bluuebunny/crossref_metadata_2025 huggingface dataset:
Tooth Loss Suppresses Hippocampal Neurogenesis and Leads to Cognitive Dysfunction in Juvenile Sprague–Dawley Rats
Authors: Hu Jiangqi , Wang Xiaoyu , Kong Wei , Jiang Qingsong
Published: April 2022

Background

Both animal studies and prospective observational studies on patients with neurodegenerative disease have reported a positive link between oral diseases and cognitive function. However, the effect of early tooth loss on hippocampal morphology remains unknown.

Methods

In this study, 6-week-old, male, juvenile Sprague–Dawley (SD) rats were randomized into the control (C) and tooth loss (TL) groups. In the TL group, all right maxillary molars of SD rats were extracted, while in the C group, no teeth were extracted. After 3 months, the learning and memory behavior were examined by Morris Water Maze (MWM), and the protein expression and mechanic signaling pathways were analyzed by real-time polymerase chain reaction, and cresyl violet staining.

Results

Two days after the operation, the body weight of both groups recovered and gradually returned to the level before operation. Three months after tooth extraction, the completion time of the C group in the MWM was significantly shorter than the TL group. The mRNA expression of BDNF, TrkB, AKT1, and NR2B in the C group were significantly higher than in the TL group. The pyramidal neurons in the TL group was fewer than in the C group.

Conclusion

Tooth loss in the juvenile SD rats will reduce the number of pyramidal neurons in the hippocampus, inhibit the expression of BDNF, TrkB, AKT1, and NR2B, and eventually lead to cognitive dysfunction.
Simultaneous Quantification of Mitochondrial Mature Frataxin and Extra-Mitochondrial Frataxin Isoform E in Friedreich’s Ataxia Blood
Authors: Wang Qingqing , Laboureur Laurent , Weng Liwei , Eskenazi Nicolas M. , Hauser Lauren A. , Mesaros Clementina , Lynch David R. , Blair Ian A.
Published: April 2022

Friedreich’s ataxia (FRDA) is an autosomal recessive disease caused by an intronic guanine-adenine-adenine (GAA) triplet expansion in the frataxin (FXN) gene, which leads to reduced expression of full-length frataxin (1–210) also known as isoform 1. Full-length frataxin has a mitochondrial targeting sequence, which facilitates its translocation into mitochondria where it is processed through cleavage at G41-L42 and K80-S81 by mitochondrial processing (MPP) to release mitochondrial mature frataxin (81–210). Alternative splicing of FXN also leads to expression of N-terminally acetylated extra-mitochondrial frataxin (76–210) named isoform E because it was discovered in erythrocytes. Frataxin isoforms are undetectable in serum or plasma, and originally whole blood could not be used as a biomarker in brief therapeutic trials because it is present in erythrocytes, which have a half-life of 115-days and so frataxin levels would remain unaltered. Therefore, an assay was developed for analyzing frataxin in platelets, which have a half-life of only 10-days. However, our discovery that isoform E is only present in erythrocytes, whereas, mature frataxin is present primarily in short-lived peripheral blood mononuclear cells (PBMCs), granulocytes, and platelets, meant that both proteins could be quantified in whole blood samples. We now report a quantitative assay for frataxin proteoforms in whole blood from healthy controls and FRDA patients. The assay is based on stable isotope dilution coupled with immunoprecipitation (IP) and two-dimensional-nano-ultrahigh performance liquid chromatography/parallel reaction monitoring/high resolution mass spectrometry (2D-nano-UHPLC-PRM/HRMS). The lower limit of quantification was 0.5 ng/mL for each proteoform and the assays had 100% sensitivity and specificity for discriminating between healthy controls (n = 11) and FRDA cases (N = 100 in year-1, N = 22 in year-2,3). The mean levels of mature frataxin in whole blood from healthy controls and homozygous FRDA patients were significantly different (p < 0.0001) at 7.5 ± 1.5 ng/mL and 2.1 ± 1.2 ng/mL, respectively. The mean levels of isoform E in whole blood from healthy controls and homozygous FRDA patients were significantly different (p < 0.0001) at 26.8 ± 4.1 ng/mL and 4.7 ± 3.3 ng/mL, respectively. The mean levels of total frataxin in whole blood from healthy controls and homozygous FRDA patients were significantly different (p < 0.0001) at 34.2 ± 4.3 ng/mL and 6.8 ± 4.0 ng/mL, respectively. The assay will make it possible to rigorously monitor the natural history of the disease and explore the potential role of isoform E in etiology of the disease. It will also facilitate the assessment of therapeutic interventions (including gene therapy approaches) that attempt to increase frataxin protein expression as a treatment for this devastating disease.
To Stick or Not to Stick: The Multiple Roles of Cell Adhesion Molecules in Neural Circuit Assembly
Authors: Moreland Trevor , Poulain Fabienne E.
Published: April 2022

Precise wiring of neural circuits is essential for brain connectivity and function. During development, axons respond to diverse cues present in the extracellular matrix or at the surface of other cells to navigate to specific targets, where they establish precise connections with post-synaptic partners. Cell adhesion molecules (CAMs) represent a large group of structurally diverse proteins well known to mediate adhesion for neural circuit assembly. Through their adhesive properties, CAMs act as major regulators of axon navigation, fasciculation, and synapse formation. While the adhesive functions of CAMs have been known for decades, more recent studies have unraveled essential, non-adhesive functions as well. CAMs notably act as guidance cues and modulate guidance signaling pathways for axon pathfinding, initiate contact-mediated repulsion for spatial organization of axonal arbors, and refine neuronal projections during circuit maturation. In this review, we summarize the classical adhesive functions of CAMs in axonal development and further discuss the increasing number of other non-adhesive functions CAMs play in neural circuit assembly.
Phenotypic and Genotypic Characteristics of SCN1A Associated Seizure Diseases
Authors: Chen Chunhong , Fang Fang , Wang Xu , Lv Junlan , Wang Xiaohui , Jin Hong
Published: April 2022

