Background:Over the past decade, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has significantly improved owing to the development of anti-angiogenic targeted drugs such as sunitinib, pazopanib, and sorafenib. However, biomarkers that can identify patients with mRCC who may rapidly develop drug resistance are still lacking. Approximately 25% of patients experience rapid disease progression [progression-free survival (PFS) ≤3 months]. Currently, there is a lack of effective noninvasive biomarkers to identify resistant patients prior to treatment. This study aimed to identify plasma biomarkers associated with therapeutic resistance and develop a predictive model for clinical decision-making. Methods:Plasma proteomic analysis was conducted in 159 patients with mRCC treated with targeted therapy. Patients were divided into training and validation cohorts. Candidate protein biomarkers were initially screened using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and further validated using enzyme-linked immunosorbent assay (ELISA). A predictive nomogram was subsequently developed using logistic regression analysis and assessed for discrimination and calibration performance. Immunohistochemistry (IHC) was performed to compare protein expression levels in corresponding tumor tissue samples. Results:Four plasma proteins-chitotriosidase-1 (CHIT1), interleukin-6 receptor (IL-6R), neuronal cell adhesion molecule (NRCAM), and ecto-5'-nucleotidase (NT5E)-were identified as significant predictors of intrinsic resistance. The nomogram incorporating these biomarkers exhibited a high predictive accuracy, with a concordance index (C-index) of 0.956 and 0.869 for the training and validation cohorts, respectively. Notably, while the plasma concentrations of these proteins were significantly elevated in resistant patients, their expression levels in tumor tissues showed no significant differences, underscoring their utility as circulating, noninvasive biomarkers. Conclusions:We developed and validated a plasma protein-based nomogram to predict mRCC resistance to targeted therapy. The four identified biomarkers allow noninvasive identification of high-risk patients and offer a practical tool for early clinical stratification. This model may assist clinicians in avoiding ineffective treatment and optimizing therapeutic strategies for patients with mRCC.

PURPOSE:To investigate the feasibility and safety of robot-assisted partial nephrectomy (RAPN) to treat large (T2) cystic renal-cell carcinoma. METHODS:A multinational study was conducted worldwide. Patients with renal tumors larger than 7cm who underwent partial nephrectomy between December 2007 and July 2017 were recruited retrospectively. The patients were divided into solid tumor group (143 cases) and cystic tumor group (28 cases). Baseline parameters, tumor characteristics, perioperative variables, and pathological outcomes were collected. RESULTS:Between cystic and solid tumors, no statistically significant differences were detected in age, gender, BMI, ASA score, clinical tumor size, laterality, or R.E.N.A.L nephrometry score. Operating time, warm ischemic time, estimated blood loss, complications, histology outcomes, and margin status were comparable. Pathology of 6 cystic tumors came back benign (21.4%). In solid tumors, 6 intraoperative bleeding require transfusion, 1 ureteral damage, and 3 postoperative urinary fistulas were observed. In cystic tumors, conversion to radical nephrectomy happened in one case, because of sticky fat and the risk of cyst rupture. In two cases, postoperative bleeding was treated with embolism. The longest follow-up was 113 months. In cystic group, 1 recurrence or metastasis was observed, while in solid group, 14 cases were observed. CONCLUSION:RAPN can be safely performed to treat large (T2) cystic renal-cell carcinoma. Patients with cystic renal-cell carcinoma exhibited favorable renal function recovery after robot-assisted partial nephrectomy (RAPN), which maximally preserved normal renal tissue and its function. Further studies are needed to better understand the role of RAPN for these challenging cases.

