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To provide an overview of techniques for prevention, immediate diagnosis, and treatment strategies of intraoperative pulmonary embolism caused by renal tumor thrombus shedding.A total of 290 patients admitted into our medical center from March 2015 to May 2021 were retrospectively analyzed. All patients underwent radical nephrectomy with tumor thrombectomy. Six patients were diagnosed as pulmonary embolism during the perioperative period, of which two patients had tumor thrombus shedding. One patient underwent thoracotomy and thrombectomy, one patient underwent interventional thrombectomy, and four patients underwent conservative treatment. All patients have gone through our diagnosis and strategy flow chart. Demographic data, tumor characteristics, tumor thrombus characteristics, and follow-up data were collected.In the preoperative risk factor assessment, of the 253 patients who entered the follow-up, 163 were women, 48 were older than 60 years old, and 83 had a duration of more than 2 months. In addition, 27 patients had tumor thrombus with bland thrombus, and 43 patients had floating tumor thrombus. 78 patients underwent postoperative anticoagulation after evaluation. The average follow-up time was 23.3 For acute pulmonary embolism during nephrectomy and tumor thrombectomy, management strategies can be used to deal with intraoperative emergencies and provide reference.

Interfacing with the human body, wearable and implantable bioelectronics are a compelling platform technology for healthcare monitoring and medical therapeutics. However, clinical adoption of these devices is largely shadowed by their weakness in humidity resistance, stretchability, durability, and biocompatibility. In this work, we report a self-powered waterproof biomechanical sensor with stretchability up to 440% using the giant magnetoelastic effect in a soft polymer system. By manipulating the magnetic dipole alignment, the sensor achieved a particularly broad sensing range from 3.5 Pa to 2000 kPa, with a response time of ∼3 ms. To validate the excellent performance of the magnetoelastic sensor in biomonitoring, both

Intestinal barrier dysfunction is inflammatory bowel disease's hallmark. Berberine (BBR) has manifested its anti-inflammatory properties in colitis. For exploring the molecular mechanism of BBR's impacts on colitis, application of a dextran sodium sulfate-induced mouse colitis

The high moisture level of exhaled gases unavoidably limits the sensitivity of breath analysis via wearable bioelectronics. Inspired by pulmonary lobe expansion/contraction observed during respiration, a respiration-driven triboelectric sensor (RTS) was devised for simultaneous respiratory biomechanical monitoring and exhaled acetone concentration analysis. A tin oxide-doped polyethyleneimine membrane was devised to play a dual role as both a triboelectric layer and an acetone sensing material. The prepared RTS exhibited excellent ability in measuring respiratory flow rate (2-8 L/min) and breath frequency (0.33-0.8 Hz). Furthermore, the RTS presented good performance in biochemical acetone sensing (2-10 ppm range at high moisture levels), which was validated via finite element analysis. This work has led to the development of a novel real-time active respiratory monitoring system and strengthened triboelectric-chemisorption coupling sensing mechanism.

Traditional public health systems are suffering from limited, delayed, and inefficient medical services, especially when confronted with the pandemic and the aging population. Fusing traditional textiles with diagnostic, therapeutic, and protective medical devices can unlock electronic textiles (e-textiles) as point-of-care platform technologies on the human body, continuously monitoring vital signs and implementing round-the-clock treatment protocols in close proximity to the patient. This review comprehensively summarizes the research advances on e-textiles for wearable point-of-care systems. We start with a brief introduction to emphasize the significance of e-textiles in the current healthcare system. Then, we describe textile sensors for diagnosis, textile therapeutic devices for medical treatment, and textile protective devices for prevention, by highlighting their working mechanisms, representative materials, and clinical application scenarios. Afterward, we detail e-textiles' connection technologies as the gateway for real-time data transmission and processing in the context of 5G technologies and Internet of Things. Finally, we provide new insights into the remaining challenges and future directions in the field of e-textiles. Fueled by advances in chemistry and materials science, textile-based diagnostic devices, therapeutic devices, protective medical devices, and communication units are expected to interact synergistically to construct intelligent, wearable point-of-care textile platforms, ultimately illuminating the future of healthcare system in the Internet of Things era.

Background Circular RNAs (circRNAs) are crucial in the regulation of gene expression and biological processes. However, in colorectal cancer, the expression characteristics and biological function of circRNA_0006174 (circ_0006174) is not fully understood. This work is aimed to investigate the biological function of circ_0006174 in colorectal cancer and its molecular mechanism. Methods Circ_0006174, microRNA-142-3p and X-linked inhibitor of apoptosis expression levels were detected in colorectal cancer tissues and cells using quantitative real-time polymerase chain reaction analysis or Western blot. The effects of circ_0006174 on colorectal cancer cell proliferation, apoptosis, migration and invasion were detected using the cell counting kit-8 method, bromodeoxyuridine experiments, flow cytometry analysis and Transwell experiments. The targeting relationship among circ_0006174, microRNA-142-3p and X-linked inhibitor of apoptosis was analysed by bioinformatics prediction, dual-luciferase reporter experiment and RNA immunoprecipitation experiment. Results Circ_0006174 was up-regulated in colorectal cancer tissues as well as in cell lines, and its high expression was remarkably associated with enlarged tumour volume and advanced tumour, node, metastasis stage of the patients. Circ_0006174 overexpression enhanced colorectal cancer cell proliferation, migration and invasion, and inhibited colorectal cancer cell apoptosis; while knocking down circ_0006174 caused the opposite effects. Circ_0006174 directly targeted and negatively regulated microRNA-142-3p expression, and X-linked inhibitor of apoptosis, a target gene of microRNA-142-3p, could be indirectly and positively modulated by circ_0006174. Conclusion Circ_0006174 facilitates colorectal cancer cell proliferation, migration and invasion, and represses colorectal cancer cell apoptosis by regulating microRNA-142-3p/X-linked inhibitor of apoptosis axis.

Background We aimed to compare the oncological outcomes between the oblique occlusion technique and the traditional technique for robot-assisted radical nephrectomy (RARN) with inferior vena cava (IVC) thrombectomy, and to explore the safety and effectiveness of the oblique occlusion technique. Methods Overall, 21 patients with renal cell carcinoma (RCC) and IVC tumor thrombus (TT) were admitted to our hospital from August 2019 to June 2020. All the patients underwent RARN with IVC thrombectomy, of which the IVC oblique occlusion technique was used in 11 patients and traditional occlusion technique was used in 10 patients. The oblique occlusion technique refers to oblique blocking from the upper corner of the right renal vein to the lower corner of the left renal vein using a vessel tourniquet or a vessel clamp (left RCC with IVCTT as an example). Results Compared with patients in the traditional group, those in the oblique group had lower serum creatinine at follow-up (3 month) (95 ± 21.1 vs. 131 ± 30.7 μmol/L, P = 0.03). There was no significant difference in operation time [149 (IQR 143–245) min vs. 148 (IQR 108–261) min, p = 0.86], IVC clamping time [18 (IQR 12–20) min vs. 20 (IQR 14–23) min, p = 0.41], and estimated intraoperative blood loss [300 (IQR 100–800) mL vs. 500 (IQR 175–738) mL, p = 0.51] between both groups. During a 16-month (range, 15–23 months) follow-up period, two cases progressed in the oblique group and three cases progressed in the traditional group. Conclusions The modified IVC oblique occlusion technique procedure is relatively safe and effective in RARN with IVC thrombectomy. The IVC oblique occlusion technique may play a role in the protection of renal function.

