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Down-regulation or loss of MHC class I expression is a major mechanism used by cancer cells to evade immunosurveillance and increase their oncogenic potential. MHC I mediated antigen presentation is a complex regulatory process, controlled by antigen processing machinery (APM) dictating immune response. Transcriptional regulation of the APM that can modulate gene expression profile and their correlation to MHC I mediated antigen presentation in cancer cells remain enigmatic. Here, we reveal that Scaffold/Matrix-Associated Region 1- binding protein (SMAR1), positively regulates MHC I surface expression by down-regulating calnexin, an important component of antigen processing machinery (APM) in cancer cells. SMAR1, a bonafide MAR binding protein acts as a transcriptional repressor of several oncogenes. It is down-regulated in higher grades of cancers either through proteasomal degradation or through loss of heterozygosity (LOH) at the Chr.16q24.3 locus where the human homolog of SMAR1 (BANP) has been mapped. It binds to a short MAR region of the calnexin promoter forming a repressor complex in association with GATA2 and HDAC1. A reverse correlation between SMAR1 and calnexin was thus observed in SMAR1-LOH cells and also in tissues from breast cancer patients. To further extrapolate our findings, influenza A (H1N1) virus infection assay was performed. Upon viral infection, the levels of SMAR1 significantly increased resulting in reduced calnexin expression and increased MHC I presentation. Taken together, our observations establish that increased expression of SMAR1 in cancers can positively regulate MHC I surface expression thereby leading to higher chances of tumor regression and elimination of cancer cells.

Scaffold/matrix attachment regions (S/MARs) are DNA elements that serve to compartmentalize the chromatin into structural and functional domains. These elements are involved in control of gene expression which governs the phenotype and also plays role in disease biology. Therefore, genome-wide understanding of these elements holds great therapeutic promise. Several attempts have been made toward identification of S/MARs in genomes of various organisms including human. However, a comprehensive genome-wide map of human S/MARs is yet not available. Toward this objective, ChIP-Seq data of 14 S/MAR binding proteins were analyzed and the binding site coordinates of these proteins were used to prepare a non-redundant S/MAR dataset of human genome. Along with co-ordinate (location) details of S/MARs, the dataset also revealed details of S/MAR features, namely, length, inter-SMAR length (the chromatin loop size), nucleotide repeats, motif abundance, chromosomal distribution and genomic context. S/MARs identified in present study and their subsequent analysis also suggests that these elements act as hotspots for integration of retroviruses. Therefore, these data will help toward better understanding of genome functioning and designing effective anti-viral therapeutics. In order to facilitate user friendly browsing and retrieval of the data obtained in present study, a web interface, MARome (http://bioinfo.net.in/MARome), has been developed.

Large pyogenic liver abscess is a rare and difficult to treat entity in pediatric patients. Percutaneous drainage rather than open surgical drainage has become more common in recent years, even for large abscesses. Percutaneous drainage can be complicated by catheter obstruction. We present the case of a 16-year-old male presenting with abdominal pain, fever, and chills. He was diagnosed with a 9-centimeter liver abscess. A CT-guided percutaneous drainage was placed. The catheter initially drained well, but then became occluded. Tissue plasminogen activator was instilled into the catheter every 6 hours for a total of five doses, resulting in increased drainage and improved clinical state of the patient. To our knowledge, this is the first reported use of tissue plasminogen activator in pyogenic liver abscess in the pediatric population.

In this thesis we address three main problems in clique detection in the area of Graph Theory. i) Most of current methods for clique detection are time consuming (can take exponential time to the size of input graph), so there is a practical limit on size of input graph. In this thesis we propose three different methods for estimating the number of cliques. We examine these methods for various graphs and conclude that they efficiently find the number of cliques within 5% error typically. ii) We compare various versions of the Bron-Kerbosch (BK) clique listing algorithm to discover a method of combining the best features of different versions. We test our new versions of BK for various inputs. iii) We study the characteristics of cliques in random graphs as a function of size and density.

