The role of occlusion and micro-incontinence in the pathogenesis of penile lichen sclerosus: an observational study of pro-inflammatory cytokines' gene expression.

PURPOSE: To assess the expression of selected cytokines in penile lichen sclerosus (PLS) and associate them with the occurrence of micro-incontinence (MI) in different stages of PLS. METHODS: The skin biopsies from 49 PLS affected, and 13 from nonlesional foreskins (healthy control adult males undergoing circumcision due to phimosis caused by short frenulum) were obtained. All specimens were used for RNA extraction and RT-qPCR. Quantitative assessment of the gene expression of interleukin 1-A (IL-1A), interleukin 1-B (IL-1B), interleukin 1 receptor antagonist (IL-1RN), interleukin 6 (IL-6), transforming growth factor ß1 (TGF-ß1), and interferon-gamma (INF-γ) was performed. To determinate the presence of MI, the patients were asked about voiding patterns, especially leaking tiny drops of urine from the urethral meatus after urination. RESULTS: IL-1A, IL-6, and INF-γ mRNA levels were approximately 150, 16, and 59 times higher in PLS than in control samples, respectively. The highest IL-1A mRNA levels were observed in early PLS (n = 13), INF-γ in moderate PLS (n = 32), while IL-6 in severe PLS (n = 4). MI was noted in 45 PLS patients vs. 0 in control (p < 0.0001). IL-1A and IL-6 vs control ratios were concentration (ca.) 400 and 30 times higher, respectively, in MI PLS samples than in PLS without MI. CONCLUSION: Occlusion and irritating urine effect are associated with the clinical progression of penile LS with increased mRNA expression of IL-1A, INF-γ, and IL-6 pro-inflammatory cytokines in the foreskin.

The relationship between interleukin-13 and angiogenin in patients with bladder cancer.

Participation of anti-inflammatory interleukin-13 (IL-13) in the process of carcinogenesis was well studied. Angiogenesis plays a key role in the process of tumour growth and metastasis. Higher expression of angiogenin (ANG) have been proven in many types of cancers. The aim of the study was to more fully understand the significance of plasma IL-13 as an immunomodulator and ANG as a stimulator of the angiogenesis process in patients with bladder cancer (BC) and to investigate the relationship between parameters. These parameters were examined in the group of BC patients and in subgroups of BC depending on clinical stage: non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC), histopathologic malignancy low grade (LG), high grade (HG) and in primary and recurrent BC. The level of IL-13 and ANG in the plasma of BC patients and controls were measured by enzyme-linked immunosorbent assay. All calculations were done using the STATISTICA 13.3 (TIBCO software Inc.). Plasma levels of IL-13 and ANG were significantly higher in BC patients and in all patient subgroups examined than in the controls (p < 0.001). A negative significant correlation was found between ANG and IL-13 levels in BC-patients. Based on the receiver operating characteristic curves (ROC), IL-13 had good diagnostic value in BC. The presented results may suggest a relationship between angiogenesis and inflammation in the pathogenesis of bladder cancer and the development of this disease. With the increase of IL-13 level in BC-patients plasma, the ANG level decreased.

Coherent transfer of topological interface states.

We demonstrate the controlled coherent transfer of topological interface states in a one-dimensional non-Hermitian chain of interacting Bose-Einstein condensates. The topological protection stems from a spatially patterned pump in an open-dissipative system. As a test bed setup of the proposed phenomenon, we consider a chain of coupled micropillars with embedded quantum wells, possessing exciton-polariton resonances. The transfer of an interface state is driven by spatially localised, adiabatic pump modulation in the vicinity of the interface state. The stochastic calculations prove the coherent nature of the interface state transfer. For appropriate system parameters the coherence degree is preserved after multiple transitions, paving the way towards long-range transfer of a coherent quantum state.

Uroplakin IIIa Is a Marker in Bladder Cancer but Seems Not to Reflect Chemical Carcinogenesis.

