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Suicide risk stratification and individual-level prediction among major depressive disorder (MDD) is important but unrecognized. Here, we construct models to detect suicidality in MDD using machine learning (ML) and whole-brain functional connectivity (FC).A cross-sectional assessment was conducted on 200 subjects, including 126 MDD with high suicide risk (HSR; 73 patients with suicidal ideation [SI], 53 patients with suicidal attempts [SA]), 36 patients with low suicide risk (LSR) and 38 healthy controls (HCs). Whole-brain FC features were calculated, the least absolute shrinkage and selection operator (LASSO) method was used for feature selection. A support vector machine (SVM) was performed to build models to distinguish MDD from HCs, and for suicide risk stratification among MDD. Leave-one-out cross-validation (LOOCV) was performed for validation.The models constructed using SVM on whole-brain FC had powerful classification efficiency in screening MDD from HCs (accuracy = 88.50 %), and in suicide risk stratification among MDD patients (with accuracy = 84.56 % and 74.60 % in classifying patients with HSR or LSR, and SA or SI, respectively). Subsequent analysis demonstrated that intra-network dysconnectivity in the sensorimotor network and inter-network dysconnectivity between the default and dorsal attention network could characterize HSR and SA in MDD, separately.This study was a single center cohort study without external validation.These findings indicate ML approaches are useful in suicide risk stratification among MDD based on whole-brain FC, which may help to identify individuals with different suicide risks in MDD and provide an individual-level prediction.

The olfactory function decline of patients with postoperative pituitary adenoma is a common phenomenon. In order to establish a surgical access to the skull base, the upper turbinate, posterior ethmoid chamber and sphenoid sinus need to be operated. We can objectively understand the patient's nasal situation through the scale during the hospital stay, but we know little about the patient's actual feelings and troubles in the home rehabilitation phase.A qualitative study based on 15 semi-structured face-to-face interviews in a provincial comprehensive hospital was conducted. Participants were purposively selected until data saturation. Each interview was digitally recorded and lasted from 30 to 45 minutes. A trained and experienced interviewer collected all data. The Colaizzi method was used to analyze the data.A total of six themes were obtained, namely, the patient's perception of symptoms and any accompanying symptoms and signs related to olfactory function decline, negative emotions, decreased appetite, decreased sleep quality, decreased libido, and the need for the continuous care of patients.A widespread occurrence of impaired smell and nasal function in patients with pituitary adenoma after endoscopic transsphenoidal surgery. It was also noted that nurses should intensify the postoperative nasal care of patients and develop good preventive measures to reduce their postoperative discomfort.

Background: The most widely used noninvasive screening tests for colorectal cancer are fecal occult blood tests. Stool DNA test was developed in recent years. However, direct comparative analyses of these tests within the same population are still sparse. Methods: A total of 2,842 participants who visited outpatient clinics or cancer screening centers were enrolled. Stool DNA test-I (KRAS, BMP3, NDRG4, and hemoglobin immunochemical tests), stool DNA test-II (SDC2 and SFRP2 tests), and fecal immunochemical test (FIT) alone were performed and colonoscopy was used as the gold standard among 2,240 participants. Forty-two and 302 participants had colorectal cancer and advanced adenomas (AA), respectively. Results: The sensitivity for colorectal cancer of stool DNA test-I, -II, and FIT was 90.5%, 92.9%, and 81.0%, respectively. The sensitivity for advanced neoplasm (AN; colorectal cancer plus AA) of stool DNA test-I, -II, and FIT was 34.9%, 42.2%, and 25.9%, respectively. The specificity of stool DNA test-I, -II, and FIT was 91.4%, 93.3%, and 96.8%, respectively, among those with negative results on colonoscopy. When the specificity of FIT was adjusted to match that of stool DNA tests by changing the threshold, no significant difference was seen in the sensitivities among the three tests for detecting colorectal cancer. For AN, the sensitivity of FIT was higher than DNA test-I and similar to DNA test-II under the same specificities. Conclusions: There was no significant advantage of the two stool DNA tests compared with FIT in detecting colorectal cancer or AN in this study. Impact: Our findings do not support extensive use of stool DNA tests instead of FIT.

Esophageal ambulatory reflux monitoring is the current gold standard for the diagnosis of gastroesophageal reflux disease (GERD). In order to facilitate standardized procedure and improve diagnostic accuracy, clinical guidelines for ambulatory esophageal reflux monitoring were developed based on thorough literature search and working group conference by experts in gastrointestinal motility. Indications, contraindications, methodology, and reporting of ambulatory esophageal reflux monitoring were discussed in these clinical guidelines.

Extensive lymph node metastasis (ELM) can occur in some patients with T1 papillary thyroid cancer (PTC). However, the risk factors for ELM in patients with T1 PTC have not been fully explored. In this study, we aimed to examine the association between extranodal extension (ENE) and ELM in patients with T1 PTC.We identified 645 consecutive patients who had T1 PTC initially resected at our centre. Clinical and pathological data were reviewed. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for ELM.ELM was identified in 3.9% of T1 PTC patients, and ENE was identified in 8.1% of patients. ENE was associated with male sex, large tumour size, more positive nodes, and comprehensive surgical treatment. In multivariate analysis, three variables were independently associated with ELM, including ENE (odds ratio [OR], 11.15; 95% confidence interval [CI], 4.54 to 27.30; P 0.001), age (OR, 0.96; 95% CI, 0.93 to 0.99; P = 0.022), and tumour size (OR, 1.18; 95% CI, 1.06 to 1.31; P = 0.002). Bilateral multifocality and sex were not independently associated with ELM.ENE is a strong independent predictor of ELM in patients with T1 PTC. Patients with ENE-positive nodes might need extensive neck dissection.

The clinical significance and regulators of IL-13Rα2 in itch and atopic dermatitis (AD) remain unclear. To identify disease-driven regulatory circuits of IL-13Rα2, transcriptomic/pathological analysis was performed in skin from patients with AD, psoriasis, healthy subjects, and murine AD model. Functionality was investigated in sensory neurons, keratinocytes and animal model, by using knockdown (KD), calcium imaging, RNA-seq, cytokine arrays, pharmacological assays, and behavioural investigations. In our study, an upregulated IL-13Rα2 expression was revealed in skin of AD patients, but not psoriasis, in a disease activity-dependent manner. In cultured human keratinocytes, IL-13 increased IL-13Rα2 transcription levels, and this were downregulated by IL-13Rα1KD. IL-13Rα2KD reduced transcription levels of EDNRA, CCL20, CCL26. In contrast, sensory neuron-derived IL-13Rα2 was upregulated by TLR2 heterodimer agonists, Pam3CSK4 and FSL-1. In a mouse cheek model, pre-administration of Pam3CSK4 and FSL-1 enhanced IL-13-elicited scratching behaviour. Consistently, in cultured sensory neurons Pam3CSK4 enhanced IL-13-elicted calcium transients, increased number of responders, and orchestrated chemerin, CCL17 and CCL22 release. These release was inhibited by IL-13Rα2KD. Collectively, IL-13 regulates keratinocyte-derived IL-13Rα2 and TLR2 to modulate neuronal IL-13Rα2, thereby promoting neurogenic inflammation and exacerbating AD and itch. Thus, the cutaneous IL-13-IL-13Rα2 and neuronal TLR2-IL-13Rα2 pathway represent important targets to treat AD and itch.