Background Suboptimal oral antibiotic prescriptions (OAPs) are prevalent at discharge and contribute to treatment failure, resistance, toxicity, and excess costs. Syndrome-specific prescribing patterns have not been widely described at discharge, nor have specific reasons for excessive treatment durations (the most commonly cited prescribing error). Methods Retrospective cohort of patients discharged from a general medicine service at an academic hospital with ≥1 OAP for urinary tract infection (UTI), skin and soft tissue infection (SSTI), or lower respiratory tract infection (LRTI). Study period varied to include a random sample of encounters occurring after the most recent institutional guideline update for each syndrome. Exclusions: multiple infectious indications, discharge against medical advice, parenteral antibiotics at discharge, pregnancy, cystic fibrosis, and immunocompromising conditions. Discharge OAPs were assessed for suboptimal selection, dose, frequency, or duration according to institutional guidelines (with secondary adjudication). Results Analysis included 160 encounters: 70 UTIs, 66 SSTIs, and 24 LRTIs. Of 71 (44%) culture-positive infections, Enterobacterales (61%) and Streptococcus spp. (15%) were most often identified. In total, 180 OAPs were issued – most commonly cefpodoxime (21%), cefadroxil (18%), and doxycycline (17%). Overall, 99 (62%) encounters were associated with a suboptimal discharge OAP. Of 138 suboptimal characteristics identified, suboptimal duration was most frequent (57%), specifically excessive duration (45%). Proportion of suboptimal OAPs and their underlying reasons are analyzed by syndrome in Figures 1 and 2, respectively. Miscalculation (39%), intentional selection of guideline-discordant duration (29%), and omission of inpatient antibiotic days (19%) were the most frequent reasons for suboptimal duration (Fig. 3). Conclusion Suboptimal discharge OAPs were common for all studied syndromes, most notably SSTI. Excessive duration was a key driver, with reasons for inappropriate duration previously undescribed. Duration miscalculation and selection of appropriate treatment duration are key areas to focus electronic health record enhancements, provider education, and antimicrobial stewardship efforts. Disclosures All Authors: No reported disclosures

The microbial communities that live in symbiosis with the mucosal surfaces of animals provide the host with defense strategies against pathogens. These microbial communities are largely shaped by the environment and the host genetics. Triploid Atlantic salmon (Salmo salar) are being considered for aquaculture as they are reproductively sterile and thus cannot contaminate the natural gene pool. It has not been previously investigated how the microbiome of triploid salmon compares to that of their diploid counterparts. In this study, we compare the steady-state skin and gill microbiome of both diploid and triploid salmon, and determine the effects of salmonid alphavirus 3 experimental infection on their microbial composition. Our results show limited differences in the skin-associated microbiome between triploid and diploid salmon, irrespective of infection. In the gills, we observed a high incidence of the bacterial pathogen Candidatus Branchiomonas, with higher abundance in diploid compared to triploid control fish. Diploid salmon infected with SAV3 showed greater histopathological signs of epitheliocystis compared to controls, a phenomenon not observed in triploid fish. Our results indicate that ploidy can affect the alpha diversity of the gills but not the skin-associated microbial community. Importantly, during a natural outbreak of Branchiomonas sp. the gill microbiome of diploid Atlantic salmon became significantly more dominated by this pathogen than in triploid animals. Thus, our results suggest that ploidy may play a role on Atlantic salmon gill health and provide insights into co-infection with SAV3 and C. Branchiomonas in Atlantic salmon.

Introduction. Hepatopulmonary fusion is a very rare finding associated with right-sided congenital diaphragmatic hernia. With less than 50 reported cases, management and outcomes of hepatopulmonary fusion are poorly understood. This report highlights that clinical presentation is not a reliable indicator of outcomes in this rare disease. Case Presentation. A term neonate admitted for tachypnea and complete opacification of the right hemithorax was diagnosed with right-sided congenital diaphragmatic hernia. Preoperative respiratory support was minimal, and the only symptom exhibited was tachypnea. During surgical repair, fusion of the lung and liver were noted, consistent with a diagnosis of hepatopulmonary fusion. Postoperatively, the patient’s pulmonary hypertension worsened and required extracorporeal membrane oxygenation. Conclusions. Many patients with hepatopulmonary fusion and only mild symptoms die postoperatively from severe pulmonary hypertension and progressive respiratory failure. Preoperative clinical status is not indicative of postoperative outcomes, and literature suggests that patients who require less support preoperatively have high mortality rates. The availability of ECMO for postoperative complications may be necessary in patients requiring repair of hepatopulmonary fusion.

A Zika self-amplifying mRNA vaccine delivered by a flexible bedside mixing formulation induces protective immunity in NHPs., Zika virus (ZIKV) is the cause of a pandemic associated with microcephaly in newborns and Guillain-Barre syndrome in adults. Currently, there are no available treatments or vaccines for ZIKV, and the development of a safe and effective vaccine is a high priority for many global health organizations. We describe the development of ZIKV vaccine candidates using the self-amplifying messenger RNA (SAM) platform technology delivered by cationic nanoemulsion (CNE) that allows bedside mixing and is particularly useful for rapid responses to pandemic outbreaks. Two immunizations of either of the two lead SAM (CNE) vaccine candidates elicited potent neutralizing antibody responses to ZIKV in mice and nonhuman primates. Both SAM (CNE) vaccines protected these animals from ZIKV challenge, with one candidate providing complete protection against ZIKV infection in nonhuman primates. The data provide a preclinical proof of concept that a SAM (CNE) vaccine candidate can rapidly elicit protective immunity against ZIKV.