Circular RNAs (circRNAs) are novel RNA transcripts that participate in cancer development. Nonetheless, in colorectal cancer (CRC), the information ~circRNA expression and function is largely unknown. The present study aimed to investigate the expression, function and underlying mechanism of circ_0006174 in CRC. Reverse transcription‑quantitative PCR analysis was performed to detect circ_0006174, miR‑1205 and calcium‑binding epidermal growth factor domain‑containing protein 1 (CCBE1) expression levels in CRC tissues and cell lines. Circ_0006174 knockdown CRC cell models were established. CCK‑8, TUNEL and Transwell methods were utilized to explore the function of circ_0006174 on the malignant phenotype of CRC cells. Moreover, a xenograft nude mouse model was constructed to verify the effects of circ_0006174 on lung metastasis

Objective To describe the clinical characteristics of renal cell carcinoma (RCC) with venous tumor thrombus (VTT) and bland thrombus (BT), and to evaluate the influence of BT on surgical treatment and cancer‐specific survival (CSS) of RCC with VTT. Methods We retrospectively reviewed clinical data of 123 patients with RCC and VTT, who underwent surgical treatment in our center between February 2015 and May 2018. Patients were divided into the BT group (21 patients) and non‐BT group (102 patients). Chi‐square and Mann‐Whitney U test were used for categorical and continuous variables respectively. Univariable log‐rank tests and multivariable Cox regressions were conducted to evaluate the prognostic significance of each variable. Kaplan‐Meier plots were performed to evaluate the influence of BT. Results In the delayed phase of enhanced magnetic resonance imaging (MRI), BT and VTT had difference. Patients were divided according to the relative position of BT: proximal end BT (one patients), contralateral renal vein BT (two patients), distal end BT (12 patients), and multiple BT (six patients). The average length of BT was 8.4 ± 5.8 cm (range: 0.6‐20.0 cm). Patients with BT had longer operative time (P = .001), more surgical blood loss (P = .004), higher proportion of open surgery (P = .006), more postoperative complications (P = .011). BT (hazard ratio [HR] = 3.323, P = .007) were independent risk factors for poor prognosis. Conclusions In the delayed phase of enhanced MRI, BT showed no obvious enhancement, while VTT usually showed enhancement. This was an important basis for preoperative imaging diagnosis of BT. The presence of BT increases the difficulty of surgery, and is correlated with adverse survival outcomes in patients with RCC and VTT., MRI is an important examination for RCC patients with VTT and BT. BT has adverse influence on surgical treatment and survival.

Inactivating mutations in the liver kinase B1 (LKB1) tumor suppressor gene underlie Peutz-Jeghers syndrome (PJS) and occur frequently in various human cancers. We previously showed that LKB1 regulates centrosome duplication via PLK1. Here, we report that LKB1 further helps to maintain genomic stability through negative regulation of survivin, a member of the chromosomal passenger complex (CPC) that mediates CPC targeting to the centromere. We found that loss of LKB1 led to accumulation of misaligned and lagging chromosomes at metaphase and anaphase and increased the appearance of multi- and micro-nucleated cells. Ectopic LKB1 expression reduced these features and improved mitotic fidelity in LKB1-deficient cells. Through pharmacological and genetic manipulations, we showed that LKB1-mediated repression of survivin is independent of AMPK, but requires p53. Consistent with the key influence of LKB1 on survivin expression, immunohistochemical analysis indicated that survivin is highly expressed in intestinal polyps from a PJS patient. Lastly, we reaffirm a potential therapeutic avenue to treat LKB1-mutated tumors by demonstrating the increased sensitivity to survivin inhibitors of LKB1-deficient cells.

Background. Radical nephrectomy and thrombectomy is the standard surgical procedure for the treatment of renal cell carcinoma (RCC) with tumor thrombus (TT). But the estimation of intra-operative blood loss is only based on the surgeon's experience. Therefore, our study aimed to develop Peking University Third Hospital score (PKUTH score) for the prediction of intra-operative blood loss volume in radical nephrectomy and thrombectomy. Methods. The clinical data of 153 cases of renal mass with renal vein (RV) or inferior vena cava tumor thrombus admitted to Department of Urology, Peking University Third Hospital from January 2015 to May 2018 were retrospectively analyzed. The total amount of blood loss during operation is equal to the amount of blood sucked out by the aspirator plus the amount of blood in the blood-soaked gauze. Univariate linear analysis was used to analyze risk factors for intra-operative blood loss, then significant factors were included in subsequent multivariable linear regression analysis. Results. The final multivariable model included the following three factors: open operative approach (P

How to discriminate different risks of recurrent nasopharyngeal carcinoma (rNPC) patients and guide individual treatment has become of great importance. This study aimed to explore the associations between deep learning signatures and biological functions as well as survival in (rNPC) patients.A total of 420 rNPC patients with PET/CT imaging and follow-up of overall survival (OS) were retrospectively enrolled. All patients were randomly divided into a training set (n = 269) and test set (n = 151) with a 6:4 ratio. We constructed multi-modality deep learning signatures from PET and CT images with a light-weighted deep convolutional neural network EfficienetNet-lite0 and survival loss DeepSurvLoss. An integrated nomogram was constructed incorporating clinical factors and deep learning signatures from PET/CT. Clinical nomogram and single-modality deep learning nomograms were also built for comparison. Furthermore, the association between biological functions and survival risks generated from an integrated nomogram was analyzed by RNA sequencing (RNA-seq).The C-index of the integrated nomogram incorporating age, rT-stage, and deep learning PET/CT signature was 0.741 (95% CI: 0.688-0.794) in the training set and 0.732 (95% CI: 0.679-0.785) in the test set. The nomogram stratified patients into two groups with high risk and low risk in both the training set and test set with hazard ratios (HR) of 4.56 (95% CI: 2.80-7.42, p 0.001) and 4.05 (95% CI: 2.21-7.43, p 0.001), respectively. The C-index of the integrated nomogram was significantly higher than the clinical nomogram and single-modality nomograms. When stratified by sex, N-stage, or EBV DNA, risk prediction of our integrated nomogram was valid in all patient subgroups. Further subgroup analysis showed that patients with a low-risk could benefit from surgery and re-irradiation, while there was no difference in survival rates between patients treated by chemotherapy in the high-risk and low-risk groups. RNA sequencing (RNA-seq) of data further explored the mechanism of high- and low-risk patients from the genetic and molecular level.Our study demonstrated that PET/CT-based deep learning signatures showed satisfactory prognostic predictive performance in rNPC patients. The nomogram incorporating deep learning signatures successfully divided patients into different risks and had great potential to guide individual treatment: patients with a low-risk were supposed to be treated with surgery and re-irradiation, while for high-risk patients, the application of palliative chemotherapy may be sufficient.

Purpose To explore the effect of tumor thrombus growing against the direction of venous return (GADVR) tumor thrombus on the choice of surgical approach, the impact on the complexity of the surgery and the prognosis. Methods We retrospectively analyzed the clinicopathological data of 213 patients, who underwent surgery in a single center of Peking University Third Hospital between January 2016 and June 2020. For right renal cell carcinoma (RCC) and venous tumor thrombus (VTT), imaging revealed a filling defect in the left renal vein, which was significantly enhanced in enhanced imaging, suggesting that the tumor thrombus grew against the direction of venous return into the left renal vein. For left RCC and VTT, at least one of the left renal vein branches has tumor thrombus. The branches include the left adrenal vein, the left gonadal vein (testicular vein or ovarian vein), and the left ascending lumbar vein. The patients were divided into two groups according to whether they were GADVR tumor thrombus, and we compare the clinicopathological characteristics of GADVR tumor thrombus and non-GADVR tumor thrombus. Univariate and multivariate Cox regression analyses were performed to explore the risk factors that affect the prognosis of patients with RCC and VTT. Kaplan–Meier plots were conducted to evaluate the effect of GADVR on progression-free survival (PFS). Results Compared with non-GADVR tumor thrombus, patients with GADVR tumor thrombus had a higher proportion of open surgery (76.2% vs. 52.1%, P = 0.035), a higher proportion of tumor thrombus adhering to the inferior vena cava (IVC) vessel wall (81% vs. 45.8%, P = 0.002), a higher proportion of segmental resection of the IVC vessel wall (61.9% vs. 15.6%, P Conclusion GADVR tumor thrombus is a characteristic feature of tumor thrombus, with an incidence of 9.9%. It has a higher proportion of open surgery and higher surgical complexity, which is an independent risk factor for PFS.

