Molecular genetic and clinical characteristic analysis of primary signet ring cell carcinoma of urinary bladder identified by a novel OR2L5 mutation.

To get a better understanding of the genetic basis of primary signet ring cell carcinoma (SRCC) of the bladder, which is highly rare and not yet explored. First, by using immunohistochemistry to find histological pathological characteristics. Second, a massively parallel whole-exome sequencing (WES) was performed on a 58-year-old male patient who had painless macroscopic hematuria and was pathologically diagnosed with primary SRCC of the bladder, followed by comparing with genes of ordinary urothelial cancer (UC) from TCGA. Furthermore, a population-based analysis using the SEER database was performed to investigate the prognosis (SRCC vs. UC). We identified 63 copy number variations (CNVs) with gain counts and 181 CNVs with loss counts. Totally 4515 mutations were discovered in C > T with a success rate of greater than 89%. The most frequently mutated pathway was RTK-RAS which has 85 genes involved in carcinogenic signaling. Final screening on predisposing genes is performed after filtering based on ACMG. Moreover, several driver genes, including NBN, KCTD18, SPATA13, ANKRD36, OR2L5, MALRD1, and LSMEM1, were detected. Sanger sequencing of germline DNA revealed the presence of a mutant base A/G of OR2L5 in the sequence, which was discovered for the first time in primary SRCC of the bladder. Furthermore, the immunohistochemical profile showed that primary SRCC of the bladder were positive for CK7, CK20, GATA-3, and expression of CK(AE1/AE2), EMA, and Ki67. In the SEER-based study, the patients with primary SRCC of the bladder got a worse prognosis compared to those with UC with median months overall survival (OS) 14 vs. 41, respectively, P = 0001, even after adjusting the variables in the Cox regression model, the SRCC of the bladder showed worse survival HR = 1.119, 95% CI = (1.081-1.328), P = 0.0001. These results imply that suppression of potential driver mutations may be a viable adjuvant treatment approach for primary SRCC in the bladder in place of standard chemotherapy, a possibility that warrants further clinical investigation.

Analysis of genetic profiling, pathomics signature, and prognostic features of primary lymphoepithelioma-like carcinoma of the renal pelvis.

The genetic features of primary lymphoepithelioma-like carcinoma (LELC) of the upper urinary tract have not been systematically explored. In this study, tumor mutation profiling was performed using whole-genome sequencing in two patients with LELC of the renal pelvis. Novel candidate variants relevant to known disease genes were selected using rare-variant burden analysis. Subsequently, a population-based study was performed using the Surveillance, Epidemiology, and End Results (SEER), PubMed, MEDLINE, Embase, and Scopus databases to explore clinical features and prognostic risk factors. Immunohistochemical analysis revealed seven positive cytokeratin-associated markers in tumor cells and five positive lymphocyte-associated markers in and around the tumor area. Sub-sequently, we identified KDM6A as the susceptibility gene and LEPR as the driver gene by Sanger sequencing in case 2 of LELC of the renal pelvis. Three mutation sites of the existing targeted drugs were screened: CA9, a therapeutic target for zonisamide; ARVCF, a therapeutic target for bupropion; and PLOD3, a therapeutic target for vitamin C. In a population-based study, patients with primary LELC of the upper urinary tract had clinical outcomes similar to those of patients with primary upper urinary tract urothelial carcinoma (UUT-UC) before and after propensity score matching at 1 : 5. Focal subtype was an independent prognostic factor for the overall survival of patients with LELC of the upper urinary tract. The carcinogenesis of primary LELC may be due to different genetic variations, including single-nucleotide variants, insertion and deletions, structural variations, and repeat regions, which may provide the basis for clinical diagnosis and treatment. The prognosis of LELC in the upper urinary tract is similar to that of UUT-UC. We suggest that the focal subtype can serve as a prognostic factor for LELC of the upper urinary tract; however, further studies are required to confirm this.