Amyand's hernia is an exceedingly rare condition in which the appendix is found in an inguinal hernia. The appendix can be normal, inflamed, infected, or perforated. Here, we present a case of perforated appendicitis in an Amyand's hernia in an extremely preterm infant with subsequent post-operative complications including necrotic bowel and venous thrombosis of the mesentery. This article stresses the importance of complications that can arise in Amyand's hernia, especially in an extremely preterm infant.

Background. Medical and interventional therapies for older adults with acute myocardial infarction (AMI) reduce mortality and improve outcomes in selected patients, but there are also risks associated with treatments. Shared decision making (SDM) may be useful in the management of such patients, but to date, patients’ and cardiologists’ perspectives on SDM in the setting of AMI remain poorly understood. Accordingly, we performed a qualitative study eliciting patients’ and cardiologists’ perceptions of SDM in this scenario. Methods. We conducted 20 in-depth, semistructured interviews with older patients (age ≥70) post-AMI and 20 interviews with cardiologists. The interviews were transcribed and analyzed using ATLAS.ti. Two investigators independently coded transcripts using the constant comparative method, and an integrative, team-based process was used to identify themes. Results. Six major themes emerged: 1) patients felt their only choice was to undergo an invasive procedure; 2) patients placed a high level of trust and gratitude toward physicians; 3) patients wanted to be more informed about the procedures they underwent; 4) for cardiologists, patients’ age was not a major contraindication to intervention, while cognitive impairment and functional limitation were; 5) while cardiologists intuitively understood the concept of SDM, interpretations varied; and 6) cardiologists considered SDM to be useful in the setting of non-ST elevated myocardial infarction (NSTEMI) but not ST-elevated myocardial infarction (STEMI). Conclusions. Patients viewed intervention as “the only choice,” whereas cardiologists saw a need for balancing risks and benefits in treating older adults post-NSTEMI. This discrepancy implies there is room to improve communication of risks and benefits to older patients. A decision aid informed by the needs of older adults could help to better convey patient-specific risk and increase choice awareness.

A 29-year-old primipara woman (162 cm, 78 kg) at 36-week gestation was admitted from the ER with the complaint of severe headache localized to the left frontal area for 3 months, accompanied by nausea/vomiting of 1 week duration.

Disease outbreaks in fish aquaculture are often of concern due to the possibility of pathogen transmission to fish in neighbouring farms and to wild fish populations. To be able to assess the risk and manage transmission and outbreak scenarios, it is of great importance to understand the impact of various biological and physical conditions affecting the survival of the pathogen in the environment. In this study, we examined the effect of temperature on the viability of salmonid alphavirus subtype 3 (SAV3) in three separate experiments using SAV3 in culture medium, SAV3 in seawater or SAV3 shed by infected fish mimicking the virus produced at marine sites during outbreaks. SAV cultured on CHH-1 cells and cultured SAV mixed with seawater were incubated at different temperatures over a period of 4 weeks and 2 weeks, respectively. The surviving virus was quantified by two in vitro methods, RT-qPCR and a 50% tissue culture infectious dose (TCID50) assay. In addition, seawater containing SAV shed by Atlantic salmon post-smolts was incubated at different temperatures over 4 weeks. The viability of SAV shed by SAV-infected fish was examined both by in vitro methods and assayed in vivo using recently seawater-transferred post-smolts. The survival of SAV decreased with increasing temperature in all three experiments. Generally, the titre of SAV propagated in cell culture was more stable in culture medium compared to SAV diluted in seawater or shed by infected fish. Cells could be infected with a low titre of SAV, 24 TCID50 L−1 of seawater, whereas a SAV concentration above 448 TCID50 L−1 of seawater was required for successful SAV transmission to the post-smolts in the in vivo assay. SAV3 shed by infected fish at a starting titre of 882 TCID50 L−1 of seawater was completely inactivated after three and four weeks of incubation at 16 °C and 12 °C, respectively, as analysed by the TCID50 in vitro assay. In addition, the TCID50 resulted in a higher sensitivity than RT-qPCR, especially at very low virus titres, probably due to the multiplication of the virus in cells and the possibility of analysing a greater volume of sample in the assay compared to RT-qPCR. The information acquired in the present study may be incorporated into pathogen dispersal models in order to aid understanding and management of SAV outbreaks. Calculation of the risk of transmission would provide new prospects for the control of pancreas disease.