Although SCN1A variants result in a wide range of phenotypes, genotype-phenotype associations are not well established. We aimed to explore the phenotypic characteristics of SCN1A associated seizure diseases and establish genotype-phenotype correlations. We retrospectively analyzed clinical data and results of genetic testing in 41 patients carrying SCN1A variants. Patients were divided into two groups based on their clinical manifestations: the Dravet Syndrome (DS) and non-DS groups. In the DS group, the age of seizure onset was significantly earlier and ranged from 3 to 11 months, with a median age of 6 months, than in the non-DS group, where it ranged from 7 months to 2 years, with a median age of 10 and a half months. In DS group, onset of seizures in 11 patients was febrile, in seven was afebrile, in two was febrile/afebrile and one patient developed fever post seizure. In the non-DS group, onset in all patients was febrile. While in the DS group, three patients had unilateral clonic seizures at onset, and the rest had generalized or secondary generalized seizures at onset, while in the non-DS group, all patients had generalized or secondary generalized seizures without unilateral clonic seizures. The duration of seizure in the DS group was significantly longer and ranged from 2 to 70 min (median, 20 min), than in the non-DS group where it ranged from 1 to 30 min (median, 5 min). Thirty-one patients harbored de novo variants, and nine patients had inherited variants. Localization of missense variants in the voltage sensor region (S4) or pore-forming region (S5–S6) was seen in seven of the 11 patients in the DS group and seven of the 17 patients in the non-DS group. The phenotypes of SCN1A-related seizure disease were diverse and spread over a continuous spectrum from mild to severe. The phenotypes demonstrate commonalities and individualistic differences and are not solely determined by variant location or type, but also due to functional changes, genetic modifiers as well as other known and unknown factors.
What Level Should Preoperative Albumin of Thoracic and Lumbar Tuberculosis Patients Be Reached: A Case-Controlled Study
Authors: Jiang Guanyin , Zhu Yong , Luo Wei , Zhang Wei , Qin Wanyuan , Ou Yunsheng
Published: April 2022

Objective

To explore the risk factors of hypoalbuminemia in patients with thoracic and lumbar tuberculosis and develop a scoring scale, according to which the patients with thoracic and lumbar tuberculosis were divided into 2 groups to, respectively calculate the perioperative albumin changes and to find out the preoperative albumin recommended value.

Methods

A total of 166 patients with thoracic and lumbar tuberculosis, who underwent spinal focus debridement between January 2012 to May 2020, were identified into 2 groups: with and without postoperative hypoalbuminemia (n = 131 and n = 35, respectively), recording and analyzing clinical characteristics by multivariate analysis to establish a scoring scale. Using this scale, patients with spinal tuberculosis were divided into a high-risk group and a low-risk group, and then, calculated the average decrease of postoperative albumin in both groups. Combined with the diagnostic threshold of hypoalbuminemia, we proposed the preoperative albumin safe values of the patients with thoracic and lumbar tuberculosis.

Results

A total of 131 of 166 patients experienced postoperative hypoalbuminemia after spinal focus debridement. Multivariate binary logistic regression analysis identified pulmonary tuberculosis (adjusted odds ratio = 0.270, p = 0.012), pre-operative serum albumin value (adjusted odds ratio = 0.754, p < 0.001), and operation time (adjusted odds ratio = 1.017, p = 0.002) as independent risk factors for the occurrence of postoperative hypoalbuminemia in patients with thoracic and lumbar tuberculosis. According to the OR value, the risk factors are assigned to make the scoring scale, the receiver operating characteristic (ROC) curve indicates that postoperative hypoalbuminemia rises when the score is greater than or equal to 4 points. The scoring scale is tested in the derivation set (166 patients) showed: sensitivity-51.9%, specificity-91.4%, and in the validation set (102 patients) showed: sensitivity-63.6% and specificity-86.1%. The perioperative albumin decreased value is 4.71 ± 2.66 g/L in the low-risk group and 8.99 ± 3.37 g/L in the high-risk group (p < 0.001).

Conclusion

Complicated with pulmonary tuberculosis, low preoperative albumin value and long operation time can lead to postoperative hypoalbuminemia in patients with thoracic and lumbar tuberculosis. The scoring scale can effectively assist physicians to evaluate whether patients with thoracic and lumbar tuberculosis develop hypoalbuminemia after surgery. The scale is simple and reliable and has clinical guiding significance. For low-risk patients and high-risk patients, preoperative albumin values should reach 40 and 44 g/L, respectively, to effectively avoid postoperative hypoalbuminemia.
Dietary ε-Polylysine Affects on Gut Microbiota and Plasma Metabolites Profiling in Mice
Authors: Zhang Xuelei , Xu Baoyang , Hou Zhenping , Xie Chunlin , Niu Yaorong , Dai Qiuzhong , Yan Xianghua , Wu Duanqin
Published: April 2022

