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Renal organic cation transporters are downregulated by nitric oxide (NO) in rat endotoxemia. NO generated by inducible NO synthase (iNOS) is substantially increased in the renal cortex after renal ischemia-reperfusion (I/R) injury. Therefore, we investigated the effects of iNOS-specific NO inhibition on the expression of the organic cation transporters rOct1 and rOct2 (Slc22a1 and Slc22a2, respectively) after I/R injury both in vivo and in vitro. In vivo, N6-(1-iminoethyl)-l-lysine (L-NIL) completely inhibited NO generation after I/R injury. Moreover, L-NIL abolished the ischemia-induced downregulation of rOct1 and rOct2 as determined by qPCR and Western blotting. Functional evidence was obtained by measuring the fractional excretion (FE) of the endogenous organic cation serotonin. Concordant with the expression of the rate-limiting organic cation transporter, the FE of serotonin decreased after I/R injury and was totally abolished by L-NIL. In vitro, ischemia downregulated both rOct1 and rOct2, which were also abolished by L-NIL; the same was true for the uptake of the organic cation MPP. We showed that renal I/R injury downregulates rOct1 and rOct2, which is most probably mediated via NO. In principle, this may be an autocrine effect of proximal tubular epithelial cells. We conclude that rOct1, or rOct1 and rOct2 limit the rate of the renal excretion of serotonin. [ABSTRACT FROM AUTHOR]

Abstract: We present the results of deriving the Israel–Stewart equations of relativistic dissipative fluid dynamics from kinetic theory via Grad’s 14-moment expansion. Working consistently to second order in the Knudsen number, these equations contain several new terms which are absent in previous treatments. [Copyright &y& Elsevier]

Short laser pulses were used for generating surface acoustic waves (SAW’s) on optically opaque solids via the thermoelastic effect. The spatial and temporal shapes of the laser pulses were either a spot or a line of variable total width δ=2a with a Gaussian power distribution. Maximal efficiency is obtained when a=vRτ(vR[ATOTHER]@B:[/ATOTHER]Rayleigh velocity, 2τ: total laser-pulse length). This condition is caused by interference effects between the individual frequency components radiating from the area of the thermoelastic source. If the intensity of the laser beam were 100% modulated at a given frequency, maximal efficiency would occur if kR=(2)1/2/a (kR[ATOTHER]@B:[/ATOTHER]wave vector of the SAW’s). [ABSTRACT FROM AUTHOR]

Optical detection of ultrasonic signals of 7.5 MHz center frequency has been carried out by heterodyne interferometry at the rough surface of an aluminum sample. The distorted wave front was reconstructed by optical phase conjugation leading to an increase of the light-gathering power of the interferometer. [ABSTRACT FROM AUTHOR]

Ischemic acute renal failure (iARF) was described to reduce renal extraction of the organic anion para-aminohippurate (PAH) in humans. The rate-limiting step of renal organic anion secretion is its basolateral uptake into proximal tubular cells. This process is mediated by the organic anion transporters OAT1 and OAT3, which both have a broad spectrum of substrates including a variety of pharmaceutics and toxins. Using a rat model of iARF, we investigated whether impairing the secretion of the organic anion PAH might be associated with downregulation of OAT1 or OAT3. Inulin and PAH clearance was determined starting from 6 up to 336 h after ischemia-reperfusion (1/R) injury. Net secretion of PAH was calculated and OAT1 as well as OAT3 expression was analyzed by RT-PCR and Western blotting. lnulin and PAH clearance along with PAH net secretion were initially diminished after I/R injury with a gradual recovery during follow-up. This initial impairment after iARF was accompanied by decreased mRNA and protein levels of OAT1 and OAT3 in clamped animals compared with sham-operated controls. In correlation to the improvement of kidney function, both mRNA and protein levels of OAT1 and OAT3 were upregulated during the follow-up. Thus decreased expression of OAT1 and OAT3 is sufficient to explain the decline of PAH secretion after iARF. As a result, this may have substantial impact on excretion kinetics and half-life of organic anions. As a consequence, the biological effects of a variety of organic anions may be affected after iARF. [ABSTRACT FROM AUTHOR]

Background: Inverted sinonasal (Schneiderian) papilloma (ISP) is a locally aggressive neoplasm often associated with sinonasal squamous cell carcinoma (SNSCC). While the etiology of ISP is not well understood, human papillomavirus (HPV) has been detected in a subset of cases. Our group recently identified activating somatic EGFR mutations in the majority of ISP and ISP-associated SNSCC. However, the relationship between EGFR mutations and HPV infection has not been explored. Patients and methods: We evaluated 58 ISP and 22 ISP-associated SNSCC (including 13 patients with matched ISP/SNSCC samples), as well as 14 SNSCC without clinical or pathologic evidence of an associated ISP. Formalin-fixed, paraffin-embedded samples were evaluated for EGFR mutations using Sanger sequencing and for HPV infection using GP5+/GP6+PCR. HPV subtyping based on the L1 sequence was done for HPV positive cases including temporally distinct tumors for four patients. Clinicopathologic data including progression free survival was also analyzed. Results: All ISP and ISP-associated SNSCC demonstrated either an EGFR mutation or HPV infection. HPV and EGFR mutation were mutually exclusive in all cases of ISP-associated SNSCC and all but one ISP; this case was only weakly HPV positive, and analysis of a prior temporally distinct ISP specimen from this patient failed to show HPV infection, suggesting transient infection/incidental colonization. HPV subtypes in ISP and ISP-associated SNSCC were predominantly low-risk, in contrast with SNSCC without ISP association, which showed frequent high-risk HPV. All paired ISP and associated SNSCC samples demonstrated concordant HPV status and EGFR genotypes. ISP progression to SNSCC was significantly associated with the presence of HPV infection and the absence of an EGFR mutation (log-rank=9.620, P=0.002). Conclusions: Collectively our data show that EGFR mutations and HPV infection represent essential, alternative oncogenic mechanisms in ISP and ISP-associated SNSCC. [ABSTRACT FROM AUTHOR]

