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Cancer immunotherapies such as tumor vaccines, chimeric antigen receptor T cells and immune checkpoint blockades, have attracted tremendous attention. Among them, tumor vaccines prime immune response by delivering antigens and adjuvants to the antigen presenting cells (APCs), thus enhancing antitumor immunotherapy. Despite tumor vaccines have made considerable achievements in tumor immunotherapy, it remains challenging to efficiently deliver tumor vaccines to activate the dendritic cells (DCs) in lymph nodes (LNs). Rational design of nanovaccines on the basis of biomedical nanotechnology has emerged as one of the most promising strategies for boosting the outcomes of cancer immunotherapy. In recent years, great efforts have been made in exploiting various nanocarrier-based LNs-targeting tumor nanovaccines. In view of the rapid advances in this field, we here aim to summarize the latest progression in LNs-targeting nanovaccines for cancer immunotherapy, with special attention to various nano-vehicles developed for LNs-targeting delivery of tumor vaccines, including lipid-based nanoparticles, polymeric nanocarriers, inorganic nanocarriers and biomimetic nanosystems. Moreover, the recent trends in nanovaccines-based combination cancer immunotherapy are provided. Finally, the rationality, advantages and challenges of LNs-targeting nanovaccines for clinical translation and application are spotlighted.

Gastrointestinal stromal tumors (GISTs) with a diameter of2 cm are called small GISTs. Currently, endoscopic ultrasound (EUS) is widely used as a regular follow-up method for GISTs, which can also provide a preliminary basis for judging the malignancy potential of lesions. However, there are no studies on the accuracy of EUS to assess the malignant potential of small GISTs.To evaluate the efficacy of EUS in the diagnosis and risk assessment of small GISTs.We collected data from patients with small GISTs who were admitted to Shengjing Hospital of China Medical University between October 2014 and July 2019. The accurate diagnosis and risk classifications of patients were based on the pathological assessment according to the modified National Institute of Health criteria after endoscopic resection or laparoscopic surgery. Preoperative EUS features (marginal irregularity, cystic changes, homogeneity, ulceration, and strong echogenic foci) were retrospectively analyzed. The assessment results based on EUS features were compared with the pathological features.A total of 256 patients (69 men and 187 women) were enrolled. Pathological results included 232, 16, 7, and 1 very low-, low-, intermediate-, and high-risk cases, respectively. The most frequent tumor location was the gastric fundus (78.1%), and mitoses were calculated as5/50 high power field in 8 (3.1%) patients. Marginal irregularity, ulceration, strong echo foci, and heterogeneity were detected in 1 (0.4%), 2 (0.8%), 22 (8.6%), and 67 (65.1%) patients, respectively. However, cystic changes were not detected. Tumor size was positively correlated with the mitotic index (Small GISTs (diameters1.48 cm) with positive EUS features should receive intensive surveillance or undergo endoscopic surgery. EUS and dissection are efficient diagnostic and therapeutic approaches for small GISTs.

Ultrasound is more widely used than mammography for early diagnosis of breast cancer in China as most Chinese women have small and dense mammary glands. This study compared the diagnostic performance of ultrasound and mammography for breast cancer among Chinese women with suspected breast lesions.From November 2019 to November 2021, we compared the results of ultrasound and mammography for breast lesion diagnosis in 2737 consecutive participants with suspected breast lesions; all patients underwent biopsies. We measured the sensitivity, specificity, and diagnostic accuracy separately.Among the 2737 participants, 2844 breast lesions were detected, including 1935 (68.0%) breast cancers and 909 (32.0%) benign lesions. Of the breast cancers, ultrasound detected 1851 (95.7%), whereas mammography detected 1527 (78.9%). The sensitivity of ultrasound for breast cancer diagnosis was significantly higher than that of mammography (95.7% vs. 78.9%, p 0.001), whereas the specificity was significantly lower than that of mammography (42.9% vs. 62.3%, p 0.001). The receiver operating characteristic curves revealed that ultrasound was more accurate in detecting breast cancer than mammography (76.8% vs. 71.3%, p 0.001). Age, body mass index, and breast density did not influence ultrasound sensitivity and accuracy.Ultrasound is more sensitive and accurate than mammography and detects more breast cancers with a lower specificity.

Activation of the stimulator of interferon genes (STING) pathway to achieve antitumor response is an attractive approach for cancer immunotherapy. In this study, we report the identification of

This study aimed to detect the predictors of vein graft disease (VGD) progression between 1 week and 1 year after surgery and to evaluate the impact of secondary prevention medications.A total of 218 consecutive patients underwent surgical coronary revascularization were evaluated by coronary computed tomography angiography both at 1-week and 1-year follow-up. Logistic regression analyses were performed to investigate the predictors of VGD progression. A risk score (0-4) was set up to evaluate implementation result of secondary prevention measures according to 1-year follow-up result. Association between VGD progression and the risk score was assessed.VGD progression occurred in 11.3% of saphenous vein grafts (SVG) and 22.1% of patients. At the patient level, poor vein graft (odds ratio [OR] = 4.25), noncontrolled hyperlipidemia (OR = 3.01), and diabetes mellitus (DM) (OR = 2.96) were predictors, while diameter of SVG (mm, OR = 0.35) was protective factor. At the graft level, DM (OR = 3.52), noncontrolled hyperlipidemia (OR = 2.33), and peripheral artery disease (PAD) (OR = 2.20) were predictors, while number of SVGs (OR = 0.63), diameter of SVG (mm, OR = 0.39), and mean graft flow25 ml/min (OR = 0.35) were protective factors. VGD progression was significantly associated with the risk score at both the patient (OR = 1.52) and the graft level (OR = 1.38).Poor vein graft, noncontrolled hyperlipidemia and DM were predictors of VGD progression between 1 week and 1 year after surgery at the patient level, while larger SVG diameter was a protective factor. DM, PAD and noncontrolled hyperlipidemia were predictors at the graft level, while a number of SVGs, larger SVG diameter, and mean graft flow25 ml/min were protective factors. Implementation failure of secondary prevention medications was associated with VGD progression from as early as 1 year after surgery.

Fluoride is an essential micronutrient for humans. Nonetheless, when the amount of fluoride ion is greater than required, it will cause skeletal fluorosis and dental fluorosis to threaten human health. In this paper, a series of sodium alginate (SA)-based foam materials are prepared by freeze-drying technique and anchored with the nano-activated alumina (nAl2O3) in the SA to obtain a novel adsorbent of SA-nAl2O3 foam used for fluoride ions removal. The SA-nAl2O3 foam morphology was further explored and confirmed that nAl2O3 existed stably in the SA. The adsorption results showed that the maximal fluoride ion adsorption capacity was 5.09 mg/g with 20 mg/L fluorine solutions at a pH of 3. The adsorption isotherm fitted adequately to the Langmuir isotherm model, which demonstrated that the adsorption process is closer to monolayer adsorption. The adsorption kinetics behavior of SA-nAl2O3 foam was described by a pseudo-second-order model, and the adsorption process occurred by chemisorption. Adsorption thermodynamics analysis emphasized that the adsorption process was spontaneous and endothermic. The main mechanism of the foam is ion exchange. The SA-nAl2O3 foam exhibited excellent regeneration performance and stability after three cycles.

