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Neoadjuvant chemotherapy followed by surgery for locoregionally advanced penile carcinoma (LAPSCC) is associated with severe toxicity and a 1-year survival probability of ∼50%. We aimed to evaluate the safety and efficacy of chemoradiotherapy (CRT) as the primary treatment for LAPSCC and the association of high-risk human papillomavirus (hrHPV) with the outcome. This was a prospective, single-center, single-arm study of CRT in LAPSCC, defined as a large/inoperable primary tumor, large palpable nodes, suspicion of extranodal extension or pelvic nodal involvement, and no distant metastases. CRT consisted of 49.5 Gy (33 × 1.5 Gy) on affected inguinal and pelvic areas combined with intravenous mitomycin C on day 1 and capecitabine on radiation days. Primary tumors and positron emission tomography/computed tomography–positive deposits received a boost of 59.4 Gy (33 × 1.8 Gy). The response was evaluated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography. If feasible, patients with residual/recurrent disease underwent salvage surgery. The primary endpoint was 1-year progression-free survival (PFS), reached when 1-year PFS was ≥50%. Other endpoints were 2-year PFS, overall survival, and toxicity rates. Kaplan-Meier survival curves were compared using the log-rank test. Thirty-three patients were included: 29 (88%) with stage IV disease (T4 any-N M0 and/or any-T N3 M0) and 8 (24%) with hrHPV-positive disease. Median follow-up was 41 months. Thirty-two completed CRT. Eleven (33%) experienced ≥1 grade 3 treatment-related adverse event. There were no grade 4 or 5 treatment-related events. Twenty-four patients (73%) responded, including 13 (39%) complete responses. Nine patients (27%) underwent salvage surgery, and an additional 8 patients underwent later surgery (together 52%). One- and 2-year PFS were 34% and 31%, respectively. One- and 2-year overall survival were 73% and 46%, respectively. No significant difference between patients with hrHPV-positive and -negative tumors was observed. CRT is a viable treatment option for LAPSCC with acceptable toxicity. CRT can result in an enduring response. If patients have residual tumor, salvage surgery is feasible. HrHPV status was not associated with outcomes. [ABSTRACT FROM AUTHOR]

The FACE-Q Skin Cancer module is a patient-reported outcome measure (PROM) for facial skin cancer. It has been anglicised for the UK population and undergone psychometric testing using classical test theory. In this study, further evaluation of construct validity using Rasch measurement theory and hypothesis testing was performed. Patients were prospectively recruited to the Patient-Reported Outcome Measures In Skin Cancer Reconstruction (PROMISCR) study and asked to complete the anglicised FACE-Q Skin Cancer module. The scalability and unidimensionality of the data were assessed with a Mokken analysis prior to Rasch analysis. Response thresholds, targeting, fit statistics, local dependency, and internal consistency were examined for all items and subscales. Four a priori hypotheses were tested to evaluate the convergent and divergent validity. We additionally hypothesised that the median 'cancer worry' score would be lower in post-operative than pre-operative patients. 239 patients self-completed the questionnaire between August 2017 and May 2019. Of the ten subscales assessed, five showed relative fit to the Rasch model. Unidimensionality was present for all five subscales, with most demonstrating ordered item thresholds and appropriate fit statistics. Two items in the 'cancer worry' subscale had either disordered or very close response thresholds. Subscales of the FACE-Q Skin Cancer module demonstrated convergent and divergent validity with relevant Skin Cancer Index comparators (p < 0.001). Median 'cancer worry' was lower in post-operative patients (44 vs 39, p < 0.001). The anglicised FACE-Q Skin Cancer module shows psychometric validity through hypothesis testing, and both classical and modern test theory. [ABSTRACT FROM AUTHOR]