BACKGROUND HNENL (Head and Neck Extra nodal Non-Hodgkin’s Lymphoma) contributes for

Pancreas disease (PD) caused by salmonid alphavirus (SAV) severely affects salmonid aquaculture during the seawater phase. To characterize immune cells in target tissues for SAV infection, heart, pancreas and pyloric caeca were analysed from two groups of fish adapted to seawater for 2 and 9 weeks. The sections were scored for the relative abundance of cells expressing MHC class II, IgM, CD3, CD8 or neutrophil/granulocyte markers using immuno-histochemical techniques. In general, necrosis of tissue was more severe in fish infected at 2 weeks post-seawater transfer (wpt) compared with those infected at 9 wpt. At 9 wpt, there were higher numbers of MHC II+ cells in heart, pancreas and pyloric caeca, IgM+ cells in heart and pancreas, and CD3+ cells in pancreas compared to those infected at 2 wpt. The majority of the immune cells infiltrating PD-affected tissues were MHC II+ and CD3+ cells suggesting that antigen-presenting cells and T lymphocytes are the main types of immune cells responding to SAV infection. All the investigated cell types were also observed in pyloric caeca of infected fish, suggesting that this tissue may play a role in the immune response to SAV.

Pancreas disease (PD) caused by salmonid alphavirus (SAV) is the most serious viral disease in Norwegian aquaculture. Study of the immune response to SAV will aid preventative measures including vaccine development. The innate immune response was studied in Atlantic salmon infected by either bath immersion (BI) or by intra-muscular (i.m.) injection (IM) with SAV subtype 3, two and nine weeks after seawater transfer (Phases A and B respectively). Phase A results have been previously published (Moore et al., 2017) and Phase B results are presented here together with a comparison of results achieved in Phase A. There was a rapid accumulation of infected fish in the IM-B (IM Phase B) group and all fish sampled were SAV RNA positive by 7 dpi (days post infection). In contrast, only a few SAV RNA positive (infected) fish were identified at 14, 21 and 28 dpi in the BI-B (BI Phase B) group. Differences in the transcription of several immune genes were apparent when compared between the infected fish in the IM-B and BI-B groups. Transcription of the analysed genes peaked at 7 dpi in the IM-B group and at 14 dpi in the BI-B group. However, this latter finding was difficult to interpret due to the low prevalence of SAV positive fish in this group. Additionally, fish positive for SAV RNA in the BI-B group showed higher transcription of IL-1β, IFNγ and CXCL11_L1, all genes associated with the inflammatory response, compared to the IM-B group. Histopathological changes in the heart were restricted to the IM-B group, while (immune) cell filtration into the pancreas was observed in both groups. Compared to the Phase A fish that were exposed to SAV3 two weeks after seawater transfer, the Phase B fish in the current paper, showed a higher and more sustained innate immune gene transcription in response to the SAV3 infection. In addition, the basal transcription of several innate immune genes in non-infected control fish in Phase B (CT-B) was also significantly different when compared to Phase A control fish (CT-A).

Purpose The purpose of this study was to establish a dosimetric correlation between the bladder volume and its effects on the dose received by the organs at risk (OARs) (urinary bladder, rectum, and sigmoid) during computed tomography (CT)-guided high-dose-rate (HDR) brachytherapy in carcinoma cervix, and to determine an optimum bladder volume to limit the dose to OARs. Material and methods Seventy-five intracavitary applications in patients of carcinoma cervix (stage IIB, IIIA, IIIB, IVA) treated with external beam radiotherapy with concurrent chemotherapy followed by CT-based HDR intracavitary brachytherapy (tandem and ovoid type) at our institute between July 2014 to January 2016 were studied. The bladder volume at the time of imaging was noted and was correlated with the radiation dose received by bladder, rectum, and sigmoid colon. Results Dose volume histogram (DVH) parameters of the bladder increases by elevating the volume of the bladder. Rectum dose does not follow a continuous increasing trend. It increases up to a bladder volume of 110 cc and then starts decreasing. The highest rectal dose observed was in the bladder volume, range 70-110 cc. The minimum doses were recorded when the bladder volume was > 170 cc. Sigmoid colon DVH parameters follow a similar trend as that of the rectum. Conclusions A relationship exists between the volume of the OARs and the dose received by them. A bladder volume of about 70 cm3 or less proved better for achieving the prescribed dose limits of bladder, rectum, and sigmoid. The correlations between the bladder volume and the doses received by the OARs were not significant.

[Aims/hypothesis] A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents., [Methods] Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT., [Results] KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks., [Conclusions/interpretation] KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans., This study was supported financially by Galvani Bioelectronics (formerly the Bioelectronics R&D unit at GlaxoSmithKline). JFS and BFM are supported by PhD Grants from the Portuguese Foundation for Science and Technology (reference PD/BD/105890/2014 and PD/BD/128336/2017, respectively). Data in the present manuscript has been filed with the International Bureau WO/2016/72875. International application no. PCT/PT2015/000047.