Immunohistochemical analysis of PD-L1 and tumor-infiltrating immune cells expression in the tumor microenvironment of primary signet ring cell carcinoma of the prostate.

Primary signet ring cell carcinoma (SRCC) of the prostate is a rare neoplasm. However, its potential tumorigenic mechanism, clinicopathological features, and prognostic outcome have not been systematically described. To determine the pathogenic mechanism, we detected distributions of programmed cell death-ligand 1 (PD-L1), programmed death 1 (PD-1), and cellular components in the tumor microenvironment, including tumor-infiltrating lymphocytes (CD4 and CD8), tumor-associated macrophages (TAMs; CD163 and CD68), and tumor-associated fibroblasts (vimentin and alpha-smooth muscle actin [α-SMA]), in tumor tissues from four patients with primary prostatic SRCC compared with corresponding adjacent tissues and tumor tissues from 30 patients with prostate adenocarcinoma (PCa) by immunohistochemical staining. We found higher expression of PD-L1, CD163, and CD68 in primary SRCC specimens than that in both corresponding adjacent nontumor specimens and PCa specimens with different Gleason scores, indicating that TAMs may participate in the malignant biological behavior of primary SRCC of the prostate. For further analysis, we searched electronic journal databases and Surveillance, Epidemiology, and End Results (SEER) to identify 200 eligible patients including our four cases. According to Kaplan-Meier survival curve analysis, patients <68 years old, with radical prostatectomy (RP), Gleason score of 7-8, and lower clinical stage had longer overall survival (OS). Moreover, Cox multivariate analysis indicated that race (hazard ratio [HR] = 1.422), surgical approach (HR = 1.654), and Gleason score (HR = 2.162) were independent prognostic factors for OS. Therefore, primary SRCC of the prostate represents a distinct and aggressive subtype of prostate cancer associated with a higher distribution of PD-L1 and TAMs, which warrants further clinical investigation.

Primary adrenal tuberculosis infection in patients with Behcet's disease presenting as isolated adrenal metastasis by 18F-FDG PET/CT: a rare case report and literature review.

Primary adrenal tuberculosis (TB) is a rare type of extrapulmonary tuberculosis (EPTB). A pathological biopsy is usually required to make a definite diagnosis due to nonspecific symptoms. Antituberculous chemotherapy is the main treatment regimen, and cortisol replacement therapy should be added when adrenal insufficiency is involved. Here, we present a 59-year-old man who had recurrence of oral and genital aphthosis for 3 years and was diagnosed with Behcet's disease (BD), which was cured by thalidomide. After 10 days of admission, the patient had sudden abdominal pain in the right upper quadrant with high fever and was diagnosed with acute cholecystitis attack, which was treated by percutaneous transhepatic gallbladder drainage (PTGBD). Further contrast-enhanced CT showed a right adrenal mass with a diameter of 2.0 cm, and PET-CT indicated intense 18F-fluorodeoxyglucose (18F-FDG) uptake in the right adrenal mass with a maximum standardized uptake value (SUVmax) of 15.2. As a metastatic adrenal mass was suspected, the patient underwent retroperitoneal laparoscopic adrenalectomy. Histopathological and immunohistochemical analysis revealed primary adrenal TB. After routine anti-tuberculosis treatment with isoniazid, rifampin, pyrazinamide and ethambutol for six months, the patient was cured and discharged. In summary, primary unilateral adrenal TB without adrenal insufficiency is difficult to diagnose only on the basis of clinical manifestations and examinations. Further studies are needed to develop an easier and more accurate diagnostic examination.

Remarkable damage in talc caused by electron beam irradiation with a dose of up to 1000 kGy: lattice shrinkage in the Z- and Y-axis and corresponding intrinsic microstructural transformation process speculation.

