Dynamic changes of SCGN expression imply different phases of clear cell renal cell carcinoma progression.

The secretagogin (SCGN) was originally identified as a secreted calcium-binding protein present in the cytoplasm. Recent studies have found that SCGN has a close relationship with cancer. However, its role in the occurrence, progression, and prognosis of clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we utilized a mutual authentication method based on public databases and clinical samples to determine the role of SCGN in the progression and prognosis of ccRCC. Firstly, we comprehensively analyzed the expression characteristics of SCGN in ccRCC in several public databases. Subsequently, we systematically evaluated SCGN expression on 252 microarrays of ccRCC tissues from different grades. It was found that SCGN was absent in all the normal kidney tissues and significantly overexpressed in ccRCC tumor tissues. In addition, the expression level of SCGN gradually decreased with an increase in tumor grade, and the percentage of SCGN staining positivity over 50% was 86.7% (13/15) and 73.4% (58/79) in Grade1 and Grade2, respectively, while it was only 8.3% (12/144) in Grade3, and the expression of SCGN was completely absent in Grade4 (0/14) and distant metastasis group (0/4). Additionally, the expression of SCGN was strongly correlated with the patient's prognosis, with the higher the expression levels of SCGN being associated with longer overall survival and disease-free survival of patients. In conclusion, our results suggest that reduced expression of SCGN in cancer cells is correlated with the progression and prognosis of ccRCC.

ALK-Rearranged Renal Cell Carcinoma: A Multi-Institutional Study of 9 Cases With Expanding the Morphologic and Molecular Genetic Spectrum.

ALK-rearranged renal cell carcinoma (ALK-RCC) is rare, molecularly defined RCC subtype in the recently published fifth edition of World Health Organization classification of tumors. In this study, we described 9 ALK-RCCs from a clinicopathologic, immunohistochemical, and molecular genetic aspect, supporting and extending upon the observations by previous studies regarding this rare subgroup of RCC. There were 6 male and 3 female patients with ages ranging from 14 to 59 years (mean, 34.4 years). None of the patients had sickle cell trait. The diagnosis was based on radical or partial nephrectomy specimen for 8 patients and on biopsy specimen for 1. Tumor size ranged from 2.5 to 7.2 cm (mean, 2.8 cm). Follow-up was available for 6 of 9 patients (6-36 months); 5 had no tumor recurrence or metastasis and 1 developed lung metastasis at 24 months. The patient was subsequently treated with resection of the metastatic tumor followed by crizotinib-targeted therapy, and he was alive without tumor 12 months later. Histologically, the tumors showed a mixed growth of multiple patterns, including papillary, solid, tubular, tubulocystic, cribriform, and corded, often set in a mucinous background. The neoplastic cells had predominantly eosinophilic cytoplasm. Focally, clear cytoplasm with polarized nuclei and subnuclear vacuoles (n = 1), and pale foamy cytoplasm (n = 1) were observed on the tumor cells. The biopsied tumor showed solid growth of elongated tubules merging with bland spindle cells. Other common and uncommon features included psammomatous microcalcifications (n = 5), rhabdoid cells (n = 4), prominent intracytoplasmic vacuoles (n = 4), prominent chronic inflammatory infiltrate (n = 3), signet ring cell morphology (n = 2), and pleomorphic cells (n = 2). By immunohistochemistry, all 9 tumors were diffusely positive for ALK(5A4) and 4 of 8 tested cases showed reactivity for TFE3 protein. By fluorescence in situ hybridization analysis, ALK rearrangement was identified in all the 9 tumors; none of the tested tumors harbored TFE3 rearrangement (0/4) or gains of chromosomes 7 and 17 (0/3). ALK fusion partners were identified by RNA-sequencing in all 8 cases analyzed, including EML4 (n = 2), STRN (n = 1), TPM3 (n = 1), KIF5B (n = 1), HOOK1 (n = 1), SLIT1 (n = 1), and TPM1(3'UTR) (n = 1). Our study further expands the morphologic and molecular genetic spectrum of ALK-RCC.

