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Abstract Objective To characterize the retinal microvasculature and structure in subjective cognitive decline (SCD) and identify the potential biomarker for the early stage of the Alzheimer's disease (AD) spectrum. Methods In this study, 35 patients with SCD, 36 with cognitive impairment, and 29 with normal cognition (NC) were enrolled. Optical coherence tomography angiography was employed to assess retinal vascular density, fovea avascular zone area, and retinal thickness. The parameters reflecting retinal perfusion and structure were compared among the three groups. In addition, the association between retinal parameters, cerebral blood flow (CBF), and peripheral blood biomarkers in the SCD stage was analyzed. Results The superficial vascular complex (SVC) vascular density in the macula and retinal nerve fiber layer thickness in the peripapillary were significantly reduced in individuals with SCD compared to NC. Furthermore, there was a positive correlation between macular ganglion cell complex thickness and CBF in SCD. Interpretation The retinal microvasculature and structure exhibit alterations in individuals with SCD. Macular ganglion cell complex thickness demonstrates correlations with cerebral perfusion. The retina holds potential as a novel biomarker for early detection of AD.

Arterial agenesis is a rare condition and has been reported to affect the internal carotid artery, common carotid artery, and pulmonary artery. However, to the best of our knowledge, it has not yet been reported to affect the subclavian arteries. We present a case of asymptomatic bilateral subclavian artery agenesis and left subclavian artery aneurysm. This patient's abnormal vasculature was found incidentally. Despite being asymptomatic, repair of the aneurysm via vertebral transposition and ligation of the subclavian artery was performed to prevent eventual thrombosis, emboli, and stroke.

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a congenital, autosomal-dominant disorder characterized by a triad of macrocephaly, lipomatosis, and pigmentation of the glans penis. The symptoms of this rare syndrome vary greatly and include multiple hamartomatous polyps, macrocephaly, increased birth weight, developmental delay, and intellectual disability. Vascular abnormalities, including arteriovenous malformations (AVMs), have rarely been reported as part of the vascular manifestations associated with BRRS. Congenital AVMs can rarely progress, resulting in limb- or life-threatening complications. We present the case of a young man with BRRS diagnosed in childhood and presenting with three AVMs involving the right upper extremity and chest. We also provide a brief literature summary of reported cases of BRRS with AVMs. Our paper highlights the importance of recognizing and understanding the vascular manifestations in patients with BRRS. Knowledge of the association between BRRS and AVMs is crucial for guiding patient diagnosis and management, optimizing treatment strategies, and improving overall patient outcomes.

Fever is one of the most common clinical conditions and is characterized by pyrogenic infection, malignancy, inflammation, and tissue damage, among others. Ellagic acid (EA) can inhibit the expression of related proteins on the pathway by blocking the nuclear factor kappa-B(NF-κB) signaling pathway, inhibit the levels of pro-inflammatory factors interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α), increase the level of anti-inflammatory factor IL-10, and effectively alleviate inflammatory symptoms. In addition, EA can also reduce the levels of malondialdehyde(MDA) and nitric oxide(NO) in the body, increase the activities of superoxide dismutase (SOD), glutathione (GSH), and catalase(CAT), scavenge oxidative free radicals, inhibit lipid oxidation, and achieve antipyretic and anti-inflammatory effects. The purpose of this study was to establish the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, prostaglandin E2(PGE2), and cyclic adenosine monophosphate(cAMP), and clarify the mechanism of the cyclooxidase-2(COX-2)/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism. Compared to lipopolysaccharide (LPS)- treated animals, subsequent administration of EA significantly lowered the LPS-induced rectal temperature increase (p < 0.05 or p < 0.01), significantly increased serum SOD and GSH levels (p < 0.05 or p < 0.01), and significantly decreased serum MDA, IL-1β, IL-6, and TNF-α levels (p < 0.05 or p < 0.01). In addition, compared to LPS-treated animals, subsequent administration of EA significantly decreased cerebrospinal fluid cAMP and PGE2 levels (p < 0.05 or p < 0.01), significantly decreased cAMP, significantly increased 5-HT levels (p < 0.05 or p < 0.01), and significantly down-regulated p-NF-κB p65 and COX-2 protein levels in the hypothalamus. Subsequent gas chromatography mass spectrometry(GC-MS) metabolite analysis indicated that 12 differential metabolites were detected in serum isolated 4 h after LPS treatment, and 10 differential metabolites were detected in serum collected 7 h after LPS treatment. Next, Pearson correlation analysis was used to systematically characterize the relationship between the identified metabolites and TNF-α, IL-6, MDA, SOD, PGE2, and cAMP. The levels of propionic acid, pyridine, and L-valine were up-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α and increased the activity of GSH. The levels of inositol, urea, and 2-monopalmitin were down-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α, increased the activity of SOD and GSH, reduced the inflammatory response, and alleviated the oxidative stress state. Combined with the results of the metabolic pathway analysis, we suggest that the pathways of the galactose metabolism, synthesis and degradation of ketone bodies, as well as ascorbic acid and aldehyde acid metabolism are closely related to the antipyretic and anti-inflammatory effects of EA. Our study established the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, PGE2, and cAMP, and clarified the mechanism of the COX-2/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism.

In order to investigate the hydrogen embrittlement sensitivity of the low-grade pipeline steel in medium-pressure hydrogen environment，the hydrogen embrittlement sensitivity of L245 steel in air environment and 4 MPa hydrogen environment was studied by smooth and notched slow tensile tests，combined with macroscopic and microscopic fracture characterization and analysis.Results showed that the loss rates of tensile strength，area reduction，and elongation of the L245 steel smooth samples under slow stretching in 4 MPa hydrogen were 5.2%，4.8%，and -0.1%，respectively.However，the loss rates of tensile strength，area reduction and tensile displacement of the notched samples under slow stretching in 4 MPa hydrogen were 19.1%，45.6%and 15.4%，respectively，indicating the occurrence of hydrogen embrittlement.The slow tensile fracture mode of the L245 steel smooth sample in air was ductile fracture.After the notch was opened，the crack source of the smooth samples started at a certain position of the notch and expanded inward in the way of quasi-cleavage fracture，accelerating the fracture process of the sample，but the overall fracture method was still ductile fracture.In contrast，the crack source generated at the necking position when the L245 steel smooth sample was exposed to 4 MPa hydrogen.After the notch was opened，a significant increase in the quasi-cleavage fracture area generated from the notch position towards the interior，which rapidly accelerated the fracture process，and the hydrogen-induced ductile fracture occurred in the center.The fracture mode of L245 steel after notch opening in 4 MPa hydrogen gas was a combination of quasicleavage fracture and hydrogen induced ductile fracture.

