Miracle-dz/UniFAR-FTUs huggingface dataset:
Superiority of TPGS-loaded micelles in the brain delivery of vinpocetine via administration of thermosensitive intranasal gel

Background: Vinpocetine (VPN) is a synthetic derivative of the Vinca minor alkaloids. The drug is characterized by a short half-life, limited water solubility and high hepatic first-pass effect. The objective was to develop different lipid-based nanocarriers (NCs) loaded into a thermosensitive in situ gelling (ISG) system to improve VPN bioavailability and brain targeting via intranasal (IN) delivery. Methods: Different lipid-based NCs were developed and characterized for vesicle size, zeta potential, VPN entrapment efficiency (EE) and morphological characterization using transmission electron microscope (TEM). The prepared NCs were loaded into ISG formulations and characterized for their mucoadhesive properties. Ex-vivo permeation and histological study of the nasal mucosa were conducted. Pharmacokinetic and brain tissue distribution were investigated and compared to a marketed VPN product following administration of a single dose to rats. Results: VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. Conclusion: VPN-loaded TPGS-micelles ISG formulation is a successful brain drug delivery system with enhanced bioavailability for drugs with poor bioavailability and those that are frequently administered.
Association of tumor differentiation and prognosis in patients with rectal cancer undergoing neoadjuvant chemoradiation therapy

Abstract Background and objective Neoadjuvant chemoradiation therapy (NCRT) followed by radical resection has been a common practice for patients with locally advanced rectal cancer. This study aimed to analyse the association of tumor differentiation and prognosis in rectal-cancer patients undergoing NCRT. Methods Patients with locally advanced, non-mucinous rectal cancer who underwent NCRT followed by radical resection between 2007 and 2017 were identified from an electronic health record system at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). Multivariable logistic regression and multivariate Cox regression were performed to analyse the association of response to NCRT and survival with clinicopathological characteristics of all these patients. Results We identified 325 patients (241 males and 84 females; mean age, 54.4 ± 11.2 years) who underwent NCRT followed by radical resection, including 26 (8.0%) with poorly-differentiated rectal cancer, 182 (56.0%) with moderately-differentiated cancer and 117 (36.0%) with well differentiated cancer. Propensity score matching analysis and multivariable logistic regression analysis results showed that tumor differentiation was significantly associated with response to NCRT. In the poor differentiation and non-poor differentiation groups, the 3-year overall survival (OS) rates were 74.6 and 93.5%, respectively, whereas the 3-year local recurrence rates were 18.6 and 3.7%, respectively. Multivariable Cox regression analyses revealed that poor differentiation was an independent risk factor for local recurrence and OS. Conclusions Among the patients with locally advanced, non-mucinous rectal cancer, the patients with poorly-differentiated cancer who underwent NCRT had a worse response to NCRT and poorer prognosis than those with moderately- and well-differentiated diseases.
Association of salivary C-reactive protein with the obesity measures and markers in children

Objective Overweight and obesity is a pro-inflammatory state. This study aimed to examine the level of the salivary obesity markers in normal weight (NW) and overweight/obese (OW/OB) children, association with the obesity measures and the interrelations between the biomarkers. Subjects and methods Seventy-six children (40 normal weight and 36 overweight/obese) were recruited for this study. Body weight, height, and waist circumference measurement were obtained. The saliva sample was collected from all the participants. According to the Center for Disease Control and Prevention (CDC), the participants were classified into the normal weight or overweight/obese depending upon the body mass index (BMI) percentile ranking. The obesity panel of salivary markers resistin, C-C Motif Chemokine Ligand 2 (CCL2)/monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), complement factor D, and interleukin-10 (IL-10) were determined using human magnetic Luminex performance assay. The receiver operating characteristics (ROC) analysis was used to determine the area under the curve (AUC) to identify the best salivary biomarker in children. Linear regression and Pearson’s correlation analyses to determine the association between the parameters. Results The obesity biomarkers resistin, MCP-1, TNF-α, IL-6 and CRP were significantly high in overweight/obese compared to normal weight. Salivary CRP (AUC: 0.866, 95% CI: 0.780–0.952; p<0.0001) showed superiority area under ROC curves with good discriminatory power than resistin, MCP-1, TNF-α, and IL-6. BMI z-score, WC z-score, and WHtR z-score showed a significant association (p<0.0001) with CRP. The CRP significantly (p<0.0001) correlated with resistin, CCL2/MCP-1, TNF-α, IL-6, and IL-10 by linear regression and Pearson’s correlation analysis. Conclusion Increased level of salivary CRP in children may be considered as a non-invasive marker for childhood obesity for detection of the risk factors for the development of metabolic dysregulation.
Habitual sugar intake and cognitive impairment among multi-ethnic Malaysian older adults