BACKGROUND: Uroplakins are glycoproteins investigated as potential markers of urothelial carcinoma. However, their role in chemical carcinogenesis is uncertain. In this study the diagnostic value of plasma and urine uroplakin IIIa (UPIIIa) levels in bladder cancer (BC) was investigated, particularly in the aspect of environmental exposure to chemical carcinogens, measured by DNA damage and detoxification ability in the BC smoking group. The correlation between uroplakin, 8-OHdG, and GSTπ was investigated. MATERIAL AND METHODS: This study included 61 BC patients and 33 healthy controls. UPIIIa, 8-OHdG, and GSTπ levels were estimated by the immunoenzymatic method (ELISA). RESULTS: UPIIIa levels were elevated in BC patients in plasma (p≤0.001) and in urine (p≤0.001), as were 8-OHdG and GSTπ levels in urine. Moreover, the 8-OHdG level was higher in invasive or high grade tumors. A positive correlation between UPIIIa/GSTπ and 8-OHdG/GSTπ was observed, but no UPIIIa/8-OHdG correlation was noted. CONCLUSION: The study showed the diagnostic value of urine and plasma UPIIIa in BC (good sensitivity, specificity, and predictive value). The lack of UPIIIa correlation with 8-OHdG and smoking suggests that UPIIIa does not reflect the environmental exposure. The increased levels of 8-OHdG and GSTπ in the invasive tumor stage indicate their value in BC monitoring.

Single-shot condensation of exciton polaritons and the hole burning effect.

A bosonic condensate of exciton polaritons in a semiconductor microcavity is a macroscopic quantum state subject to pumping and decay. The fundamental nature of this driven-dissipative condensate is still under debate. Here, we gain an insight into spontaneous condensation by imaging long-lifetime exciton polaritons in a high-quality inorganic microcavity in a single-shot optical excitation regime, without averaging over multiple condensate realisations. We demonstrate that condensation is strongly influenced by an incoherent reservoir and that the reservoir depletion, the so-called spatial hole burning, is critical for the transition to the ground state. Condensates of photon-like polaritons exhibit strong shot-to-shot fluctuations and density filamentation due to the effective self-focusing associated with the reservoir depletion. In contrast, condensates of exciton-like polaritons display smoother spatial density distributions and are second-order coherent. Our observations show that the single-shot measurements offer a unique opportunity to study fundamental properties of non-equilibrium condensation in the presence of a reservoir.

Publisher Correction: Single-shot condensation of exciton polaritons and the hole burning effect.

The original PDF version of this Article had an incorrect Published online date of 25 December 2018; it should have been 9 August 2018. This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.

Efficacy and Safety of Mammalian Target of Rapamycin Inhibitor Use-Long-term Follow-up of First Tuberous Sclerosis Complex Patient Treated De Novo With Sirolimus After Kidney Transplantation: A Case Report.

Mammalian target of rapamycin inhibitors (mTORI) are increasingly used in the treatment of tuberous sclerosis complex (TSC) and as immunosuppressants after organ transplantation. In TSC patients, mTORI are the treatment of choice after kidney transplantation. It is still under debate if benefits from long-term mTORI use will not be limited by side effects. MATERIALS AND METHODS: We report long-term follow-up data of the first TSC patient after kidney transplantation treated with sirolimus de novo. In 2005, a female patient was transplanted with a kidney graft after bilateral nephrectomy due to angiomyolipoma. Initial immunosuppressive treatment consisted of antithymocyte globulin, methylprednisolone, tacrolimus, and, due to TSC diagnosis, sirolimus. Creatinine level at discharge was 1.2 mg/dL. RESULTS: Long-term mTORI use resulted in skin lesion regression (angiofibromas, "confetti" skin lesions, shagreen patch) and disease stabilization in brain, abdominal, and chest magnetic resonance imaging/computed tomography scans. Pulmonary function tests showed improvement in restriction and slow deterioration in obstruction and diffusion parameters. Sirolimus related adverse reactions were hyperlipidemia and hypertriglyceridemia and respiratory and urinary tract infections. No gastrointestinal or hematologic symptoms occurred. Sirolimus concentrations ranged between 1.7 and 8.2 ng/mL (mean 4.01 ± 2.09 ng/mL). Since 2009 proteinuria and slow increase in creatinine level have been observed. No biopsy was performed to establish etiology and potential association with mTORI. In 2017 creatinine level was 2.2 mg/dL. CONCLUSION: The case of the patient confirms clinical effectiveness and acceptable safety of long-term mTORI treatment. Long-term mTORI use requires meticulous patient observation to optimize dosage, achieve immunosuppressive effect, and improve TSC manifestations with minimal side effects.