Neurosurgery-specific research plays a critical role in improving outcomes in patients with neurosurgical diseases. Despite the high burden of neurosurgical diseases in Ethiopia, little is known about types of neurosurgical research from Ethiopia. The goal of this scoping review is to assess the quantity and types of neurosurgical research published in peer-reviewed journals by authors from Ethiopia.PubMed, CINAHL, Embase, and Scopus were searched for Ethiopian neurosurgery literature published from 2001 to 2021. We selected articles based on the following criteria: articles must 1) discuss topics within neurosurgery and 2) focus on clinical practice and/or public health in Ethiopia. We collected data on research originality, study designs, and clinical versus public health research. The frequencies and percentages of categorical variables were reported. All analyses were conducted using Jamovi software.Of the 362 results, 89 neurosurgical research articles were included in the final analysis. Of the 89 articles, case reports/series were most common (28.7%), followed by retrospective cohort (20.7%) and prospective cohort studies (18.4%). There were 8 literature reviews (9.2%) and 1 systematic review and meta-analysis (1.1%). No randomized controlled trial was found. Of all articles, 66 (75.9%) focused on clinical practice, and 21 (23.6%) were related to the public health aspect of neurosurgery. Forty-two articles (48.3%) included authors only from Ethiopia; 37 articles (42.5%) involved collaboration between Ethiopian and authors from another country, and 8 articles (9.2%) did not have Ethiopian authors.Neurosurgery research from Ethiopia is lacking, despite its high disease burden. Case reports/series and cohort studies remain the mainstay, with few systematic reviews and no randomized controlled trial. International collaboration accounts for approximately half of Ethiopian neurosurgery research output. Further research support and infrastructure should be developed to encourage neurosurgery articles from Ethiopia.

Catechol-O-methyltransferase (COMT) inhibitors are widely used as an add-on treatment to levodopa in adults with Parkinson's disease. It has been evidenced that the second-generation COMT inhibitors entacapone and tolcapone are potent inhibitors on human UDP-glucosyltransferases (UGTs), while the effect of the third-generation COMT inhibitor opicapone on human UGTs activities is unclear. The purpose of this study is to systemically investigate the effects of opicapone on human UGTs activities, and also to assess the potential risk of drug-drug interactions (DDIs) associated with opicapone. Our results indicated that opicapone is a broad-spectrum inhibitor of UGTs. Particularly, opicapone exhibited potent inhibition against UGT1A1, 1A7, 1A8, 1A9, and 1A10, with a range of inhibition constant K

To evaluate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing neutropenia during multiple cycles of chemotherapy in patients with non-small cell lung cancer (NSCLC).In a multicenter, prospective, randomized trial, patients with NSCLC were randomly assigned in a 2:1 ratio to treatment group (PEG-rhG-CSF as primary prophylactic therapy) or control group. Patients in the control group were administered rhG-CSF when white blood cell count was2.0 × 10Between January 2019 and July 2021, 130 patients were enrolled (treatment group: n = 87, control group: n = 43). The incidence of grade 3/4 neutropenia in the treatment group was significantly lower than that in the control group (1.15% vs. 11.63%, p 0.05). The mean duration of grade 3/4 neutropenia for the treatment and control group was 2.00 and 3.75 days, respectively. There were no statistical differences in the incidence of FN, delay rate of chemotherapy, prolonged time of chemotherapy, and antibiotic use between the two groups (all p 0.05). Adverse events were reported in 47.13% of patients in the treatment group and 48.84% patients in the control group.Primary prophylactic treatment with PEG-rhG-CSF could reduce the incidence of neutropenia in patients with NSCLC during multiple cycles of chemotherapy, with acceptable safety and tolerability.

Rapid and effective differentiation and quantification of a small molecule drug, such as fentanyl, in bodily fluids are major challenges for diagnosis and personal medication. However, the current toxicology methods used to measure drug concentration and metabolites require laboratory-based testing, which is not an efficient or cost-effective way to treat patients in a timely manner. Here, we show an assay for monitoring fentanyl levels by combining the intermolecular interaction-enabled small molecule recognition (iMSR) with differential impedance analysis of conjugated polymers. The differential interactions with the designed anchor interface were transduced through the perturbance of the electric status of the flexible conducting polymer. This assay showed excellent fentanyl selectivity against common interferences, as well as in variable body fluids through either testing strips or skin patches. Directly using the patient blood, the sensor provided 1%-5% of the average deviation compared to the "gold" standard method LC-MS results in the medically relevant fentanyl range of 20-90 nM. The superior sensing properties, in conjunction with mechanical flexibility and compatibility, enabled point-of-care detection and provided a promising avenue for applications beyond the scope of biomarker detection.

Ewing sarcoma breakpoint region 1 (EWSR1) is a member of FET (FUS/EWSR1/TAF15) RNA-binding family of proteins. The Ewing sarcoma oncoprotein EWS-FLI1 has been extensively studied, while much less is known about EWSR1 itself, especially the potential role of EWSR1 in response to DNA damage. Here, we found that UV irradiation induces acetylation of EWSR1, which is required for its nucleoli translocation. We identified K423, K432, K438, K640, and K643 as the major acetylation sites, p300/CBP and HDAC3/HDAC10 as the major acetyltransferases and deacetylases, respectively. Mechanically, UV-induced EWSR1 acetylation repressed its interaction with spliceosomal component U1C, which caused abnormal splicing of CHK2, suppressing the activity of CHK2 in response to UV irradiation. Taken together, our findings uncover acetylation as a novel regulatory modification of EWSR1, and is essential for its function in DNA damage response.

