bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Phase Angle, but Not Inflammation and Overhydration, With Physical Function in Peritoneal Dialysis Patients
Authors: Silva Vanessa Mota , Silva Maryanne Zilli Canedo , Vogt Barbara Perez , Reis Nayrana Soares Carmo , Costa Fabiana Lourenço , Dorna Mariana Souza , Minicucci Marcos Ferreira , Caramori Jacqueline Costa Teixeira
Published: May 2021

Introduction: Muscle mass depletion, overhydration, and inflammatory state have been related to impaired physical function in chronic kidney disease patients. The relationship between bioelectrical impedance analysis (BIA) parameters, such as hydration status and phase angle (PhA), with physical function in peritoneal dialysis (PD), is still not well-established. Therefore, the objective was to evaluate the association of BIA parameters (overhydration index and PhA) and inflammatory markers with physical function in patients on PD.

Methods: The present cross-sectional study enrolled PD patients. Multifrequency BIA was performed to obtain overhydration index and PhA. The Short Physical Performance Battery (SPPB) test battery was applied to assess physical function. The time to complete the 4-m gait test and sit-to-stand test was also considered for physical function assessment. The inflammatory markers tumor necrosis factor-alpha and C-reactive protein levels were determined. Multiple linear regression models were performed, with the physical function variables as dependent variables, adjusted for age, diabetes, and sex.

Results: Forty-nine PD patients were enrolled, 53.1% (n = 26) women; mean age, 55.5 ± 16.3 years. There were significant correlations between PhA and SPPB (r = 0.550, p < 0.001), time of 4-m gait test (r = −0.613, p < 0.001) and sit-to-stand test and (r = −0.547, p < 0.001). Overhydration index was significantly correlated with SPPB, 4-m gait test (r = 0.339, p = 0.017), and sit-to-stand test (r = 0.335, p = 0.019). Inflammatory markers were not significantly correlated with physical function parameters. In the multiple linear regression analysis, PhA was associated with physical function parameters, even after adjustments. Overhydration index was associated with all physical function tests only in the models with no adjustments.

Conclusion: PhA was independently associated with physical function in PD patients. Inflammatory markers and overhydration index were not associated with physical function.
Toxicities of Immunotherapy for Small Cell Lung Cancer
Authors: Fu Yang , Zheng Yue , Wang Pei-Pei , Ding Zhen-Yu
Published: May 2021

Small cell lung cancer (SCLC), composing 15–20% of lung cancer, is a fatal disease with extremely poor prognosis. In the past two decades, etoposide platinum doublet chemotherapy remained the only choice of therapy, with disappointing overall survival ≤1 year for the metastatic disease. Novel treatments including immunotherapy are urgently needed and extensively explored. Recently, in two phase III trials, atezolizumab and durvalumab were shown to bring survival benefit to patients. While immunotherapy brings better outcome, it is accompanied by adverse events different from traditional treatments. Although these immune-related adverse events (irAEs) are generally mild and can be managed, some irAEs (myocarditis, pneumonitis) may be severe and even life-threatening. Accompanying with the increasing application of immunotherapy in clinical practice, the irAEs should not be overlooked. In this review, the irAEs profile in clinical trials of immunotherapy for SCLC will be summarized, also its unique features compared with irAEs in other malignancies will be explored. This review may be helpful for the appropriate clinical use of immunotherapy for SCLC.
Circulating Tumor Cell and Metabolites as Novel Biomarkers for Early-Stage Lung Cancer Diagnosis
Authors: Wan Lingling , Liu Qingyi , Liang Di , Guo Yongdong , Liu Guangjie , Ren Jinxia , He Yutong , Shan Baoen
Published: May 2021

Background

Lung cancer is a malignant tumor that has the highest morbidity and mortality rate among all cancers. Early diagnosis of lung cancer is a key factor in reducing mortality and improving prognosis.

Methods

In this study, we performed CTC next-generation sequencing (NGS) in early-stage lung cancer patients to identify lung cancer-related gene mutations. Meanwhile, a serum liquid chromatography-tandem mass spectrometry (LC-MS) untargeted metabolomics analysis was performed in the CTC-positive patients. To screen potential diagnostic markers for early lung cancer.

Results

62.5% (30/48) of lung cancer patients had ≥1 CTC. By CTC NGS, we found that > 50% of patients had 4 commonly mutated genes, namely, NOTCH1, IGF2, EGFR, and PTCH1. 47.37% (9/19) patients had ARIDH1 mutations. Additionally, 30 CTC-positive patients and 30 healthy volunteers were subjected to LC-MS untargeted metabolomics analysis. We found 100 different metabolites, and 10 different metabolites were identified through analysis, which may have potential clinical application value in the diagnosis of CTC-positive early-stage lung cancer (AUC >0.9).

Conclusions

Our results indicate that NGS of CTC and metabolomics may provide new tumor markers for the early diagnosis of lung cancer.
A Novel Invadopodia-Specific Marker for Invasive and Pro-Metastatic Cancer Stem Cells
Authors: Huang Shenq-Shyang , Liao Wen-Ying , Hsu Chung-Chi , Chan Tze-Sian , Liao Tai-Yan , Yang Pei-Ming , Chen Li-Tzong , Sung Shian-Ying , Tsai Kelvin K.
Published: May 2021

Introduction

Stem-like cancer cells or cancer stem cells (CSCs) may comprise a phenotypically and functionally heterogeneous subset of cells, whereas the molecular markers reflecting this CSC hierarchy remain elusive. The glycolytic enzyme alpha-enolase (ENO1) present on the surface of malignant tumor cells has been identified as a metastasis-promoting factor through its function of activating plasminogen. The expression pattern of surface ENO1 (sENO1) concerning cell-to-cell or CSC heterogeneity and its functional roles await further investigation.