Given the antibacterial effects of ε-polylysine acting on cell membranes, and that glycerol phospholipids are important components of the cell membrane, we hypothesized that ε-polylysine may regulate glycerophospholipid metabolism by modifying the gut microbiota. To test this hypothesis, we treated post-weaning C57 mice with different levels of ε-polylysine (0, 300, 600, and 1,200 ppm) in their basic diet. The growth performance and morphology of intestine were then determined. Modification of the gut microbiota and their function were analyzed using 16S rDNA sequencing. Metabolite identification was performed using the LC-MS method. The results showed that body weight decreased with an increasing supplemental level of ε-polylysine from 5 to 7 weeks (P < 0.05), but no significant difference was observed after 8 weeks (P > 0.05). Supplementation with 1,200 ppm ε-polylysine changed the morphology of the jejunum and ileum, increased the villus length, decreased the crypt depth of the jejunum, and decreased the villus length and crypt depth of the ileum (P < 0.05). ε-Polylysine shifted the intestine microbiota by changing alpha diversity (Chao 1, observed species, Shannon, and Simpson indices) and varied at different times. ε-polylysine decreased Firmicutes and increased Bacteroidetes at 4 week, but increased Firmicutes and decreased Bacteroidetes at 10 week. ε-Polylysine regulated genera associated with lipid metabolism such as Parabacteroides, Odoribacter, Akkermansia, Alistipes, Lachnospiraceae UCG-001, Collinsella, Ruminococcaceae, and Intestinimonas. During the adult period, the genera Alistipes, Lachnospiraceae UCG-001, and Streptomyces were positively associated with PC, PE, LysoPC, LysoPE, 1-Arachidonoylglycerophosphoinositol and OHOHA-PS (R > 0.6, P < 0.001), but changes in Blautia, Christensenellaceae R-7 group, Odoribacter, Allobaculum, Ruminococcaceae UCG-004, Ruminococcaceae UCG-005, and Lachnospiraceae UCG-010 were negatively correlated with glycerophospholipid metabolites (R < −0.6, P < 0.001). The abundance of glycerophospholipid metabolites, including PC, PE, lysoPC, and lysoPE, were decreased by ε-polylysine. Furthermore, ε-polylysine reduced the incidence of the genera including Ruminococcus, Prevotella, Prevotellaceae, Butyricimonas, and Escherichia-Shigella and reduced the abundance of Faecalibaculum, Christensenellaceae R-7 group, Coriobacteriaceae UCG-002. In conclusion, ε-polylysine modified gut microbiota composition and function while also restraining pathogenic bacteria. The glycerophospholipid metabolism pathway and associated metabolites may be regulated by intestinal bacteria.
Increased Relative Abundance of Ruminoccocus Is Associated With Reduced Cardiovascular Risk in an Obese Population
Authors: Lakshmanan Arun Prasath , Al Zaidan Sara , Bangarusamy Dhinoth Kumar , Al-Shamari Sahar , Elhag Wahiba , Terranegra Annalisa
Published: April 2022

Background

Obesity is a complex disease with underlying genetic, environmental, psychological, physiological, medical, and epigenetic factors. Obesity can cause various disorders, including cardiovascular diseases (CVDs), that are among the most prevalent chronic conditions in Qatar. Recent studies have highlighted the significant roles of the gut microbiome in improving the pathology of various diseases, including obesity. Thus, in this study, we aimed to investigate the effects of dietary intake and gut microbial composition in modulating the risk of CVD development in obese Qatari adults.

Methods

We enrolled 46 adult subjects (18–65 years of age) who were classified based on their CVD risk scores, calculated using the Framingham formula, into a CVD no-risk group (score of <10%, n = 36) and CVD risk group (score of ≥10%, n = 10). For each study subject, we measured the gut microbial composition with a 16s rDNA sequencing method that targeted the v3-v4 region using Illumina Miseq, and their nutritional status was recorded based on 24-h dietary recall. Dietary intake, bacterial taxa summary, diversity index, microbial markers, pathway analysis, and network correlation were determined for the study subjects.

Results

The CVD risk group showed a lower intake of vitamin D, reduced relative abundance of genera Ruminococcus and Bifidobacterium, no change in bacterial diversity, and higher levels of taurine, hypotaurine, and lipoic acid metabolism than the CVD no-risk group. Besides, the relative abundance of genus Ruminococcus was positively correlated with the intake of protein, monounsaturated fat, vitamin A, and vitamin D.

Conclusion

Taken together, our results suggest that the genus Ruminococcus could be used as a microbial marker, and its reduced relative abundance could mediate the risk of CVDs in the Obese Qatari population.
RETRACTED: The Association Between Diet and Cardio-Metabolic Risk on Cognitive Performance: A Cross-Sectional Study of Middle-Aged Australian Adults
Authors: Gauci Sarah , Young Lauren M. , Arnoldy Lizanne , Scholey Andrew , White David J. , Lassemillante Annie-Claude , Meyer Denny , Pipingas Andrew
Published: April 2022