To reduce the polluted areas caused by the migration of radioactive or toxic matter, a clear understanding of soil matrix stability, especially the lattice, is essential under irradiation conditions like those of ß-ray irradiation. In reality, the matrix of soil or clay is silicate, with talc being one of the most simple species with a similar structure to that matter, exhibiting "2 : 1" stacking and a complete crystal. Therefore, in this work, it was irradiated by an electron beam in air with dose up to 1000 kGy. Then, variations in lattice and the intrinsic microstructural transformation process, especially in terms of defect formation and transformation, were explored. The main results show that irradiation led to talc lattice plane shrinkage and amorphization. Shrinkage and amorphization levels in the Z-axis were more serious than those in the Y-axis. For a 1000 kGy-irradiated sample, the shrinkage level of the (002) lattice plane was close to 2% near 0.2 Å and that of (020) was close to 1.3% near 0.06 Å. Variation in the (002) lattice plane was more obvious than that of (020). The main mechanisms involve the cleavage of tetrahedral Si-O and linkage of tetrahedra and octahedra. Tetrahedral Si-O cleavage was visible, leading to serious amorphization. Nevertheless, lattice plane shrinkage, especially in the Z-axis, was mainly caused by linkage cleavage in this direction. In addition to linkage cleavage, dehydroxylation and H2O volatilization occurred, coupled with H2O radiolysis. Nevertheless, those factors are secondary to lattice variation.

Influence of radiation damage on the structure and chemical durability of titanites.

Previous studies on chemical durability of radioactive waste forms mainly focused on samples containing no radionuclides. We performed a hydrothermal experiment with several variably self-irradiated natural titanites and the leaching results indicate that radiation damage has some influence over chemical durability through its ability to change the microstructures of materials, including cracks, holes, interconnected amorphous clusters, and nano-sized defects. However, chemical durability is not influenced if the variation in local microstructures induced by radiation damage is insignificant.

Intensive study on structure transformation of muscovite single crystal under high-dose γ-ray irradiation and mechanism speculation.

Intensive study on structure transformation of muscovite single crystal under high-dose γ-ray irradiation is essential for its use in irradiation detection and also beneficial for mechanism cognition on defect formation within a matrix of clay used in the disposal of high-level radioactive waste (HLRW). In this work, muscovite single crystal was irradiated with Co-60 γ ray in air at a dose rate of 54 Gy min-1 with doses of 0-1000 kGy. Then, structure transformation and mechanism were explored by Raman spectrum, Fourier-transform infrared spectrum, X-ray diffraction, thermogravimetric analysis, CA, scanning electron microscope and atomic force microscopy. The main results show that variations in the chemical/crystalline structure are dose-dependent. Low-dose irradiation sufficiently destroyed the structure, removing Si-OH, thus declining hydrophilicity. With dose increase up to 100 kGy, CA increased from 20° to 40°. Except for hydrophilicity variation, shrink occurred in the (004) lattice plane which later recovered; the variation range at 500 kGy irradiation was 0.5% close to 0.02 Å. The main mechanisms involved were framework break and H2O radiolysis. Framework break results in Si-OH removal and H2O radiolysis results in extra OH introduction. The extra introduced OH probably results in Si-OH bond regeneration, lattice plane shrink and recovered surface hydrophilicity. The importance of framework break and H2O radiolysis on structure transformation is dose-dependence. At low doses, framework break seems more important while at high doses H2O radiolysis is important. Generally, variations in the chemical structure and surface property are nonlinear and less at high doses. This indicates using the chemical structure or surface property variation to describe irradiation is correct at low doses but not at high doses. This finding is meaningful for realizing whether muscovite is suitable for detecting high-dose irradiation or not, and mechanism exploration is efficient for identifying the procedure for defect formation within the matrix of clay used in disposal HLRW in practice.

Intensive evaluation of radiation stability of phlogopite single crystals under high doses of γ-ray irradiation.

