Association between Parvovirus B19 and thyroid/celiac autoantibodies among T1DM pediatric patients.

OBJECTIVE: In recent years, an overwhelming association between Pediatric Type 1 Diabetes Mellitus (T1DM) and autoimmune diseases has been largely reported. The current study was designed to determine a possible association between autoimmune thyroiditis (AIT), celiac disease (CD) - associated autoantibodies, and Parvovirus B19 infection among pediatric T1DM cases in the southwestern region of Saudi Arabia. PATIENTS AND METHODS: Blood samples from age groups 1-18 years attending the Diabetic Clinic were collected over a period of 12 months. Serum anti-thyroid peroxidase (TPO), anti-thyroglobulin (TG), anti-tissue transglutaminase immunoglobulin A (TG-IgA), endomysial IgA (EMA-IgA), Parvovirus B19-IgG and IgM antibodies were detected by standard methods. RESULTS: The results showed the prevalence of autoantibodies against thyroid and CD among pediatric T1DM patients to be 44 (25%) and 25 (14.4%), respectively. The prevalence of antibodies against B19 was 70 (40%). Further determination of the prevalence of Parvovirus B19-IgG antibodies and thyroid antibodies among T1DM pediatric patients revealed that there was a significant association between them with a p<0.0491. CONCLUSIONS: The prevalence of autoantibodies against the thyroid was higher among the seropositive Parvovirus B19 children with T1DM. A positive association between the prevalence of autoantibodies against thyroid disease and the increase in the duration of diabetes was also noted. Hence, periodic screening of T1DM patients for B19 antibodies and autoantibodies for thyroid is crucial.

Shrimp classification for white spot syndrome detection through enhanced gated recurrent unit-based wild geese migration optimization algorithm.

The major dangerous viral infection for cultivated shrimps is WSSV. The virus is extremely dangerous, spreads swiftly, and may result in up to 100% mortality in 3-10 days. The vast wrapped double stranded DNA virus known as WSSV describes a member of the Nimaviridae viral family's species Whispovirus. It impacts a variety of crustacean hosts but predominantly marine shrimp species that are raised for commercial purposes. The entire age groups are affected by the virus, which leads to widespread mortality. Mesodermal and ectodermal tissues, like the lymph nodes, gills, and cuticular epithelium, represents the centres of infection. Complete genome sequencing related to the WSSV strains from Thailand, China, and Taiwan has identified minute genetic variations amongst them. There exist conflicting findings on the causes of WSSV pathogenicity, which involve variations in the size associated with the genome, the count of tandem repeats, and the availability or lack of certain proteins. Hence, this paper plans to perform the shrimp classification for the WSSV on the basis of novel deep learning methodology. Initially, the data is gathered from the farms as well as internet sources. Next, the pre-processing of the gathered shrimp images is accomplished using the LBP technique. These pre-processed images undergo the segmentation process utilizing the TGVFCMS approach. The extraction of the features from these segmented images is performed by the PLDA technique. In the final step, the classification of the shrimp into healthy shrimp and WSSV affected shrimp is done by the EGRU, in which the parameter tuning is accomplished by the wild GMO algorithm with the consideration of accuracy maximization as the major objective function. Performance indicators for accuracy have been compared with those of various conventional methods, and the results show that the methodology is capable of accurately identifying the shrimp WSSV illness.

Three-dimensional volumetric evaluation of root resorption in maxillary anteriors following en-masse retraction with varying force vectors - a randomized control trial.

