Correlation of APE1 with VEGFA and CD163+ macrophage infiltration in bladder cancer and their prognostic significance

The present study sought to estimate the applicability of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), vascular endothelial growth factor A (VEGFA) expression and CD163+ tumor‑associated macrophage (TAM) ratio as prognostic factors in bladder cancer (BCa). A total of 127 patients with bladder urothelial cancer who underwent radical cystectomy at Daping Hospital were recruited between January 2013 and January 2017, including 45 cases of non‑muscle invasive BCa (NMIBC) and 82 of MIBC. Immunohistochemical detection of APE1, VEGFA and CD163, as well as multiple immunofluorescence staining for APE1, VEGFA, CD163 and CD34, were performed on tissue samples. For APE1 and VEGFA, the staining was graded based on intensity (0‑3), while CD163 was graded (0‑3) based on the percentage of positively stained cells. The prognostic value of APE1, VEGF and CD163 was assessed using Kaplan‑Meier and Cox regression analysis. The results suggested that in BCa, high APE1 expression was associated with high VEGFA expression and more infiltration of CD163+ TAM. Furthermore, high expression of APE1 was associated with lymphovascular invasion of BCa, as well as reduced survival time. This indicates that APE1 may be associated with CD163+ TAM infiltration in BCa, with VEGFA as a possible influencing factor

Germline SDHB and SDHD Mutations in Pheochromocytoma and Paraganglioma Patients

Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD（succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were: c343C\u3eT and c.541-542A\u3eG in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C\u3eT and c.541-2A\u3eG carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL

Genotype-phenotype correlation in patients with 21-hydroxylase deficiency.

INTRODUCTION: 21-hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia (CAH). However, patients with 21OHD manifest various phenotypes due to a wide-spectrum residual enzyme activity of different CYP21A2 mutations. METHODS: A total of 15 individuals from three unrelated families were included in this study. Target Capture-Based Deep Sequencing and Restriction Fragment Length Polymorphism was conducted on peripheral blood DNA of the three probands to identify potential mutations/deletions in CYP21A2; Sanger sequencing was conducted with the DNA from the family members of the probands. RESULTS: Dramatically different phenotypes were seen in the three probands of CAH with different compound heterozygous mutations in CYP21A2. Proband 1 manifested simple virilizing with mutations of 30-kb deletion/c.[188A\u3eT;518T\u3eA], the latter is a novel double mutants classified as SV associated mutation. Although both probands carry the same compound mutations [293-13C\u3eG]:[518T\u3eA], gonadal dysfunction and giant bilateral adrenal myelolipoma were diagnosed for proband 2 and proband 3, respectively. CONCLUSION: Both gender and mutations contribute to the phenotypes, and patients with the same compound mutations and gender could present with different phenotypes. Genetic analysis could help the etiologic diagnosis, especially for atypical 21OHD patients

Formation conditions and enrichment mechanisms of the Jurassic lacustrine organic-rich shale in the East Fukang Sag, Junggar Basin, NW China: A reassessment based on organic geochemistry

Chemical composition of sediments is often used to evaluate paleoclimate condition, provenance, tectonic setting, depositional condition, and paleoproductivity. However, the validity of these proxies has long been questioned. The comprehensive use of organic and inorganic multi-indicators in combination when interpreting issues related to terrestrial shales should be advocated. The paleodepositional environment, origin of organic matter (OM) and factor controlling OM accumulation in the Early Jurassic Badaowan (J1b) and Sangonghe (J1s) as well as Middle Jurassic Xishanyao (J2x) lacustrine shales in the East Fukang Sag are reassessed by using organic geochemical characteristics of the OM. Some previous knowledge is updated, and some knowledge is further supported by more evidence. The typical clay-rich shale developed under a lacustrine sedimental environment, and the thermal maturity of these organic-rich shales has entered the oil window and formed economic hydrocarbon potential for the tight-oil and shale-oil reservoirs. The paleoclimate conditions of the study area were warm and humid from the Early to Middle Jurassic periods but were colder and drier after the Middle Jurassic period. The salinity of the water column ranged from freshwater to brackish conditions. The J2x Formation was deposited under oxic conditions, while J1b and J1s formations developed under suboxic and reducing environmental conditions. The J2x Formation OM mainly derived from higher plants was deposited in a terrestrial environment,while the OM of J1b and J1s formations was a mixed OM derived from higher plants and bacteria with little algae deposited under bay/estuary environments alternated with terrestrial environments. It is effective to reflect the paleoclimate by element index and judge the salinity by the updated element thresholds, but it is not effective to evaluate the paleoredox conditions by common elemental ratios and to evaluate the paleoproductivity by Ba in the study area

