Abstract Background The transcription factor sex determining region Y (SRY)-box 2 (SOX2) (3q26.3–q27) has been recently identified as a recurrently activated major oncogene in squamous cell carcinoma ...of various sites. Its prognostic value in head and neck squamous cell carcinoma (HNSCC) is currently unclear. Aim To correlate SOX2 protein expression with the occurrence of occult lymph node metastasis and relapse free survival in early oral SCC. Methods SOX2 expression in 120 T1/T2 oral SCC patients was evaluated using a tissue microarray technique. Intensity of SOX2 expression was quantified by assessing the Intensity/Reactivity Scores (IRSs). These scores were correlated with the lymph node status of biopsied sentinel lymph nodes and recurrence. Log rank univariate and Cox regression multivariate analysis was used to determine statistical significance. Results Twenty-six of 120 primary tumours (21.7%) showed high SOX2 expression. High expression levels of SOX2 significantly correlated with negative lymph node status in univariate ( p = 0.001) and multivariate analysis ( p = 0.003). Sensitivity was found to be 95.6% with a negative predictive value of 92.3%. Specificity was 32% with a positive predictive value of 45.7%. Conclusion SOX2 up-regulation is frequent in early SCC of the oral cavity and associated with decreased risk of lymphatic metastasis. SOX2 immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity.
Abstract Purpose Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood renal tumour. Only a few homogeneously treated CCSK cohorts have been reported. This study aims to describe clinical ...characteristics and survival of CCSK patients treated according to recent International Society of Pediatric Oncology (SIOP) protocols. Patients and methods We analysed the prospectively collected data of patients with a histologically verified CCSK, entered onto SIOP 93-01/2001 trials. Results A total of 191 CCSK patients (64% male) were analysed, with a median age at diagnosis of 2.6 years. Stage distribution for stages I, II, III and IV was 42%, 23%, 28% and 7%, respectively. Pre-operative chemotherapy was administered to 169/191 patients. All patients underwent total nephrectomy and 189/191 patients received post-operative chemotherapy. Radiotherapy was applied in 2/80 stage I, 33/44 stage II, 44/54 stage III and 6/13 stage IV patients. Five year event-free survival (EFS) and overall survival (OS) were 79% (95% confidence interval (CI): 73–85%) and 86% (95% CI: 80–92%) respectively. Stage IV disease and young age were significant adverse prognostic factors for event-free survival. Factors such as gender, tumour volume and type of initial treatment were not found to be prognostic for EFS and OS. Conclusion In this largest SIOP cohort described so far, overall outcome of CCSK is reasonable, although treatment of young and advanced-stage disease patients is challenging. As further intensification of treatment is hampered by direct and late toxicity, future directions should include the development of targeted therapy based on specific molecular aberrations of CCSK.
Key points
Changes in nerve conduction velocity following an impulse (i.e. velocity recovery cycles) reflect after‐potentials, and can provide an indication of altered nerve membrane properties.
This ...study used microneurography to assess the effects of ischaemia on single human sympathetic fibres innervating the dorsum of the foot.
It was found that velocity recovery cycles can distinguish whether a sympathetic nerve fibre is depolarized or not.
The method may be used to detect membrane depolarization of sympathetic nerve fibres in human patients when autonomic neuropathy is suspected.
The aim of this study was to determine whether velocity recovery cycles (VRCs) could detect the effects of ischaemia on sympathetic nerve fibres. VRCs of human sympathetic nerve fibres of the superficial peroneal nerve innervating the dorsum of the foot were recorded by microneurography in seven healthy volunteers. Sympathetic nerve fibres were identified by studying their response to manoeuvres increasing sympathetic outflow and by measuring activity‐dependent slowing at 2 Hz stimulation. VRCs were assessed at rest, during 30 min of induced limb ischaemia and during 20 min of recovery after ischaemia. From each VRC was measured the relative refractory period (RRP), the supernormality and the time to peak supernormality (SN@). During ischaemia, RRP increased from the baseline value of 37.4 ± 8.7 ms (mean ± SEM) to 67.1 ± 12.1 ms (P < 0.01) and SN@ increased from 68.6 ± 9.8 ms to 133.8 ± 11.0 ms (P < 0.005). The difference between SN@ and RRP separated ischaemic from non‐ischaemic sympathetic nerve fibres. It is concluded that these sympathetic nerve fibres are sensitive to ischaemia, and that VRCs provide a method to study changes of axonal membrane potential of human sympathetic nerve fibres in vivo.