Discovery of novel piperidine-containing thymol derivatives as potent antifungal agents for crop protection.

BACKGROUND: Plant fungal diseases pose a significant threat to crop production. The extensive use of chemical pesticides has led to growing environmental safety risks and pesticide resistance of various plant pathogens. Therefore, it is an urgent task to explore novel eco-friendly fungicidal agents with high efficacy to combat fungal infection. RESULTS: In this study, we rationally designed a series of novel thymol derivatives by incorporation of the sulfonamide moiety and evaluated their biological activities against plant pathogenic fungi. The bioassay results underscored the remarkable in vitro antifungal activity of compounds 5m and 5t against Phytophthora capsici (P. capsici), with EC50 values of 8.420 and 8.414 µg/mL, respectively. Their efficacies were superior to that of widely used commercial fungicides azoxystrobin (AZO, 20.649 µg/mL) and cabendazim (CAB, 251.625 µg/mL). Furthermore, compound 5v exhibited excellent in vitro antifungal activity against Sclerotinia sclerotiorum (S. sclerotiorum), with an EC50 value of 12.829 µg/mL, significantly outperforming AZO (63.629 µg/mL). In vivo bioassays demonstrated the impactful activity of compound 5v against S. sclerotiorum, achieving over 98% curative and protective efficacies at the concentration of 200 µg/mL. Further mechanistic investigations unveiled that compound 5v induced mycelial shrinkage and collapse in S. sclerotiorum, resulting in organelle damage and the accumulation of antioxidant enzyme activity. CONCLUSION: The significant antifungal efficacy of the prepared thymol derivatives shall encourage further exploration of compound 5v as a promising candidate to develop novel fungicides for crop protection. © 2024 Society of Chemical Industry.

Construction and Validation of a Mutation-Related Model in Papillary Renal Cell Carcinoma and Associated Immune Infiltration.

BACKGROUND: To improve the clinical evaluation of the prognosis of papillary renal cell carcinoma (PRCC), we screened a model to predict the survival of patients with mutations in related genes. METHODS: We downloaded RNA sequencing information from all patients with PRCC in TCGA. We first analyzed the differences in genes and the enrichment of these differences. Then, by selecting mutant genes, constructing a protein-protein interaction network, least absolute shrinkage and selection operator regression, and multivariable Cox regression, a prognosis model was constructed. Additionally, the model was validated using external data sets. We analyzed the immune infiltration of PRCC and the correlation between the model and popular targets. Finally, we performed tissue microarray analysis and immunohistochemistry to verify the expression levels of the three genes. RESULTS: We constructed a three-gene (never in mitosis gene A-related kinase 2 [NEK2], centromere protein A [CENPA], and GINS complex subunit 2 [GINS2]) model. The verification results indicated that the model had a good prediction effect. We also developed a visual nomogram. Enrichment analysis revealed the major pathways involved in muscle system processes. Immunoassays showed that the expression level of CENPA was positively correlated with PD-1 and CTLA4 expression levels. Immunohistochemical and tissue microarray results showed that these three genes were highly expressed in PRCC, which was consistent with the predicted results in the database. CONCLUSION: We constructed and verified a three-gene model to predict the patient survival. The results show that the model has a good prediction effect.

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.

Acquired cystic disease-associated renal cell carcinoma with PTCH1 mutation: a case report.

Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is an extremely rare kidney tumor seen mainly in patients with end-stage renal disease. Currently, there are few reports on this type of tumor. We describe the case of a 58-year-old man who had been receiving peritoneal dialysis for more than nine years due to chronic renal insufficiency and uremia. One year after undergoing left renal clear cell renal cell carcinoma resection, a space-occupying lesion was found in the right kidney for which he underwent right nephrectomy. The histopathology of this tumor showed solid or tubular cell arrangements, with some areas of cyst formation. Vacuoles of varying sizes were present in the cytoplasm, and varying amounts of calcium oxalate crystals were found in the tumor cells or interstitium. The pathological diagnosis was ACD-RCC. Next-generation sequencing detected mutations in the PTCH1, MTOR, FAT1, SOS1, RECQL4, and CDC73 genes in the right renal tumor. This is a rare case of a patient with ACD-RCC in the right kidney and clear cell renal cell carcinoma in the left kidney. The findings suggest that mutations in PTCH1 associated with ACD-RCC may have acted as oncogenic drivers for the development of ACKD-RCC, together with providing insight into mechanisms underlying ACD-RCC development, as well as diagnostic and treatment options.