Cancer remains a leading global cause of mortality, making early detection crucial for improving survival outcomes. The study aims to develop a machine learning-enabled blood-derived exosomal RNA profiling platform for multi-cancer detection and localization. In this multi-phase, multi-center study, we analyzed RNA from exosomes derived from peripheral blood plasma in 818 participants across eight cancer types during the discovery phase. Machine learning techniques were applied to identify potential pan-cancer biomarkers. During the screening and model validation phases, the sample size was progressively expanded to 1,385 participants in two steps, while the candidate biomarkers were refined into a set of 12 exosomal tumor RNA signatures (ETR.sig). In the subsequent model construction phase, diagnostic models were developed using the expanded cohort and ETR.sig. Statistical analyses included the calculation of receiver operating characteristic (ROC) curves and AUC values to assess the models' ability to distinguish cancer cases from controls and determine tumor origins. To further validate and explore the biological relevance of the identified biomarkers, we integrated tissue RNA-seq, single-cell data, and clinical information. Machine learning analysis initially identified 33 candidate biomarkers, which were narrowed down to 20 ETR.sig in the screening phase and 12 ETR.sig in the validation phase. In the model construction phase, a diagnostic model based on ETR.sig, built using the Random Forest (RF) algorithm, showed excellent performance with an AUC of 0.915 for distinguishing pan-cancer from controls. The multi-class classification model also demonstrated strong classification power, with macro-average and micro-average AUCs of 0.983 and 0.985, respectively, for differentiating between eight cancer types. Additionally, tumor origin classification using the RF-based diagnostic models achieved high AUC values: BRCA 0.976, COAD 0.98, KIRC 0.947, LIHC 0.967, LUAD 0.853, OV 0.972, PAAD 0.977, and PRAD 0.898. Integration of tissue RNA-seq, single-cell data, and clinical information revealed key associations between ETR.sig-related genes and tumor development. The study demonstrates the robust potential of exosomal RNA as a minimally invasive biomarker resource for cancer detection. The developed ETR.sig platform offers a promising tool for precision oncology and broad-spectrum cancer screening, integrating advanced computational models with nanoscale vesicle biology for accurate and rapid diagnosis.

CD70, which is a ligand belonging to tumour necrosis factors, exhibits aberrant overexpression among multiple hematologic and solid malignancies and has drawn extensive research enthusiasm as a target to treat and diagnose cancers. CD70-targeted immuno-PET/CT is an emerging approach for cancer diagnosis, with the potential to improve tumour detection, assist disease staging, and monitor therapeutic response. CD70-targeted therapeutic approaches, involving antibody-drug conjugates, CAR-T, CAR-NK, and monoclonal antibodies, have shown encouraging activity in preclinical models and preliminary signals of efficacy in early clinical studies. In addition to these monotherapies, increasing efforts have focused on rational combination strategies that aim to enhance antitumor efficacy, reverse immune suppression, and overcome resistance. This review comprehensively summarizes the diagnostic and therapeutic advances in CD70-targeted strategies, discusses ongoing barriers, and outlines future directions to advance CD70-targeted imaging and therapeutic strategies through mechanistic research and clinical translation. Key points CD70 is aberrantly overexpressed in diverse malignancies with limited normal tissue expression. CD70-targeted immuno-PET/CT improves tumour detection, staging, and treatment monitoring. Multiple CD70-targeted therapies, including CAR-T and CAR-NK, are under active investigation. Rational combination strategies are emerging to enhance antitumor efficacy.

OBJECTIVE:To explore the role of artificial intelligence based augmented reality intraoperative real-time navigation in minimally invasive partial nephrectomy to standardize renal hilum dissection procedures and improve operative efficiency. MATERIALS AND METHODS:A three-dimensional (3D) model by intelligent/interactive qualitative and quantitative analysis was created from patient-specific cross-sectional computed tomography imaging, and the semi-transparent picture were holographically projected on the surgeon console in Da Vinci or monitor in laparoscopy. We developed an artificial intelligence auto-matching technique to generate real-time augmented reality (AR) images by one or two points indicated by the surgeon. The size, rotation, and transparency of the three-dimensional model were manipulated automatically to overlap anatomy in the operative field. We performed laparoscopic nephrectomy or robotic-assisted partial nephrectomy utilizing this technique and evaluated the accuracy of renal vascular localization. We developed a renal hilum difficulty score based on this technique and assigned scores to anatomical relationship between arteries and veins. RESULTS:A total of 105 patients were finally included in this study, with 46 patients underwent partial nephrectomy with AR real-time navigation. In group AR-navigation, a significantly higher rate of patients had lower renal hilum exposure time. Operation time, WIT, estimated blood loss, and complications rates were comparable in both groups. No differences were found in hospital stay, pathological subtype, and stage. Patients were classified into complex and simple renal hilum score groups. Renal hilum exposure time was significantly shorter in the AR real-time navigation group compared to no navigation group, especially in the complex renal hilum score group. CONCLUSION:AI based intraoperative navigation renders a surgical roadmap, provides a standard renal hilum dissecting procedures, and avoid time consuming or unnecessary renal hilum dissection with relatively low complications rates.

