Search

A bidirectional relationship between insomnia and depression has been observed. However, few studies have used network analysis to explore the interaction patterns in that association at the symptom level. This study aimed to estimate network structures of insomnia and depressive symptoms among shift workers, as well as to compare the differences in network properties between individuals without and with insomnia symptoms and/or at risk of depression. A total of 1883 shift workers were included in our study. Insomnia symptoms were evaluated by three items based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, and depressive symptoms were assessed by the Center for Epidemiologic Studies Depression Scale. Network analyses were used for the statistical analysis. "Difficulty initiating sleep", "Hard to get started", and "Depressed mood" with higher expected influence (EI) values were identified as the most central symptoms within the insomnia-depressive networks among shift workers. The significant differences between individuals without and with insomnia symptoms and/or at risk of depression were observed in symptoms of "Difficulty initiating sleep" and "Hard to get started". "Depressed mood", "Difficulty initiating sleep", or "Hard to get started" were the most key symptoms that trigger and sustain the structure of insomnia and depressive symptom among shift workers. Hence, timely intervention for the above three symptoms in future research or clinical practice (e.g., cognitive behavioral therapy for insomnia) may be crucial in alleviating insomnia and depressive symptoms among shift workers.

In this work, a positively charged chitosan-grafted-polyarginine (CS-N-PArg) as the macro-molecular NO donor, and a negatively charged acetalated starch (AcSt-O-PAsp) as a glucose donor, have been synthesized. To achieve the multi-enzymatic cascade system for local generation of self-supply glucose to increase the H

Melanoma is a malignant skin cancer that is prone to metastasis in the early stage and has a poor prognosis. Immunomodulatory therapy for melanoma has been a hot research topic in recent years. However, low immune cell infiltration and loss of tumor immunogenicity may occur in tumors, resulting in low response rates to immunotherapy. Thus, immunomodulatory therapy is usually used in combination with chemotherapy and radiotherapy. Development of combined therapeutic strategies with low systemic toxicity, high immune responsiveness and long-term inhibition of metastasis and recurrence of melanoma is the goal of current research. In this study, the insoluble immune adjuvant imiquimod (R837) was prepared as nanocrystals and coated with polydopamine (PDA) to form R837@PDA, which was then loaded into chitosan hydrogel (CGP) to form the drug-loaded gel system, R837@PDA@CGP (RPC), to combine immunomodulation effects, induction of immunogenic cell death (ICD) effects and immune-enhancement effects. After treatment with RPC, ICD in melanoma was induced, and the infiltration rate of cytotoxic T cells (CTLs) in melanoma was also significantly enhanced, which turned the tumor itself into an in situ vaccine and boosted the cancer-immunity cycle at the tumor site. Therefore, melanoma growth, metastasis and recurrence were notably inhibited.

Mesenchymal stem cells (MSCs) have been demonstrated as promising cell sources for tissue regeneration due to their capability of self-regeneration, differentiation and immunomodulation. MSCs also exert extensive paracrine effects through release of trophic factors and extracellular vesicles. However, despite extended exploration of MSCs in pre-clinical studies, the results are far from satisfactory due to the poor engraftment and low level of survival after implantation. Hypoxia preconditioning has been proposed as an engineering approach to improve the therapeutic potential of MSCs. During in vitro culture, hypoxic conditions can promote MSC proliferation, survival and migration through various cellular responses to the reduction of oxygen tension. The multilineage differentiation potential of MSCs is altered under hypoxia, with consistent reports of enhanced chondrogenesis. Hypoxia also stimulates the paracrine activities of MSCs and increases the production of secretome both in terms of soluble factors as well as extracellular vesicles. The secretome from hypoxia preconditioned MSCs play important roles in promoting cell proliferation and migration, enhancing angiogenesis while inhibiting apoptosis and inflammation. In this review, we summarise current knowledge of hypoxia-induced changes in MSCs and discuss the application of hypoxia preconditioned MSCs as well as hypoxic secretome in different kinds of disease models.

BACKGROUND: Recent research suggested that COVID-19-related multiple mental health problems were associated with an increased risk for suicidal ideations (SIs), but population-based data demonstrating these associations are scarce. This study aimed to estimate the cumulative effects of psychological risk factors on SIs during the outbreak and remission periods of COVID-19 using a cumulative risk model, as well as sex differences.METHODS: A total of 68,685 college students in China participated in the survey during two phases of the pandemic (T1 and T2). Mental health risks (acute stress, depression, anxiety, insomnia, and obsessive-compulsive symptoms) and sociodemographic characteristics were measured at T1, and SIs were assessed at T1 and T2. Hierarchical regression analysis was used to determine the combined effect of multiple mental health problems on SIs at T1 and T2.RESULTS: The prevalence of SIs increased from the early periods of the COVID-19 pandemic (7.6%) to the later periods (10.0%). Depression was a powerful risk factor for SIs during the COVID-19 pandemic. Individuals with >3 mental risks would be most likely to experience rapidly increasing SIs during the early periods of the COVID-19 pandemic. Sex exerted different effects on the cumulative risk model of SIs.CONCLUSIONS: Interventions, such as mental health education and improving utilization of student support services, should be implemented. There is a crucial need for early intervention and prevention efforts aimed at males with greater than three mental health problems.

Avascular necrosis (AVN) is a major complication after closed reduction for developmental dysplasia of the hip. The factors that predispose to AVN remain controversial. The purpose of this study was to analyze the risk factors, especially patient factors, such as age at reduction, grade of dislocation, and ossific nucleus development, related to AVN.We retrospectively reviewed children with dysplasia of the hip treated by closed reduction between 1997 and 2006. AVN was evaluated using Salter criteria and Kalamchi and MacEwen classification. Related factors were analyzed.One hundred and eight children (140 hips) with an average age of 16.6 months at closed reduction (range: 6-24 mo) were included in the study. For an average duration of 10.1 years (range 7-16 y) of follow-up, 44 hips (31.4%) developed AVN. Grade II or higher AVN occurred in 14 hips (10%). The incidence of AVN increased with the grade of dislocation ( P =0.022) and underdevelopment of the ossific nucleus ( P0.001). Underdevelopment of the ossific nucleus was also found to be positively correlated with the dislocation grade ( P =0.047). The age at the time of reduction, sex, and side were not significant factors. Children who underwent secondary operation were all older than 1 year at reduction.High-grade dislocation correlates with the underdevelopment of the ossific nucleus. Patients with these 2 characteristics are predisposed to AVN. As underdevelopment of the ossific nucleus occurred regardless of age, it is not advisable to delay reduction because it does not alter the AVN rate, and instead, it increases the secondary operation rate.Level IV case series.

Sleep disturbance may cause psychotic-like experiences (PLEs). The present study aimed to exam their rate of co-occurrence and investigate whether resilience buffers the association.A total of 50,625 junior high school students were assessed using the self-compiled socio-demographics and sleep questionnaires, 8-item Positive Subscale of the Community Assessment of Psychic Experiences, 10-item Connor-Davidson Resilience Scale, Patient Health Questionnaire and Generalized Anxiety Disorder Questionnaire.In this sample, 15.8% participants had frequent PLEs in the past month, where 40.1% exhibited comorbid sleep disturbance. Sleep disturbance positively associated with the onset of frequent PLEs, after adjusting for socio-demographics, depression and anxiety. Moderation analysis showed resilience buffers the association between sleep disturbance and PLEs, with a higher level of resilience, the positive effect of sleep disturbance on PLEs would be diminished to a greater extent.These findings suggested that early attention should be drawn to adolescents with sleep disturbance. Intervention strategies should be enhancing resilience, increasing sleep duration and improving sleep quality.