Aβ42 is one of the most extensively studied blood and Cerebrospinal fluid (CSF) biomarkers for the diagnosis of symptomatic and prodromal Alzheimer’s disease (AD). Because of the heterogeneity and transient nature of Aβ42 oligomers (Aβ42Os), the development of technologies for dynamically detecting changes in the blood or CSF levels of Aβ42 monomers (Aβ42Ms) and Aβ42Os is essential for the accurate diagnosis of AD. The currently commonly used Aβ42 ELISA test kits usually mis-detected the elevated Aβ42Os, leading to incomplete analysis and underestimation of soluble Aβ42, resulting in a comprised performance in AD diagnosis. Herein, we developed a dual-target lateral flow immunoassay (dLFI) using anti-Aβ42 monoclonal antibodies 1F12 and 2C6 for the rapid and point-of-care detection of Aβ42Ms and Aβ42Os in blood samples within 30 min for AD diagnosis. By naked eye observation, the visual detection limit of Aβ42Ms or/and Aβ42Os in dLFI was 154 pg/mL. The test results for dLFI were similar to those observed in the enzyme-linked immunosorbent assay (ELISA). Therefore, this paper-based dLFI provides a practical and rapid method for the on-site detection of two biomarkers in blood or CSF samples without the need for additional expertise or equipment. Graphical Abstract

Purpose Stereotactic radiosurgery (SRS) has become a standard approach for the treatment of patients with few metastatic brain lesions. However, the optimal treatment approach for the use radiotherapy in the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) remain unclear. This study aimed to compare the survival outcomes and intracranial local control in NSCLC patients with 1–4 BMs who are treated with SRS using linear accelerators (LINAC-SRS), whole-brain radiotherapy (WBRT), or WBRT plus radiotherapy boost (WBRT + RTB). Materials and methods We retrospectively analyzed 156 NSCLC patients with 1–4 BMs who received LINAC-SRS, WBRT, and WBRT + RTB. The median overall survival (OS), intracranial progression-free survival (iPFS), and distant brain failure-free survival (DBF-FS) and related prognostic factors were analyzed. Results The median follow-up period was 31.6 months. The median OS times in the LINAC-SRS, WBRT, and WBRT + RTB groups were not reached, 33.3 months and 27.9 months, respectively. The difference in survival rate was non-significant (P = 0.909). The 2-year iPFS and DBF-FS rates in the LINAC-SRS, WBRT and WBRT + RTB groups were 51.6% and 37.5%; 42.0% and 50.4%; and 51.1% and 56.1%, respectively. There was no significant difference in 2-year iPFS or DBF-FS among the three groups (P = 0.572 for iPFS, P = 0.628 for DBF-FS). Multivariate analysis showed that the independent adverse prognostic factors for OS, iPFS, and DBF-FS were neurological symptoms, recursive partitioning analysis (RPA) class, and targeted therapy. Conclusion LINAC-SRS did not result in significantly superior survival times or intracranial local control compared to WBRT or WBRT + RTB in the treatment of NSCLC patients with 1–4 BMs.

BackgroundBile reflux can cause inflammation, gastric mucosa atrophy, and diseases such as stomach cancer. Alkaline bile flowing back into the stomach affects the intragastric environment and can alter the gastric bacterial community. We sought to identify the characteristics of the stomach mucosal microbiota in patients with bile reflux.MethodsGastric mucosal samples were collected from 52 and 40 chronic gastritis patients with and without bile reflux, respectively. The bacterial profile was determined using 16S rRNA gene analysis.ResultsIn the absence of H. pylori infection, the richness (based on the Sobs and Chao1 indices; P Comamonas, Halomonas, Bradymonas, Pseudomonas, Marinobacter, Arthrobacter, and Shewanella were enriched in patients with bile reflux, the genera, Haemophilus, Porphyromonas, and Subdoligranulum, were enriched in those without bile reflux.ConclusionOur results demonstrate that bile reflux significantly alters the composition of the gastric microbiota.

Disease uncertainty widely exists among family caregivers of patients with moderate and severe craniocerebral injury. This negative emotional reaction will reduce the ability of family caregivers to make decisions during the critical stage of the patient, causing serious effects on the rescue and prognosis of patients with moderate and severe craniocerebral injury. Therefore, this article aims to understand the state of the uncertainty of the disease of family caregivers of patients with moderate and severe craniocerebral injury in China, to analyze the influencing factors, and to explore the specific resource of the uncertainty of the disease combined with qualitative study. The outcomes will provide a theoretical basis for formulating an accurate clinical nursing intervention strategy.This study was conducted in the neurosurgery ward. A total of 214 family caregivers were evaluated using five previously validated scales: (i) Mishel Uncertainty in Illness Scale for family member, (ii) Simplified Coping Style Questionnaire, (iii) Social Support Rating Scale, and (iv) Self-Rating Anxiety Scale, (v) Zarit Caregiver Burden Interview. Kolmogorov-Smirnov was used to test the normality of the data distribution. The potential determinants of disease uncertainty were evaluated using the univariate statistical analysis. A multivariate linear regression model was adopted to assess the predictors of disease uncertainty in family caregivers of patients with moderate and severe craniocerebral injury. Objective sampling method was used to conduct semi-structured interviews with 17 family caregivers of patients with moderate and severe craniocerebral injury, and Colaizzi 7-step analysis method was used to analyze and summarize the interview data.The evaluated participants exhibited critically high levels of perceived uncertainty. The results of multiple linear regression showed that the influencing factors of family caregivers' disease uncertainty were anxiety, number of other caregivers, GOS, negative coping style, and caregiver burden. The qualitative research focuses on two main topics: the sources of disease uncertainty among family caregivers of patients with moderate and severe craniocerebral injury and experience to cope with the situation.The main cause of disease uncertainty of family caregivers of patients with moderate and severe craniocerebral injury is that patients' disease progression and prognosis as well as caregivers' own pressure of responsibility and negative mental status. Furthermore, caregivers' own pressure of responsibility and negative mental status are not clear. Therefore, helping family caregivers adopt positive coping approaches, guiding them to actively seek support from family and society, improving their nursing skills, and understanding of disease progression and prognosis all play an important role in alleviating the uncertainty of the disease.

Social anhedonia, or the loss of motivation in and pleasure from social engagement, is an important feature in understanding the etiology and outcome of various psychopathologies. While the Revised Social Anhedonia Scale (RSAS) represents one of the most commonly used self-report measures of social anhedonia, little is known regarding the construct comparability across populations. We examined measurement invariance of the full and brief RSAS in a diverse, international sample of 14,064 participants across nine epidemiological dimensions, including gender, age, ethnicity, education, community income, continent, migrant status, ethnic density, and urbanicity. Both the full and brief RSAS, as represented by a three-factor structure, achieved metric invariance for all dimensions. The full version showed considerable scalar noninvariance for ethnicity and continent, which was significantly reduced in the brief version. These findings suggest that while the scales measure the same construct across diverse groups, mean comparisons are only appropriate for the brief, and not the full, version. Future research may consider using the brief RSAS to ensure cross-national comparability. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The recovery of blood supply after a period of myocardial ischaemia does not restore the heart function and instead results in a serious dysfunction called myocardial ischaemia-reperfusion injury (IRI), which involves several complex pathophysiological processes. Mitochondria have a wide range of functions in maintaining the cellular energy supply, cell signalling and programmed cell death. When mitochondrial function is insufficient or disordered, it may have adverse effects on myocardial ischaemia-reperfusion and therefore mitochondrial dysfunction caused by oxidative stress a core molecular mechanism of IRI. Peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) is an important antioxidant molecule found in mitochondria. However, its role in IRI has not yet been systematically summarized. In this review, we speculate the role of PGC-1α as a key regulator of mitonuclear communication, which may interacts with nuclear factor, erythroid 2 like -1 and -2 (NRF-1/2) to inhibit mitochondrial oxidative stress, promote the clearance of damaged mitochondria, enhance mitochondrial biogenesis, and reduce the burden of IRI.

A 2-pyridone modified zinc phthalocyanine (denoted ZnPc-PYR) achieves a one stone for three birds outcome in the photodynamic therapy (PDT) treatment of cancer. ZnPc-PYR can be excited by both 665 and 808 nm light to treat superficial and deep tumors, store and slowly release singlet oxygen (1O2) to improve its utilization and downregulate the HIF-1 (hypoxia-inducible factor 1) expression level to enhance the tumor cell's sensitivity to PDT treatment under hypoxic conditions.