Clinicopathological, Immunohistochemical, and Molecular Characteristics of Pigmented Microcystic Chromophobe Renal Cell Carcinoma with Favorable Prognosis.

Background. Pigmented microcystic chromophobe renal cell carcinoma (RCC) is a subtype of chromophobe RCC. Its distinct histopathologic features are microcystic and microtubular pattern, pigmentation, and microcalcifications. Pigmented microcystic chromophobe RCC has ultrastructure, immunophenotypic structure, and molecular results similar to chromophobe RCC. Methods. We report five tumors of pigmented microcystic chromophobe RCC. Morphological observation and immunohistochemical examination were performed, and clinical and molecular features were analyzed. Results. Microscopically, all five tumors showed brown pigmentation, microcystic, and tubular cystic structures, one tumor presented microscopic calcifications. All tumors were positive for EMA, AE1/AE3, PAX8, KRT7, KIT (CD117), claudin 7, KRT8, and E-cadherin, and three tumors expressed P504S. All tumors were negative for vimentin, CA9, KRT20, TFE3, TFEB, Melan-A, HMB45, FH, SDHB, and GATA3. Ki-67 index varied from less than 1% to 2%. In three tumors, next-generation sequencing of the 688 gene was performed, the results found gene variants with potential clinical significance such as JMJD1C, MYCL, TP53, PI3KCA, KRAS, APC, GLI1, LRRK2, and gene variants with unclear clinical significance such as NTRK1 and RAD50; All patients remained alive over a follow-up period of 8-46 months without tumor recurrence and sarcomatoid transformation. Conclusions. Pigmented microcystic chromophobe RCC has a relatively benign biological behavior, and distant metastases and sarcomatoid transformation are rare. This overview of five additional tumors of pigmented microcystic chromophobe RCC offers further insight into this special subtype of chromophobe RCC.

Long non-coding RNA HIF1A-AS2 promotes carcinogenesis by enhancing Gli1-mediated HIF1α expression in clear cell renal cell carcinoma.

BACKGROUND: The most common urologic tumor in humans with the highest incidence rate is clear cell renal cell carcinoma (ccRCC). Long non-coding RNAs (lncRNAs) act as regulatory factors in several tumors. Here, we studied ccRCC regulated by hypoxia-inducible factor 1α (HIF1α)-antisense RNA 2 (AS2) or HIF1A-AS2. METHODS: We performed wound-healing, transwell, and CCK-8 assays by decreasing or increasing the HIF1A-AS2 expression in RCC cell lines. Western blotting and qRT-PCR were used to identify the expression of downstream genes of the HIF1A-AS2 pathway. Gli1 and HIF1A-AS2 relationship was assessed using RIP and RNA pull-down assays. Lastly, transcriptome sequencing was performed on kidney cancer cells that had been knocked down to find possible regulatory mechanisms. RESULTS: Our results suggest that high expression of HIF1A-AS2 may promote RCC cell proliferation and Gli1 expression as a downstream factor. Furthermore, they have physical binding sites and together regulate HIF1α to encourage the development of ccRCC. HIF1A-AS2 lncRNA may offer a new molecular target for ccRCC treatment. CONCLUSION: lncRNA HIF1A-AS2 affects ccRCC development by regulating HIF1a expression through Gli1.

SMARCB1/INI1-deficient epithelioid and myxoid neoplasms in paratesticular region: Expanding the clinicopathologic and molecular spectrum.