Despite previous research has illustrated there is high-coexistence between posttraumatic stress disorder (PTSD) and posttraumatic growth (PTG) in the aftermath of traumatic events, few studies have conceptualized the coexistence mechanism of the two psychological phenomena. Using the network analysis, this study aimed to identify the key bridge symptoms and compare sex differences between PTSD symptoms and PTG elements in survivors 10 years after the Wenchuan earthquake in China. A total of 744 survivors 10 years after the Wenchuan earthquake in China completed self-reported questionnaires on demographics, PTSD symptoms (4-item of Posttraumatic Stress Disorder Checklist), and PTG (10-item of Posttraumatic Growth Inventory). Network analysis was used to identify the network structure of PTSD symptoms and elements of PTG, along with bridge symptoms. Additionally, sex differences in the network structure were compared by the Network Comparison Test. Results revealed that the network of PTSD symptoms and elements of PTG was robust to stability and accuracy tests. The key bridge symptoms in the network were "Stronger religious faith", "Changed priorities", and "Easily startled". There were significant differences in network global strength across sex, and network structure across the severity of property loss other than house damage. Future interventions targeting the three key bridge symptoms are expected to relieve the severity of PTSD and promote growth following exposure to traumatic events.

Diet is an important exposure route for phthalates, such as di-iso-butyl phthalate (DiBP), dibutyl phthalate (DBP), bis(2-ethylhexyl) phthalate (DEHP), and benzyl butyl phthalate (BBP). In this study, we aimed to estimate phthalate exposure in the diet of pregnant women and assess the health risk. A total of 517 pregnant women in the first trimester were recruited, and food frequency questionnaires were collected. A simple distribution assessment method was used to estimate daily exposure, and the hazard index (HI) method was used to assess cumulative risk. The maximum daily dietary exposure to DEHP, DBP, DiBP, and BBP was 5.25, 3.17, 2.59, and 0.58 μg/kg bw/day, respectively, and did not exceed the safety limit values. Cereals and vegetables were the main sources of the estimated daily intake (EDI) of phthalates in the diet. The cumulative risk assessment, based on the European Food Safety Authority tolerable daily intake (TDI) and the US Environmental Protection Agency reference dose (RfD), did not exceed the threshold of 1. DiBP, DBP, and DEHP had higher hazard quotient (HQ) values for cumulative health risk than BBP. In conclusion, a low health risk was posed by the cumulative dietary exposure to phthalates for pregnant women in Beijing.

Fragment crystallizable (Fc) fusion is commonly used for extending the half-life of biotherapeutics such as cytokines. In this work, we studied the pharmacokinetics of Fc-fused interleukin-10 (IL-10) proteins that exhibited potent antitumor activity in mouse syngeneic tumor models. At pharmacologically active doses of ≥0.1 mg/kg, both mouse Fc-mouse IL-10 and human Fc-human IL-10, constructed as the C terminus of the Fc domain fused with IL-10 via a glycine-serine polypeptide linker, exhibited nonlinear pharmacokinetics after intravenous administration to mice at the doses of 0.05, 0.5, and 5 mg/kg. With a nominal dose ratio of 1:10:100; the ratio of the area under the curve for mouse Fc-mouse IL-10 and human Fc-human IL-10 was 1:181:1830 and 1:75:633, respectively. In contrast, recombinant mouse or human IL-10 proteins exhibited linear pharmacokinetics in mice. Compartmental analysis, using the Michaelis-Menten equation with the in vitro IL-10 receptor alpha binding affinity inputted as the K

Atherosclerosis (AS) is one of the most common vascular diseases. The endothelial injury theory indicates that atherosclerotic plaque is the result of endothelial cell injury. Recent studies have revealed that circRNAs are abnormally expressed in AS cell models, which are implicated in the regulation of various cell behaviors. In this study, we showed the downregulation of circNMD3 in AS, and studied its role in the model of endothelial cell injury by proliferation and apoptosis assay, caspase 3 activity assay, and ELISA. We also identified and validated its downstream targets by luciferase reporter assay, RNA pull-down experiment, Western blot, and RT-qPCR. CircNMD3 overexpression or miR-498 knockdown could inhibit the ox-LDL (oxidatively modified low-density lipoprotein)-induced injury in HUVEC (human umbilical vein endothelial cells), while the co-transfection of miR-498 mimic or siRNA targeting BAMBI (BMP and activin membrane bound inhibitor) attenuated the protective effect of circNMD3 overexpression. Overall, our data suggest that circNMD3 regulates the miR-498/BAMBI axis in endothelial cells to protect ox-LDL-induced damages. As a molecular sponge of miR-498, circNMD3 regulates the level of miR-498, which in turn modulates BAMBI expression and suppresses ox-LDL-induced injury in HUVECs.

Background: Copper complex has been gaining much attention in anticancer research as a targeted agent since cancer cells uptake more copper than non-cancerous cells. Our group synthesised a ternary copper complex, which is composed of 1,10-phenanthroline and tyrosine [Cu(phen)(L-tyr)Cl].3H20. These two payloads have been designed to cleave DNA and inhibit protein degradation system (proteasome) concurrently in cancer cells, making this copper complex a dual-target compound. Objective: The current study was carried out to investigate the mode of cell death and the role of autophagy induced by [Cu(phen)(L-tyr)Cl].3H20 in MCF-7 and MDA-MB-231 breast cancer cells. Methods: Growth inhibition of [Cu(phen)(L-tyr)Cl].3H20 towards MDA-MB-231 and human non-cancerous MCF10A breast cells was determined by MTT assay. Annexin-V-FITC/PI and cell cycle analysis were evaluated by flow cytometry. The expression of p53, Bax, caspase-9, caspase-7, caspase-3 and LC3 was determined using western blot analysis. The cells were then co-treated with hydroxychloroquine to ascertain the role of autophagy induced by [Cu(phen)(L-tyr)Cl].3H20. Results: [Cu(phen)(L-tyr)Cl].3H20 inhibited the growth of cancer cells dose-dependently with less toxicity towards MCF10A cells. Additionally, [Cu(phen)(L-tyr)Cl].3H20 induced apoptosis and cell cycle arrest towards MCF-7 and MDA-MB-231 breast cancer cells possibly via regulation of p53, Bax, caspase-9, caspase-3 and capase-7. The expression of LC3II was upregulated in both cancer cell lines upon treatment with [Cu(phen)(L-tyr) Cl].3H20, indicating the induction of autophagy. Co-treatment with autophagy inhibitor hydroxychloroquine significantly enhanced growth inhibition of both cell lines, suggesting that autophagy induced by [Cu(phen)(L-tyr) Cl].3H20 in both breast cancer cells promoted cell survival. Conclusion: [Cu(phen)(L-tyr)Cl].3H20 holds great potential to be developed for breast cancer treatment.