Adherence to different dietary patterns has been linked to the development of cognitive decline; yet little is known about whether this relationship is present in middle age. The current study aimed to explore the relationship between different dietary patterns, cognitive performance, and potential cardio-metabolic mechanisms for this relationship. Participants were recruited using a diet screening tool to ensure that the cohort had a range of diet quality ranging from relatively poor to relatively healthy. In a sample of 141 middle-aged adults (age: M = 52.84 years, SD = 6.87 years), multiple 24 h diet recalls were collected and used to score adherence to the Mediterranean diet, dietary approaches to stop hypertension (DASH) diet, and Mediterranean–DASH diet intervention for neurodegenerative delay (MIND) diet. Metabolic risk was assessed using the metabolic syndrome severity score (MetSSS) and arterial stiffness. Cognitive performance was assessed using the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB). Adherence to the MIND diet was significantly related to Stroop Processing domain (β = 0.19, p = 0.035). None of the dietary patterns were significantly related to MetSSS or arterial stiffness. However, adherence to the DASH diet was significantly associated with two cardio-metabolic measures including lower augmentation index (β = −0.17, p = 0.032) and lowered cholesterol (β = −0.18, p = 0.041). Interestingly, two cardio-metabolic risk factors were also associated with better cognitive performance: MetSSS (β = 0.21, p = 0.010) and waist circumference (β = 0.22, p = 0.020). Together these findings suggest that diet in middle age may be important for cognitive functioning and cardio-metabolic risk. However, more research is needed in the form of randomized controlled trials to confirm the direction of these relationships.
Tuning the Physicochemical, Structural, and Antimicrobial Attributes of Whey-Based Poly (L-Lactic Acid) (PLLA) Films by Chitosan Nanoparticles
Authors: Garavand Farhad , Rouhi Milad , Jafarzadeh Shima , Khodaei Diako , Cacciotti Ilaria , Zargar Masoumeh , Razavi Seyed Hadi
Published: April 2022

Recently, the research and innovation to produce raw materials from microbial processes has gained much attention due to their economic and environmental impacts. Lactic acid is a very important microbial product due to its wide application in the food, pharmaceutical, cosmetic, and chemical industries. In the current study, poly (L-lactic acid) (PLLA) was produced by the ring opening polymerization (ROP) technique of L-lactic acid recovered from whey fermentation, and was used for the production of nanocomposites films reinforced with chitosan nanoparticles (CNPs) (average diameter ca. 100–200 nm). Three different CNPs concentrations, namely 1, 3, and 5% w/w, were tested, and their influence on the physical, mechanical, thermal, antibacterial and structural attributes of PLLA film was assessed. The results showed that the addition of CNPs up to 3% caused a significant improvement in water vapor permeability, appearance, tensile strength and elongation at break. The antibacterial properties of nanocomposites followed a dose-depended pattern as a result of CNPs addition. Therefore, the best inhibitory effects on Escherichia coli and Staphylococcus aureus was made by the addition of 5% of CNPs and lower dosages slightly affected the growth of pathogens or didn't cause any inhibitory effects (in 1% of CNPs). It can be concluded that the incorporation of CNPs into the PLLA matrix allows to improve the structural, thermal, physical, mechanical and antibacterial properties of the polymer, generating promising systems for food packaging and biomedical applications.
Rhamnolipids Regulate Lipid Metabolism, Immune Response, and Gut Microbiota in Rats
Authors: Zhang Bing , Qin Songke , Wu Yanping , Zhang Ruiqiang , Xu Yinglei , Yang Caimei
Published: April 2022

Objectives

Gut microbes influence lipid metabolism and immune responses that are key features of metabolic disorders. This study examined effects of bacterial rhamnolipids (RLS) on lipid metabolism, immune response, and gut microbiota in rats.

Methods

Twenty-four Sprague-Dawley rats were randomly divided into three groups and gavage-fed for seven weeks with normal saline (NCO group), 50 mg/kg bw RLS (RLS1 group), and 100 mg/kg bw RLS (RLS2 group).

Results

Compared with those of the NCO group, the RLS1 and RLS2 groups showed significantly decreased fat weight, relative fat weight, and adipocyte size (P < 0.05). Furthermore, RLS1 and RLS2 significantly decreased concentrations of triglycerides, low-density lipoprotein-cholesterol, and non-esterified fatty acids and increased high-density lipoprotein-cholesterol levels (P < 0.05). However, the total cholesterol content among the three groups (P > 0.05) were not significantly different. Serum concentrations of interleukin-1β, interleukin-6, and tumor necrosis factor-α were significantly lower in the RLS2 group than those in the NCO group (P < 0.05). The relative mRNA expression of fatty acid synthase was significantly decreased, while those of carnitine palmitoyltransferase-1, carnitine palmitoyltransferase-2, and peroxisome proliferator-activated receptor-gamma coactivator-1α were significantly increased in the RLS2 group compared with those in the NCO group (P < 0.05). Moreover, the relative abundances of Lactobacillus, Roseburia, Ruminococcus-1, and Parabacteroides were significantly higher in the RLS2 group than those in the NCO group (P < 0.05).

Conclusion

Our findings suggest that RLS reduces fat deposition, inhibits inflammation, regulates intestinal flora, and promotes the proliferation of beneficial bacteria in rats.
Effects of Air Frying on French Fries: The Indication Role of Physicochemical Properties on the Formation of Maillard Hazards, and the Changes of Starch Digestibility
Authors: Dong Lu , Qiu Cai-yi , Wang Rui-can , Zhang Yan , Wang Jin , Liu Jing-min , Yu Hua-ning , Wang Shuo
Published: April 2022