Objective: In the last decade, immunotherapy has revolutionized cancer care and became a mainstream therapy along with surgery, chemotherapy and radiation. Unfortunately, only a limited number of cancers exhibit intrinsic sensitivity to immunotherapies and the overall response rate is only 20-25%. Therefore, there is a strong impetus to identify treatments which can sensitize patients to immunotherapies. Fusion utilizes targeted alpha therapy (TAT) which enables delivery of alpha particle emitting isotopes (actinium 225) to the targeted tumor cells. The rationale for the combination of TAT and immunotherapy stems from known immune stimulating properties of radiation, leading to release of tumor-associated antigens, maturation of antigen-presenting cells (APCs) and in turn activation and proliferation of CD8+ T cells. Therefore, we have hypothesized that combination of TAT with immunotherapy will lead to a robust therapeutic effect resulting in a synergistic response as compared to monotherapy alone. Methods: The syngeneic CT26 colon cancer model was used to evaluate therapeutic efficacy of combination treatment with actinium 225-radiolabelled IGF-1R antibody (mAb), FPI-1792, and checkpoint inhibitors. FPI-1792 was used as a surrogate therapeutic that cross-reacts with mouse IGF1R. Mice with subcutaneous tumors (tumor volume ~175 mm3) were treated with either vehicle, an anti-CTLA-4 mAb (5 mg/kg) or anti-PD-1 mAb alone (5 mg/kg), FPI-1792 alone (375 kBq/kg) or the respective combinations. CD8+ T cells infiltration was evaluated via flow cytometry. Results: While only transient tumor growth suppression was detected in animals treated with either checkpoint inhibitors or FPI-1792 alone, complete tumor regression was observed in 13 out of 15 mice treated with combination therapies, indicating development of potent synergy in the combination groups. To investigate whether animals with regressing tumors will be able to reject a secondary tumor, all surviving animals were re-challenged with CT26 cells on the contralateral flank. Rejection of the secondary tumors was detected in 87% of mice previously treated with either FPI-1792 alone or a combination therapy, while tumors grew in all control animals. To gain a better understanding of the mechanism responsible for tumor regression, tumors were collected 14 days post re-challenge and analyzed via flow cytometry. An increased frequency of CD8+ T cells was observed in mice treated with combination therapy as compared to untreated animals (5-20% vs 1-2%, respectively). Importantly, high frequency of AH1 antigen-specific T cells was detected using a tetramer staining - 30-70% in the treated animals as compared to 2-3% in the control mice. Conclusions: The combination of targeted alpha therapy with checkpoint inhibitors led to tumor regression in a CT26 syngeneic model. Moreover, mice re-challenged with the same tumor on the contralateral flank were protected due to development of a strong immune response. Finally, increased frequency of antigen specific CD8+ T cells in re-challenged tumors suggests that combined treatment can break T cell tolerance and elicit a strong CD8+ T cell mediated immune response, culminating in tumor rejection. Citation Format: Sonal Patel, Natalie Grinshtein, Ryan Simms, Meiduo Hu, John Valliant, Eric Burak. Combination of IGF-1R targeted alpha therapy with checkpoint inhibitors results in synergistic efficacy in a syngeneic colorectal tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB155.

There are limited data regarding the ability to crush tablets or open capsules for antiretroviral agents. This lack of data is problematic when encountering patients who cannot swallow these tablets or capsules, especially for patients who are mechanically ventilated. Furthermore, many antir

Background Central line-associated bloodstream infections result in thousands of deaths and billions of dollars annually. At the Augusta University Medical Center (AUMC), it was identified that ~50% of peripherally inserted central venous catheters (PICCs) that were placed for intravenous (IV) antibiotic administration were unnecessary. A novel initiative was implemented, which required antimicrobial stewardship/infectious diseases approval for PICC insertions if the indication was for IV antibiotic administration only. The objective of this study was to determine the impact of this initiative. Methods A retrospective observational study was conducted at the AUMC. All adult patients with a PICC line insertion order for IV antibiotic administration, between December 2017 and May 2019 were included. The vascular access team would forward requests for PICC insertions to the antimicrobial stewardship pharmacist. The pharmacist would approve/disapprove the PICC or recommend an infectious diseases consult. The variables collected were: infection types, infectious diseases consultation, reason for PICC denial and 30-day PICC-related complications. Results A total of 215 requests for PICC insertion (for IV antibiotics) were placed. Of these, 54% of the requests were denied, while 46% were approved. The reasons for PICC denial included: midline catheter preferred (47%), switched to oral antibiotics (33%), further work-up required (10%), or no antibiotics needed (7%). The types of infections treated were: bone and joint infections (28%), urinary tract infections (13%), intra-abdominal infections (12%), endocarditis/endovascular infections (11%), skin soft tissue infections (9%), pneumonia (7%), catheter-related bloodstream infections (6%), central nervous system infections (6%), bacteremia (4%) and others (4%).The infectious diseases consult team was involved in the care of 79% of the patients. Of those that received a PICC line, only 5% experienced any PICC-related complications. The overall cost savings for PICCs that were denied was ~ $294,000. Conclusion Mandatory antimicrobial stewardship/infectious diseases approval for PICC insertion can decrease healthcare cost and reduce the number of unnecessary PICC lines placed. Disclosures All Authors: No reported disclosures