Magnetoelastic effect characterizes the change of materials’ magnetic properties under mechanical deformation, which is conventionally observed in some rigid metals or metal alloys. Here we show magnetoelastic effect can also exist in 1D soft fibers with stronger magnetomechanical coupling than that in traditional rigid counterparts. This effect is explained by a wavy chain model based on the magnetic dipole-dipole interaction and demagnetizing factor. To facilitate practical applications, we further invented a textile magnetoelastic generator (MEG), weaving the 1D soft fibers with conductive yarns to couple the observed magnetoelastic effect with magnetic induction, which paves a new way for biomechanical-to-electrical energy conversion with short-circuit current density of 0.63 mA cm−2, internal impedance of 180 Ω, and intrinsic waterproofness. Textile MEG was demonstrated to convert the arterial pulse into electrical signals with a low detection limit of 0.05 kPa, even with heavy perspiration or in underwater situations without encapsulations., The authors invented a textile magnetoelastic generator, weaving 1D soft fibers with conductive yarns to couple the observed magnetoelastic effect with magnetic induction, which paves a new way for biomechanical-to-electrical energy conversion.

Wearable bioelectronics for continuous and reliable pulse wave monitoring against body motion and perspiration remains a great challenge and highly desired. Here, a low-cost, lightweight, and mechanically durable textile triboelectric sensor that can convert subtle skin deformation caused by arterial pulsatility into electricity for high-fidelity and continuous pulse waveform monitoring in an ambulatory and sweaty setting is developed. The sensor holds a signal-to-noise ratio of 23.3 dB, a response time of 40 ms, and a sensitivity of 0.21 μA kPa(−1). With the assistance of machine learning algorithms, the textile triboelectric sensor can continuously and precisely measure systolic and diastolic pressure, and the accuracy is validated via a commercial blood pressure cuff at the hospital. Additionally, a customized cellphone application (APP) based on built-in algorithm is developed for one-click health data sharing and data-driven cardiovascular diagnosis. The textile triboelectric sensor enabled wireless biomonitoring system is expected to offer a practical paradigm for continuous and personalized cardiovascular system characterization in the era of the Internet of Things.

To investigate perioperative clinicopathological predictors and establish a predictive nomogram for survival in patients with renal cell carcinoma and venous tumor thrombus undergoing nephrectomy and thrombectomy.Patients with renal cell carcinoma and venous tumor thrombus undergoing nephrectomy and thrombectomy were included in the study between January 2014 and June 2020. Cox regression analysis was used for univariate and multivariate survival analyses. A predictive nomogram for survival was established and internally validated using bootstrap resampling method.A total of 228 patients were enrolled in this study. The median age was 60 years (interquartile range 53-66 years), consisting of 174 (76.3%) males and 54 (23.7%) females. The median follow-up time was 17.5 months (range 1-74 months), 26.8% (61 of 228) patients died of all causes. In multivariable analysis, hemoglobin less than the lower limit of normal (hazard ratio 1.73; 95% confidence interval 1.01-2.96; P = 0.045), sarcomatoid feature (hazard ratio 3.67; 95% confidence interval 1.97-6.82; P 0.001), perirenal fat invasion (hazard ratio 1.80; 95% confidence interval 1.05-3.09; P = 0.033), histological subtype (hazard ratio 2.74; 95% confidence interval 1.39-5.41; P = 0.004), and metastasis at surgery (hazard ratio 1.71; 95% confidence interval 1.01-2.90; P = 0.047) were independently associated with overall survival. The result of internal validation presented that the predictive performance of the nomogram for survival measured by C-index was 0.77.We developed a predictive nomogram with well-internal validation for survival in patients with renal cell carcinoma and venous tumor thrombus, which can greatly promote risk stratification and treatment planning.

Background: Induction chemotherapy (ICT) plus concurrent chemoradiotherapy (CCRT) and CCRT alone were the optional treatment regimens in locoregionally advanced nasopharyngeal carcinoma (NPC) patients. Currently, the choice of them remains equivocal in clinical practice. We aimed to develop a deep learning-based model for treatment decision in NPC. Methods: A total of 1872 patients with stage T3N1M0 NPC were enrolled from four Chinese centres and received either ICT+CCRT or CCRT. A nomogram was constructed for predicting the prognosis of patients with different treatment regimens using multi-task deep learning radiomics and pre-treatment MR images, based on which an optimal treatment regimen was recommended. Model performance was assessed by the concordance index (C-index) and the Kaplan-Meier estimator. Findings: The nomogram showed excellent prognostic ability for disease-free survival in both the CCRT (C-index range: 0.888-0.921) and ICT+CCRT (C-index range: 0.784-0.830) groups. According to the prognostic difference between treatments using the nomogram, patients were divided into the ICT-preferred and CCRT-preferred groups. In the ICT-preferred group, patients receiving ICT+CCRT exhibited prolonged survival over those receiving CCRT in the internal and external test cohorts (hazard ratio [HR]: 0.17, p

Circular RNAs (circRNAs) feature prominently in regulating the malignant biological behaviors of colorectal cancer (CRC), including cell viability, cell cycle progression, apoptosis, migration, invasion, and so on. This study is performed to probe into the biological function and molecular mechanism of circ_0087862 in CRC. The expression profile of GSE138589 was available from Gene Expression Omnibus (GEO), and the differentially expressed circRNAs were analyzed by GEO2R. The expression of circ_0087862, miR‐142‐3p, and BACH1 mRNA in CRC tissues and cells was measured by qRT‐PCR. CCK‐8 assay was employed to determine the proliferation of CRC cells. Scratch wound healing and transwell assays were used to examine the migration and invasion of CRC cells. The targeting relationships between circ_0087862 and miR‐142‐3p, and between miR‐142‐3p and BACH1 3′UTR were verified by dual‐luciferase reporter gene assay and RIP assay. BACH1 protein expression was probed by western blot. Circ_0087862 was highly expressed in CRC tissues and cell lines. Knocking down circ_0087862 significantly restrained the multiplication, migration and invasion of CRC cells. miR‐142‐3p inhibition weakened the impact of circ_0087862 knockdown on CRC cells. Circ_0087862 regulated BACH1 expressions by targeting miR‐142‐3p. Circ_0087862 regulates BACH1 expressions through sponging miR‐142‐3p, and promotes the proliferation, migration, and invasion of CRC cells.