Background: Direct oral anticoagulants (DOACs) are the guideline-recommended therapy for some hypercoagulable diseases but are used off-label for left ventricular thrombus (LVT) owing to a paucity of evidence. We performed a meta-analysis to assess the safety and efficacy of DOACs compared with vitamin K antagonists (VKAs) for LVT treatment. Methods: We comprehensively searched PubMed, EMBASE, Cochrane Library, and Web of Science databases for studies that compared DOACs with VKAs for LVT treatment. Outcome indicators included stroke or systemic embolism (SSE), thrombus resolution, bleeding, and death. The Newcastle-Ottawa scale was used to evaluate the quality of included studies. Data were analyzed using Review Manager 5.3, and the meta-analysis is registered at PROSPERO (CRD 42020211376). Results: We included 12 observational studies (n = 2262 patients). SSE was similar for DOACs and VKAs groups (odds ratio (OR) = 1.01, 95% confidence interval (CI) 0.66-1.54, P = 0.95). For thrombus resolution, DOACs were not significantly different to VKAs (OR = 1.15, 95% CI 0.54-2.45, P = 0.71). DOACs and VKAs had a similar bleeding risk (OR = 0.78, 95% CI 0.45-1.35, P = 0.37). DOACs and VKAs groups had a comparable mortality (OR = 0.91, 95% CI 0.50-1.65, P = 0.76). Subgroup analysis showed that post-acute myocardial infarction (AMI) patients using DOACs had a lower risk of SSE (OR = 0.24, 95% CI 0.07-0.87, P = 0.03) and bleeding (OR = 0.38, 95% CI 0.18-0.81, P = 0.01). Conclusion: DOACs and VKAs showed no difference in the safety and efficacy of patients with LVT. DOACs might be superior to VKAs for LVT treatment in post-AMI patients. Registration No: A review protocol (number: CRD 42020211376) was registered in the PROSPERO International prospective register of systematic reviews.

Fluorine is one of the essential trace elements for human life activities, but excessive intake of fluoride poses a great risk to people's health. In this paper, a series of mixed matrix membrane (MMM)-based polysulfone for removing fluoride were prepared by phase inversion, and their properties, adsorption capacity, adsorption isotherms, adsorption kinetics of fluoride ions, and mechanism were all investigated. The results confirmed that the MMM contained a large number of hydroxyl and aluminum functional groups due to resin being added. The MMM exhibited the best fluorine ion adsorption capacity of 2.502 mg/g at a pH of 6 with the initial concentration of 6 mg/L. As well, adsorption kinetics of fluorine ion on MMM followed the pseudo-second-order model, while the adsorption behavior of fluorine ion on MMM was well simulated by the Langmuir isotherm model. The adsorption capacity of MMM remained stable after six cycles and the regeneration efficiency was still above 80%, resulting in a long-term stability adequate for fluorine ion removal. Complexation and ion exchange played a key role in the fluorine ion adsorption of MMM. These results indicated the MMM as novel type of absorbent had an excellent capacity for removing fluoride.

Patients with chronic kidney disease (CKD) have high residual risk of cardiovascular events, whether the residual risk is associated with elevated level of lipoprotein(a) [Lp(a)] is unascertained. We aimed to explore the impact of Lp(a) levels on the risk of major adverse clinical events (MACEs) in CKD patients hospitalized for acute coronary syndrome (ACS) compared to those without CKD.The data of patients hospitalized for ACS were collected at the China-Japan Friendship Hospital from January 2015 to December 2019. Patients were divided into 2 groups according to renal function: non-CKD group (eGFR≥60 ml/min/1.73 mA total of 1306 patients were enrolled. Patients with CKD had higher Lp(a) concentrations compared with those without CKD. During a median follow-up of 3.9 years, an elevated Lp(a) value was an independent predictor for MACEs in the overall population. Patients with a high Lp(a) level had higher risk of MACEs than those with a low Lp(a) level, regardless of renal function. The association between higher Lp(a) levels and MACEs remained consistent using the cut-off value of median (11.57 mg/dL), 30 mg/dL and 50 mg/dL in patients with CKD. On the contrary, Lp(a) higher than 50 mg/dL was associated with significantly higher risk of MACEs in patients without CKD.We confirmed that a high Lp(a) level was associated with long term adverse outcomes in ASC patients, especially in those with CKD.

Antibiotic resistance is currently a world health crisis that urges the development of new antibacterial substances. To this end, natural products, including flavonoids, alkaloids, terpenoids, steroids, peptides and organic acids play a vital role in the development of medicines and thus constitute a rich source in clinical practices, providing an important source of drugs directly or for the screen of lead compounds for new antibiotic development. Because membrane proteins, which comprise more than 60% of the current clinical drug targets, play crucial roles in signal transduction, transport, bacterial pathogenicity and drug resistance, as well as immunogenicity, it is our aim to summarize those natural products with different structures that target bacterial membrane proteins, such as efflux pumps and enzymes, to provide an overview for the development of new antibiotics to deal with antibiotic resistance.

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)–keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.

Triple-negative breast cancer (TNBC) has a high propensity for organ-specific metastasis. However, the underlying mechanisms are not well understood. Here we show that the primary TNBC tumor-derived C-X-C motif chemokines 1/2/8 (CXCL1/2/8) stimulate lung-resident fibroblasts to produce the C-C motif chemokines 2/7 (CCL2/7), which, in turn, activate cholesterol synthesis in lung-colonizing TNBC cells and induce angiogenesis at lung metastatic sites. Inhibiting cholesterol synthesis in lung-colonizing breast tumor cells by pulmonary administration of simvastatin-carrying HER3-targeting nanoparticles reduces angiogenesis and growth of lung metastases in a syngeneic TNBC mouse model. Our findings reveal a novel, chemokine-regulated mechanism for the cholesterol synthesis pathway and a critical role of metastatic site-specific cholesterol synthesis in the pulmonary tropism of TNBC metastasis. The study has implications for the unresolved epidemiological observation that use of cholesterol-lowering drugs has no effect on breast cancer incidence but can unexpectedly reduce breast cancer mortality, suggesting interventions of cholesterol synthesis in lung metastases as an effective treatment to improve survival in individuals with TNBC.

Sleep disturbance is common in patients with Alzheimer’s disease (AD), and orexin A is a pivotal neurotransmitter for bidirectionally regulating the amyloid-β (Aβ) deposition of AD brain and poor sleep. In the present study, we examined the characteristic of sleep–wake architecture in APPswe/PSldE9 (APP/PS1) and Aβ-treated mice using electroencephalogram (EEG) and electromyographic (EMG) analysis. We compared the expression of orexin A, distribution, and morphology of the corresponding orexin A-positive neurons using innovative methods including three-dimensional reconstruction and brain tissue clearing between wild type (WT) and APP/PS1 mice. Results from our study demonstrated that increased wakefulness and reduced NREM sleep were seen in APP/PS1 and Aβ treated mice, while the expression of orexin A was significantly upregulated. Higher density and distribution of orexin A-positive neurons were seen in APP/PS1 mice, with a location of 1.06 mm–2.30 mm away from the anterior fontanelle compared to 1.34 mm–2.18 mm away from the anterior fontanelle in WT mice. These results suggested that the population and distribution of orexin A may play an important role in the progression of AD.