Applicants in the 2020-2021 residency interview cycle were unable to attend in-person meetings or visit prospective sites of future training. Instead, they relied on printed or digital media for information. Over the past few years, many graduate medical education programs have increased the use of social media to disseminate information to attract and retain faculty, staff, and trainees. Previous studies have quantified the relative presence of social media in residency programs, but there has been limited work on the assessment of social media platforms that applicants use to evaluate internal medicine programs. To more effectively target residency applicants through social media, we sought to understand the use of social media in general and specifically in the residency application process of an incoming intern class recruited during the 2020-2021 interview season. We administered an anonymous survey after matching to a single institution’s 2021 class of 40 internal medicine interns in both categorical and preliminary tracks. The group surveyed came from US medical schools (MD and DO degrees) and international programs. The group surveyed comprised 66% women and 16.7% underrepresented groups as defined by Association of American Medical Colleges guidelines. Our data found that the internal medicine residency applicants mostly used hospital websites and Instagram to evaluate programs. Twitter, which is often assumed to be highly used in academic circles, was rarely used. Our work suggests that a better understanding of the use of digital resources by applicants can allow programs to reach residency applicants in a meaningful way.

Abstract Aim To examine and analyze the level of spiritual care competency among community nurses. Design The study employed a cross‐sectional design. Methods From May to July 2022, 442 nurses from community health clinics were chosen as survey respondents using the convenience sample method. The General Information Questionnaire, the version in Chinese of the Nurses' Spiritual Caregiving Awareness Scale and the Chinese version of the Spiritual Caregiving Competence Scale were used in the survey. There were 442 questionnaires distributed, 422 were collected, and the response rate was 95.4%. Results The amount of spiritual care competencies of community nurses was positively correlated with the level of spiritual awareness. Simultaneously, their level of education, religious beliefs, marital status and the degree of knowledge of spirituality were all influenced.

Conventional quality control methodologies are inadequate for fully elucidating the aberrant patterns of product quality. A multitude of factors influence product quality, yet the limited number of controlled quality characteristics is insufficient for accurately diagnosing quality abnormalities. Additionally, there are asymmetries in data collection, data pre-processing, and model interpretation. In this context, a quality anomaly recognition and diagnosis model for the complex product manufacturing process is constructed based on a deep residual network, support vector machine (SVM), and Shapley additive explanation (SHAP). Given the numerous complex product quality characteristic indexes and unpredictable accidental factors in the production process, it is necessary to mine the deep relationship between quality characteristic data and quality state. This mining is achieved by utilizing the strong feature extraction ability of the deep residual shrinkage network (DRSN) through self-learning. The symmetry of the data within the model has also been taken into account to ensure a more balanced and comprehensive analysis. The excellent binary classification ability of the support vector machine is combined with the DRSN to identify the quality anomaly state. The SHAP interpretable model is employed to diagnose the quality anomaly problem of a single product and to identify and diagnose quality anomalies in the manufacturing process of complex products. The effectiveness of the model is validated through case analysis. The accuracy of the DRSN-SVM quality anomaly recognition model reaches 99%, as demonstrated by example analysis, and the model exhibits faster convergence and significantly higher accuracy compared with the naive Bayesian model classification and support vector machine classification models.

ObjectiveThe objective of this study was to explore the learning preferences and habits of medical students during the pandemic home e-learning, and to investigate the incidence of adverse emotions, optimistic character level and coping style. To explore the influencing factors of adverse emotions.MethodsA cross-sectional survey was conducted in China from March to June 2022. Medical students were recruited from three universities in China, and a questionnaire survey was conducted. The questionnaires consisted of a “e-learning preferences and habits questionnaire”, life orientation test questionnaire (LOT-R), and simple coping style questionnaire (SCSQ). Finally, a total of 492 medical students who met the inclusion and exclusion criteria became the research subjects and completed the survey.ResultsA total of 57.7% believed they experienced no adverse emotions during home e-learning. ① During the COVID-19 pandemic, the score of optimistic personality of medical students was (7.25 ± 1.933), and the score of pessimistic personality was (5.82 ± 2.240). The score of positive coping was (21.75 ± 5.379), and the score of negative coping was (11.75 ± 3.611). ② The occurrence of medical students' adverse emotions during e-learning was influenced by “Whether there is a private, quiet space to study”, “Degree of knowledge mastery”, “Physical discomfort or not”, “Keep a regular schedule or not”, “Optimistic personality tendency”.ConclusionThis study demonstrates the during home e-learning, most medical students have their own learning equipment and can meet their learning needs. Their favorite mobile device to use is a mobile phone, and their favorite method of teaching is to provide course playback. More than half of medical students believe that they have some inconvenience in conducting research during home e-learning. With regard to teacher's real-time screen, the largest number of medical students support teachers turning on live screens so that they feel like they are interacting with the teacher. The preference for blended teaching is highest among medical students. In general, medical students were highly adaptive of the newest e-learning approach. Based on the statistic analysis, the factors that “Whether there is a private, quiet space to study”, “Degree of knowledge mastery”, “Physical discomfort or not”, “Keep a regular schedule or not”, and “Optimistic personality tendency” may be the influencing factors for the occurrence of adverse emotions.