Facial skin cancer is common, and its treatment affects patient's health-related quality of life (HRQoL), as demonstrated by patient-reported outcome measures (PROMs). In this study, we anglicise and validate the novel FACE-Q Skin Cancer Module for the UK population. Anglicisation of the FACE-Q Skin Cancer Module followed international guidance for cross-cultural adaptation. Cognitive interviews were performed, producing a reconciled and harmonised version for validation. Patients undergoing facial skin cancer excision were prospectively recruited and asked to complete the anglicised FACE-Q Skin Cancer Module, along with the Skin Cancer Index (SCI) and European Quality of Life-Five Dimensions (ED-5D) questionnaire, pre-operatively and 6–8 weeks post-operatively. Data were analysed using classical test theory. Ethical approval was obtained (REC: 16/WM/0445). One hundred and ten patients were recruited between August 2017 and July 2018. Internal consistency was high (Cronbach's alpha 0.867–0.967). All subscales had a single-factor solution using principal component analysis. Construct validity, as measured between the FACE-Q subscales and SCI subscales, was good, with >75% of a priori predictions confirmed. Pearson's r for item–total correlation was >0.80 for several items, and significant ceiling effects are shown in 7 of the 10 subscales, suggesting some item redundancy. The UK version of this well-designed PROM demonstrates good face and construct validity. There is however a degree of redundancy within the scales, and further work using Rasch analysis on a larger sample will help address this. [ABSTRACT FROM AUTHOR]

The International Consortium for Health Outcome Measurement (ICHOM) has recently agreed upon a core outcome set for the comprehensive appraisal of cleft care, which puts a greater emphasis on patient-reported outcome measures (PROMs) and, in particular, the CLEFT-Q. The CLEFT-Q comprises 12 scales with a total of 110 items, aimed to be answered by children as young as 8 years old. In this study, we aimed to use computerised adaptive testing (CAT) to reduce the number of items needed to predict results for each CLEFT-Q scale. We used an open-source CAT simulation package to run item responses over each of the full-length scales and its CAT counterpart at varying degrees of precision, estimated by standard error (SE). The mean number of items needed to achieve a given SE was recorded for each scale's CAT, and the correlations between results from the full-length scales and those predicted by the CAT versions were calculated. Using CATs for each of the 12 CLEFT-Q scales, we reduced the number of questions that participants needed to answer, that is, from 110 to a mean of 43.1 (range 34–60, SE < 0.55) while maintaining a 97% correlation between scores obtained with CAT and full-length scales. CAT is likely to play a fundamental role in the uptake of PROMs into clinical practice given the high degree of accuracy achievable with substantially fewer items. [ABSTRACT FROM AUTHOR]

Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in brain serotonin synthesis. The TPH2 gene has frequently been investigated in relation to psychiatric morbidity. The aim of the present review is to integrate results from association studies between TPH2 single nucleotide polymorphisms (SNPs) and various psychiatric disorders, which we furthermore quantified with meta-analysis. We reviewed 166 studies investigating 69 TPH2 SNPs in a broad range of psychiatric disorders, including over 30,000 patients. According to our meta-analysis, TPH2 polymorphisms show strongest associations with mood disorders, suicide (attempt) and schizophrenia. Despite small effect sizes, we conclude that TPH2 SNPs in the coding and non-coding areas (rs4570625, rs11178997, rs11178998, rs10748185, rs1843809, rs4290270, rs17110747) are each associated with one or more psychopathological conditions. Our findings highlight the possible common serotonergic mechanisms of the investigated psychiatric disorders. Yet, the functional relevance of most TPH2 polymorphisms is unclear. Characterizing how exactly the different TPH2 variants influence the serotonergic neurotransmission is a next necessary step in understanding the psychiatric disorders where serotonin is implicated. [ABSTRACT FROM AUTHOR]

