Promoting CO2 Electroreduction Over Nano-Socketed Cu/Perovskite Heterostructures via A-Site-Valence-Controlled Oxygen Vacancies.

Despite the intriguing potential, nano-socketed Cu/perovskite heterostructures for CO2 electroreduction (CO2 RR) are still in their infancy and rational optimization of their CO2 RR properties is lacking. Here, an effective strategy is reported to promote CO2 -to-C2+ conversion over nano-socketed Cu/perovskite heterostructures by A-site-valence-controlled oxygen vacancies. For the proof-of-concept catalysts of Cu/La0.3-x Sr0.6+x TiO3-δ (x from 0 to 0.3), their oxygen vacancy concentrations increase controllably with the decreased A-site valences (or the increased x values). In flow cells, their activity and selectivity for C2+ present positive correlations with the oxygen vacancy concentrations. Among them, the Cu/Sr0.9 TiO3-δ with most oxygen vacancies shows the optimal activity and selectivity for C2+ . And relative to the Cu/La0.3 Sr0.6 TiO3-δ with minimum oxygen vacancies, the Cu/Sr0.9 TiO3-δ exhibits marked improvements (up to 2.4 folds) in activity and selectivity for C2+ . The experiments and theoretical calculations suggest that the optimized performance can be attributed to the merits provided by oxygen vacancies, including the accelerated charge transfer, enhanced adsorption/activation of reaction species, and reduced energy barrier for C─C coupling. Moreover, when explored in a membrane-electrode assembly electrolyzer, the Cu/Sr0.9 TiO3-δ catalyst shows excellent activity, selectivity (43.9%), and stability for C2 H4 at industrial current densities, being the most effective perovskite-based catalyst for CO2 -to-C2 H4 conversion.

MR Spectroscopy for Detecting Fumarate Hydratase Deficiency in Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome.

Background Noninvasive in vivo detection of fumarate accumulation may help identify fumarate hydratase deficiency in renal cancer related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Purpose To investigate the feasibility of MR spectroscopy (MRS) in detecting elevated fumarate levels in HLRCC-associated renal cancers. Materials and Methods This study included an experimental xenograft mouse model and prospective clinical cohort. First, MRS was performed on patient-derived tumor xenograft models and control models to detect fumarate. Then, consecutive participants with clinical suspicion of HLRCC-associated renal tumors were enrolled. For the detection of fumarate, MRS results were classified as detected, borderline, undetected, or technical failure. The sensitivity, specificity, and accuracy of MRS for diagnosing HLRCC-associated renal cancer were assessed. The signal-to-noise ratio (SNR) of the fumarate peak was calculated and evaluated with receiver operating characteristic curve analysis. Results Fumarate peaks were detected at 6.54 parts per million in all three patient-derived xenograft models. A total of 38 participants (21 men; mean age, 47 years [range, 18-71 years]) with 46 lesions were analyzed. All primary HLRCC-associated renal cancers showed a fumarate peak; among the seven metastatic HLRCC-associated lesions, a fumarate peak was detected in three lesions and borderline in two. When only detected peaks were regarded as positive findings, the sensitivity, specificity, and accuracy of MRS at the lesion level were 69% (nine of 13 lesions), 100% (33 of 33 lesions), and 91% (42 of 46 lesions), respectively. When borderline peaks were also included as a positive finding, the sensitivity, specificity, and accuracy reached 85% (11 of 13 lesions), 88% (29 of 33 lesions), and 87% (40 of 46 lesions), respectively. The SNR of fumarate showed an area under the receiver operating characteristic curve of 0.87 for classifying HLRCC-associated tumors. Conclusion MR spectroscopy of fumarate was sensitive and specific for hereditary leiomyomatosis and renal cell carcinoma-associated tumors. © RSNA, 2022 Online supplemental material is available for this article.

Novel D-π-A type near-infrared fluorescent probes for the detection of Aß40 aggregates.