BACKGROUND: Root resorption in orthodontics is associated with direction and magnitude of force application as primary etiological factors. Well-controlled trials that utilize three-dimensional segmentation to detect volumetric changes in tooth structure are required to assess the quantitative nature of root resorption. OBJECTIVE: To assess the severity of root resorption (RR) during retraction of maxillary anteriors with three different force vectors (with and without skeletal anchorage) via cone-beam computed tomography (CBCT) superimpositions. TRIAL DESIGN: Three-arm parallel randomized clinical trial (RCT). MATERIALS AND METHODS: Forty-two (16 males, 26 females) patients, (17-28 years), in permanent dentition with bimaxillary protrusion were randomly allocated to three groups of 14 patients each using block randomization (1:1:1 ratio) and allocation concealment. En-masse anterior retraction post first premolar extractions was carried out with modified force vectors in the three groups based on anchorage type [Molar, Mini-implant and Infrazygomatic crest (IZC) bone screws]. Volumetric root loss and linear dimensional changes were blindly assessed on initial (T0) and final (T1, end of space closure) CBCT scans. Normality distribution of values was done using Shapiro-Wilk's test. ANOVA and Post-hoc Tukey HSD test were done to compare measurements between groups at significance levels (P < .05). RESULTS: Forty patients were analysed (14, 14, and 12 in three groups). Significant volumetric loss was noted in all groups. Central incisors demonstrated a significant reduction in IZC group (81.5 ± 21.1 mm3 ) compared to conventional (50.1 ± 26.5 mm3 ) and mini-implant groups (76.1 ± 27.6 mm3 ). Canines demonstrated a significant reduction in mini-implant group (108.9 ± 33.9 mm3 ) compared to conventional (68.8 ± 42.5 mm3 ) and IZC groups (103.1 ± 29.1 mm3 ). Regarding linear parameters, central incisors and canines revealed significant root length reduction in both skeletal anchorage groups. Lateral incisors showed no significant changes between groups. CONCLUSIONS: Intrusive force vectors generated during skeletally anchored retraction can predispose anteriors to an increased risk of resorption. Greater loss of root volume was noted in the centrals and canines when retracted with skeletal anchorage. LIMITATIONS: Small sample size and variations during CBCT acquisition. HARMS: Low-dose CBCT scans were taken at T0 and T1 treatment intervals.

Preconception vitamin D and miscarriage in a prospective cohort study.

STUDY QUESTION: Is preconception vitamin D level associated with the risk of miscarriage? SUMMARY ANSWER: Preconception vitamin D levels are not associated with the risk of miscarriage in a population of women conceiving naturally. WHAT IS KNOWN ALREADY: In humans, low vitamin D has been associated with prolonged menstrual cycles, delayed ovulation and a lower probability of conception. Animal and in vitro data indicate that vitamin D may affect implantation. STUDY DESIGN, SIZE, DURATION: This prospective time-to-pregnancy study included 362 women who were trying to conceive naturally between 2008 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included participants who had been trying to conceive naturally for 3 months or less at enrollment and aged 30-44 years. A preconception blood sample was collected and 25-hydroxyvitamin D [25(OH)D] was measured. Women who conceived (N = 362) were at risk of a miscarriage from the day of a reported positive pregnancy test until either a participant-reported pregnancy loss or 20 weeks post day of last menstrual period, whichever came first. Gestational age was defined by ovulation. Time to miscarriage (days) or censoring was modeled using a multivariate Cox proportional hazards model. Multiple imputation was performed for missing covariates and missing day of ovulation. MAIN RESULTS AND THE ROLE OF CHANCE: The mean age was 33 years (SD: 3.0 years). Mean 25(OH)D was lower among those who reported their race as African-American and those with a higher BMI. After adjustment for age, race, BMI, education, exercise, alcohol and caffeine intake, compared to the referent group (30-<40 ng/ml), the hazard ratio (HR) and 95% CI for those with a low 25(OH)D level (<30 ng/ml) was 1.10 (CI: 0.62, 1.91). Among participants with a higher 25(OH)D level (≥40 ng/ml), the HR was 1.07 (CI: 0.62, 1.84). LIMITATIONS, REASONS FOR CAUTION: This study was limited by a 25(OH)D measurement at only a single time point. A large percentage of women in this study had sufficient vitamin D levels, which may have limited our power to detect an effect of deficiency. Women in this study were older (30-44 years), and predominantly reported their race as White which may limit generalizability. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study do not suggest an association between preconception vitamin D and miscarriage. Future research should focus on women at greater risk for miscarriage or in populations at risk for vitamin D deficiency or on supplementation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01ES103333). This research was also supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) under award numbers R00HD079659 and R01HD067683. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Iliotibial band enthesopathy: an unusual cause of lateral knee pain post total knee replacement.