PurposeTo investigate the effective connectivity (EC) changes after multisite repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG).MethodWe selected 51 patients with mild or moderate Alzheimer's disease (AD) and delivered 10 Hz rTMS over the left dorsal lateral prefrontal cortex (DLPFC) and the lateral temporal lobe (LTL) combined with COG or sham stimulation for 4 weeks. The selected AD patients were divided into real (real rTMS+COG, n = 11) or sham (sham rTMS+COG, n = 8) groups to undergo neuropsychological assessment, resting-state fMRI, and 3D brain structural imaging before (T0), immediately at the end of treatment (T4), and 4 weeks after treatment (T8). A 2 × 3 factorial design with “time” as the within-subjects factor (three levels: T0, T4, and T8) and “group” as the between-subjects factor (two levels: real and sham) was used to investigate the EC changes related to the stimulation targets in the rest of the brain, as well as the causal interactions among seven resting-state networks based on Granger causality analysis (GCA).ResultsAt the voxel level, the EC changes from the left DLPFC out to the left inferior parietal lobe and the left superior frontal gyrus, as well as from the left LTL out to the left orbital frontal cortex, had a significant group × time interaction effect. At the network level, a significant interaction effect was identified in the increase in EC from the limbic network out to the default mode network. The decrease in EC at the voxel level and the increase in EC at the network level were both associated with the improved ability to perform activities of daily living and cognitive function.ConclusionMultisite rTMS combined with cognitive training can modulate effective connectivity in patients with AD, resulting in improved ability to perform activities of daily living and cognitive function.

Purpose: To determine the treatment patterns and outcomes of pediatric retinal detachments (RDs) associated with hereditary vitreoretinopathies. Design: Retrospective cohort analysis using IRIS® Registry (Intelligent Research in Sight) database. Participants: Patients < 18 years old with a rhegmatogenous RD and a systemic disorder associated with vitreoretinal degeneration (e.g., Stickler syndrome) or other malformation of the vitreous from 2013-2019. Methods: Cases were identified using International Classification of Diseases, Ninth and Tenth Revisions (ICD-9, ICD-10) diagnostic codes from the IRIS® Registry cohort. Other hereditary vitreoretinopathies that are not encoded by specific ICD code(s) were captured by text search. Nonspecific vitreous abnormality ICD codes were also included. Exclusion criteria included traumatic retinal detachments using ICD codes for ocular trauma and serous or exudative retinal detachment. Surgical procedures were identified using Current Procedural Terminology (CPT) codes for repair of retinal detachment. Baseline demographic information collected included age, gender, race/ethnicity, geographic region of the provider location, and health insurance status. Main Outcome Measures: Main outcomes measured in this study were average time to first surgery, number of eyes presenting with bilateral detachments, and choice of initial surgical procedure. Results: A total of 2115 eyes of 1722 patients were identified (mean age, 10.4 years; 58% male). The median time to first surgery was 7 days (interquartile range, 40 days). One thousand four hundred seven eyes of 1134 patients had ≥ 1 year of follow-up, with 506 eyes (36%) developing a fellow eye RD. Thirty-three percent of patients presenting with bilateral detachments, and 349 eyes had initial RD surgery within 1 year of the index date documented by CPT code. Fellow eye detachment occurred a mean of 32 days after initial presentation. The mean number of surgeries per eye within 1 year was 1.68. Best-corrected visual acuity did not improve from a baseline 20/54 to 20/62. The initial procedure was most commonly complex RD repair (n = 176), followed by scleral buckle (n = 102), pars plana vitrectomy (n = 89), laser (n = 59), cryotherapy (n = 5), and pneumatic retinopexy (n = 5). There were 51 new diagnoses of glaucoma and 37 new diagnoses of aphakia within 1 year after the surgical procedure. Conclusions: IRIS Registry data provide insight into rare pediatric vitreoretinopathy-associated RDs, which have a high rate of reoperation and fellow eye involvement. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Background: Simulations by transport codes are indispensable for extracting valuable physical information from heavy-ion collisions. Pion observables such as the π-/π+ yield ratio are expected to be sensitive to the symmetry energy at high densities. Purpose: To evaluate, understand, and reduce the uncertainties in transport-code results originating from different approximations in handling the production of Δ resonances and pions. Methods: We compare ten transport codes under controlled conditions for a system confined in a box, with periodic boundary conditions, and initialized with nucleons at saturation density and at a temperature of 60 MeV. The reactions NN↔NΔ and Δ↔Nπ are implemented, but the Pauli blocking and the mean-field potential are deactivated in the present comparison. Thus, these are cascade calculations including pions and Δ resonances. Results are compared to those from the two reference cases of a chemically equilibrated ideal gas mixture and of the rate equation. Results: For the numbers of Δ and π, deviations from the reference values are observed in many codes, and they depend significantly on the size of the time step. These deviations are tied to different ways in ordering the sequence of reactions, such as collisions and decays, that take place in the same time step. Better agreements with the reference values are seen in the reaction rates and the number ratios among the isospin species of Δ and π. Both the reaction rates and the number ratios are, however, affected by the correlations between particle positions, which are absent in the Boltzmann equation, but are induced by the way particle scatterings are treated in many of the transport calculations. The uncertainty in the transport-code predictions of the π-/π+ ratio, after letting the existing Δ resonances decay, is found to be within a few percent for the system initialized at n/p=1.5. Conclusions: The uncertainty in the final π-/π+ ratio in this simplified case of particles in a box is sufficiently small so that it does not strongly impact constraining the high-density symmetry energy from heavy-ion collisions. Most of the sources of uncertainties have been understood, and individual codes may be further improved in future applications. This investigation will be extended in the future to heavy-ion collisions to ensure the problems identified here remain under control.