Aberrant accumulation of Amyloid-ß (Aß) peptide is closely related to Alzheimer's disease. Thus, it is important to develop featured probes for the specific detection of Aß species. Herein, we designed and synthesized a novel near-infrared fluorescent probe SDPY based on the D-π-A architecture for the detection of Aß aggregates. The probe SDPY displayed higher affinity for Aß40 aggregates over Aß42 aggregates in solution (Kd = 164 nM vs. 2.1 µM). In addition, SDPY showed excellent anti-interference against a wide range of other substances. Furthermore, SDPY was capable of labeling Aß40 aggregates better than Aß42 aggregates in the brain sections of AD transgenic mouse models.

Predictive value of single-nucleotide polymorphism signature for recurrence in localised renal cell carcinoma: a retrospective analysis and multicentre validation study.

BACKGROUND: Identification of high-risk localised renal cell carcinoma is key for the selection of patients for adjuvant treatment who are at truly higher risk of reccurrence. We developed a classifier based on single-nucleotide polymorphisms (SNPs) to improve the predictive accuracy for renal cell carcinoma recurrence and investigated whether intratumour heterogeneity affected the precision of the classifier. METHODS: In this retrospective analysis and multicentre validation study, we used paraffin-embedded specimens from the training set of 227 patients from Sun Yat-sen University (Guangzhou, Guangdong, China) with localised clear cell renal cell carcinoma to examine 44 potential recurrence-associated SNPs, which were identified by exploratory bioinformatics analyses of a genome-wide association study from The Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) dataset (n=114, 906 600 SNPs). We developed a six-SNP-based classifier by use of LASSO Cox regression, based on the association between SNP status and patients' recurrence-free survival. Intratumour heterogeneity was investigated from two other regions within the same tumours in the training set. The six-SNP-based classifier was validated in the internal testing set (n=226), the independent validation set (Chinese multicentre study; 428 patients treated between Jan 1, 2004 and Dec 31, 2012, at three hospitals in China), and TCGA set (441 retrospectively identified patients who underwent resection between 1998 and 2010 for localised clear cell renal cell carcinoma in the USA). The main outcome was recurrence-free survival; the secondary outcome was overall survival. FINDINGS: Although intratumour heterogeneity was found in 48 (23%) of 206 cases in the internal testing set with complete SNP information, the predictive accuracy of the six-SNP-based classifier was similar in the three different regions of the training set (areas under the curve [AUC] at 5 years: 0·749 [95% CI 0·660-0·826] in region 1, 0·734 [0·651-0·814] in region 2, and 0·736 [0·649-0·824] in region 3). The six-SNP-based classifier precisely predicted recurrence-free survival of patients in three validation sets (hazard ratio [HR] 5·32 [95% CI 2·81-10·07] in the internal testing set, 5·39 [3·38-8·59] in the independent validation set, and 4·62 [2·48-8·61] in the TCGA set; all p<0·0001), independently of patient age or sex and tumour stage, grade, or necrosis. The classifier and the clinicopathological risk factors (tumour stage, grade, and necrosis) were combined to construct a nomogram, which had a predictive accuracy significantly higher than that of each variable alone (AUC at 5 years 0·811 [95% CI 0·756-0·861]). INTERPRETATION: Our six-SNP-based classifier could be a practical and reliable predictor that can complement the existing staging system for prediction of localised renal cell carcinoma recurrence after surgery, which might enable physicians to make more informed treatment decisions about adjuvant therapy. Intratumour heterogeneity does not seem to hamper the accuracy of the six-SNP-based classifier as a reliable predictor of recurrence. The classifier has the potential to guide treatment decisions for patients at differing risks of recurrence. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Provincial Science and Technology Foundation of China, and Guangzhou Science and Technology Foundation of China.

CXCL1-LCN2 paracrine axis promotes progression of prostate cancer via the Src activation and epithelial-mesenchymal transition.