To investigate the safety and feasibility of using a novel purpose-built single-port robotic system (the SHURUI Robotic Surgical System) with deformable surgical instruments to perform retroperitoneal single-port partial nephrectomy. A prospective study was conducted to recruit patients with a single renal tumor no more than 4 cm. Robot-assisted single-port partial nephrectomy was performed by using the novel purpose-built single-port robotic system with deformable surgical instruments. Patients’ demographics, tumor characteristics, and perioperative parameters were recorded and analyzed. Sixteen patients were recruited to the study. The median tumor size was 2.0 cm (IQR: 1.2–2.4 cm). The median R.E.N.A.L score was 6 (IQR: 4–4.5). In 3 cases, pure single-port surgery was carried out, and all the assistance was through the robotic port. Median docking time was 15.5 min (IQR: 14.25–22.25 min). Median operating time was 148.5 min (IQR: 178–238.5 min). Median console time was 107 min (IQR: 92.75–149.75 min). Median warm ischemic time was 26.5 min (IQR: 24.5–30 min). Median blood loss was 17.5 ml (IQR: 10–50 ml). Retroperitoneal partial nephrectomy can be safely performed with this novel purpose-built single-port robotic system (SHURUI) with deformable surgical instruments. Further studies are needed to fully evaluate the role of this new platform.

Prostate cancer (PCa) is the most common malignant tumor in men. Currently, there are few prognosis indicators for predicting PCa outcomes and guiding treatments. Here, we perform comprehensive proteomic profiling of 918 tissue specimens from 306 Chinese patients with PCa using data-independent acquisition mass spectrometry (DIA-MS). We identify over 10,000 proteins and define three molecular subtypes of PCa with significant clinical and proteomic differences. We develop a 16-protein panel that effectively predicts biochemical recurrence (BCR) for patients with PCa, which is validated in six published datasets and one additional 99-biopsy-sample cohort by targeted proteomics. Interestingly, this 16-protein panel effectively predicts BCR across different International Society of Urological Pathology (ISUP) grades and pathological stages and outperforms the D'Amico risk classification system in BCR prediction. Furthermore, double knockout of NUDT5 and SEPTIN8, two components from the 16-protein panel, significantly suppresses the PCa cells to proliferate, invade, and migrate, suggesting the combination of NUDT5 and SEPTIN8 may provide new approaches for PCa treatment.

Abstract Renal oncocytosis is a very rare oncologically indolent form of renal neoplasia characterized by diffuse involvement of renal parenchyma by numerous oncocytic nodules. We describe contrast-enhanced CT and 99mTc-MIBI SPECT/CT findings in a patient with renal oncocytosis presenting with metachronous bilateral renal tumors. Contrast-enhanced CT showed numerous tumors ranging from several millimeters up to 3.9 cm in the left kidney. The tumors showed hypervascularity in the corticomedullary phase and washout in the excretory phase mimicking renal cell carcinoma. The larger tumors showed higher 99mTc-MIBI uptake than the adjacent renal parenchyma, suggesting renal oncocytoma confirmed by biopsy.