Wnt signaling is one of the central mechanisms regulating tissue morphogenesis during embryogenesis and repair. The pivot of this signaling cascade is the Wnt ligand, which binds to receptors belonging to the Frizzled family or the ROR1/ROR2 and RYK family. This interaction governs the downstream signaling cascade (canonical/non-canonical), ultimately extending its effect on the cellular cytoskeleton, transcriptional control of proliferation and differentiation, and organelle dynamics. Anomalous Wnt signaling has been associated with several cancers, the most prominent ones being colorectal, breast, lung, oral, cervical, and hematopoietic malignancies. It extends its effect on tumorigenesis by modulating the tumor microenvironment via fine crosstalk between transformed cells and infiltrating immune cells, such as leukocytes. This review is an attempt to highlight the latest developments in the understanding of Wnt signaling in the context of tumors and their microenvironment. A dynamic process known as immunoediting governs the fate of tumor progression based on the correlation of various signaling pathways in the tumor microenvironment and immune cells. Cancer cells also undergo a series of mutations in the tumor suppressor gene, which favors tumorigenesis. Wnt signaling, and its crosstalk with various immune cells, has both negative as well as positive effects on tumor progression. On one hand, it helps in the maintenance and renewal of the leucocytes. On the other hand, it promotes immune tolerance, limiting the antitumor response. Wnt signaling also plays a role in epithelial-mesenchymal transition (EMT), thereby promoting the maintenance of Cancer Stem Cells (CSCs). Furthermore, we have summarized the ongoing strategies used to target aberrant Wnt signaling as a novel therapeutic intervention to combat various cancers and their limitations.

Objective: To describe an unusual presentation of a follicle-stimulating hormone-secreting pituitary adenoma leading to ovarian hyperstimulation syndrome. We also discuss the pathophysiology and subsequent management of these tumors.Methods: This is a case report and review of the literature. A 37-year-old female with menorrhagia was found to have bilateral multilocular adnexal cysts with concern for ovarian hyperstimulation syndrome.Results: Labs revealed elevated follicle-stimulating hormone, and an eminent estradiol level. Pituitary magnetic resonance imaging revealed a macroadenoma with cavernous sinus invasion. The patient went on to have a successful transsphenoidal resection with normalization of hormones and subsequent resumption of menstrual cycles.Conclusion: With the help of this case report, we illustrate the pathogenesis of functioning gonadotroph adenomas as well as the management challenges associated with these tumors. Our case is unique in its presentation with severe hyperestrogenemia and cavernous sinus invasion pointing towards a clinically aggressive adenoma. It is important to increase awareness of these tumors to ensure timely and effective management of their complications.Abbreviations: FGA = functioning gonadotroph adenoma FSH = follicle-stimulating hormone LH = luteinizing hormone MRI = magnetic resonance imaging OHSS = ovarian hyperstimulation syndrome

Increased prevalence of metabolic syndrome like obesity, heart diseases, and diabetes is an emerging public health problem. Susceptibility to such diseases has always been attributed to environmental and genetic factors which certainly play a pivotal role but cannot be the sole causal factor leading to metabolic syndrome. Epigenetics – a mediator between genetics and environment – is emerging as a potential candidate to explain the increase in the prevalence of such metabolic diseases. Changes in the epigenetic landscape marked by DNA methylation, histone methylation, and acetylation can lead to obesity, insulin resistance, diabetes, and vascular dysfunction in both animals and humans. Nutritional programming during early stages of life can manipulate the metabolism and the physiology of the organism. This is where the importance of optimal maternal nutrition comes into play. Both maternal under- and overnutrition have the potential to adversely affect the etiology of metabolic disorders in the developing fetus by changing the epigenetic marks. Various macronutrients and micronutrients in the maternal diet have also been shown to be exhibiting specific effect on the future health of the offspring. Though the role of epigenetics in fetal programming of metabolic syndrome is constantly being well understood, research on the therapeutic aspect is still in its infancy. Interventions and manipulation of dietary supplementation which potentially can make changes in the epigenetic marks can be the future therapeutic targets for chronic metabolic syndrome.