Background: Sugar is widely consumed in Malaysia, and the excessive intake of sugar has been associated with cognitive functions. However, the association between sugar intake and cognitive impairment among Malaysian older adults is yet to be determined. Purpose: The objective of this study was to evaluate the associations between types and sources of sugar intake and cognitive functions and to identify their risk in predicting cognitive impairment (MMSE score <24). Subjects and methods: A total of 1,209 subjects aged ≥60 years were recruited through multi-stage random sampling from selected states in Malaysia. Dietary intake was derived using a 7-day dietary history questionnaire and supplemented with a quantitative food frequency questionnaire for added sugar intake. Results: The prevalence of cognitive impairment as defined by Mini-Mental State Examination (MMSE) less than 24 was 31.9%, while the prevalence of mild cognitive impairment was 13.1%. The median (IQR) for total sugar intake was 44.60 g/day (26.21–68.81) or 8 tsp, and free sugar intake was 33.08 g/day (17.48–57.26) or 6 tsp. The higher intake of total sugars, free sugars, sucrose, lactose, sugar-sweetened beverages, sugar-sweetened cakes, and dessert was found to be significantly associated with a lower MMSE score, after adjusting for covariates. On the other hand, the consumption of cooked dishes and fruits was significantly associated with a better MMSE score. The adjusted OR for risk of cognitive impairment (MMSE score <24) was 3.30 (95% CI 2.15–5.08) for total sugars and 3.58 (95% CI 2.32–5.52) for free sugars, comparing the highest with the lowest intake percentiles. Conclusion: Excessive sugar consumption among older adults showed a notable association with poor cognitive functions, but longitudinal studies and clinical trials are further needed to clarify the direction of causality and to investigate the underlying mechanism.
MicroRNA-27a downregulates the expression of Hsp90 and enhances the radiosensitivity in esophageal squamous cell carcinoma

Purpose Accumulating evidence suggests that microRNAs (miRNAs) possess diverse cellular regulatory roles in radiation responses. In this study, we aimed to identify the role of miR-27a in esophageal squamous cell carcinoma (ESCC) radiosensitivity by exploring the relationship between miR-27a and heat shock protein 90 (Hsp90). Materials and methods We performed quantitative real-time polymerase chain reaction (qRT-PCR) to detect miR-27a expression in the plasma of ESCC patients and healthy volunteers. The expression of Hsp90 and its key client proteins associated with radioresistance were analyzed by Western blotting. Then, the effects of miR-27a on proliferation, apoptosis, cell cycle and radiosensitivity in ESCC cell lines were determined by CCK-8, flow cytometry, and clonogenic survival assay. We also generated subcutaneous tumors to explore whether miR-27a enhanced radiosensitivity in vivo. Results In our current study, we found that miR-27a expression was downregulated in the plasma of ESCC patients compared with that of healthy volunteers. Overexpression of miR-27a in ESCC cell lines caused a reduction of Hsp90 mRNA and protein. We also demonstrated that upregulation of miR-27a induced degradation of Hsp90 key client proteins associated with radioresistance. In related functional experiments, miR-27a significantly inhibited growth, increased radiation-induced apoptosis, induced cell cycle arrest in G0/G1 phase and enhanced ESCC radiosensitivity both in vitro and in vivo. Conclusion From these findings, we concluded that miR-27a may contribute to radiosensitivity by modulating Hsp90 expression. Moreover, miR-27a-based therapy utilized to target Hsp90 could be contemplated as a compelling alternative for sensitize ESCC to radiotherapy with fewer side effects.
Targeted delivery of doxorubicin to HER2 positive tumor models