Iliotibial band (ITB) pathology is one of the main causes of lateral knee pain. The enthesopathy of the ITB at its insertion post total knee replacement (TKR) is a rare cause of lateral knee pain. We describe a series of cases of ITB enthesopathy with sonographic findings and management.

TI VIBE inversion MRI - An alternative to CT for imaging of hip pain.

INTRODUCTION: MR and CT are excellent complimentary diagnostic modalities for evaluation of hip pain which are often used together along with radiographs. However, CT involves radiation, which is a concern particularly in younger patients. T1VIBE is a 3D gradient echo MR sequence with high intrinsic contrast between the bone and soft tissues with multiplanar capabilities. AIM: We performed a study to assess if TIVIBE can be used to complement MR for evaluation of hip pain in young adults and to see if measurements and angles can be calculated using T1VIBE inversion images with similar accuracy to CT scan. MATERIAL AND METHODS: A retrospective review of 50 patients aged less than 40 years, who had MR (including TIVIBE) and CT of pelvis was performed. Post surgical patients were excluded. Some important measurements such as Centre edge angle, Tonnis' angle, anterior acetabular sector angle, posterior acetabular sector angle and acetabular version were independently measured by two readers on T1 VIBE inversion and CT images separately and measurements were compared. One reader performed the measurements again to assess for intra-observer error. RESULTS: There was a female predominance (37 F, 13M) with an average age of 27.6 years (range of 17-39). There was no significant difference in the measurements between CT and TI VIBE inversion and there was good intra and interobservor reliability. CONCLUSION: TI VIBE inversion sequence can be used as an alternative to CT with added advantage of alleviating the radiation exposure.

Innovations for the future of breast surgery.

BACKGROUND: Future innovations in science and technology with an impact on multimodal breast cancer management from a surgical perspective are discussed in this narrative review. The work was undertaken in response to the Commission on the Future of Surgery project initiated by the Royal College of Surgeons of England. METHODS: Expert opinion was sought around themes of surgical de-escalation, reduction in treatment morbidities, and improving the accuracy of breast-conserving surgery in terms of margin status. There was emphasis on how the primacy of surgical excision in an era of oncoplastic and reconstructive surgery is increasingly being challenged, with more effective systemic therapies that target residual disease burden, and permit response-adapted approaches to both breast and axillary surgery. RESULTS: Technologies for intraoperative margin assessment can potentially half re-excision rates after breast-conserving surgery, and sentinel lymph node biopsy will become a therapeutic procedure for many patients with node-positive disease treated either with surgery or chemotherapy as the primary modality. Genomic profiling of tumours can aid in the selection of patients for neoadjuvant and adjuvant therapies as well as prevention strategies. Molecular subtypes are predictive of response to induction therapies and reductive approaches to surgery in the breast or axilla. CONCLUSION: Treatments are increasingly being tailored and based on improved understanding of tumour biology and relevant biomarkers to determine absolute benefit and permit delivery of cost-effective healthcare. Patient involvement is crucial for breast cancer studies to ensure relevance and outcome measures that are objective, meaningful, and patient-centred.

This article describes how future innovations in science and technology influence the management of breast cancer from a surgical perspective. This work was undertaken in response to the Commission on the Future of Surgery project initiated by the Royal College of Surgeons of England.

Paraplegia Secondary to Plasmacytoma of the Lumbar Spine.

BACKGROUND: Solitary plasmacytoma of bone has a predilection for the axial skeleton, most commonly affecting the thoracic spine. We report the case of a patient who presented with acute on chronic back pain and developed severe neurologic deficits within several hours of admission secondary to a pathologic fracture of L1. METHODS: The patient underwent an urgent magnetic resonance imaging scan followed by T12 to L2 posterior decompression and T11 to L3 posterior instrumented stabilization. Subsequent histopathologic examination of specimens taken at the time of surgery found this to be secondary to a plasmacytoma affecting the lumbar spine. RESULTS: At follow-up, recovery has been rapid and extensive, with the patient remaining under hematologic review because of the risk for developing multiple myeloma. CONCLUSIONS: The unique features of this case relate to the location of the plasmacytoma and the neurologic signs; to our knowledge this is the first reported case in the literature of paraplegia secondary to a lumbar spine plasmacytoma.