Background: Radical nephrectomy with thrombectomy is one of the most difficult and complicated urological operations. But the roles of renal tumor volume and thrombus level in surgical complexity and prognostic outcome are not clear. This study aimed to evaluate the surgical complexity and prognostic outcome between the volume of renal cell carcinoma (RCC) and the level of venous tumor thrombus. Methods: The clinical data of 67 RCC cases with renal vein or inferior vena cava (IVC) tumor thrombus from January 2015 to May 2018 were retrospectively analyzed. Among these 67 cases, 21 (31.3%) were small tumors with high-level thrombus (tumor ≤7 cm in diameter and thrombus Neves Level II–IV), while 46 (68.7%) were large tumors with low-level thrombus group (tumor >7 cm in diameter and thrombus Level 0–I). Clinical features, operation details, and pathology data were collected. Univariable and multivariable logistic regression analyses were applied to evaluate the risk factors for small tumor with high-level thrombus. Results: Patients with small tumors and high-level thrombus were more likely to have longer operative time (421.9 ± 135.1 min vs. 282.2 ± 101.9 min, t = 4.685, P < 0.001), more surgical bleeding volume (1200 [325, 2900] mL vs. 500 [180, 1000] mL, U = 270.000, P = 0.004), more surgical blood transfusion volume (800 [0, 1400] mL vs. 0 [0, 800] mL, U = 287.500, P = 0.004), more plasma transfusion volume (0 [0, 800] mL vs. 0 [0, 0] mL, U = 319.000, P = 0.004), higher percentage of open operative approach (76.2% vs. 32.6%, χ2 = 11.015, P = 0.001), higher percentage of IVC resection (33.3% vs. 0%, χ2 = 17.122, P < 0.001), and higher percentage of post-operative complications (52.4% vs. 19.6%, χ2 = 7.415, P = 0.010) than patients with large tumors and low-level thrombus. In multivariate analysis, decreased hemoglobin (Hb) (odds ratio [OR]: 0.956, 95% confidence interval [CI]: 0.926–0.986, P = 0.005) and non-sarcomatoid differentiation (OR: 0.050, 95% CI: 0.004–0.664, P = 0.023) were more likely to form small tumors with high-level tumor thrombus rather than large tumor with small tumor thrombus. The estimated mean cancerspecific survival times of small tumor with high-level thrombus and large tumor with low-level thrombus were 31.6 ± 3.8 months and 32.5 ± 2.9 months, without statistical significance (P = 0.955). After univariate and multivariate Cox proportional hazard survival regression analyses, only distant metastasis (hazard ratio [HR]: 3.839, P = 0.002), sarcomatoid differentiation (HR: 7.923, P < 0.001), alkaline phosphatase (HR: 2.661, P = 0.025), and severe post-operative complications (HR: 10.326, P = 0.001) were independent predictors of prognosis. Conclusions: The level of the tumor thrombus was more important than the diameter of the primary kidney tumor in affecting the complexity of surgery. In the same T3 stage, neither the renal tumor diameter nor the tumor thrombus level was an independent risk factor for prognosis. Key words: Inferior vena cava; Tumor thrombus; Renal cell carcinoma; Cancer-specific survival; Prognosis; Neves classification

Purpose To explore the safety and effectiveness of delayed occlusion of the proximal inferior vena cava (DOPI) technique in retroperitoneal laparoscopic radical nephrectomy (LRN) and thrombectomy for renal tumor with level II-III venous tumor thrombus (VTT). Materials and methods From August 2016 to October 2018, a total of 145 patients with renal tumor and VTT were admitted to our centre. Seventy-five patients underwent laparoscopic surgery, and 70 patients underwent open surgery. Among these patients, 17 patients underwent retroperitoneal LRN and thrombectomy with the DOPI technique. Clinical data were collected retrospectively, and a descriptive statistical analysis was conducted. Results All the patients successfully underwent retroperitoneal laparoscopic surgery. The mean operation time was 345.9 ± 182.9 min, the mean estimated blood loss was 466.7 ± 245.5 ml. Postoperative complications occurred in three patients, including two patients of Clavien grading system level IVa and one patient of level II. There were no complications related to carbon dioxide pneumoperitoneum, such as gas embolism, acidosis, and subcutaneous emphysema. During 21 months of median follow-up time, no local recurrence was found, and distant metastasis occurred in four patients. Cancer-specific death occurred in two patients. Conclusions The DOPI technique is safe and feasible in the treatment of renal tumor and level II-III VTT. With the DOPI technique, the procedures of dissociating and exposing proximal inferior vena cava are simplified.

The magnetoelastic effect—the variation of the magnetic properties of a material under mechanical stress—is usually observed in rigid alloys, whose mechanical modulus is significantly different from that of human tissues, thus limiting their use in bioelectronics applications. Here, we observed a giant magnetoelastic effect in a soft system based on micromagnets dispersed in a silicone matrix, reaching a magnetomechanical coupling factor indicating up to four times more enhancement than in rigid counterparts. The results are interpreted using a wavy chain model, showing how mechanical stress changes the micromagnets’ spacing and dipole alignment, thus altering the magnetic field generated by the composite. Combined with liquid-metal coils patterned on polydimethylsiloxane working as a magnetic induction layer, the soft magnetoelastic composite is used for stretchable and water-resistant magnetoelastic generators adhering conformably to human skin. Such devices can be used as wearable or implantable power generators and biomedical sensors, opening alternative avenues for human-body-centred applications. Micromagnets dispersed in a polymer matrix are used to realize a soft magnetoelastic generator with high magnetomechanical coupling factor, used for wearable and implantable power generation and sensing applications.

Background To analyze the influence of inferior vena cava (IVC) interruption for perioperative and oncological results in patients with renal cell carcinoma and tumor thrombus and summarize the surgical strategies of IVC interruption for different situations. Methods We retrospectively analyzed the clinical and pathological data of 103 patients in our center. Patients were divided into two groups with 32 cases (31.1%) underwent IVC interruption (Group 1) while 71 cases (68.9%) did not. For comparison of continuous variables, the Mann–Whitney U test was used. For comparison of categorical variables, Chi-square tests were used. A propensity score based matching method was used to eliminate possible bias. Kaplan–Meier plots were performed to evaluate the influence of IVC interruption on overall survival and cancer specific survival. All the statistical analyses were performed using SPSS 24. A P value Results Among the 32 patients who underwent IVC interruption, the median age was 61 years and the median tumor size was 7.7 cm. There were 28 males and 23 tumors were on the right side. We successfully matched 29 patients who underwent IVC interruption to 29 patients without this procedure in 1:1 ratio. No significant differences existed in baseline characteristics between the groups. The comparison of perioperative data showed that patients who underwent IVC interruption had significantly longer median postoperative hospital stays (13 vs 9 days, P = 0.022) and a higher overall postoperative complication rate (79.3 vs 51.7%, P = 0.027). According to the side and shape of tumor thrombus, it could be divided into four categories. There were 15 cases (46.9%) with right filled-type tumor thrombus (RFTT), 8 cases (25.0%) with right non-filled-type tumor thrombus (RNFTT), 1 case (3.1%) with left filled-type tumor thrombus (LFTT) and 8 cases (25.0%) with left non-filled-type tumor thrombus (LNFTT). According to different categories, different surgical procedures were adopted. Conclusions IVC interruption will increase the incidence of overall postoperative complications, but not the risk of major postoperative complications. Tumor thrombus should be divided into four categories, and different sides and shapes of renal tumor thrombus need different operative procedure of IVC interruption.

Wearable respiratory monitoring is a fast, non-invasive, and convenient approach to provide early recognition of human health abnormalities like restrictive and obstructive lung diseases. Here, a computational fluid dynamics assisted on-mask sensor network is reported, which can overcome different user facial contours and environmental interferences to collect highly accurate respiratory signals. Inspired by cribellate silk, Rayleigh-instability-induced spindle-knot fibers are knitted for the fabrication of permeable and moisture-proof textile triboelectric sensors that hold a decent signal-to-noise ratio of 51.2 dB, a response time of 0.28 s, and a sensitivity of 0.46 V kPa

Background Autosomal recessive cutis laxa type IC (ARCL IC, MIM: #613177) results from a mutation in the LTBP4 gene (MIM: #604710) on chromosome 19q13. Case presentation A 28-day-old Chinese infant with generalized cutis laxa accompanied by impaired pulmonary, gastrointestinal, genitourinary, retinal hemorrhage, abnormality of coagulation and hyperbilirubinemia was admitted to our hospital. To find out the possible causes of these symptoms, whole-exome sequencing was performed on the infant. Two novel pathogenic frame-shift variants [c.605_606delGT (p.Ser204fs * 8) and c.1719delC (p.Arg574fs * 199)] of the LTBP4 gene associated with ARCL IC were found which was later verified by Sanger sequencing. The pathogenicity of mutations was subsequently assessed by several software programs and databases. In addition, an analytical review on the clinical phenotypes of the disease previously reported in literature was performed. Conclusions This is the first report of a Chinese infant with ARCL IC in China due to novel pathogenic variations of LTBP4. Our study extends the cutis laxa type IC mutation spectrum as well as the phenotypes associated with the disease in different populations.