Giant Bilateral Adrenal Myelolipomas in Two Chinese Families with Congenital Adrenal Hyperplasia

CONTEXT AND OBJECTIVES: Congenital adrenal hyperplasia (CAH) is one of the most prevalent, and potentially severe, genetic inborn errors of steroid synthesis directly affecting metabolism. Most patients are diagnosed and treated at an early age. There have been very limited reports of adults with CAH-associated adrenal myelolipomas. We aimed to analyze two families with CAH-associated giant adrenal myelolipomas caused by defects in CYP21A2 and CYP17A1 genes. PARTICIPANTS AND METHODS: A total of 14 individuals from two unrelated families were identified with either CYP21A2 or CYP17A1 mutations. Of note, 5 patients were found with adrenal myelolipomas. Total DNA isolated from the peripheral blood of the two probands was screened for potential mutations in the following susceptibility genes of CAH: CYP21A2, CYP11B1, CYP17A1, HSD17B3, HSD3B2, ARMC5, and STAR using Target Capture-Based Deep Sequencing; and Sanger sequencing was conducted for the family members to detect the potential mutations. RESULTS: In family 1, molecular genetics sequencing revealed a compound heterozygous mutation (c.293-13C\u3eG / c.518T\u3eA, p.I173N) in CYP12A2 in the patient and his brother. In family 2, all three female patients with adrenal myelolipomas were found to have a compound heterozygous mutation (c.1118A\u3eT, p.H373L / c.1459_1467del9, p.D487_F489del) in CYP17A1. CONCLUSION: To avoid giant CAH-associated adrenal myelolipomas in adults, it is important to identify CAH early so appropriate treatment can be initiated to interrupt the chronic adrenal hyperstimulation resulting from increased ACTH. Genetic testing and counseling could be useful in CAH

PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma.

For clear cell renal cell carcinoma (ccRCC), lipid deposition plays important roles in the development, metastasis, and drug resistance. However, the molecular mechanisms underlying lipid deposition in ccRCC remain largely unknown. By conducting an unbiased CRISPR-Cas9 screening, we identified the epigenetic regulator plant homeodomain finger protein 8 (PHF8) as an important regulator in ccRCC lipid deposition. Moreover, PHF8 is regulated by von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) axis and essential for VHL deficiency-induced lipid deposition. PHF8 transcriptionally up-regulates glutamate-ammonia ligase (GLUL), which promotes the lipid deposition and ccRCC progression. Mechanistically, by forming a complex with c-MYC, PHF8 up-regulates TEA domain transcription factor 1 (TEAD1) in a histone demethylation-dependent manner. Subsequently, TEAD1 up-regulates GLUL transcriptionally. Pharmacological inhibition of GLUL by l-methionine sulfoximine not only repressed ccRCC lipid deposition and tumor growth but also enhanced the anticancer effects of everolimus. Thus, the PHF8-GLUL axis represents a potential therapeutic target for ccRCC treatment

LSD1 Promotes Bladder Cancer Progression by Upregulating LEF1 and Enhancing EMT.