PurposeRespiratory motion causes mismatches between PET images of the myocardium and the corresponding cardiac MR images in cardiac integrated PET/MR. The mismatch may affect the attenuation correction and the diagnosis of non-ischemic cardiomyopathies. In this study, we present a two-stage cardiac PET and MR Late Gadolinium Enhancement (LGE) co-registration method, which seeks to improve diagnostic accuracy of non-ischemic cardiomyopathies via better image co-registration using an integrated whole-body PET/MR system.MethodsThe proposed PET and LGE two-stage co-registration method was evaluated through comparison with one-stage direct co-registration and no-registration. One hundred and ninety-one slices of LGE and forty lesions were studied. Two trained nuclear medicine physicians independently assessed the displacement between LGE and PET to qualitatively evaluate the co-registration quality. The changes of the mean SUV in the normal myocardium and the LGE-enhanced lesions before and after image co-registration were measured to quantitatively evaluate the accuracy and value of image co-registration.ResultsThe two-stage method had an improved image registration score (4.93±0.89) compared with the no-registration method (3.49±0.84, p value ConclusionThe proposed two-stage registration method significantly improved the co-registration between PET and LGE in integrated PET/MR imaging. The technique may improve diagnostic accuracy of non-ischemic cardiomyopathies via better image co-registration.Registered No.DF-2020-085, 2020.04.30

The potential of micronutrients, including vitamins and minerals, to prevent Alzheimer's disease (AD) has attracted much attention. However, the causal associations between micronutrient levels or supplements and AD risk remain unclear. We performed a two-sample Mendelian randomization (2SMR) analysis to evaluate the causal associations between micronutrient levels and supplements and AD risk. A total of 60 genome-wide association studies (GWAS) related to five types of vitamins (vitamins A, B, C, D, and E) and seven types of minerals (magnesium, calcium, iron, copper, zinc, selenium, and phosphorus) were included. For vitamins, using the data source provided by two GWAS, the analysis of 2SMR indicated that the vitamin D level was causally associated with a decreased risk of AD (IVW, OR: 0.474, 95%CI: 0.269-0.834

Background To identify risk factors associated with the prognosis of pertussis in infants ( Methods A retrospective study on infants hospitalized with pertussis January 2017 to June 2019. The infants were divided into two groups according to the severity of disease: severe pertussis and non-severe pertussis groups. We collected all case data from medical records including socio-demographics, clinical manifestations, and auxiliary examinations. Univariate analysis and Logistic regression were used. Results Finally, a total of 84 infants with severe pertussis and 586 infants with non-severe pertussis were admitted. The data of 75% of the cases (severe pertussis group, n = 63; non-severe pertussis group, n = 189) were randomly selected for univariate and multivariate logistic regression analysis. The results showed rural area [P = 0.002, OR = 6.831, 95% CI (2.013–23.175)], hospital stay (days) [P = 0.002, OR = 1.304, 95% CI (1.107–1.536)], fever [P = 0.040, OR = 2.965, 95% CI (1.050–8.375)], cyanosis [P = 0.008, OR = 3.799, 95% CI (1.419–10.174)], pulmonary rales [P = 0.021, OR = 4.022, 95% CI (1.228–13.168)], breathing heavily [P = 0.001, OR = 58.811, 95% CI (5.503–628.507)] and abnormal liver function [P Conclusions The findings indicated risk factor prediction models may be useful for the early identification of severe pertussis in infants.

KRAS mutation is the most frequent oncogenic aberration in colorectal cancer (CRC). The molecular mechanism and clinical implications of KRAS mutation in CRC remain unclear and show high heterogeneity within these tumors.

PLK1 is a promising target for clinical treatment of diverse malignancies including ovarian cancer (OC), in which PLK1 over-expression is often correlated with poor prognosis and short survival. PLK1 can be blocked with small molecular inhibitors like volasertib (Vol) or silenced with PLK1-specific siRNA (siPLK1), hence effectively suppressing tumor growth. Surprisingly, despite intensive work on molecular inhibitor and siRNA therapeutics, there is no direct comparison between them reported for targeted tumor therapy. Herein, we employing folate as a ligand and polymersomes as a nanovehicle performed a comparative study on Vol and siPLK1 in inhibiting OC in vitro and in vivo. Folate-targeted polymersomal Vol and siPLK1 (termed as FA-Ps-Vol and FA-Ps-siPLK1, respectively) were both nano-sized and stable, and displayed an optimal FA density of 20% for SKOV-3 cells. Notably, FA-Ps-Vol and FA-Ps-siPLK1 exhibited an IC50 of 193 and 770 nM, respectively, to SKOV-3 cells, indicating a greater potency of Vol than siPLK1. The markedly increased uptake for FA-Ps-Vol and FA-Ps-siPLK1 compared with respective non-targeted controls by SKOV-3 tumor xenografts in mice confirmed that FA mediates strong OC-targeting in vivo. Intriguingly, FA-Ps-Vol while greatly lessening toxic effects of Vol potently repressed tumor growth with a remarkable tumor inhibition rate (TIR) of 97% at 20 mg (i.e. 32.4 µmol) Vol equiv./kg. FA-Ps-siPLK1 achieved effective tumor inhibition (TIR = ca. 87% or 90%) at 2 or 4 mg (i.e. 0.15 or 0.3 µmol) siPLK1 equiv./kg without causing adverse effects. This comparative study highlights that molecular inhibitor has the advantage of easy dose escalation and potent protein inhibition at the expense of certain adverse effects while siRNA therapeutics has low toxicity with moderate protein inhibition in vivo. Statement of significance PLK1 is a promising target for the development of innovative and specific treatments against diverse malignancies. Interestingly, despite intensive work on molecular inhibitors and siRNA against PLK1, little work has been directed to compare their efficacy in targeted tumor therapy. Here, we employed folate as a ligand and polymersomes as a nanovehicle and have performed a comparative study on volasertib and siPLK1 in inhibiting ovarian cancer in vitro and in vivo. Our data show that the dose of volasertib can be easily escalated to induce prominent antitumor efficacy at the expense of certain adverse effects, while siPLK1 brings about moderate protein inhibition and antitumor therapy without causing toxicity at two-orders-of-magnitude lower dose.

The olfactory dysfunction can signal and act as a potential biomarker of preclinical AD. However, the precise regulatory mechanism of olfactory function on the neural pathogenesis of AD is still unclear. The impairment of neural networks in olfaction system has been shown to be tightly associated with AD. As key brain regions of the olfactory system, the olfactory bulb (OB) and the piriform cortex (PCx) have a profound influence on the olfactory function. Therefore, this review will explore the mechanism of olfactory dysfunction in preclinical AD in the perspective of abnormal neural networks in the OB and PCx and their associated brain regions, especially from two aspects of aberrant oscillations and synaptic plasticity damages, which help better understand the underlying mechanism of olfactory neural network damages related to AD.

