Integrative single-cell and spatial transcriptomic analyses identify a pathogenic cholangiocyte niche and TNFRSF12A as therapeutic target for biliary atresia.

BACKGROUND AND AIMS: Biliary atresia (BA) is a devastating fibroinflammatory biliary disease that is the leading indication for pediatric liver transplants worldwide. Although cholangiocytes are the primary target cells, the pathogenic mechanisms involving cholangiocytes remain elusive. Here, we aimed to characterize the pathogenic role of cholangiocytes in BA. APPROACH AND RESULTS: Integration of single-cell RNA sequencing of 12 liver tissues (from 9 BA and 3 controls) and the spatial transcriptome of another four liver sections (from 2 BA and 2 controls) provided a comprehensive spatial liver cell atlas of BA. In particular, we identified a cholangiocyte-enriched spatial niche with infiltration of activated HSCs, activated portal fibroblasts, macrovascular endothelial cells, and TREM2 + macrophages that were elevated in the portal triad of BA. This niche was positively correlated with bile duct profiles, liver fibrosis, and poor survival in 2 independent cohorts of patients with BA. Using integrative bioinformatics analyses to mine the cell-cell communication and regulatory network in BA cholangiocytes, we uncovered the fibroinflammatory phenotype of cholangiocytes with TNFSF12-TNFRSF12A as a significant signal. Genetic ablation or blockade of TNFRSF12A suppresses liver injury, inflammation, and bile duct profiles in a mouse model of disease. Using human biliary organoids, we revealed that BA organoids expressed higher levels of CCL2 in response to TNFSF12 stimulation and promoted monocyte chemotaxis via the CCL2-CCR2 axis. CONCLUSIONS: Pathogenic cholangiocytes-enriched niche identifies TNFRSF12A as a potential therapeutic target for BA.

A TGF-ß-dominant chemoresistant phenotype of hepatoblastoma associated with aflatoxin exposure in children.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common liver cancer in children, posing a serious threat to children's health. Chemoresistance is the leading cause of mortality in patients with HB. A more explicit definition of the features of chemotherapy resistance in HB represents a fundamental urgent need. APPROACH AND RESULTS: We performed an integrative analysis including single-cell RNA sequencing, whole-exome sequencing, and bulk RNA sequencing in 180 HB samples, to reveal genomic features, transcriptomic profiles, and the immune microenvironment of HB. Multicolor immunohistochemistry staining and in vitro experiments were performed for validation. Here, we reported four HB transcriptional subtypes primarily defined by differential expression of transcription factors. Among them, the S2A subtype, characterized by strong expression of progenitor ( MYCN , MIXL1 ) and mesenchymal transcription factors ( TWIST1 , TBX5 ), was defined as a new chemoresistant subtype. The S2A subtype showed increased TGF-ß cancer-associated fibroblast and an immunosuppressive microenvironment induced by the upregulated TGF-ß of HB. Interestingly, the S2A subtype enriched SBS24 signature and significantly higher serum aflatoxin B1-albumin (AFB1-ALB) level in comparison with other subtypes. Functional assays indicated that aflatoxin promotes HB to upregulate TGF-ß. Furthermore, clinical prognostic analysis showed that serum AFB1-ALB is a potential indicator of HB chemoresistance and prognosis. CONCLUSIONS: Our studies offer new insights into the relationship between aflatoxin and HB chemoresistance and provide important implications for its diagnosis and treatment.

Lattice matching enables construction of CaS@NaYF4 heterostructure with synergistically enhanced water resistance and luminescence for antibiotic detection.

Rare earth (RE)-doped CaS phosphors have been widely used as light-emitting components in various fields. Nevertheless, the application of nanosized CaS particles is still significantly limited by their poor water resistance and weak luminescence. Herein, a lattice-matching strategy is developed by growing an inert shell of cubic NaYF4 phase on the CaS luminescent core. Due to their similarity in crystal structure, a uniform core-shell heterostructure (CaS:Ce3+@NaYF4) can be obtained, which effectively protects the CaS:Ce3+ core from degradation in aqueous environment and enhances its luminescence intensity. As a proof of concept, a label-free aptasensor is further constructed by combining core-shell CaS:Ce3+@NaYF4 and Au nanoparticles (AuNPs) for the ultrasensitive detection of kanamycin antibiotics. Based on the efficient FRET process, the detection linear range of kanamycin spans from 100 to 1000 nM with a detection limit of 7.8 nM. Besides, the aptasensor shows excellent selectivity towards kanamycin antibiotics, and has been successfully applied to the detection of kanamycin spiked in tap water and milk samples, demonstrating its high potential for sensing applications.