Key points
Changes in nerve conduction velocity following an impulse (i.e. velocity recovery cycles) reflect after‐potentials, and can provide an indication of altered nerve membrane properties.
This study used microneurography to assess the effects of ischaemia on single human sympathetic fibres innervating the dorsum of the foot.
It was found that velocity recovery cycles can distinguish whether a sympathetic nerve fibre is depolarized or not.
The method may be used to detect membrane depolarization of sympathetic nerve fibres in human patients when autonomic neuropathy is suspected.
Consequences of prenatal exposure to ethanol (E) include morphological, physiological, and cognitive deficits and are collectively classified as fetal alcohol spectrum disorders. Adult prenatal E ...exposed offspring show insulin resistance, and given that in utero hyperglycemic environment can cause metabolic disorders in subsequent generations; we investigated the effects of grandmaternal E on functional glucose and insulin responses of the second generation. Sprague-Dawley (S) rat dams, mated with S males, received E-containing liquid diet and two different control diets between gestational days 8 and 20. Additionally, because prenatal E-induced behavioral deficits can be reversed by simultaneous thyroxine (T4) treatment, another group of dams received 0.3 mg/l T4 in their E diet. Their first-generation (F1) offspring were mated with control Brown Norway (B) males or females to produce SB and BS F2 progeny. Dams consuming E during pregnancy were hyperglycemic, and their F1 offspring showed insulin resistance in the glucose tolerance test (GTT). However, F2 responses to GTT varied based on the sex of prenatal E-exposed parent. BS F2 females, and both male and female SB F2 progeny, displayed hypoglycemic and hyperinsulinemic GTT response patterns. Although administering T4 to E dams normalized thyroid function of the F1 generation, it did not reverse their prenatal E-induced metabolic dysfunction. In contrast, administration of T4 to the alcohol-consuming grandmother reversed or alleviated the aberrant GTT responses of the F2 progeny. Prenatal E-induced dysregulation of glucose metabolism can affect the next generation, possibly via ethanol effects on the germline of the F1 fetus.
We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of ...specific chromosomal aberrations including monosomal (MK
), complex (CK
) and hypodiploid (HK
) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK
(n=22) as a new independent risk factor for poor event-free survival (EFS 23±9% vs 53±2% for all other patients, P=0.0003), even after exclusion of four patients with monosomy 7 (EFS 28±11%, P=0.0081). CK
patients without MK had a better prognosis (n=47, EFS 47±8%, P=0.46) than those with MK
(n=12, EFS 25±13%, P=0.024). HK
(n=37, EFS 44±8% for total cohort, P=0.3) influenced outcome only when t(8;21) patients were excluded (remaining n=16, EFS 9±8%, P<0.0001). An extremely poor outcome was observed for MK
/HK
patients (n=10, EFS 10±10%, P<0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n=16, EFS 25±11%, P=0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.
Tef (Eragrostis tef) is an orphan crop that is widely grown in East Africa, primarily in Ethiopia as a staple crop. It is becoming popular in the Western world owing to its nutritious and gluten-free ...grains and the forage quality of its biomass. Tef is also considered to have a high antioxidant capacity based on cell-free studies. However, the antioxidant activity of tef has never been validated using a physiologically relevant cell model. The purpose of this study was to investigate the antioxidant capacity of tef grain extracts using a mammalian cell model. We hypothesized that the tef grain extracts are capable of modulating the cellular antioxidant response via the modulation of glutathione (GSH) biosynthetic pathways. Therefore, we evaluated the antioxidant activity of purified tef grain extracts in the human acute monocytic leukemia (THP-1) cell line. Our findings revealed that the organic fraction of grain extracts increased the cellular GSH level, which was more evident for brown-colored tef than the ivory variety. Moreover, a brown-tef fraction increased the expressions of GSH-pathway genes, including γ-glutamate cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits and glutathione reductase (GR), an enzyme that plays a key role in GSH biosynthesis, suggesting that tef extracts may modulate GSH metabolism. Several compounds were uniquely identified via mass spectrometry (MS) in GSH-modulating brown-tef samples, including 4-oxo-β-apo-13-carotenone, γ-linolenic acid (methyl ester), 4,4′-(2,3-dimethyl-1,4-butanediyl)bis-phenol (also referred to as 8,8′-lignan-4,4′-diol), and (3β)-3-2-4-(Acetylamino)phenoxyacetyloxyolean-12-en-28-oic acid. Tef possesses antioxidant activity due to the presence of phytochemicals that can act as direct antioxidants, as well as modulators of antioxidant-response genes, indicating its potential role in alleviating diseases triggered by oxidative stresses. To the best of our knowledge, this is the first report revealing the antioxidant ability of tef extracts in a physiologically relevant human cell model.