Increased expression of the gene encoding stearoyl-CoA desaturase 1 in human bladder cancer.

Bladder cancer is a common disease and a significant cause of death worldwide. There is thus great interest in identifying a diagnostic and prognostic biomarker, as well as gaining an understanding of the molecular basis of bladder cancer. Stearoyl-CoA desaturase 1 gene (SCD1) is highly overexpressed in many human cancers. However, the expression of SCD1 has not yet been investigated in patients with bladder cancer. Here, we document that (a) the SCD1 is highly overexpressed in human bladder cancer; (b) high expression of SCD1 is more frequently observed in the late stage of disease and patients with lymph node metastasis; (c) bladder cancer patients with a higher SCD1 mRNA level have a poorer survival rate than those with normal SCD1 expression. Overall, this is the first report to indicate an association between SCD1 mRNA level and clinical indicators of human bladder cancer. Our study has provided evidence supporting the potential role of SCD1 as a biomarker for human bladder cancer prognosis.

Preliminary Evaluation of the Diagnostic Usefulness of Uroplakin 2 with an Assessment of the Antioxidant Potential of Patients with Bladder Cancer.

BACKGROUND: Urothelial carcinoma is the most common type of bladder cancer (BC). It makes up more than 90% of all bladder cancers. Uroplakins are tissue-specific, glycoproteins, playing a role in the construction and function of urothelium. The emergence of uroplakins in the urine and/or plasma may be of potential importance in the early detection of BC. In our study, the diagnostic value of plasma and urine uroplakin 2 (UP2) concentration in bladder cancer was investigated, with an assessment of the antioxidant potential of BC patients. The correlation between UP2, total antioxidant capacity (TAC), and concentration of glutathione (GSH) was also examined. MATERIALS AND METHODS: This study included 61 BC patients and 33 healthy controls. UP2 concentration was estimated by the immunoenzymatic method (ELISA). TAC and GSH were determined in spectrophotometrically methods. RESULTS: UP2 concentration in BC patients was significantly higher (p≤0.001) both in plasma and in urine compared to the control groups (C). TAC concentration in urine (p≤0.001) and GSH concentration in plasma (p=0.047) were significantly lower in BC group compared to the C group. The high specificity and sensitivity for UPK2 in plasma (76%, 80%, respectively) and urine (88%, 84%, respectively) were observed. Positive correlations were observed between concentration of UP2 in plasma and TAC concentration in urine and between UP2 concentration in plasma and GSH concentration in the same material. CONCLUSION: The study showed the early diagnostic value of urine and plasma UP2 in BC. There was a decrease in UP2 concentration in the urine of patients with the development of BC. The decrease of antioxidant systems (TAC, GSH) indicates their relationship with the BC process. Based on the obtained results, it is justified to continue the study in a larger group of patients with BC.

Doubly Dressed Bosons: Exciton Polaritons in a Strong Terahertz Field.

We demonstrate the existence of a novel quasiparticle, an exciton in a semiconductor doubly dressed with two photons of different wavelengths: a near infrared cavity photon and terahertz (THz) photon, with the THz coupling strength approaching the ultrastrong coupling regime. This quasiparticle is composed of three different bosons, being a mixture of a matter-light quasiparticle. Our observations are confirmed by a detailed theoretical analysis, treating quantum mechanically all three bosonic fields. The doubly dressed quasiparticles retain the bosonic nature of their constituents, but their internal quantum structure strongly depends on the intensity of the applied terahertz field.

Robust HPLC-MS/MS method for levofloxacin and ciprofloxacin determination in human prostate tissue.