Impact of bariatric surgery on cardiovascular outcomes and mortality: a population-based cohort study.

BACKGROUND: Cohort studies have shown that bariatric surgery may reduce the incidence of and mortality from cardiovascular disease (CVD), but studies using real-world data are limited. This study examined the impact of bariatric surgery on incident CVD, hypertension and atrial fibrillation, and all-cause mortality. METHODS: A retrospective, matched, controlled cohort study of The Health Improvement Network primary care database (from 1 January 1990 to 31 January 2018) was performed (approximately 6 per cent of the UK population). Adults with a BMI of 30 kg/m2 or above who did not have gastric cancer were included as the exposed group. Each exposed patient, who had undergone bariatric surgery, was matched for age, sex, BMI and presence of type 2 diabetes mellitus (T2DM) with two controls who had not had bariatric surgery. RESULTS: A total of 5170 exposed and 9995 control participants were included; their mean(s.d.) age was 45·3(10·5) years and 21·5 per cent (3265 of 15 165 participants) had T2DM. Median follow-up was 3·9 (i.q.r. 1·8- 6·4) years. Mean(s.d.) percentage weight loss was 20·0(13·2) and 0·8(9·5) per cent in exposed and control groups respectively. Overall, bariatric surgery was not associated with a significantly lower CVD risk (adjusted hazard ratio (HR) 0·80; 95 per cent c.i. 0·62 to 1·02; P = 0·074). Only in the gastric bypass group was a significant impact on CVD observed (HR 0·53, 0·34 to 0·81; P = 0·003). Bariatric surgery was associated with significant reduction in all-cause mortality (adjusted HR 0·70, 0·55 to 0·89; P = 0·004), hypertension (adjusted HR 0·41, 0·34 to 0·50; P < 0·001) and heart failure (adjusted HR 0·57, 0·34 to 0·96; P = 0·033). Outcomes were similar in patients with and those without T2DM (exposed versus controls), except for incident atrial fibrillation, which was reduced in the T2DM group. CONCLUSION: Bariatric surgery is associated with a reduced risk of hypertension, heart failure and mortality, compared with routine care. Gastric bypass was associated with reduced risk of CVD compared to routine care.

ANTECEDENTES: Estudios de cohortes han mostrado que la cirugía bariátrica puede reducir la incidencia de enfermedad cardiovascular (cardiovascular disease, CVD) y la mortalidad, pero los estudios basados en datos del mundo real son limitados. Este estudio examinaba el impacto de la cirugía bariátrica (bariatric surgery, BS) en la incidencia de CVD, hipertensión, fibrilación auricular (FA) y mortalidad por cualquier causa. MÉTODOS: Se realizó un estudio retrospectivo de cohortes, controlado por emparejamiento, a partir de la base de datos de atención primaria del The Health Improvement Network (THIN) (1/1/1990 y 31/1/2018) (aproximadamente el 6% de la población del Reino Unido UK). En el grupo de exposición, se incluyeron adultos con un índice de masa corporal (IMC) ≥ 30 kg/m2 que no tenían cáncer gástrico. Cada paciente expuesto (había sido operado de BS) fue emparejado por edad, sexo, IMC y presencia de diabetes tipo 2 (T2D) con 2 controles (sin BS). RESULTADOS: Se incluyeron un total de 5.170 sujetos expuestos y 9.995 participantes controles. La edad media (DE) fue 45,3 (10,5) años, 21,5% (n = 3.265) tenían T2D. La mediana de seguimiento era de 3,9 años (rango intercuartílico 1,8- 6,4). La media ± desviación estándar del % de pérdida de peso fue del 20,0 ± 13,2% en el grupo BS versus 0,8 ± 9,5% en los grupos control. Globalmente, la BS no se asoció con una CVD significativamente más baja (cociente de riesgos instantáneos ajustados, adjusted hazard ratio, HR 0,80; i.c. del 0,62- 1,02, P = 0,074). Solo en el grupo del bypass gástrico se observó un impacto significativo en CVD (0,53, 0,34- 0,81, P = 0,003). BS se asoció con una reducción significativa en la mortalidad de cualquier causa (0,70; i.c. Del 95% 0,55- 0,89, P = 0,004), hipertensión (0,41; 0,34- 0,50, P < 0,001), e insuficiencia cardiaca (0,57, 0,34- 0,96; P = 0.033). Los resultados fueron similares en aquellos pacientes con y sin T2D (expuesto versus control) excepto en la FA incidental que se redujo en el grupo T2D. CONCLUSIONES: La práctica de BS se asoció con una reducción del riesgo de insuficiencia cardiaca y mortalidad.