Methods

The cell-to-cell expression heterogeneity of sENO1 was profiled in malignant cells from different types of cancers using flow cytometry. The subcellular localization of sENO1 and its functional roles in the invadopodia formation and cancer cell invasiveness were investigated using a series of imaging, molecular, and in vitro and in vivo functional studies.

Results

We showed here that ENO1 is specifically localized to the invadopodial surface of a significant subset (11.1%-63.9%) of CSCs in human gastric and prostate adenocarcinomas. sENO1+ CSCs have stronger mesenchymal properties than their sENO1- counterparts. The subsequent functional studies confirmed the remarkable pro-invasive and pro-metastatic capacities of sENO1+ CSCs. Mechanistically, inhibiting the surface localization of ENO1 by downregulating caveolin-1 expression compromised invadopodia biogenesis, proteolysis, and CSC invasiveness.

Conclusions

Our study identified the specific expression of ENO1 on the invadopodial surface of a subset of highly invasive and pro-metastatic CSCs. sENO1 may provide a diagnostically and/or therapeutically exploitable target to improve the outcome of patients with aggressive and metastatic cancers.
Overexpression of Multifunctional Protein p32 Promotes a Malignant Phenotype in Colorectal Cancer Cells
Authors: Egusquiza-Alvarez Carlos Alejandro , Castañeda-Patlán M. Cristina , Albarran-Gutierrez Sara , Gonzalez-Aguilar Héctor , Moreno-Londoño Angela P. , Maldonado Vilma , Melendez-Zajgla Jorge , Robles-Flores Martha
Published: May 2021

p32 is a multifunctional and multicompartmental protein that has been found upregulated in numerous adenocarcinomas, including colorectal malignancy. High levels of p32 expression have been correlated with poor prognosis in colorectal cancer. However, the functions performed by p32 in colorectal cancer have not been characterized. Here we show that p32 is overexpressed in colorectal cancer cell lines compared to non-malignant colon cells. Colon cancer cells also display higher nuclear levels of p32 than nuclear levels found in non-malignant cells. Moreover, we demonstrate that p32 regulates the expression levels of genes tightly related to malignant phenotypes such as HAS-2 and PDCD4. Remarkably, we demonstrate that knockdown of p32 negatively affects Akt/mTOR signaling activation, inhibits the migration ability of colon malignant cells, and sensitizes them to cell death induced by oxidative stress and chemotherapeutic agents, but not to cell death induced by nutritional stress. In addition, knockdown of p32 significantly decreased clonogenic capacity and in vivo tumorigenesis in a xenograft mice model. Altogether, our results demonstrate that p32 is an important promoter of malignant phenotype in colorectal cancer cells, suggesting that it could be used as a therapeutic target in colorectal cancer treatment.
Prevalence of TP-53/Rb-1 Co-Mutation in Large Cell Neuroendocrine Carcinoma
Authors: Saghaeiannejad Esfahani Hoda , Vela Cory M. , Chauhan Aman
Published: May 2021

Introduction

Large cell neuroendocrine carcinoma (LCNEC) is a rare and highly aggressive high-grade neuroendocrine neoplasm, which can arise from anywhere in the body. Due to its rarity there is a lacuna in our understanding of LCNEC’s molecular biology. In 2016, Rekhtman and colleagues presented one of the largest molecular sequencing series of pulmonary LCNEC. They differentiated genomic profiles of LCNEC into two major subsets: small cell lung cancer (SCLC)-like, characterized by TP53 + RB1 co-mutation/loss, and non-small cell lung cancer (NSCLC)-like, characterized by the lack of co-altered TP53 + RB1. This finding is of significance because at present LCNEC patients are often treated like SCLC. However, the universal genomic SCLC biomarker of TP53 and RB1 co-mutation was only found in 40% of their cohort. Since then various other scientists have looked into molecular profiling of LCNEC with markedly discordant results. The objective of this study was to conduct a systematic review of publicly available next generation sequencing (NGS) data to evaluate the prevalence of TP53 + RB1 co-mutation in LCNEC.

Method

We conducted a literature search using PubMed. Seven studies including 302 patients with pulmonary LCNEC and four studies including 20 patients with extra-pulmonary LCNEC underwent final analysis.

Results

The prevalence of TP53 + RB1 co-mutation was 36% (109/302) among pulmonary LCNEC patients and 35% (7/20) among the extra-thoracic LCNEC cohort. This finding is in stark contrast to >90% TP53 + RB1 co-mutation in SCLC.

Conclusion

It is now well established that LCNEC is molecularly distinct from SCLC. LCNEC seems to have two molecularly defined sub-cohort based on TP53 + RB1 co-mutation status. Future studies should look into prognostic and predictive implication of TP53 + RB1 co-mutation status in LCNEC. Prospective studies should be designed to characterize molecular subtypes and direct treatment accordingly. We are currently conducting a prospective pilot clinical trial wherein LCNEC patients are treated based on TP53 + RB1 co-mutation status. The study is currently enrolling. “Next Generation Sequencing-Based Stratification of Front Line Treatment of Neuroendocrine Carcinoma (PRECISION-NEC).