Predictive model containing gene signature and shear wave elastography to predict patient outcomes after Kasai surgery in biliary atresia.

AIMS: Infants with biliary atresia (BA) are treated with Kasai portoenterostomy (KPE) surgery, but many BA patients need subsequent salvage liver transplants. The aim of this study is to develop a comprehensive gene-clinical model based on two-dimensional shear wave elastography (2DSWE), liver gene expression, and other clinical parameters to predict response to KPE for BA patients. METHODS: Differentially expressed gene patterns between liver samples of BA (n = 102) and non-BA control (n = 14) were identified using RNA sequencing analysis. Biliary atresia patients were then randomly assigned to training and validation cohorts. Gene classifier based on the differentially expressed genes was built in the training cohort. Nomogram models with and without gene classifier were further constructed and validated for predicting native liver survival of BA patients. The utility of the nomograms was compared by C-index. RESULTS: Using the least absolute shrinkage and selection operator model, we generated a nine-gene prognostic classifier. The nomogram based on the nine-gene classifier, age, preoperative 2DSWE, and albumin had the better C-index compared to gene classifier alone in the training cohort (0.83 [0.76-0.90] vs. 0.69 [0.61-0.77], p = 0.003) and the validation cohort (0.74 [0.67-0.82] vs. 0.62 [0.55-0.70], p = 0.001). Using risk scores developed from the nomogram, the 12-month survival rates of BA patients with native liver were 35.7% (95% confidence interval [CI], 22.7-56.3) in the high-risk group and 80.8% (95% CI, 63.4-100.0) in the low-risk group in the validation cohort. CONCLUSIONS: The comprehensive genetic-clinical nomogram based on preoperative 2DSWE, liver gene expression, and other clinical parameters can accurately predict response to KPE.

Saline-Aided Ultrasound Versus Upper Gastrointestinal Series in Neonates and Infants With Suspected Upper Gastrointestinal Obstruction: A Prospective Multicenter Comparative Study.

BACKGROUND. Use of upper gastrointestinal (UGI) series to diagnose UGI obstruction in neonates and infants has raised concern about increased radiation sensitivity of developing organs. OBJECTIVE. The purpose of this study was to assess the diagnostic performance of saline-aided ultrasound (US) in comparison with UGI series in evaluation for UGI obstruction in neonates and infants. METHODS. In this prospective multicenter study at three hospitals, inpatients were enrolled who were younger than 1 year and had suspected UGI obstruction between June 2015 and May 2018; patients with US evidence of malrotation or pyloric stenosis were ineligible. Enrolled patients underwent both saline-aided US (saline solution administered through a nasogastric tube) and UGI series. Surgical findings or at least 1-year of clinical follow-up findings served as the reference for presence of UGI obstruction. UGI obstruction was classified in terms of level (proximal vs distal) and cause. Two radiologists independently interpreted saline-aided US examinations to assess interobserver agreement and then reached consensus. Two other radiologists assessed upper GI series in consensus. Diagnostic performance for the presence and level of UGI obstruction was compared between modalities. Causes of obstruction were assessed with saline-aided US. RESULTS. A total of 209 neonates were included (116 boys, 93 girls; median age, 5 days; 124 (59.3%) patients had UGI obstruction (proximal in 108 patients). Saline-aided US had strong interobserver agreement for presence (κ = 0.87) and level (κ = 0.85) of obstruction. For presence of UGI obstruction, accuracy, sensitivity, and specificity were 94.7%, 98.4%, and 89.4% for saline-aided US and 89.5%, 95.2%, and 81.2% for UGI series. For obstruction level, accuracy, sensitivity, and specificity were 90.3%, 97.2%, and 56.3% for saline-aided US versus 87.1%, 92.6%, and 50.0% for UGI series. Accuracy for presence was significantly higher for saline-aided US (p = .02); otherwise, these metrics were not different between tests (p > .05). For causes of UGI obstruction (annular pancreas, duodenal web, duodenal atresia, and duodenal stenosis), the accuracy of saline-aided US ranged from 75.0% to 95.2%. CONCLUSION. Saline-aided US has high diagnostic performance for presence and level of UGI obstruction in neonates and infants, comparing favorably with UGI series. Saline-aided US may have additional utility in evaluating causes of obstruction. CLINICAL IMPACT. Saline-aided US may serve as an initial screening modality for UGI obstruction in neonates and infants. TRIAL REGISTRATION. Chinese Clinical Trial Registry ChiCTR-DCC-15006232.