Epithelial-to-mesenchymal transition (EMT) is one of the important underlying molecular mechanisms for most types of cancers including bladder cancer. The precise underlying molecular mechanism in EMT-mediated bladder cancer progression is far from completed. LSD1, a histone lysine-specific demethylase, is known to promote cancer cell proliferation, metastasis, and chemoresistance. We found in this study that LSD1 is highly upregulated in bladder cancer specimens, especially those underwent chemotherapy, and the elevated levels of LSD1 are highly associated with bladder cancer grades, metastasis status, and prognosis. Inhibiting or knockdown LSD1 repressed not only EMT process but also cancer progression. Mechanistically, LSD1 complexes with β-catenin to transcriptionally upregulate LEF1 and subsequently enhances EMT-mediated cancer progression. More importantly, LSD1 specific inhibitor GSK2879552 is capable of repressing tumor progression in patient-derived tumor xenograft. These findings altogether suggest that LSD1 can serve as not only a prognostic biomarker but also a promising therapeutic target in bladder cancer treatment

Novel Genotype-Phenotype Correlations in Five Chinese Families with Von Hippel-Lindau Disease.

CONTEXT: Von Hippel-Lindau (VHL) disease manifests as a variety of benign and malignant neoplasms. Previous studies of VHL disease have documented several genotype-phenotype correlations; however, many such correlations are still unknown. Increased identification of new mutations and patients with previously described mutations will allow us to better understand how VHL mutations influence disease phenotypes. PATIENTS AND DESIGN: A total of 45 individuals from five unrelated families were evaluated, of which 21 patients were either diagnosed with VHL disease or showed strong evidence related to this disease. We compared the patients\u27 gene sequencing results with their medical records including computed tomography or magnetic resonance imaging scans, eye examinations, and laboratory/pathological examinations. Patients were also interviewed to obtain information regarding their family history. RESULTS: We identified four missense mutations: c. 239G\u3eT (p.Ser80Ile), linked with VHL Type 2B, was associated with renal cell carcinoma (RCC), pheochromocytoma (Pheo), and hemangioma (HB) in the cerebellum; c. 232A\u3eT (p.Asn78Tyr) manifested as RCC alone and likely caused VHL Type 1; c.500G\u3eA (p.Arg167Gln) mutation was more likely to cause VHL Type 2 than Type 1 as it preferentially induced Pheo and HB in the retina, cerebellum, and spinal cord; c.293A\u3eG (p.Try98Cys) was associated with Pheo and thus likely induced VHL Type 2. CONCLUSIONS: Characterizing VHL disease genotype-phenotype correlations can enhance the ability to predict the risk of individual patients developing different VHL-related phenotypes. Ultimately, such insight will improve the diagnostics, surveillance, and treatment of VHL patients

A Novel Germline ARMC5 Mutation in a Patient with Bilateral Macronodular Adrenal Hyperplasia: A Case Report

BACKGROUND: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing\u27s syndrome (CS). BMAH is predominantly believed to be caused by two mutations, a germline and somatic one, respectively, as described in the two-hit hypothesis. In many familial cases of BMAH, mutations in armadillo repeat containing 5 (ARMC5), a putative tumor suppressor gene, are thought to induce the disorder. The objective of this study was to report a case in which the patient presented with BMAH induced by a novel heterozygous germline ARMC5 mutation (c. 517C \u3e T, p. Arg173*) alone rather than a two-hit mutation. CASE PRESENTATION: A 51-year-old woman was identified with masses in the bilateral adrenals. Serum cortisol levels were increased significantly both in the morning (08:00 AM) and late at night (24:00 AM), while plasma adrenocorticotropic hormone was normal. The patient underwent a left adrenalectomy and histopathology substantiated the BMAH diagnosis. WES of the germline DNA discovered a novel heterozygous germline ARMC5 mutation (c. 517C \u3e T, p. Arg173*) and in silico analysis predicted that the mutation significantly impaired protein function, resulting in inactivated ARMC5. Subsequently, WES of the tumor specimen identified 79 somatic single nucleotide polymorphisms (SNPs)/insertion-deletion (indel) mutations, including 32 missense/nonsense/splice/stop-loss mutations. None of these mutations were CS-related. CONCLUSIONS: A novel germline ARMC5 mutation (c. 517C \u3e T, p. Arg173*) was identified that induced BMAH alone without a second mutation. ARMC5 sequencing may improve the identification of clinical forms of BMAH and allow earlier diagnosis of this disease