To compare outcomes of robotic-assisted partial nephrectomy (RAPN) and minimally invasive radical nephrectomy (MIS-RN) for complex renal masses (CRM). We conducted a retrospective multicenter analysis of CRM patients who underwent MIS-RN and RAPN. CRM was defined as RENAL score 10–12. Primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS), recurrence, and complications. Multivariable analysis (MVA) and Kaplan–Meier Analysis (KMA) were used to analyze functional and survival outcomes for RN vs. PN by pathological stage. 926 patients were analyzed (MIS-RN = 437/RAPN = 489; median follow-up 24.0 months). MVA demonstrated lack of transfusion (HR = 1.63, p = 0.005), low-grade (HR = 1.18, p = 0.018) and smaller tumor size (HR = 1.05, p < 0.001) were associated with OS. Younger age (HR = 1.01, p = 0.017), high-grade (HR = 1.18, p = 0.017), smaller tumor size (HR = 1.05, p < 0.001), and lack of transfusion (HR = 1.39, p = 0.038) were associated with CSS. Increasing tumor size (HR = 1.18, p < 0.001), high-grade (HR = 3.21, p < 0.001), and increasing age (HR = 1.02, p = 0.009) were independent risk factors for recurrence. Type of surgery was not associated with major complications (p = 0.094). For KMA of MIS-RN vs. RAPN for pT1, pT2 and pT3, 5-year OS was 85

Abstract Prostatic ductal adenocarcinoma is an uncommon aggressive subtype of prostate carcinoma. It is more likely to present with advanced stage and lower prostate-specific antigen. We describe FDG PET/CT findings in a case of pure prostatic ductal adenocarcinoma with lymph node, bone and lung metastases, normal serum prostate-specific antigen level, and elevated serum carbohydrate antigen 19-9 and carbohydrate antigen 724 levels. The primary tumor, and lymph node and bone metastases were hypermetabolic. All the bone metastases were osteolytic. The multiple lung metastases showed no significant FDG uptake, which may be due to small size.

ABSTRACT:Extrarenal retroperitoneal angiomyolipomas are rare benign tumors that may mimic other benign or malignant retroperitoneal tumors. We describe 68 Ga-FAPI-04 PET/MRI findings in a case of tuberous sclerosis complex with an extrarenal retroperitoneal angiomyolipoma and multiple angiomyolipomas involving bilateral kidneys. The extrarenal retroperitoneal angiomyolipoma and most of the renal angiomyolipomas were 68 Ga-FAPI-04-avid. One left renal angiomyolipoma with extensive hemorrhage and fibrosis had no significant 68 Ga-FAPI-04 uptake. Angiomyolipoma should be included in the differential diagnosis of FAPI-avid renal or extrarenal retroperitoneal lesions.

ABSTRACT:Sarcomatoid renal cell carcinoma is an uncommon high-grade malignancy with poor prognosis. We describe 68 Ga-FAPI-04 PET/CT findings in a patient with a small (1.8 cm in the maximum diameter) sarcomatoid clear cell renal cell carcinoma with widespread metastatic disease. Both the primary renal tumor and its metastases in bones, lymph nodes, adrenals, and liver showed increased 68 Ga-FAPI-04 uptake. The primary renal tumor showed hypovascularity on contrast-enhanced CT, mimicking papillary renal cell carcinoma. This case indicates FAPI PET/CT may be useful for detecting and staging of this unusual malignancy.

Abstract Primary mucinous tumors involving the prostate gland are rare. We describe MRI and 18F-PSMA-11 PET/MRI findings in a case of prostate adenocarcinoma with mucinous features. The prostate tumor showed inhomogeneous hyperintensity on T2-weighted images due to high extracellular mucin content and inhomogeneous 18F-PSMA-11 uptake with SUVmax of 12.5. This case indicates PSMA PET imaging may be helpful for detection of this uncommon variant of prostate adenocarcinoma.

