Effect of cadmium on polystyrene transport in parsley roots planted in a split-root system and assessment of the combined toxic effects.

Micro and nanoplastics (MPs/NPs) coupled with heavy metals are prevalent in both aquatic and terrestrial ecosystems. Their ecological toxicity and combined adverse effects have obtained significant concern. Past studies primarily focused on how MPs/NPs influence the behavior of heavy metals. Yet, the possible effects of heavy metals on MP/NP transport and toxicity within co-contaminated systems are still not well-understood. In this study, we conducted split-root experiments to explore the transport and toxicity of polystyrene (PS) particles of varying sizes in parsley seedlings, both with and without the addition of cadmium (Cd). Both the PS-NPs (100 nm) and PS-MPs (300 nm) traveled from the PS-spiked roots (Roots-1) to the non-PS-spiked roots (Roots-2), with or without Cd, possibly because of phloem transport. Furthermore, the presence of Cd reduced the accumulation and movement of PS-NP/MP in the roots, likely due to the increased positive charge (Cd2+) on the PS surface. PS-NPs/MPs in both Roots-1 and Roots-2 were observed using transmission electron microscopy (TEM). When Cd was added to either Roots-1 (PS + Cd|H) or Roots-2 (PS|Cd), there was a minor reduction in the chlorophyll a and carotenoids content in leaves with PS|H. The adverse impacts of MPs|H on both indicators were influenced by the MP concentration. However, chlorophyll b significantly increased in the PS|H, PS + Cd|H, and PS|Cd treatments. Consequently, the chlorophyll a/b ratio declined, indicating inhibition of photosynthesis. The dehydrogenase content showed a minor change in Roots-1 and Roots-2 without Cd stress, whereas it significantly decreased on the Cd-spiked side and subsequently inhibited root growth. In contrast, the marked rise in glutathione (GSH) levels within Cd-spiked roots suggested, based on Gaussian analysis, that GSH and Cd chelation were instrumental in mitigating Cd toxicity. When Cd was introduced to both Roots-1 and Roots-2 simultaneously (PS + Cd|Cd), the aforementioned index showed a notable decline.

Analysis of hemorrhage upon ultrasound-guided percutaneous renal biopsy in China: a retrospective study.

PURPOSE: Ultrasound-guided percutaneous renal biopsy (PRB) has been considered as a golden standard for CKD diagnosis and is employed to identify potential therapeutic targets since 1950s. Post-biopsy hemorrhage is the most common complication, while severe bleeding complication might cause nephrectomy or death. Therefore, how to reduce the occurrence of complications while ensuring the success of PRB is always a clinical research topic. METHODS: This study retrospectively collected and established a renal biopsy database of each patient who underwent ultrasound-guided PRB at a tertiary teaching hospital from September 2017 to December 2020 through the Health Information System. All the data were statistically processed by SPSS software. RESULTS: A total of 1146 patients underwent PRB for various reasons. The overall rate of post-biopsy hemorrhage was 37.70% (432/1146). Of those bleedings, minor bleeding after PRB was found in 337 (29.41%), middle bleeding 84 (7.33%), major bleeding 11 (0.96%). Besides that, there were 96 patients (8.38%) reported their discomfort symptoms. There was no death. Females were at significantly increased risk of hemorrhagic complication than males (OR = 2.017, CI = 1.531-2.658). While the risk for hemorrhagic complication significantly decreased as BMI and platelet before renal biopsy increased (OR = 0.956, CI = 0.924-0.989; OR = 0.998, CI = 0.996-1.000). As the APTT time prolonged, the risk for hemorrhagic complication significantly increased (OR = 1.072, CI = 1.023-1.123). Those patients whose albumin were higher, also had higher risk for hemorrhagic complication than other patients (OR = 1.020, CI = 1.000-1.041). Specifically, postoperative urination within 4 h increased the risk for hemorrhagic complication (OR = 1.741, CI = 1.176-2.576). CONCLUSION: Our analysis finds that the incidence of post-biopsy bleeding complication is 37.70%, and its risk is associated with female, lower BMI, lower platelet before renal biopsy, prolonged APTT, higher albumin, and postoperative urination within 4 h. The findings highlighted the importance of perioperative management for renal biopsy, including adequate risk assessment, tailored careful observation after PRB. And medical staff should pay more attention to fluid management after ultrasound-guided PRB.