Background The NLRP3 inflammasome activation is the molecular basis of Helicobacter pylori (Hp)-associated gastritis. Tripartite motif (TRIM) 31 is involved in diverse pathological events. However, whether TRIM31 plays a role in the activation of NLRP3 inflammasome in Hp infection is not clarified. Methods A mouse model of chronic Hp infection was established, and the gastric tissues were subjected to the polymerase chain reaction, western blotting, histopathological analysis, and RNA sequencing. The mitochondrial membrane potential and ROS in the human gastric epithelium GES-1 cells with or without Hp infection were measured by flow cytometry. GES-1 cells with or without TRIM31 knockdown were transfected with mCherry-EGFP-LC3 adenovirus. After rapamycin and bafilomycin A1 stimulation, autophagy flux in the above primed GES-1 cells was assessed by laser confocal microscope. Lysosomal acidification and expression levels of cathepsin B and cathepsin D in GES-1 cells with Hp infection were measured. Results NLRP3 inflammasome was activated in the gastric tissues of mice with chronic Hp infection in vivo and the GES-1 cells with Hp infection in vitro. TRIM31 was downregulated in Hp infection. TRIM31 negatively regulated the NLRP3 inflammasome activation. Enhanced ROS, impaired autophagy flux, and decreased expression of lysosomal cathepsin B and cathepsin D were observed in TRIM31-deficient GES-1 cells with Hp infection. In turn, inhibition of ROS led to the decreased expression of NLRP3 inflammasome. Conclusions Together, our data identified that TRIM31 negatively regulated the activation of NLRP3 inflammasome in Hp-associated gastritis by affecting ROS and autophagy of gastric epithelial cells.

Context The prevalence of sarcopenia in patients with diabetes is 3 times higher than that in patients without diabetes and is associated with a poor prognosis. Objective To investigate the global pooled prevalence and risk factors of sarcopenia in patients with diabetes. Data Sources Relevant studies published until November 30, 2020, were identified from the PubMed, Embase, Web of Science, WanFang, CNKI, VIP, and CBM databases. Study Selection Participants with age ≥ 18 years with clinically diagnosed diabetes. Sex and diabetes type were not restricted. Data Extraction The data were extracted by 2 reviewers independently using a standard data collection form. Data Synthesis The pooled prevalence of sarcopenia in patients with diabetes was 18% (95% CI, 16-20); subgroup analysis showed that sarcopenia was more prevalent in males than in females, as well as being more prevalent in Asia than in South America and Oceania. Age (odds ratio [OR], 1.10), glycated hemoglobin (HbA1c) (OR = 1.16), visceral fat area (VFA) (OR = 1.03), diabetic nephropathy (OR = 2.54), duration of diabetes (OR = 1.06), and high-sensitivity C-reactive protein (hs-CRP) (OR = 1.33) were risk factors for sarcopenia in patients with diabetes. Conclusions Sarcopenia was more prevalent in patients with diabetes. Age, HbA1c, VFA, diabetic nephropathy, duration of diabetes, and hs-CRP were the probable risk factors. In the future, medical staff should not only pay attention to the early screening of sarcopenia in high-risk groups, but also provide information on its prevention.

RATIONALE AND OBJECTIVES Skeletal muscle mass measurement is the most important element for diagnosing sarcopenia. MRI has an excellent soft-tissue contrast, which can non-invasively assess abdominal skeletal muscle area (SMA) as well as CT. This study aimed to assess the validity and reliability of abdominal SMA measurement by comparing CT and MRI based on the fat image of IDEAL-IQ sequence at the lumbar level mid-L3. MATERIALS AND METHODS CT and MRI images of 32 patients diagnosed with various kidney diseases were used to analyze intra-observer variability among abdominal SMA measurements. This was done to evaluate the correlation of SMA between CT and fat images of MRI. SMA images were segmented using Materialise Mimics software before quantification. Interobserver reliability and validation of measurements was evaluated by two independent investigators. Abdominal SMA reproducibility and correlation between CT and MRI were then assessed using the intraclass correlation coefficient (ICC), coefficient of variation (CV), Bland-Altman plot, and Pearson's correlation coefficient respectively. RESULTS The interobserver reliability of MRI was excellent. The CV value was 2.82% while the ICC values ranged between 0.996 and 0.999. Validity was high (CV was 1.7% and ICC ranged between 0.986 and 0.996) for measurements by MRI and CT. Bland Altman analysis revealed an average difference of 2.2% between MRI and CT. The Pearson's correlation coefficient was 0.995 (p < 0.0001). This result revealed that there was a strong correlation between the two technologies. CONCLUSION MRI exhibited good interobserver reliability and excellent agreement with CT for quantification of abdominal SMA.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756

The self-expanding metal stent (SEMS) is a versatile, palliative treatment method for unresectable, malignant, non-vascular strictures. Colorectal cancer (CRC) is one of the candidates for the application of the SEMS, in combination with the photothermal ablation (PTA) technique that enhances its therapeutic efficacy. The objective of this study was to investigate the efficacy of stent-mediated PTA therapy in an endoscopy-guided, orthotopic rectal cancer model. A total of 30 of 40 mice with the tumor size of grade 4 were included and were divided into three groups of 10 mice each. Group A underwent a gold nanoparticle (AuNP)-coated SEMS but no near-infrared (NIR) irradiation, group B received an uncoated control SEMS with NIR irradiation, and group C received a AuNP-coated SEMS and NIR irradiation together. Colonoscopy and in vivo imaging, immunohistochemical analysis, and quantitative reverse-transcription polymerase chain reaction of major tumor markers were performed. Stent placement and PTA were technically successful using colonoscopy. The tumor grade reduction after PTA is significant in group C, compared with groups A or B (p < 0.001). Molecular analysis validated this observation with a significantly reduced Mapk1 proliferation marker or increased Jnk expression. Histological analysis confirmed the localized PTA therapy using AuNP-coated SEMS profoundly ablated tumor outgrowth through the stent. Our results indicate that this novel strategy of localized PTA therapy could be a promising option for palliative treatment of CRC and to support prolonged stent patency with a decreased tumor volume.