BACKGROUND: Mechanisms driving the progression of castration-resistant prostate cancer are believed to relate substantially to the tumor microenvironment. However, the cross-talks between tumor epithelial cell, stromal cells, and immune cells are yet to be fully elucidated. The present study aims to determine the role of chemokine and neutrophil derived cytokine paracrine axis in mediating the interaction between tumor cells, stromal myofibroblasts, and neutrophils in the tumor microenvironment of prostate cancer. METHODS: To identify myofibroblasts and neutrophil derived specific proteins affecting progression of prostate cancer, bioinformatics analyses were firstly performed in independent human prostate cancer gene expression data sets from the GEO data bank. Expression of stromal myofibroblasts secretory chemokine CXCL1 and neutrophil derived cytokine LCN2 was evaluated in prostate tissues via immunohistochemistry assay. We further investigated the effect of CXCL1 and LCN2 on prostate cancer using in vivo and in vitro models, and explored the underlying signal transduction pathways. RESULTS: A CXCL1-LCN2 paracrine network was confirmed in prostate cancer tissue samples, which was correlated with the biochemical recurrence of prostate cancer. Of note, CXCL1-LCN2 axis activates Src signaling, triggers the epithelial-mesenchymal transition (EMT), consequently promotes the migration of prostate cancer cells, leading to enhanced tumor metastasis. CONCLUSIONS: Our findings may provide enhanced insight into the interactions of carcinoma-stromal cells and immune cells linked to prostate cancer progression, wherein CXCL1-LCN2 axis is a key contributor to prostate cancer cells migration. These data indicate tumor microenvironment and Src signaling pathway may be potential therapeutic targets of prostate cancer treatment.

Overexpression of cannabinoid receptor 1 promotes renal cell carcinoma progression.

Renal cell carcinoma (RCC) is a common urologic tumor with a poor prognosis. Cannabinoid receptor 1 (CB1), which is a G protein-coupled receptor, has recently been reported to participate in the genesis and development of various cancers. However, the exact role of CB1 in RCC is unknown. The aim of this study was to determine the role of CB1 in RCC cell lines and RCC prognosis, thus underlying its potential as a therapeutic target. Immunohistochemistry and western blots were performed to investigate the expression of CB1 in RCC tissues and to determine its clinicopathological significance in RCC patients. Additionally, we explored CB1 expression in RCC cell lines and evaluated the effect of AM251, a CB1 inverse agonist, and in vitro siRNA knockdown of CB1 on the cellular proliferation, migration, and apoptosis of RCC cell lines. CB1 was overexpressed in cancerous tissues compared with adjacent normal tissues. Furthermore, CB1 expression levels were an independent risk factor for overall survival for RCC patients. AM251 significantly decreased tumor cell proliferation and induced cell apoptosis by upregulating the expression of the pro-apoptotic protein Bax and decreasing the expression of the anti-apoptotic proteins survivin and Bcl-2. Migration of the RCC cell lines was also significantly inhibited after treatment with AM251 compared with untreated control groups. In addition, knockdown of CB1 expression significantly decreased cell proliferation and invasion and significantly increased apoptosis of RCC cells. CB1 expression is functionally associated to cellular proliferation, apoptosis, and invasion ability of RCC. Our data suggest that CB1 might be a potential target for RCC clinical therapy.

Experimental Study on Rebar Corrosion Using the Galvanic Sensor Combined with the Electronic Resistance Technique.

In this paper, a new kind of carbon steel (CS) and stainless steel (SS) galvanic sensor system was developed for the study of rebar corrosion in different pore solution conditions. Through the special design of the CS and SS electronic coupons, the electronic resistance (ER) method and zero resistance ammeter (ZRA) technique were used simultaneously for the measurement of both the galvanic current and the corrosion depth. The corrosion processes in different solution conditions were also studied by linear polarization resistance (LPR) and the measurements of polarization curves. The test result shows that the galvanic current noise can provide detailed information of the corrosion processes. When localized corrosion occurs, the corrosion rate measured by the ER method is lower than the real corrosion rate. However, the value measured by the LPR method is higher than the real corrosion rate. The galvanic current and the corrosion current measured by the LPR method shows linear correlation in chloride-containing saturated Ca(OH)2 solution. The relationship between the corrosion current differences measured by the CS electronic coupons and the galvanic current between the CS and SS electronic coupons can also be used to evaluate the localized corrosion in reinforced concrete.

The HSP90 inhibitor 17-AAG exhibits potent antitumor activity for pheochromocytoma in a xenograft model.