A Small Intestinal Stromal Tumor Detection Method Based on an Attention Balance Feature Pyramid.

Small intestinal stromal tumor (SIST) is a common gastrointestinal tumor. Currently, SIST diagnosis relies on clinical radiologists reviewing CT images from medical imaging sensors. However, this method is inefficient and greatly affected by subjective factors. The automatic detection method for stromal tumors based on computer vision technology can better solve these problems. However, in CT images, SIST have different shapes and sizes, blurred edge texture, and little difference from surrounding normal tissues, which to a large extent challenges the use of computer vision technology for the automatic detection of stromal tumors. Furthermore, there are the following issues in the research on the detection and recognition of SIST. After analyzing mainstream target detection models on SIST data, it was discovered that there is an imbalance in the features at different levels during the feature fusion stage of the network model. Therefore, this paper proposes an algorithm, based on the attention balance feature pyramid (ABFP), for detecting SIST with unbalanced feature fusion in the target detection model. By combining weighted multi-level feature maps from the backbone network, the algorithm creates a balanced semantic feature map. Spatial attention and channel attention modules are then introduced to enhance this map. In the feature fusion stage, the algorithm scales the enhanced balanced semantic feature map to the size of each level feature map and enhances the original feature information with the original feature map, effectively addressing the imbalance between deep and shallow features. Consequently, the SIST detection model's detection performance is significantly improved, and the method is highly versatile. Experimental results show that the ABFP method can enhance traditional target detection methods, and is compatible with various models and feature fusion strategies.

Malignancy-associated membranous nephropathy: focus on diagnosis and treatment.

BACKGROUND: The clinicopathological features of malignancy-associated membranous nephropathy have been described previously, but information about diagnosis and treatment remains limited. METHODS: Patients with malignancy-associated membranous nephropathy in a tertiary hospital in China between June 2012 and October 2021 were retrospectively reviewed. RESULTS: Forty-two patients with malignancy-associated membranous nephropathy were identified. Compared to patients with idiopathic membranous nephropathy, patients with malignancy-associated membranous nephropathy were older and less frequently showed glomerular phospholipase A2 receptor staining (37.9% vs 85.0%) and IgG4 predominant deposition (66.7% vs 95.0%). At diagnosis of membranous nephropathy, the malignancy was unknown in 67% (28/42) of patients and was detected only by tumor screening. Among the 19 patients with concurrent diagnosis of cancer and biopsy-proven membranous nephropathy, 15 received anticancer treatment alone initially. Six of the 10 patients who attained cancer remission achieved remission of membranous nephropathy, while none of the 5 patients without remission of cancer did, suggesting a causal relationship between the two diseases. Some patients with persistent or relapsing membranous nephropathy following cancer remission achieved remission of membranous nephropathy after immunosuppressive therapy. Over a median follow-up of 24 months, 25% (10/40) of patients died, mainly due to neoplasia. CONCLUSIONS: Tumor screening is important in patients with membranous nephropathy, especially in elderly patients and patients with negative phospholipase A2 receptor or non-IgG4 predominant deposition. Remission of membranous nephropathy can be observed following remission of cancer in some cases. Immunosuppressive therapy may be considered if membranous nephropathy does not remit after remission of cancer.

Utility of video-assisted method for identifying and preserving the external branch of the superior laryngeal nerve during thyroidectomy.