Systematic Review

ClinicalTrials.gov, identifier NCT04452292.
The Role and Clinical Implications of the Retinoblastoma (RB)-E2F Pathway in Gastric Cancer
Authors: Wu Tianyi , Wu Lizhao
Published: May 2021

Gastric cancer is the most common malignant tumor in the digestive tract, with very high morbidity and mortality in developing countries. The pathogenesis of gastric cancer is a complex biological process mediated by abnormal regulation of proto-oncogenes and tumor suppressor genes. Although there have been some in-depth studies on gastric cancer at the molecular level, the specific mechanism has not been fully elucidated. RB family proteins (including RB, p130, and p107) are involved in cell cycle regulation, a process that largely depends on members of theE2Fgene family that encode transcriptional activators and repressors. In gastric cancer, inactivation of the RB-E2F pathway serves as a core transcriptional mechanism that drives cell cycle progression, and is regulated by cyclins, cyclin-dependent kinases, cyclin-dependent kinase inhibitors, p53,Helicobacter pyloriand some other upstream molecules. The E2F proteins are encoded by eight genes (i.e.E2F1toE2F8), each of which may play a specific role in gastric cancer. Interestingly, a single E2F such as E2F1 can activate or repress transcription, and enhance or inhibit cell proliferation, depending on the cell environment. Thus, the function of the E2F transcription factor family is very complex and needs further exploration. Importantly, the presence ofH. pyloriin stomach mucosa may affect the RB and p53 tumor suppressor systems, thereby promoting the occurrence of gastric cancer. This review aims to summarize recent research progress on important roles of the complex RB-E2F signaling network in the development and effective treatment of gastric cancer.
Whole-Exome Sequencing Analysis of Oral Squamous Cell Carcinoma Delineated by Tobacco Usage Habits
Authors: Patel Krishna , Bhat Firdous Ahmad , Patil Shankargouda , Routray Samapika , Mohanty Neeta , Nair Bipin , Sidransky David , Ganesh Mandakulutur S. , Ray Jay Gopal , Gowda Harsha , Chatterjee Aditi
Published: May 2021

Oral squamous cell carcinoma (OSCC) is a common cancer of the oral cavity in India. Cigarette smoking and chewing tobacco are known risk factors associated with OSCC. However, genomic alterations in OSCC with varied tobacco consumption history are not well-characterized. In this study, we carried out whole-exome sequencing to characterize the mutational landscape of OSCC tumors from subjects with different tobacco consumption habits. We identified several frequently mutated genes, including TP53, NOTCH1, CASP8, RYR2, LRP2, CDKN2A, and ATM. TP53 and HRAS exhibited mutually exclusive mutation patterns. We identified recurrent amplifications in the 1q31, 7q35, 14q11, 22q11, and 22q13 regions and observed amplification of EGFR in 25% of samples with tobacco consumption history. We observed genomic alterations in several genes associated with PTK6 signaling. We observed alterations in clinically actionable targets including ERBB4, HRAS, EGFR, NOTCH1, NOTCH4, and NOTCH3. We observed enrichment of signature 29 in 40% of OSCC samples from tobacco chewers. Signature 15 associated with defective DNA mismatch repair was enriched in 80% of OSCC samples. NOTCH1 was mutated in 36% of samples and harbored truncating as well as missense variants. We observed copy number alterations in 67% of OSCC samples. Several genes associated with non-receptor tyrosine kinase signaling were affected in OSCC. These molecules can serve as potential candidates for therapeutic targeting in OSCC.
Preoperative Predictors of Lymph Node Metastasis in Colon Cancer
Authors: Xu Yansong , Chen Yi , Long Chenyan , Zhong Huage , Liang Fangfang , Huang Ling-xu , Wei Chuanyi , Lu Shaolong , Tang Weizhong
Published: May 2021

Background

Lymph node metastasis (LNM) is a well-established prognostic factor for colon cancer. Preoperative LNM evaluation is relevant for planning colon cancer treatment. The aim of this study was to construct and evaluate a nomogram for predicting LNM in primary colon cancer according to pathological features.

Patients and Methods

Six-hundred patients with clinicopathologically confirmed colon cancer (481 cases in the training set and 119 cases in the validation set) were enrolled in the Affiliated Cancer Hospital of Guangxi Medical University from January 2010 to December 2019. The expression of molecular markers (p53 and β-catenin) was determined by immunohistochemistry. Multivariate logistic regression was used to screen out independent risk factors, and a nomogram was established. The accuracy and discriminability of the nomogram were evaluated by consistency index and calibration curve.

Results

Univariate logistic analysis revealed that LNM in colon cancer is significantly correlated (P <0.05) with tumor size, grading, stage, preoperative carcinoembryonic antigen (CEA) level, and peripheral nerve infiltration (PNI). Multivariate logistic regression analysis confirmed that CEA, grading, and PNI were independent prognostic factors of LNM (P <0.05). The nomogram for predicting LNM risk showed acceptable consistency and calibration capability in the training and validation sets.

Conclusions

Preoperative CEA level, grading, and PNI were independent risk factor for LNM. Based on the present parameters, the constructed prediction model of LNM has potential application value.
N-Myristoylation by NMT1 Is POTEE-Dependent to Stimulate Liver Tumorigenesis via Differentially Regulating Ubiquitination of Targets
Authors: Zhu Guoqing , Wang Feng , Li Haojie , Zhang Xiao , Wu Qi , Liu Ya , Qian Mingping , Guo Susu , Yang Yueyue , Xue Xiangfei , Sun Fenyong , Qiao Yongxia , Pan Qiuhui
Published: May 2021

Background

A tremendous amount of studies have suggested that post-translational modifications (PTMs) play pivotal roles during tumorigenesis. Compared to other PTMs, lipid modification is less studied. Recently, N-myristoylation, one type of lipid modification, has been paid attention to the field of cancer. However, whether and how N-myristoylation exerts its roles in liver tumorigenesis still remains unclear.