This study focused on the formation of Maillard hazards in air fried fries, highlighting the correlation between the resultant physical properties of the fries and the formation of Maillard hazards. In the meantime, the effects of air frying on the in vitro starch digestibility of fries were explored. Potato strips were fried at various temperatures (180–200°C) and time (12–24 min). Results indicated that the extent of browning, hardness, and the contents of Maillard hazards (acrylamide, 5-hydroxymethylfurfural, methylglyoxal, and glyoxal) all increased steadily with air frying temperature and time. Moisture content were negatively correlated (p < 0.001) with Maillard hazards content and physicochemical properties except for L* with the correlation coefficients range from −0.53 to 0.94, and positively correlated with L* value with correlation coefficient was 0.91, hence, reducing the Maillard hazard exposure while maintaining the desired product quality can be achieved by controlling the moisture content of the air fried French fries. Compared with deep frying (180°C−6 min), air frying decreased acrylamide and 5-hydroxymethylfurfural content with the maximum reduction rate were 47.31 and 57.04%, respectively. In addition, the in vitro digestion results suggested that air frying resulted in higher levels of slowly digestible starch (48.54–58.42%) and lower levels of resistant starch (20.08–29.34%) as compared to those from deep frying (45.59 ± 4.89 and 35.22 ± 0.65%, respectively), which might contribute to more balanced blood sugar levels after consumption. Based on the above results, it was concluded that air frying can reduce the formation of food hazards and was relatively healthier.
Secondary Bile Acids and Tumorigenesis in Colorectal Cancer
Authors: Liu Yujing , Zhang Shengan , Zhou Wenjun , Hu Dan , Xu Hanchen , Ji Guang
Published: April 2022

Colorectal cancer (CRC) is one of the most common and deadly cancers in the world and is a typical inflammatory tumor. In recent years, the incidence of CRC has been increasing year by year. There is evidence that the intake of high-fat diet and overweight are associated with the incidence of CRC, among which bile acids play a key role in the pathogenesis of the disease. Studies on the relationship between bile acid metabolism and the occurrence of CRC have gradually become a hot topic, improving the understanding of metabolic factors in the etiology of colorectal cancer. Meanwhile, intestinal flora also plays an important role in the occurrence and development of CRC In this review, the classification of bile acids and their role in promoting the occurrence of CRC are discussed, and we highlights how a high-fat diet affects bile acid metabolism and destroys the integrity of the intestinal barrier and the effects of gut bacteria.
Radiomics Model for Predicting TP53 Status Using CT and Machine Learning Approach in Laryngeal Squamous Cell Carcinoma
Authors: Tian Ruxian , Li Yumei , Jia Chuanliang , Mou Yakui , Zhang Haicheng , Wu Xinxin , Li Jingjing , Yu Guohua , Mao Ning , Song Xicheng
Published: April 2022

Objective

We aim to establish and validate computed tomography (CT)-based radiomics model for predicting TP53 status in patients with laryngeal squamous cell carcinoma (LSCC).

Methods

We divided all patients into a training set 1 (n=66) and a testing set 1 (n=30) to establish and validate radiomics model to predict TP53. Radiomics features were selected by analysis of variance (ANOVA) and the least absolute shrinkage and selection operator (Lasso) regression analysis. Five radiomics models were established by using K-Nearest Neighbor, logistics regressive, linear-support vector machine (SVM), gaussian-SVM, and polynomial-SVM in training set 1. We also divided all patients into a training set 2 and a testing set 2 according to different CT equipment to establish and evaluate the stability of the radiomics models.

Results

After ANOVA and subsequent Lasso regression analysis, 22 radiomics features were selected to build the radiomics model in training set 1. The radiomics model based on linear-SVM has the best predictive performance of the five models, and the area under the receiver operating characteristic curve in training set 1 and testing set 1 were 0.831(95% confidence interval [CI] 0.692–0.970) and 0.797(95% CI 0.632–0.957) respectively. The specificity, sensitivity, and accuracy were 0.971(95% CI 0.834–0.999), 0.714(95% CI 0.535–0.848), and 0.843(95% CI 0.657–0.928) in training set 1 and 0.750(95% CI 0.500–0.938), 0.786(95% CI 0.571–1.000), and 0.667(95% CI 0.467–0.720) in testing set 1, respectively. In addition, the radiomics model also achieved stable prediction results even in different CT equipment. Decision curve analysis showed that the radiomics model for predicting TP53 status could benefit LSCC patients.

Conclusion

We developed and validated a relatively optimal radiomics model for TP53 status prediction by trying five different machine learning methods in patients with LSCC. It shown great potential of radiomics features for predicting TP53 status preoperatively and guiding clinical treatment.
Outcomes From Cytotoxic Chemotherapy Following Progression on Immunotherapy in Metastatic Melanoma: An Institutional Case-Series
Authors: Gaughan Elizabeth M. , Horton Bethany J.
Published: April 2022

Introduction

The role of chemotherapy in the management of advanced melanoma is limited due to low response rates and short survival. Improved outcomes to chemotherapy administered after immunotherapy for metastatic melanoma and other solid tumors have been reported. We studied the outcomes of subjects treated at the University of Virginia (UVA) with chemotherapy following progression on prior systemic immunotherapy and compared the results with the existing literature.

Materials and Methods

Subjects were identified through an institutional database of patients treated with immunotherapy at UVA. Demographic, pathologic and clinical factors were collected, along with dates of therapy, investigator-assessed best response as per Response Evaluation Criteria for Solid Tumors version 1.1 and dates of death or last follow up. Kaplan-Meier survival estimates and log-rank tests were used to perform time to event analysis of progression free survival and overall survival.

Results

Forty-five patients were identified who met the inclusion criteria including 24 men and 21 women with a median age of 61 years. All patients had received at least one line of immunotherapy including 64.4% with prior anti-PD1 treatment. The cytotoxic chemotherapy regimens used included carboplatin with paclitaxel (55.6%), temozolomide (31.1%) and nab-paclitaxel (13.3%). The overall response rate for cytotoxic chemotherapy 22.2% and the disease control rate was 35.6%. The median progression-free survival was 1.7 months and median overall survival was 4.7 months. Nineteen (42.2%) patients survived greater than 6 months and seven (15.5%) patients survived over 12 months. Fourteen patients were able to proceed to further therapy.