Abstract Background Beiging of white fat plays an important role in energy metabolism. Beige adipocytes contribute to the regulation of body weight and body temperature through expenditure of chemical energy to produce heat, and they have therefore recently attracted considerable attention as potential targets for therapeutic approaches in metabolic disorders, including obesity. All adipocytes, including beige adipocytes, differentiate from mesenchymal stem cells (MSCs), which may provide an important path for clinical intervention; however, the mechanism of beiging of human adipose cell-derived MSCs is not fully understood. Here, we provide insights on the role of IRISIN, which is known to be secreted by skeletal muscle and promote beiging of white fat. Results We established an IRISIN-induced mesenchymal stem cell beiging model and found that IRISIN protein interacts with the MSC membrane protein TRPC3. This interaction results in calcium influx and consequential activation of Erk and Akt signaling pathways, which causes phosphorylation of PPARγ. The phosphorylated PPARγ enters the nucleus and binds the UCP1 promoter region. Furthermore, the role of TRPC3 in the beiging of MSCs was largely abolished in Trpc3−/− mice. We additionally demonstrate that the calcium concentration in the brain of mice increases upon IRISIN stimulation, followed by an increase in the content of excitatory amino acids and norepinephrine, while Trpc3−/− mice exhibit the reverse effect. Conclusions We found that TRPC3 is a key factor in irisin-induced beiging of MSCs, which may provide a new target pathway in addressing metabolic disorders. Our results additionally suggest that the interaction of irisin with TRPC3 may affect multiple tissues, including the brain. Graphical abstract

Background and purposeHypoperfusion of the posterior cingulate cortex (PCC) and precuneus has consistently been reported in patients with Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG) is effective in alleviating the symptoms of patients with mild AD. This study investigated the effects of rTMS-COG therapy on cerebral blood flow (CBF), with a special interest in the PCC/precuneus, and whether observed CBF changes are associated with changes in neuropsychological assessments in AD.Materials and methodsTwenty-one patients with mild or moderate AD were randomly divided into real rTMS (n = 11) and sham treatment (n = 10) groups, both combined with COG. Neuro-navigated 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex (DLPFC) and then the left lateral temporal lobe (LTL) for 20 min each day for 4 weeks in the real rTMS group. All patients with AD underwent neuropsychological assessment, pseudo-continuous arterial spin labeling, and structural 3D T1-weighted MRI before treatment (T0), immediately after treatment (T1), and 4 weeks after treatment (T2). CBF in the precuneus, PCC, and stimulation targets at the region-of-interest (ROI) level, as well as whole-brain CBF changes at the voxel level, were compared between the two groups at three timepoints.ResultsrTMS-COG therapy revealed significant group × time interactions for the Mini-Mental State Examination (F = 5.339, p = 0.023, η2 = 0.433) and activities of daily living (F = 5.409, p = 0.039, η2 = 0.436) scores. The regional CBF in the precuneus showed a significant group × time interaction (F = 5.833, p = 0.027, η2 = 0.593). For voxel-level analysis, a significant group main effect was found in the left limbic lobe cluster, with the maximal peak in the left parahippocampus (p < 0.001, uncorrected, peak at [−16 −8 −24]). Simple effects analysis indicated that rTMS-COG therapy induced a decrease in CBF in the precuneus at T1 (p = 0.007) and an increase in the left parahippocampus at T2 (p=0.008). CBF decrease in the precuneus was correlated with better cognitive function immediately after treatment (T1) (r =−0.732, p=0.025).ConclusionNeuropsychological assessments showed immediate and long-term effects on cognitive function and activities of daily living after rTMS-COG therapy. CBF changes induced by high-frequency rTMS-COG therapy are region-dependent, showing immediate effects in the precuneus and long-term effects in the left parahippocampus. These results provide imaging evidence to understand the underlying neurobiological mechanism for the application of rTMS-COG in AD.

Background: Malignant melanoma is a common malignant tumor and one of the tumors with the fastest growing incidence. The effect of microRNAs on the biological processing of malignant melanoma cells also have been reported. This study explores the ability of miR-498 to regulate the progression of malignant melanoma cells. Methods: The expression of miR-498 was detected by RT-qPCR. The proliferation, invasion, and migration of malignant melanoma cells were measured by cell counting kit-8, clone formation, and transwell assays. Flow cytometry assay detected the percentage of apoptotic cells. Western blot was used to detect the expression of markers related to epithelial–mesenchymal transition. The correction of miR-498 and UBE2T was explored by dual-luciferase assay and Western blot. Results: Overexpression of miR-498 inhibited the proliferation, invasion, migration, and induced cell apoptosis of M14 and A375 cells. In addition, the expression of epithelial–mesenchymal transition-related factors was altered by the overexpression of miR-498. miR-498 can directly target UBE2T 3'-UTR and inhibit UBE2T protein expression. The overexpression of UBE2T reversed the inhibitory effects of miR-498 on the progression of malignant melanoma cells. Furthermore, UBE2T mRNA was significantly highly expressed in malignant melanoma tissues. The high expression of UBE2T was associated with the poor overall survival rate of malignant melanoma patients. Conclusions: Altogether, our findings demonstrated that miR-498 significantly inhibited the proliferation, invasion, migration, and induced apoptosis of malignant melanoma cells and confirmed that miR-498 regulated malignant melanoma cell progression by targeting UBE2T.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are a risk factor for the development of adenocarcinoma. However, the presence of a component of sarcomatoid carcinoma in the malignant tumor has rarely been described in the literature. A 30-year-old Chinese woman was admitted to our hospital with vague abdominal pain and a poor appetite for 2 months. Computed tomography revealed a huge, unilocular, solid-cystic mass in the pancreatic body, and tail. The patient underwent an en bloc resection of the distal pancreatic tumor with splenectomy and regional lymphadenectomy. Pathologic examination revealed an IPMN associated tubular adenocarcinoma containing a component of sarcomatoid (spindle-shaped cell) carcinoma. Immunohistochemical results revealed that the mononuclear spindle-shaped cells were positive for both pan-cytokeratin and vimentin. There was no evidence of perineural or vascular infiltration, lymph nodal metastasis, or positive surgical margins. The patient developed local recurrence 3 months after surgery for which she received chemoradiotherapy at another hospital. Distant metastases were detected 6 months after the surgery and the patient expired 9 months after surgical resection. We concluded that the presence of sarcomatoid change in IPMN-associated pancreatic adenocarcinoma may indicate poor prognosis.