Objective. To explore the associations between glucocorticoid use and the clinical outcome of patients with severe pneumonia. Methods. Medical databases including PubMed, EMBASE, and ScienceDirect were searched for relevant literature. Two independent researchers extracted the primary endpoint from the included literature. The Cochrane Q test and I 2 statistics were used to evaluate the interstudy heterogeneity. The combined risk estimates were calculated by random effect model, and the source of heterogeneity was evaluated by subgroup analysis. Funnel plot and Egger’s test were used to assess publication bias. P < 0.05 denoted statistical significance. Results. A total of 12 literature, including 8171 patients with 1083 deaths, were included in this study for meta-analysis. The use of glucocorticoids significantly increased the mortality ( RR = 1.44 , 95% CI: 1.13, 1.84, P < 0.001 ), the risk of requiring mechanical ventilation ( RR = 1.62 , 95% CI: 1.30, 2.02, P < 0.001 ), and the incidence of nosocomial infection ( RR = 1.36 , 95% CI: 1.01, 1.82, P = 0.04 ) in patients with severe pneumonia as compared with the control group. In addition, the use of glucocorticoids did not seem to be associated with length of treatment in the intensive care unit ( mean difference = 1.47 , 95% CI: -1.04, 3.96, P = 0.25 ) and the length of hospital stay ( mean difference = 0.55 , 95% CI: -3.90, 4.99, P = 0.81 ). Conclusion. The use of glucocorticoids may increase the mortality, the incidence of hospital-acquired pneumonia, and the need for mechanical ventilation in patients with severe pneumonia.

Atopic dermatitis (AD) is a chronic skin disease, which is associated with intense itch, skin barrier dysfunction and eczematous lesions. Aberrant IL-20 expression has been implicated in numerous inflammatory diseases, including psoriasis. However, the role of IL-20 in AD remains unknown. Here, RNA-seq, Q-PCR, and immunocytochemistry were utilized to examine disease-driven changes of IL-20 and its cognate receptor subunits in skin from healthy human subjects, AD patients and murine AD-models. Calcium imaging, knockdown and cytokine array were used to investigate IL-20-evoked responses in keratinocytes and sensory neurons. The murine cheek model and behavioral scoring were employed to evaluate IL-20-elicited sensations in vivo. We found that transcripts and protein of IL-20 were upregulated in skin from human AD and murine AD-like models. Topical MC903 treatment in mice ear enhanced IL-20R1 expression in the trigeminal sensory ganglia, suggesting a lesion-associated and epidermal-driven mechanism for sensitization of sensory IL-20 signaling. IL-20 triggered calcium influx in both keratinocytes and sensory neurons, and promoted their AD-related molecule release and transcription of itch-related genes. In sensory neurons, IL-20 application increased TLR2 transcripts, implicating a link between innate immune response and IL-20. In a murine cheek model of acute itch, intradermal injection IL-20 and IL-13 elicited significant itch-like behavior, though only when co-injected. Our findings provide novel insights into IL-20 function in peripheral (skin-derived) itch and clinically relevant intercellular neuron-epidermal communication, highlighting a role of IL-20 signaling in the pathophysiology of AD, thus forming a new basis for the development of a novel antipruritic strategy via interrupting IL-20 epidermal pathways.

Major depressive disorder (MDD) is a severe brain disease associated with a significant risk of suicide. Identification of suicidality is sometimes life-saving for MDD patients. We aimed to explore the use of dynamic functional network connectivity (dFNC) for suicidality detection in MDD patients. A total of 173 MDD patients, including 48 without suicide risk (NS), 74 with suicide ideation (SI), and 51 having attempted suicide (SA), participated in the present study. Thirty-eight healthy controls were also recruited for comparison. A sliding window approach was used to derive the dFNC, and the K-means clustering method was used to cluster the windowed dFNC. A linear support vector machine was used for classification, and leave-one-out cross-validation was performed for validation. Other machine learning methods were also used for comparison. MDD patients had widespread hypoconnectivity in both the strongly connected states (states 2 and 5) and the weakly connected state (state 4), while the dysfunctional connectivity within the weakly connected state (state 4) was mainly driven by suicidal attempts. Furthermore, dFNC matrices, especially the weakly connected state, could be used to distinguish MDD from healthy controls (area under curve [AUC] = 82), and even to identify suicidality in MDD patients (AUC = 78 for NS vs. SI, AUC = 88 for NS vs. SA, and AUC = 74 for SA vs. SI), with vision-related and default-related inter-network connectivity serving as important features. Thus, the dFNC abnormalities observed in this study might further improve our understanding of the neural substrates of suicidality in MDD patients.

Individuals at risk for schizophrenia-spectrum disorders display abnormalities related to motivational salience, or the ability of stimuli to elicit attention due to associations with rewards or punishments. However, the nature of these abnormalities is unclear because most focus on responses to stimuli from broad “pleasant” and “unpleasant” categories and ignore the variation of motivational salience within these categories. In two groups at risk for schizophrenia-spectrum disorders—a Social Anhedonia group and a Psychotic-like Experiences group—and a control group, the current study examined event-related potential components sensitive to motivational salience—the Early Posterior Negativity (EPN), reflecting earlier selective attention, and the Late Positive Potential (LPP), reflecting sustained attention. Compared to controls, the Social Anhedonia group showed smaller increases in the EPN in response to erotica and smaller increases in the LPP as the motivational salience of pleasant images increased (excitinglarger increases in LPP amplitudes as the motivational salience of pleasant images increased. Also, both at-risk groups showed larger increases in the LPP to threatening images but smaller increases to mutilation images. These findings suggest that examining abnormalities beyond those associated with broad categories may be a way to identify mechanisms of dysfunction.

Purpose Lung cancer is the leading cause of cancer-related mortality. STEAP1 and STEAP2 are overexpressed in various cancers. The purpose of this study was to evaluate the expression and prognostic value of STEAP1 and STEAP2 in patients with lung cancer. Methods The mRNA expression and protein expression of STEAP1 and STEAP2 and their prognostic characteristics were examined using Oncomine, GEPIA, and Kaplan-Meier (KM) plotters. The correlation analysis of STEAP1 and STEAP2 gene and protein levels was conducted using GeneMANIA and STRING. KEGG pathway analysis was used to explore the related signal pathways of STEAP 1 and STEAP2. Immunohistochemical methods were used to compare the expression of STEAP2 in normal lung and non-small cell lung cancer (NSCLC) tissues. Real-time quantitative polymerase chain reaction, western blotting, and immunocytochemistry were used to evaluate the expression of STEAP1 and STEAP2 in three lung cancer cell lines and normal lung epithelial cell lines. Results Analysis of the Oncomine database and GEPIA showed that STEAP1 was upregulated and STEAP2 was downregulated in lung cancer tissue, and both expressions were related to the clinical stage of lung cancer. Immunohistochemical analysis showed that STEAP1 protein expression was significantly upregulated in lung cancer compared to that in adjacent tissues. The expression of STEAP1 was positively correlated with the migration and invasion abilities of lung cancer cells. Compared with paracancer tissues, the expression of STEAP2 protein in lung cancer was significantly downregulated and was correlated with the histological grade of squamous cell carcinoma, pathological classification of adenocarcinoma, tumor, lymph node, and metastasis clinical stage, and lymph node metastasis. The expression of STEAP2 was negatively correlated with the migration and invasion abilities of lung cancer cells. The KM curve showed that the downregulation of STEAP1 expression and upregulation of STEAP2 expression were related to a good lung cancer prognosis. Conclusion STEAP1 and STEAP2 are expected to be potential diagnostic and prognostic markers for lung cancer, which may provide more accurate prognostic indicators for lung cancer.