Using national multi-purpose regional geochemical survey (NMPRGS) data, this overview systematically summarizes the pollution levels and health risks posed by 8 heavy metals (As, Cd, Pb, Zn, Hg, Cu, Cr and Ni) in urban soils of 86 cities above the prefecture level in Yangtze River Economic Belt (YREB). Meanwhile, the spatial distribution and main sources of heavy metal pollutants in urban soils of key cities are described in detail. On a regional scale, Hg and Cd contamination in urban soils of YREB is most prominent, and As, Cu, Pb and Zn contamination exists in several cities, while Cr and Ni contamination is almost not shown. The type of industrialization and the history of urbanization affect the soil heavy metal pollution in majority cities, and the influence of geological background on the content of heavy metals in urban soils cannot be ignored. Specifically, the urban pollution of Cd, As, Pb and Zn is mainly concentrated in Hunan and Hubei Provinces, which are highly developed in mining industry, especially in Zhuzhou, Chenzhou, Huangshi and Xiangtan cities, while the major soil Hg pollution occurs in Zhejiang and Jiangsu Provinces with rapid economic development, where Shaoxing, Ningbo, Suzhou and Wuxi are the key polluted cities. Heavy metals in the urban soils investigated generally posed low non-carcinogenic and carcinogenic risks to the adults. However, the non-carcinogenic risk to minors in some cities (e.g., Chenzhou and Huangshi) should be given cautious attention.

Radioresistance is a common cause of treatment failure in many cancers, including non-small cell lung cancer (NSCLC). Circular RNA (circRNA) has been shown to be involved in the radiosensitivity of many cancers. However, the role and mechanism of circ_0007580 in the radiosensitivity of NSCLC remain unclear.The expression levels of circ_0007580, miR-598 and thrombospondin 2 (THBS2) were estimated by quantitative real-time PCR. The radiosensitivity of cells was measured using colony formation assay. Cell proliferation and apoptosis were assessed by performing cell counting kit 8 assay, colony formation assay, flow cytometry, and by detecting caspase-3 and caspase-9 activities. Protein expression was determined using western blot analysis.Our data showed that circ_0007580 was highly expressed and miR-598 was lowly expressed in radioresistant NSCLC tissues. Functional experiments suggested that circ_0007580 silencing could improve the radiosensitivity of cells by suppressing cell proliferation and increasing apoptosis. MiR-598 was confirmed to be a target of circ_0007580, and its inhibitor could reverse the regulation of circ_0007580 on the radiosensitivity of NSCLC cells. MiR-598 was found to target THBS2. The suppressive effect of miR-598 on the radiosensitivity of cells could be reversed by THBS2 overexpression. Additionally, circ_0007580 could sponge miR-598 to regulate THBS2. In vivo experiments showed that knockdown of circ_0007580 enhanced the radiosensitivity of NSCLC tumors.Our results revealed that circ_0007580 might be a target for improving the radiosensitivity of NSCLC, which was mainly achieved by regulating the miR-598/THBS2 axis.

Neuropathic pain (NP) results from a lesion or disease of the nervous system and accompanied by chronic pain, leading a serious public health issue and economic burden. In terms of the NP mechanisms remaining poorly understood, circular RNAs (circRNAs), owing to their high stability and evolutionary conservation, are expected to be used as potential therapeutic targets or diagnostic biomarkers. In this review, we concisely discuss the characteristics and biological functions of circRNAs. As emerging evidence we reviewed, deregulation of circRNAs (e.g., circ-Filip1l, circHIPK3, ciRS-7, circRNA.2837, circ-Ankib1 and circAnks1a) were involved in NP development. It suggested that specific circRNAs modulated through sponging their target miRNAs and thus regulated the homologous downstream mRNAs and proteins in neuropathic pain. These findings provide a theoretical basis for circRNAs use as biomarkers and therapeutic targets in neuropathic pain.

Purpose Triple pelvic osteotomy (TPO) is often performed to improve femoral head coverage, correct deformity, and stabilize the hip joint in a variety of pediatric orthopaedic conditions. After the TPO was first reported, many modifications were developed to simplify or improve the procedure, however, because of the specific anatomy with several critical nerves and vessels passing through the approaches, extensive exposure and prolonged intraoperative fluoroscopy are often required for TPO. This report introduces a novel, minimally-invasive surgical approach that minimizes the time of intraoperative fluoroscopy and size of the surgical incision, and reviews our experience. Methods A total of 48 hips in 43 patients with a mean age of 8.3±1.7 years (range: 6.0 to 12.2 y) were included in this study. Of these, 21 patients (22 hips) had Legg-Calve-Perthes disease (LCPD) and 22 patients (26 hips) had developmental dysplasia of the hip (DDH). The TPOs were performed using the novel, minimally-invasive TPO approach, with a mean postoperative follow-up of 38 months (range: 24 to 54 mo) in the DDH group and 44 months (range: 23 to 58 mo) in the LCPD group. The acetabular index (AI), femoral head migration rate (MP), center edge angle (CEA) and the Severin and Stulberg classification systems were used to evaluate the preoperative and postoperative results. SPSS software was used to analyze the data. Results The AI decreased from 33.8 degrees±9.2 to 2.9 degrees±10.1, the lateral CEA increased from -10.8 degrees±23.8 to 34.1 degrees±9.9, and the femoral head MP decreased from 64.0%±19.8% to 1.1%±2.6% in the DDH group at last follow-up, indicating significant improvement. The AI decreased from 20.8 degrees±4.7 to -1.3 degrees±7.3, the lateral CEA increased from 6.8 degrees±11.5 to 42.3 degrees±6.4, and the femoral head MP decreased from 42.2%±13.0% to 1.3%±3.3% in the LCPD group at last follow-up, also indicating significant improvement. Conclusion This approach can simplify the TPO, making the complex operation safer, more effective, and capable of achieving satisfactory correction.

Inhibition of TGFβ signaling in concert with a checkpoint blockade has been shown to provide improved and durable antitumor immune response in mouse models. However, on-target adverse cardiovascular effects have limited the clinical use of TGFβ receptor (TGFβR) inhibitors in cancer therapy. To restrict the activity of TGFβR inhibitors to tumor tissues and thereby widen the therapeutic index, a series of tumor-activated prodrugs of a selective small molecule TGFβR1 inhibitor 1 were prepared by appending 1 to a serine protease substrate and a half-life extension fatty acid carbon chain. The prodrugs were shown to be selectively metabolized in tumor tissues relative to the heart and blood and demonstrated a prolonged favorable increase in the tumor-to-heart ratio of the active drug in tissue distribution studies. Once-weekly administration of the most tissue-selective compound 10 provided anti-tumor efficacy comparable to the parent compound and reduced systemic exposure of the active drug.