Summary Introduction Strattice™, a porcine acellular dermal matrix, has emerged as a product to augment implant-based breast reconstruction. It aims to resolve problems related to poor tissue coverage of the implant. Presently, evidence justifying the use of Strattice in breast reconstruction is lacking. The objective of this study is to assess the clinical outcomes of a patient cohort that underwent single-stage implant-based breast reconstruction with the additional use of Strattice. Methods We conducted a retrospective chart review of patients who underwent single-stage breast reconstruction with the use of Strattice. All cases of breast reconstruction after oncologic or prophylactic mastectomy between 2010 and 2014 in one of eight different centres in the Netherlands were included. Patient demographics, treatment characteristics and clinical outcome data were collected. The outcomes were presented using descriptive statistics, and the associations were evaluated using Fisher's exact test. Results Eighty-eight patients who underwent either unilateral (60 patients) or bilateral (25 patients) ( n = 110 breasts) single-stage breast reconstruction with the use of Strattice were identified. The indication for mastectomy was therapeutic in 69.1% (76) of cases and prophylactic in 30.9% (34) of cases. The reported minor complications included seroma (20.9%), skin necrosis (20.0%), wound dehiscence (11.8%), erythema/inflammation (14.5%) and infection (11.8%). In 22 breasts (22.7%), reoperation was necessary, with explantation of the implant in 11 breasts (11.8%). Conclusions In this cohort, the total complication rate was very high (78%). Although most complications were minor, reoperation was performed in 22.7%, with explantation of the implant in 11.8% of breasts. We suggest that patient selection, experience of the surgeon and handling of early complications are factors playing a crucial role in the success of the operation. The use of a Strattice sheet in single-stage implant-based breast reconstruction may be a promising technique, but more evidence from prospective, randomized studies is necessary to justify its use. Level of evidence : IV. [ABSTRACT FROM AUTHOR]

Objective: Systemic arterial hypertension is a strong and prevalent cardiovascular risk factor. Currently, information on the very long-term prognostic value of single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in patients with systemic arterial hypertension is lacking. The aim of this study was to assess the value of stress (99m)Tc-tetrofosmin MPI for the prediction of very long-term outcome in these patients.Methods: The study population consisted of 608 patients with systemic arterial hypertension who underwent exercise or dobutamine stress (99m)Tc-tetrofosmin MPI for the assessment of known or suspected coronary artery disease. Follow-up was successful in 600 (99%) patients. The endpoints were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival cures were constructed and univariate and multivariate analyses were performed to identify predictors of very long-term outcome.Results: The mean age of the patients was 59 ± 10 years, and 65% of them were male. MPI findings were normal in 301 patients (50%). Myocardial perfusion abnormalities were fixed in 162 (27%) and reversible in 137 (23%) patients. During a median 8.1-year follow-up, 241 (40%) patients died (121 cardiac deaths), 52 (9%) had a nonfatal myocardial infarction, and 128 (21%) underwent coronary revascularization. Survival curves in patients with a low vs a high summed difference score diverged up to 5 years after the test was performed. Multivariate analyses demonstrated that SPECT MPI provided incremental prognostic information up to 5 years after the test.Conclusions: Stress (99m)Tc-tetrofosmin MPI provides incremental prognostic information for the prediction of cardiovascular outcome in patients with systemic arterial hypertension. Patients with normal stress MPI have a significantly better prognosis as compared with those with an abnormal study, up to 5 years after the test is performed. [ABSTRACT FROM AUTHOR]

Objective: Systemic arterial hypertension is a strong and prevalent cardiovascular risk factor. Currently, information on the very long-term prognostic value of single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in patients with systemic arterial hypertension is lacking. The aim of this study was to assess the value of stress 99mTc-tetrofosmin MPI for the prediction of very long-term outcome in these patients. Methods: The study population consisted of 608 patients with systemic arterial hypertension who underwent exercise or dobutamine stress 99mTc-tetrofosmin MPI for the assessment of known or suspected coronary artery disease. Follow-up was successful in 600 (99%) patients. The endpoints were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival cures were constructed and univariate and multivariate analyses were performed to identify predictors of very long-term outcome. Results: The mean age of the patients was 59 ± 10 years, and 65% of them were male. MPI findings were normal in 301 patients (50%). Myocardial perfusion abnormalities were fixed in 162 (27%) and reversible in 137 (23%) patients. During a median 8.1-year follow-up, 241 (40%) patients died (121 cardiac deaths), 52 (9%) had a nonfatal myocardial infarction, and 128 (21%) underwent coronary revascularization. Survival curves in patients with a low vs a high summed difference score diverged up to 5 years after the test was performed. Multivariate analyses demonstrated that SPECT MPI provided incremental prognostic information up to 5 years after the test. Conclusions: Stress 99mTc-tetrofosmin MPI provides incremental prognostic information for the prediction of cardiovascular outcome in patients with systemic arterial hypertension. Patients with normal stress MPI have a significantly better prognosis as compared with those with an abnormal study, up to 5 years after the test is performed. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported a favorable outcome of patients with normal single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). The aim of this study was to assess the very long-term prognosis of patients with known coronary artery disease (CAD) and normal SPECT MPI results. Methods: The population consisted of 266 patients with known CAD (defined as a healed myocardial infarction and/or a previous coronary revascularization), who underwent exercise bicycle or dobutamine-atropine stress SPECT MPI and had normal perfusion during stress and at rest. End points during follow-up were all-cause mortality, cardiac mortality, and nonfatal myocardial infarction. Univariate and multivariate analyses were performed to identify predictors of long-term outcome. Results: Follow-up was completed in 261 (98%) patients. During a median follow-up of 12 years, 94 (36%) patients died, of which 26 (10%) died due to cardiac causes, and 15 (6%) had a nonfatal myocardial infarction. The annualized mortality rate was 3.1%, annualized cardiac mortality rate was 0.9%, and the annualized event rate for cardiac death and/or nonfatal infarction was 1.2%. Independent predictors of total mortality were age, diabetes mellitus, and rate-pressure product at peak stress. Independent predictors of cardiac mortality were age, male gender, and rate-pressure product at peak stress. Conclusion: Patients with known CAD and a normal SPECT MPI study have a favorable long-term prognosis. Clinical and stress test variables can be used to identify patients with a higher risk status. [ABSTRACT FROM AUTHOR]