Fluoroquinolones are the drugs of choice in the prevention of bacterial infections after transrectal ultrasound guided prostate biopsy. In order to improve assessment of antibacterial efficacy in the target tissue a simple, selective, rapid and robust HPLC-ESI-MS/MS method for the determination of levofloxacin and ciprofloxacin concentrations in human prostate bioptates was developed and validated. Preparation procedure for prostate samples (10mg) was carried out using homogenization and filtration steps. Analyses were performed within 3.5min using RP C18 column in the isocratic elution mode with mobile phase composed of a mixture of 0.1% formic acid aqueous solution and 0.1% formic acid methanol solution (v/v; 79:21). The method was linear between 0.3µg/g and 15µg/g for levofloxacin and ciprofloxacin with coefficient of correlation (r) ≥0.999. The limit of detection and the limit of quantification for levofloxacin were 0.06µg/g and 0.2µg/g and for ciprofloxacin were 0.04µg/g and 0.13µg/g, respectively. Average concentrations (±SD) of levofloxacin and ciprofloxacin obtained from patients tissue were 5.4±2.2µg/g and 3.9±1.5µg/g, respectively. Additionally, during validation procedure a novel, experimental design approach was applied for the robustness study. For evaluation of analytical method robustness, Plackett-Burman design was employed and for sample preparation method robustness Fractional Factorial design was used. The developed and validated method was successfully applied to examine prostate tissue samples obtained from patients enrolled into a clinical study. Up to now, there has been no other HPLC-ESI-MS/MS method reported for the simultaneous determination of levofloxacin and ciprofloxacin in human prostatic tissue.

Ultra-high performance liquid chromatographic determination of levofloxacin in human plasma and prostate tissue with use of experimental design optimization procedures.

Fluoroquinolones are considered as gold standard for the prevention of bacterial infections after transrectal ultrasound guided prostate biopsy. However, recent studies reported that fluoroquinolone- resistant bacterial strains are responsible for gradually increasing number of infections after transrectal prostate biopsy. In daily clinical practice, antibacterial efficacy is evaluated only in vitro, by measuring the reaction of bacteria with an antimicrobial agent in culture media (i.e. calculation of minimal inhibitory concentration). Such approach, however, has no relation to the treated tissue characteristics and might be highly misleading. Thus, the objective of this study was to develop, with the use of Design of Experiments approach, a reliable, specific and sensitive ultra-high performance liquid chromatography- diode array detection method for the quantitative analysis of levofloxacin in plasma and prostate tissue samples obtained from patients undergoing prostate biopsy. Moreover, correlation study between concentrations observed in plasma samples vs prostatic tissue samples was performed, resulting in better understanding, evaluation and optimization of the fluoroquinolone-based antimicrobial prophylaxis during transrectal ultrasound guided prostate biopsy. Box-Behnken design was employed to optimize chromatographic conditions of the isocratic elution program in order to obtain desirable retention time, peak symmetry and resolution of levofloxacine and ciprofloxacine (internal standard) peaks. Fractional Factorial design 2(4-1) with four center points was used for screening of significant factors affecting levofloxacin extraction from the prostatic tissue. Due to the limited number of tissue samples the prostatic sample preparation procedure was further optimized using Central Composite design. Design of Experiments approach was also utilized for evaluation of parameter robustness. The method was found linear over the range of 0.030-10µg/mL for human plasma and 0.300-30µg/g for human prostate tissue samples. The intra-day and inter-day variability for levofloxacine from both plasma and prostate samples were less than 10%, with accuracies between 93 and 108% of the nominal values. The limit of detection and the limit of quantification for human plasma were 0.01µg/mL and 0.03µg/mL, respectively. For the prostate tissue, the limit of detection and the limit of quantification were 0.1µg/g and 0.3µg/g, respectively. The average recoveries of levofloxacin were in the range from 99 to 106%. Also, the method fulfills requirements of robustness what was determined and proved by Design of Experiments. The developed method was successfully applied to examine prostate tissue and plasma samples from 140 hospitalized patients enrolled into the clinical study, 12h after oral administration of LVF at a dose of 500mg. The mean (±SD) LVF concentration in prostate was 6.22±3.52µg/g and in plasma 2.54±1.14µg/mL. Due to simplicity of the method and relative small amount of sample needed for the assay, the method can be applied in clinical practice for monitoring of LVF concentrations in plasma and prostate gland.

The influence of the time-of-day administration of sunitinib on the penetration through the blood-brain and blood-aqueous humour barriers in rabbits.