The occurrence of pelvic malignancies along with an ectopic kidney is a rare finding. In the patients of early stage carcinoma of cervix presenting with pelvic kidney, surgery is preferred to radiation to avoid irradiating the kidney. However, advanced stage carcinoma of cervix in such scenario poses a therapeutic dilemma and conformal radiotherapy in the form of intensity-modulated radiotherapy (IMRT) is preferred option. This helps to achieve the desired dose to the target while reducing the dose to the surrounding organs at risk particularly to the pelvic kidney. Herein, we present a case of International Federation of Gynecology and Obstetrics Stage IIB carcinoma of cervix having ectopic right pelvic kidney in a 40-year-old female, and the patient was successfully treated with chemoradiotherapy in IMRT technique. The patient is disease free with normal renal function at 2-year follow-up. The previously reported cases of pelvic malignancies with ectopic kidney in the literature are discussed here briefly.

Planar wire array (PWA) experiments were performed on Michigan Accelerator for Inductive Z-pinch Experiments, the University of Michigan’s low-impedance linear transformer driver (LTD)-driven generator ( $0.1~\Omega $ , 0.5–1 MA, and 100–200 ns), for the first time. It was demonstrated that Al wire arrays [both double PWA (DPWA) and single PWA (SPWA)] can be successfully imploded at LTD generator even at the relatively low current of 0.3–0.5 MA. In particular, implosion characteristics and radiative properties of PWAs of different load configurations [for DPWA from Al and stainless steel wires with different wire diameters, interwire gaps, and interplanar gaps (IPGs) and for Al SPWA of different array widths and number of wires] were studied. The major difference from the DPWA experiments on high-impedance Zebra accelerator was in the current rise time that was influenced by the load inductance and was increased up to about 150 ns during the first campaign (and was even longer in the second campaign). The implosion dynamics of DPWAs strongly depends on the critical load parameter, the aspect ratio (the ratio of the array width to IPG) as for Al DPWAs on high-impedance Zebra, but some differences were observed, for low-aspect ratio loads in particular. Analysis of X-ray images and spectroscopy indicates that K-shell Al plasmas from Al PWAs reached the electron temperatures up to more than 450 eV and densities up to $2\times 10^{20}$ cm $^{\mathrm {-3}}$ . Despite the low mass of the loads, opacity effects were observed in the most prominent K-shell Al lines almost in every shot.

Viral diseases are responsible for high rates of mortality and subsequent economic losses in modern aquaculture. The nervous necrosis virus (NNV) produces viral encephalopathy and retinopathy (VER), which affects the central nervous system, is considered one of the most serious viral diseases in marine aquaculture. Although some studies have localized NNV in the retina cells, none has dealt with immunity in the retina. Thus, for the first time, we intravitreally infected healthy specimens of European sea bass (Dicentrarchus labrax) with NNV with the aim of characterizing the immune response in the retina. Ultrastructural analysis detected important retinal injuries and structure degradation, including pycnosis, hydropic degeneration and vacuolization in some cell layers as well as myelin sheaths in the optic nerve fibres. Immunohistochemistry demonstrated that NNV re- plicated in the eyes. Regarding retinal immunity, NNV infection elicited the transcription of genes encoding proteins involved in the interferon (IFN) and cell-mediated cytotoxicity (CMC) responses as well as B and T cell markers, demonstrating that viral replication influences innate and adaptive responses. Further studies are needed to understand the retina immunity and whether the main retinal function, vision, is affected by noda- virus., Detección de nodavirus en el mar Mediterráneo. Implicación y riesgo para la acuicultura, NODAMED, SI

Salmonid alphavirus (SAV) causes pancreas disease (PD) in Atlantic salmon (Salmo salar L.) and disease outbreaks are mainly detected after seawater transfer. The influence of the smoltification process on the immune responses, specifically the adaptive response of Atlantic salmon after SAV infection, is not fully understood. In this study, Atlantic salmon post-smolts were infected by either bath immersion (BI) or intramuscular injection (IM) with SAV subtype 3, 2 weeks (Phase A) or 9 weeks (Phase B) after seawater transfer. The transcript levels of genes related to cellular, humoral and inflammatory responses were evaluated on head kidney samples collected at 3, 7, 14, 21, and 28 days post-infection (dpi). Corresponding negative control groups (CT) were established accordingly. Significant differences were found between both phases and between the IM and BI groups. The anti-inflammatory cytokine IL-10 was up-regulated in Phase A at a higher level than in Phase B. High mRNA levels of the genes RIG-1, SOCS1 and STAT1 were observed in all groups except the BI-B group (BI-Phase B). Moreover, the IM-B group showed a higher regulation of genes related to cellular responses, such as CD40, MHCII, and IL-15, that indicated the activation of a strong cell-mediated immune response. CD40 mRNA levels were elevated one week earlier in the BI-B group than in the BI-A group (BI-Phase A). A significant up-regulation of IgM and IgT genes was seen in both IM groups, but the presence of neutralizing antibodies to SAV was detected only in Phase B fish at 21 and 28 dpi. In addition, we found differences in the basal levels of some of the analysed genes between non-infected control groups of both phases. Findings suggest that Atlantic salmon post-smolts adapted for a longer time to seawater before they come into contact with SAV, developed a stronger humoral and cell-mediated immune response during a SAV infection. acceptedVersion