COVID-19 caused by a novel coronavirus (SARS-CoV-2) has been spreading all over the world since the end of 2019, and no specific drug has been developed yet. 3C-like protease (3CLpro) acts as an important part of the replication of novel coronavirus and is a promising target for the development of anticoronavirus drugs. In this paper, eight machine learning models were constructed using naïve Bayesian (NB) and recursive partitioning (RP) algorithms for 3CLpro on the basis of optimized two-dimensional (2D) molecular descriptors (MDs) combined with ECFP_4, ECFP_6, and MACCS molecular fingerprints. The optimal models were selected according to the results of 5-fold cross verification, test set verification, and external test set verification. A total of 5766 natural compounds from the internal natural product database were predicted, among which 369 chemical components were predicted to be active compounds by the optimal models and the EstPGood values were more than 0.6, as predicted by the NB (MD + ECFP_6) model. Through ADMET analysis, 31 compounds were selected for further biological activity determination by the fluorescence resonance energy transfer (FRET) method and cytopathic effect (CPE) detection. The results indicated that (+)-shikonin, shikonin, scutellarein, and 5,3′,4′-trihydroxyflavone showed certain activity in inhibiting SARS-CoV-2 3CLpro with the half-maximal inhibitory concentration (IC50) values ranging from 4.38 to 87.76 μM. In the CPE assay, 5,3′,4′-trihydroxyflavone showed a certain antiviral effect with an IC50 value of 8.22 μM. The binding mechanism of 5,3′,4′-trihydroxyflavone with SARS-CoV-2 3CLpro was further revealed through CDOCKER analysis. In this study, 3CLpro prediction models were constructed based on machine learning algorithms for the prediction of active compounds, and the activity of potential inhibitors was determined by the FRET method and CPE assay, which provide important information for further discovery and development of antinovel coronavirus drugs.

Zhixin Zhang,&ast; Ying Shi,&ast; Haiyan Zheng, Zihuai Zhou, Zhifang Wu, Dongni Shen, Yiru Wang, Yizhou Zhang, Zhe Wang, Baiping Fu Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 310006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhe Wang; Baiping Fu Tel +86-571-87217427Fax +86-571-87217427Email 7319012@zju.edu.cn; fbp@zju.edu.cnObjective: This study investigated the effects of mineralizing film consisting of hydroxypropyl methylcellulose (HPMC) and amorphous fluorinated calcium phosphate (AFCP) nanoparticles on enamel white spot lesions (WSLs).Material and Methods: The AFCP nanoparticles and mineralizing film were prepared via nanoprecipitation and solvent evaporation, respectively. They were characterized with Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), transmission electron microscopy (TEM), selected area electron diffraction (SAED), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), inductively coupled plasma atomic emission spectrometry (ICP-AES), and fluoride ion selective electrode. Thirty-two human enamel slices (4 mm × 4 mm × 1.5 mm) were highly polished and randomly assigned to four groups: negative control (no treatment); pure HPMC film; mineralizing film; GC Tooth Mousse Plus® (contains 10% CPP-ACP and 0.2% NaF). Subsequently, samples were challenged by a modified pH-cycling and characterized by color measurement, Micro-CT, SEM/EDX, and nanoindentation.Results: The mineralizing film could sustain release of Ca, P and F ions over 24 h and maintain AFCP nanoparticles in metastable state over 8∼ 12 h. During 4 weeks of pH cycling, the mineralizing film group exhibited least color change (∆E), mineral loss and lesion depth (120 ± 10 μm) among four groups (p < 0.05). SEM findings revealed that the porosities among enamel crystals increased in negative control and pure HPMC film groups after pH cycling, whereas in mineralizing film group, the original microstructure of enamel was well conserved and mineral deposits were detected between enamel prisms. Mineralizing film group demonstrated a least reduction of nanomechanical properties such as elastic modulus of 77.02 ± 6.84 GPa and hardness of 3.62 ± 0.57 GPa (p < 0.05).Conclusion: The mineralizing film might be a promising strategy for prevention and management of WSLs via inhibiting enamel demineralization and promoting enamel remineralization.Keywords: mineralizing film, white spot lesions, color, micro-CT, SEM/EDX, nanoindentation

Background Osteonecrosis of the femoral head (ONFH) is a common but intractable disease that appears to involve lipid metabolic disorders. Although numerous studies have demonstrated that high blood levels of low-density lipoprotein (LDL) are closely associated with ONFH, there is limited evidence to explain the pathological role of LDL. Pathological and in vitro studies were performed to investigate the role of disordered metabolism of LDL and oxidized LDL (ox-LDL) in the femoral head in the pathology of ONFH. Methods Nineteen femoral head specimens from patients with ONFH were obtained for immunohistochemistry analysis. Murine long-bone osteocyte Y4 cells were used to study the effects of LDL/ox-LDL on cell viability, apoptosis, and metabolism process of LDL/ox-LDL in osteocytes in normoxic and hypoxic environments. Results In the pathological specimens, marked accumulation of LDL/ox-LDL was observed in osteocytes/lacunae of necrotic regions compared with healthy regions. In vitro studies showed that ox-LDL, rather than LDL, reduced the viability and enhanced apoptosis of osteocytes. Pathological sections indicated that the accumulation of ox-LDL was significantly associated with impaired blood supply. Exposure to a hypoxic environment appeared to be a key factor leading to LDL/ox-LDL accumulation by enhancing internalisation and oxidation of LDL in osteocytes. Conclusions The accumulation of LDL/ox-LDL in the necrotic region may contribute to the pathology of ONFH. These findings could provide new insights into the prevention and treatment of ONFH.

Low-dose rivaroxaban is often given to patients with atrial fibrillation (AF) around the world, but the rationale for its use remains unclear. We aimed to compare the efficacy and safety of standard- or low-dose rivaroxaban in patients with AF through systematic review of literature with meta-analysis.We searched PubMed, Web of Science, EMBASE, Clinical Trials.gov, the Cochrane Library, and Bayer trial website from inception of each database until June 2020. Randomized controlled trials (RCTs) and cohort studies were included in the meta-analysis. A random-effects model was employed to calculate the pooled effect estimates.Two RCTs and 17 cohort studies were included in the qualitative analysis. Indirect comparison of RCTs showed no significant difference between the two rivaroxaban dosages in risk of efficacy or safety outcomes (p 0.05). Indirect comparison of cohort studies showed a lower risk of MACE among Caucasians in standard-dose group (HR 0.779; 95% CI 0.687-0.884; p 0.001). Bleeding outcomes did not differ significantly between the two dosage regimens in Asian or Caucasian populations, except that the standard dose was associated with higher risk of major bleeding among elderly Caucasian patients (HR 1.329; 95% CI 1.141-1.547; p 0.001). The quality of evidence was rated ranging from very low to low for all the efficacy and safety outcomes.In Caucasians with AF, standard-dose rivaroxaban may prevent MACE significantly better than low-dose treatment. Further studies in Asians are needed to verify the advantages of the standard dose.