Clear cell sarcoma of the kidney (CCSK) is an uncommon paediatric renal tumour. Relapses occur in about 15% of the patients. Since detailed clinical information on relapsed CCSK is scarce, the ...current study aims to describe outcome of patients with relapsed CCSK treated according to recent European protocols.
We analysed prospectively collected data of all CCSK patients who developed a relapse after complete remission at the end of primary treatment, entered onto SIOP and AIEOP trials between 1992 and 2012.
Thirty-seven of 237 CCSK patients (16%) treated according to SIOP and AIEOP protocols developed a relapse. Median time from initial diagnosis to relapse was 17 months (range, 5.5 months - 6.6 years). Thirt-five out of thirty-seven relapses (95%) were metastatic; the most common sites of relapse were the brain (n=13), lungs (n=7) and bone (n=5). Relapse treatment consisted of chemotherapy (n=30), surgery (n=19) and/or radiotherapy (n=18), followed by high-dose chemotherapy and autologous bone marrow transplantation (ABMT) in 14 patients. Twenty-two out of thirty-seven patients (59%) achieved a second complete remission (CR); 15 of whom (68%) developed a second relapse. Five-year event-free survival (EFS) after relapse was 18% (95% CI: 4%-32%), and 5-year overall survival (OS) was 26% (95% CI: 10%-42%).
In this largest series of relapsed CCSK patients ever described, overall outcome is poor. Most relapses are metastatic and brain relapses are more common than previously recognised. Intensive treatment aiming for local control, followed by high dose chemotherapy and ABMT, seems to be of benefit to enhance survival. Novel development of targeted therapy is urgently required.
Abstract Background Revisional bariatric surgery may be necessary due to inadequate weight loss or postoperative complications of the primary operation. We sought to identify the reasons for ...revision, characteristics of the surgery, and outcomes. We hypothesize that revisional surgery, although technically challenging, can produce desirable outcomes. Methods Patients undergoing bariatric surgery at our institution between 1998 and 2007 were reviewed from a prospective database. Patients who had revisional surgery were compared to those who had primary surgery. Results We have identified 46 of 1,038 patients who underwent revisional surgery. Twenty of 46 had a primary Roux-en-Y gastric bypass. The most common indication for revisions is inadequate weight loss secondary to gastrogastric fistula (15/20). Leaks occurred more frequently following revisional surgeries (11% vs 1.2%), but intensive care unit (ICU) utilization was less (11% vs 4.4%) and mortality was lower (0% vs .3%) with bariatric revision surgery. Conclusions Although we saw a 9-fold increase in leaks, a 2-5 fold increase in ICU utilization, and 1.5-fold increase in length of stay, our mortality rate was zero. In experienced hands, bariatric revision surgery can be performed to produce desirable outcomes.
Bioactivity-directed fractionation of the organic extracts of two filamentous fungi of the Bionectriaceae, strains MSX 64546 and MSX 59553 from the Mycosynthetix library, led to the isolation of a ...new dimeric epipolythiodioxopiperazine alkaloid, verticillin H (1), along with six related analogs, Sch 52900 (2), verticillin A (3), gliocladicillin C (4), Sch 52901 (5), 11'-deoxyverticillin A (6) and gliocladicillin A (7). The structures of compounds 1-7 were determined by extensive NMR and HRMS analyses, as well as by comparisons to the literature. All compounds (1-7) were evaluated for cytotoxicity against a panel of human cancer cell lines, displaying IC(50) values ranging from 1.2 μM to 10 nM. Compounds 1-5 were examined for activity in the NF-κB assay, where compounds 2 and 3 revealed activity in the sub-micromolar range. Additionally, compounds 1, 3 and 4 were tested for EGFR inhibition using an enzymatic assay, while compound 3 was examined against an overexpressing EGFR(+ve) cancer cell line.
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