Background: Open radical nephrectomy (ORN) is a practical procedure for treating patients with large renal carcinomas >10 cm in size, and few studies have focused on feasibility and safety of laparoscopic radical nephrectomy (LRN). The current study was to assess the safety and effectiveness of LRN and ORN in large renal carcinoma patients by propensity matched pair analysis. Methods: In this cohort study, a retrospective review of radical nephrectomy data from October 2010 to October 2018 at Changhai Hospital was conducted. Patients with renal carcinomas >10 cm in size by pre-operative images were included. Patients' demographics including age, gender, body mass index (BMI), tumor size, operation time, hospitalization days, etc. were collected. Renal tumor patients undergoing LRN or ORN were match-paired by gender, BMI, age, and tumor size. Peri-operative outcomes including estimated blood loss and complications were compared. The follow-up contents included survival time, disease progression, and cause of death, and cancer-specific and progression-free survival were estimated via Kaplan-Meier curve analysis. Results: Among 92 patients with clinical T2b renal masses, 37 pairs were matched. The average tumor sizes of the LRN and ORN groups were 11.37 +/- 0.30 and 11.67 +/- 0.33 cm (P=0.375), respectively. The average operating time for LRN was slightly longer (204.32 +/- 11.17 vs. 192.78 +/- 8.50 min, P=0.414). Estimated blood loss (EBL) (336.49 +/- 63.58 mL for LRN vs. 545.95 +/- 74.52 mL for ORN, P=0.036), the length of postoperative stay [6.0 (5.0-9.0) for LRN vs. 9.0 (6.0-11.5) days for ORN, P=0.015], and removal time of the drainage tube [4.0 (3.0-5.0) days for LRN vs. 5.0 (4.0-6.0) for ORN, P<0.001] were less than in the LRN group. The pathological subtype and Fuhrman grade were comparable. Both groups were followed up for a similar period, and no difference was observed in 5-year survival rates. Conclusions: Considering the conversion rates and overall complication rates, it seems that LRN for large renal carcinomas demonstrated equivalent peri-operative safety and effectiveness compared with ORN, with no adverse effects on midterm oncological outcomes.

In the past decades, numerous surgical robotic systems have been developed to improve dexterity, precision, and ergonomics in minimally invasive surgery (MIS). These robotic systems usually have different forms to accommodate the requirements from either multiport or single-port procedures. Unlike the design consensus in the multiport systems where distal-wristed and straight-stemmed instruments are maneuvered by patient-side manipulators, different approaches are still being explored to verify the fulfillment of the clinical and functional requirements from single-port procedures. No systems have been shown to satisfactorily handle both the multiport and the single-port procedures. Utilizing the previously proposed dual continuum mechanism to realize a payload-enhanced multidegree of freedom surgical instrument with a tight bending wrist for intra-abdomen dexterity, it was found that the locations and the number of channels of the access ports can be freely configured. A modular surgical robotic platform is, hence, proposed for handling multiport, single-port, and for the first time hybrid-port procedures. The design concepts, system descriptions, teleoperation kinematics, experimental characterizations, and animal studies are reported. It is expected that suitable invasiveness, where a minimal number of skin incisions can always be used to treat a condition, is to be achieved by the proposed system. True potentials of the proposed system are to be verified in the coming larger scale animal studies and clinical trials.

Background There are no proven tumor biomarkers for the early diagnosis of clear cell renal cell carcinoma (ccRCC) thus far. This study aimed to identify novel biomarkers of ccRCC based on exosomal mRNA (emRNA) profiling and develop emRNA-based signatures for the early detection of ccRCC. Methods Four hundred eighty-eight participants, including 226 localized ccRCCs, 73 patients with benign renal masses, and 189 healthy controls, were recruited. Circulating emRNA sequencing was performed in 12 ccRCCs and 22 healthy controls in the discovery phase. The candidate emRNAs were evaluated with 108 ccRCCs and 70 healthy controls in the test and training phases. The emRNA-based signatures were developed by logistic regression analysis and validated with additional cohorts of 106 ccRCCs, 97 healthy controls, and 73 benign individuals. Results Five emRNAs, CUL9, KMT2D, PBRM1, PREX2, and SETD2, were identified as novel potential biomarkers of ccRCC. We further developed an early diagnostic signature that comprised KMT2D and PREX2 and a differential diagnostic signature that comprised CUL9, KMT2D, and PREX2 for RCC detection. The early diagnostic signature displayed high accuracy in distinguishing ccRCCs from healthy controls, with areas under the receiver operating characteristic curve (AUCs) of 0.836 and 0.830 in the training and validation cohorts, respectively. The differential diagnostic signature also showed great performance in distinguishing ccRCCs from benign renal masses (AUC = 0.816), including solid masses (AUC = 0.810) and cystic masses (AUC = 0.832). Conclusions We established and validated novel emRNA-based signatures for the early detection of ccRCC and differential diagnosis of uncertain renal masses. These signatures could be promising and noninvasive biomarkers for ccRCC detection and thus improve the prognosis of ccRCC patients.