Current suicidal ideation and suicide attempts among psychiatric patients during the COVID-19 pandemic were studied through systematic review and meta-analysis. We searched the following electronic databases using the relevant search terms: Medline, Embase, PubMed and Web of Science, with the search time as of January 31,2022. Forest plots were obtained using Stata statistical software and a random-effects model was used to conduct a meta-analysis of the prevalence of suicidal ideation. We found 21 eligible studies, 11 of which provided suitable data for meta-analysis. 10 studies explored current suicidal ideation and reported a pooled prevalence of 20.4% (95%CI 14.0-26.8). Six studies examined suicide attempts, with a pooled prevalence of 11.4% (95%CI 6.2-16.6). The prevalence of suicidal ideation and suicide attempts varied by the study method used and by the study sites. This work highlights the need for real-time monitoring of suicidal ideation and suicide in psychiatric patients during the covid-19 pandemic r to inform clinical practice and help identify research questions for future epidemiological studies.

Inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract, is a global health care problem. Compelling evidence shows sex differences regarding the prevalence, pathophysiology, clinical presentation, and treatment outcome of IBD. Sex hormones, including estrogen, progesterone, and androgen, have been proposed to have a role in the pathogenesis of sexual dimorphism in IBD. Clinical and experimental data support the modulatory effects of sex hormones on various clinical characteristics of the disease, including intestinal barrier dysfunction and mucosal immune activation. Additionally, the potential role of sex hormones in the modulation of gut microbiota is attracting increasing attention. Here, we discuss the sex dimorphic disease profile and address the potential mechanisms involved in the sex-specific pathogenesis of IBD. Improved understanding of these sex differences in the clinic could improve the knowledge of patients with IBD with heterogeneous disease profiles.

Phosphatidylinositol 3 kinase (PI3K)/AKT (also called protein kinase B, PKB) signalling regulates various cellular processes, such as apoptosis, cell proliferation, the cell cycle, protein synthesis, glucose metabolism, and telomere activity. Corneal epithelial cells (CECs) are the outermost cells of the cornea; they maintain good optical performance and act as a physical and immune barrier. Various growth factors, including epidermal growth factor receptor (EGFR) ligands, insulin-like growth factor 1 (IGF1), neurokinin 1 (NK-1), and insulin activate the PI3K/AKT signalling pathway by binding their receptors and promote antiapoptotic, anti-inflammatory, proliferative, and migratory functions and wound healing in the corneal epithelium (CE). Reactive oxygen species (ROS) regulate apoptosis and inflammation in CECs in a concentration-dependent manner. Extreme environments induce excess ROS accumulation, inhibit PI3K/AKT, and cause apoptosis and inflammation in CECs. However, at low or moderate levels, ROS activate PI3K/AKT signalling, inhibiting apoptosis and stimulating proliferation of healthy CECs. Diabetes-associated hyperglycaemia directly inhibit PI3K/AKT signalling by increasing ROS and endoplasmic reticulum (ER) stress levels or suppressing the expression of growth factors receptors and cause diabetic keratopathy (DK) in CECs. Similarly, hyperosmolarity and ROS accumulation suppress PI3K/AKT signalling in dry eye disease (DED). However, significant overactivation of the PI3K/AKT signalling pathway, which mediates inflammation in CECs, is observed in both infectious and noninfectious keratitis. Overall, upon activation by growth factors and NK-1, PI3K/AKT signalling promotes the proliferation, migration, and anti-apoptosis of CECs, and these processes can be regulated by ROS in a concentration-dependent manner. Moreover, PI3K/AKT signalling pathway is inhibited in CECs from individuals with DK and DED, but is overactivated by keratitis.

Stigma, besides aggravating the damage caused by the disease, may also lead to unhealthy characteristics in patients and unhealthy situations in society. Individuals with acromegaly disease may suffer from stigma concerns, and the associated factors remain largely unknown. Therefore, the present cross-sectional study aimed to investigate the levels of perceived stigma in patients with acromegaly and explore the associated factors.A total of 138 patients with acromegaly were evaluated for having stigma using five previously validated scales: (i) the Stigma Scale for Chronic Illness, (ii) the Hamilton Anxiety Scale, (iii) the Rosenberg Self-Esteem Scale, (iv) the Body Image Concern scale, and (v) the Acromegaly Quality of Life scale. The potential determinants of stigma were evaluated using the univariate statistical analysis. A multivariate linear regression model was adopted to assess the predictors of stigma in patients with acromegaly. Pearson's correlation analysis was performed to analyze the relationship between stigma and the quality of life of the patients.Among the 138 respondents, 102 provided consent for participation.The evaluated patients exhibited critically high levels of perceived stigma. The multiple regression analysis revealed high BMI, serious body image concerns, inferiority complex personality, and critical levels of anxiety as the potential predictors of stigma in patients with acromegaly. The overall stigma and internalized stigma were significantly correlated with QoL in these patients.The patients with acromegaly exhibited critically high levels of perceived stigma, which led to psychological distress and disruptions in their daily lives. This finding highlights the importance of addressing the stigma concerns and the necessity for providing additional support to these patients in this regard during follow-up sessions. Further research should focus on developing intervention strategies to decrease the levels of perceived stigma in patients with acromegaly to promote their quality of life and for the psychosocial rehabilitation of these patients.

To explore the genetic etiology of a neonate with suggestive features of Cornelia de Lange Syndrome (CdLS).Chromosome karyotyping, copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) were carried out for the child. Meanwhile, peripheral venous blood samples were taken from his parents for verifying the suspected pathogenic variants detected in the child.The child has exhibited developmental delay, microcephaly, ptosis, micrognathia, and low ear setting, and was suspected as CdLS. No abnormality was found by karyotyping and CNV-seq analysis. WES has detected 5 heterogeneous variants and 1 hemizygous variant on the X chromosome. Combining the genetic pattern and result of family verification, a hemizygous C.3500TC (p.ile1167thr) of the SMC1A gene was predicted to underlay the clinical manifestations of the patient. This variant was not recorded in the dbSNP and gnomAD database. PolyPhen2, Provean, SIFT all predicted the variant to be harmful, and PhastCons conservative prediction is was a conservative mutation. ACMG variant classification standard evidence supports are PM2, PP2, and PP3.The novel c.3500TC (p.Ile1167Thr) missense mutation of the SMC1A gene probably underlay the genetic etiology of CdLS in this child. Above results has enriched the mutation spectrum of CdLS type II, and facilitated clinical counseling for this family.

Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes (TAC1, tachykinin precursor 1, &nbsp, CALCB, calcitonin gene-related peptide 2, HTR3A, 5-hydroxytryptamine receptor 3A, NPY2R, neuropeptide Y receptor Y2, GPR52, G protein-coupled receptor 52, SCN9A, sodium voltage-gated channel alpha subunit 9, TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief.

Utilizing catalase-mimicking nanozymes to produce O2 is an effective method to overcome tumor hypoxia. However, it is challenging to fabricate nanozymes with ultrahigh catalytic activity. Palladium nanosheet (Pd NS), a photothermal agent for photothermal therapy (PTT), has superior catalase-mimicking activity. Here, titanium dioxide (TiO2 ) is used to modify Pd NS (denoted Pd@TiO2 ) by a simple one-step method to improve its catalytic activity about 8 times. The enhancement mechanism's fundamental insights are discussed through experiments and density functional theory calculations. Next, zinc phthalocyanine is loaded on Pd@TiO2 to form a nanomotor (denoted PTZCs) with the synergistic activities of photodynamic therapy and PTT. PTZCs inherit the catalase activity of Pd@TiO2 to facilitate the decomposition of endogenous H2 O2 to O2 , which can relieve tumor hypoxia and propel PTZC migration to expand the reach of PTZCs, further enhancing its synergistic treatment outcome both in vitro and in vivo. It is proposed that this work can provide a simple and effective strategy for catalytic activity enhancement and bring a critical new perspective to studying and guiding the nanozyme design.