This study aims to investigate the effect of heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in the malignant pheochromocytoma using a xenograft mouse model. Treatment with 17-AAG induced a marked reduction in the volume and weight of PC12 pheochromocytoma cell tumor xenografts in mice. Furthermore, 17-AAG also significantly inhibited the expression of HSP90 and its client proteins. Our results validated HSP90 as an important target in pheochromocytoma and provided rationale for the testing of HSP90 inhibitors as a promising therapeutic agent in the antitumor therapy of pheochromocytoma.

Cancer-associated fibroblasts promote renal cell carcinoma progression.

The aim of this study was to determine the effect of cancer-associated fibroblasts (CAFs) on renal cell carcinoma (RCC) tumor proliferation, migration, and development of drug resistance, thus underlying their potential as therapeutic targets in RCC patients. CAFs were grown in primary cultures. The in vitro model of interaction of RCC cell lines with CAFs was established. The influence of CAFs on the proliferation and migration ability as well as sensitivity to everolimus of RCC cells was further analyzed. Furthermore, Western blotting analysis was performed to examine the mechanisms mediating the effect of CAFs on RCC cells. The results of the MTT assay showed that coculture with CAFs increased the proliferation activity of both 786-O and Caki-1 cells compared with serum-free medium controls. The migration ability of RCC cell lines was also significantly enhanced after coculture treatment compared with untreated control. The inhibition effect of everolimus on 786-O and Caki-1 cells abrogated in cocultures with CAFs. The sensitivity of both two cell lines to everolimus was dramatically decreased when cocultured with CAFs. RCC cells cocultured with CAFs resulted in the activation of both proliferation-related (Erks) and survival-related (Akt) pathways. These data indicate that CAFs have an important role in supporting and promoting RCC. The interaction of CAFs with RCC cell lines stimulates tumor cell proliferation and migration and induces resistance to everolimus in RCC cells, suggesting that target of the tumor microenvironment may be a novel targeted therapies for RCC.

Molecular markers and targeted therapies for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a lethal disease with poor prognosis and lack of effective therapeutic options. Systemic treatment is often employed to treat patients with advanced ACC, but outcomes are disappointing. During the last decade, some of the causative genetic mutations in sporadic ACCs have been identified. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers. Preclinical investigations and clinical trials of tyrosine kinase inhibitors and anti-angiogenic compounds have been initiated to seek target therapy of ACCs. This review summarizes the current view of molecular alterations involved in the pathophysiology of adrenocortical carcinogenesis. The rationale for testing targeted therapies of ACC is also presented.

The impact of smoking on survival in renal cell carcinoma: a systematic review and meta-analysis.

Epidemiological evidence suggests that cigarette smoking is the best-established risk factor for renal cell cancer (RCC). However, the effect of smoking on survival of RCC patients remains debated. We therefore conducted a meta-analysis to investigate the impact of smoking status on overall mortality (OM), disease-specific mortality (DSM), overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) in patients with RCC. We searched Medline, Embase, and the Cochrane Central Search Library for published studies that analyzed the effect of smoking on survival or mortality of RCC. We selected 14 articles according to predefined inclusion criteria. The smoking status was categorized into never smokers and ever smokers (former smokers and/or current smokers). Summary hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated with a fixed or random effects model. Overall, 14 studies including 343,993 RCC cases were accepted for meta-analysis. Ever smoking was significantly correlated with OM (HR 1.30, 95 % CI 1.07-1.58), while no associated with poorer DSM (HR 1.23, 95 % CI 0.96-1.57). Further analysis found current (HR 1.57, 95 % CI 1.20-2.06) but not former smoking (HR 1.14, 95 % CI 0.79-1.63) was associated with a significantly increased risk of OM. Meanwhile, current smoking was associated with poorer DSM (HR 1.50, 95 % CI 1.10-2.05) in subgroup analysis. Ever smoking was significantly associated with poorer OS (HR 1.45; 95 % CI 1.00-2.09) and poorer CSS (HR 1.01; 95 % CI 1.00-1.02), compared with never smokers. Current smoking was associated with poorer PFS (HR 2.94, 95 % CI 1.89-4.58). This review provides preliminary evidence that current smoking in a patient with RCC is associated with poorer survival, demonstrating active smoking to be an independent risk for prognosis of RCC. Smoking cessation should be recommended for RCC patients.

Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma.