Triple-negative breast cancer (TNBC) is a severe threat to women’s health because of its aggressive nature, early age of onset, and high recurrence rate. Therefore, in this study, we aimed to evaluate the anti-tumor effects of Gallic acid (GA) on the TNBC HCC1806 cells in vitro. The cell proliferation was detected by MTT and plate clone formation assays, cell apoptosis, cell cycle, and mitochondrial membrane potential (MMP) were analyzed by flow cytometry and Hoechst 33258 staining assays, and the intracellular reactive oxygen species (ROS) accumulation were also investigated. Real-Time PCR and western blot were examined to explore the mechanism of action. The results indicated that GA suppressed HCC1806 cells proliferation and promoted HCC1806 cells apoptosis. Meanwhile, GA treatment changed the morphology of the HCC1806 cells. In addition, GA blocked the HCC1806 cells cycle in the S phase, and it induced cells apoptosis accompanied by ROS accumulation and MMP depolarization. Real-Time PCR results suggested that GA increased Bax, Caspase-3, Caspase-9, P53, JINK and P38 mRNA expression, and decreased Bcl-2, PI3K, AKT and EGFR mRNA expression. Western blotting results suggested that GA increased Bax, cleaved-Caspase-3, cleaved-Caspase-9, P53, P-ERK1/2, P-JNK, P-P38 proteins expression, and decreased Bcl-2, P-PI3K, P-AKT, P-EGFR proteins expression. Furthermore, molecular docking suggested that GA has the high affinity for PI3K, AKT, EGFR, ERK1/2, JNK, and P38. In conclusion, GA could suppress HCC1806 cells proliferation and promote HCC1806 cells apoptosis through the mitochondrial apoptosis pathway and induces ROS generation which further inhibits PI3K/AKT/EGFR and activates MAPK signaling pathways. Our study will provide some new references for using GA in the treatment of TNBC.

BackgroundObservational studies have suggested that peripheral immune disorders are associated with amyotrophic lateral sclerosis (ALS). Previous studies predominantly focused on changes in adaptive immunity. However, emerging evidence showed natural killer (NK) cells, an essential component of innate immunity, were involved in the degeneration of motor neurons. However, the causal relationship between dysregulated NK cells-related immune traits and ALS remains unclear.ObjectiveThis study aimed to explore the causal relationship between NK cells-related immune traits and the risk of ALS.Materials and methodsSingle nucleotide polymorphisms (SNPs) significantly associated with NK cells-related immune traits were selected as instrumental variables to estimate their causal effects on ALS. SNPs from a genome-wide association study (GWAS) on NK cells-related immune traits were used as exposure instruments, including an absolute NK-cells count, absolute HLA-DR+ NK-cells count, NK cells/lymphocytes, NK cells/CD3– lymphocytes, HLA DR+ NK cells/NK cells, HLA DR+ NK cells/CD3– lymphocytes, and the median fluorescence intensities of CD16–CD56+ on NK cells and HLA-DR+ NK cells. Summary-level GWAS statistics of ALS were used as the outcome data. Exposure and outcome data were analyzed using the two-sample Mendelian randomization (MR) method.ResultsEach one standard deviation increase in the expression levels of CD16–CD56+ on NK cells and HLA-DR+ NK cells were associated with a lower risk of ALS in both the MR-Egger and inverse variance weighted methods (P < 0.05). The results proved robust under all sensitivity analyses. Neither instrumental outliers nor heterogeneity were detected.ConclusionOur results suggest that higher expression levels of CD16–CD56+ on NK cells and HLA-DR+ NK cells are associated with a lower risk of ALS.

Abstract Lung squamous cell carcinoma (LUSC) possesses a poor prognosis even for stages I–III resected patients. Reliable prognostic biomarkers that can stratify and predict clinical outcomes for stage I–III resected LUSC patients are urgently needed. Based on gene expression of LUSC tissue samples from five public datasets, consisting of 687 cases, we developed an immune-related prognostic model (IPM) according to immune genes from ImmPort database. Then, we comprehensively analyzed the immune microenvironment and mutation burden that are significantly associated with this model. According to the IPM, patients were stratified into high- and low-risk groups with markedly distinct survival benefits. We found that patients with high immune risk possessed a higher proportion of immunosuppressive cells such as macrophages M0, and presented higher expression of CD47, CD73, SIRPA, and TIM-3. Moreover, When further stratified based on the tumor mutation burden (TMB) and risk score, patients with high TMB and low immune risk had a remarkable prolonged overall survival compared to patients with low TMB and high immune risk. Finally, a nomogram combing the IPM with clinical factors was established to provide a more precise evaluation of prognosis. The proposed immune relevant model is a promising biomarker for predicting overall survival in stage I–III LUSC. Thus, it may shed light on identifying patient subset at high risk of adverse prognosis from an immunological perspective.