Methods

Parallel reaction monitoring (PRM) was conducted to evaluate the expression of protein modification enzymes in paired tissues. Liver conditionally knocking NMT1 out mice model was used to assess the critical roles of N-myristoylation during liver tumorigenesis. Proteomics isobaric tags for relative and absolute quantification (iTraq) was performed to identify proteins that changed while NMT1 was knocked down. The click chemistry assay was used to evaluate the N-myristoylation levels of proteins.

Results

Here, N-myristolyation and its enzyme NMT1, but not NMT2, were found to be critical in liver cancer. Two categories of proteins, i.e., N-myristolyation down-regulated proteins (NDP, including LXN, RPL29, and FAU) and N-myristolyation up-regulated proteins (NUP, including AHSG, ALB, and TF), were revealed negatively and positively regulated by NMT1, respectively. Both NDP and NUP could be N-myristolyated by NMT1 indispensable of POTEE. However, N-myristolyation decreased and increased stability of NDP and NUP, respectively. Mechanistically, NDP-specific binding protein RPL7A facilitated HIST1H4H, which has ubiquitin E3 ligase function, to ubiquitinate NDP. By contrast, NUP-specific binding protein HBB prevented NUP from ubiquitination by HIST1H4H. Notably, function of RPL7A and HBB was all NMT1-dependent. Moreover, NDP suppressed while NUP stimulated transformative phenotypes. Clinically, higher levels of NMT1 and NUP with lower levels of NDP had worse prognostic outcome.

Conclusion

Collectively, N-myristolyation by NMT1 suppresses anti-tumorigenic NDP, whereas it stimulates pro-tumorigenic NUP by interfering their ubiquitination to finally result in a pro-tumorigenic outcome in liver cancer. Targeting N-myristolyation and NMT1 might be helpful to treat liver cancer.
Immunological Effects of Histotripsy for Cancer Therapy
Authors: Hendricks-Wenger Alissa , Hutchison Ruby , Vlaisavljevich Eli , Allen Irving Coy
Published: May 2021

Cancer is the second leading cause of death worldwide despite major advancements in diagnosis and therapy over the past century. One of the most debilitating aspects of cancer is the burden brought on by metastatic disease. Therefore, an ideal treatment protocol would address not only debulking larger primary tumors but also circulating tumor cells and distant metastases. To address this need, the use of immune modulating therapies has become a pillar in the oncology armamentarium. A therapeutic option that has recently emerged is the use of focal ablation therapies that can destroy a tumor through various physical or mechanical mechanisms and release a cellular lysate with the potential to stimulate an immune response. Histotripsy is a non-invasive, non-ionizing, non-thermal, ultrasound guided ablation technology that has shown promise over the past decade as a debulking therapy. As histotripsy therapies have developed, the full picture of the accompanying immune response has revealed a wide range of immunogenic mechanisms that include DAMP and anti-tumor mediator release, changes in local cellular immune populations, development of a systemic immune response, and therapeutic synergism with the inclusion of checkpoint inhibitor therapies. These studies also suggest that there is an immune effect from histotripsy therapies across multiple murine tumor types that may be reproducible. Overall, the effects of histotripsy on tumors show a positive effect on immunomodulation.
Development and Validation of a Nomogram Based on Nutritional Indicators and Tumor Markers for Prognosis Prediction of Pancreatic Ductal Adenocarcinoma
Authors: Li Haoran , Zhou Fang , Cao Zhifei , Tang Yuchen , Huang Yujie , Li Ye , Yi Bin , Yang Jian , Du Peng , Zhu Dongming , Zhou Jian
Published: May 2021

Purpose

This study aimed to develop and validate a nomogram with preoperative nutritional indicators and tumor markers for predicting prognosis of patients with pancreatic ductal adenocarcinoma (PDAC).

Methods

We performed a bicentric, retrospective study including 155 eligible patients with PDAC. Patients were divided into a training group (n = 95), an internal validation group (n = 34), an external validation group (n = 26), and an entire validation group (n = 60). Cox regression analysis was conducted in the training group to identify independent prognostic factors to construct a nomogram for overall survival (OS) prediction. The performance of the nomogram was assessed in validation groups and through comparison with controlling nutritional status (CONUT) and prognostic nutrition index (PNI).

Results

The least absolute shrinkage and selection operator (LASSO) regression, univariate and multivariate Cox regression analysis revealed that serum albumin and lymphocyte count were independent protective factors while CA19-9 and diabetes were independent risk factors. The concordance index (C-index) of the nomogram in the training, internal validation, external validation and entire validation groups were 0.777, 0.769, 0.759 and 0.774 respectively. The areas under curve (AUC) of the nomogram in each group were 0.861, 0.845, 0.773, and 0.814. C-index and AUC of the nomogram were better than those of CONUT and PNI in the training and validation groups. The net reclassification index (NRI), integrated discrimination improvement (IDI) and decision curve analysis showed improvement of accuracy of the nomogram in predicting OS and better net benefit in guiding clinical decisions in comparison with CONUT and PNI.