Development of a performance measurement system for general practitioners' office in China's primary healthcare.

BACKGROUND: General practitioners are the main providers of primary care services. To better strengthen the important role of general practitioners in primary healthcare services, China is promoting the general practitioners' office system. There is a lack of well-accepted methods to measure the performance of general practitioner offices in China. We thus aim to develop a systematic and operable performance measurement system for evaluating the general practitioner's office. METHODS: We establish an index pool of the performance measurement system of general practitioners' offices by a cross-sectional study and the literature research method and adopt the focus group method to establish the preliminary system. The Delphi method is then used to conduct three rounds of consultation to modify indices, which aims to form the final indicator system. We determine the weight of each index by the analytic hierarchy process method, which together with the final indicator system constitutes the final performance measurement system. Finally, we select three offices from three different cities in Sichuan Province, China, as case offices to conduct the case study, aiming to assess its credibility. RESULTS: Our results show that the first office scored 958.5 points, the second scored 768.1 points, and the third scored 947.7 points, which corresponds to the reality of these three offices, meaning that the performance measurement system is effective and manoeuvrable. CONCLUSIONS: Our study provides support for standardizing the functions of China's general practitioner's office, improving the health service quality of generalists, and providing a theoretical basis for the standardization of the general practitioner's office.

Percutaneous ultrasound-guided cholecystocholangiography with microbubbles combined with liver biopsy for the assessment of suspected biliary atresia.

BACKGROUND: Percutaneous ultrasound (US)-guided cholecystocholangiography is effective in diagnosing biliary atresia for infants with a gallbladder >1.5 cm in length on US. However, whether it is still effective for other types of gallbladders needs further clarification. OBJECTIVE: To evaluate the diagnostic performance and safety of percutaneous US-guided cholecystocholangiography combined with liver biopsy in children with suspected biliary atresia and with different types of gallbladders on US. MATERIALS AND METHODS: Sixty-five infants were referred for percutaneous US-guided cholecystocholangiography with microbubbles and liver biopsy after an equivocal (n=39) or highly suspected (n=26) US diagnosis of biliary atresia. Two radiologists evaluated US and percutaneous US-guided cholecystocholangiography images in consensus. One pathologist independently evaluated liver specimens. We used the unpaired t-test, Mann-Whitney U test and chi-square test to analyze the data. RESULTS: Of the 65 infants, 59 (90.8%) underwent a successful percutaneous US-guided cholecystocholangiography, with both sensitivity and specificity of 100%. All six infants for whom puncture failed had contracted gallbladders. The sensitivity and specificity of liver biopsy in the diagnosis of biliary atresia were 89.7% (26/29) and 83.3% (30/36), respectively. When percutaneous US-guided cholecystocholangiography and liver biopsy were combined, all infants gained correct diagnosis, and in 35 infants (97.2%, 35/36) biliary atresia could be excluded without intraoperative cholangiography. Twenty-two of 65 infants (33.8%) had fluid collections around the liver related to puncture. None of these complications needed treatment. CONCLUSION: Percutaneous US-guided cholecystocholangiography combined with liver biopsy appears safe and effective for excluding or confirming biliary atresia in cholestatic infants with a dilated gallbladder on US.

Treatment optimization for recurrent hepatoblastoma: retrospective study from a hepatoblastoma cohort in Southern China.