Self-healing conductive elastomers have been widely used in smart electronic devices, such as wearable sensors. However, nano fillers hinder the flow of polymer segments, which make the development of conductive elastomer with rapid repair and high ductility a challenge. In this work, thioctic acid (TA) was grafted onto amino-modified polysiloxane (PDMS-NH2) by dehydration condensation of amino group and carboxyl group. By introducing gold nanoparticles, a dynamic network based on S-Au interaction was constructed. The dynamic gold cross-linking could effectively dissipate the energy exerted by external force and improve the extensibility of conductive elastomer. In addition, S-Au interaction had a good optothermal effect, so that the elastomer rapidly healed under NIR irradiation, and the repair efficiency reached 92%. We further evaluated the performance of the conductive elastomer as a strain sensor. The sample could accurately monitor the bending of human joints and small muscle state changes. This kind of self-healable conductive elastomer based on dynamic S-Au interaction has great potential in the fields of interpersonal interaction and health monitoring.

Background Acupuncture is an important component of traditional Chinese medicine which is used to treat an array of health conditions. This study evaluates the effectiveness of acupuncture in the management of restless leg syndrome (RLS). Methods A comprehensive literature survey was conducted in electronic databases to identify studies evaluating the effectiveness of acupuncture in the treatment of RLS. Cure, marked effect, effective, ineffective, and total effective rates of individual studies were pooled to achieve their respective overall estimates and a meta-analysis of mean change from baseline in International Restless Legs Syndrome Rating Scale (IRLSRS) was performed. Results A total of 18 studies were included in this meta-analysis, among which 640 RLS patients were treated with acupuncture alone or combined with other therapies (acupuncture group) and 447 RLS patients were treated with non-acupuncture therapies (control group). Cure, marked effect, and effective rates were 47.8% [95% confidence interval (CI): 38.3% to 57.3%], 27.4% (95% CI: 20.3% to 34.8%), and 24.2% (95% CI: 16.9% to 31.5%) in patients treated with acupuncture either alone or combination with other treatments, and 21.7% (95% CI: 20.7% to 22.7%), 28.0% (95% CI: 20.0% to 32.9%), and 22.3% (95% CI: 17.0% to 27.6%) in patients treated with non-acupuncture therapies, respectively. The ineffective rate was 4.7% (95% CI: 4.3% to 5.0%) in the acupuncture group and 32.9% (95% CI: 22.2% to 43.7%) in non-acupuncture groups. IRLSRS scores improved significantly after acupuncture treatment [mean change from baseline -9.45 (95% CI: -18.42 to -0.49); P=0.04]. Discussion Although the overall quality of the included studies was low, the results of this meta-analysis suggested that acupuncture is an effective treatment option for RLS. Well-designed randomized controlled trials especially those involving a sham-acupuncture arm are needed to confirm these outcomes.

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

Traumatic brain injury (TBI) disproportionately affects children within low- and middle-income countries (LMICs). Prehospital emergency care can mitigate secondary brain injury and improve outcomes. Here, we systematically review clinical practice guidelines (CPGs) for pediatric TBI with the goal to inform LMICs prehospital care. A systematic search was conducted in PubMed/Medline, Embase, and Web of Science databases. We appraised evidence-based CPGs addressing prehospital management of pediatric TBI using the Appraisal of Guidelines for Research & Evaluation (AGREE) tool. CPGs were rated as high-quality if ≥ 5 (out of 6) AGREE domains scored > 60%. Of the 326 articles identified, 10 CPGs were included in analysis. All 10 were developed in HICs, and 4 were rated as high-quality. A total of 154 pediatric prehospital recommendations were grouped into three subcategories, initial assessment (35.7%), prehospital treatment (38.3%), and triage (26.0%). Of these, 79 (51.3%) were evidence-based with grading, and 31 (20.1%) were consensus-based without direct evidence. Currently available CPGs for prehospital pediatric TBI management were all developed in HICs. Four CPGs have high-quality, and recommendations from these can serve as frameworks for LMICs or resource-limited settings. Context-specific evaluation and implementation of evidence-based recommendations allow LMIC settings to respond to the public health crisis of pediatric TBI and address gaps in trauma care systems.

Endoscopy for revealing the orifice of congenital H-type tracheoesophageal fistula (cTEF) is important for diagnostics and therapeutics. To facilitate the identification and catheterization of cTEF, we developed a new modified flexible endoscopy technique using a laryngeal mask with intermittent airflow. A retrospective case series study was conducted from April 2016 to July 2019 at a national regional children's medical center. Twelve infants with cTEF underwent this flexible endoscopy technique. The intermittent positive pressure airflow through laryngeal mask was able to reveal the orifice of cTEF easily in tracheal lumen. Under the visual flexible endoscope, cannulation with a 3-French ureteral catheter in fistula was successfully used in all cases. There were no immediate or delayed complications. This case series shows that the flexible endoscopy technique is a safe, easy, and technically efficient approach for diagnosis and cannulation of cTEF.

Ribosomal S6 protein kinase 4 (RSK4) was identified to be a promising target for the treatment of esophageal squamous cell carcinoma (ESCC) in our previous research, whose current treatments are primarily chemotherapy and radiotherapy due to the lack of targeted therapy. However, few potent and specific RSK4 inhibitors are reported. In this study, a series of 1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones derivatives were designed and synthesized as novel and potent RSK4 inhibitors. Compound 14f was identified with potent RSK4 inhibitory activity both in vitro and in vivo. 14f significantly inhibited the proliferation and invasion of ESCC cells in vitro with IC50 values of 0.57 and 0.98 μM, respectively. It dose dependently inhibited the phosphorylation of RSK4 downstream substrates while exerting little effect on the substrates of RSK1-3 in ESCC cells. The markedly suppressed tumor growth and no observed toxicity to main organs in the ESCC xenograft mouse model suggested 14f to be a promising RSK4-targeting agent for ESCC treatment.

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI’s Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

Nanoparticles hold great promise in tumor targeting and molecular imaging because they can co-deliver therapeutic drugs and imaging agents to the tumor site with a single entity. Nanoparticles modified with ligands against moieties overexpressed on tumor tissues have gained increasing attention due to their active targeting mechanisms. Peptides are well suited for nanoparticle targeting modifications because they are small, easy to synthesize and typically non-immunogenic. Herein, we review the peptide-modified nanoparticles used for tumor targeting therapy and molecular imaging based on the classification of peptide-targeting ligands. The development of targeting peptides and nanoparticles will also be discussed.

Osimertinib is the only third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) approved by Food and Drug Administration (FDA). This study aimed to know the inhibitory effect of osimertinib on human UDP-glucosyltransferases (UGTs) and human liver microsomes (HLMs), as well as to identify its potential to cause drug-drug interaction (DDI) arising from the modulation of UGT activity. High inhibitory effect of osimertinib was shown towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A10, 2B7 and 2B15. Especially, osimertinib exhibited competitive inhibition against UGT1A1 with a Ki,u of 0.87 ± 0.12 μM. It also noncompetitively inhibited SN-38 glucuronidation in pooled HLMs with a Ki,u of 3.32 ± 0.25 μM. Results from quantitative prediction study indicated that osimertinib administered at 80 mg/day may result in a 4.83 % increase in the AUC of drugs mainly metabolized by UGT1A1, implying low risk of DDI via liver metabolism. However, the ratios of [I]gut/Ki,u are much higher than 11 in HLMs and recombinant UGT1A1, indicating a risk for interaction in intestine. The effects of osimertinib on intestinal UGT should be paid more attention on to avoid unnecessary clinical DDI risks.