Objective: There are no data regarding the long-term prognostic value of single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in obese patients. The aim of this study was to examine the value of stress (99m)Tc-tetrofosmin MPI findings for the prediction of very long-term outcome in obese patients.Methods: The study population consisted of 261 patients with a body mass index ≥30 kg/m(2) who underwent exercise or pharmacological stress (99m)Tc-tetrofosmin MPI for the assessment of known or suspected coronary artery disease. Endpoints during follow-up were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival cures were constructed and univariate and multivariate analyses were performed to identify predictors of very long-term outcome.Results: The mean age was 59 ± 10 years, 42% of the patients was male, and the body mass index was on average 37 ± 7 kg/m(2). MPI findings were normal in 109 patients (42%). Myocardial perfusion abnormalities were fixed in 62 patients (24%) and reversible in 90 patients (34%). During a median 12-year follow-up, 91 (35%) patients died, and 27 (10%) had a nonfatal myocardial infarction. Survival curves were compared using the log-rank test at subsequent follow-up durations. Obese patients with a normal stress (99m)Tc-tetrofosmin study had a significantly better prognosis as compared with those with an abnormal study, up to 6 years after the test was performed.Conclusion: Stress (99m)Tc-tetrofosmin MPI provides valuable prognostic information for the prediction of outcome in obese patients. Obese patients with a normal stress (99m)Tc-tetrofosmin study have a significantly better prognosis as compared with those with an abnormal study, up to 6 years after the test is performed. [ABSTRACT FROM AUTHOR]

Objective: There are no data regarding the long-term prognostic value of single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in obese patients. The aim of this study was to examine the value of stress Tc-tetrofosmin MPI findings for the prediction of very long-term outcome in obese patients. Methods: The study population consisted of 261 patients with a body mass index ≥30 kg/m who underwent exercise or pharmacological stress Tc-tetrofosmin MPI for the assessment of known or suspected coronary artery disease. Endpoints during follow-up were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival cures were constructed and univariate and multivariate analyses were performed to identify predictors of very long-term outcome. Results: The mean age was 59 ± 10 years, 42% of the patients was male, and the body mass index was on average 37 ± 7 kg/m. MPI findings were normal in 109 patients (42%). Myocardial perfusion abnormalities were fixed in 62 patients (24%) and reversible in 90 patients (34%). During a median 12-year follow-up, 91 (35%) patients died, and 27 (10%) had a nonfatal myocardial infarction. Survival curves were compared using the log-rank test at subsequent follow-up durations. Obese patients with a normal stress Tc-tetrofosmin study had a significantly better prognosis as compared with those with an abnormal study, up to 6 years after the test was performed. Conclusion: Stress Tc-tetrofosmin MPI provides valuable prognostic information for the prediction of outcome in obese patients. Obese patients with a normal stress Tc-tetrofosmin study have a significantly better prognosis as compared with those with an abnormal study, up to 6 years after the test is performed. [ABSTRACT FROM AUTHOR]