PURPOSE: The present study aimed to explore the clinical characteristics and optimal treatments of RHB patients. METHODS: We retrospectively collected 42 RHB cases and 161 primary HB (PHB) cases. Clinical characteristics were compared between RHB and PHB patients. The risk factors related to overall survival (OS) and progression-free survival (PFS) in RHB patients were explored by COX regression analysis. Patients were further divided into curable and refractory subgroup by treatments. Propensity score match (PSM) analysis was performed to match recurrent curable patients from 145 curable PHB patients from the same cohort. PFS was further compared between 34 pairs of primary and recurrent curative HB patients. RESULTS: Recurrence treatment and number of relapsed tumors were significantly related with both OS and PFS of RHB patients (p < 0.05). Chemotherapy regimen alteration was also risk factor of PFS for RHB (HR = 4.26; 95% CI = 1.54-11.78; p = 0.005). RHB patients underwent curable treatment had better prognosis, compared with recurrent refractory subgroup (p < 0.001). Matched curable PHB patients demonstrated no significant difference of 3-year PFS with curable RHB patients (p = 0.540). CONCLUSION: Curable RHB patients might get benefit from surgery or ablation with similar prognosis with primary curable HB patients.

Optimization Algorithm for Delay Estimation Based on Singular Value Decomposition and Improved GCC-PHAT Weighting.

The accuracy of time delay estimation seriously affects the accuracy of sound source localization. In order to improve the accuracy of time delay estimation under the condition of low SNR, a delay estimation optimization algorithm based on singular value decomposition and improved GCC-PHAT weighting (GCC-PHAT-ργ weighting) is proposed. Firstly, the acoustic signal collected by the acoustic sensor array is subjected to singular value decomposition and noise reduction processing to improve the signal-to-noise ratio of the signal; then, the cross-correlation operation is performed, and the cross-correlation function is processed by the GCC-PHAT-ργ weighting method to obtain the cross-power spectrum; finally, the inverse transformation is performed to obtain the generalized correlation time domain function, and the peak detection is performed to obtain the delay difference. The experiment was carried out in a large outdoor pool, and the experimental data were processed to compare the time delay estimation performance of three methods: GCC-PHAT weighting, SVD-GCC-PHAT weighting (meaning: GCC-PHAT weighting based on singular value decomposition) and SVD-GCC-PHAT-ργ weighting (meaning: GCC-PHAT-ργ weighting based on singular value decomposition). The results show that the delay estimation optimization algorithm based on SVD-GCC-PHAT-ργ improves the delay estimation accuracy by at least 37.95% compared with the other two methods. The new optimization algorithm has good delay estimation performance.

Development of a pediatric liver CEUS criterion to classify benign and malignant liver lesions in pediatric patients: a pilot study.

OBJECTIVES: To analyze the contrast-enhanced ultrasound (CEUS) characteristics of pediatric patients with focal liver lesions (FLLs) and develop a pediatric liver CEUS criterion to improve the diagnostic performance of CEUS in differentiating pediatric benign and malignant liver lesions. METHODS: Between March 2011 and May 2020, patients < 18 years who underwent CEUS were retrospectively evaluated. The CEUS characteristics of FLLs were analyzed. A pediatric liver CEUS criterion categorized as CEUS-1 to CEUS-5 was developed. The diagnostic performance of the criterion (i.e., sensitivity, specificity, PPV, and NPV) was assessed. Chi-square and Mann-Whitney tests were used. RESULTS: After exclusion, the study included 130 lesions (mean diameter, 7.1 cm; range, 0.8-17.0 cm) from 130 patients (mean age, 36.0 months; range, 0.03-204.0 months; 74 boys). Hyperenhancement with washout in patients < 5 years or with early washout (≤ 45 s) was used to predict hepatoblastoma, with a sensitivity and specificity of 90.7% (95% confidence interval [CI]: 77.9%, 97.4%) and 93.6% (95% CI: 84.3%, 98.2%), respectively. Peripheral discontinuous globular hyperenhancement was used to diagnose hemangioma, with a sensitivity and specificity of 84.6% (95% CI: 65.1%, 95.6%) and 100% (95% CI: 95.4%, 100.0%), respectively. The rates of malignancies within the pediatric liver CEUS-1, CEUS-2, CEUS-3, CEUS-4, and CEUS-5 categories were 0.0%, 0.0%, 5.6%, 50.0%, and 96.1%, respectively. Besides, the incidences of hepatoblastoma in pediatric liver CEUS-3, CEUS-4, and CEUS-5 were 5.6%, 16.7%, and 67.5%, respectively. CONCLUSIONS: The pediatric liver CEUS criterion is useful in differentiating benign focal liver lesions from malignancies, especially hepatoblastoma from hemangioma. KEY POINTS: • Hyperenhancement with washout in patients