Background: The EBSLN is vulnerable to damage during thyroidectomy, results in voice related complications, negatively affect patient quality of life, routine identification of the EBSLN prior to surgical manipulation is necessary for a complication-free thyroidectomy. We aimed to validate a video-assisted procedure for identifying and preserving the external branch of the superior laryngeal nerve (EBSLN) during thyroidectomy and analyze the EBSLN Cernea classification and the localization of the nerve entry point (NEP) from the insertion of the sternothyroid muscle. Methods: A prospective descriptive study was performed; 134 patients, who scheduled for lobectomy with an intraglandular tumor max diameter ≤ 4 cm and without extrathyroidal extension, were randomly divided into the video-assisted surgery (VAS) and conventional open surgery (COS) groups. We used the video-assisted surgical procedure for visually identifying the EBSLN directly, and compared the differences in the visual identification rate and total identification rate of the two groups. We also measured the localization of the NEP using the insertion of the sternothyroid muscle as a reference. Results: There was no statistically significant difference in clinical characteristics between the two groups. The visual identification rate and total identification rate were significantly higher in the VAS group than the COS group (91.04% vs. 77.61%, 100% vs. 89.6%). The EBSLN injury rate was 0 in both groups. The mean vertical distance (VD) of the NEP from the sternal thyroid insertion was 1.18 mm (SD 1.12 mm, range, 0-5 mm), with approximately 88.97% of the results occurring within the 0-2 mm range. The mean horizontal distance (HD) was 9.33 mm (SD 5.03 mm, range, 0-30 mm), with over 92.13% of the results occurring within the 5-15 mm range. Conclusion: Both the visual and total identification rates of the EBSLN were significantly higher in the VAS group. This method provided a good visual exposure rate of the EBSLN, aiding in identifying and protecting the EBSLN during thyroidectomy.

Antimalarial activity and sensitization of chrysosplenetin against artemisinin-resistant genotype Plasmodium berghei K173 potentially via dual-mechanism of maintaining host P-glycoprotein homeostasis mediated by NF-κB p52 or PXR/CAR signaling pathways and regulating heme/haemozoin metabolism.

This study investigated antimalarial efficacy and sensitization of chrysosplenetin against artemisinin-resistant Plasmodium berghei K173 and potential molecular mechanism. Our data indicated a risk of artemisinin resistance because a higher parasitaemia% and lower inhibition% under artemisinin treatment against resistant parasites than those in the sensitive groups were observed. Two non-antimalarial components, verapamil and chrysosplentin, being P-gp inhibitors, possessed a strong efficacy against resistant parasites but it was not the case for Bcrp inhibitor novobiocin. Artemisinin-chrysosplenetin combination improved artemisinin susceptibility of resistant P. berghei. Artemisinin activated intestinal P-gp and Abcb1/Abcg2 expressions and suppressed Bcrp whereas chrysosplenetin reversed them. Resistant parasite infection led to a decreased haemozoin in organs or an increased heme in peripheral bloods compared with the sensitives; however, that in Abcb1-deficient knockout (KO)-resistant mice reversely got increased or decreased versus wild type (WT)-resistant animals. Chrysosplenetin as well as rifampin (nuclear receptor agonist) increased the transcription levels of PXR/CAR while showed a versatile regulation on hepatic and enternal PXR/CAR in WT- or KO-sensitive or -resistant parasites. Oppositely, hepatic and enteric NF-κB p52 mRNA decreased conformably in WT but increased in KO-resistant mice. NF-κB pathway potentially involved in the mechanism of chrysosplenetin on inhibiting P-gp expressions while PXR/CAR play a more complicated role in this mechanism.

A model for predicting degree of malignancy in patients with intraductal papillary mucinous neoplasm.

Background/Objectives: There is no predictive model available to address early stage malignant intraductal papillary mucinous neoplasm (IPMN) including high grade dysplasia (HGD) and pT1a (invasive component≤0.5 cm). The aim of this study was to establish an objective and sufficient model to predict the degree of malignancy in patients with IPMN, which can be easily applied in daily practice and adopted for any type of lesion. Methods: A retrospective cohort study of 309 patients who underwent surgical resection for IPMN was performed. Members of the cohort were randomly allocated to the training or testing set. A detection tree model and random forest model were used for a 3-class classification to distinguish low grade dysplasia (LGD), HGD/pT1a IPMN, and invasive intraductal papillary mucinous cancer (I-IPMC) beyond pT1a. Results: Of the 309 patients, 54 (17.4%) had early stage malignancy (19 HGD, 35 pT1a), 49 (15.9%) had I-IPMC beyond pT1a, and 206 (66.7%) had LGD IPMN. We proposed a 3-class classification model using a random forest algorithm, and the model had an accuracy of 99.5% with the training set, and displayed an accuracy of 96.0% with the testing set. We used SHAP for interpretation of the model and showed the top five factors (mural nodule size, main pancreatic duct diameter, CA19-9 levels, lesion edge and common bile duct dilation) were most likely to influence the 3-class classification results in terms of interpretation of the random forest model. Conclusions: This predictive model will help assess an individual's risk for different stages of IPMN malignancy and may help identify patients with IPMN who require surgery.