Summary: Hereditary diffuse gastric cancer is an autosomal dominant cancer syndrome characterized by highly penetrant diffuse gastric cancer. It is caused by germ line mutations in CDH1, encoding the cell-cell adhesion protein E-cadherin. Pancreatic ductal adenocarcinoma is one of the most dismal malignancies in humans. Although absent E-cadherin expression in pancreatic ductal adenocarcinoma is related to a higher tumor grade and a worse prognosis, there have been no reports of pancreatic ductal adenocarcinoma associated with hereditary diffuse gastric cancer. Here, we describe a patient with hereditary diffuse gastric cancer who was subsequently diagnosed with pancreatic ductal adenocarcinoma. To investigate if the previously identified CDH1 germ line mutation initiated pancreatic ductal adenocarcinoma development, we performed mutational and proteomic analyses. We conclude that the pancreatic ductal adenocarcinoma did not occur in the context of the germ line CDH1 mutation but rather appeared as a sporadic event. Immunohistochemistry ultimately proved to be the most valuable tool of investigation as persistent CDH1 staining in the pancreatic ductal adenocarcinoma unequivocally revealed E-cadherin expression. [ABSTRACT FROM AUTHOR]

Pioneer plant species were observed growing on mined areas despite unfavourable conditions such as extreme pH, high salinity and phytotoxic levels of several elements. This study evaluated the contribution of pioneer species to the accumulation of soil organic matter (SOM). We collected 51 samples from 17 non-vegetated, natural and pioneer-vegetated sites in five highly saline mined areas in the Sierra de Cartagena (Spain). The composition of SOM was determined using total C, N and S elemental anlayzer, pyrolysis and solid state 13C NMR spectroscopy. Results showed that pioneer species like Lygeum spartum had contributed ∼11kgSOMkg−1 soil into the Balsa Rosa sites since 1991; it will take ∼120 years of continuous growth for this plant to increase the SOM level comparable to natural site. In the Portman Bay area, Sarconia ramosissima and Phragmites australis can contribute SOM equivalent to present day SOM in natural sites in the next 30 years. Low quality SOM (C/N>20) deposited by pioneer plants was dominated by lignin-derived organic compounds such as phenols, guaiacols, syringols and aromatics while polyssacharides and alkyls were the major components in high quality SOM (C/N<20). The addition of SOM to mine wastes is similar to early stages of soil formation and with time, we expect the formation of well-developed Ah horizon on the surface of mine wastes. The presence of P. australis on several sites makes it a very good candidate for successful revegetation of hostile conditions found in many mined sites. [Copyright &y& Elsevier]

Mid-infrared spectra of freeze-dried sucrose and lactose systems were acquired over a range of temperatures (30–200 °C) and water contents (0–6.3%). Starting from the glassy state, the experimental conditions were selected to cover the main thermal transitions: the glass–rubber transition, the crystallisation and, for some samples, the subsequent melting. The FTIR spectra were very sensitive to the physical state. While subtle but systematic spectral differences between the glassy and rubbery states were detectable throughout the spectrum, a very pronounced increase in spectral resolution was observed as crystallisation occurred and was followed by the expected spectral broadening during melting. The temperatures at which these changes occurred were in satisfactory agreement with the transition temperatures measured by differential scanning calorimetry (DSC). The increase in molecular mobility as a result of increasing temperature or plasticisation by water led to a significant shift of the O&z.sbnd;H stretching band to higher wavenumbers indicating a weakening of hydrogen bonding. This shift reached a maximum as the DSC measured crystallisation temperature range was approached. As expected, the crystallisation led to a highly effective hydrogen bonding network. This was more significant for lactose than for sucrose. No significant step change in hydrogen bonding was observed at Tg. As anticipated, the temperature at which these transitions occurred decreased with increasing water content but overlapped when observed in the context of the shifted temperature (T−Tg). [Copyright &y& Elsevier]