The evaluation of radiation stability of clay is important for the disposal of high-level radioactive waste (HLRW). In this study, phlogopite single crystals were irradiated by Co-60 γ-rays in air at a dose rate of 3.254 kGy h-1 with doses up to 1000 kGy. Subsequently, the radiation stability and mechanism of radiation damage were explored by RS, FT-ATR, XRD, TGA, CA, and SEM techniques. In general, phlogopite single crystals show worthwhile radiation resistance toward their chemical structure but poor radiation stability toward their crystalline structure. Upon irradiation, their chemical structure changed slightly, while their crystalline structure varied obviously. For the 1000 kGy-irradiated sample, the interlayer space d of the (001) lattice plane increased by more than 1% with a value close to 0.13 Å, showing expansion. This could be mainly ascribed to H2O radiolysis and framework breakage: the former seems more important. These variations had a considerable impact on surface hydrophilicity, while they had marginal impacts on thermal stability and morphology: the effect on surface hydrophilicity is dose-dependent. A lower dose of irradiation sufficiently reduced the hydrophilicity, while a higher dose recovered the hydrophilicity. For instance, the CA increased from 14° to 28° with dose increases from 0 kGy to 200 kGy and then decreased to approximately 20° as the dose continued to increase to 1000 kGy. In general, the crystalline structure is more sensitive toward γ-ray irradiation and phlogopites could be regarded as poorly radiation-resistant. In this procedure, H2O radiolysis occupies a crucial role and seems to be the dominant factor. This finding is meaningful to evaluate the radiation stability of clay matrixes and to understand the microscopic property variations in clays used in practice when they are under irradiation.

Liquid gating elastomeric porous system with dynamically controllable gas/liquid transport.

The development of membrane technology is central to fields ranging from resource harvesting to medicine, but the existing designs are unable to handle the complex sorting of multiphase substances required for many systems. Especially, the dynamic multiphase transport and separation under a steady-state applied pressure have great benefits for membrane science, but have not been realized at present. Moreover, the incorporation of precisely dynamic control with avoidance of contamination of membranes remains elusive. We show a versatile strategy for creating elastomeric microporous membrane-based systems that can finely control and dynamically modulate the sorting of a wide range of gases and liquids under a steady-state applied pressure, nearly eliminate fouling, and can be easily applied over many size scales, pressures, and environments. Experiments and theoretical calculation demonstrate the stability of our system and the tunability of the critical pressure. Dynamic transport of gas and liquid can be achieved through our gating interfacial design and the controllable pores' deformation without changing the applied pressure. Therefore, we believe that this system will bring new opportunities for many applications, such as gas-involved chemical reactions, fuel cells, multiphase separation, multiphase flow, multiphase microreactors, colloidal particle synthesis, and sizing nano/microparticles.

Is Overexpression of Ki-67 a Prognostic Biomarker of Upper Tract Urinary Carcinoma? A Retrospective Cohort Study and Meta-Analysis.

BACKGROUND: Upper tract urinary carcinoma (UTUC) is a relatively uncommon but aggressive disease. The Ki-67 antigen is a classic marker of cellular proliferation, but there is still controversy regarding the significance and importance of Ki-67 in tumor progression. METHODS: In this study, we first detected Ki-67 expression in UTUC patients by immunohistochemistry (IHC). Subsequently, we quantitatively combined the results with those from the published literature in a meta-analysis after searching several databases. RESULTS: IHC results demonstrated that patients with muscle-invasive tumors (T2-T4) had higher Ki-67 expression than those with non-muscle-invasive tumors (Tis-T1), suggesting that high Ki-67 expression may be associated with the aggressive form of UTUC. Kaplan-Meier curves showed that patients with high Ki-67 expression had significantly poorer cancer-specific survival (CSS) and disease-free survival (DFS). Furthermore, multivariate analysis suggested that Ki-67 expression was an independent prognostic factor for CSS (hazard ratio, HR=3.196) and DFS (HR=3.517) in UTUC patients. Then, a meta-analysis of the published literature investigating Ki-67 expression and its effects on UTUC prognosis was conducted. After searching the PubMed, Medline, Embase, Cochrane Library and Scopus databases, 12 articles met the eligibility criteria for this analysis. The eligible studies included a total of 1740 patients with a mean number of 82 patients per study (range, 38-475). The combined results showed that increased Ki-67 levels were associated with poor survival and disease progression, with a pooled HR estimate of 2.081 and 2.791, respectively. In subgroup analysis, the pooled HR was statistically significant for cancer-specific survival (HR=2.276), metastasis-free survival (HR=3.008) and disease-free survival (HR=6.336). CONCLUSIONS: In conclusion, high Ki-67 expression was associated with poor survival in patients with UTUC, as well as a high risk of disease progression, although these findings need to be interpreted with caution. Large-scale, adequately designed, prospective trials are needed to further confirm the value of Ki-67 in prognosis of UTUC patients.