Fever is one of the most common clinical conditions and is characterized by pyrogenic infection, malignancy, inflammation, and tissue damage, among others. Ellagic acid (EA) can inhibit the expression of related proteins on the pathway by blocking the nuclear factor kappa-B(NF-κB) signaling pathway, inhibit the levels of pro-inflammatory factors interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α), increase the level of anti-inflammatory factor IL-10, and effectively alleviate inflammatory symptoms. In addition, EA can also reduce the levels of malondialdehyde(MDA) and nitric oxide(NO) in the body, increase the activities of superoxide dismutase (SOD), glutathione (GSH), and catalase(CAT), scavenge oxidative free radicals, inhibit lipid oxidation, and achieve antipyretic and anti-inflammatory effects. The purpose of this study was to establish the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, prostaglandin E2(PGE2), and cyclic adenosine monophosphate(cAMP), and clarify the mechanism of the cyclooxidase-2(COX-2)/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism. Compared to lipopolysaccharide (LPS)- treated animals, subsequent administration of EA significantly lowered the LPS-induced rectal temperature increase (p < 0.05 or p < 0.01), significantly increased serum SOD and GSH levels (p < 0.05 or p < 0.01), and significantly decreased serum MDA, IL-1β, IL-6, and TNF-α levels (p < 0.05 or p < 0.01). In addition, compared to LPS-treated animals, subsequent administration of EA significantly decreased cerebrospinal fluid cAMP and PGE2 levels (p < 0.05 or p < 0.01), significantly decreased cAMP, significantly increased 5-HT levels (p < 0.05 or p < 0.01), and significantly down-regulated p-NF-κB p65 and COX-2 protein levels in the hypothalamus. Subsequent gas chromatography mass spectrometry(GC-MS) metabolite analysis indicated that 12 differential metabolites were detected in serum isolated 4 h after LPS treatment, and 10 differential metabolites were detected in serum collected 7 h after LPS treatment. Next, Pearson correlation analysis was used to systematically characterize the relationship between the identified metabolites and TNF-α, IL-6, MDA, SOD, PGE2, and cAMP. The levels of propionic acid, pyridine, and L-valine were up-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α and increased the activity of GSH. The levels of inositol, urea, and 2-monopalmitin were down-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α, increased the activity of SOD and GSH, reduced the inflammatory response, and alleviated the oxidative stress state. Combined with the results of the metabolic pathway analysis, we suggest that the pathways of the galactose metabolism, synthesis and degradation of ketone bodies, as well as ascorbic acid and aldehyde acid metabolism are closely related to the antipyretic and anti-inflammatory effects of EA. Our study established the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, PGE2, and cAMP, and clarified the mechanism of the COX-2/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests immune involvement in the pathology of multiple system atrophy (MSA). Research on detailed peripheral immune indices, however, is relatively sparse, and is one of the intriguing aspects of MSA yet to be elucidated. A total of 26 MSA patients and 56 age-and sex-matched healthy controls (HC) were enrolled in the current case-control study to delineate the peripheral immune traits of MSA patients. The ratio of CD4+/CD8+ T cells, natural killer cells, CD28 expression on both CD4+ T cells and CD8+ T cells increased in MSA patients compared to HC, but CD8+ T cells and active marker (HLA-DR) expression on total T cells decreased (p < 0.05). This study sheds light on the dysregulation of cellular immunity in MSA, pointing to future mechanistic research.

Diabetes group visits (GVs) have been shown to improve glycemic control and quality of care. However, little is known about the patient and clinician experience. We trained staff to conduct a 6-month GV intervention at six community health centers (CHCs) for adults with uncontrolled diabetes. Patient satisfaction was analyzed using postintervention surveys. Clinician satisfaction was analyzed through pre and posttraining surveys and 1:1 semistructured interviews. Twenty-seven staff and clinicians were trained. Fifty-one adult patients were enrolled and 90% reported high satisfaction with the program. Patients enjoyed longer visits with peer support and felt better equipped to manage barriers to diabetes control. 88% of staff reported that they enjoyed taking part in the program and noted improved team morale, professional development, and increased interdisciplinary collaboration. Perceived challenges of GVs included time investment for a new program, integration into workflow, and staff turnover. Patient and staff satisfaction was high across multiple domains. Staff noted many benefits but reported challenges with patient recruitment and retention as well as the time needed to implement GVs.

The main treatment of breast cancer includes surgical resection, radiotherapy, chemotherapy, endocrine therapy, and molecular targeted therapy, but the outcomes remain unsatisfactory. Previous studies demonstrated that echinacoside, microRNA (miRNA/miR)-4306 and miR-4508 were associated with lymph node metastasis, chemoresistance and self-renewal capability in breast cancer, but in-depth studies on the underlying mechanism of their anticancer effects have not been performed to date. In order to identify the role of miR-4306 and miR-4508, and the mechanism of the antitumor effect of echinacoside in breast cancer, the present study first examined the expression of miR-4306 and miR-4508 in breast cancer tissues to examine their possible role in the development of breast cancer, then evaluated the effect of echinacoside on the expression of miR-4306 and miR-4508 on the viability, apoptosis, cell cycle, migration, and invasion abilities of breast cancer cells to explore the anti-cancer effect of echinacoside and the involvement of miR-4306 and miR-4508. Finally, the breast cancer cells and mice bearing breast cancer xenografts were treated with echinacoside and inhibitors of miR-4508 or miR-4306 to confirm their role on the anticancer effect of echinacoside. The results showed that miR-4306 and miR-4508 were decreased in breast cancer tissues and cells. Echinacoside inhibited cell proliferation, invasion and migration, and promoted the apoptosis of breast cancer cells by downregulating the expression of miR-4306 and miR-4508. In conclusion, this is the first study to show the association between echinacoside and miRNAs in cancer. The present study elucidates an underlying molecular mechanism of the antitumor effect of echinacoside on breast cancer, and thus may contribute to preventive and therapeutic strategies for breast cancer.

Chronic sleep insufficiency is becoming a common issue in the young population nowadays, mostly due to life habits and work stress. Studies in animal models of neurological diseases reported that it would accelerate neurodegeneration progression and exacerbate interstitial metabolic waste accumulation in the brain. In this paper, we study whether chronic sleep insufficiency leads to neurodegenerative diseases in young wild-type animals without a genetic pre-disposition. To this aim, we modeled chronic sleep fragmentation (SF) in young wild-type mice. We detected pathological hyperphosphorylated-tau (Ser396/Tau5) and gliosis in the SF hippocampus. 18F-labeled fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET) further revealed a significant increase in brain glucose metabolism, especially in the hypothalamus, hippocampus and amygdala. Hippocampal RNAseq indicated that immunological and inflammatory pathways were significantly altered in 1.5-month SF mice. More interestingly, differential expression gene lists from stress mouse models showed differential expression patterns between 1.5-month SF and control mice, while Alzheimer's disease, normal aging, and APOEε4 mutation mouse models did not exhibit any significant pattern. In summary, 1.5-month sleep fragmentation could generate AD-like pathological changes including tauopathy and gliosis, mainly linked to stress, as the incremented glucose metabolism observed with PET imaging suggested. Further investigation will show whether SF could eventually lead to chronic neurodegeneration if the stress condition is prolonged in time.