OBJECTIVE: Sunitinib is a multiple tyrosine kinase inhibitor (TKI) that exerts anti-tumor and antiangiogenic activity. It is used for the treatment of metastatic gastrointestinal stromal tumours, renal cell carcinoma and pancreatic neuroendocrine tumours. A few studies confirm the anti-tumour activity of sunitinib in brain tumours and uveal melanoma, as well as its efficacy in the reduction of brain metastases of some primary cancers. Therefore, the penetration of sunitinib through the blood-brain barrier (BBB) and blood-aqueous humour barrier (BAB) is an issue of growing interest. The aim of the study was to investigate the influence of the time-of-day administration on the penetration of sunitinib into the cerebrospinal fluid (CSF) and aqueous humour (AH). MATERIALS AND METHODS: The rabbits were divided into two groups: I (control group)--receiving sunitinib at 8 a.m., and II--receiving sunitinib at 8 p.m. Sunitinib was administered p.o. at a single dose of 25 mg. The concentrations of sunitinib and its active metabolite (SU12662) in the plasma, CSF, AH were measured with the validated HPLC-UV method. RESULTS: The plasma AUC0-t for sunitinib in group I was 2051.8 ng × h/mL, whereas in group II it was 3069.3 ng × h/mL. The aqueous humour AUC0-t for sunitinib in thr groups were 43.2 and 76.3 ng × h/mL, respectively. The cerebrospinal AUC0-t for sunitinib in groups I and II were 55.5 and 66.3 ng × h/mL, respectively. CONCLUSIONS: After the evening administration (8 p.m.) the exposure to sunitinib in the rabbits' plasma, AH and CSF was higher than after the morning administration (8 a.m.), but the degree of sunitinib penetration through the BAB and BBB was very low (< 5%) and comparable in both groups.

Real-space collapse of a polariton condensate.

Microcavity polaritons are two-dimensional bosonic fluids with strong nonlinearities, composed of coupled photonic and electronic excitations. In their condensed form, they display quantum hydrodynamic features similar to atomic Bose-Einstein condensates, such as long-range coherence, superfluidity and quantized vorticity. Here we report the unique phenomenology that is observed when a pulse of light impacts the polariton vacuum: the fluid which is suddenly created does not splash but instead coheres into a very bright spot. The real-space collapse into a sharp peak is at odd with the repulsive interactions of polaritons and their positive mass, suggesting that an unconventional mechanism is at play. Our modelling devises a possible explanation in the self-trapping due to a local heating of the crystal lattice, that can be described as a collective polaron formed by a polariton condensate. These observations hint at the polariton fluid dynamics in conditions of extreme intensities and ultrafast times.

Fluoroquinolone-based antimicrobial prophylaxis in patients undergoing transrectal ultrasound-guided prostate biopsy.

The aim of this study was to establish the prevalence of resistance to fluoroquinolones in Escherichia coli strains isolated from patients undergoing transrectal ultrasound-guided prostate biopsy (TRUS-Bx) and to evaluate the incidence of possible infectious complications associated with this procedure. One hundred and four patients undergoing a TRUS-Bx in a single medical centre were prospectively enrolled in this study. In all patients, pre-biopsy rectal swabs were obtained. The analysis determined the antimicrobial susceptibility of E. coli strains to levofloxacin, ciprofloxacin and a panel of other antibiotics. Before biopsy, each of the men received a levofloxacin-based prophylaxis. Telephone follow-up was used to identify patients who had complications after TRUS-Bx. Fluoroquinolone-resistant strains were isolated from 9.62 % of the patients. In all cases, there were related to E. coli and all those strains were resistant to both levofloxacin and ciprofloxacin. Fluoroquinolones showed greater antimicrobial activity against E. coli (p < 0.05) than ampicillin, amoxicillin/clavulanate and cephalothin. Minor infectious complications occurred in three patients (2.91 %). The relation between the resistance of E. coli to fluoroquinolones and the risk of readmission, as well as infectious complications, was statistically significant (p < 0.05). Despite recent reports of increasing prevalence of fluoroquinolone-resistant E. coli and the associated increase of severe infectious complications, the presented results have not confirmed this phenomenon. Resistance to fluoroquinolones of E. coli strains isolated from rectal swab cultures prior to TRUS-Bx is the risk factor for readmission and infectious complications after this procedure.