Background and Aims: Emerging studies indicate that long noncoding RNAs (lncRNAs) play a role as prognostic markers in many cancers, including liver cancer. Here, we focused on the lncRNA lung cancer-associated transcript 1 (LUCAT1) for liver cancer prognosis. Methods: RNA-seq and phenotype data were downloaded from the Cancer Genome Atlas (TCGA). Chisquare tests were used to evaluate the correlations between LUCAT1 expression and clinical features. Survival analysis and Cox regression analysis were used to compare different LUCAT1 expression groups (optimal cutoff value determined by ROC). The log-rank test was used to calculate the p-value of the Kaplan-Meier curves. A ROC curve was used to evaluate the diagnostic value. Gene Set Enrichment Analysis (GSEA) was performed, and competing endogenous RNA (ceRNA) networks were constructed to explore the potential mechanism. Results: Data mining of the TCGA -Liver Hepatocellular Carcinoma (LIHC) RNA-seq data of 371 patients showed the overexpression of LUCAT1 in cancerous tissue. High LUCAT1 expression was associated with age (p=0.007), histologic grade (p=0.009), T classification (p=0.022), and survival status (p=0.002). High LUCAT1 patients had a poorer overall survival and relapse-free survival than low LUCAT1 patients. Multivariate analysis identified LUCAT1 as an independent risk factor for poor survival. The ROC curve indicated modest diagnostic performance. GSEA revealed the related signaling pathways, and the ceRNA network uncovered the underlying mechanism. Conclusion: High LUCAT1 expression is an independent prognostic factor for liver cancer.

Nitric oxide (NO) can play both prosurvival and prodeath roles in photodynamic therapy (PDT). The generation efficiency of peroxynitrite anions (ONOO-), by NO and superoxide anions (O2•-), significantly influenced the outcome. Reports indicated that such efficiency is closely related to the distance between NO and O2•-. Thus, in this manuscript, l-arginine (Arg) ethyl ester-modified zinc phthalocyanine (Arg-ZnPc) was designed and synthesized as a photosensitizer (PS) and NO donor. Post light irradiation, the guanido of Arg-ZnPc can be effectively oxidized by the generated reactive oxygen species (ROS) in the PDT process to release NO. Such a strategy could ensure O2•- and NO generation in the same place at the same time to guarantee effective ONOO- formation. In addition, NO has other multiple synergistic cancer treatment functions, including tumor tissue vasodilatation for drug extravasation promotion, P-glycoprotein (P-gp) downregulation for drug efflux inhibition, and glutathione depletion for cancer cell endogenous antioxidant defense destruction. In vitro and in vivo results indicated that the effective ONOO- formation and multiple functions of Arg-ZnPc could synergistically enhance its PDT activity and ensure satisfactory cancer treatment outcome.

Liver cancer is a high morbidity and low survival disease all over the world. Chromosomal instability is hallmark of liver cancer. Microtubule-associated serine and threonine kinase 2 (MAST2), as a microtubule associated protein, may involve in tumorous chromosomal instability and plays important roles in cell proliferation and survival. The role of MAST2 in liver cancer has not been well elucidated, which is the aim of our study. In this study, The Cancer Genome Atlas database was used to study the MAST2 mRNA expression in liver cancer, and Chi-squared tests were performed to test the correlation between clinical features and MAST2 expression. ROC curve was performed to examined the diagnostic capacity. The prognostic value of MAST2 in liver cancer was assessed through Kaplan–Meier curves as well as Cox analysis. Our results showed MAST2 was upregulated in liver cancer, and the area under the curve (AUC) was 0.925 and indicated powerful diagnostic capability. High MAST2 expression was associated with advanced clinical status such as histological type (p = 0.0059), histologic grade (p = 0.0142), stage (p = 0.0008), T classification (p = 0.0028), N classification (p = 0.0107), survival status (p = 0.0062), and poor prognosis of patients. Importantly, MAST2 was an independent risk factor for patients’ prognosis after adjusting for other risk factors including stage, T classification, and residual tumor. In total, MAST2 is a potential diagnostic and prognostic biomarker of liver cancer.

Background and Objective. Liver cancer is a common malignant tumor with few poor diagnostic and prognostic markers, which greatly shortens the potential life span of patients. The RNA-binding protein la ribonucleoprotein 4B (LARP4B) has a la motif (lam) that is important in the process of cancer. We aimed to explore the role of LARP4B in the diagnosis and prognosis of liver cancer. Methods. The Cancer Genome Atlas (TCGA) database was searched to detect LARP4B gene expression in liver cancer. The clinical relevance and diagnostic ability of LARP4B were evaluated by a chi-squared test and a receiver operating characteristic (ROC) curve, respectively. Survival and risk factors of patients with liver cancer were assessed by survival analysis and univariate/multivariate Cox regression model. Additionally, we carried out gene set enrichment analysis (GSEA) to identify LARP4B-related signaling pathways in liver cancer. Results. LARP4B mRNA was highly expressed in liver cancer tissues and was correlated with survival status. The chi-squared test showed that LARP4B had clinical relevance, while ROC curves showed that LARP4B had good diagnostic ability. Survival analysis showed that liver cancer patients with high LARP4B expression had shorter overall/relapse-free survival. The univariate/multivariate Cox regression model indicated that high LARP4B expression may be an independent risk factor for the prognosis of liver cancer patients. Finally, we found that genes involved in the G2M checkpoint, E2F targets, and mitotic spindle were differentially enriched in the high LARP4B-expression phenotype. Conclusions. LARP4B is a potential independent biomarker for diagnosis and prognosis in liver cancer patients.

Dracorhodin perchlorate (DP), a synthetic analogue of the anthocyanin red pigment dracorhodin, has been shown to exert various pharmacological effects, including anticancer activity. However, its effects on human esophageal squamous cell carcinoma (ESCC) cells have not been previously investigated, and the molecular mechanisms underlying its anticancer activity remain unclear. In the present study, it was demonstrated that DP significantly reduced the viability of ESCC cells compared with that noted in normal human liver LO2 cells. Treatment with DP induced G2/M phase cell cycle arrest through upregulation of p21 and p27, and downregulation of cyclin B1 and Cdc2. Furthermore, DP treatment induced caspase‑dependent apoptosis, which could be reversed by exposure to Z‑VAD‑FMK, a caspase inhibitor. Western blotting demonstrated that DP induced apoptosis through extrinsic and intrinsic pathways by upregulating death receptor 4 (DR4), DR5, cleaved caspase‑3/‑7/‑9 and cleaved poly (ADP‑ribose) polymerase (PARP), and by decreasing total PARP, total caspase‑3/7, Bcl‑2 and caspase‑9/‑10. Moreover, DP treatment decreased the phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), AKT, and forkhead box O3a (FOXO3a) in ESCC cells, indicating that the activity of the JAK2/STAT3 and AKT/FOXO3a signaling pathways was inhibited. Therefore, DP is a promising therapeutic agent for ESCC.

Progranulin (PGRN) plays critical roles in inflammation, tumorigenesis, and neurodegeneration. PGRN levels in blood and cerebrospinal fluid (CSF) are being increasingly investigated as potential biomarkers for these disorders. However, the value of CSF PGRN as a biomarker has been limited because currently available commercial enzyme-linked immunosorbent assay (ELISA) kits have suboptimal sensitivity for detecting CSF PGRN. In this study, pairs of monoclonal antibodies (MAbs) were first screened from eleven monoclonal antiPGRN antibodies using indirect ELISA, then a sandwich ELISA was established using the 2 optimized MAbs. This system displayed high sensitivity, with a lower limit of detection of 60.0 pg/mL and a lower limit of quantification of 150 pg/mL. By using this ELISA system, we showed varied CSF PGRN levels in different brain disorders. For example, as compared with the normal controls, patients with Alzheimer disease or multiple sclerosis showed mildly increased CSF PGRN; those with aseptic encephalitis or neuropsychiatric systemic lupus erythematosus showed moderately increased CSF PGRN; those with bacterial leptomeningitis showed severely increased CSF PGRN. Additionally, determining CSF PGRN levels could monitor CNS metastasis and CSF seeding of carcinomas. These results indicate that this system can be valuable in studying the diagnostic and prognostic value of CSF PGRN in brain disorders.

