched controls, but differences in white matter microstructure in specific regions indicating an enhanced maturation. However, neurodevelopmental outcome was equal in both groups. Further studies are needed to better understand brain maturation in preterm infants exposed to GDM.
Disparate Outcomes, Biologic and Therapeutic Differences in Pediatric versus Adult Patients with Ewing Sarcoma
Authors: Wytiaz Victoria , Schwartz Eric , Rice John D. , Zhao Lili , Jasty Rama , Schuetze Scott , Chugh Rashmi
Published: October 2023

Introduction: Ewing sarcoma (ES) is a small blue round cell sarcoma affecting a wide age spectrum. Clinical advances predominately stem from pediatric research consortia clinical trials. In most series, adults have poorer outcomes when compared to children. The aim of this study was to perform a detailed evaluation of factors potentially accounting for this difference. Methods: A single institution retrospective chart review was conducted on patients with ES diagnosed from 2005 to 2015, identified using a free-text search engine with the keywords “Ewing sarcoma” as well as a corresponding pathologic database. Data were analyzed based on age, pediatric (age <18) and adult (age >18 years), using a multivariate analysis model. Results: Eighty-eight ES patients (34 pediatric, 54 adult) were identified with a median age of 13 (range 3–18) and 31 (range 19–70) in their respective cohorts. Five-year overall survival (OS) was higher in pediatric patients (73.5% vs. 48.1%, p = 0.0213). By stage, 5-year OS in pediatric versus adult patients was 65% versus 20% (p = 0.0530) in metastatic (n = 32) and 68.1% versus 58.8% (p = 0.278) in localized (n = 56) patients. Lung-only metastases were present in 83% of metastatic pediatric patients versus 35% of adult metastatic patients. Pediatric patients received more cycles of first-line chemotherapy (13.8 vs. 11.4, p = 0.001), independent of stage. More cycles of chemotherapy correlated with improved OS (HR: 0.864, CI: 0.773–0.967) and progression-free survival (HR: 0.897, CI: 0.808–0.996). Conclusions: Outcome differences were most notable in patients with metastatic disease, although not statistically significant. Our series found differences in presentation between pediatric and adult populations with adult patients receiving fewer cycles of chemotherapy. This may suggest that both variations in underlying disease biology and potentially differences in treatment may account for outcome disparities.
The Role of Vascular Biomarkers in Outcomes of Patients with Kidney Disease
Authors: Shi Audrey , Mansour Sherry G.
Published: October 2023

Background: Vascular biomarkers may explain the link between acute kidney injury (AKI) and poor long-term outcomes such as cardiovascular disease (CVD). Vessel injury is exceedingly common in AKI and contributes to the development of kidney fibrosis and CVD. As prominent determinants of vessel stability in the body, angiopoietins and other prominent vascular biomarkers may explain this biological link. Summary: Angiopoietin-1 (Angpt-1) promotes vessel stability by decreasing inflammation, apoptosis, and vessel permeability. By contrast, angiopoietin-2 (Angpt-2) blocks the binding of Angpt-1 to its receptor and thus contributes to vessel instability and permeability. Based on our findings, higher levels of Angpt-1 relative to Angpt-2 were strongly associated with less risk of kidney disease progression, heart failure, and death in hospitalized patients with AKI. In chronic kidney disease patients, it has been shown that endothelial damage in glomerular vasculature triggers Angpt-2 secretion, leading to poor outcomes such as CVD and mortality. Furthermore, in kidney transplant recipients, Angpt-2 levels significantly decrease after transplantation suggesting that transplantation may reduce Angpt-2 levels and decrease rates of poor outcomes. Other vascular health pathways – such as vascular endothelial growth factor and placental growth factor – were associated with improved rates of survival after cardiac surgery in participants with and without AKI. Key Messages: Vascular health biomarkers provide actionable pathways for clinical intervention in reducing CVD and mortality for AKI patients. There is great need for future research that focuses on developing robust prognostic vascular biomarker panels in order to help identify high-risk AKI survivors who may benefit from targeted follow-up and therapy, with the intention to prevent kidney and cardiac complications.
Is There Any Risk for Metabolic Syndrome in Children and Adolescents with Psychiatric Disorders?
Authors: Bilaç Öznur , Tahıllıoğlu Akın , Çakır Burak , Kavurma Canem , Önder Arif , Ercan Eyüp Sabri
Published: October 2023