Objective To review the outcomes of surgical management in the pediatric patients with extremity chondroblastoma. Especially the risk factors of recurrence and growth disorder. And discuss a potential method to decrease the rate of growth disorder by preventing the premature physeal closure. Methods Fifteen girls and twenty‐seven boys aged from two to 14 years (mean, 11 years) with histologically proven chondroblastoma, who presented from January 2011 to June 2018 at our Hospital, were retrospectively reviewed. Clinical data, radiographic images, histological findings, treatment, functional outcomes, and local recurrence rate were analyzed. Surgical treatment included complete curettage of the tumor and the walls of the lesion followed by bone grafting, No adjuvant methods were used. Recurrence was defined as a return of symptoms and an expansion radiolucency at the operated site. It was confirmed by the histopathological analysis. When recurrence was diagnosed, the medical data were analyzed to detect the effect of different factors on local recurrence. Functional outcome was measured according to Sailhan's functional criteria, designed to provide a standardized method of assessing pediatric chondroblastoma patient postoperatively. Results The proximal part of the femur was the most frequently involved site. All the patients had at least 24 months of follow‐up; mean duration was 30 months (range, 24–60 months). The local recurrence rate was 9.5%. Three resolved after repeat surgeries without further recurrence, one had a second recurrence and received another more aggressive curettage. Local recurrence of chondroblastoma was associated with age (P 0.05). No pulmonary metastasis was noted at latest follow‐up. Five patients suffered from premature closure of physis due to physis injury. Thirty‐one patients (73.8%) had a good outcome, and all returned to normal unrestricted activities. Six patients (14.3%) had a fair outcome due to occasional pain, asymmetric range of motion, or radiographic joint changes without arthritis. And five patients (11.9%) had a poor outcome because of chronic pain, loss of joint motion impairing normal life activities, or a limb‐length discrepancy and limp. Conclusions Aggressive curettage and bone grafting resulted in local control and good outcomes in most pediatric patients. Being less than 12 years of age was the risk factor for recurrence. For those growing patients, premature physeal closure was observed after the curettage, interpositional technique with PMMA would be a good choice for prevention., Chondroblastoma occurs most frequently in the proximal femur with significant male predilection. Aggressive curettage and bone grafting resulted in local control and good outcomes in most pediatric patients. Being less than 12 year of age was the risk factor for recurrence. For those growing patients, premature physeal closure was observed after the curettage, interpositional technique with PMMA would be a good choice for prevention.

Background SENP1 (sentrin/small ubiquitin‐like modifier‐specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload‐induced cardiac remodeling and dysfunction. Methods and Results We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac‐specific SENP1 knockdown markedly exacerbated transverse aortic constriction‐induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus‐mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1‐JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte‐specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy‐promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post‐transverse aortic constriction. Conclusions Our study provided evidence that SENP1 protected against pressure overload‐induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.

This paper is aimed at investigating the efficacy of combining internal fixation using prefabricated rib-locking titanium plate with ultrasound-guided thoracic paravertebral nerve blockade in treating multiple rib fractures among the elderly.Retrospective analysis of 221 elderly patients with multiple rib fractures treated from February 2016 to November 2020. According to whether surgery was performed, they were divided into the plate-blockage combination group (surgical group, 102 cases) and conservative treatment group (non-surgical group, 119 cases). The surgical group consisted of 58 males and 44 females aged from 60 to 85 years old, with an average of (67.2±3.6 ) years old, who suffered from 3 to 12 rib fractures with an average of (5.3±2.1) fractures. The non-surgical group consisted of 66 males and 53 females aged from 60 to 84 years old with an average of (66.8±3.2) years old, who suffered from 2 to 11 rib fractures with an average of(6.1±2.3) fractures. The clinical data, efficacies observed, and complications associated with both groups were compared and analyzed.There was no significant difference in preoperative clinical data between two groups (For elderly patients with severe multiple rib fractures, the proposed plate-blockade combination can timely and effectively relieve pain, restore thoracic stability, shorten hospital stay, and reduce the incidence of complications such as pulmonary infections and acute respiratory distress syndrome(ARDS) compared with non-surgical treatments. Prefabricated rib-locking titanium plates have proved to demonstrate high clinical efficacy in treating multiple rib fractures among the elderly.

Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.

Developing Type-I photosensitizers is considered as an efficient approach to overcome the deficiency of traditional photodynamic therapy (PDT) for hypoxic tumors. However, it remains a challenge to design photosensitizers for generating reactive oxygen species by the Type-I process. Herein, we report a series of α,β-linked BODIPY dimers and a trimer that exclusively generate superoxide radical (O2-. ) by the Type-I process upon light irradiation. The triplet formation originates from an effective excited-state relaxation from the initially populated singlet (S1 ) to triplet (T1 ) states via an intermediate triplet (T2 ) state. The low reduction potential and ultralong lifetime of the T1 state facilitate the efficient generation of O2-. by inter-molecular charge transfer to molecular oxygen. The energy gap of T1 -S0 is smaller than that between 3 O2 and 1 O2 thereby precluding the generation of singlet oxygen by the Type-II process. The trimer exhibits superior PDT performance under the hypoxic environment.

Growing evidence has indicated that circular RNAs (circRNAs) play a pivotal role as functional RNAs in diverse cancers. However, most circRNAs involved in esophageal squamous cell carcinoma (ESCC) remain undefined, and the underlying molecular mechanisms mediated by circRNAs are largely unclear. Here, we screened human circRNA expression profiles in ESCC tissues and found significantly increased expression of hsa_circ_0000277 (termed circPDE3B) in ESCC tissues and cell lines compared to the normal controls. Moreover, higher circPDE3B expression in patients with ESCC was correlated with advanced tumor-node-metastasis (TNM) stage and dismal prognosis. Functional experiments demonstrated that circPDE3B promoted the tumorigenesis and metastasis of ESCC cells in vitro and in vivo. Mechanistically, bioinformatics analysis, a dual-luciferase reporter assay, and anti-AGO2 RNA immunoprecipitation showed that circPDE3B could act as a competing endogenous RNA (ceRNA) by harboring miR-4766-5p to eliminate the inhibitory effect on the target gene laminin α1 (LAMA1). In addition, LAMA1 was significantly upregulated in ESCC tissues and was positively associated with the aggressive oncogenic phenotype. More importantly, rescue experiments revealed that the oncogenic role of circPDE3B in ESCC is partly dependent on the miR-4766-5p/LAMA1 axis. Furthermore, bioinformatics analysis combined with validation experiments showed that epithelial-mesenchymal transition (EMT) activation was involved in the oncogenic functions of the circPDE3B–miR-4766-5p/LAMA1 axis in ESCC. Taken together, we demonstrate for the first time that the circPDE3B/miR-4766-5p/LAMA1 axis functions as an oncogenic factor in promoting ESCC cell proliferation, migration, and invasion by inducing EMT, implying its potential prognostic and therapeutic significance in ESCC.

Thin-film electronics pliably laminated onto the epidermis for noninvasive, specific, and multifunctional sensing are ideal wearable systems for health monitoring and information technologies. However, it remains a critical challenge to fabricate ultrathin and compliant skin-like sensors with high imperceptibility and sensitivities. Here we report a design of conductive hydrogen-substituted graphdiyne (HsGDY) nanofilms with conjugated porous structure and inherent softness for on-skin sensors that allow minimization of stress and discomfort with wear. Dominated by the subtle deformation-induced changes in the interdomain tunneling conductance, the engineered HsGDY sensors show continuous and accurate results. Real-time noninvasive spatial mapping of dynamic/static strains in both tensile/compressive directions monitors various body motions with high sensitivity (GF ∼22.6, under 2% strain), fast response (∼60 ms), and long-term durability (∼5000 cycles). Moreover, such devices can dynamically distinguish between the temperature difference and frequency of air inhaled and exhaled through the nostril, revealing a quantitative assessment of the movement/health of the human body. The proof-of-concept strategy provides an alternative route for the design of next-generation wearable organic bioelectronics with multiple electronic functionalities.