There is an emerging subjective-objective deficit paradox in schizotypy. Individuals with schizotypy report severe subjective complaints in several key functional domains commensurate with that of individuals with schizophrenia. However, objective assessments of the same domains show relatively intact performance. We examined whether this subjective-objective deficit paradox extends to two closely linked affective processes: emotion regulation and awareness. Individuals with elevated social anhedonia (SocAnh; n = 61) and elevated perceptual aberration/magical ideation (PerMag; n = 73) were compared to control participants (n = 81) on subjective and objective measures of emotion regulation and awareness. Subjective measures included self-report questionnaires assessing regulatory ability, attention to emotion, and emotional clarity. Implicit emotion regulation was assessed by the Emotion Regulation-Implicit Association Test (ER-IAT) while objective emotional awareness was assessed by the Levels of Emotional Awareness Scale (LEAS), a performance-based test. Results showed that both SocAnh and PerMag groups reported notable deficits in almost all subjective measures relative to controls (composite ds 0.55). In contrast, performance on ER-IAT and LEAS was very similar to controls (composite ds 0.11). The current study suggests that the subjective-objective deficit paradox extends to emotion regulation and awareness, highlighting the importance of higher-order cognitive bias in understanding emotional abnormalities in schizotypy.

Progranulin has multiple functions in several physiological and pathological processes, including embryonic development, wound repair, tumorigenesis, inflammation and neurodegeneration. To investigate the transcriptional regulation of the PGRN gene, a luciferase knock-in reporter system was established in HEK293 cells by integrating luciferase gene in the genome controlled by the endogenous PGRN promoter using CRISPR/Cas9. PCR results demonstrated the site-specific integration of the exogenous luciferase gene into the genome. To validate the novel luciferase knock-in system, a CRISPR/Cas9 transcription activation/repression system for the PGRN gene was constructed and applied to the knock-in system. In addition, phorbol ester (phorbol 12-myristate, 13-acetate), previously reported as activating the expression of PGRN, was applied to the system. The results indicated that luciferase activity was directly correlated with the activity of the PGRN endogenous promoter. This novel system will be a useful tool for investigating the transcriptional regulation of PGRN, and it has great potential in screening the drugs targeting PGRN.

Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that affects people of all ages. It is characterized by chronic eczema, constant pruritus, and severe discomfort. AD often progresses from mild annoyance to intractable pruritic inflammatory lesions associated with exacerbated skin sensitivity. The T helper-2 (Th2) response is mainly linked to the acute and subacute phase, whereas Th1 response has been associated in addition with the chronic phase. IL-17, IL-22, TSLP, and IL-31 also play a role in AD. Transient receptor potential (TRP) cation channels play a significant role in neuroinflammation, itch and pain, indicating neuroimmune circuits in AD. However, the Th2-driven cutaneous sensitization of TRP channels is underappreciated. Emerging findings suggest that critical Th2-related cytokines cause potentiation of TRP channels, thereby exaggerating inflammation and itch sensation. Evidence involves the following: (i) IL-13 enhances TRPV1 and TRPA1 transcription levels; (ii) IL-31 sensitizes TRPV1 via transcriptional and channel modulation, and indirectly modulates TRPV3 in keratinocytes; (iii) The Th2-cytokine TSLP increases TRPA1 synthesis in sensory neurons. These changes could be further enhanced by other Th2 cytokines, including IL-4, IL-25, and IL-33, which are inducers for IL-13, IL-31, or TSLP in skin. Taken together, this review highlights that Th2 cytokines potentiate TRP channels through diverse mechanisms under different inflammatory and pruritic conditions, and link this effect to distinct signaling cascades in AD. This review strengthens the notion that interrupting Th2-driven modulation of TRP channels will inhibit transition from acute to chronic AD, thereby aiding the development of effective therapeutics and treatment optimization.

The prognostic value of Ki-67 in nasopharyngeal carcinoma (NPC) was controversial according to previous studies. We aimed to clarify the association between K-67 expression and survival in NPC through meta-analysis. We conducted a meta-analysis to explore the potential prognostic effect of Ki-67 on overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS) in NPC. A total of 13 studies comprising 1314 NPC patients were included. High Ki-67 expression was associated with poor OS (hazard ratio [HR]= 2.70, 95% confidence interval [CI]= 1.97–3.71, P

Mitochondrial apoptosis is one of the main mechanisms for cancer cells to overcome chemoresistance. Hexokinase 2 (HK2) can resist cancer cell apoptosis by expressing on mitochondria and binding to voltage-dependent anion channel 1 (VDAC1). We previously reported that peroxisome proliferator-activated receptor coactivator 1 α (PGC1α) is highly expressed in ovarian cancer cisplatin-resistant cells. However, the underlying mechanism remains unclear. Therefore, we evaluated the interaction between PGC1α and HK2 in ovarian cancer cisplatin-resistant cells. We found that the knockdown of PGC1α promotes the apoptosis of ovarian cancer cisplatin-resistant cells and increases their sensitivity to cisplatin. In addition, we found that the knockdown of PGC1α affects the mitochondrial membrane potential and the binding of HK2 and VDAC1. As the heat shock protein 70 (HSP70) family can help protein transport, we detected it and found that PGC1α can promote HSP70 gene transcription. Furthermore, HSP70 can promote an increase of HK2 expression on mitochondria and an increase of binding to VDAC1. Based on these results, PGC1α may reduce apoptosis through the HSP70/HK2/VDAC1 signaling pathway, thus promoting cisplatin resistance of ovarian cancer. These findings provide strong theoretical support for PGC1α as a potential therapeutic target of cisplatin resistance in ovarian cancer.

Ovarian cancer (OC), a common malignant heterogeneous gynecological tumor, is the primary cause of cancer-related death in women worldwide. Adenylate kinase (AK) 7 belongs to the adenylate kinase (AK) family and is a cytosolic isoform of AK. Recent studies have demonstrated that AK7 is expressed in several human diseases, including cancer. However, there is a scarcity of reports on the relationship between AK7 and OC. Here, we compared the expression of AK7 in normal and cancerous ovarian tissues from The Cancer Genome Atlas database and used the c2 test to assess the correlation between AK7 levels and the clinical symptoms of OC. Finally, the prognostic significance of AK7 in OC was determined using the Kaplan-Meier analyses and Cox regression and performed gene set enrichment analysis to detect any relevant signaling pathways. We found that AK7 levels were substantially downregulated in OC than that in normal ovarian tissues (P

PURPOSE: Microdissection testicular sperm extraction (micro-TESE) could retrieve sperm from the testicles to help the non-obstructive azoospermia (NOA) patients to get their biological children, but also would cause damage to the testicles. Therefore, it is necessary to preoperatively predict the micro-TESE outcome in NOA patients. For this purpose, we aim to develop a model based on extracellular vesicles’ (EVs) piRNAs (EV-piRNAs) in seminal plasma. METHODS: To identify EV-piRNAs that were associated with spermatogenic ability, small RNA-seq was performed between the NOA group (n = 8) and normal group (n = 8). Validation of EV-piRNA expression in seminal plasma EVs and testicles tissues was used to select EV-piRNAs for the model. Candidate EV-piRNAs were further selected by LASSO regression analysis. Binary logistic regression analysis was used for the models’ calculation formula. ROC analysis and Hosmer–Lemeshow test was used to assess the models’ performance in the training (n = 20) and validation (n = 25) cohorts. RESULTS: We identified 8 EV-piRNAs which were associated with spermatogenic ability. Two EV-piRNAs (pir-60351 and pir-61927) were selected by LASSO regression analysis. Finally, we developed a favorable model based on the expression of pir-61927 with good discrimination wherein the AUC was 0.82 (95% CI: 0.63~1.00, p = 0.016) in the training cohort and 0.83 (95% CI: 0.66~1.00, p = 0.005) in the validation cohort, as well as good calibration. CONCLUSIONS: A favorable model based on the expression of pir-61927 in seminal plasma EVs was established to predict the micro-TESE outcome in NOA patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02101-8.