Fumarate hydratase (FH) deficient renal cell carcinoma (RCC) is a type of tumor with definite metabolic disorder, but the mechanism of metabolic remodeling is still unclear. LncRNA was reported to closely correlate with cancer metabolism, however the biological role of LncRNA in the development of progression of FH-deficent RCC was not well studied either. FH-deficient RCC samples were collected in my hospital and used for RNA-sequencing and Mass spectrometry analysis. FH-deficient RCC cell line UOK262 and control pFH cells were used for in vitro experiments, including proliferation assay, transwell assay, western-blot, mass spectrometry and so on. PDX mouse model was used for further drug inhibition experiments in vivo. In this study, we analyzed the profiles of LncRNA and mRNA in FH-deficienct RCC samples, and we found that the LncRNA-MIR4435-2GH was specifically highly expressed in FH-deficient RCC compared with ccRCC. In vitro experiments demonstrated that MIR4435-2HG was regulated by Fumarate through histone demethylation, and the deletion of this gene could inhibit glutamine metabolism. RNA-pulldown experiments showed that MIR4435-2HG specifically binds to STAT1, which can transcriptionally activate GLS1. GLS1 inhibitor CB-839 could significantly suppress tumor growth in PDX tumor models. This study analyzed the molecular mechanism of MIR4435-2HG in regulating metabolic remodeling of FH-deficient RCC in clinical samples, cells and animal models by combining transcriptional and metabolic methods. We found that that GLS1 was a therapeutic target for this tumor, and MIR4435-2HG can be used as a drug sensitivity marker.

Fumarate Hydratase-Deficient Renal Cell Carcinoma With Predominant Tubulocystic Features Mimics Tubulocystic Renal Cell Carcinoma.

CONTEXT.­: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) rarely exhibits a predominant tubulocystic architecture with few other components. RCC with pure tubules and cysts lined by eosinophilic tumor cells with prominent nucleoli would raise the diagnosis of tubulocystic RCC. It is important to differentiate the 2 entities because they lead to different outcomes. OBJECTIVE.­: To address the concern, a multicenter study was implemented to explore useful clinicopathologic features in differentiation between tubulocystic FH-deficient RCC and tubulocystic RCC. DESIGN.­: Clinical factors included age, sex, tumor size, and outcome. Morphologic factors included cell morphology, presence or absence of a nontubulocystic component, and stromal findings. Immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing were performed to explore the protein expression and molecular profiles of the 2 entities. RESULTS.­: We evaluated 6 patients with tubulocystic RCC and 10 patients with tubulocystic FH-deficient RCC. Tubulocystic RCC exhibited a small size (<4.0 cm, pT1a), low Ki-67 index (<5%), retained FH, and negative 2SC expression. Tubulocystic FH-deficient RCC had a relatively large size and a high Ki-67 index. Perinucleolar haloes, loss of FH, and 2SC positivity were always observed. Pure tubulocystic architecture was not observed in FH-deficient RCC, because focal nontubulocystic components can always be seen. CONCLUSIONS.­: We emphasized multiple sectioning to identify a nontubulocystic architecture to exclude tubulocystic RCC. Moreover, tumor size, FH/2SC staining, and the Ki-67 index can differentiate tubulocystic FH-deficient RCC from tubulocystic RCC. The diagnosis of tubulocystic RCC was not recommended in renal mass biopsy because of the limited tissues sampled.

Effect of HSP90 inhibitor in pheochromocytoma PC12 cells: an experimental investigation.

This study aims to investigate whether the expression of heat shock protein 90 (HSP90) is associated with the malignant pheochromocytoma (PHEO) and the effects of 17-allylamino-17-demethoxygeldanamcyin (17-AAG) on the expression of vascular endothelial growth factor (VEGF) in PHEO cell line PC12. The expression of HSP90 was investigated in 38 paraffin-embedded samples of PHEO patients using immunohistochemistry. The time and concentration effects of 17-AAG were investigated in PHEO PC12 cells. Cell proliferation was measured by MTT assay and cell counting. Apoptosis was detected by flow cytometry. Positive staining for HSP90 was found in 14 of 17 malignant (82.35%) and in 5 of 21 (23.81%) benign PHEOs. There existed a significant statistical difference between the malignant group and the benign ones (P < 0.001). 17-AAG inhibited the proliferation of HCC cells in a time- and concentration-dependent manner. The apoptosis rates of PC12 cells after treatment with 0.1 µmol/L for 6, 12, 24, and 48 h were significantly higher than that in blank control group. 17-AAG significantly downregulated VEGF-165 protein level in PC12 cells. This study has confirmed that the specific HSP90 inhibitor 17-AAG can play a therapeutic role in malignant PHEO treatment, and HSP90 qualifies as a promising new target in malignant PHEO.