Combining Serum Procalcitonin Level, Thromboelastography, and Platelet Count to Predict Short-term Development of Septic Shock in Intensive Care Unit.

OBJECTIVE: Despite the recent advances in diagnosis and treatment, sepsis continues to lead to high morbidity and mortality. Early diagnosis and prompt treatment are essential to save lives. However, most biomarkers can only help to diagnose sepsis, but cannot predict the development of septic shock in high-risk patients. The present study determined whether the combined measurement of procalcitonin (PCT), thromboelastography (TEG) and platelet (PLT) count can predict the development of septic shock. METHODS: A retrospective study was conducted on 175 septic patients who were admitted to the intensive care unit between January 2017 and February 2021. These patients were divided into two groups: 73 patients who developed septic shock were assigned to the septic shock group, while the remaining 102 patients were assigned to the sepsis group. Then, the demographic, clinical and laboratory data were recorded, and the predictive values of PCT, TEG and PLT count for the development of septic shock were analyzed. RESULTS: Compared to the sepsis group, the septic shock group had statistically lower PLT count and TEG measurements in the R value, K value, α angle, maximum amplitude, and coagulation index, but had longer prothrombin time (DT), longer activated partial thromboplastin time (APTT), and higher PCT levels. Furthermore, the Sequential Organ Failure Assessment (SOFA) score was higher in the septic shock group. The multivariate logistic regression analysis revealed that PCT, TEG and PLT count were associated with the development of septic shock. The area under the curve analysis revealed that the combined measurement of PCT, TEG and PLT count can be used to predict the development of septic shock with higher accuracy, when compared to individual measurements. CONCLUSION: The combined measurement of PCT, TEG and PLT count is a novel approach to predict the development of septic shock in high-risk patients.

The impact of blood pressure on the risk of postbiopsy bleeding during the whole procedure of percutaneous kidney biopsy.

PURPOSE: To investigate whether BP is related to postbiopsy bleeding in patients undergoing native percutaneous kidney biopsy (PKB) and to evaluate the dynamic changes in blood pressure (BP) pre- and post-kidney biopsy. METHODS: A retrospective cross-sectional study was conducted. The whole-procedural systolic (SBP) and diastolic (DBP) BP for patients undergoing ultrasound-guided native PKB from October 2017 to December 2020 were recorded in the study. Propensity score matching was used to minimize selection bias. SBP and DBP were analyzed as the main risk factors for bleeding complications. Receiver operating characteristic (ROC) curves were employed to explore the optimal BP thresholds to differentiate between bleeding and nonbleeding. The rates of major bleeding complications were analyzed according to BP thresholds through logistic analysis. RESULTS: Of 1146 biopsies, 432 (37.7%) patients suffered from postbiopsy bleeding, 88 (7.7%) patients had major bleeding complications, and 344 (30.0%) patients had minor bleeding complications. In the original data, for patients with SBP ≥ 160 mmHg before PKB, the rate of major bleeding complications was 17.6% (7.5% for SBP < 160 mmHg), and the rate of major bleeding complications was 19.0% in patients with DBP ≥ 100 mmHg (7.5% for DBP < 100 mmHg). For patients with DBP ≥ 85 mmHg to 100 mmHg after PKB, the rate of major bleeding complications ranged from 9.5 to 17.5%. The rate of major bleeding complications was lower (6.6-7.3%) in patients with DBP < 100 mmHg to 85 mmHg. CONCLUSION: Patients who have high-level BP during the native PKB perioperative period are at higher risk for postbiopsy bleeding. High-level BP here does not refer to traditional hypertension according to the guidelines for the diagnosis and treatment of hypertension, but rather BP above a certain threshold related to bleeding risk.