Multimodal Treatment of Children With Sacrococcygeal Yolk Sac Tumor: Retrospective Analysis of Clinicopathology Characteristics and Relapse-free Survival.

The aim of the study was to explore the clinicopathologic characteristics of sacrococcygeal yolk sac tumor (SYST) associated with relapse and the role of sensitivity to neoadjuvant chemotherapy in predicting outcome. The authors investigated prognostic factors of age, stage, initial tumor size, pathologic response to neoadjuvant chemotherapy, and alfa fetoprotein. A total of 26 patients with SYST were enrolled. Neoadjuvant chemotherapy was administered to 20 cases. Six patients underwent resection as initial therapy. Recurrence occurred in 12 patients. Nine patients with specimens exhibiting no malignant component after chemotherapy did not experience recurrence. By contrast, relapses occurred in 7 of 11 patients with viable residual tumor after neoadjuvant chemotherapy. All relapsed patients still achieved partial remission or complete remission after salvage therapy. Five-year relapse-free survival and overall survival rates were 55.2% and 100%, respectively (median follow-up, 59.5 mo; range, 16 to 155). Patients with complete necrosis after neoadjuvant chemotherapy had a better outcome compared with children with viable residual tumor. Relapse-free survival of pediatric SYSTs in this cohort were still low and warrants the multidisciplinary effort.

Postsurgical Management of Dilated Biliary Tract in Children: Ultrasound-Guided Percutaneous Transhepatic Cholangial Drainage and Subsequent Percutaneous Ultrasound Cholangiography.

OBJECTIVE. The purpose of this study was to evaluate the feasibility of ultrasound (US)-guided percutaneous transhepatic cholangial drainage (PTCD) and consequent percutaneous US cholangiography in managing the dilated biliary tracts of children who have undergone hepatobiliary surgery. SUBJECTS AND METHODS. Sixteen children (11 boys, five girls; age range, 3-144 months) who underwent hepatobiliary surgery from December 2016 to October 2018 and had US evidence of biliary dilatation were included. All patients had undergone US-guided PTCD because of elevated postoperative serum bilirubin levels or bile duct infection. Immediately after the PTCD procedure, diluted sulphur hexafluoride microbubbles dispersion was injected through the PTCD tube to evaluate the anastomosis and the intrahepatic bile duct tree. Laboratory results, including those of serum bilirubin measurement, liver function tests, and routine blood tests, were evaluated before and after PTCD. Nine of 16 patients also underwent percutaneous transhepatic cholangiography (PTC). The percutaneous US cholangiography findings were evaluated and compared with the PTC findings. RESULTS. Liver enzyme levels decreased after PTCD with a statistically significant difference from the values before PTCD. Percutaneous US cholangiography showed that the anastomosis in 6 of the 16 patients (37.5%) was patent and depicted the morphologic featuresof intrahepatic bile duct tree in five of these patients. In the other 10 patients, the anastomosis was completely obstructed, and percutaneous US cholangiography depicted the morphologic features of intrahepatic bile duct tree in eight patients. In the nine patients who underwent PTC, the percutaneous US cholangiographic findings were the same as the PTC findings. CONCLUSION. US-guided PTCD is helpful in relieving jaundice and inflammation in children who have undergone hepatobiliary surgery and have biliary dilatation. Findings at consequent percutaneous US cholangiography are comparable to those of PTC in depicting the anastomosis in these patients.

Increased PARP1-DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1-DNA trapping is correlated with PARP1 inhibitor's cytotoxicity.