Conclusions

The nomogram incorporating four preoperative nutritional and tumor markers including serum albumin concentration, lymphocyte count, CA19-9 and diabetes mellitus could predict the prognosis more accurately than CONUT and PNI and may serve as a clinical decision support tool to determine what treatment options to choose.
Nivolumab Versus Regorafenib in Patients With Hepatocellular Carcinoma After Sorafenib Failure
Authors: Kuo Yuan-Hung , Yen Yi-Hao , Chen Yen-Yang , Kee Kwong-Ming , Hung Chao-Hung , Lu Sheng-Nan , Hu Tsung-Hui , Chen Chien-Hung , Wang Jing-Houng
Published: May 2021

Background

Nivolumab and regorafenib are approved second-line therapies for patients with hepatocellular carcinoma (HCC) after sorafenib failure. This study compared the effectiveness of nivolumab and regorafenib following sorafenib.

Methods

We retrospectively enrolled HCC patients who had undergone nivolumab or regorafenib after sorafenib failure. Treatment response, treatment-related adverse events (TRAE) and clinical outcomes of study patients were recorded and analyzed.

Results

A total of 90 patients (male/female: 67/23, mean age: 63 years) were enrolled, including 32 patients in the Nivolumab group and 58 patients in the Regorafenib group. The Nivolumab group had better objective response rates (16% vs 6.4%) and disease control rates (44% vs 31.9%) than the Regorafenib group, but there was no statistical difference. The comparison of time to progression (3.0 months vs 2.6 months, p=0.786) and overall survival (OS) (14 months vs 11 months, p = 0.763) between Nivolumab and Regorafenib groups were also insignificant. Regarding number of TRAE incidences, the Nivolumab group was significantly lower than the Regorafenib group (37.5% vs 68%). After cession of nivolumab/regorafenib, 34 patients (37.8%) (Nivolumab group/Regorafenib group: 11/23) could afford the following therapies. Concerning sequential systemic therapies, 17 patients (18.9%) received third-line therapy, whereas six patients (6.7%) could move to fourth-line therapy. In multivariable analysis, patients who achieved disease control were associated with improved OS (hazard ratio, 0.18; 95% confidence interval, 0.07–0.46; p<0.001) after adjusting Child-Pugh class and post-treatment.

Conclusions

After sorafenib failure, using nivolumab or regorafenib both illustrated promising treatment outcomes.
Jejunoileal Atresia: A National Cohort Study
Authors: Schmedding Andrea , Hutter Martin , Gfroerer Stefan , Rolle Udo
Published: May 2021

Purpose: Jejunoileal atresia (JIA) is a rare disease. We aimed to determine the overall incidence of this malformation and associated malformations in a national cohort. Furthermore, we compared the treatment results of this cohort with the current literature.

Methods: Data from the major health insurance company, which covers ~30% of the German population, were analyzed. All patients with ICD-10-Code Q41.1-9 (atresia of jejunum, ileum, other parts and not designated parts of the small bowel) who underwent any surgical procedure for small bowel were analyzed in a 10-year period between 2007 and 2016.

Results: A total of 435 patients were included in the study. The incidence was 2.1 per 10,000 live births. The male:female ratio was 1:2. Sixty-four percent were premature, 21% had associated cardiac anomalies, 16% had abdominal wall defects, 7% had urogenital malformations, and 7% had cystic fibrosis. Sixty percent of all patients with jejunoileal atresia, 57% of patients with accompanying abdominal wall defects and 72% of patients with associated cystic fibrosis required ostomy as the initial procedure. In 25% of all patients, only one intestinal operation was coded. In 39% of patients, two operations were coded. Twelve percent of all patients required feeding gastrostomy or jejunostomy. Sixteen percent of all patients presented with liver-related complications, i.e., cholestasis or liver insufficiency. Six patients underwent an intestinal lengthening procedure (2 Bianchi, 4 STEP). In five patients, initial lengthening was performed within 1 year after the first intestinal operation. Mortality until 1 year after initial surgery was 5%. Of those who died, 88% were premature, 34% had cardiac anomalies and 16% had abdominal wall defects. None had cystic fibrosis. Patients with ostomy significantly more often needed operative central venous line or operative feeding tube. Short bowel was coded significantly more often in these patients.

Conclusion: Patients with JIA present with low mortality. The rate of ostomies is higher than in literature. To give clinical recommendations for the initial surgical approach, further clinical research is needed.
Predictors of Diffusing Capacity in Children With Sickle Cell Disease: A Longitudinal Study
Authors: Mondal Pritish , Midya Vishal , Khokhar Arshjot , Sathianathan Shyama , Forno Erick
Published: May 2021

Background: Gas exchange abnormalities in Sickle Cell Disease (SCD) may represent cardiopulmonary deterioration. Identifying predictors of these abnormalities in children with SCD (C-SCD) may help us understand disease progression and develop informed management decisions.

Objectives: To identify pulmonary function tests (PFT) estimates and biomarkers of disease severity that are associated with and predict abnormal diffusing capacity (DLCO) in C-SCD.

Methods: We obtained PFT data from 51 C-SCD (median age:12.4 years, male: female = 29:22) (115 observations) and 22 controls (median age:11.1 years, male: female = 8:14), formulated a rank list of DLCO predictors based on machine learning algorithms (XGBoost) or linear mixed-effect models, and compared estimated DLCO to the measured values. Finally, we evaluated the association between measured or estimated DLCO and clinical outcomes, including SCD crises, pulmonary hypertension, and nocturnal desaturation.

Results: Hemoglobin-adjusted DLCO (%) and several PFT indices were diminished in C-SCD compared to controls. Both statistical approaches ranked FVC (%), neutrophils (%), and FEF25−75 (%) as the top three predictors of DLCO. XGBoost had superior performance compared to the linear model. Both measured and estimated DLCO demonstrated a significant association with SCD severity: higher DLCO, estimated by XGBoost, was associated with fewer SCD crises [beta = −0.084 (95%CI: −0.13, −0.033)] and lower TRJV [beta = −0.009 (−0.017, −0.001)], but not with nocturnal desaturation (p = 0.12).