Peptides play important roles in regulating biological processes and form the basis of a multiplicity of therapeutic drugs. To date, only about 300 peptides in human have confirmed bioactivity, although tens of thousands have been reported in the literature. The majority of these are inactive degradation products of endogenous proteins and peptides, presenting a needle-in-a-haystack problem of identifying the most promising candidate peptides from large-scale peptidomics experiments to test for bioactivity. To address this challenge, we conducted a comprehensive analysis of the mammalian peptidome across seven tissues in four different mouse strains and used the data to train a machine learning model that predicts hundreds of peptide candidates based on patterns in the mass spectrometry data. We provide in silico validation examples and experimental confirmation of bioactivity for two peptides, demonstrating the utility of this resource for discovering lead peptides for further characterization and therapeutic development.

To identify the potential factors responsible for the individual variability of dabigatran, we investigated the genetic variations associated with clinical outcomes and pharmacodynamics (PD) in Chinese patients with nonvalvular atrial fibrillation (NVAF).Chinese patients with NVAF taking dabigatran etexilate with therapeutic doses were enrolled. The primary (bleeding events) and secondary (thromboembolic and major adverse cardiac events) outcomes for a 2-year follow-up were evaluated. Peak and trough PD parameters (anti-FIIa activity, activated partial thromboplastin time and prothrombin time) were detected. Whole-exome sequencing, genome-wide sequencing and candidate gene association analyses were performed.There were 170 patients with NVAF treated with dabigatran (110 mg twice daily) who were finally included. Two single-nucleotide polymorphisms (SNPs) were significantly related with bleeding, which include UBASH3B rs2276408 (odds ratio [OR] = 8.79, 95% confidence interval [CI]: 2.99-25.83, p = 7.77 × 10Genetic variations indeed affected bleeding and PD in Chinese patients with NVAF treated with dabigatran. The functions of these suggestive genes and SNPs might further be explored and verified in more in vivo and in vitro investigations.

(1) Background: The purpose of this study was to evaluate the effect of gene polymorphisms on prothrombin time (PT) and activated partial thromboplastin time (APTT) in a healthy Chinese population. (2) Methods: A total of 403 healthy volunteers from a series of novel oral anticoagulants (NOACs) bioequivalence trials in China were included. Coagulation tests for PT and APTT were performed in the central lab at Peking University First Hospital. Whole-exome sequencing (WES) and genome-wide association analysis were performed. (3) Results: In the correlation analysis of PT, 105 SNPs from 84 genes reached the genome-wide significance threshold (p < 1 × 10−5). Zinc Finger Protein 594 (ZNF594) rs184838268 (p = 4.50 × 10−19) was most significantly related to PT, and Actinin Alpha 1 (ACTN1) was found to interact most with other candidate genes. Significant associations with previously reported candidate genes Aurora Kinase B (AURKB), Complement C5(C5), Clock Circadian Regulator (CLOCK), and Histone Deacetylase 9(HDAC9) were detected in our dataset (p < 1 × 10−5). PiggyBac Transposable Element Derived 2(PGBD2) rs75935520 (p = 4.49 × 10−6), Bromodomain Adjacent To Zinc Finger Domain 2A(BAZ2A) rs199970765 (p = 5.69 × 10−6) and Protogenin (PRTG) rs80064850 (p = 8.69 × 10−6) were significantly correlated with APTT (p < 1 × 10−5). The heritability values of PT and APTT were 0.83 and 0.64, respectively; (4) Conclusion: The PT and APTT of healthy populations are affected by genetic polymorphisms. ZNF594 and ACTN1 variants could be novel genetic markers of PT, while PRTG polymorphisms might be associated with APTT levels. The findings could be attributed to ethnic differences, and need further investigation.

East Asians have a higher risk of bleeding than Europeans when treated with ticagrelor. This study aimed to explore genetic indicators related to the high bleeding propensity in East Asian patients with acute coronary syndrome (ACS) using ticagrelor.A multicenter prospective cohort study.Four sub center hospitals participating the study.Between March 2018 and July 2021, 208 patients with ACS were administered ticagrelor and underwent genetic testing.Patients were enrolled and followed up for bleeding events for 12 months. Single-nucleotide polymorphisms (SNPs) were detected using whole-exome sequencing. SNPs significantly associated with cumulative bleeding events within 1-, 6-, and 12-month follow-ups were selected (p 0.01). Among these, SNPs showing a difference of ≥2 fold in their distribution frequency among East Asians and Europeans were selected.Among all patients, 96.60% received ticagrelor plus aspirin or cilostazol, and 42.3% suffered from bleeding events during 12-month follow-up. Furthermore, 22 SNPs of 15 genes were found to have a significant association with cumulative bleeding events within 1-, 6-, and 12-month follow-ups. Among these SNPs, FIG4 rs2295837 (AT) variant had the strongest association with bleeding events within 1 month (p = 1.28 × 10Fifteen genes, including PROK2, HRNR, and FIG4, were potential biomarkers of high bleeding propensity in East Asian patients with ACS using ticagrelor.

Oxaliplatin-based chemotherapy is a standard treatment for advanced colorectal cancer (CRC) patients. However, chemoresistance-induced resistance is an essential cause for mortality. Therefore, it is necessary to study the mechanism of drug resistance in CRC.Here, we established two strains of patient-derived organoids (PDOs) selected from oxaliplatin-resistant and treatment-naïve CRC patients. To dissect the drug-resistant mechanisms, these CRC-PDOs were subjected to single-cell RNA sequencing (scRNA-Seq).We found that the drug sensitivity test outcome from these organoids subjected to oxaliplatin and 5-FU exposure was consistent with the clinic readout. CRC-PDOs well recapitulated the morphology and histology of their parental biopsies based on HE and IHC staining of pathological biomarkers. The scRNA-Seq data filtered drug-resistant cell populations and related signaling pathways (e.g. oxidative phosphorylation and ATP metabolic process). The data also revealed several putative drug resistant-driven genes (STMN1, VEGFA and NDRG1) and transcription factors (E2F1, BRCA1, MYBL2, CDX2 and CDX1).We generated an oxaliplatin-resistant CRC organoid model that was employed to provide potential therapeutic targets for treating CRC patients exhibiting oxaliplatin-resistance.