SMARCB1/INI1-deficient soft tissue tumors with epithelioid and myxoid features are diverse and mainly include soft tissue myoepithelial tumor, extraskeletal myxoid chondrosarcoma, and the recently described myoepithelioma-like tumor of the vulvar region and myxoepithelioid tumor with chordoid features. Because of their overlapping features, the accurate diagnosis and classification of these tumors are often challenging. Herein, we report two unique cases of SMARCB1/INI1-deficient soft tissue neoplasm with epithelioid and myxoid features occurring in male paratesticular region. The first case was a 52-year-old man presented with an intermittent painful left paratesticular mass for 1 year. The second case was a 41-year-old man presented with a painless paratesticular mass on the right side for 3 months. Both patients underwent an orchiectomy. After 6 and 26 months of follow-up, both were alive with no evidence of recurrence or metastasis. In both cases, the tumor was relatively well-demarcated and showed monomorphic round to epithelioid cells arranged in a nested, trabecular, reticular, and corded pattern, setting in a myxohyalinized and vascularized matrix. The tumor cells showed relatively uniform round nuclei with vesicular chromatin and variably prominent nucleoli. No rhabdoid cells were identified. Mitoses numbered 3 and 2 per 10 high-power fields. Tumor necrosis or lymphovascular invasion was absent. Immunohistochemically, both tumors expressed epithelial membrane antigen (focal), calponin (focal), and CD99. SMARCB1/INI1 expression was deficient in both cases. In addition, case 1 diffusely expressed pan-cytokeratin, and case 2 diffusely expressed CD34 and synaptophysin. Molecular genetically, case 1 showed SMARCB1 homozygous deletion as detected by fluorescence in-situ hybridization (FISH), and case 2 demonstrated SMARCB1 copy number deletions by next-generation sequencing and SMARCB1 monoallelic deletion by FISH. Both cases lacked EWSR1 rearrangements by FISH. The overall clinicopathologic profiles of the two cases made it difficult to classify them as one of the established categories of SMARCB1/INI1-deficient mesenchymal tumors. Our study further expands the clinicopathologic and molecular spectrum of SMARCB1/INI1-deficient epithelioid and myxoid neoplasms and highlights the challenges to diagnose these tumors.

Mutated ASXL1 upregulates mTOR expression in renal cell carcinoma with fibromyomatous stroma.

Renal cell carcinoma with fibromyomatous stroma (RCC FMS), defined as an "emerging entity" in the 2016 WHO classification and recommended to be a novel entity by GUPS, is represented by tumor cells with clear to mildly eosinophilic cytoplasm displaying elongated and branching tubules and papillae. A fibromyomatous stroma could be observed in these tumors. These tumors are immunopositive for CK7 and featured by ELOC and/or TSC/mTOR gene mutations. In the 2022 WHO classification, ELOC mutated RCC is classified as a molecularly defined RCCs as an individual renal entity. However, there are limited descriptions of TSC/mTOR alterations in RCC FMS. Herein, we reported a case of 28-year-old woman with RCC FMS with intact ELOC and TSC/mTOR genes but ASXL1 mutation. The tumor cells were positive for mTOR expression. This case may indicate that altered mTOR expression, but not limited to mutated TSC/mTOR gene, that participates in the pathogenesis of RCC FMS.

Clinicopathological and molecular analysis of microsatellite instability in prostate cancer: a multi-institutional study in China.