The influence of the time-of-day administration of the drug on the pharmacokinetics of sunitinib in rabbits.

OBJECTIVES: At present it is known that the adjustment of the anticancer therapy to the circadian rhythms in tissues reduces the toxicity of the treatment. Chronotherapy also increases the efficacy of the anticancer treatment, which has been proved for many drugs. Sunitinib is a tyrosine kinase inhibitor, which is broadly used for the treatment of numerous cancers. The aim of the study was a comparison of the concentrations and pharmacokinetics of sunitinib after a single administration to rabbits at 08:00 (control group) and 20:00. Additionally, the effect of sunitinib on glucose levels was investigated. MATERIALS AND METHODS: The research was carried out on two groups of rabbits: I08:00, a group with the drug administered at 08:00 (n=8) and II20:00, a group with the drug administered at 20:00 (n=8). The rabbits were treated with sunitinib at an oral dose of 25 mg. Plasma concentrations of sunitinib and its metabolite (SU12662) were measured with a validated HPLC method with UV detection. RESULTS: The comparison of the sunitinib Cmax and AUC0-t in the group with sunitinib administered at 20:00 with the control group gave the ratios of 2.20 (90% confidence interval (CI) (2.17; 2.22) and 1.64 (1.61; 1.68), respectively. Statistically significant differences between the groups under analysis were revealed for Cmax (p < 0.0001), AUC0-t (p = 0.0079), AUC0-∞ (p = 0.0149), and tmax (p = 0.0085). The mean glycemia drop was higher in group I08:00. than in group II20:00 (22.7% vs. 14.3%; p = 0.0622). The glycemia values returned to the initial values in 24 h after the administration of the drug in both groups. CONCLUSIONS: The research proved a significant influence of the time-of-day administration on the pharmacokinetics of sunitinib.

Organ-sparing surgery of the bilateral testicular large cell calcifying sertoli cell tumor in patient with atypical Peutz-Jeghers syndrome.

Large cell calcifying sertoli cell tumor (LCCSCT) is an exceptionally rare neoplasm originating from sperm cord cells. The tumors have relatively low malignant potential and unlikely proceed to metastasis formation. The lesions may occur in an isolated form or in ca. 40% of cases may be associated with genetic abnormalities, by and large Peutz-Jeghers syndrome and Carney complex. At presentation, 20% of LCCSCT cases are bilateral and/or multifocal. Owning to characteristic skin lesions and particular hyperechoic ultrasound image of the tumor, preliminary diagnosis of the syndromic LCCSCT is possible in the preoperative period. Consequently, testicle organ-sparing procedure can be attempted, which is especially justified in bilateral lesions. Here, we report a case of a bilateral LCCSCT in a 20-year-old man with atypical Peutz-Jeghers syndrome due to amplification of the exon 1 of STK11 gene who was successfully treated with bilateral testicle-sparing tumorectomies.

Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband.

It is important to have accurate knowledge of the range of cancers associated with various CHEK2 mutations, and of the lifetime risks of cancer associated with each. We wished to establish the relationship between family history, mutation type and cancer risk in families with a CHEK2 mutation. We obtained a blood sample and pedigree information from 2012 unselected women with breast cancer, from 2007 men with prostate cancer and from 1934 patients with colon cancer, from hospitals throughout Poland. Genetic testing was carried out for four founder CHEK2 mutations on all 5953 specimens and 533 carriers were identified. We estimated the risk to age 75 for any cancer in the 2544 first-degree relatives to be 22.3%. After adjusting for mutation type, the risk of breast cancer was much higher among relatives of probands with breast cancer than among relatives of patients with prostate or colon cancer (HR=3.6; 95% CI=2.1-6.2; P=0.0001). Similarly, the risk of prostate cancer was higher among relatives of probands with prostate cancer than among relatives of patients with breast or colon cancer (HR=4.4; 95% CI=2.2-8.7; P=0.0001) and the risk of colon cancer was higher among relatives of probands with colon cancer than among relatives of patients with prostate or breast cancer (HR=4.2; 95% CI=2.4-7.8; P=0.0001). These analyses suggest that the risk of cancer in a carrier of a CHEK2 mutation is dependent on the family history of cancer.