Gestational dyslipidaemia and adverse birthweight outcomes: a systematic review and meta-analysis.

BACKGROUND: Low and high birthweight is known to increase the risk of acute and longer-term adverse outcomes, such as stillbirth, infant mortality, obesity, type 2 diabetes and cardiovascular diseases. Gestational dyslipidaemia is associated with a numbers of adverse birth outcomes, but evidence regarding birthweight is still inconsistent to reliably inform clinical practice and treatment recommendations. OBJECTIVE: The aim of this study was to explore the relationship between maternal gestational dyslipidaemia and neonatal health outcomes, namely, birthweight, metabolic factors and inflammatory parameters. METHODS: We searched systematically Embase, MEDLINE, PubMed, CINAHL Plus and Cochrane Library up to 1 August 2016 (with an updated search in MEDLINE at the end of July 2017) for longitudinal studies that assessed the association of maternal lipid levels during pregnancy with neonatal birthweight, or metabolic and inflammatory parameters up to 3 years old. RESULTS: Data from 46 publications including 31,402 pregnancies suggest that maternal high triglycerides and low high-density-lipoprotein cholesterol levels throughout pregnancy are associated with increased birthweight, higher risk of large for gestational age and macrosomia and lower risk of small-for-gestational age. The findings were consistent across the studied populations, but stronger associations were observed in women who were overweight or obese prior to pregnancy. CONCLUSIONS: This meta-analysis suggested that the potential under-recognized adverse effects of intrauterine exposure to maternal dyslipidaemia may warrant further investigation into the relationship between maternal dyslipidaemia and birthweight in large prospective cohorts or in randomized trials.

Mastectomy for risk reduction or symmetry in women without high risk gene mutation: A review.

BACKGROUND: Prophylactic or 'risk-reducing' mastectomy refers to the procedure of completely removing a healthy breast in order to reduce the risk of developing breast cancer. This may be bilateral or may be performed to the contralateral breast as part of the treatment of a proven breast cancer. The rate of this procedure being performed has been shown to be increasing over the last two decades. Recent guidance for Breast clinicians has been issued over the last 12 months by both The Association of Breast Surgery of Great Britain and Ireland (ABSGBI) and the American Society of Breast Surgeons (ASBrS). This review aims to look at the evidence behind the current decision making for patients requesting to undergo this increasingly popular procedure. METHOD: We undertook a review of the relevant literature via Medline using the PubMed interface for the key words 'Breast Cancer', 'Mastectomy', 'Prophylactic', 'Contra-lateral' and 'Risk-reducing' for papers from October 1991 to 2016. The Association of Breast Surgery guidance on the topic was published this year and was therefore included and referenced. Following review of the evidence, we have categorised patients into different groups, based on their background and evidence currently available to support the decision. RESULTS: Clear evidence exists to support offering contralateral prophylactic mastectomy (CPM) to women who are high-risk gene carriers for Breast cancer. For those without, no survival benefit is evident however other quality of life measures may be improved with access to the procedure. CONCLUSION: For those women who are not high-risk gene carriers for breast cancer but have other factors that may increase their risk (strong family history, tumour characteristics) more evidence is needed as the benefit of CPM and all decisions to undertake it should occur through a multidisciplinary team approach.