Background and Objective: Liver cancer is a malignancy with a poor prognosis. G protein signaling modulator 2 is mainly related to cell division and cell cycle regulation. In this review, the relationship between G protein signaling modulator 2 and clinical characteristics of patients with liver cancer has been explored, especially with respect to its prognostic value. Methods: G protein signaling modulator 2 messenger RNA expression and clinicopathological characteristics of patients with liver cancer were obtained from The Cancer Genome Atlas. The expression level of G protein signaling modulator 2 RNA-Seq was validated by using Gene Expression Omnibus. Chi-square test was performed to evaluate the relationship between G protein signaling modulator 2 expression and clinical characteristics. The threshold value of G protein signaling modulator 2 in the diagnosis of liver cancer was evaluated by a receiver–operating characteristic curve. Cox regression analysis and Kaplan-Meier curves were performed to evaluate the relationship between G protein signaling modulator 2 and liver cancer prognosis, which included overall and residual-free survival, and explored the prognostic value of G protein signaling modulator 2. Liver cancer survival analyses were validated by using the data of G protein signaling modulator 2 RNA-Seq from the International Cancer Genome Consortium. Results: The expression level of G protein signaling modulator 2 messenger RNA was remarkably higher in liver cancer than that in healthy tissues ( P < 2.2 × e−16), which was also validated by data from the GSE14520 database. In addition, high G protein signaling modulator 2 expression significantly correlated with histological grade ( P = .020), vital status ( P < .001), clinical ( P = .001), and T stage ( P = .001). The receiver–operating characteristic curves showed G protein signaling modulator 2 to be an advantageous diagnostic molecule for liver cancer (area under curve = 0.893). Furthermore, the results of Cox analysis and Kaplan-Meier curves suggested that the upregulation of G protein signaling modulator 2 expression is linked to poor prognosis and G protein signaling modulator 2 messenger RNA could be an independent predictor for liver cancer, which was validated by data from the International Cancer Genome Consortium database. Conclusions: G protein signaling modulator 2 messenger RNA was overexpressed in liver cancer, and G protein signaling modulator 2 is an independent prognostic factor. G protein signaling modulator 2 is expected to be a treatment target for cancer.

Objectives Enterochromaffin (EC) cells have been associated with functional gastrointestinal disorders such as IBS. Recently, we found that glial cell‐derived neurotrophic factor (GDNF)‐rearranged during transfection (RET) localized in EC cells in human colonic epithelia. Here, we examine the role of GDNF‐RET in the pathophysiology of diarrhoea‐predominant irritable bowel syndrome (IBS‐D). Materials and Methods GDNF was assessed by ELISA and immunohistochemistry in biopsies from IBS‐D patients and healthy controls. Stress was induced by using a wrap‐restraint stress (WRS) procedure to serve as an acute stress‐induced IBS model. The function of GDNF‐RET axis to intestinal stem cell (ISC) homeostasis, and EC cell numbers were assessed in vivo and in vitro. Results GDNF‐RET was expressed in EC cells in human colon. GDNF was significantly increased in IBS‐D patients. WRS mice showed increased GDNF‐RET levels in colon. WRS induced visceral hypersensitivity by expanding of ISC and differentiation of EC cell via GDNF‐RET. Furthermore, GDNF‐treated mice recapitulated the phenotype of WRS mice. In vitro, GDNF treatment amplified Wnt signal and increased serotonin levels in colonic organoids in a dose‐dependent manner. Conclusions We identified GDNF‐RET was presented in colonic epithelium of patients with IBS‐D. GDNF‐RET played important roles in regulating ISC and EC cell differentiation. Our findings, thus, provide RET inhibitor as new therapeutic targets for treatment of patients with IBS‐D., GDNF‐RET was expressed in enterochromaffin (EC) cells in human colon. GDNF protein levels were increased in IBS‐D patients. GDNF‐RET indirectly promotes intestinal stem cell (ISC) proliferation through Wnt signal. GDNF‐RET promotes differentiation of ISC, leading to increased density of EC cells in acute stress model.

The emergence of the new coronavirus (nCoV-19) has impacted human health on a global scale, while the interaction between the virus and the host is the foundation of the disease. The viral genome codes a cluster of proteins, each with a unique function in the event of host invasion or viral development. Under the current adverse situation, we employ virtual screening tools in searching for drugs and natural products which have been already deposited in DrugBank in an attempt to accelerate the drug discovery process. This study provides an initial evaluation of current drug candidates from various reports using our systemic in silico drug screening based on structures of viral proteins and human ACE2 receptor. Additionally, we have built an interactive online platform (https://shennongproject.ai/) for browsing these results with the visual display of a small molecule docked on its potential target protein, without installing any specialized structural software. With continuous maintenance and incorporation of data from laboratory work, it may serve not only as the assessment tool for the new drug discovery but also an educational web site for the public.

Motivational abnormalities represent a key area of dysfunction in individuals with, or at risk for, schizophrenia and severely limit broad domains of functioning in these populations. The aberrant salience hypothesis posits that motivational abnormalities are the result of an over-attribution of salience to nonpleasurable stimuli but an under-attribution of salience to pleasurable ones. Consequently, people "want" what they do not "like" but do not "want" what they "like." However, it is unclear how this hypothesis manifests in schizophrenia risk beyond monetary rewards. The current research provided a multimodal investigation of the aberrant salience hypothesis in people with elevated psychotic-like experiences (PLEs) who are at risk for developing psychosis. Study 1 examined the link between liking and incentive salience using a neurobiological indicator of incentive salience (contingent negative variation/CNV) in 23 PLEs and 21 Control participants. The PLEs group showed diminished CNV reactivity to pleasant (vs. neutral) social images, which was driven by an augmented response to neutral stimuli. Study 2 examined liking, incentive salience, and conscious wanting experience using a psychological indicator of incentive salience (positive spontaneous thoughts/PSTs) in 38 PLEs and 246 Control participants. The PLEs group showed diminished correspondence between liking, PSTs, and conscious wanting across diverse reward contexts. Collectively, individuals with PLEs over-attribute salience to neutral stimuli and, to a lesser degree, under-attribute salience to rewards. Findings of the current research support abnormal salience attribution as a trait-like feature implicated in the pathophysiology and development of schizophrenia and provide valuable insights on research and treatment of this illness.

Introduction: The pandemic caused by the coronavirus disease 2019 (COVID-19) infection has exposed vulnerable populations to an unprecedented global health crisis. Research reported that Chinese traditional medicine injections were used in patients with COVID-19 infection and showed significant effects, and there have been no systematic review and meta-analyses to investigate the effects and safety of Chinese traditional medicine injections. Materials and methods: This systematic review and meta-analysis protocol is based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement. The literature search will involve Cochran library, Web of science, PubMed, MEDLINE, Embase, China Biology Medicine Database, China National Knowledge Infrastructure Database, VIP, Wang Fang database, and China Clinical Trial Registration Center for articles and research published form December 2019. This search will include randomized controlled trials and nonrandomized studies. The Cochrane Collaboration's tool for randomized controlled trial studies and the Quality Assessment Tool for Quantitative Studies for nonrandomized studies will be used to assess the risk of bias among the studies included in the systematic review. Review Manager 5.3 software will be used for the meta-analysis, and odds ratio are calculated as the primary outcomes. Subgroup analyses will then be performed based on the characteristics of the interventions and populations included in the studies examined. Ethics and dissemination: This systematic review protocol is designed to provide evidence regarding the effects and safety of Chinese traditional medicine injections on patients with COVID-19, such evidence may be useful and important for clinical treatment decisions. The results should be disseminated through publication in a peer-reviewed journal. Since the data and results used in the systematic review will be extracted exclusively from published studies, approval from an ethics committee will not be required.