Background Exosomes are natural nanovesicles with unique characteristics, such as long circulating half-life, the intrinsic ability to target tissues, biocompatibility, and minimal or no inherent systemic toxicity. Mesenchymal stem cells produce large amounts of exosomes with regenerative properties and more stability in human plasma. TUBO breast cancer cell lines overexpress rat HER2/neu protein. Methods Targeted exosomes were isolated from transduced bone marrow mesenchymal stem cells. Doxorubicin was encapsulated into exosomes by electroporation. Flow cytometry was used to assess the attachment of exosomes to the target cells. The in vitro cytotoxicity effect of targeted doxorubicin-loaded exosomes on TUBO cells was determined using MTT assay. Selective delivery of doxorubicin to tumor tissues was analyzed by measuring the auto-fluorescence of doxorubicin by in vivo imaging system. Moreover, tumor growth inhibition and body weight were monitored following injection of free doxorubicin, and targeted and untargeted doxorubicin-loaded exosomes in a TUBO breast cancer model. Finally, mouse tissues were examined for the presence of intrinsic ﬂuorescence of doxorubicin. Results Flow cytometry results revealed significant differences in binding of targeted exosomes to HER2-positive (46.05%) and HER2-negative (13.9%) cells. The results of MTT assay showed that cytotoxicity of targeted doxorubicin-loaded exosomes was higher than free doxorubicin at 72 hours. Selective distribution of targeted doxorubicin-loaded exosomes in the target tissues of the murine breast cancer model suggested specific delivery of doxorubicin by targeted exosomes, rather than untargeted exosomes. Free doxorubicin and untargeted doxorubicin-loaded exosomes showed insignificant effects, whereas targeted doxorubicin-loaded exosomes reduced the tumor growth rate. Conclusion Herein, we report efficient delivery of targeted doxorubicin-loaded exosomes in vitro, corroborated with a significant reduction of murine breast cancer model tumor growth rate.
Impact of pre-transplant infection management on the outcome of living-donor liver transplantation in Egypt

Background and aim Liver transplantation (LT) has emerged as an established therapeutic option for patients with chronic liver disease. Patients with end-stage liver disease are at high risk of infection with multidrug-resistant organisms, which may affect the outcome of LT. The aim of this study was to evaluate the impact of pre-transplant infection on the outcome of living-donor LT. Methods Prospective follow-up was done for 50 patients with chronic liver disease who had had LT performed from September 2013 to December 2017. We divided patients into group 1 (patients who had had infection within 3 months before transplantation with adequate treatment [n=20]), and group 2 (patients without infection [n=30]). Both groups were followed for 4 months post-operatively. Results Patients with high Model for End-Stage Liver Disease scores were more susceptible to infection pre- and post-operatively, and chest infection was the most common infection pre-transplant. There were no significant statistical differences regarding hospital and ICU stay and post-operative course between the groups, but the mortality rate was higher in group 1 (40%) than in group 2 (23.3%), and the causes of mortality in the group 1 were mainly due to medical causes (infections and sepsis, 75%) versus 28.6% in group 2. Conclusion Liver-cell failure and concomitant infection 3 months before LT with adequate treatment had no significant statistical differences regarding hospital, ICU stay, or medical complications, but post-operative infection and mortality rate were more frequent in group 1 and the causes of mortality were mainly medical.
SRv6 Network Programming