Objective: We aimed to investigate the risk of antipsychotic drug treatment in the development of metabolic syndrome (MetS) in children and adolescents and to determine which psychiatric disorder is more associated with MetS in the pediatric population. Methods: The sample consisted of 118 children and adolescents (88 used psychotropic medication). The hemogram, fasting blood glucose, lipid profile, weight, and blood pressure levels of all the participants and information regarding medication doses of the patient group at the sixth month of the treatment process were obtained. Results: Bipolar disorder (BPD) was the only psychiatric disorder associated with MetS. Quetiapine and valproic acid were found to have increasing effects on MetS. Weight gain and the increase in systolic and diastolic blood pressure significantly increased the likelihood of MetS. Hierarchical logistic regression analyses revealed that quetiapine increased the risk of MetS through weight gain, and valproic acid increased MetS risk through systolic blood pressure. Conclusion: Especially BPD and psychotropic use in children and adolescents disrupt metabolic regulation and pose a risk for MetS. Determining the risk factors causing MetS, especially in children and adolescents, plays a significant role in preventing mortality and morbidity at advanced ages.
Massive Intoxication with 70 Tablets of Apixaban: A Case Report
Authors: Kobayashi Tadahiro , Saito Satoko , Takada Masayuki , Sakaguchi Kento , Takahashi Kazunori , Tanaka Ken , Kawamae Kaneyuki , Nakane Masaki
Published: October 2023

Apixaban is a direct oral anticoagulation agent that exerts its effect through the direct inhibition of factor Xa. We treated a case of massive intoxication with 70 tablets of apixaban and have presented the clinical course of the associated anti-Xa activities. A 49-year-old woman was admitted to the emergency department approximately 1.5 h after impulsive self-intoxication with 175 mg of apixaban. She developed coagulopathy with prothrombin time-international normalized ratio (PT-INR) of 3.65, activated partial thromboplastin time of 56.5 s, and antithrombin activity (AT) of >150% (at 1.5 h post-ingestion). The patient’s initial and peak anti-Xa activity was 17.7 IU/mL, and its elimination displayed first-order kinetics with a half-life of 10.5 h. The patient’s anti-Xa activity was within the therapeutic dose range at 26 h post-ingestion, and she recovered without experiencing any bleeding complications. Her coagulopathy also returned to normal level at the same timing. This result suggests that PT-INR and AT can be used as substitute markers of overwhelmed anticoagulation following massive overdose of apixaban. A case of apixaban overdose with associated anti-Xa activities was presented. There was favorable resolution of anticoagulation without specific treatments.
Functional Characterization of Gonadotropin-Releasing Hormone and Corazonin Signaling Systems in Pacific Abalone: Toward Reclassification of Invertebrate Neuropeptides
Authors: Kim Mi Ae , Kim Tae Ha , Kannan Priyadharshini , Kho Kang Hee , Park Keunwan , Sohn Young Chang
Published: October 2023