This study aimed to identify potential essential genes and pathways in diabetes of the exocrine pancreas (DEP) and explore possible molecular mechanisms. The array dataset GSE76895 was downloaded from the Gene Expression Omnibus database. Pancreatic tissue samples from 20 Diabetes of the exocrine pancreas and 32 nondiabetic individuals were selected for analysis. GEO2R analyzed differentially expressed genes (DEGs) in the 2 groups. Gene ontology annotation, Kyoto Encyclopedia of Genes Genomes and Reactome pathway enrichment analyses and Gene Set Enrichment Analysis were performed in this study. Protein-protein interaction (PPI) networks were constructed using Cytoscape software, and core networks were identified using MCODE plugins. A total of 62 genes, including 59 up-regulated and 3 down-regulated genes, were differentially expressed in DEP samples compared with nondiabetic patients. PPI network with 53 nodes and 138 edges was established. HLA-DRA is identified as the central gene of the PPI network and maybe a marker gene for DEP. Furthermore, up-regulated DEGs are mainly enriched in pathways related to the immune system and infection. The results of this study suggest that HLA-DRA and immune system pathways may play essential roles in DEP.

The main purpose of the study was to evaluate the activity and selectivity ofWe established a subcutaneous tumor model, and usedThere was a significant positive correlation (r = 0.88, p 0.05) between the microvascular density (41.20 ± 18.60) and tumor to nontumor ratio (T/M), which was based on the value ofBoth

PurposeThe Corona Virus Disease 2019 (COVID-19) pandemic has become a challenge of world. The latest research has proved that Xuanfei Baidu granule (XFBD) significantly improved patient’s clinical symptoms, the compound drug improves immunity by increasing the number of white blood cells and lymphocytes, and exerts anti-inflammatory effects. However, the analysis of the effective monomer components of XFBD and its mechanism of action in the treatment of COVID-19 is currently lacking. Therefore, this study used computer simulation to study the effective monomer components of XFBD and its therapeutic mechanism.MethodsWe screened out the key active ingredients in XFBD through TCMSP database. Besides GeneCards database was used to search disease gene targets and screen intersection gene targets. The intersection gene targets were analyzed by GO and KEGG. The disease-core gene target-drug network was analyzed and molecular docking was used for verification. Molecular dynamics simulation verification was carried out to combine the active ingredient and the target with a stable combination. The supercomputer platform was used to measure and analyze the number of hydrogen bonds, the binding free energy, the stability of protein target at the residue level, the solvent accessible surface area, and the radius of gyration.ResultsXFBD had 1308 gene targets, COVID-19 had 4600 gene targets, the intersection gene targets were 548. GO and KEGG analysis showed that XFBD played a vital role by the signaling pathways of immune response and inflammation. Molecular docking showed that I-SPD, Pachypodol and Vestitol in XFBD played a role in treating COVID-19 by acting on NLRP3, CSF2, and relieve the clinical symptoms of SARS-CoV-2 infection. Molecular dynamics was used to prove the binding stability of active ingredients and protein targets, CSF2/I-SPD combination has the strongest binding energy.ConclusionFor the first time, it was found that the important active chemical components in XFBD, such as I-SPD, Pachypodol and Vestitol, reduce inflammatory response and apoptosis by inhibiting the activation of NLRP3, and reduce the production of inflammatory factors and chemotaxis of inflammatory cells by inhibiting the activation of CSF2. Therefore, XFBD can effectively alleviate the clinical symptoms of COVID-19 through NLRP3 and CSF2.

Scholars are divided over whether narrative/storytelling occupies a central position in health-related behaviour or in the health-related issues discussed on social media platforms. This study explored Chinese COVID-19 vaccination expressions on Douyin, China’s biggest short-video sharing social media platform, and found that narration is still the most important tool employed by Chinese users when talking about COVID-19 vaccinations on Douyin, emphasizing nationalism and widespread optimism. Most of the narratives employed by Chinese users come from a first-person perspective. Nationalism, as manifested in the support expressed for national policies, rather than the external platform characteristics of memetics, makes the Chinese users’ expressions about COVID-19 vaccinations similar on Douyin. Douyin seems to have become a ‘pilgrimage platform’ for the Chinese public to express their patriotic sentiment and their trust in the country and the government.

Aims The objective of this study was to evaluate the clinical and radiological outcomes of patients younger than six months of age with developmental dysplasia of the hip (DDH) managed by either a Pavlik harness or Tübingen hip flexion splint. Methods Records of 251 consecutive infants with a mean age of 89 days (SD 47), diagnosed with DDH between January 2015 and December 2018, were retrospectively reviewed. Inclusion criteria for patients with DDH were: younger than 180 days at the time of diagnosis; ultrasound Graf classification of IIc or greater; treatment by Pavlik harness or Tübingen splint; and no prior treatment history. All patients underwent hip ultrasound every seven days during the first three weeks of treatment and subsequently every three to four weeks until completion of treatment. If no signs of improvement were found after three weeks, the Pavlik harness or Tübingen splint was discontinued. Statistical analysis was performed. Results The study included 251 patients with Graf grades IIc to IV in 18 males and 233 females with DDH. Mean follow-up time was 22 months (SD 10). A total of 116 hips were graded as Graf IIc (39.1%), nine as grade D (3.0%), 100 as grade III (33.7%), and 72 as grade IV (24.2%). There were 109 patients (128 hips) in the Pavlik group and 142 patients (169 hips) in the Tübingen group (p = 0.227). The Tübingen group showed a 69.8% success rate in Graf III and Graf IV hips while the success rate was significantly lower in the Pavlik group, 53.9% (p = 0.033). For infants older than three months of age, the Tübingen group showed a 71.4% success rate, and the Pavlik group a 54.4% success rate (p = 0.047). Conclusion The Tübingen splint should be the preferred treatment option for children older than three months, and for those with severe forms of DDH such as Graf grade III and IV, who are younger than six months at time of diagnosis. The Tübingen hip flexion splint is a valid alternative to the Pavlik harness for older infants and those with more severe DDH. Cite this article: Bone Joint J 2021;103-B(5):991–998.

Background As the COVID-19 pandemic has posed substantial impacts on individual's daily routine and psychological state. For the first time at great scale, Chinese college students had their educational activities moved online in spring 2020. Due to this unexpected isolation and unconventional learning method, their mental health following returning to school is worth investigating. Methods Between June 1 and June 15, 2020, a total of 8,921 returning college students’ mental health status were assessed using instruments designed for psychiatric disorders, namely the 9-Item Patient Heath Questionnaire (PHQ-9), 7-Item Generalized Anxiety Disorder Scale (GAD-7), 6-Item Impact of Event Scale (IES-6), Youth Self Rating Insomnia Scale (YSIS), and self-developed questionnaire. Results Our results showed that 8.7%, 4.2%, 10.5%, and 6.1% of the participants experienced depression, anxiety, acute stress, and insomnia, respectively, with a total of 19.8% reporting having at least one psychiatric symptom following their return to school. Sophomore and Senior year, and presence of previous psychiatric conditions contribute to the increased occurrence of psychiatric issues. The level of impact by COVID-19 on one's daily functioning is also positively associated with poor mental health. Conclusions Our findings suggested no significant increase in the prevalence of psychiatric symptoms, following the first batch of students’ return to school. These findings aim to complement the current understanding of the psychiatric impact of COVID-19 on students and assist school principals to plan their return-to-school approaches in a mental-health sensitive way.