Objective: To analyze the recurrence and survival outcomes of glansectomy in patients with penile squamous cell carcinoma.Materials and Methods: We performed a retrospective review of 410 patients across 5 international tertiary referral centers between 1999 and 2016. All patients had tumors involving the glans penis and underwent glansectomy as primary treatment. The Kaplan-Meier method and log-rank test were used to calculate survival and recurrence. Median follow-up was 42 months (interquartile range [IQR] 29-56).Results: The median age was 64 years (IQR 53-72). Median tumor size was 2.2 cm (IQR 1.5-3.0). A total of 240 patients (58.5%) had pT2 disease, whereas only 43 patients (10.5%) had pT3 or pT4 disease. The majority of the cohort had poorly differentiated tumors (43.7%). Most recurrences were local at 7.6% (31 patients). Only 14 patients (3.4%) had regional recurrence and 9 patients (2.2%) had distant recurrence. When stratified by pathologic stage, tumors that were pT2 or higher were (P < .001) and were more likely to be poorly differentiated (P < .001). There were no differences in recurrence location among pathologic stages (P = .15). The 1-, 2-, and 5-year recurrence-free survival were 98%, 94%, and 78%, respectively. There were no differences in overall survival when stratified by stage (P = .67).Conclusion: Glansectomy is an oncologically safe treatment modality for squamous cell carcinoma of the glans in appropriately selected invasive tumors. [ABSTRACT FROM AUTHOR]

Summary Hypothalamic-pituitary-adrenal (HPA)-axis dysregulation is a prominent finding in more severe Major Depressive Disorder (MDD), and is characterized by increased baseline cortisol levels at awakening (BCL), blunted cortisol awakening response (CAR) and increased area under the cortisol curve (AUC). Selective serotonin reuptake inhibitors (SSRIs) appear to normalize HPA-axis dysfunction, but this is hardly investigated longitudinally. We studied salivary BCL, CAR and AUC at awakening and 30 min thereafter. We compared measurements in initially drug-free MDD-patients with healthy controls (HCs) at study-entry. In patients, we repeated measures after 6 and 12 weeks’ treatment with the SSRI paroxetine. Non-responding patients received a randomized dose-escalation after six weeks’ treatment. We found no significant study-entry differences in BLC, CAR or AUC between MDD-patients ( n = 70) and controls ( n = 51). In MDD-patients, we found general decreases of BCL and AUC during paroxetine treatment ( p ≤ 0.007), especially in late and non-responders. Importantly, while overall CAR did not change significantly over time, it robustly increased over 12 weeks especially when patients achieved remission ( p ≤ 0.041). The dose-escalation intervention did not significantly influence CAR or other cortisol parameters. In conclusion, paroxetine seems to interfere with HPA-axis dysregulation, reflected in significant overall decreases in BCL and AUC during treatment. Paroxetine appears to decrease HPA-axis set-point in MDD, which might result in increased HPA-axis activity over time, which is further improved when patients achieve remission (ISRCTN register nr. ISRCTN44111488). [ABSTRACT FROM AUTHOR]

Abstract: We have previously reported in vivo preservation of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, following treatment with physiological doses of melatonin, in a 6-hydroxydopamine model of Parkinson''s disease. Based on these findings, we postulated that melatonin would similarly modulate the expression of TH in vitro. Therefore, using human SH-SY5Y neuroblastoma cells which can differentiate into dopaminergic neurons following treatment with retinoic acid, we first examined whether these cells express melatonin receptors. Subsequently, the physiological dose-dependent effects of melatonin on TH expression were examined in both undifferentiated and differentiated cells. The novel detection of the G protein-coupled melatonin MT1 receptor in SH-SY5Y cells by RT-PCR was confirmed by sequencing and Western blotting. In addition, following treatment of SH-SY5Y cells with melatonin (0.1–100nM) for 24h, Western analysis revealed a significant increase in TH protein levels. A biphasic response, with significant increases in TH protein at 0.5 and 1nM melatonin and a reversal at higher doses was seen in undifferentiated cells; whereas in differentiated cells, melatonin was effective at doses of 1 and 100nM. These findings suggest a physiological role for melatonin in modulating TH expression, possibly via the MT1 receptor. [Copyright &y& Elsevier]