Pseudoileus caused by primary visceral myopathy in a Han Chinese patient with a rare MYH11 mutation: A case report.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a syndrome of intestinal motor dysfunction caused by intestinal nerve, muscle, and/or Cajal stromal cell lesions. CIPO is a serious category of gastrointestinal dynamic dysfunction, which can eventually lead to the death of patients with intestinal failure. Due to considerable phenotypic heterogeneity, the estimated incidence of CIPO is 1/476190 and 1/416666 in men and women, respectively. According to the etiology, CIPO can be divided into idiopathic and secondary, of which the latter is the most common, often secondary to tumor, virus infection, connective tissue disease, neurological diseases, and endocrine diseases. Idiopathic CIPO in the intestinal tract is divided into visceral myopathy, neuropathy, and stromal cell lesions according to the location. Surgery is usually not recommended for CIPO, because it often does not benefit patients with CIPO, and postoperative intestinal obstruction is likely to occur, which may even worsen the condition. CASE SUMMARY: Here, we describe the case of a 43-year-old male Han Chinese patient with a 15-year history of recurrent abdominal distention with no clear cause. The results of physical, biochemical, and other relevant examinations showed no clear abnormalities. Contrast-enhanced computed tomography (CT) indicated a large duodenum, clear expansion of the intestinal lumen, and CIPO. Whole exome sequencing (WES) of the patient and his mother confirmed the diagnosis of primary familial visceral myopathy type 2 chronic pseudoileus with a rare heterozygous gene mutation in MYH11. This is the second reported case of CIPO with a heterozygous MYH11 [NM_001040113.1: c.5819delC (p.Pro1940Hisfs*91)] mutation. CONCLUSION: This case report indicates that physicians can perform routine clinical examinations, CT, and WES to achieve a diagnosis and treatment of CIPO in early disease stages.

Case report: Balloon compression for cervical chyle leakage post neck dissection.

Postoperative chyle leakage (CL) is a rare but severe complication after neck dissection, and most patients with this complication can be treated conservatively. However, in patients with high-flow leakage, efficient and well-tolerated conservative treatment options are still lacking, and the treatments can be complicated. In this study, we report a case with CL of 1100 ml/day after neck dissection that was successfully treated by balloon compression.

Combined inhibition of FGFR4 and VEGFR signaling enhances efficacy in FGF19 driven hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive liver malignancy that is difficult to treat with no approved biomarker based targeted therapies. FGF19-FGFR4 signaling blockade has been recently identified as a promising avenue for treatment of a subset of HCC patients. Using HCC relevant xenograft and PDX models, we show that Lenvatinib, an approved multi-kinase inhibitor, strongly enhanced the efficacy of FGFR4 inhibitor H3B-6527. This enhanced combination effect is not due to enhanced FGFR4 inhibition and it is likely due to cell non-autonomous VEGFR activity of Lenvatinib. This cell non-autonomous mode of action was further supported by strong in vivo combination efficacy with the mouse specific VEGFR2 antibody, DC101, which cannot cell-autonomously inhibit pathways in human xenografts. Mechanistic studies showed that the combination resulted in enhanced efficacy through increased anti-angiogenic and anti-tumorigenic activities. Overall, our results indicate that this combination can be a highly effective treatment option for FGF19 driven HCC patients, and provide preclinical validation of a combination that can be readily tested in the clinical setting.

Magnetically Guided Capsule Endoscopy and Magnetic Resonance Enterography in Children With Crohn's Disease: Manifestations and the Value of Assessing Disease Activity.

Objective: To investigate the value of magnetically guided capsule endoscopy (MGCE) and magnetic resonance enterography (MRE) in assessing the activity of pediatric Crohn's disease. Methods: Clinical data from 82 subjects with pediatric Crohn's disease, who underwent MGCE and MRE from October 2018 to March 2021 were analyzed retrospectively. Pairwise comparisons of several indexes, including MaRIA, CECDAI, PCDAI, and SES-CD, were performed by Spearman's rank correlation test and kappa consistency analysis. CECDAI and MaRIA values predicted whether patients were moderately or severely active (PCDAI ≥30) clinically by logistic regression analysis. The area under the receiver operating characteristic curve (AUC) quantified the evaluation value of moderate to severe activity of pediatric CD. Results: In judging the severity of CD in the small intestine, the correlation coefficient between CECDAI and MaRIA was 0.406 (p < 0.05), and the kappa value of the consistency analysis was 0.299 (p < 0.05). MaRIA was weakly correlated with PCDAI (r = 0.254, p < 0.05), and they were weakly consistent in assessing the activity of Crohn's disease (kappa = 0.135, p < 0.05). For predicting clinically moderate to severe activity, the fitted AUC based on CECDAI and MarRIA was 0.917, which was higher than applying a single parameter (CECDAI = 0.725, MarRIA = 0.899, respectively). MaRIA and serum albumin were significantly and negatively correlated (r = -1.064, p < 0.05). The consistency of the detection rate of gastric ulcers by MGCE and gastroscopy was moderate (kappa = 0.586, p < 0.05), and the detection rate of ulcers in the terminal ileum between MGCE and colonoscopy showed high consistency (kappa = 0.609, p < 0.05). Conclusions: MGCE and MRE are valuable, non-invasive methods for evaluating small bowel lesions in children with CD. The combined application of MGCE and MRE can better characterize the disease activity.