The role of unilateral adrenalectomy in corticotropin-independent bilateral adrenocortical hyperplasias.

BACKGROUND: The objective of the present study was twofold: to demonstrate our experience with unilateral adrenalectomy in the treatment of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS) caused by bilateral adrenocortical hyperplasias, and to evaluate the long-term results as evidenced by the main laboratory and clinical findings. METHODS: From February 2000 to August 2009, unilateral adrenalectomy was performed on 27 patients with ACTH-independent CS and bilateral adrenocortical hyperplasias, including 14 patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and 13 patients with primary pigmented nodular adrenocortical disease (PPNAD). Signs and symptoms of CS, endocrine examinations, and radiographic imaging were evaluated preoperatively and postoperatively. RESULTS: At a median follow-up of 69 months (range: 23-120 months) for AIMAH and 47 months (range: 16-113 months) for PPNAD, 25 patients were cured by unilateral adrenalectomy. Serum cortisol level, daily urinary free cortisol (UFC), and plasma ACTH regained the normal range in both AIMAH and PPNAD patients at monthly follow-up visits; the circadian serum cortisol rhythm returned to normal, and a normal responsiveness to overnight low-dose dexamethasone administration (LDDST) became obvious. Both systolic and diastolic blood pressure (BP) levels were significantly reduced: 85 % of patients recovered normal BP levels, and the remaining patients need antihypertensive drugs, but at a reduced dose. No surgery-related morbidity occurred, and there was no sign of further enlargement of the residual adrenal gland after successful unilateral adrenalectomy. One patient with PPNAD and another patient with AIMAH with similar weights and sizes of the bilateral adrenals needed contralateral adrenalectomy. CONCLUSIONS: Unilateral adrenalectomy may be the suitable treatment for selected patients with AIMAH and PPNAD. It can achieve long-term remission of CS and improve glycemic control and BP values.

Electrochemical Study on the Macro-Cell Corrosion of Pipeline Steel Partially Covered by Different Kinds of Mineral Deposits.

This study presents the impact of mineral deposits (SiO2, Al2O3, and CaCO3) on the corrosion behavior of X65 pipeline steel in CO2-containing brine solution with low pH. The study investigates the initiation and propagation of under deposit corrosion (UDC) using a wire beam electrode (WBE) partially covered by different mineral deposit layers, in conjunction with electrochemical measurements and surface characterization. The results indicate that the corrosion behavior varies, depending on the characteristics of the deposit. During the test period, the Al2O3-covered steel acted as the main anode with more negative potential, while the bare steel acted as the cathode. The SiO2-covered steel acted as the cathode with more positive potential and a localized FeCO3 layer formed beneath the silica mineral. The CaCO3-covered steel initially acted as an anode with a more negative potential but transformed into the cathode at the end of the test. Additionally, shallow and small pits were observed beneath the deposits with the depth in the sequence Al2O3 > SiO2 > CaCO3.

Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase-deficient renal cell carcinoma.

Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening, and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified 2 tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as excellent plasma biomarkers for early diagnosis. These 2 molecules reliably reflected the FH mutation status and tumor mass. We further identified the enzymatic cooperativity by which these biomarkers are produced within the tumor microenvironment. Longitudinal monitoring of patients demonstrated that these circulating biomarkers can be used for reporting on treatment efficacy and identifying recurrent or metastatic tumors.

Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma.