Background: The present study aimed to examine the diagnostic and prognostic value of HN1 in terms of overall survival (OS) and recurrence-free survival (RFS) in liver cancer and its potential regulatory signaling pathway. Methods: We obtained clinical data and HN1 RNA-seq expression data of liver cancer patients from The Cancer Genome Atlas database, and analyzed the differences and clinical association of HN1 expression in different clinical features. We uesd receiver-operating characteristic curve to evaluate the diagnosis capability of HN1. We analyzed and evaluated the prognostic significance of HN1 by Kaplan–Meier curves and Cox analysis. Gene Set Enrichment Analysis (GSEA) was used to identify signaling pathways related to HN1 expression. Results: HN1 mRNA was up-regulated in liver cancer, and was associated with age, histologic grade, stage, T classification, M classification, and vital status. HN1 mRNA had ideal specificity and sensitivity for the diagnosis (AUC = 0.855). Besides, the analysis of Kaplan–Meier curves and Cox model showed that HN1 mRNA was strongly associated with the overall survival and could be well-predicted liver cancer prognosis, as an independent prognostic variable. GSEA analysis identified three signaling pathways that were enriched in the presence of high HN1 expression. Conclusion: HN1 serves as a biomarker of diagnosis and prognosis in liver cancer.

Liver cancer is a disease with high mortality; it is often diagnosed at intermediate and advanced stages and has a high recurrence rate. ROS restriction and adequate energy supply play significant roles in liver cancer. SLC25A11, a member of the malate-aspartate shuttle (MAS), regulates electroneutral exchange between 2-oxoglutarate and other dicarboxylates. It transports glutathione (GSH) from the cytoplasm into mitochondria to maintain GSH levels to limit ROS production. Moreover, SLC25A11 is essential for ATP generation in cancers as it regulates NADH transportation from the cytoplasm to mitochondria. The purpose of this research was to investigate the prognostic value of SLC25A11 in liver cancer. The Cancer Genome Atlas database was used to analyze the levels of SLC25A11 in liver cancer. Fisher’s exact and chi-square tests were used to evaluate the relationship between SLC25A11 expression and clinical characteristics. Finally, we explored the value of SLC25A11 in prognosis by Cox analysis and Kaplan-Meier curves. Our results revealed that SLC25A11 was downregulated in liver cancer compared to normal controls. Low expression of SLC25A11 was associated with clinical stage, vital status, histologic grade, overall survival (OS) and relapse-free survival (RFS). Liver cancer patients with low SLC25A11 expression had shorter OS and RFS than patients with high SLC25A11 expression. Multivariate analysis showed that the expression of SLC25A11 was an independent predictor of RFS and OS. In conclusion, this study identified that SLC25A11 serves as a new prognostic marker for liver cancer.

Radon exposure is the most frequent cause of lung cancer in non-smokers. The high linear energy transfer alpha-particles from radon decay cause the accumulation of multiple genetic changes and lead to cancer development. Epithelial-mesenchymal transition (EMT) plays an important role in oncogenesis. However, the mechanisms underlying chronic radon exposure-induced EMT attributed to carcinogenesis are not understood. This study aimed to explore the EMT and potential molecular mechanisms induced by repeated radon exposure. The EMT model of 16HBE and BEAS-2B cells was established with radon exposure (20000 Bq/m3, 20 min each time every 3 days). We found repeated radon exposure facilitated epithelial cell migration, proliferation, reduced cell adhesion and ability to undergo EMT through a decrease in epithelial markers and an increase in mesenchymal markers. Radon regulated the expression of matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 2 (TIMP2) to disrupt the balance of MMP2/TIMP2. In vivo, BALB/c mice were exposed to 105 Bq/m3 radon gas for cumulative doses of 60 and 120 Working Level Months (WLM). Radon inhalation caused lung damage and fibrosis in mice, which was aggravated with the increase of exposure dose. EMT-like transformation also occurred in lung tissues of radon-exposure mice. Moreover, radon radiation increased p-PI3K, p-AKT and p-mTOR in cells and mice. Radon reduced the GSK-3β level and elevated the active β-catenin in 16HBE cells. The m-TOR and AKT inhibitors attenuated radon exposure-induced EMT by regulation related biomarkers. These data demonstrated that radon exposure induced EMT through the PI3K/AKT/mTOR pathway in epithelial cells and lung tissue.

Liver cancer is a devastating disease for humans with poor prognosis. Although the survival rate of patients with liver cancer has improved in the past decades, the recurrence and metastasis of liver cancer are still obstacles for us. Inositol polyphosphate-5-phosphatase K (INPP5K) belongs to the family of phosphoinositide 5-phosphatases (PI 5-phosphatases), which have been reported to be associated with cell migration, polarity, adhesion, and cell invasion, especially in cancers. However, there have been few studies on the correlation of INPP5K and liver cancer. In this study, we explored the prognostic significance of INPP5K in liver cancer through bioinformatics analysis of data collected from The Cancer Genome Atlas (TCGA) database. Chi-square and Fisher exact tests were used to evaluate the relationship between INPP5K expression and clinical characteristics. Our results showed that low INPP5K expression was correlated with poor outcomes in liver cancer patients. Univariate and multivariate Cox analyses demonstrated that low INPP5K mRNA expression played a significant role in shortening overall survival (OS) and relapse-free survival (RFS), which might serve as the useful biomarker and prognostic factor for liver cancer. In conclusion, low INPP5K mRNA expression is an independent risk factor for poor prognosis in liver cancer.

Background and object: Emerging evidence shows that non-coding RNA functions as new gene regulators and prognostic markers in several cancers, including liver cancer. Here, we focused on the small nucleolar RNA host gene 4 (SNHG4) in liver cancer prognosis based on The Cancer Genome Atlas (TCGA) data. Methods: The expression data and clinical information were downloaded from TCGA. Chi-square tests evaluated the correlation between SNHG4 expression and clinical parameters. Differences in survival between high and low expression groups (optic cutoff value determined by ROC) from Cox regression analysis were compared, and P-value was calculated by a log-rank test. Kaplan–Meier curves were compared with the log-rank test. GSEA and ceRNA network were conducted to explore the potential mechanism. Results: Data mining of lncRNA expression data for 371 patients with primary tumor revealed overexpression of SNHG4 in liver cancer. High SNHG4 expression was correlated with histological type (P = 0.01), histologic grade (P = 0.001), stage (P = 0.01), T classification (P = 0.004) and survival status (P = 0.013). Patients with high SNHG4 expression had poor overall survival and relapse-free survival compared with those with low SNHG4 expression. Multivariate analysis identified SNHG4 as an independent prognostic factor of poor survival in liver cancer. GSEA revealed related signaling pathway and ceRNA network explored the further mechanism. Conclusion: High SNHG4 expression is an independent predictor of poor prognosis in liver cancer.

The determination of the amyloid β (Aβ) peptide and its aggregation intermediates helps to understand the pathological mechanism of Alzheimer's disease (AD) caused by toxic amyloid fragments. Because of the transient and heterogeneous properties of Aβ aggregates, it is very difficult to dynamically detect Aβ and its aggregation intermediates. Herein, we successfully constructed a two-dimensional manganese dioxide (MnO

Fibroblast growth factor 19 (FGF19) promotes tumor growth in various types of cancer, but its function has not been investigated in the context of colorectal adenoma. Here, we report that FGF19 expression was greater in colorectal adenoma than in normal tissues, as measured by an enzyme-linked immunosorbent assay, quantitative reverse-transcription PCR and immunohistochemistry. FGF19 expression was also elevated in a subset of human colon cancer cell lines. Moreover, FGF receptor 4 (FGFR4), the cognate receptor for FGF19, was upregulated in colorectal adenoma tissues. Lipid levels and body mass index values strongly correlated with FGF19 and FGFR4 levels in patients with colon adenomas. These observations indicate that the FGF19/FGFR4 pathway may be involved in the development of neoplasia, and that FGF19 may be a valuable diagnostic marker for the identification of patients with colorectal adenomas.