Background We aimed to explore the causal analysis, clinical characteristics and treatment strategies of laparoscopic conversion to open approach (LCTOA) in radical nephrectomy and tumor thrombectomy. Methods We included all patients with Mayo level I–III renal tumors with inferior vena cava (IVC) tumor thrombus who underwent laparoscopic radical nephrectomy and tumor thrombectomy as the first choice from May 2015 to July 2019. Results There were 70 cases of renal tumor with IVC tumor thrombus treated with a laparoscopic approach as the first choice; 31 Mayo level I, 30 Mayo level II, and 9 Mayo level III. A completely laparoscopic approach was performed in 51 cases (72.9%), and 19 cases (27.1%) underwent active or passive LCTOA. The LCTOA group had higher median preoperative serum creatinine (110.0 μmol/L vs 92.0 μmol/L; P = 0.026), longer postoperative hospital stay (9 days vs 7 days; P = 0.008), longer median operation time (374 min vs 311 min; P = 0.017), higher median intraoperative hemorrhage volume (1300 vs 600 ml; P = 0.020), and higher proportion of male patients (94.7% vs 66.7%; P = 0.016) vs the completely laparoscopic group, respectively. Although preoperative serum creatinine and gender were risk factors in the univariate analysis, multivariate analysis revealed no independent risk factors for LCTOA. We divided the reasons for LCTOA into active conversion and passive conversion; 4 (21.1%) cases underwent active conversion, and 15 (78.9%) underwent passive conversion. Most of the patients undergoing passive conversion had multiple concurrent risk factors, among which perirenal adhesion (30.9%), organ invasion (16.4%), and IVC adhesion (25.5%) were the most common. Fourteen (73.7%) cases underwent renal treatment, and 5 (26.3%) cases underwent tumor thrombus treatment. Conclusions The LCTOA group had a higher median preoperative serum creatinine concentration, longer hospital stay, longer median operation time, and higher median intraoperative hemorrhage volume. However, none of the predictors in our study was an independent risk factor for LCTOA. Perirenal adhesion, organ invasion, and IVC adhesion were the most common causes of LCTOA. Considering the limitations of this study, studies with large sample sizes are required to validate our conclusions.

Purpose. Developed a preoperative prediction model based on multimodality imaging to evaluate the probability of inferior vena cava (IVC) vascular wall invasion due to tumor infiltration. Materials and Methods. We retrospectively analyzed the clinical data of 110 patients with renal cell carcinoma (RCC) with level I-IV tumor thrombus who underwent radical nephrectomy and IVC thrombectomy between January 2014 and April 2019. The patients were categorized into two groups: 86 patients were used to establish the imaging model, and the data validation was conducted in 24 patients. We measured the imaging parameters and used logistic regression to evaluate the uni- and multivariable associations of the clinical and radiographic features of IVC resection and established an image prediction model to assess the probability of IVC vascular wall invasion. Results. In all of the patients, 46.5% (40/86) had IVC vascular wall invasion. The residual IVC blood flow (OR 0.170 [0.047-0.611]; P = 0.007 ), maximum coronal IVC diameter in mm (OR 1.203 [1.065-1.360]; P = 0.003 ), and presence of bland thrombus (OR 3.216 [0.870-11.887]; P = 0.080 ) were independent risk factors of IVC vascular wall invasion. We predicted vascular wall invasion if the probability was >42% as calculated by: Ln Pre / 1 − pre = 0.185 × maximum cornal IVC diameter + 1.168 × bland thrombus – 1.770 × residual IVC blood flow – 5.857 . To predict IVC vascular wall invasion, a rate of 76/86 (88.4%) was consistent with the actual treatment, and in the validation patients, 21/26 (80.8%) was consistent with the actual treatment. Conclusions. Our model of multimodal imaging associated with IVC vascular wall invasion may be used for preoperative evaluation and prediction of the probability of partial or segmental IVC resection.

Although PD-1/PD-L1 immunotherapy has been used successfully in treating many cancers, metastatic colorectal cancer (CRC) patients are not as responsive. B7-H3 is a promising target for immunotherapy and we found it to have the highest expression among B7-CD28 family members in CRC. Thus, the aim of the present study was to investigate B7-H3 expression in a large CRC cohort. B7-H3, B7-H4, and PD-L1 protein levels and differential lymphocyte infiltration were evaluated in tissue microarrays from 805 primary tumors and matched metastases. The relationships between immune markers, patient characteristics, and survival outcomes were determined. B7-H3 (50.9%) was detected in more primary tumors than B7-H4 (29.1%) or PD-L1 (29.2%), and elevated B7-H3 expression was associated with advanced overall stage. Co-expression of B7-H3 only with B7-H4 or PD-L1 was infrequent in primary tumors (6.3%, 5.7%, respectively). Moreover, B7-H3 in primary tumors was positively correlated with their respective expression at metastatic sites (ρ = 0.631; p 0.001). No significant relationships between B7-H4 and PD-L1 and survival were observed; however, B7-H3 overexpression in primary tumors was significantly related to decreased disease-free survival. A positive relationship between B7-H3 expression and high density CD45RO T cell was observed in primary tumors, whereas B7-H4 and PD-L1 overexpression were related to CD3 T-cell infiltration. In conclusion, compared with B7-H4 and PD-L1, B7-H3 expression exhibited a higher prevalence and was significantly related to aggressiveness, worse prognosis and CD45RO T-cell infiltration in primary tumors. Further exploration of this potential target of immunotherapy in CRC patients is warranted.

Circular RNAs (circRNAs) are key regulators in the development of many cancers. The present study was aimed to investigate the mechanism by which circ_0007919 affected colorectal cancer (CRC) progression.The differentially expressed circRNA was screened out by analyzing the expression profile of circRNAs of CRC tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for detecting the expressions of circ_0007919, miR-942-5p, and ten-eleven translocation 1 (TET1) mRNA in CRC tissues and cell lines. Cell growth and migration were assessed by cell counting kit-8 (CCK-8) 5-bromo-2'-deoxyuridine (BrdU) and scratch assays. Bioinformatics analysis and dual-luciferase reporter assay were conducted to predict and validate the targeted relationships between circ_0007919 and miR-942-5p, as well as between miR-942-5p and TET1 mRNA. Besides, Western blot was conducted for detecting TET1 protein expression in CRC cells. It was revealed that, in CRC tissues and cell lines, circ_0007919 and TET1 expressions were reduced whereas miR-942-5p expression was enhanced. It was also revealed that circ_0007919 overexpression markedly suppressed CRC cell growth and migration. In addition, circ_0007919 could competitively bind with miR-942-5p to increase the expression of miR-942-5p's target gene TET1. Collectively, circ_0007919 inhibits CRC cell growth and migration via regulating the miR-942-5p/TET1 axis. This study helps to better understand the molecular mechanism of CRC progression.

Biodegradable polymeric nanomaterials can be directly broken down by intracellular processes, offering a desirable way to solve toxicity issues for cancer diagnosis and treatment. Among them, aliphatic polycarbonates are approved for application in biological fields by the United States Food and Drug Administration (FDA), however, high hydrophobicity, deficient functionality and improper degradation offer significant room for improvement in these materials. Methods: To achieve progress in this direction, herein, we demonstrate that CO2-based amphiphilic polycarbonates (APC) with improved hydrophilicity and processability can be used as a reliable and efficient platform for tumor imaging. To better investigate their potential, we devised a convenient strategy through conjugation of APC with gadolinium (Gd). Results: The resulting polymeric micelles (APC-DTPA/Gd) exhibit excellent magnetic resonance imaging performance, simultaneously enabling real-time visualization of bioaccumulation and decomposition of polymeric micelles in vivo. Importantly, these micelles can be degraded to renally cleared products within a reasonable timescale without evidence of toxicity. Conclusion: Our findings may help the development of CO2-based amphiphilic polycarbonate for cancer diagnosis and treatment, accompanied by their low-toxicity degradation pathway.