Abstract: We have reported that valproic acid upregulates melatonin MT1 receptor expression in rat C6 glioma cells. In addition to its anticonvulsant and mood stabilizing properties, valproic acid can also inhibit the growth of cancer cells. Since the melatonin MT1 receptor has been implicated in the oncostatic action of melatonin on human MCF-7 breast cancer cells, the effect of valproic acid on its expression was examined in this cell line. Treatment of MCF-7 cells with valproic acid (0.5 or 1 mM) for 24 or 72 h caused a significant increase in melatonin MT1 receptor mRNA or protein expression, as shown by reverse transcription-polymerase chain reaction (RT-PCR) analysis and western blotting, respectively. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays revealed a concentration-dependent inhibition of MCF-7 cell proliferation by valproic acid (0.5, 1.0 or 5 mM), but melatonin (1 or 10 nM) was ineffective alone or in combination with valproic acid, in the first (MCF-7A) subline examined. However, in subsequent experiments using a different (MCF-7B) subline, which expressed higher levels of MT1 receptor mRNA and showed modest sensitivity to melatonin, a combination of this hormone with valproic acid produced a significant synergistic inhibition of cell proliferation. These findings indicate that clinically relevant concentrations of valproic acid upregulate melatonin MT1 receptor expression in human breast cancer cells. Moreover, the enhanced antiproliferative effect observed with a combination of valproic acid and melatonin suggests that a similar therapeutic approach may be beneficial in breast cancer. [Copyright &y& Elsevier]

Abstract: A recently developed technique, based on ultrasonic wave propagation, was applied to study the effect of storage time on the retrogradation process of wheat starch extrudates during storage at room temperature. A specifically designed experimental set-up enabled to propagate in situ ultrasonic waves continuously for several days at constant water content and storage temperature (∼34% water and 25°C). The velocity and the attenuation of the ultrasonic waves changed as a result of the recrystallisation process of amylopectin molecules of wheat starch samples during storage. The propagation of ultrasonic waves, acting as a dynamic mechanical deformation at high frequency (10 MHz), gave access to the complex longitudinal modulus that, compared to the complex Young modulus obtained from low frequency DMA, enabled a better insight of the changes in viscoelastic behaviour of starch extrudates during retrogradation. The results of the ultrasonic monitoring of starch retrogradation were correlated with those obtained from X-ray diffraction and differential scanning calorimetry. The present study demonstrated the potential of the ultrasonic technique in detecting the changes in physical properties of concentrated starch systems. [Copyright &y& Elsevier]

Introduction: Although the trend towards penile sparing therapy is increasing for penile squamous cell carcinoma, outcomes for laser ablation therapy have not been widely reported. We assessed the clinical outcomes of penile cancer patients treated with only laser ablation.Materials and Methods: A retrospective review was performed on 161 patients across 5 multi-center tertiary referral centers from 1985 to 2015. All patients underwent penile sparing surgery with only laser ablation for squamous cell carcinoma of the penis. Laser ablation was performed with neodymium-doped yttrium aluminum garnet or carbon dioxide. Overall and recurrence-free survival was calculated using the Kaplan-Meier method and compared with the log rank test.Results: A total of 161 patients underwent laser ablation for penile cancer. The median age was 62 (IQR: 52-71) years and median follow-up was 57.7 (IQR: 28-90) months. The majority of patients were pTa/Tis (59, 37%) or pT1a (62, 39%). Only 19 (12%) had a poorly differentiated grade. The 5-year recurrence-free survival was 46%. When stratified by stage, the 5-year local recurrence-free survival was pTa/Tis: 50%; pT1a: 41%; pT1b: 38%; and pT2: 52%. The inguinal/pelvic nodal recurrence was pTa/Tis: 2%; pT1a: 5%; pT1b: 18%; and pT2: 22%. There were no differences among stages with respect to recurrence-free survival (P = 0.98) or overall survival (P = 0.20).Conclusion: Laser ablation therapy is safe for appropriately selected patients with penile squamous cell carcinoma. Due to the increased risk of nodal recurrence, laser ablation coupled with diagnostic nodal staging is indicated for patients with pT1b or higher. [ABSTRACT FROM AUTHOR]