PARP1 inhibitors (PARPis) are used clinically during cancer therapy and are thought to exert their cytotoxicity through PARP1 polymerase inhibition and PARP1-DNA trapping. Here, we showed no significant correlation between PARP1-DNA trapping and cytotoxicity induced by PARPis. We complemented PARP1-knockout sublines with wild-type PARP1 and 11 mutants with different point mutations that affect the polymerase activity. When examining the PARPi talazoparib, the induced cytotoxicity was highly significantly correlated with cellular PARP1 polymerase activity, but not with its PARP1-DNA trapping or polymerase inhibition. Similarly, talazoparib's PARP1-DNA trapping revealed significant correlation with the polymerase activity rather than its inhibition. Differently, however, when evaluating purified wild-type and mutated PARP1, we identified an almost linear relationship between PARPis' inhibiting PARP1 dissociation from DNA and their cytotoxicity in 17 cancer cell lines. In contrast, no significant correlation existed between PARP1 polymerase inhibition in the histone-based systems and the cytotoxicity. After careful comparisons on different methods and detection targets, we conclude that the PARPi-mediated increase in PARP1-DNA binding by inhibiting autoPARylation of PARP1 on DNA rather than in PARP1-DNA trapping is correlated with PARPi's cytotoxicity. Accordingly, we established a new PARPi screening model that more closely predicts cytotoxicity.

Th17-associated cytokines multiplex testing indicates the potential of macrophage inflammatory protein-3 alpha in the diagnosis of biliary atresia.

BACKGROUND & AIMS: Biliary atresia (BA) is a neonatal obliterative cholangiopathy with high prevalence in south China. Accurate identification of BA among infants with obstructive jaundice is still difficult by noninvasive diagnostic tools. Th17 cells have been reported closely related with the development of BA, which suggest that Th17-associated cytokines were potential biomarkers for the diagnosis of BA patients. METHODS: In the training study, 76 infants who were divided into 2 groups, including BA group (n = 31) and non-BA jaundice group (n = 45). Clinical and routine laboratory data were collected from all subjects. Totally 25 Th17-associated cytokines were tested and compared between groups. The diagnostic value of each differential cytokine was evaluated by the area under the receiver operating characteristic curve (AUC). The best potential diagnostic biomarker was further validated in a cohort including 68 jaundice infants from our partnering institution in a blinded fashion. RESULTS: Data from the training study showed that gamma-glutamyl transferase (GGT) and clay stool would be helpful in the identification of BA patients in jaundice subjects. Th17-associated cytokines assay indicated that IL-17F, IL-10, macrophage inflammatory protein-3alpha (MIP3a), IL-22, IL-13, IL-33, IL-6, IL-17E, IL-27, IL-31, TNF-a and TNF-b were differentially expressed in BA patients, and the AUC of MIP3a was higher than other markers. MIP3a alone or combined with other laboratory data would significantly increase the diagnostic accuracy of BA. The diagnostic value of MIP3a was further confirmed in our validation study. CONCLUSION: MIP3a alone or combined with other laboratory data would significantly increase the diagnostic accuracy of BA.

Toward a Better Understanding of Hemiwicking: A Simple Model to Comprehensive Prediction.

The hemiwicking state has attracted much interest because of numerous important potential applications in inking, printing, boiling heat transfer, and condensation. However, the mechanism of the emergence of hemiwicking has not been well understood, especially the effects of geometry of patterned surfaces on the hemiwicking state has not been systematically investigated. Here, we presented a new method to study the critical conditions for hemiwicking on patterned surfaces. By minimizing the variation of the free energy, we obtain the corresponding stable height of the hemiwicking film and find that it is easier for a droplet to be in the hemiwicking state if the pillar surface has small spacing, large radius and height, and a small intrinsic contact angle. Our established model is applied to a flat-topped cylindrical pillar-patterned surface, and the modeling results are in well agreement with experiments and other existing theories. Besides, our model is also applied to other kinds of patterned surfaces including hemispherical-topped cylindrical and conical pillars, about which the other existing theories are deficient. Our theoretical results not only are in well agreement with the experimental observations but also provide some important predictions, which implies that the established model could be applicable to understanding the basic physical mechanism of the hemiwicking state and be useful in guiding the design and fabrication of hemiwicking surfaces.

An analytical model for the bending of radial nanowire heterostructures.