The SRv6 Network Programming framework enables a network operator or an application to specify a packet processing program by encoding a sequence of instructions in the IPv6 packet header. Each instruction is implemented on one or several nodes in the network and identified by an SRv6 Segment Identifier in the packet. This document defines the SRv6 Network Programming concept and specifies the base set of SRv6 behaviors that enables the creation of interoperable overlays with underlay optimization.
Genomics applied to the treatment of breast cancer

Breast cancer remains a major health issue in the world with 1.7 million new cases in 2012 worldwide. It is the second cause of death from cancer in western countries. Genomics have started to modify the treatment of breast cancer, and the developments should become more and more significant, especially in the present era of treatment personalization and with the implementation of new technologies. With molecular signatures, genomics enabled a de-escalation of chemotherapy and personalized treatments of localized forms of estrogen-dependent breast cancers. Genomics can also make a real contribution to constitutional genetics, so as to identify mutations in a panel of candidate genes. In this review, we will discuss the contributions of genomics applied to the treatment of breast cancer, whether already validated contributions or possible future applications linked to research data.
Upregulation of family with sequence similarity 83 member D expression enhances cell proliferation and motility via activation of Wnt/β-catenin signaling and predicts poor prognosis in gastric cancer

Background/aims Gastric cancer (GC) is the third most common cause of cancer-related death worldwide. The molecular mechanisms underlying the progression of gastric cancer are still not fully elucidated. In this study, we focused on exploring the role of family with sequence similarity 83, member D (FAM83D) in gastric cancer progression. Methods The expression of FAM83D in GC tissues was detected by immunohistochemistry (IHC) staining. FAM83D knockdown or overexpression were constructed in AGS and SGC-7901 cells with two distinct siRNA duplexes and lentivirus infection, respectively, to explore the role of FAM83D in gastric cancer progression. Nude mouse xenograft assay was used to further explore the role of FAM83D in tumorigenesis in vivo. Results We found that FAM83D mRNA and protein levels were higher in human GC tumor tissues and in GC cell lines, compared with the adjacent normal tissues and non-malignant gastric epithelial cell lines, respectively, and that higher FAM83D expression was correlated with worse overall survival (p<0.0001) and disease-free survival (p<0.0001) in GC patients. Additionally, our results showed that FAM83D overexpression significantly enhanced the proliferation, clonogenicity, and motility of GC cells, whereas FAM83D depletion caused a dramatic increase in the number of cells arrested at the G1 phase of the cell cycle. Consistent with these findings from in vitro experiment, our data also indicated that FAM83D knockdown significantly repressed GC tumor growth in vivo. Furthermore, we demonstrated that FAM83D depletion was associated with reduced Wnt/β-catenin signaling. Conclusions This study suggested that FAM83D overexpression enhanced the proliferation, clonogenicity, and motility of GC cells by activating Wnt/β-catenin signaling, and FAM83D may be a promising diagnostic and therapeutic target for human GC.
Optimal management of thymic malignancies: current perspectives

Abstract Thymic epithelial tumors (TETs) belong to orphan oncology. The incidence of TETs is about 1.3–3.2 cases per million worldwide. Following pathology, evolution and prognosis are variable. The World Health Organization classification distinguishes thymomas and thymic carcinomas. TETs are composed of thymic epithelial tumoral cells and normal lymphocytes. The mean age at diagnosis is 50–60 years-old. There are no identified risk factors. TETs are frequently associated with paraneoplastic syndromes as myasthenia gravis. The complete R0 surgical resection is the most significant prognosis factor on survival. In 2010, the French National Institute of Cancer labeled the RYTHMIC network as a specific tumor board including thoracic surgeons, oncologist, and radiation therapist to define standard of care for the management of TETs. The aim of the review was to update knowledge to optimize the standard of care.
Plausible relationship between homocysteine and obesity risk via MTHFR gene: a meta-analysis of 38,317 individuals implementing Mendelian randomization