Conclusions: In this cohort of C-CSD, DLCO was associated with PFT estimates representing restrictive lung disease (FVC, TLC), airflow obstruction (FEF25−75, FEV1/FVC, R5), and inflammation (neutrophilia). We used these indices to estimate DLCO, and show association with disease outcomes, underscoring the prediction models' clinical relevance.
Exploring the Mechanism of Total Flavonoids of Drynariae Rhizoma to Improve Large Bone Defects by Network Pharmacology and Experimental Assessment
Authors: Sun Weipeng , Li Minying , Xie Lei , Mai Zhexing , Zhang Yan , Luo Lieliang , Yan Zijian , Li Zige , Dong Hang , Huang Feng , Shen Zhen , Jiang Ziwei
Published: May 2021

Drynariae Rhizoma (DR) has been demonstrated to be effective in promoting fracture healing in clinical use. In the study, we tried to predicate potential signaling pathways and active ingredients of DR via network pharmacology, uncover its regulation mechanism to improve large bone defects by in vivo and in vitro experiment. We total discovered 18 potential active ingredients such as flavonoids and 81 corresponding targets, in which mitogen-activated protein kinase (MAPK) signaling pathway has the highest correlation with bone defects in pathway and functional enrichment analysis. Therefore, we hypothesized that flavonoids in DR improve large bone defects by activating MAPK signaling pathway. Animal experiments were carried out and all rats randomly divided into TFDR low, medium, and high dosage group, model group and control group. 12 weeks after treatment, according to X-ray and Micro-CT, TFDR medium dosage group significantly promote new bone mineralization compared with other groups. The results of HE and Masson staining and in vitro ALP level of BMSC also demonstrated the formation of bone matrix and mineralization in the TFDR groups. Also, angiographic imaging suggested that flavonoids in DR promoting angiogenesis in the defect area. Consistently, TFDR significantly enhanced the expression of BMP-2, RUNX-2, VEGF, HIF-1 in large bone defect rats based on ELISA and Real-Time PCR. Overall, we not only discover the active ingredients of DR in this study, but also explained how flavonoids in DR regulating MAPK signaling pathway to improve large bone defects.
Switching Between Second-Generation Antipsychotics in Patients with Schizophrenia and Schizoaffective Disorder: 10-Year Cohort Study in Brazil
Authors: Fulone Izabela , Silva Marcus Tolentino , Lopes Luciane Cruz
Published: May 2021

Objective: Switching between second-generation antipsychotics (SGAs) is a common clinical practice in the treatment of schizophrenia and schizoaffective disorders due to differences in the drugs’ tolerability and safety profiles as well as the challenge of obtaining an ideal response. However, the factors associated with SGA switching remain uncertain and related real-world data are scarce. The main objective was to identify the factors associated with the switching of SGAs in patients with schizophrenia or schizoaffective disorder.

Methods: We conducted a retrospective cohort study of outpatients with schizophrenia or schizoaffective disorder, who were aged ≥18 years and received a SGA (clozapine, olanzapine, risperidone, quetiapine or ziprasidone) from a Brazilian pharmaceutical assistance program for at least 3 months. We identified SGA users from 2008 to 2017 by using a national administrative database (Ambulatory Information System-SIA/SUS). The factors associated with the switches were evaluated by Cox proportional hazards regression and adjusted for sex and age; the confidence interval was set at 95% (95% CI).

Results: In total, 563,765 patients were included. Female sex, advanced age of ≥70 years, residence in the Brazilian northeast region, and the type of antipsychotic used were associated with an increased risk of switching (p < 0.001). The incidence of switching ranged from 37.6/100 person-years for clozapine users to 58.2/100 person-years for risperidone users. Compared to the adjusted hazard ratio, for clozapine users, the corresponding ratios for risperidone, ziprasidone, quetiapine and olanzapine were 1.59 (95% CI, 1.57–1.61), 1.41 (95% CI, 1.39–1.44), 1.25 (95% CI, 1.23–1.26) and 1.11 (95% CI, 1.10–1.12) respectively.

Conclusion: The groups most susceptible to SGA switching in real-life setting were older individuals, women, and those living in the Brazilian northeast region. Risperidone was associated with the highest risk of switching and as expected, clozapine was associated with the lowest risk of switching than that associated with the other SGAs.
Inhibition of ASIC1a-Mediated ERS Improves the Activation of HSCs and Copper Transport Under Copper Load
Authors: Kong Lingjin , Huang Huiping , Luan Shaohua , Liu Hui , Ye Manping , Wu Fanrong
Published: May 2021