Introduction: The proposed evolutionary origins and corresponding nomenclature of bilaterian gonadotropin-releasing hormone (GnRH)-related neuropeptides have changed tremendously with the aid of receptor deorphanization. However, the reclassification of the GnRH and corazonin (CRZ) signaling systems in Lophotrochozoa remains unclear. Methods: We characterized GnRH and CRZ receptors in the mollusk Pacific abalone, Haliotis discus hannai (Hdh), by phylogenetic and gene expression analyses, bioluminescence-based reporter, Western blotting, substitution of peptide amino acids, in vivo neuropeptide injection, and RNA interference assays. Results: Two Hdh CRZ-like receptors (Hdh-CRZR-A and Hdh-CRZR-B) and three Hdh GnRH-like receptors (Hdh-GnRHR1-A, Hdh-GnRHR1-B, and Hdh-GnRHR2) were identified. In phylogenetic analysis, Hdh-CRZR-A and -B grouped within the CRZ-type receptors, whereas Hdh-GnRHR1-A/-B and Hdh-GnRHR2 clustered within the GnRH/adipokinetic hormone (AKH)/CRZ-related peptide-type receptors. Hdh-CRZR-A/-B and Hdh-GnRHR1-A were activated by Hdh-CRZ (pQNYHFSNGWHA-NH2) and Hdh-GnRH (pQISFSPNWGT-NH2), respectively. Hdh-CRZR-A/-B dually coupled with the Gαq and Gαs signaling pathways, whereas Hdh-GnRHR1-A was linked only with Gαq signaling. Analysis of substituted peptides, [I2S3]Hdh-CRZ and [N2Y3H4]Hdh-GnRH, and in silico docking models revealed that the N-terminal amino acids of the peptides are critical for the selectivity of Hdh-CRZR and Hdh-GnRHR. Two precursor transcripts for Hdh-CRZ and Hdh-GnRH peptides and their receptors were mainly expressed in the neural ganglia, and their levels increased in starved abalones. Injection of Hdh-CRZ peptide into abalones decreased food consumption, whereas Hdh-CRZR knockdown increased food consumption. Moreover, Hdh-CRZ induced germinal vesicle breakdown in mature oocytes. Conclusion: Characterization of Hdh-CRZRs and Hdh-GnRHRs and their cognate peptides provides new insight into the evolutionary route of GnRH-related signaling systems in bilaterians.
Machine Learning for the Prediction of Survival Post-Allogeneic Hematopoietic Cell Transplantation: A Single-Center Experience
Authors: Shourabizadeh Hamed , Aleman Dionne M. , Rousseau Louis-Martin , Law Arjun D. , Viswabandya Auro , Michelis Fotios V.
Published: October 2023

Introduction: Prediction of outcomes following allogeneic hematopoietic cell transplantation (HCT) remains a major challenge. Machine learning (ML) is a computational procedure that may facilitate the generation of HCT prediction models. We sought to investigate the prognostic potential of multiple ML algorithms when applied to a large single-center allogeneic HCT database. Methods: Our registry included 2,697 patients that underwent allogeneic HCT from January 1976 to December 2017. 45 pretransplant baseline variables were included in the predictive assessment of each ML algorithm on overall survival (OS) as determined by area under the curve (AUC). Pretransplant variables used in the EBMT ML study (Shouval et al., 2015) were used as a benchmark for comparison. Results: On the entire dataset, the random forest (RF) algorithm performed best (AUC 0.71 ± 0.04) compared to the second-best model, logistic regression (LR) (AUC = 0.69 ± 0.04) (p < 0.001). Both algorithms demonstrated improved AUC scores using all 45 variables compared to the limited variables examined by the EBMT study. Survival at 100 days post-HCT using RF on the full dataset discriminated patients into different prognostic groups with different 2-year OS (p < 0.0001). We then examined the ML methods that allow for significant individual variable identification, including LR and RF, and identified matched related donors (HR = 0.49, p < 0.0001), increasing TBI dose (HR = 1.60, p = 0.006), increasing recipient age (HR = 1.92, p < 0.0001), higher baseline Hb (HR = 0.59, p = 0.0002), and increased baseline FEV1 (HR = 0.73, p = 0.02), among others. Conclusion: The application of multiple ML techniques on single-center allogeneic HCT databases warrants further investigation and may provide a useful tool to identify variables with prognostic potential.