In a genetically isolated community in the Netherlands four severe recessive genetic disorders occur at relatively high frequency (pontocerebellar hypoplasia type 2 (PCH2), fetal akinesia deformation sequence (FADS), rhizomelic chondrodysplasia punctata type 1 (RCDP1), and osteogenesis imperfecta (OI) type IIB/III. Over the past decades multiple patients with these disorders have been identified. This warranted the start of a preconception outpatient clinic, in 2012, aimed at couples planning a pregnancy. The aim of our study was to evaluate the offer of targeted genetic carrier screening as a method to identify high-risk couples for having affected offspring in this high-risk subpopulation. In one year, 203 individuals (92 couples and 19 individuals) were counseled. In total, 65 of 196 (33.2%) tested individuals were carriers of at least one disease, five (7.7%) of them being carriers of two diseases. Carrier frequencies of PCH2, FADS, RCDP1, and OI were 14.3%, 11.2%, 6.1%, and 4.1% respectively. In individuals with a positive family history for one of the diseases, the carrier frequency was 57.8%; for those with a negative family history this was 25.8%. Four PCH2 carrier-couples were identified. Thus, targeted (preconception) carrier screening in this genetically isolated population in which a high prevalence of specific disorders occurs detects a high number of carriers, and is likely to be more effective compared to cascade genetic testing. Our findings and set-up can be seen as a model for carrier screening in other high-risk subpopulations and contributes to the discussion about the way carrier screening can be offered and organized in the general population. [ABSTRACT FROM AUTHOR]

Ligand-dependent activation of the Hedgehog (Hh) signaling pathway has been implicated in both tumor initiation and metastasis of pancreatic ductal adenocarcinoma (PDAC). Prior studies in genetically engineered mouse models (GEMMs) have assessed the role of Hh signaling by cell autonomous expression of a constitutively active Gli2 within epithelial cells. On the contrary, aberrant pathway reactivation in the human exocrine pancreas occurs principally as a consequence of Sonic Hh ligand (Shh) overexpression from epithelial cells. To recapitulate the cognate pathophysiology of Hh signaling observed in the human pancreas, we examined GEMM where Hh ligand is conditionally overexpressed within the mature exocrine pancreas using a tamoxifen-inducible Elastase-Cre promoter (Ela-CreERT2;LSL-mShh). We also facilitated potential cell autonomous epithelial responsiveness to secreted Hh ligand by generating compound transgenic mice with concomitant expression of the Hh receptor Smoothened (Ela- CreERT2;LSL-mShh;LSL-mSmo). Of interest, none of these mice developed intraductal precursor lesions or PDAC during the follow-up period of up to 12 months after tamoxifen induction. Instead, all animals demonstrated marked expansion of stromal cells, consistent with the previously described epithelial-to-stromal paracrine Hh signaling. Hh responsiveness was mirrored by the expression of primary cilia within the expanded mesenchymal compartment and the absence within mature acinar cells. In the absence of cooperating mutations, Hh ligand overexpression in the mature exocrine pancreas is insufficient to induce neoplasia, even when epithelial cells coexpress the Smo receptor. This autochthonous model serves as a platform for studying epithelial stromal interactions in pancreatic carcinogenesis. [ABSTRACT FROM AUTHOR]

We report the crystal structure of E. coli ketopantoate hydroxymethyltransferase (KPHMT) at 1.9 A˚ resolution, in complex with its product, ketopantoate. KPHMT catalyzes the first step in the biosynthesis of pantothenate (vitamin B5), the precursor of coenzyme A and the acyl carrier protein cofactor. The structure of the decameric enzyme was solved by multiwavelength anomalous dispersion to locate 160 selenomethionine sites and phase 560 kDa of protein, making it the largest structure solved by this approach. KPHMT adopts the (βα)8 barrel fold and is a member of the phosphoenolpyruvate/pyruvate superfamily. The active site contains a ketopantoate bidentately coordinated to Mg2+. Similar binding is likely for the substrate, α-ketoisovalerate, orienting the C3 for deprotonation. [Copyright &y& Elsevier]