Discussion

Our results reveal that receipt of immunotherapy prior to chemotherapy for metastatic melanoma does not appear to improve the benefit of chemotherapy. The palliation of symptoms, maintenance of performance status and disease control may be valuable for some patients during this time of robust research and discovery for metastatic melanoma.
Chemotherapy Decision-Making and Survival Outcomes in Older Women With Early Triple-Negative Breast Cancer: Evidence From Real-World Practice
Authors: Xiu Meng , Zhang Pin , Li Qing , Yuan Peng , Wang Jiayu , Luo Yang , Ma Fei , Cai Ruigang , Fan Ying , Li Qiao , Xu Binghe
Published: April 2022

Data regarding chemotherapy options and benefits in older women with early triple-negative breast cancer (TNBC) are limited. Our study aimed to assess the effects of adjuvant chemotherapy on recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS) rates in elderly TNBC patients. Patients aged ≥65 years diagnosed with stage I-III TNBC (except T1aN0) between 2010 and 2016 were retrospectively included. Multivariate Cox regression was performed to minimize bias. A total of 177 patients were included with a median age of 69 years (range, 65-86), almost all had a Charlson Comorbidity Index of 0-2, and 127 (71.8%) received chemotherapy. Patients who received chemotherapy were younger, had more advanced-stage disease and had better ECOG performance status (P<0.05). Among the 127 patients who were administered chemotherapy, 45 (35%) received taxane plus carboplatin, 36 (28%) received anthracycline-and-taxane-based regimens, and 23 (18%) received taxane-based regimens. The regimen options differed based on patient age and tumour stage (P<0.05). Nearly 80% of the patients completed ≥6 cycles of chemotherapy, and half had their dosage decreased. After adjustment for confounding factors, patients who received ≥6 cycles of chemotherapy were found to have improved RFS rates (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.09-0.87; P=0.027), and receipt of chemotherapy (≥1 cycle) was associated with better BCSS (HR, 0.19; 95% CI, 0.04-0.97; P=0.046) and OS (HR, 0.26; 95% CI, 0.08-0.87; P=0.029) rates. These results support the considering the risk for recurrence and performing individualized assessments when determining the appropriate chemotherapy approach for older women with early TNBC.
High N-Cadherin Protein Expression in Ovarian Cancer Predicts Poor Survival and Triggers Cell Invasion
Authors: Assidi Mourad
Published: April 2022

Ovarian cancer (OC) is among the most lethal cancer among all gynaecological malignancies. Since most OC patients are diagnosed only at advanced stages mainly because of their imperceptible/nonspecific symptoms, survival rates are low. Therefore, more molecular biomarkers are needed to achieve more effective molecular stratification for better prognostic and theranostic outcomes. The cadherin family, particularly N-cadherin (N-CAD; also known as CDH2), is critical for cell-cell adhesion and epithelial- mesenchymal transition (EMT) of cancer. N-CAD protein has also been shown to be overexpressed in many advanced carcinomas. The aim of this study was to investigate the expression patterns of N-CAD protein, determine their correlations with the clinicopathological features of OC patients, and evaluate its prognostic value and involvement in EMT and metastasis. Protein expression of N-CAD was studied in 117 formalin-fixed and paraffin-embedded (FFPE) blocks from patients diagnosed with OC using Tissue Microarray and immunohistochemistry techniques. The N-CAD protein was overexpressed in 58% of our OC cohort. Furthermore, its cytoplasmic overexpression was significantly correlated with tumor grade (p= 0.05), tumor subtype (p= 0.05), tumor necrosis (p= 0.01), and age at menarche (p= 0.002). Interestingly, Kaplan-Meier analysis showed a significant correlation of disease-free survival (DFS) with OC patients with cytoplasmic N-CAD overexpression (p< 0.03, log rank). Patients with high N-CAD expression have approximately twice the recurrence rate at 5-year follow-up. The results of this study demonstrate a poor prognostic role of N-CAD overexpression in OC, which is reflected in higher recurrence and death rates of OC and its molecular contribution to EMT and distant metastasis. Therefore, OC patients with overexpressed N-CAD need to be monitored more frequently and closely. Further studies with larger patient cohorts are needed to validate these findings, demystify the role of N-CAD in OC pathophysiology, and further investigate its role as a potential therapeutic target.
Lactate Induces the Expressions of MCT1 and HCAR1 to Promote Tumor Growth and Progression in Glioblastoma
Authors: Longhitano Lucia , Vicario Nunzio , Tibullo Daniele , Giallongo Cesarina , Broggi Giuseppe , Caltabiano Rosario , Barbagallo Giuseppe Maria Vincenzo , Altieri Roberto , Baghini Marta , Di Rosa Michelino , Parenti Rosalba , Giordano Antonio , Mione Maria Caterina , Li Volti Giovanni
Published: April 2022