The androgen receptor (AR) is expressed in prostate fibroblasts in addition to normal prostate epithelial cells and prostate cancer (PCa) cells. Moreover, AR activation in fibroblasts dramatically influences prostate cancer (PCa) cell behavior. Androgen deprivation leads to deregulation of AR downstream target genes in both fibroblasts and PCa cells. Here, we identified LIM domain only 2 (LMO2) as an AR target gene in prostate fibroblasts using ChIP-seq and revealed that LMO2 can be repressed directly by AR through binding to androgen response elements (AREs), which results in LMO2 overexpression after AR deactivation due to normal prostate fibroblasts to cancer-associated fibroblasts (CAFs) transformation or androgen deprivation therapy. Next, we investigated the mechanisms of LMO2 overexpression in fibroblasts and the role of this event in non-cell-autonomous promotion of PCa cells growth in the androgen-independent manner through paracrine release of IL-11 and FGF-9. Collectively, our data suggest that AR deactivation deregulates LMO2 expression in prostate fibroblasts, which induces castration resistance in PCa cells non-cell-autonomously through IL-11 and FGF-9.

Clarifying the signaling pathway associated with nitric oxide (NO) and glutathione (GSH) in cardiovascular disease therapy is important for understanding its physiological and pathological processes but is challenging due to the lack of efficient analytical techniques. Herein, we report a BODIPY-based fluorescent probe for recognition of NO and GSH in sequence with high sensitivity and selectivity. The probe exhibits turn-on fluorescence triggered by NO, followed by red-shifted emission in the presence of GSH. The sequentially activated mechanism allows the visualization of NO-induced GSH upregulation in drug-treated endothelial cells and zebrafish for the first time, revealing a signal pathway during the therapy. We hope that it can be used as a convenient and efficient tool for the study of the interplay between NO and GSH and for the screening of effective drugs for cardiovascular disease therapy.

Background:. Texture analysis (TA) can quantify intra-tumor heterogeneity using standard medical images. The present study aimed to assess the application of positron emission tomography (PET) TA in the differential diagnosis of gastric cancer and gastric lymphoma. Methods:. The pre-treatment PET images of 79 patients (45 gastric cancer, 34 gastric lymphoma) between January 2013 and February 2018 were retrospectively reviewed. Standard uptake values (SUVs), first-order texture features, and second-order texture features of the grey-level co-occurrence matrix (GLCM) were analyzed. The differences in features among different groups were analyzed by the two-way Mann-Whitney test, and receiver operating characteristic (ROC) analysis was used to estimate the diagnostic efficacy. Results:. InertiaGLCM was significantly lower in gastric cancer than that in gastric lymphoma (4975.61 vs. 11,425.30, z = −3.238, P = 0.001), and it was found to be the most discriminating texture feature in differentiating gastric lymphoma and gastric cancer. The area under the curve (AUC) of inertiaGLCM was higher than the AUCs of SUVmax and SUVmean (0.714 vs. 0.649 and 0.666, respectively). SUVmax and SUVmean were significantly lower in low-grade gastric lymphoma than those in high grade gastric lymphoma (3.30 vs. 11.80, 2.40 vs. 7.50, z = −2.792 and −3.007, P = 0.005 and 0.003, respectively). SUVs and first-order grey-level intensity features were not significantly different between low-grade gastric lymphoma and gastric cancer. EntropyGLCM12 was significantly lower in low-grade gastric lymphoma than that in gastric cancer (6.95 vs. 9.14, z = −2.542, P = 0.011) and had an AUC of 0.770 in the ROC analysis of differentiating low-grade gastric lymphoma and gastric cancer. Conclusions:. InertiaGLCM and entropyGLCM were the most discriminating features in differentiating gastric lymphoma from gastric cancer and low-grade gastric lymphoma from gastric cancer, respectively. PET TA can improve the differential diagnosis of gastric neoplasms, especially in tumors with similar degrees of fluorodeoxyglucose uptake.

Transforming growth factor beta (TGF-β) is a pleiotropic cytokine that has a wide array of biological effects. For decades, tumor biology implicated TGF-β as an attractive therapeutic target due to its immunosuppressive effects. Toward this end, multiple pharmaceutical companies developed a number of drug modalities that specifically target the TGF-β pathway. BMS-986260 is a small molecule, selective TGF-βR1 kinase inhibitor that was under preclinical development for oncology. In vivo studies across mouse, rat, dog, and monkey and cryopreserved hepatocytes predicted human pharmacokinetics (PK) and distribution of BMS-986260. Efficacy studies of BMS-986260 were undertaken in the MC38 murine colon cancer model, and target engagement, as measured by phosphorylation of SMAD2/3, was assessed in whole blood to predict the clinical efficacious dose. The human clearance is predicted to be low, 4.25 ml/min/kg. BMS-986260 provided a durable and robust antitumor response at 3.75 mg/kg daily and 1.88 mg/kg twice-daily dosing regimens. Phosphorylation of SMAD2/3 was 3.5-fold less potent in human monocytes than other preclinical species. Taken together, the projected clinical efficacious dose was 600 mg QD or 210 mg BID for 3 days followed by a 4-day drug holiday. Mechanism-based cardiovascular findings in the rat ultimately led to the termination of BMS-986260. This study describes the preclinical PK characterization and pharmacodynamics-based efficacious dose projection of a novel small molecule TGF-βR1 inhibitor.

To investigate the possible role of physical activity (PA) on sleep disturbance in breast cancer patients. Literature in PubMed, Embase, and the Cochrane Library was systematically searched until January 30, 2020. Randomized controlled trials that focused on the role of PA interventions on sleep disturbance were selected. The main outcome measures included the global Pittsburgh Sleep Quality Index (PSQI) score and PSQI subscales. Subgroup analysis was performed based on the study area and intervention time. The stability and authenticity of the results were measured by sensitivity analysis and publication bias analysis, respectively. Six articles were included in this meta-analysis. There were no significant differences in global PSQI scores between the PA intervention group and the usual care group (P = 0.057). As for PSQI subscales, PA intervention could improve sleep quality (weighted mean difference = 0.22; 95% confidence interval 0.04–0.40; P = 0.018). There were no significant differences in sleep duration, sleep medication, sleep latency, habitual sleep efficiency, and daytime dysfunction between the two groups (all P > 0.05). PA serves as an effective intervention to improve sleep quality.

Although human/eukaryotic ribosomal protein L14 (RPL14/eL14) is known to be associated with a variety of cancers, its role in nasopharyngeal carcinoma (NPC) remains unclear. The aim of this study was to explore the impact of RPL14(eL14) in NPC. The results of quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemical staining revealed that the expression of RPL14(eL14) significantly reduced in NPC tissues and cells. Furthermore, the protein expression of RPL14(eL14) was linked to NPC-related clinical pathological features, including the T and N classification of Tumor Node Metastasis (TNM) staging (all p, Graphical Abstract

Defining the precise relationship between resistance mutations and quantitative phenotypic drug susceptibility testing will increase the value of whole-genome sequencing (WGS) for predicting tuberculosis drug resistance. However, a large number of WGS data sets currently lack corresponding quantitative phenotypic data-the MICs. Using MYCOTBI plates, we determined the MICs to nine antituberculosis drugs for 154 clinical multidrug-resistant tuberculosis isolates from the Shenzhen Center for Chronic Disease Control in Shenzhen, China. Comparing MICs with predicted drug-resistance profiles inferred by WGS showed that WGS could predict the levels of resistance to isoniazid, rifampicin, streptomycin, fluoroquinolones, and aminoglycosides. We also found some mutations that may not be associated with drug resistance, such as EmbB D328G, mutations in the