Background Machine learning (ML) encompasses a wide variety of methods by which artificial intelligence learns to perform tasks when exposed to data. Although detection of myocardial infarction has been facilitated with introduction of troponins, the diagnosis of acute coronary syndromes (ACS) without myocardial damage (without elevation of serum troponin) remains subjective, and its accuracy remains highly dependent on clinical skills of the health care professionals. Application of a ML algorithm may expedite management of ACS for either early discharge or early initiation of ACS management. We aim to summarize the published studies of ML for diagnosis of ACS. Methods We searched electronic databases, including PubMed, Embase, and Web of Science from inception up to January 13, 2019, for studies that evaluated ML algorithms for the diagnosis of ACS in patients presenting with chest pain. We then used random-effects bivariate meta-analysis models to summarize the studies. Results We retained 9 studies that evaluated ML in a total of 6292 patients. The prevalence of ACS in the evaluated cohorts ranged from relatively rare (7%) to common (57%). The pooled sensitivity and specificity were 0.95 and 0.90, respectively. The positive predictive values ranged from 0.64 to 1.0, and the negative predictive values ranged from 0.91 to 1.0. The positive and negative likelihood ratios ranged from 1.6 to 33.0 and 0.01 to 0.13, respectively. Conclusions The excellent sensitivity, negative likelihood ratio, and negative predictive values suggest that ML may be useful as an initial triage tool for ruling out ACS.

Liver kinase B1 (LKB1) functions as a tumor suppressor encoded by STK11, a gene that mutated in Peutz-Jeghers syndrome and in sporadic cancers. Previous studies showed that LKB1 participates in IR- and ROS-induced DNA damage response (DDR). However, the impact of LKB1 mutations on targeted cancer therapy remains unknown. Herein, we demonstrated that LKB1 formed DNA damage-induced nuclear foci and co-localized with ataxia telangiectasia mutated kinase (ATM), γ-H2AX, and breast cancer susceptibility 1 (BRCA1). ATM mediated LKB1 phosphorylation at Thr 363 following the exposure of cells to ionizing radiation (IR). LKB1 interacted with BRCA1, a downstream effector in DDR that is recruited to sites of DNA damage and functions directly in homologous recombination (HR) DNA repair. LKB1 deficient cells exhibited delayed DNA repair due to insufficient HR. Notably, LKB1 deficiency sensitized cells to poly (ADP-ribose) polymerase (PARP) inhibitors. Thus, we have demonstrated a novel function of LKB1 in DNA damage response. Cancer cells lacking LKB1 are more susceptible to DNA damage-based therapy and, in particular, to drugs that further impair DNA repair, such as PARP inhibitors.

Helicobacter pylori (H. pylori) infection is the most important factor in the development of gastric cancer. Heparanase (HPA) is involved in tissue remodelling and cell migration, which leads to inflammation and tumour metastasis. The current study aimed was to explore whether a H. pylori infection leads to an increase in the level of HPA in gastric cancer and to investigate the specific mechanism underlying this association. Reverse transcription‑polymerase chain reaction and western blotting were used to detect HPA mRNA and protein expression, respectively, in MKN‑45 cells infected by H. pylori, MKN‑45 cells treated with the mitogen‑activated protein kinase (MAPK) inhibitor SB203580 and MKN‑45 cells transfected with small interfering RNA against HPA. MAPK and nuclear factor (NF)‑κB expression were determined by western blotting in the different cells group. Cell Counting Kit‑8, Transwell method, and Scratch and Clone tests were conducted to detect proliferation, invasion, migration and clone formation ability of gastric cancer cells. It was demonstrated that HPA mRNA expression was highest at 6 h post‑infection, while the expression of the HPA protein was highest at 24 h post‑infection in H. pylori‑infected gastric cancer cells. Furthermore, it was demonstrated that H. pylori infection significantly enhanced the expression of MAPK and NF‑κB in MKN‑45 cells at the mRNA and protein levels. SB203580 significantly decreased the expression of NF‑κB in MKN‑45 cells infected with H. pylori. Exposure to SB203580 also significantly decreased the expression of HPA. In the present study, the inhibition of HPA significantly lowered H. pylori‑induced cell proliferation, suggesting that H. pylori infection induces the proliferation of gastric cancer cells through the upregulation of HPA. Taken together, the results of the present study demonstrated that HPA serves a critical role in the development of gastric cancer in H. pylori‑infected cells, which may be an important mechanism through which H. pylori infection leads to gastric cancer. In addition, H. pylori infection promotes the proliferation, invasion and metastasis of gastric cancer cells through the upregulation of HPA expression, and this is likely mediated via the MAPK and NF‑κB signalling pathways. These data suggest that HPA can be used as a therapeutic target in gastric cancer, particularly in cases induced by H. pylori infection.

Background/aim Our study aimed to investigate a reliable diagnostic approach for tuberculous peritonitis (TBP) by comparing the commonly used diagnostic tools. Materials and methods Fifty-one patients had received a series of diagnoses, including laparoscopy, erythrocyte sedimentation rate (ESR), cancer antigen 125 (CA125), tuberculin skin test, tuberculosis antibody in serum (TB-Ab), the T-SPOT.TB test, or adenosine deaminase (ADA) in ascitic fluid. The positive rate of each method was calculated and the differences of positive rates between laparoscopy and laboratory tests that had higher positive rates were analyzed by McNemar chi-square test. Results The most common symptoms and signs of 51 patients were fever (86.3%), abdominal mass (78.4%), abdominal distension (62.7%), abdominal pain (74.5%), and weight loss (66.7%). Furthermore, the positive rates of CA125, laparoscopy, T-SPOT.TB test, and ESR were relatively higher than those of the other three methods (tuberculin skin test, TB-Ab, and ascitic ADA). Additionally, there was no significant difference (P > 0.05) in the positive rates between the diagnoses of laparoscopy and those three laboratory tests. Conclusion CA125, laparoscopy, T-SPOT.TB test, and ESR had a stronger diagnostic power for TBP, and they are reliable alternatives for the diagnosis of TBP.

To explore whether the intake of dietary carotenoids could protect against skeletal fluorosis in Guizhou province in which coal-burning fluorosis is endemic.A case-control study of 196 patients with skeletal fluorosis and 196 age and gender-matched controls was conducted in Zhijin, Guizhou Province. Face-to-face interviews were conducted to assess habitual dietary intake using a 75-item food frequency questionnaire and various covariates with structured questionnaires. Urinary fluoride was measured using an ion-selective electrode method. The genotype of superoxide dismutase 2 (SOD2) rs11968525 was detected by TaqMan method.We observed significant dose-dependent inverse associations of skeletal fluorosis with intake of β-carotene, lutein/zeaxanthin, lycopene, and total carotenoids (P-trend = 0.002 to 0.018), whereas α-carotene and β-cryptoxanthin intakes were not found to be related to skeletal fluorosis, after adjustment for potential confounders. The adjusted ORs and 95% CI of skeletal fluorosis for the highest versus lowest quartile were 0.30 (0.10, 0.86) for β-carotene, 0.23 (0.08, 0.66) for lycopene, 0.26 (0.10, 0.75) for lutein/zeaxanthin and 0.34 (0.14, 0.74) for total carotenoids (all P-trend0.05). Stratified analyses showed that the protective effects of lutein/zeaxanthin and total carotenoids on skeletal fluorosis were more evident for individuals with the AG+AA genotypes of SOD2 (rs11968525).Increased intakes of β-carotene, lutein/zeaxanthin, lycopene, and total carotenoids are independently associated with a lower risk of coal-burning skeletal fluorosis. SOD2 (rs11968525) polymorphisms might modify the inverse associations between dietary carotenoids and skeletal fluorosis.