A nonlinear model of cell interaction with an acoustic field.

A theoretical and experimental nonlinear analysis of cellular response/displacement to ultrasound excitations is presented. Linear cell models can predict the resonant frequency (fR∼5MHz), but only a nonlinear analysis can reveal the amount of mechanical energy that couples into the cell and the bifurcation behavior of the cell when it is excited near resonance. The cell dynamics is described by the nonlinear viscoelastic constitutive behavior of the cytoplasm, nucleus and their respective membranes, in the presence of a fluid with an oscillating pressure field. The method of multiple scales is used to derive the amplitude of oscillation of the cytoplasm and nucleus as a function of frequency. A major finding is the existence of multiple solutions for a range of sub-resonant frequencies. At positive detuning (f>fR), the mechanical energy that couples into the cell is small, it is higher at resonance but significantly higher at sub-resonant frequencies in the multiplicity range. Experimentally it was shown when 3.5MHz is approached sub- and supra-resonance and 6.5MHz is approached sub-resonance, gene expression was statistically higher than that when stimulated directly. Thus, there exists an optimal range of frequencies for ultrasound treatment - in the region of multiplicity where deformation and thus mechanical energy coupling is maximized. The ultrasound protocol must be designed to operate at the solution associated with the higher mechanical energy - thus the start-up conditions should be in the domain of attraction of the high energy solution.

DRD4 and DAT1 VNTR Genotyping in Children with Attention Deficit Hyperactivity Disorder.

The dopamine receptor-D4 and the dopamine transporter have been investigated for their role in attention deficit hyperactivity disorder (ADHD) in children. Reports of their genetic association with ADHD have shown mixed results. The aim of the study was to evaluate the association of variable number tandem repeats (VNTRs) of the DRD4 and DAT1 genes with ADHD in children. A pilot 1:1 case control study, with 44 clinically confirmed ADHD cases and 44 age/gender matched healthy controls, was conducted at a tertiary care centre in Mumbai. Variable number tandem repeats of DRD4 exon 3, DAT1 intron 8 and 3'UTR were genotyped by PCR-AGE. Several allele repeats of the genes were observed in the screened subjects. Statistical significance was observed for the 10R/10R genotype of the DAT1 3'UTR VNTR between cases and controls.

Breast reconstruction in older patients: A literature review of the decision-making process.

AIM: Women not undergoing breast reconstruction after mastectomy tend to be older. This review aims to aid in effective, evidence-based choices regarding breast reconstruction in an older population, appraising the influencing patient factors described in the literature and those directing the reconstructive surgeon. This may refute current misconceptions and ensure surgical decisions are made based on evidence without ageist assumptions. The review forms the basis of an evidence-based algorithm addressing each step of the decision-making process. METHOD: A literature search was conducted using PubMed, Medline, Evidence.nhs.uk and the Cochrane database. Search terms initially were breast reconstruction, mastectomy, elderly, older, decision, reasons and rationale. A separate literature search was performed for each of the individual 'steps' in the decision-making process. RESULTS: Overall, 44 papers were obtained. For each section of the decision-making process, titles and abstracts were screened for relevance. Only English language papers were included. CONCLUSION: If reconstruction is oncologically plausible and co-morbidities and frailty formally assessed, older women should be actively informed about breast reconstruction, receive support and engage in 'shared decision-making'. The older patient is less likely to do research independently. Amongst other factors, body image, cancer fears, employment and carer responsibilities play a part in the decision. With adequate preoperative and frailty assessment and early involvement of the geriatrician and anaesthetist, microsurgical reconstruction is safe. Autologous reconstruction has better long-term outcomes than implant-based reconstructions in this age group, correlating with improved survival and longevity of reconstruction. Age alone should not be considered a contraindication to breast reconstruction.