Background: Microsatellite instability (MSI), or mismatch repair-deficiency (dMMR), is rare in prostate cancers (PCas). The histological and molecular features of PCas with MSI/dMMR are incompletely described. Thus, we sought to identify the characteristics of PCas with MSI/dMMR. Methods and results: We analyzed 1,141 primary treatment-naive PCas by MMR-related protein immunohistochemistry (MLH1, PMS2, MSH2, and MSH6). We identified eight cases exhibiting MSI/dMMR (0.7%, 8/1141). Of these, six tumors had both MSH2 and MSH6 protein loss, one had both MLH1 and PMS2 protein loss, and one had only MSH6 loss. Histologically, MSI/dMMR-PCas frequently demonstrated high histological grade (Grade Group 4 or 5), ductal/intraductal histology (6/8 cases), pleomorphic giant-cell features (4/8 cases), and conspicuous tumor lymphocytic infiltration (8/8 cases). Polymerase chain reaction-based analysis of seven MSI/dMMR tumors revealed two MSI-H tumors with loss of both MSH2 and MSH6 proteins. Subsequently, the seven cases underwent next-generation sequencing (NGS) analysis with a highly validated targeted panel; four were MSI. All cases had a high tumor mutation burden (median: 45.3 mutations/Mb). Overall, the MSI/dMMR-PCas showed a high frequency of DNA damage-repair pathway gene changes, including five with pathogenic somatic or germline MMR gene mutations. Activating mutations in the MAPK pathway, PI3K pathway, and WNT/ß-catenin pathway were common. TMPRSS2::ERG rearrangement was identified in one case (1/7, 14.3%). Conclusions: Several pathological features are associated with MSI/dMMR in PCas. Identification of these features may help to select patients for genetic screening. As MSI/dMMR-PCas are enriched for actionable mutations, patients should be offered NGS to guide standard-of-care treatment.

The heterogeneity and clonal evolution analysis of the advanced prostate cancer with castration resistance.

BACKGROUND: Nowadays, the incidence rate of advanced and metastatic prostate cancer at the first time of diagnosis grows higher in China yearly. At present, androgen deprivation therapy (ADT) is the primary treatment of advanced prostate cancer. However, after several years of ADT, most patients will ultimately progress to castration-resistant prostate cancer (CRPC). Previous studies mainly focus on Caucasian and very few on East Asian patients. METHODS: In this study, the pre- and post-ADT tumor samples were collected from five Chinese patients with advanced prostate cancer. The whole-exome sequencing, tumor heterogeneity, and clonal evolution pattern were analyzed. RESULTS: The results showed that the gene mutation pattern and heterogeneity changed significantly after androgen deprivation therapy. Tumor Mutational Burden (TMB) and Copy Number Alteration (CNA) were substantially reduced in the post-treatment group, but the Mutant-allele tumor heterogeneity (MATH), Socio-Demographic Index (SDI), Intratumor heterogeneity (ITH), and weighted Genome Instability Index (wGII) had no significant difference. According to the clone types and characteristics, the presence of main clones in five pre-and post-treatment samples, the clonal evolution pattern can be further classified into two sub-groups (the Homogeneous origin clonal model or the Heterogeneous origin clonal model). The Progression-free survival (PFS) of the patients with the "Homogeneous origin clonal model" was shorter than the "Heterogeneous origin clonal model". The longer PFS might relate to MUC7 and MUC5B mutations repaired. ZNF91 mutation might be responsible for resistance to ADT resistance. CONCLUSION: Our findings revealed potential genetic regulators to predict the castration resistance and provide insights into the castration resistance processes in advanced prostate cancer. The crosstalk between clonal evolution patterns and tumor microenvironment may also play a role in castration resistance. A multicenter-research including larger populations with different background are needed to confirm our conclusion in the future.

The Development of Aldehyde Catalytic System.

Aldehyde catalysts have proven to be highly effective in facilitating and accelerating a wide range of challenging transformations in organic chemistry. This article is structured into three main sections, focusing on the utilization of aldehydes as organocatalysts, the aldehydes/transition metals catalytic systems, and photochemical initiators. Finally, we provide a concise summary of the advancements in this fascinating research field, offering our perspectives and insights.

Carbene-Catalyzed Atroposelective Annulation for Quick Access to Axially Chiral Thiazine Derivatives.

An N-heterocyclic carbene (NHC)-catalyzed atroposelective annulation reaction is disclosed for quick and efficient access to thiazine derivatives. A series of axially chiral thiazine derivatives bearing various substituents and substitution patterns were produced in moderate to high yields with moderate to excellent optical purities. Preliminary studies revealed that some of our products exhibit promising antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) that causes rice bacterial blight.

Exploration of clinicopathological features of rearranged renal cell carcinoma and TFE3, TFEB, and ALK staining performance in renal entities.