Objective Numerous studies have explored the role of methylenetetrahydrofolate reductase gene (MTHFR) C677T polymorphism and homocysteine (Hcy) concentration in obesity, but the results are inconsistent. Hence, we performed a meta-analysis implementing Mendelian randomization approach to test the assumption that the increased Hcy concentration is plausibly related to the elevated risk of obesity. Methods Eligible studies were selected based on several inclusion and exclusion criteria. Correlations between MTHFR C677T and obesity risk, MTHFR C677T and Hcy concentration in obesity, Hcy concentration, and obesity were estimated by ORs, effect size and standard mean difference with their corresponding 95% CIs, respectively. Furthermore, Mendelian randomization analysis was performed to estimate the relationship between Hcy level and obesity. Results Consequently, this meta-analysis implemented with Mendelian randomization approach was conducted among 8,622 cases and 29,695 controls. The results indicated that MTHFR C677T is associated with an increased risk of obesity (for T vs C: OR=1.06, 95% CI=1.02–1.10; for TT vs CC: OR=1.13, 95% CI=1.03–1.24). Moreover, in obese subjects, the pooled Hcy concentration in individuals of TT genotype was 2.91 mmol/L (95% CI: 0.27–5.55) higher than that in individuals of CC genotype. Furthermore, the pooled Hcy concentration in subjects with obesity was 0.74 mmol/L (95% CI: 0.36–1.12) higher than that in controls. The evaluated plausible OR associated with obesity was 1.23 for 5 μmol/L Hcy level increase. Conclusions Through this meta-analysis, we emphasize a strong relationship between Hcy level and obesity by virtue of MTHFR C677T polymorphism.
Alterations of amplitude of low-frequency fluctuation in treatment-resistant versus non-treatment-resistant depression patients

Purpose We used parcellation based on 264 putative functional areas to explore the difference of amplitude of low-frequency fluctuation (ALFF) between refractory depression and non-refractory depression patients. Patients and methods Sixty first episode drug-naive patients with major depressive disorder (MDD) and 20 healthy controls (HCs) were recruited in this study; the MDD group was divided into a refractory depression (TRD) group (n=15) and a non-refractory depression (non-TRD) group (n=18) according to the treatment effect following up for 2 years. All the subjects underwent magnetic resonance imaging scanning and performed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and all the patients with MDD finished the 17-item Hamilton Depression Rating Scale (HAMD17). We used a parcellation based on 264 putative functional areas to explore the difference of ALFF measures in the three groups. The correlation between the abnormal ALFF value and characteristics of MDD was examined. Results RBANS total scores and index scores in the HCs were significantly different from that of the MDD group. HAMD-17 in the TRD group was significantly higher than that of non-TRD group. Relative to HCs, MDD groups showed significantly lower ALFF within the right default mode network, which was positively correlated with the immediate memory and language in the MDD group. Compared with the non-TRD group, the TRD group showed higher ALFF in the right sensory/somatomotor hand, right auditory and left default mode network. Conclusion Dysfunction of the somatosensory areas, right auditory and left default mode network may be a marker for specific psychopathology symptoms of TRD.
Acceptability of a Wellness Group Program for Veterans With Symptoms of Posttraumatic Stress Disorder

Background Although there are effective evidence-based treatments for posttraumatic stress disorder (PTSD), many individuals drop out or do not benefit from treatment. There is a need for new treatments, including approaches that are nontrauma focused. Objective The purpose of this program evaluation was to investigate the acceptability of a Wellness Group designed to promote healthy behaviors and adaptive coping when offered to veterans with PTSD. Methods Nine veterans in a PTSD outpatient clinic enrolled in a 12-week, 24-session Wellness Group. Acceptability of the intervention was evaluated with attendance data, questionnaires, and interviews. Results Group attendance rates were high and no participants dropped out of treatment. Treatment satisfaction was high and all veterans reported gains in at least 3 of the 8 Wellness domains covered. Interview data supported the findings that veterans had positive reactions to the group. Conclusion A Wellness approach may offer a low-cost alternative or supplementary treatment for veterans with PTSD that is highly acceptable and may improve health behaviors, quality of life, and coping skills.