MDS patients may present with monocytic marrow proliferation not fulfilling criteria for CMML. We analyzed MDS patients with or without a marrow monocytic proliferation by following up the amount of monocytic proliferation and characterizing their molecular profile. 315 MDS patients of Duesseldorf MDS registry were divided into two groups: A) 183 patients with monocytic esterase positive cells in marrow and monocytes between 101 and 900/μl in blood and B) 132 patients without monocytic esterase positive cells in marrow and monocytes in blood ≤100/μl. Twenty patients of each group were screened with regard to ASXL1, TET2, RUNX1, SETBP1, NRAS, and SRSF2 using Illumina myeloid panel. Group A patients were older, had significantly higher WBC, hemoglobin levels, neutrophils and platelets. CMML evolution rates were 4.9% and 1.5%, respectively (p = n.s.). TET2, NRAS and SRFS2 mutation frequencies were higher in group A and four patients had coexisting TET2 and SRFS2 mutation, which was shown to be characteristic but not specific for CMML. MDS patients with marrow monocytic proliferation have a more CMML-like pheno- and genotype and develop CMML more often. Those patients could potentially be very early stages of CMML or represent a CMML-like myeloid neoplasma with marrow adherence of the monocytic cell population. [ABSTRACT FROM AUTHOR]

Background: Comprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging. Patients and methods: We developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing. Results: We identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599_V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 overexpression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations. Conclusions: Our results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized medicine applications. [ABSTRACT FROM AUTHOR]

About 40% of patients with myelodysplastic syndromes (MDSs) present with a normal karyotype, and they are facing different courses of disease. To advance the biological understanding and to find molecular prognostic markers, we performed a high-resolution oligonucleotide array study of 107 MDS patients (French American British) with a normal karyotype and clinical follow-up through the Duesseldorf MDS registry. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor-associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 deletion had an additional 5q31.2 deletion of the acute myeloid leukemia/MDS region, the smallest deletion identified so far and including the putative tumor suppressor (ts) genes, EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as a ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total, 42/107 (39%) cases had genomic imbalances. These patients had an inferior survival as compared with the rest of the patients (P=0.002). This study emphasizes the heterogeneity of MDS, but points to interesting genes that may have diagnostic and prognostic impact. [ABSTRACT FROM AUTHOR]

The canonical Wnt signalling pathway plays a key role during embryogenesis and defects in this pathway have been implicated in the pathogenesis of various types of tumours, including breast cancer. The gene for secreted frizzled-related protein 1 (SFRP1) encodes a soluble Wnt antagonist and is located in a chromosomal region (8p22–p12) that is often deleted in breast cancer. In colon, lung, bladder and ovarian cancer SFRP1 expression is frequently inactivated by promoter methylation. We have previously shown that loss of SFRP1 protein expression is a common event in breast tumours that is associated with poor overall survival in patients with early breast cancer. To investigate the cause of SFRP1 loss in breast cancer, we performed mutation, methylation and expression analysis in human primary breast tumours and breast cell lines. No SFRP1 gene mutations were detected. However, promoter methylation of SFRP1 was frequently observed in both primary breast cancer (61%, n=130) and cell lines analysed by methylation-specific polymerase chain reaction (MSP). We found a tight correlation (P<0.001) between methylation and loss of SFRP1 expression in primary breast cancer tissue. SFRP1 expression was restored after treatment of tumour cell lines with the demethylating agent 5-aza-2′-deoxycytidine. Most interestingly, SFRP1 promoter methylation was an independent factor for adverse patient survival in Kaplan–Meier analysis. Our results indicate that promoter hypermethylation is the predominant mechanism of SFRP1 gene silencing in human breast cancer and that SFRP1 gene inactivation in breast cancer is associated with unfavourable prognosis.Oncogene (2006) 25, 3479–3488. doi:10.1038/sj.onc.1209386; published online 30 January 2006 [ABSTRACT FROM AUTHOR]

Mutations commonly associated with acute myeloid leukemia (AML), such as CEBPA, FLT3, IDH1/2 and NPM1 are rarely found in chronic myelomonocytic leukemia (CMML) and their prognostic significance in CMML has not been clearly identified. In 127 CMML patients, we have retrospectively analyzed next-generation sequencing and PCR data from analyses of bone marrow samples performed at diagnosis of CMML. Seven patients harbored CEBPA mutations, eight FLT3 mutations, 12 IDH1 mutations, 26 IDH2 mutations and 11 NPM1 mutations. CMML patients harboring CEBPA, FLT3, and/or NPM1 mutations (mutCFN)were more frequently associated with the myeloproliferative subtype (MP-CMML) , a high prevalence of severe cytopenia, and elevated blast counts. Regardless of their CPSS-Mol classification, mutCFN CMML patients had a poor prognosis, and the multivariate analysis identified mutCFN as an independent marker of overall survival. The genetic profile of these mutCFN CMML patients closely resembled that of AML, with higher-risk clinical characteristics. Our findings lead us to suggest including the assessment of these mutations in CMML prognostic models and treating these patients with AML-type therapies, including intensive chemotherapy and allogeneic stem cell transplantation, whenever feasible, and consider certain targeted therapies approved for use in AML., (Copyright © 2024 American Society of Hematology.)