Hepatolenticular degeneration (HLD) is an autosomal recessive genetic disease caused by the toxic accumulation of copper in the liver. Excessive copper will disrupt the redox balance in cells and tissues, causing ischemia, hypoxia, and inflammation. Acid-sensitive ion channel 1a is a cationic channel activated by extracellular acid and allowing Ca2+ and Na+ to flow into cells. Its expression appears in inflammation, arthritis, fibrotic tissue, and damaged environment, but its role in hepatolenticular degeneration has not been studied. This study established a Wistar rat model of high copper accumulation and used CuSO4 to induce the activation of HSC-T6 in an in vitro experiment. In vivo, Wistar rats were examined to determine the serum copper concentration, serum ALT and AST activities, and liver copper accumulation, and liver tissue HE staining and immunohistochemical analyses were conducted. The expression of ASIC1a, α-SMA, Collagen-Ι, GRP78, XBP1, ATP7B, and CCS were detected. Besides, immunofluorescence technology can detect the expression of the phosphorylated protein in vitro. It is suggested that ASIC1a is involved in the quality control of the endoplasmic reticulum, which degrades mutant ATP7B and increases the accumulation of copper. After blocking or silencing the expression of ASIC1a, ELISA can detect the level of inflammatory factors, the expression of endoplasmic reticulum stress-related factors, and ATP7B was improved in a higher copper environment reduction of copper deposition was observed in liver Timm’s staining. Collectively, we conclude that ASIC1a is involved in the HSC activation induced by copper accumulation and promotes the occurrence of hepatolenticular fibrosis.
Protective Effects of Sacubitril/Valsartan on Cardiac Fibrosis and Function in Rats With Experimental Myocardial Infarction Involves Inhibition of Collagen Synthesis by Myocardial Fibroblasts Through Downregulating TGF-β1/Smads Pathway
Authors: Wu Meifang , Guo Yanguang , Wu Ying , Xu Kaizu , Lin Liming
Published: May 2021

Objectives: To investigate the effect and mechanism of sacubitril/valsartan on myocardial fibrosis in rats following experimental myocardial infarction and in TGF-β1-treated myocardial fibroblasts.

Methods: Male Sprague-Dawley (SD) rats were subjected to coronary artery ligation to establish myocardial infarction and intragastrically fed vehicle, valsartan (Val, 32 mg/kg, once-daily) or sacubitril/valsartan (Sac/Val, 68 mg/kg, once-daily) for 4 weeks. In parallel, myocardial fibroblasts (MFs) isolated from neonatal SD rats were exposed to hypoxia and treated with TGF-β1 (5 ng/ml) plus vehicle, Val (107–10–5 M) or Sac/Val (107–105 M). Rat cardiac function and fibrosis were measured by echocardiography and histological method, respectively. MFs viability and collagen synthesis were determined by cell counting kit-8 and enzyme-linked immunosorbent assay, respectively. Protein expressions of TGF-β1, Smad3, phosphorylated Smad3 (p-Smad3), and p-Smad3 subcellular localization were detected by immunoblotting and immunocytochemistry.

Results: Sac/Val significantly improved cardiac structure and function in rats after myocardial infarction, including decreased left ventricular end-diastolic diameter and interventricular septal thickness, increased ejection fraction, and reduced myocardial collagen volume fraction and type Ⅰ and type Ⅲ collagen levels, and this effect was superior to that of Val. Besides, Sac/Val inhibited myocardial TGF-β1 and p-Smad3 protein expression better than Val. Mechanically, Sac/Val significantly attenuated TGF-β1-induced proliferation and collagen synthesis of MFs, and inhibit Smad3 phosphorylation and nucleus translocation, and this effect outperformed Val. Overexpression and silencing of Smad3 enhanced and reversed the inhibitory effects of Sac/Val on TGF-β1-induced collagen synthesis by MFs, respectively.

Conclusions: Sacubitril/valsartan improves cardiac function and fibrosis in rats after experimental myocardial infarction, and this effect is related to the inhibition of collagen synthesis in myocardial fibroblasts by inhibiting the TGF/Smads signaling pathway.
Relationship Between Cerebrovascular Reactivity and Cognition Among People With Risk of Cognitive Decline
Authors: Kim Donghoon , Hughes Timothy M. , Lipford Megan E. , Craft Suzanne , Baker Laura D. , Lockhart Samuel N. , Whitlow Christopher T. , Okonmah-Obazee Stephanie E. , Hugenschmidt Christina E. , Bobinski Matthew , Jung Youngkyoo
Published: May 2021

Vascular risk factors (e.g., obesity and hypertension) are associated with cerebral small vessel disease, Alzheimer’s disease (AD) pathology, and dementia. Reduced perfusion may reflect the impaired ability of blood vessels to regulate blood flow in reaction to varying circumstances such as hypercapnia (increased end-tidal partial pressures of CO2). It has been shown that cerebrovascular reactivity (CVR) measured with blood-oxygen-level-dependent (BOLD) MRI is correlated with cognitive performance and alterations of CVR may be an indicator of vascular disfunction leading to cognitive decline. However, the underlying mechanism of CVR alterations in BOLD signal may not be straight-forward because BOLD signal is affected by multiple physiological parameters, such as cerebral blood flow (CBF), cerebral blood volume, and oxygen metabolism. Arterial spin labeling (ASL) MRI quantitatively measures blood flow in the brain providing images of local CBF. Therefore, in this study, we measured CBF and its changes using a dynamic ASL technique during a hypercapnia challenge and tested if CBF or CVR was related to cognitive performance using the Mini-mental state examination (MMSE) score. Seventy-eight participants underwent cognitive testing and MRI including ASL during a hypercapnia challenge with a RespirAct computer-controlled gas blender, targeting 10 mmHg higher end-tidal CO2 level than the baseline while end-tidal O2 level was maintained. Pseudo-continuous ASL (PCASL) was collected during a 2-min baseline and a 2-min hypercapnic period. CVR was obtained by calculating a percent change of CBF per the end-tidal CO2 elevation in mmHg between the baseline and the hypercapnic challenge. Multivariate regression analyses demonstrated that baseline resting CBF has no significant relationship with MMSE, while lower CVR in the whole brain gray matter (β = 0.689, p = 0.005) and white matter (β = 0.578, p = 0.016) are related to lower MMSE score. In addition, region of interest (ROI) based analysis showed positive relationships between MMSE score and CVR in 26 out of 122 gray matter ROIs.
Proteomics and Epidemiological Models of Human Aging
Authors: Ubaida-Mohien Ceereena , Moaddel Ruin , Moore Ann Zenobia , Kuo Pei-Lun , Faghri Faraz , Tharakan Ravi , Tanaka Toshiko , Nalls Mike A. , Ferrucci Luigi
Published: May 2021