Supercritical CO2 Foaming of Radiation Cross-Linked Isotactic Polypropylene in the Presence of TAIC.

Since the maximum foaming temperature window is only about 4 °C for supercritical CO2 (scCO2) foaming of pristine polypropylene, it is important to raise the melt strength of polypropylene in order to more easily achieve scCO2 foaming. In this work, radiation cross-linked isotactic polypropylene, assisted by the addition of a polyfunctional monomer (triallylisocyanurate, TAIC), was employed in the scCO2 foaming process in order to understand the benefits of radiation cross-linking. Due to significantly enhanced melt strength and the decreased degree of crystallinity caused by cross-linking, the scCO2 foaming behavior of polypropylene was dramatically changed. The cell size distribution, cell diameter, cell density, volume expansion ratio, and foaming rate of radiation-cross-linked polypropylene under different foaming conditions were analyzed and compared. It was found that radiation cross-linking favors the foamability and formation of well-defined cell structures. The optimal absorbed dose with the addition of 2 wt % TAIC was 30 kGy. Additionally, the foaming temperature window was expanded to about 8 °C, making the handling of scCO2 foaming of isotactic polypropylene much easier.

Combination of OipA, BabA, and SabA as candidate biomarkers for predicting Helicobacter pylori-related gastric cancer.

Helicobacter pylori (H. pylori ) infection is a major cause of chronic gastritis and is highly related to duodenal ulcer (DU) and gastric cancer (GC). To identify H. pylori-related GC biomarkers with high seropositivity in GC patients, differences in levels of protein expression between H. pylori from GC and DU patients were analyzed by isobaric tag for relative and absolute quantitation (iTRAQ). In total, 99 proteins showed increased expression (>1.5-fold) in GC patients compared to DU patients, and 40 of these proteins were categorized by KEGG pathway. The four human disease-related adhesin identified, AlpA, OipA, BabA, and SabA, were potential GC-related antigens, with a higher seropositivity in GC patients (n = 76) than in non-GC patients (n = 100). Discrimination between GC and non-GC patients was improved using multiple antigens, with an odds ratio of 9.16 (95% CI, 2.99-28.07; p < 0.0001) for three antigens recognized. The optimized combination of OipA, BabA, and SabA gave a 77.3% correct prediction rate. A GC-related protein microarray was further developed using these antigens. The combination of OipA, BabA, and SabA showed significant improvement in the diagnostic accuracy and the protein microarray containing above antigens should provide a rapid and convenient diagnosis of H. pylori-associated GC.

High-dose dual therapy is superior to standard first-line or rescue therapy for Helicobacter pylori infection.