Review and analyze the characteristics of bone marrow cell morphology in patients with Epstein-Barr virus (EBV) infection, and explore the diagnostic value of bone marrow cell morphology for the early identification of EBV infection.A total of 33 patients with EBV-DNA positive detection in the First Affiliated Hospital of Guangxi Medical University from January 2018 to May 2021 were collected as the research objects. Bone marrow cell morphology and peripheral blood cell analysis were performed, and the significance in disease diagnosis was analyzed by statistical methods.The sampling satisfaction of 33 patients with EBV infection was 100%. In the clinical diagnosis of all cases, 7 cases were IM, 17 cases were EBV-HLH, 3 cases were lymphoma, 2 cases were EBV-associated lymphoid hyperplasia, and 4 cases were not diagnosed. Among them, 31 patients had active bone marrow hyperplasia or above, 26 patients had active granulocytic hyperplasia or above, 21 patients had active erythroid hyperplasia or above, and 17 cases of megakaryocyte production platelet function decreased. The abnormal components of bone marrow mainly indude atypical lymphocyte cells (33 cases), hemophagocytic cells (22 cases), abnormal histiocyte (10 cases).According to the proliferation of granulocytes, erythrocytes and megakaryocytes in the bone marrow, and the emergence of abnormal components such as atypical lymphocytes, hemophagocyte, abnormal histiocyte. Bone marrow cell morphological examination can indicate the possibility of EBV infection, which is certain diagnostic value for early identification of EBV infection.EB病毒感染患者骨髓细胞形态学特点分析.回顾分析EB病毒（EBV）感染患者的骨髓细胞形态学的特征，探讨骨髓细胞形态学对早期识别EBV感染的诊断价值.收集广西医科大学第一附属医院2018年1月至2021年5月EBV-DNA检测阳性的患者33例作为研究对象，进行骨髓细胞形态学检查、外周血细胞分析，用统计学方法分析其在疾病诊断中的意义.EBV感染患者取材33例，满意度100%。临床诊断IM 7例，EBV-HLH 17例，淋巴瘤3例，EBV相关淋巴增殖性疾病2例，未能明确诊断4例。其中31例出现骨髓增生活跃或以上，26例出现粒系增生活跃或以上，21例出现红系增生活跃或以上，17例出现巨核细胞产血小板功能减低。骨髓异常成分主要有异型淋巴细胞（33例），噬血细胞（22例），异常组织细胞（10例）.根据骨髓粒、红、巨三系造血细胞增生情况的改变，以及异型淋巴细胞细胞、噬血细胞、异常组织细胞等异常成分的出现，骨髓细胞形态学检查可以提示感染EBV的可能性，对早期识别EBV感染有一定的诊断价值.

Accurate prediction of human clearance (CL) and volume of distribution at steady state (V

miR‐30d‐5p suppresses cell proliferation, G1/S transition and autophagy, and promotes apoptosis by targeting autophagy‐related gene 5 in renal cell carcinoma., Previous reports have shown that miR‐30d‐5p functions as a tumor suppressor in prostate cancer and gallbladder carcinoma, but its role in renal cell carcinoma (RCC) remains elusive. This study was designed to explore the functional role of miR‐30d‐5p in proliferation and autophagy of RCC. Our results show that miR‐30d‐5p is significantly down‐regulated in RCC tissues compared with normal tissues. miR‐30d‐5p overexpression suppressed cell proliferation, cell‐cycle G1/S transition and autophagy, but promoted apoptosis in RCC cell lines (786‐O and ACHN). Intriguingly, autophagy‐related gene 5 (ATG5) was directly targeted by miR‐30d‐5p, as shown using luciferase reporter assay and biotin‐avidin pull‐down assay. Moreover, overexpression of ATG5 attenuated the inhibitory effect of miR‐30d‐5p on proliferation and autophagy in 786‐O cells. These results suggest that miR‐30d‐5p suppresses proliferation and autophagy in RCC cells by targeting ATG5, and this pathway may be a suitable basis for the design of novel cancer therapeutics.

Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven-based, and risk-based approach for selecting FIH starting doses.

De novo cancer-targeting immunostimulatory peptides have been designed and developed as synthetic antibody mimics. A series of bifunctional peptides incorporating NKp30-binding and NK-cell-activating domains were synthesized as linear dimers and then extended into branching trimeric peptides by the incorporation of GRP78-targeting and tumor-cell-binding sequences. A selected trimeric peptide from this small set of peptides displayed binding capabilities on GRP78+ HepG2 and A549 target cells. Cell binding diminished in the presence of an anti-GRP78 peptide blocker, thus suggesting GRP78-binding dependence. Similarly, the selected trimeric peptide was also found to exhibit NK cell binding in an NKp30-dependent manner, which translated into NK cell activation as indicated by cytokine secretion. In co-culture, fluorescence microscopy revealed that the target GFP-expressing A549 cells were visibly associated with the effector NK cells when pre-activated with lead trimeric peptide. Accordingly, A549 cells were found to be compromised, as evidenced by the loss of GFP signal and notable detection of early-/late-stage apoptosis. Investigation of the immunological markers related to toxicity revealed detectable secretion of pro-inflammatory cytokines and chemokines, including IFN-γ, TNF-α, and IL-8. Furthermore, administration of peptide-activated NK cells into A549-tumor-bearing mice resulted in a consistent decrease in tumor growth when compared to the untreated control group. Taken together, the identification of a lead trimeric peptide capable of targeting and activating NK cells' immunotoxicity directly towards GRP78+ /B7H6- tumors provides a novel proof-of-concept for the development of cancer-targeting immunostimulatory peptide ligands that mimic antibody-targeting and -activating functions related to cancer immunotherapy applications.

The outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread worldwide. This study sought to share our experiences with in-hospital management and outcomes of acute myocardial infarction (AMI) during the COVID-19 pandemic. We retrospectively analyzed consecutive AMI patients, including those with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI), from February 1, 2020, to April 15, 2020 (during the COVID-19 pandemic), and from January 1, 2019, to December 31, 2019 (before the COVID-19 pandemic), respectively. Fifty-three AMI patients (31 STEMI, 22 NSTEMI) during the COVID-19 pandemic were matched to 53 AMI patients before the pandemic. Baseline characteristics were comparable between the matched patients. STEMI patients during the COVID-19 pandemic had a longer delay time, less primary or remedial PCI and more emergency thrombolysis than those before the pandemic. Less coronary angiography and stenting were performed in AMI patients during the COVID-19 pandemic than before the pandemic. There were no statistically significant differences in the clinical outcomes between the matched patients. However, STEMI patients during the COVID-19 pandemic had a 4-fold (12.9% vs. 3.2%) increase in all-cause mortality rate compared with those before the pandemic. AMI combined with COVID-19 infection was associated with higher rates of mortality than AMI alone. This study demonstrates that the COVID-19 pandemic results in significant reperfusion delays in STEMI patients and has a marked impact on the treatment options selection in AMI patients. The mortality rate of STEMI patients exhibits an increasing trend during the pandemic of COVID-19.