TP53 mutations frequently occur in head and neck squamous cell carcinoma (HNSCC) patients without human papillomavirus infection. The recurrence rate for these patients is distinctly high. It has been actively explored to identify agents that target TP53 mutations and restore wild-type (WT) TP53 activities in HNSCC. PRIMA-1 (p53-Reactivation and Induction of Massive Apoptosis-1) and its methylated analogue PRIMA-1Met (also called APR-246) were found to be able to reestablish the DNA-binding activity of p53 mutants and reinstate the functions of WT p53. Herein we report that piperlongumine (PL), an alkaloid isolated from Piper longum L., synergizes with APR-246 to selectively induce apoptosis and autophagic cell death in HNSCC cells, whereas primary and immortalized mouse embryonic fibroblasts (MEFs) and spontaneously immortalized non-tumorigenic human skin keratinocytes (HaCat) are spared from the damage by the cotreatment. Interestingly, PL-sensitized HNSCC cells to APR-246 are TP53 mutation-independent. Instead, we demonstrated that glutathione S-transferase pi 1 (GSTP1), a GST family member that catalyzes the conjugation of GSH with electrophilic compounds to fulfill its detoxification function, is highly expressed in HNSCC tissues. Administration of PL and APR-246 significantly suppresses GSTP1 activity, resulting in the accumulation of ROS, depletion of GSH, elevation of GSSG, and DNA damage. Ectopic expression of GSTP1 or pretreatment with antioxidant N-acetyl-L-cysteine (NAC) abrogates the ROS elevation and decreases DNA damage, apoptosis, and autophagic cell death prompted by PL/APR-246. In addition, administration of PL and APR-246 impedes UMSCC10A xenograft tumor growth in SCID mice. Taken together, our data suggest that HNSCC cells are selectively sensitive to the combination of PL and APR-246 due to a remarkably synergistic effect of the cotreatment in the induction of ROS by suppression of GSTP1.

Liver kinase B1 (LKB1, also known as serine/threonine kinase 11, STK11) is a tumor suppressor mutated in Peutz-Jeghers syndrome and in a variety of sporadic cancers. Herein, we demonstrate that LKB1 controls the levels of intracellular reactive oxygen species (ROS) and protects the genome from oxidative damage. Cells lacking LKB1 exhibit markedly increased intracellular ROS levels, excessive oxidation of DNA, increased mutation rates and accumulation of DNA damage, which are effectively prevented by ectopic expression of LKB1 and by incubation with antioxidant N-acetylcysteine. The role of LKB1 in suppressing ROS is independent of AMP-activated protein kinase, a canonical substrate of LKB1. Instead, under the elevated ROS, LKB1 binds to and maintains the activity of the cdc42-PAK1 (p21-activated kinase 1) complex, which triggers the activation of p38 and its downstream signaling targets, such as ATF-2, thereby enhancing the activity of superoxide dismutase-2 and catalase, two antioxidant enzymes that protect the cells from ROS accumulation, DNA damage and loss of viability. Our results provide a new paradigm for a non-canonical tumor suppressor function of LKB1 and highlight the importance of targeting ROS signaling as a potential therapeutic strategy for cancer cells lacking LKB1.

To investigate the chemical and bioactive constituents from the stems and leaves of Micromelum integerrimum.The chemical constituents were isolated and purified by silica gel, Sephadex LH-20, and HPLC. Their structures were mainly elucidated on the basis of extensive 1D- and 2D-NMR spectroscopy and mass spectrometry. Their cytotoxicity and antimicrobial activities were tested by the SRB and turbidimetric methods, respectively.Two new phenylpropanoids and two known coumarins were obtained, and their structures were identified as microintegerrin A (1), microintegerrin B (2), scopoletin (3), and scopolin (4). All of the compounds were tested for their cytotoxicity against three cancer cell lines (HeLa, A549, and BGC-823) and for antimicrobial activity against the fungus Candida albicans and the bacterium Staphylococcus aureus.Two new phenylpropanoids 1 and 2 were isolated and identified from the stems and leaves of M. intgerrimum. None of the compounds showed cytotoxic or antimicrobial activity at the tested concentration of 20 μg·mL(-1).

LKB1 (also known as serine-threonine kinase 11, STK11) is a tumor suppressor, which is mutated or deleted in Peutz-Jeghers syndrome (PJS) and in a variety of cancers. Physiologically, LKB1 possesses multiple cellular functions in the regulation of cell bioenergetics metabolism, cell cycle arrest, embryo development, cell polarity, and apoptosis. New studies demonstrated that LKB1 may also play a role in the maintenance of function and dynamics of hematopoietic stem cells. Over the past years, personalized therapy targeting specific genetic aberrations has attracted intense interests. Within this review, several agents with potential activity against aberrant LKB1 signaling have been discussed. Potential strategies and challenges in targeting LKB1 inactivation are also considered.

The sirtuin SIRT1 is a NAD(+)-dependent histone deacetylase, a Sir2 family member, and one of seven human sirtuins. Sirtuins are conserved from archaea to mammals and regulate transcription, genome stability, longevity, and metabolism. SIRT1 regulates transcription via deacetylation of transcription factors such as PPARγ, NFκB, and the tumor suppressor protein p53. EX527 (27) is a nanomolar SIRT1 inhibitor and a micromolar SIRT2 inhibitor. To elucidate the mechanism of SIRT inhibition by 27, we determined the 2.5 Å crystal structure of the SIRT1 catalytic domain (residues 241-516) bound to NAD(+) and the 27 analogue compound 35. 35 binds deep in the catalytic cleft, displacing the NAD(+) nicotinamide and forcing the cofactor into an extended conformation. The extended NAD(+) conformation sterically prevents substrate binding. The SIRT1/NAD(+)/35 crystal structure defines a novel mechanism of histone deacetylase inhibition and provides a basis for understanding, and rationally improving, inhibition of this therapeutically important target by drug-like molecules.

High-risk human papillomaviruses (HPVs) are causative agents of anogenital cancers and a fraction of head and neck cancers. The mechanisms involved in the progression of HPV neoplasias to cancers remain largely unknown. Here, we report that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase (OGT) were markedly increased in HPV-caused cervical neoplasms relative to normal cervix, whereas O-GlcNAcase (OGA) levels were not altered. Transduction of HPV16 oncogene E6 or E6/E7 into mouse embryonic fibroblasts (MEFs) up-regulated OGT mRNA and protein, elevated the level of O-GlcNAc, and promoted cell proliferation while reducing cellular senescence. Conversely, in HPV-18-transformed HeLa cervical carcinoma cells, inhibition of O-GlcNAc with a low concentration of a chemical inhibitor impaired the transformed phenotypes in vitro. We showed that E6 elevated c-MYC via increased protein stability attributable to O-GlcNAcylation on Thr58. Reduction of HPV-mediated cell viability by a high concentration of O-GlcNAc inhibitor was partially rescued by elevated c-MYC. Finally, knockdown of OGT or O-GlcNAc inhibition in HeLa cells or in TC-1 cells, a mouse cell line transformed by HPV16 E6/E7 and activated K-RAS, reduced c-MYC and suppressed tumorigenesis and metastasis. Thus, we have uncovered a mechanism for HPV oncoprotein-mediated transformation. These findings may eventually aid in the development of effective therapeutics for HPV-associated malignancies by targeting aberrant O-GlcNAc.

Liver kinase B1 (LKB1) is mutationally inactivated in Peutz-Jeghers syndrome and in a variety of cancers including human papillomavirus (HPV)-caused cervical cancer. However, the significance of LKB1 mutations in cervical cancer initiation and progress has not been examined. Herein, we demonstrated that, in mouse embryonic fibroblasts, loss of LKB1 and transduction of HPV16 E6/E7 had an additive effect on constraining cell senescence while promoting cell proliferation and increasing glucose consumption, lactate production, and ATP generation. Knock-down of LKB1 increased and ectopic expression of LKB1 decreased glycolysis, anchorage-independent cell growth, and cell migration and invasion in HPV transformed cells. In the tumorigenesis and lung metastasis model in syngeneic mice, depletion of LKB1 markedly increased tumor metastatic colonies in lungs without affecting subcutaneous tumor growth. We showed that HPV16 E6/E7 enhanced the expression of hexokinase-ll (HK-II) in the glycolytic pathway through elevated c-MYC. Ectopic LKB1 reduced HK-II along with glycolysis. The inverse relationship between HK-II and LKB1 was also observed in normal and HPV-associated cervical lesions. We propose that LKB1 acts as a safeguard against HPV-stimulated aerobic glycolysis and tumor progression. These findings may eventually aid in the development of therapeutic strategy for HPV-associated malignancies by targeting cell metabolism.