Desensitization to Mycofenolate Mofetil: a novel 12 step protocol.

The use of MMF has become standard practice in many solid organ transplant recipients due its efficacy and favorable risk profile compared to other immunosuppressants. There has been a single case report of successful MMF desensitization. However, this protocol did not follow current Drug practice parameters. We report a successful desensitization to MMF in a double heart-kidney transplant recipient.

Super-giant magnetoresistance at room-temperature in copper nanowires due to magnetic field modulation of potential barrier heights at nanowire-contact interfaces.

We have observed a super-giant (∼10 000 000%) negative magnetoresistance at 39 mT field in Cu nanowires contacted with Au contact pads. In these nanowires, potential barriers form at the two Cu/Au interfaces because of Cu oxidation that results in an ultrathin copper oxide layer forming between Cu and Au. Current flows when electrons tunnel through, and/or thermionically emit over, these barriers. A magnetic field applied transverse to the direction of current flow along the wire deflects electrons toward one edge of the wire because of the Lorentz force, causing electron accumulation at that edge and depletion at the other. This lowers the potential barrier at the accumulated edge and raises it at the depleted edge, causing a super-giant magnetoresistance at room temperature.

P21-activated kinase 1 (Pak1) signaling influences therapeutic outcome in pancreatic cancer.

BACKGROUND: Therapeutic resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) is attributed to various cellular mechanisms and signaling molecules that influence as a single factor or in combination. DESIGN: In this study, utilizing in vitro p21-activated kinase 1 (Pak1) overexpression and knockdown cell line models along with in vivo athymic mouse tumor xenograft models and clinical samples, we demonstrate that Pak1 is a crucial signaling kinase in gemcitabine resistance. RESULTS: Pak1 kindles resistance via modulation of epithelial-mesenchymal transition and activation of pancreatic stellate cells. Our results from gemcitabine-resistant and -sensitive cell line models showed that elevated Pak1 kinase activity is required to confer gemcitabine resistance. This was substantiated by elevated levels of phosphorylated Pak1 and ribonucleotide reductase M1 levels in the majority of human PDAC tumors when compared with normal. Delineation of the signaling pathway revealed that Pak1 confers resistance to gemcitabine by preventing DNA damage, inhibiting apoptosis and regulating survival signals via NF-κB. Furthermore, we found that Pak1 is an upstream interacting substrate of transforming growth factor ß-activated kinase 1-a molecule implicated in gemcitabine resistance. Molecular mechanistic studies revealed that gemcitabine docks with the active site of Pak1; furthermore, gemcitabine treatment induces Pak1 kinase activity both in vivo and in cell-free system. Finally, results from athymic mouse tumor models illustrated that Pak1 inhibition by IPA-3 enhances the cytotoxicity of gemcitabine and brings about pancreatic tumor regression. CONCLUSION: To our knowledge, this is the first study illustrating the mechanistic role of Pak1 in causing gemcitabine resistance via multiple signaling crosstalks, and hence Pak1-specific inhibitors will prove to be a better adjuvant with existing chemotherapy modality for PDAC.

Transition from Reconstruction toward Thin Film on the (110) Surface of Strontium Titanate.

The surfaces of metal oxides often are reconstructed with a geometry and composition that is considerably different from a simple termination of the bulk. Such structures can also be viewed as ultrathin films, epitaxed on a substrate. Here, the reconstructions of the SrTiO3 (110) surface are studied combining scanning tunneling microscopy (STM), transmission electron diffraction, and X-ray absorption spectroscopy (XAS), and analyzed with density functional theory calculations. Whereas SrTiO3 (110) invariably terminates with an overlayer of titania, with increasing density its structure switches from n × 1 to 2 × n. At the same time the coordination of the Ti atoms changes from a network of corner-sharing tetrahedra to a double layer of edge-shared octahedra with bridging units of octahedrally coordinated strontium. This transition from the n × 1 to 2 × n reconstructions is a transition from a pseudomorphically stabilized tetrahedral network toward an octahedral titania thin film with stress-relief from octahedral strontia units at the surface.