Integrative Characterization of the Role of IL27 In Melanoma Using Bioinformatics Analysis.

Background: IL27 has been reported to play dual roles in cancer; however, its effects on the tumor microenvironment (TME), immunotherapy, and prognosis in melanoma remain largely unclear. This study was aimed to uncover the effects of IL27 on TME, immunotherapy and prognosis in patients with melanoma. Methods: RNA-seq data, drug sensitivity data, and clinical data were obtained from TCGA, GEO, CCLE, and CTRP. Log-rank test was used to determine the survival value of IL27. Univariate and multivariate Cox regression analyses were employed to determine the independent predictors of survival outcomes. DAVID and GSEA were used to perform gene set functional annotations. ssGSEA was used to explore the association between IL27 and immune infiltrates. ConsensusClusterPlus was used to classify melanoma tissues into hot tumors or cold tumors. Results: Clinically, IL27 was negatively correlated with Breslow depth (P = 0.00042) and positively associated with response to radiotherapy (P = 0.038). High IL27 expression showed an improved survival outcome (P = 0.00016), and could serve as an independent predictor of survival outcomes (hazard ratio: 0.32 - 0.88, P = 0.015). Functionally, elevated IL27 expression could induce an enhanced immune response and pyroptosis (R = 0.64, P = 1.2e-55), autophagy (R = 0.37, P = 7.1e-17) and apoptosis (R = 0.47, P = 1.1e-27) in patients with melanoma. Mechanistically, elevated IL27 expression was positively correlated with cytotoxic cytokines (including INFG and GZMB), enhanced immune infiltrates, and elevated CD8/Treg ratio (R = 0.14, P = 0.02), possibly driving CD8+ T cell infiltration by suppressing ß-catenin signaling in the TME. Furthermore, IL27 was significantly associated with hot tumor state, multiple predictors of response to immunotherapy, and improved drug response in patients with melanoma. Conclusions: IL27 was correlated with enriched CD8+ T cells, desirable therapeutic response and improved prognosis. It thus can be utilized as a promising modulator in the development of cytokine-based immunotherapy for melanoma.

Photocatalytic degradation of ranitidine and reduction of nitrosamine dimethylamine formation potential over MXene-Ti3C2/MoS2 under visible light irradiation.

Photocatalysis is an effective method to degrade ranitidine (RAN), which is a typical precursor of nitrosamine dimethylamine (NDMA), an extremely potent human carcinogen. Herein, MXene-Ti3C2/MoS2 composites were prepared by a hydrothermal treatment aiming to use them for the photocatalytic degradation of RAN and the reduction of NDMA formation potential (NDMA-FP) under visible light irradiation for the first time. The analysis of the morphology, chemical composition and structure of these composites as well as the results of electrochemical experiments showed that a heterojunction was formed between MoS2 and Ti3C2, which facilitated the separation of electron-hole pairs and charge transfer, and thereby the photocatalytic performance. The MXene-Ti3C2/MoS2 composite (MT-4) exhibited the best photocatalytic performance in 60 min, with the highest RAN degradation and mineralization efficiencies of 88.4% and 73.58%, and the lowest NDMA-FP of 2.01%. Active species, including •O2- radicals, h+ and •OH radicals, all contributed to the degradation of RAN, among which •OH radicals were the main active species involved in the photocatalytic activity. The mechanism of the photocatalytic degradation of RAN over MXene-Ti3C2/MoS2 photocatalyst under visible light irradiation was proposed. This work opens up a new perspective on the applications of MXene-based materials for photocatalytic degradation of challenging pollutants.

Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3.

Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties.

A large-scale drug screen identifies selective inhibitors of class I HDACs as a potential therapeutic option for SHH medulloblastoma.

BACKGROUND: Medulloblastoma (MB) is one of the most frequent malignant brain tumors of children, and a large set of these tumors is characterized by aberrant activation of the sonic hedgehog (SHH) pathway. While some tumors initially respond to inhibition of the SHH pathway component Smoothened (SMO), tumors ultimately recur due to downstream resistance mechanisms, indicating a need for novel therapeutic options. METHODS: Here we performed a targeted small-molecule screen on a stable, SHH-dependent murine MB cell line (SMB21). Comprehensive isotype profiling of histone deacetylase (HDAC) inhibitors was performed, and effects of HDAC inhibition were evaluated in cell lines both sensitive and resistant to SMO inhibition. Lastly, distinct mouse models of SHH MB were used to demonstrate pharmacologic efficacy in vivo. RESULTS: A subset of the HDAC inhibitors tested significantly inhibit tumor growth of SMB21 cells by preventing SHH pathway activation. Isotype profiling of HDAC inhibitors, together with genetic approaches suggested that concerted inhibition of multiple class I HDACs is necessary to achieve pathway inhibition. Of note, class I HDAC inhibitors were also efficacious in suppressing growth of diverse SMO inhibitor‒resistant clones of SMB21 cells. Finally, we show that the novel HDAC inhibitor quisinostat targets multiple class I HDACs, is well tolerated in mouse models, and robustly inhibits growth of SHH MB cells in vivo as well as in vitro. CONCLUSIONS: Our data provide strong evidence that quisinostat or other class I HDAC inhibitors might be therapeutically useful for patients with SHH MB, including those resistant to SMO inhibition.

Facile construction of reduced graphene oxide supported three-dimensional polyaniline/WO2.72 nanobelt-flower as a full solar spectrum light response catalyst for efficient photocatalytic conversion of bromate.

As a carcinogenic byproduct in drinking water treatment, bromate has raised global concerns on environmental and health hazard, calling for effective treatments. In the current work, a novel reduced graphene oxide supported polyaniline/WO2.72 nanobelt-flower (RGO/PANI/WO2.72) ternary composite was prepared through a solvent volatilization method for photocatalytic reduction of bromate. The prepared sample was characterized, and the influence of aqueous pH, ions and dissolved oxygen on the bromate reduction was explored. As expected, the introduction of RGO and PANI on the WO2.72 exhibited great synergistic effects on the separation of photogenerated carriers. The calculated reduction rate constant of RGO/PANI/WO2.72 was about six times as high as that of pure WO2.72. Specially, the prepared photocatalyst possessed strong optical absorption in a broad range of 250-2500 nm, and thus displaying excellent catalytic performance in utilization of all solar spectrum energy. Moreover, the RGO/PANI/WO2.72 exhibited stable photocatalytic activity in cycling test. Considered holistically, the present study offered a valuable approach for rational construction of heterogeneous structure in the development of bromate-catalyzed reduction.

[The design and assessment of a novel simulated training system for cardiac surgery].

Simulations can mimic the environment that refers to the surgery operation to improve the technical skills of the trainees. In this paper, we designed a new cardiac surgery simulative training system. The isolated pig heart was selected as the heart model. A mechanical device was designed to achieve the beating of heart model. At the same time, adjusting frequencies of mechanical movement could change the rating of heartbeat. In order to validate the rationality of the system, 12 non-medical specialty students and 12 medical specialty students were divided into two groups, which consecutively accepted seven-days of training for off-pump coronary artery bypass grafting using the cardiac surgery simulative training system. The time for completing bypass grafting before and after training were recorded. And the bridging outcomes of each trainee were assessed by 3 surgery cardiac surgeons using the object structured assessments of technical skill (OSATS) criteria. After training, each trainee could finish the bypass suturing in a shorter time than before training, and the scores of each trainee assessed by OSATS criteria were also improved. The results showed that the cardiac surgery simulative training system had better training effect in improving the surgical techniques, operation skills and proficiency of surgical instruments of trainees.