Prognostic factors influencing long-term survival after radical resection for distal bile duct cancer have not been well established because of the rarity of this malignancy. The goal of this study was to identify main prognostic factors in patients undergoing pancreatoduodenectomy for distal bile duct carcinoma. A retrospective study consisting of 122 patients with distal bile duct cancer who underwent pancreatoduodenectomy in three major university hospitals was performed to identify the main prognostic factors. Major surgical complications occurred in 40 patients (32.8%), of whom eight died (6.6%) in the hospital. Overall actuarial survival (excluding hospital deaths) at 1-, 3-, and 5-year follow-up was 82.9, 49.4, and 32.7 per cent, respectively, with a median survival of 36 months. Univariate analysis showed that papillary tumor ( P = 0.045), negative surgical margin (R0 resection, P = 0.005), earlier pT ( P = 0.005), pTNM stage ( P < 0.001), and absence of lymph node involvement ( P < 0.0001) were significant predictors of survival. On multivariate analysis, only lymph node metastasis was shown to be an independent prognostic factor of survival ( P = 0.036). Lymph node involvement was the most important survival predictor after a Whipple resection in patients with distal cholangiocarcinoma.

Human APOBEC3G (hA3G), a cytidine deaminase with two cytidine deaminase domains (CDs), has been identified as an anti-HIV-1 host factor. Although the two CDs of hA3G have been extensively characterized, there is still debate on the role of the CDs in the biological function of hA3G. In this work, we constructed three hA3G mutants CD1-1, CD2-2 and CD2-1, which contain duplicate CD1 domain, duplicate CD2 domain and position switched CD domain respectively, and investigated the effect of CD domain replacement or switch upon virion encapsidation, Vif-mediated degradation, deamination and antiviral activity of hA3G. The results showed that the two CD domains were functionally equivalent in virion encapsidation and the interaction with HIV-1 Vif of hA3G, whereas CD domain switch or replacement greatly affected the sensitivity to Vif induced degradation, editing and antiviral activity of hA3G. Although the CD2 domain was shown to possess the deamination activity, CD2-2 incorporated efficiently into HIV-1 was unable to mutate viral cDNA, suggesting that CD1 also involved in the enzymatic function. Interestingly, CD2-1 retained considerable deamination activity with a different sequence preference. Taken together, our results suggest that CD domain may play a structural role in virion encapsidation and Vif-mediated degradation of hA3G, and coordination of the two CD domains is required for its editing and antiviral activity.

Antiviral chemotherapy can select for drug-resistant viral mutants (21). For chronic infections that need long-term chemotherapy, such as infection with hepatitis B virus (HBV), the challenge to clinical therapy is substantial (27, 31). Reverse transcriptase (RT) inhibitors, such as lamivudine, adefovir, entecavir, telbivudine, and tenofovir, are potent drugs for HBV infections, but their use in the clinical setting often selects for drug resistance (13, 14, 27, 31). The incidence of lamivudine resistance rises from 15 to 32% in the first year to 67 to 69% by the fifth year of treatment (7, 9, 28). Many drug-induced mutations in the HBV polymerase gene have been characterized. For instance, rtM204I/V/S (“rt” means “resistant”), rtL180M, rtL80V/I, and rtV173L are signature mutations for lamivudine; rtN236T and rtA181T/V are signature mutations for adefovir; rtS202G/I, rtI169T, rtS184G, and rtM250V are signature mutations for entecavir; rtM204I is a signature mutation for telbivudine; and rtA194T is a signature mutation for tenofovir (9, 27, 30, 31). The mutations in RT result from the intrinsic high variability due to the lack of an editing function of the enzyme (18, 20), and they alter the three-dimensional (3D) interaction between HBV polymerase and the drugs (27). This challenges the current anti-HBV strategy, which is directed at viral enzymes. However, HBV strains rely heavily on host cell machinery to complete their life cycles. Indeed, a number of host proteins have been reported to be crucial for HBV replication (10, 17, 29). Our hypothesis is that (i) these cellular components might be drug targets to control the virus, and suppression of these cellular proteins might be able to inhibit HBV replication, and (ii) unlike those that target viral enzymes, drugs utilizing this mechanism would be active against either wild-type or drug-resistant HBV strains, because the virus is not the target of chemotherapy. However, inhibition of host proteins might be harmful to the host. The key to avoiding undesirable side effects is, first, to identify host targets that are crucial for viral replication but not essential or only conditionally required for cell survival and, second, to find compounds that selectively target these proteins. Heat stress cognate 70 (Hsc70, or HspA8) is an ATP-binding protein of the heat stress protein 70 (Hsp70) family (16). It is the form of Hsp70 that is expressed in the absence of heat or other cell stress (1). This host protein was found to be required for the reverse transcription process in experiments using duck HBV DNA polymerase (2, 8). We anticipated that downregulation of this protein in the host would inhibit HBV replication in either wild-type or drug-resistant strains. Here, we report the results of testing this novel antiviral strategy that uses Hsc70 as a drug target to inhibit HBV.

Upon removal of the regulatory insert (RI), the first nucleotide binding domain (NBD1) of human cystic fibrosis transmembrane conductance regulator (CFTR) can be heterologously expressed and purified in a form that remains stable without solubilizing mutations, stabilizing agents or the regulatory extension (RE). This protein, NBD1 387-646(Delta405-436), crystallizes as a homodimer with a head-to-tail association equivalent to the active conformation observed for NBDs from symmetric ATP transporters. The 1.7-A resolution X-ray structure shows how ATP occupies the signature LSGGQ half-site in CFTR NBD1. The DeltaF508 version of this protein also crystallizes as a homodimer and differs from the wild-type structure only in the vicinity of the disease-causing F508 deletion. A slightly longer construct crystallizes as a monomer. Comparisons of the homodimer structure with this and previously published monomeric structures show that the main effect of ATP binding at the signature site is to order the residues immediately preceding the signature sequence, residues 542-547, in a conformation compatible with nucleotide binding. These residues likely interact with a transmembrane domain intracellular loop in the full-length CFTR channel. The experiments described here show that removing the RI from NBD1 converts it into a well-behaved protein amenable to biophysical studies yielding deeper insights into CFTR function.

Natural product berberine (BBR) has been reported to have hypoglycemic and insulin-sensitizing activities; however, its mechanism remains unclear. This study was designed to investigate the molecular mechanism of BBR against insulin resistance. Here, we identify insulin receptor (InsR) as a target of BBR to increase insulin sensitivity. In cultured human liver cells, BBR increased InsR messenger RNA (mRNA) and protein expression in a dose- and time-dependent manner. Berberine increased InsR expression in the L6 rat skeletal muscle cells as well. Berberine-enhanced InsR expression improved cellular glucose consumption only in the presence of insulin. Silencing InsR gene with small interfering RNA or blocking the phosphoinositol-3-kinase diminished this effect. Berberine induced InsR gene expression through a protein kinase C (PKC)-dependent activation of its promoter. Inhibition of PKC abolished BBR-caused InsR promoter activation and InsR mRNA transcription. In animal models, treatment of type 2 diabetes mellitus rats with BBR lowered fasting blood glucose and fasting serum insulin, increased insulin sensitivity, and elevated InsR mRNA as well as PKC activity in the liver. In addition, BBR lowered blood glucose in KK-Ay type 2 but not in NOD/LtJ type 1 diabetes mellitus mice that were insulin deficient. Our results suggest that BBR is a unique natural medicine against insulin resistance in type 2 diabetes mellitus and metabolic syndrome.