BackgroundIn this study, we evaluated the prognostic value of the plasma levels of Epstein-Barr virus (EBV) DNA in patients with nasopharyngeal carcinoma (NPC) at different treatment stages.MethodsWe retrospectively analyzed the Data of 206 patients with NPC. Pre-neoadjuvant chemotherapy (pre-NACT), post-NACT, post-radiotherapy, and post-treatment plasma EBV DNA levels were used to establish prognostic nomograms. The concordance index (C-index) and calibration curves were used to compare the prognostic accuracy of the nomograms. The results were confirmed in a validation cohort consisting of patients who were tested for EBV DNA levels at all four stages of treatment. The Kaplan-Meier method was used to calculate the progression-free survival (PFS) and overall survival (OS). Survival differences were calculated using the log-rank test.ResultsEBV DNA-positive patients had worse 3-year PFS and 5-year OS than EBV DNA-negative patients; this was true for pre-NACT (PFS: 82.7% vs. 57.3%, P < 0.001; OS: 90.9% vs. 68.7%, P = 0.08) and post-NACT (PFS: 85.0% vs. 50.6%, P < 0.001; OS: 91.7% vs. 65.7%; P = 0.001) EBV DNA levels but not for post-radiotherapy (PFS: 72.2% vs. 60.9%, P = 0.192; OS: 73.1% vs. 77.2%, P = 0.472) or post-treatment (PFS: 77.3% vs. 59.2%, P = 0.063; OS: 77.5% vs. 79.7%, P = 0.644) levels. Nomograms combining pre-NACT and post-NACT EBV DNA levels had a superior prognostic ability than those of post-radiotherapy and post-treatment EBV DNA levels.ConclusionPre-NACT EBV DNA levels combined with post-NACT EBV DNA levels can more reliably predict survival outcomes in patients with NPC.

Background: Traditional Chinese medicine (TCM) is widely integrated into cancer care in China. An overview in 2011 identified 2384 randomized and non-randomized controlled trials (RCTs, non-RCTs) on TCM for cancer published in the Chinese literature. This article summarizes updated evidence of RCTs on TCM for cancer care. Methods: We searched 4 main Chinese databases: China National Knowledge Infrastructure, Chinese Scientific Journal Database, SinoMed, and Wanfang. RCTs on TCM used in cancer care were analyzed in this bibliometric study. Results: Of 5834 RCTs (477 157 cancer patients), only 62 RCTs were indexed in MEDLINE. The top 3 cancers treated were lung, stomach, and breast cancer. About 4752 RCTs (81.45%) tested TCM combined with conventional treatment, and 1082 RCTs (18.55%) used TCM alone for treating symptoms and side-effects. Herbal medicine was the most frequently used TCM modality (5087 RCTs; 87.20%). The most frequently reported outcome was symptom improvement (3712 RCTs; 63.63%) followed by quality of life (2725 RCTs; 46.71%), and biomarkers (2384 RCTs; 40.86%). The majority of RCTs (4051; 69.44%) concluded there were beneficial effects using either TCM alone or TCM plus conventional treatment compared with conventional treatment. Conclusion: Substantial randomized trials demonstrated different types/stages of cancer were treated by various TCM modalities, alone or in combination with conventional medicine. Further evaluation on the effects and safety of TCM modalities focusing on outcomes such as quality of life is required.

The Facility for Rare Isotope Beams (FRIB) will be a world-leading laboratory for the study of nuclear structure, reactions and astrophysics. Experiments with intense beams of rare isotopes produced at FRIB will guide us toward a comprehensive description of nuclei, elucidate the origin of the elements in the cosmos, help provide an understanding of matter in neutron stars and establish the scientific foundation for innovative applications of nuclear science to society. FRIB will be essential for gaining access to key regions of the nuclear chart, where the measured nuclear properties will challenge established concepts, and highlight shortcomings and needed modifications to current theory. Conversely, nuclear theory will play a critical role in providing the intellectual framework for the science at FRIB, and will provide invaluable guidance to FRIB's experimental programs. This review overviews the broad scope of the FRIB theory effort, which reaches beyond the traditional fields of nuclear structure and reactions, and nuclear astrophysics, to explore exciting interdisciplinary boundaries with other areas. © 2014 World Scientific Publishing Company.

Purpose: We examined long-term clinical outcomes among patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) treated at our institution with definitive thoracic chemoradiation therapy (CRT) and local therapy to all oligometastatic lesions. Methods and Materials: A retrospective review identified 38 patients with synchronous oligometastatic NSCLC (≤3 metastatic lesions) who were treated with definitive CRT to the primary tumor and regional lymph nodes between 1999 and 2017 at our institution. Of the 38 patients, 27 patients (71%) received induction chemotherapy, all of whom responded or stabilized with initial systemic therapy before consideration of CRT. Most patients received chemotherapy concurrently with radiation therapy (n = 32; 84%) and local therapy to the metastatic disease site(s) (n = 34; 89%). We assessed patterns of progression or failure, overall survival (OS), progression-free survival (PFS), and toxicities. Results: The median follow-up duration was 54.9 months. Most patients (84%) presented with N2 to N3 disease. The brain or central nervous system was the most common site of disease progression and occurred in 16 of 28 patients (57%) experiencing any progression and 10 of 16 patients (63%) who initially presented with brain oligometastases. Median OS was 21.1 months (95% confidence interval [CI], 15.6-49.0 months), and median PFS 9.7 months (95% CI, 8.2-14.4 months). The 1-, 2-, and 4-year OS rates were 75.7%, 45.0%, and 33.7%, respectively. On multivariate analysis, both locoregional progression (hazard ratio: 5.8; 95% CI, 2.2-15.0; P = .0003) and distant progression (hazard ratio: 6.0; 95% CI, 2.3-15.4; P = .0002), when treated as time-dependent covariates, were associated with inferior OS. Grade ≥3 esophagitis occurred in 9% and grade ≥3 pneumonitis in 5% of patients with evaluable data. Conclusions: Patients with synchronous oligometastatic NSCLC and a high regional nodal burden treated with definitive thoracic CRT experienced favorable survival outcomes and low toxicity. At our institution, treating oligometastatic disease with CRT after systemic therapy is incorporated into the treatment plan from the onset of therapy, and we monitor the neuraxis closely for progression during and after treatment. Future research should focus on novel treatment combinations, such as immunotherapy or targeted systemic therapy as appropriate to further improve tumor control and survival.