Rearranged renal cell carcinomas (RCC) are rare types of kidney cancer. The clinicopathological features of rearranged RCC require further validation. The pathological diagnosis usually depends on immunohistochemistry and molecular analysis. This study aimed to explore the expression features of anti-TFE3, TFEB, and ALK in different renal entities. In addition, we collected thirty-six TFE3-rearranged RCC, two TFEB-altered RCC, and one ALK-rearranged RCC to explore their clinicopathological features. We observed that TFE3 can sometimes be weakly expressed in non-TFE3-rearranged RCC. TFE3-rearranged RCC usually exhibited strong TFE3 expression. However, clear cell RCC and FH-deficient RCC also displayed strong TFE3 expression. TFEB also can be weakly expressed in clear cell RCC. However, ALK IHC showed a relatively high specificity and was negative for all non-ALK-rearranged RCC. The ALK-rearranged RCC was analyzed using next generation sequencing to explore gene alterations, and we identified a novel gene partner, SLIT1. ALK-rearranged RCC appears to have eosinophilic cytoplasm. Tumor cells with clear cytoplasm may exclude this diagnosis. Psammomatous bodies (22/38) and pattern multiplicity (35/38) were observed in more than half of the patients. In conclusion, weak TFE3 expression did not indicate TFE3 rearrangement. Strong TFE3 expression had a higher value for indicating TFE3-rearranged RCC, although other entities can also exhibit a strong pattern. Young age combined with morphological features (psammomatous calcification and pattern multiplicity) may indicate the diagnosis of rearranged RCC.

Exploration of Morphological Features of Clear Cell Renal Cell Carcinoma With PBRM1, SETD2, BAP1, or KDM5C Mutations.

The last decade has seen great advances in genomic profiling and prognosis-associated factors of clear cell renal cell carcinoma (RCC), the most common entity in kidney cancer. Following VHL, PBRM1, SETD2, BAP1, and KDM5C have been validated as the most common co-occurring gene mutations in clear cell RCC by multicenter studies. However, the morphological features of clear cell RCC with co-occurring gene mutations remain unclear. In this study, we presented 20 clear cell RCCs that underwent next-generation sequencing, of which 1 tumor was reclassified as ELOC-mutated RCC. PBRM1, SETD2, BAP1, and KDM5C were the most common mutations, following VHL. Morphologically, clear cell RCC with PBRM1 or KDM5C mutation usually displayed a low-grade pattern. Cystic changes and hyalinized stroma were often observed. The Ki67 index was <10%. These observations indicated good prognosis. However, mutated SETD2 may increase the malignancy of clear cell RCC with PBRM1 mutation. Two clear cell RCCs with mutated PBRM1 and SETD2 developed local or distant metastases. Clear cell RCC with BAP1 mutations always had high-grade patterns, and rhabdoid differentiation was also observed, indicating that BAP1 mutation was associated with poor outcomes. Papillary architecture was often a feature of BAP1 mutation, which is uncommon in clear cell RCC. PDL1 was positive in only one tumor with BAP1 mutation, and the positivity rate was limited to 5%. B7H3 was negative in all tumors. Morphologic findings in this small cohort may suggest why PBRM1 mutation does not correlate with decreased survival, whereas BAP1 mutation usually predicts poor outcomes.

Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG.

Genome-wide association studies have identified 270 loci conferring risk for prostate cancer (PCa), yet the underlying biology and clinical impact remain to be investigated. Here we observe an enrichment of transcription factor genes including HNF1B within PCa risk-associated regions. While focused on the 17q12/HNF1B locus, we find a strong eQTL for HNF1B and multiple potential causal variants involved in the regulation of HNF1B expression in PCa. An unbiased genome-wide co-expression analysis reveals PCa-specific somatic TMPRSS2-ERG fusion as a transcriptional mediator of this locus and the HNF1B eQTL signal is ERG fusion status dependent. We investigate the role of HNF1B and find its involvement in several pathways related to cell cycle progression and PCa severity. Furthermore, HNF1B interacts with TMPRSS2-ERG to co-occupy large proportion of genomic regions with a remarkable enrichment of additional PCa risk alleles. We finally show that HNF1B co-opts ERG fusion to mediate mechanistic and biological effects of the PCa risk-associated locus 17p13.3/VPS53/FAM57A/GEMIN4. Taken together, we report an extensive germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations underpinning PCa risk association and progression.