Human aging is associated with a decline of physical and cognitive function and high susceptibility to chronic diseases, which is influenced by genetics, epigenetics, environmental, and socio-economic status. In order to identify the factors that modulate the aging process, established measures of aging mechanisms are required, that are both robust and feasible in humans. It is also necessary to connect these measures to the phenotypes of aging and their functional consequences. In this review, we focus on how this has been addressed from an epidemiologic perspective using proteomics. The key aspects of epidemiological models of aging can be incorporated into proteomics and other omics which can provide critical detailed information on the molecular and biological processes that change with age, thus unveiling underlying mechanisms that drive multiple chronic conditions and frailty, and ideally facilitating the identification of new effective approaches for prevention and treatment.
Spaghetti Meat Abnormality in Broilers: Current Understanding and Future Research Directions
Authors: Baldi Giulia , Soglia Francesca , Petracci Massimiliano
Published: May 2021

Spaghetti meat (SM) is a recent muscular abnormality that affects the Pectoralis major muscle of fast-growing broilers. As the appellative suggests, this condition phenotypically manifests as a loss of integrity of the breast muscle, which appears soft, mushy, and sparsely tight, resembling spaghetti pasta. The incidence of SM can reach up to 20% and its occurrence exerts detrimental effects on meat composition, nutritional value, and technological properties, accounting for an overall decreased meat value and important economic losses related to the necessity to downgrade affected meats. However, due to its recentness, the causative mechanisms are still partially unknown and less investigated compared to other muscular abnormalities (i.e., White Striping and Wooden Breast), for which cellular stress and hypoxia caused by muscle hypertrophy are believed to be the main triggering factors. Within this scenario, the present review aims at providing a clear and concise summary of the available knowledge concerning SM abnormality and concurrently presenting the existing research gaps, as well as the potential future developments in the field.
Cannabinoids and Terpenes: How Production of Photo-Protectants Can Be Manipulated to Enhance Cannabis sativa L. Phytochemistry
Authors: Desaulniers Brousseau Vincent , Wu Bo-Sen , MacPherson Sarah , Morello Victorio , Lefsrud Mark
Published: May 2021

Cannabis sativaL. is cultivated for its secondary metabolites, of which the cannabinoids have documented health benefits and growing pharmaceutical potential. Recent legal cannabis production in North America and Europe has been accompanied by an increase in reported findings for optimization of naturally occurring and synthetic cannabinoid production. Of the many environmental cues that can be manipulated during plant growth in controlled environments, cannabis cultivation with different lighting spectra indicates differential production and accumulation of medically important cannabinoids, including Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and cannabigerol (CBG), as well as terpenes and flavonoids. Ultraviolet (UV) radiation shows potential in stimulating cannabinoid biosynthesis in cannabis trichomes and pre-harvest or post-harvest UV treatment merits further exploration to determine if plant secondary metabolite accumulation could be enhanced in this manner. Visible LED light can augment THC and terpene accumulation, but not CBD. Well-designed experiments with light wavelengths other than blue and red light will provide more insight into light-dependent regulatory and molecular pathways in cannabis. Lighting strategies such as subcanopy lighting and varied light spectra at different developmental stages can lower energy consumption and optimize cannabis PSM production. Although evidence demonstrates that secondary metabolites in cannabis may be modulated by the light spectrum like other plant species, several questions remain for cannabinoid production pathways in this fast-paced and growing industry. In summarizing recent research progress on light spectra and secondary metabolites in cannabis, along with pertinent light responses in model plant species, future research directions are presented.
Floral Longevity of Paphiopedilum and Cypripedium Is Associated With Floral Morphology
Authors: Zhang Feng-Ping , Feng Jing-Qiu , Huang Jia-Lin , Huang Wei , Fu Xue-Wei , Hu Hong , Zhang Shi-Bao
Published: May 2021

Floral longevity (FL) is an important trait influencing plant reproductive success by affecting the chance of insect pollination. However, it is still unclear which factors affect FL, and whether FL is evolutionarily associated with structural traits. Since construction costs and water loss by transpiration play a role in leaf longevity, we speculated that floral structures may affect the maintenance and loss of water in flowers and, therefore, FL. Here, we investigated the slipper orchid Paphiopedilum and Cypripedium, which are closely related, but strongly differ in their FL. To understand the evolutionary association of floral anatomical traits with FL, we used a phylogenetic independent comparative method to examine the relationships between 30 floral anatomical traits and FL in 18 species of Paphiopedilum and Cypripedium. Compared with Paphiopedilum species, Cypripedium species have lower values for floral traits related to drought tolerance and water retention capacity. Long FL was basically accompanied by the thicker epidermal and endodermal tissues of the floral stem, the thicker adaxial and abaxial epidermis of the flower, and low floral vein and stomatal densities. Vein density of the dorsal sepals and synsepals was negatively correlated with stomatal density. Our results supported the hypothesis that there was a correlation between FL and floral anatomical traits in slipper orchids. The ability to retain water in the flowers was associated with FL. These findings provide a new insight into the evolutionary association of floral traits with transpirational water loss for orchids under natural selection.