Evidence has shown that long non-coding RNAs (lncRNA) play pivotal roles in cancer promotion as well as suppression. But the molecular mechanism of lncRNA TMPO antisense transcript 1 (TMPO-AS1) in lung cancer (LC) remains unclear. This study mainly investigated the effect of TMPO-AS1 in LC treatment. TMPO-AS1 was tested by Kaplan-Meier method. Quantitative real time polymerase chain reaction (qRT-PCR) was employed to assess the expressions of TMPO-AS1, miR-143-3p, and CDK1 respectively in LC tissues and cell lines. TMPO-AS1, miR-143-3p and CDK1 expressions in LC cells were regulated through cell transfection, followed by MTT for cell viability detection. Besides, dual-luciferase reporter assays were performed to verify the interrelated microRNA of TMPO-AS1 and the target of miR-143-3p. Western blot experiments were used to examine the expressions of apoptosis-related proteins, and flow cytometry tested the cell apoptosis in treated cells. TMPO-AS1 and CDK1 were overexpressed in LC tissues and cells, while miR-143-3p level was suppressed. The decrease of TMPO-AS1 led to the increase of miR-143-3p, which further resulted in the reduction of CDK1. Down-regulating TMPO-AS1 reduced LC cell viability, motivated cell apoptosis, as well as promoted the expressions of Bcl and CCND1 and restrained Caspase-3 level, but all these consequences were abrogated by miR-143-3p inhibitor. Simultaneously, siCDK1 could reverse the anti-apoptosis and pro-activity functions of miR-143-3p inhibitor in LC cells. Down-regulation of TMPO-AS1 has the effects of pro-apoptosis in LC by manipulating miR-143-3p/CDK1, which is hopeful to be a novel therapy for LC patients.

Background: Rhabdomyosarcoma is the most common soft tissue tumor in children. Rhabdomyosarcoma commonly results in pain and bleeding caused by tumor compression and is prone to early metastasis and recurrence, which can seriously affect the therapeutic outcomes and long-term prognosis. Up to 37.7% of rhabdomyosarcomas may metastasize. Therefore, the molecular mechanisms underlying rhabdomyosarcoma must be explored to identify an effective target for its early diagnosis and specific treatment. Methods: A dataset of 18 rhabdomyosarcoma tissue samples and 6 healthy skeletal muscle samples was downloaded. Differentially expressed genes between rhabdomyosarcoma and healthy tissue samples were identified by GEO2R. Kyoto Encyclopedia of Genes and Genomes and gene ontology pathway enrichment analyses were performed. A protein–protein interaction network was constructed, and hub genes were identified. Expression and survival analyses of hub genes were performed. Additionally, 30 patients with rhabdomyosarcoma were recruited, and overall survival information and samples were collected. Reverse transcription quantitative real-time polymerase chain reaction assays were performed to verify the expression of MYBPC2 and MYL1 in rhabdomyosarcoma tumor tissues. The Kaplan–Meier method was used to explore overall survival based on our clinical data. Results: In total, 164 genes were up-regulated and 394 were down-regulated in rhabdomyosarcoma tumor tissues. Gene ontology analysis revealed that variations were predominantly enriched in the cell cycle, muscle contraction, muscle system processes, cytoskeleton, nucleotide binding, and cytoskeletal protein binding. The protein–protein interaction network revealed 3274 edges, and 441 nodes were constructed. Ten hub genes were identified; of these, MYBPC2 and MYL1 were significantly up-regulated in rhabdomyosarcoma. Compared with the healthy group, patients with rhabdomyosarcoma exhibiting high expression of MYBPC2 and MYL1 exhibited significantly worse overall survival. Conclusions: We found differentially expressed genes between rhabdomyosarcoma and healthy tissue samples. MYBPC2 and MYL1 may be involved in the pathogenesis of rhabdomyosarcoma and therefore deserve further exploration.

Abstract. Objective:. To explore the correlation between ischiocavernosus muscle injury (ICMI) with different types of pelvic fractures and erectile dysfunction (ED) after pelvic fracture. Design:. Retrospective analysis of a prospective database. Setting:. The study was carried out at the affiliated hospital of Zunyi Medical University. Patients/participants:. A total of 776 male patients with pelvic fracture, aged 18 to 67 years, were recruited for this study by retrospective analysis, and based on the diagnosis of ED and the presence of ICMI, the participants were divided into ED and non-ED groups as well as ICMI and non-ICMI groups. Intervention:. No. Main outcome measurements:. ICMI, the type of pelvic fracture, International Index of Erectile Function-5 scores. Computed tomography/magnetic resonance imaging scans, electromyography (motor unit potential) was used to diagnose ICMI. Results:. The International Index of Erectile Function-5 score was 19.7 ± 5.9. The incidence of ED was 27.3%, the duration time of ED was 30 ± 23 months, and the incidence of reversible ED was 39.6% and of irreversible ED was 60.4%. The incidence of ICMI was 29.4%, among which the incidence of unilateral injury was 57.9%, and the incidence of bilateral injury was 42.1%. Among all pelvic fractures, the incidence of pubic ramus fracture was 88.1%. Bilateral pubic ramus fractures, bilateral fractures of the ischial ramus, and ICMI were independent risk factors for ED after pelvic fracture. Bilateral pubic ramus fractures and pubic symphysis separation were independent risk factors for ICMI. Unilateral ICMI was an independent risk factor for reversible ED, while bilateral ICMI was an independent risk factor for irreversible ED. Conclusions:. ICMI is associated with ED and may be a cause for ED, while pubic ramus fracture, ischial ramus fracture, and pubic symphysis separation may be the main causes of ICMI. Unilateral ICMI may be the main risk factor for transient ED, and bilateral ICMI may be the main risk factor for permanent ED.