GATA3 aids in distinguishing fumarate hydratase-deficient renal cell carcinoma from papillary renal cell carcinoma.

GATA3 has been reported to be positive in clear cell papillary renal cell carcinoma and papillary renal neoplasm with reverse polarity. However, its features in high-grade RCC remain unclear. Despite the emergence of novel renal entities, FH-deficient RCC remains one of the most aggressive renal neoplasms. The diagnosis is mainly based on the loss of FH at the protein level. Previous studies have shown that inclusion-like nuclei, multiple architectural patterns, FH loss, and 2SC positivity can differentiate FH-deficient RCC from other RCC. In some FH-deficient RCC cases, FH is normally expressed and is difficult to diagnose. This study included 11 FH-deficient RCC, and GATA3 showed different expression in seven cases. However, 147 papillary renal cell carcinomas were included, and GATA3 expression was negative. A comparison of clinicopathological aspects between 11 FH-deficient RCC and 30 high-grade PRCC showed statistical significance in age, size, multiple architectural patterns, inclusion-like nuclei, and prognosis. However, PRCC exhibited similar characteristics. CK7, GATA3, and FH profiles were also statistically significant. Different chromosomal alterations were found in FH-deficient RCC, and chromosomal alterations were not different between FH-deficient RCC and PRCC. GATA3 was positive in 33 % (7/21) of collecting duct carcinomas and negative in other high-grade renal neoplasms. GATA3 is negative in PRCC, but can be positive in FH-deficient RCC and collecting duct carcinoma. GATA3 expression may indicate a worse outcome in high-grade RCC with papillary architecture. We recommend GATA3 IHC for the differential diagnosis and prognostic assessment of high-grade RCC with papillary architecture.

Asymmetric Synthesis of Structurally Sophisticated Spirocyclic Pyrano[2,3-c]pyrazole Derivatives Bearing a Chiral Quaternary Carbon Center.

A carbene-catalyzed enantio- and diastereoselective [2 + 4] cycloaddition reaction is developed for quick and efficient access to structurally complex multicyclic pyrano[2,3-c]pyrazole molecules. The reaction tolerates a broad scope of substrates bearing various substitution patterns, with the multicyclic pyrano[2,3-c]pyrazole products afforded in generally good to excellent yields and optical purities. The chiral molecules obtained from this approach has found promising applications in the development of novel bacteriacides for plant protection.

Papillary renal neoplasm with reverse polarity with a favorable prognosis should be separated from papillary renal cell carcinoma.

Papillary renal neoplasm with reverse polarity (PRNRP) is a newly documented renal entity with an easily recognizable morphology, distinct immunohistochemical profiles, and frequent KRAS mutations. The latest practice guidelines regard PRNRP as a subtype of papillary renal cell carcinoma due to the documented chromosomal alterations of 7, 17, and Y. This study included 20 patients with PRNRP and 30 patients with PRCC. Statistically significant differences were observed in size, WHO/ISUP grade, macrophages in the papillae, reverse polarity, CK7, basolateral positivity for Claudin7, GATA3 expression, KRAS mutation, and chromosomal alterations. No adverse events such as perinephric invasion, lymphovascular invasion, sarcomatoid of rhabdoid differentiation, metastasis, or recurrence were found in PRNRP. However, PRCC can cause these adverse events. Basolateral positivity for Claudin7 together with GATA3 expression indicated distal tubule derivation of PRNRP. KRAS mutations were detected in 89% (16/18) of PRNRP. No KRAS mutations were detected in PRCC. Six patients with PRNRP had one chromosomal alteration and the other 12 had no chromosomal alterations. However, only four patients with PRCC showed no chromosomal alterations. Eighteen patients had two or three chromosomal alterations. PRCC can metastasize, recur, and even cause death, whereas PRNRP has a favorable prognosis. We recommend that PRNRP should be separated from PRCC and partial nephrectomy is more suitable for PRNRP.