Tubulin polymerization promoting protein family member 3 (TPPP3) is a kind of protein that can mediate the dynamics and stability of microtubules. However, the correlations of TPPP3 between prognosis and immune infiltrates in different tumors are still unclear. The analysis of TPPP3 expression was performed via Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) website. We also used GEPIA to assess the impact of TPPPT3 on clinical outcomes. The related pathways involved in TPPP3 were analyzed by gene-set enrichment analysis (GSEA), and the correlation between TPPP3 and immune infiltration was studied by Tumor Immune Estimation Resource2.0 (TIMER 2.0). The TPPP3 expression was significantly reduced in head and neck squamous carcinoma (HNSC) compared to adjacent tissues. In addition, the low expression of TPPP3 in HNSC was significantly associated with prognosis. The pathways closely related to the low expression of TPPP3 are “Antigen Processing and Presentation,” “Primary Immunodeficiency,” and so on. The TPPP3 expression was negatively correlated with the level of CD8+ T cell, B cell, and myeloid dendritic cell infiltration in HNSC. The TPPP3 expression is closely related to multiple immunomarkers in CD8+ T cell and Myeloid dendritic cells. These data indicate that TPPP3 is associated with multiple cancers and involves multiple immune-related pathways, and TPPP3 is associated with immune infiltration levels. Besides, the TPPP3 expression may help regulate tumor-associated CD8 + T cells, DC cells in HNSC. We conclude TPPP3 can be considered as a biomarker for predicting head and neck squamous cell carcinoma prognosis and immune infiltration.

Background Anastomotic leakage is common and life-threatening complication after esophagectomy. The management of esophageal anastomotic leakage remains challenging. We aimed to determine the safety, feasibility and efficacy of three-tube method and covered metallic stent placement for the management of anastomotic leakage. Methods Twenty-six consecutive patients with anastomotic leakage were treated using three-tube method and covered metallic stent and the medical records were retrospectively assessed. All patients received placement of abscess drainage tube, jejunal feeding tube and gastrointestinal decompression tube as well as esophageal covered stent, followed by continue abscess drainage, nutritional support and anti-inflammatory treatment. Tubes and esophageal stents will be removed once anastomotic leakage heals. Results The procedure was technically successful in 23 patients (95.8%). A total of 31 covered stents were used. Esophageal stents and abscess drainage tubes were successfully removed from 14 patients. The median retention duration was 2.3 months and 2.6 months for stent and abscess drainage tubes, respectively. No perioperative death, esophageal rupture, massive hemorrhage, or other severe complications were observed during procedures. The abscess cavity had markedly decreased in 8 patients or disappeared in 16 cases. During follow-up, 8 patients died of cancer recurrence and 2 patients died of severe pulmonary infection. The 1-, 3-, 5-year survival rates were 60.1, 51.5 and 51.5%, respectively. Conclusion Three-tube method and covered metallic stent placement is safe, feasible and efficacious for treatment of anastomotic leakage after esophagectomy.

Genetic analysis for germline mutations of RET proto‐oncogene has provided a basis for individual management of medullary thyroid carcinoma (MTC) and pheochromocytoma. Most of compound mutations have more aggressive phenotypes than single point mutations, but the compound C634Y/V292M variant in MTC has never been reported. Thus, we retrospectively investigated synergistic effect of C634Y and V292M RET germline mutations in family members with multiple endocrine neoplasia type 2A. Nine of 14 family members in a northern Chinese family underwent RET mutation screening using next‐generation sequencing and PCR followed by direct bidirectional DNA sequencing. Clinical features of nine individuals were retrospectively carefully reviewed. In vitro, the scratch‐wound assay was used to investigate the difference between the cells carrying different mutations. We find no patients died of MTC. All 3 carriers of the V292M variant were asymptomatic and did not have biochemical or structural evidence of disease (age: 82, 62 and 58). Among 4 C634Y mutation carriers, 2 patients had elevated calcitonin with the highest (156 pg/mL) in an 87‐year‐old male. Two carriers of compound C634Y/V292M trans variant had bilateral MTC with pheochromocytoma or lymph node metastasis (age: 54 and 41 years, respectively). Further, the compound C634Y/V292M variant had a faster migration rate than either single point mutation in vitro (P

Background Previous studies have suggested that the right anterior insula (rAI) plays a vital role in salience processing and stress-related disorders. In this study, we aimed to investigate the relationship between rAI functional connectivity changes and individual differences in cortisol responses after acute stress, in order to provide insights into psychiatric illness vulnerabilities. Methods Thirty-five young men were enrolled in a randomized, counterbalanced two-session study, with aversive movie clip combined with electrical shocks as stress stimulation and the neutral movie clip as control stimulation. Resting-state fMRI data was acquired after movie exposure. The rAI was chosen as seed for functional connectivity analysis. We then examined the effect of acute stress on rAI functional connectivity and its association with individuals’ cortisol response. Results We found decreased rAI functional connectivity in the fronto-parietal regions, but increased functional connectivity in the visual and somatosensory areas following acute stress. Moreover, stress-induced cortisol response was significantly positively correlated with the rAI functional connectivity in the medial prefrontal cortex, and negatively correlated with the orbital-frontal cortex, lingual gyrus, and middle temporal gyrus. Limitations Only young Chinese males without any trauma experience were recruited in this study. Conclusions The results suggested tight link between specific rAI functional connectivity alterations and individual stress reactivity, which may help elucidate the potential neurobiological mechanism underlying vulnerability to stress-related disorders.

Postoperative delirium (POD) is a common, but severe complication in elderly patients undergoing surgery for colorectal cancer, but the prevalence and potential risk factors for POD were not well established. Therefore, a meta-analysis was preformed to clarify the prevalence and risk factors of POD in patients undergoing surgery for colorectal cancer. PubMed, Embase, and the Cochrane Library were systematically searched on August 2019. Studies were included if they reported the prevalence and risk factors of POD in patients undergoing colorectal cancer surgery. The guidelines for critically appraising studies of prevalence or incidence of a health problem were used to assess the quality of included studies. Pooled odds ratios (ORs) for individual risk factors were estimated using the Mantel-Haenszel methods in random effect model. Sensitive analyses based on different inclusion criteria were conducted to explore whether the current meta-analysis was enough credible and robust. Seventeen studies totaling 4472 patients undergoing colorectal cancer surgery were included. The pooled prevalence of POD is 14% (95% CI = 12–17%). Twelve significant risk factors were identified in pooled analysis including older age (OR = 1.10), sex (OR = 1.87), history of psychiatric disease (OR = 6.47), comorbidities (OR = 2.17), prognostic nutritional index (OR = 1.12), physical status (OR = 1.27), American Society of Anesthesiologists Score (ASA Scores) (OR = 1.65), history of alcohol abuse (OR = 2.23), postoperative pain management (OR = 1.91), perioperative blood transfusion (OR = 2.37), cognitive status (OR = 1.91), and lower serum level of albumin (OR = 0.58). POD is a frequent complication in patients undergoing surgery with colorectal cancer. Several risk factors including history of psychiatric disease, transfusion, comorbidities, male gender, and old age were significant predictors for POD.

Cardiac remodeling is a common characteristic of almost all forms of heart disease, including cardiac infarction, valvular diseases, hypertension, arrhythmia, dilated cardiomyopathy and other conditions. It is not merely a simple outcome induced by an increase in the workload of cardiomyocytes (CMs). The remodeling process is accompanied by abnormalities of cardiac structure as well as disturbance of cardiac function, and emerging evidence suggests that a wide range of cells in the heart participate in the initiation and development of cardiac remodeling. Other than CMs, there are numerous noncardiomyocytes (non-CMs) that regulate the process of cardiac remodeling, such as cardiac fibroblasts and immune cells (including macrophages, lymphocytes, neutrophils, and mast cells). In this review, we summarize recent knowledge regarding the definition and significant effects of various non-CMs in the pathogenesis of cardiac remodeling, with a particular emphasis on the involved signaling mechanisms. In addition, we discuss the properties of non-CMs, which serve as targets of many cardiovascular drugs that reduce adverse cardiac remodeling.