The tumor microenvironment (TME) plays a pivotal role in establishing malignancy, and it is associated with high glycolytic metabolism and lactate release through monocarboxylate transporters (MCTs). Several lines of evidence suggest that lactate also serves as a signaling molecule through its receptor hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), thus functioning as a paracrine and autocrine signaling molecule. The aim of the present study was to investigate the role of lactate in glioblastoma (GBM) progression and metabolic reprogramming in an in vitro and in vivo model. The cell proliferation, migration, and clonogenicity were tested in vitro in three different human GBM cell lines. The expressions of MCT1, MCT4, and HCAR1 were evaluated both in vitro and in a zebrafish GBM model. The results were further validated in patient-derived GBM biopsies. Our results showed that lactate significantly increased the cell proliferation, migration, and colony formation capacity of GBM cells, both in vitro and in vivo. We also showed that lactate increased the expressions of MCT1 and HCAR1. Moreover, lactate modulated the epithelial–mesenchymal transition protein markers E-cadherin and β-catenin. Interestingly, lactate induced mitochondrial mass and the OXPHOS gene, suggesting improved mitochondrial fitness. Similar effects were observed after treatment with 3,5-dihydroxybenzoic acid, a known agonist of HCAR1. Consistently, the GBM zebrafish model exhibited an altered metabolism and increased expressions of MCT1 and HCAR1, leading to high levels of extracellular lactate and, thus, supporting tumor cell proliferation. Our data from human GBM biopsies also showed that, in high proliferative GBM biopsies, Ki67-positive cells expressed significantly higher levels of MCT1 compared to low proliferative GBM cells. In conclusion, our data suggest that lactate and its transporter and receptor play a major role in GBM proliferation and migration, thus representing a potential target for new therapeutic strategies to counteract tumor progression and recurrence.
Meta-Analysis of Efficacy From CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients
Authors: Xu Li , Yan Xin , Ding Weiyue
Published: April 2022

Introduction

Immune checkpoint inhibitors (ICIs) have been approved to prolong overall survival (OS), compared to other treatments. However, the recent studies reported consistent and inconsistent results. Hence, we conducted this meta-analysis to evaluate the efficacy of ICIs.

Materials and Methods

The articles were identified by searching PubMed, Embase, and Google Scholar published up to December 2021. A total of 12,126 participants (6,450 cases and 5,676 controls) were involved in the meta-analysis. Median OS and median progression-free survival (PFS) were selected to evaluate the efficacy of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed death ligand 1 (PD-L1) inhibitors (ipilimumab, nivolumab or pembrolizumab, and atezolizumab, respectively). Utilizing the random-effect model, hazard ratios (HRs) with 95 confidence intervals (CIs) were calculated by R software.

Results

We observed a significant association between cancer patients and ICIs in OS (HR = 0.79, CI = 0.74–0.84) and PFS (HR = 0.80, CI = 0.75–0.86).

Conclusions

The meta-analysis suggested that ICIs were associated with obvious improvements in PFS and OS compared with non-ICI therapies.
A Combined Effect of G-Quadruplex and Neuro-Inducers as an Alternative Approach to Human Glioblastoma Therapy
Authors: Pavlova Galina , Kolesnikova Varvara , Samoylenkova Nadezhda , Drozd Sergey , Revishchin Alexander , Shamadykova Dzhirgala , Usachev Dmitry Y. , Kopylov Alexey
Published: April 2022

Cancer cell reprogramming based on treatment with G-quadruplex, having antiproliferative power, along with small molecules able to develop iPSCs into neurons, could create a novel approach to diminish the chance of glioblastoma recurrence and circumvent tumor resistance to conventional therapy. In this research, we have tested several combinations of factors to affect both total cell cultures, derived from tumor tissue of patients after surgical resection and two subfractions of this cell culture after dividing them into CD133-enriched and CD133-depleted populations (assuming CD133 to be a marker of glioblastoma stem-like cells). CD133+and CD133−cells exhibit different responses to the same combinations of factors; CD133+cells have stem-like properties and are more resistant. Therefore, the ability to affect CD133+cells provides a possibility to circumvent resistance to conventional therapy and to build a promising strategy for translation to improve the treatment of patients with glioblastoma.
Cellular Therapy in High-Risk Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter Syndrome
Authors: Barbanti Maria Chiara , Appleby Niamh , Kesavan Murali , Eyre Toby Andrew
Published: April 2022

Despite the development of highly effective, targeted inhibitors of B-cell proliferation and anti-apoptotic pathways in chronic lymphocytic leukemia (CLL), these treatments are not curative, and many patients will develop either intolerance or resistance to these treatments. Transformation of CLL to high-grade lymphoma—the so-called Richter syndrome (RS)—remains a highly chemoimmunotherapy-resistant disease, with the transformation occurring following targeted inhibitors for CLL treatment being particularly adverse. In light of this, cellular therapy in the form of allogenic stem cell transplantation and chimeric antigen receptor T-cell therapy continues to be explored in these entities. We reviewed the current literature assessing these treatment modalities in both high-risk CLL and RS. We also discussed their current limitations and place in treatment algorithms.
Screening Protein Prognostic Biomarkers for Stomach Adenocarcinoma Based on The Cancer Proteome Atlas
Authors: Zheng Guo-Liang , Zhang Guo-Jun , Zhao Yan , Zheng Zhi-chao
Published: April 2022