BACKGROUND & AIMS: The efficacy of treatment of Helicobacter pylori infection has decreased steadily because of increasing resistance to clarithromycin, metronidazole, and levofloxacin. Resistance to amoxicillin is generally low, and high intragastric pH increases the efficacy of amoxicillin, so we investigated whether a combination of a high-dose proton pump inhibitor and amoxicillin (dual therapy) was more effective than standard first-line or rescue therapies in eradicating H pylori. METHODS: We performed a large-scale multihospital trial to compare the efficacy of a high-dose dual therapy (HDDT) with that of standard therapies in treatment-naive (n = 450) or treatment-experienced (n = 168) patients with H pylori infection. Treatment-naive patients were randomly assigned to groups given HDDT (rabeprazole 20 mg and amoxicillin 750 mg, 4 times/day for 14 days, group A1), sequential therapy for 10 days (group B1), or clarithromycin-containing triple therapy for 7 days (group C1). Treatment-experienced patients were randomly assigned to groups given HDDT for 14 days (group A2), sequential therapy for 10 days (B2), or levofloxacin-containing triple therapy for 7 days (C2). H pylori infection was detected by using the (13)C-urea breath test. We evaluated factors associated with treatment outcomes. RESULTS: In the intention-to-treat analysis, H pylori was eradicated in 95.3% of patients in group A1 (95% confidence interval [CI], 91.9%-98.8%), 85.3% in B1 (95% CI, 79.6%-91.1%), and 80.7% in group C1 (95% CI, 74.3%-87.1%). Infection was eradicated in 89.3% of patients in group A2 (95% CI, 80.9%-97.6%), 51.8% in group B2 (95% CI, 38.3%-65.3%), and 78.6% (95% CI, 67.5%-89.7%) in group C2. The efficacy of HDDT was significantly higher than that of currently recommended regimens, irrespective of CYP2C19 genotype. Bacterial resistance to drugs was associated with treatment failure. There were no significant differences between groups in adverse events or patient adherence. CONCLUSIONS: HDDT is superior to standard regimens as empirical first-line or rescue therapy for H pylori infection, with similar safety profiles and tolerability. ClinicalTrials.gov number: NCT01163435.

Role of omeprazole dosage and cytochrome P450 2C19 genotype in patients receiving omeprazole-amoxicillin dual therapy for Helicobacter pylori eradication.

STUDY OBJECTIVE: To determine the factors that may influence Helicobacter pylori eradication in patients receiving omeprazole-amoxicillin dual therapy. DESIGN: Prospective, randomized study. SETTING: University-affiliated hospital in Taiwan. PATIENTS: A total of 128 adults (age range 20-75 yrs) with H. pylori-positive duodenal ulcer were enrolled; 121 completed the final evaluation. INTERVENTION: Patients were randomly assigned to one of four omeprazole-amoxicillin treatment groups, with each treatment administered for 2 weeks: O2A2 group (33 patients)--omeprazole 20 mg twice/day plus amoxicillin 500 mg 4 times/day; O2A1 group (32 patients)--omeprazole 20 mg twice/day plus amoxicillin 250 mg 4 times/day; O1A2 group (32 patients)--omeprazole 20 mg once/day plus amoxicillin 500 mg 4 times/day; and O1A1 group (31 patients)--omeprazole 20 mg once/day plus amoxicillin 250 mg 4 times/day. MEASUREMENTS AND MAIN RESULTS: Data were collected on H. pylori status, histologic parameters, antibiotic resistance, intragastric pH, cytochrome P450 (CYP) 2C19 genotype, and adverse reactions. The intent-to-treat cure rates (95% confidence interval [CI]) in groups O2A2, O2A1, O1A2, and O1A1 were 76% (95% CI 59-87%), 72% (95% CI 54-84%), 50% (95% CI 34-66%) and 52% (95% CI 35-68%), respectively. Eradication of H. pylori infection was statistically significantly dependent on omeprazole dosage, CYP2C19 genotype, age, gastritis status, and H. pylori density. All CYP2C19 poor metabolizers were cured, whereas the H. pylori cure rate in CYP2C19 extensive metabolizers varied from 44-76% in the different treatment groups. Eradication of H. pylori was favored in the omeprazole higher dose groups versus the lower dose groups (79% vs 53%, p=0.004). No secondary antibiotic resistance was found. Thirty-seven (95%) of 39 patients who failed with the initial treatment were cured by subsequent antibiotic susceptibility-driven proton pump inhibitor-based triple therapy. CONCLUSION: Provided a maintenance dose of amoxicillin is given every 6 hours, eradication of H. pylori infection was significantly dependent on omeprazole dosage, CYP2C19 genotype, age, gastritis status, and H. pylori density.