BACKGROUND: FH-deficient renal cell carcinoma (RCC) is a rare and exceptionally aggressive RCC subtype. There is currently limited understanding of the molecular alterations, pathogenesis, survival outcomes, and systemic therapy efficacy for this cancer. OBJECTIVE: To perform a retrospective multicenter analysis of molecular profiling and clinical outcomes for patients with FH-deficient RCC, with an emphasis on treatment response to first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI/TKI) versus bevacizumab plus erlotinib (Bev/Erlo) combination therapy in patients with advanced disease. DESIGN, SETTING, AND PARTICIPANTS: The study included 77 cases of FH-deficient RCC from 15 centers across China. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical characteristics, molecular correlates, 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging, and treatment outcomes were analyzed. RESULTS AND LIMITATIONS: A total of 77 patients were identified, including 70 cases with a germline FH alteration (hereditary leiomyomatosis RCC syndrome [HLRCC]-associated RCC) and seven patients with somatic FH loss. Recurrent pathogenic alterations were found in NF2 (six/57, 11%), CDH1 (six/57, 11%), PIK3CA (six/57, 11%), and TP53 (five/57, 8.8%). Sixty-seven patients were evaluable for response to first-line systemic therapy with Bev/Erlo (n = 12), TKI monotherapy (n = 29), or ICI/TKI (n = 26). ICI/TKI combination therapy was associated with more favorable overall survival on systemic treatment (hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04-0.90) and progression-free survival on first-line therapy (HR 0.22, 95% CI 0.07-0.71) compared to Bev/Erlo combination therapy. The main limitation is the retrospective study design. CONCLUSIONS: We described the genomic characteristics of FH-deficient RCC in an Asian population and observed a favorable response to ICI/TKI combinational therapy among patients with advanced disease. PATIENT SUMMARY: This real-world study provides evidence supporting the antitumour activity of combining molecular targeted therapy plus immunotherapy for kidney cancer deficient in fumarate hydratase. Further studies are needed to investigate the efficacy of this combination strategy in this rare cancer.

Toward Robust Histology-Prior Embedding for Endomicroscopy Image Classification.

Representation learning is the critical task for medical image analysis in computer-aided diagnosis. However, it is challenging to learn discriminative features due to the limited size of the dataset and the lack of labels. In this paper, we propose a stochastic routing normalization and neighborhood embedding framework with application to breast tissue classification by learning discriminative features of probe-based confocal laser endomicroscopy. In order to align the low-level and mid-level of pCLE and histology domain, we firstly build the domain-specific normalization module with stochastic activation strategy considering both depth-wise and feature-wise criterion. For high-level features, the latent centers are learned from the histology domain as the template for feature matching. The proposed method is evaluated on a clinical database with 700 pCLE mosaics. The accuracy of image classification with limited training samples demonstrates that the proposed method can outperform previous works on domain alignment.

Development of a novel gene signature to predict prognosis and response to PD-1 blockade in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common kidney malignancy characterized by a poor prognosis. The treatment efficacy of immune checkpoint inhibitors (ICIs) also varies widely in advanced ccRCC. We aim to construct a robust gene signature to improve the prognostic discrimination and prediction of ICIs for ccRCC patients. In this study, adopting differentially expressed genes from seven ccRCC datasets in GEO (Gene Expression Omnibus), a novel signature (FOXM1&TOP2A) was constructed in TCGA (The Cancer Genome Atlas) database by LASSO and Cox regression. Survival and time-dependent ROC analysis revealed the strong predictive ability of our signature in discovery set, two online validation sets and one tissue microarray (TMA) from our institution. High-risk group based on the signature comprises more high-grade (G3&G4) and advanced pathologic stage (stageIII/IV) tumors and presents hyperactivation of cell cycle process according to the functional analysis. Meanwhile, high-risk tumors demonstrate an immunosuppressive phenotype with more infiltrations of regulatory T cells (Tregs), macrophages and high expressions of genes negatively regulating anti-tumor immunity. Low-risk tumors have an improved response to anti-PD-1 therapy and the predictive ability of our signature is better than other recognized biomarkers in ccRCC. A nomogram containing this signature showed a high predictive accuracy with AUCs of 0.90 and 0.84 at 3 and 5 years. Overall, this robust signature could predict prognosis, evaluate immune microenvironment and response to anti-PD-1 therapy in ccRCC, which is very promising in clinical promotion.