The objective was to construct a prognostic risk model of stomach adenocarcinoma (STAD) based on The Cancer Proteome Atlas (TCPA) to search for prognostic biomarkers. Protein data and clinical data on STAD were downloaded from the TCGA database, and differential expressions of proteins between carcinoma and para-carcinoma tissues were screened using the R package. The STAD data were randomly divided into a training set and a testing set in a 1:1 ratio. Subsequently, a linear prognostic risk model of proteins was constructed using Cox regression analysis based on training set data. Based on the scores of the prognostic model, sampled patients were categorized into two groups: a high-risk group and a low-risk group. Using the testing set and the full sample, ROC curves and K-M survival analysis were conducted to measure the predictive power of the prognostic model. The target genes of proteins in the prognostic model were predicted and their biological functions were analyzed. A total of 34 differentially expressed proteins were screened (19 up-regulated, 15 down-regulated). Based on 176 cases in the training set, a prognostic model consisting of three proteins (COLLAGEN VI, CD20, TIGAR) was constructed, with moderate prediction accuracy (AUC=0.719). As shown by the Kaplan-Meier and survival status charts, the overall survival rate of the low-risk group was better than that of the high-risk group. Moreover, a total of 48 target proteins were identified to have predictive power, and the level of proteins in hsa05200 (Pathways in cancer) was the highest. According to the results of the Univariate and multivariate COX analysis, tri-protein was identified as an independent prognostic factor. Therefore, the tri-protein prognostic risk model can be used to predict the likelihood of STAD and guide clinical treatment.
PC Splice-Site Variant c.1825+5G>A Caused Intron Retention in a Patient With Pyruvate Carboxylase Deficiency: A Case Report
Authors: Tao DongYing , Zhang HuiQin , Yang Jingmin , Niu HuanHong , Zhang JingJing , Zeng Minghua , Cheng ShengQuan
Published: April 2022

Background

Pyruvate carboxylase deficiency (PCD; MIM#266150) is a rare autosomal recessive disorder characterized by a wide range of clinical features, including delayed neurodevelopment, elevated pyruvate levels, lactic acidosis, elevated ketone levels, and hyperammonemia. The pyruvate carboxylase (PC) gene was identified to be the disease-causing gene for PCD. A novel homozygous splice variant in the PC gene was identified in a Chinese boy, but the pathogenicity is still unclear. The objective of the present study was to determine the effect of this splice-site variant by reverse transcription analysis.

Methods

We reported the clinical course of a 20-month-old Chinese pediatric patient who was diagnosed with PCD using whole-exome sequencing (WES). The effects of the variant on mRNA splicing were analyzed through the transcript analysis in vivo.

Results

The results of metabolic blood and urine screening suggested PCD by employing tandem mass spectrometry. WES revealed a novel homozygous splice-site variant (c.1825+5G>A) in the PC gene. in vivo transcript analysis indicated that the splice-site variant caused the retention of 192 bp of the intron.

Conclusion

Thus, c.1825+5G>A was established as a pathogenic variant, thereby enriching the mutational spectrum of the PC gene and providing a basis for the genetic diagnosis of PCD.
Safety and Efficacy of Pamidronate in Neonatal Hypercalcemia Caused by Subcutaneous Fat Necrosis: A Case Report
Authors: Martinelli Stefano , Pitea Marco , Gatelli Italo Francesco , Raouf Tara , Barera Graziano , Vitelli Ottavio
Published: April 2022

Subcutaneous fat necrosis of the newborn (SCFN) is a panniculitis that develops in fatty areas after fetal or perinatal distress. Prognosis is generally good with complete regression, but it can be complicated by metabolic abnormalities like hypoglycemia, hypertriglyceridemia, thrombocytopenia, and also potentially life-threatening hypercalcemia. Treatments have included hydration, furosemide and corticosteroids. These treatments can be prolonged for several days and can have complications such as nephrocalcinosis. Use of bisphosphonates has been rarely reported in newborn. We describe a case of severe hypercalcemia complicating subcutaneous fat necrosis in a newborn successfully treated by a single dose of pamidronate after having obtained partial response by therapy with hyperhydration, furosemide and hydrocortisone. When high levels of calcium do not respond to first line therapy with hyperhydration and diuretic therapy, bisphosphonates treatment could be considered a valid choice to treat hypercalcemia and to avoid corticosteroids. Further studies are needed to understand if pamidronate and other bisphosphonates can be considered the first choice in hypercalcemia due to SCFN.
Non-convulsive Status Epilepticus in SEMA6B-Related Progressive Myoclonic Epilepsy: A Case Report With Literature Review
Authors: Duan Jing , Chen Yan , Hu Zhanqi , Ye Yuanzhen , Zhang Tian , Li Cong , Zeng Qi , Zhao Xia , Mai Jiahui , Sun Yang , Liu Chao , Zheng Wenxin , Xiao Yuhan , Liao Jianxiang , Chen Li
Published: April 2022

Progressive myoclonic epilepsy (PME) is a group of rare diseases characterized by progressive myoclonus, cognitive impairment, ataxia, and other neurologic deficits. PME has high genetic heterogeneity, and more than 40 genes are reportedly associated with this disorder. SEMA6B encodes a member of the semaphorin family and was first reported to cause PME in 2020. Herein, we present a rare case of PME due to a novel SEMA6B gene mutation in a 6-year-old boy born to healthy non-consanguineous Chinese parents. His developmental milestones were delayed, and he developed recurrent atonic seizures and myoclonic seizures without fever at 3 years and 11 months of age. He experienced recurrent myoclonic seizures, non-convulsive status epilepticus (NCSE), atonic seizures, and atypical absence seizures during the last 2 years. At different time points since onset, valproic acid, levetiracetam, piracetam, and clobazam were used to control the intractable seizures. Notably, NCSE was controlled by a combination of piracetam with clobazam and valproic acid instead of intravenous infusion of midazolam and phenobarbital. Due to the limited number of cases reported to date, the clinical description of our case provides a better understanding of the genotype–phenotype correlations associated with PME and indicate that piracetam may be effective against NCSE in patients with SEMA6B-related PME.