ABSTRACT:A 65-year-old man with treated prostate adenocarcinoma underwent 68Ga-PSMA-11 PET/CT scan for restaging due to significantly increased serum PSA levels. PET/CT showed bilateral adrenal masses with high 68Ga-PSMA-11 uptake. There was no other lesion suspicious for metastasis. The laboratory and imaging findings were consisted with isolated bilateral adrenal metastases from prostate adenocarcinoma. The patient received docetaxel chemotherapy in combination with androgen deprivation therapy. PSA levels gradually decreased during chemotherapy. Follow-up MRI showed the bilateral adrenal masses significantly decreased in size. This case demonstrates the usefulness of 68Ga-PSMA-11 PET/CT in identifying atypical metastasis from prostate adenocarcinoma.

Long non-coding RNAs (lncRNAs) can modulate various biological processes and behaviors in most human cancers. LncRNA EIF3J-AS1 has been reported as an oncogene in various tumors, but whether it exerts functions in malignant progression and gene expression in prostate cancer (PCa) remains unknown. In this study, we investigated the high level of EIF3J-AS1 in PCa tissues and cells, and used functional assays to show that knocking down EIF3J-AS1 inhibited PCa cell proliferation and metastatic ability. A preliminary mechanistic investigation also showed that EIF3J-AS1 may increase the expression of MAF bZIP transcription Factor G (MAFG) in PCa. The expression correlation between EIF3J-AS1 and MAFG was found to be positive in PCa tissues. Finally, rescue assays showed that MAFG might be involved in the EIF3J-AS1-mediated malignant phenotype in PCa cells. This study demonstrated that EIF3J-AS1/MAFG may play a key role in facilitating PCa progression.

Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.

Objective: To investigate the application of virtual reality training in vesicourethral anastomosis during robot-assisted radical prostatectomy (RARP). Methods: Three certified robotic urologists who underwent virtual reality training were enrolled in the study group. The other three without training were enrolled in the control group. Parameters were recorded before and after the training. Then a total of 18 patients un-dergoing RARP were enrolled and randomized assigned to receive anastomosis procedures with certified urologists who either obtained or did not obtain training. The quality of the anastomosis was evaluated. Results: For the virtual training evaluation, the overall score was significantly improved from 65.0 +/- 10.8 to 92.7 +/- 3.5 (p=0.014); the time of anastomosis was shortened; the economy of motion improved; instrument collisions decreased after training (p<0.05). Besides, the effec-tiveness of the virtual training was evaluated in the 18 real anastomosis procedures which were completed either by three urologists with training or three urologists without training. Most intriguingly, the average time of anastomosis was shortened from 40.0 +/- 12.4 min to 25.1 +/- 7.1 min (p=0.015). The parameters including time of operation, creatinine level of drainage, postoperative hospital stay and duration of catheter drainage were comparable before and after training. Two leakages, which were observed in procedures by doctors without training, needed salvage sutures by a senior doctor. Conclusions: Virtual reality training enabled surgeons to become quickly familiar with robotic system manipulation, improved their skills for vesicourethral anastomosis and shortened the learning curve, thus helping them operate with high efficacy and quality. (C) 2021 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).