Extremely thin nanowires (NWs) would bend during the heteroepitaxial growth process. This phenomenon can increase the emission intensity due to the strain fields within bent NWs. Although the growth mechanism of NW heterostructures has been widely studied in theory, the theoretical studies are centered on growth on the surface of straight NWs, and the bending mechanism on extremely thin NWs has not been clearly explored. In this contribution, we have established an analytical thermodynamic theory to study the mechanism of bending induced by heteroepitaxial growth on the surface of thin NWs. It is found that the balance between surface energy and elastic strain energy plays a crucial role in the determination of the bending of NWs. The strain relaxation energy induces bending of NWs with small radii and high deposited amounts, while the size-dependent surface energy becomes more significant and restrains the bending of NWs with large radii and low deposited amounts. The established theoretical model not only explained the bending mechanism of NWs but also provided useful information to design the epitaxial growth on the surface with a nanoscale curvature.

Acquired resistance of phosphatase and tensin homolog-deficient cells to poly(ADP-ribose) polymerase inhibitor and Ara-C mediated by 53BP1 loss and SAMHD1 overexpression.

With increasing uses of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46-71.78-fold) to all 5 PARPi, including niraparib and rucaparib, and showed higher degrees of resistance to the PARPi to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors, including PTEN mutations. The PARPi-treated variants produced less γH2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPi by approximately 76%. The variants revealed slightly different cross-resistance profiles to 13 non-PARPi anticancer drugs. All were resistant to Ara-C (6-8-fold) but showed differential resistance to 5-fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs, including cisplatin. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara-C but did not affect their PARPi sensitivity. The present study demonstrates a consistent resistance profile to PARPi and a unique cross-resistance profile to non-PARPi drugs in different PARPi-resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPi and Ara-C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure.

Percutaneous US-guided Cholecystocholangiography with Microbubbles for Assessment of Infants with US Findings Equivocal for Biliary Atresia and Gallbladder Longer than 1.5 cm: A Pilot Study.

Purpose To evaluate the feasibility of ultrasonographically (US) guided percutaneous cholecystocholangiography (PCC) for early exclusion of biliary atresia (BA) in infants suspected of having BA with equivocal US findings or indeterminate type of BA and a gallbladder longer than 1.5 cm at US. Materials and Methods This study was approved by the ethics committee; written informed parental consent was obtained. From February 2016 to December 2016, nine infants (four boys, five girls; mean age, 60.2 days; median age, 57 days; age range, 23-117 days) with conjugated hyperbilirubinemia and gallbladder longer than 1.5 cm at US were referred for US-guided PCC after US findings were equivocal for BA (n = 7) or the type of BA was unclear (n = 2). PCC was performed with a US machine with incorporated contrast pulse sequencing, contrast-specific software, and a linear transducer by injecting diluted contrast material via an 18-gauge needle. Images from US and US-guided PCC were evaluated in consensus by two radiologists. US criteria for BA were fibrotic cord sign (>2 mm) and gallbladder length-to-width ratio greater than 5.2. BA was excluded at PCC when contrast material was visualized in the gallbladder, common hepatic ducts, and common bile duct and during passage to the duodenum. Patients in whom BA was diagnosed after PCC underwent surgery or liver biopsy as the reference standard. Nonparametric and Fisher exact tests were used. Results US-guided PCC was successful in all patients. There were no procedural-related complications. BA was excluded in five of the nine patients. The median serum direct bilirubin level in these patients slightly decreased 1 week after PCC, from 91.1 µmol/L (interquartile range [IQR], 81.6-113.8 µmol/L) to 65.3 µmol/L (IQR, 57.8-74.7 µmol/L); however, this difference was not statistically significant (P = .062). BA was diagnosed in four patients, with the diagnosis confirmed at surgery (n = 2) or liver biopsy (n = 2). BA in two patients with unclear type of BA was defined as type III without patency of the common bile duct in one patient and as type III with patency of the common bile duct in the other. Conclusion In this highly selected group of infants with indeterminate type of BA or inconclusive US findings, US-guided PCC enabled the diagnosis of BA in four infants and the exclusion of BA in five. US-guided PCC may be a safe and effective tool to exclude BA early in infants with equivocal US findings. © RSNA, 2017.