Background Cardiac troponin I (cTnI) correlates with severity of myocardial injury. Nonspecific inflammation in congestive heart failure (CHF) could be assessed by C-reactive protein (CRP), haptoglobin (Hp), and ceruloplasmin (Cp) measurements. Objectives The aim of the study was to determine whether serum cTnI, CRP, Hp, and Cp concentrations differ among various stages of mitral valve disease (MVD) in dogs. Materials and methods Dogs with MVD were allocated to 3 groups (I – asymptomatic; II – mild to moderate CHF; III advanced CHF) according to the scheme of the International Small Animal Cardiac Healthy Council (ISACHC). Concentrations of cTnI, CRP, Cp, and Hp were measured in all dogs upon admission, and cTnI and CRP were measured bimonthly during a 4-month follow-up period. Results In total 46 dogs with MVD were enrolled for the cross-sectional part (21 Group I, 11 Group II, 14 Group III), and 35 dogs were included in the longitudinal study. Initial mean Cp concentrations were similar among all groups. There was a statistically significant difference in Hp and CRP concentrations between group I (n = 21, P = .019) and III (n = 14, P

Performance, efficiency, cost of the power converters and their associated control, are important considerations for the commercialization of renewable power sources. In view of this, this paper proposes a reliable and low cost power electronics interface for photovoltaic energy systems, using a single DSP controller. The proposed approach will achieve the following: (a) integrate the DC–DC converter control and inverter control by utilizing a single, low cost, fixed point Digital Signal Processor (DSP controller), (b) implement a fast converging MPP tracking method in the DC–DC converter stage and (c) reduce the size of the DC-link capacitor by using a modified pulse width modulation (PWM) technique for single phase inverter control.

Infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA IE) is associated with high morbidity and mortality. Vancomycin continues to be the primary treatment for this disease. The emergence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA), defined as a modified population analysis profile (PAP) of ≥0.9, may affect patient outcomes. The objective of this study was to evaluate the relationship of vancomycin subpopulation susceptibility and the clinical outcomes of MRSA IE. We conducted a retrospective cohort study of patients treated with vancomycin for MRSA IE from 2002 to 2013 at the Detroit Medical Center. A modified PAP was used to measure the vancomycin PAP MIC and the PAP-to-area under the curve (AUC) ratio. Treatment failure was defined as bacteremia for ≥7 days or death attributed to MRSA. Classification and regression tree (CART) analysis was used to select a failure breakpoint between the PAP-AUC ratios and the PAP MIC. A total of 202 patients were included in the study. Twenty-seven percent of the patients had left-sided IE, 19% of the strains were hVISA, and 70% of the strains were staphylococcal cassette chromosome mec element (SCC mec ) type IV. Overall treatment failure was observed in 64%; 59% had persistent bacteremia, and the 30-day attributable mortality rate was 21%. The CART breakpoint between failure and success in terms of the PAP-AUC ratio was 0.9035. On logistic regression analysis, intensive care unit (ICU) admission (adjusted odds ratio [aOR], 2.8; 95% confidence interval [CI], 1.5 to 5.2) and a PAP MIC of ≥4 mg/liter (aOR, 3.2; 95% CI, 1.3 to 8.4) were associated with failure ( P = 0.001 and 0.015, respectively). A PAP MIC of ≥4 mg/liter and ICU admission were significant for treatment failure for patients with MRSA IE. The PAP-AUC ratio of ≥0.9035 predicted failure consistent with the hVISA definition. The role of population MIC analysis in predicting outcome with MRSA infections warrants further investigation.

Background Cardiac troponin I (cTnI) is a biomarker correlated with the severity of myocardial injury. It is hypothesized that serial assessment of cTnI could provide information about the disease progression in chronic heart failure. Objective The purpose of the study was to correlate serial serum cTnI concentrations with clinical scoring and select diagnostic imaging findings in dogs managed for mitral valve degeneration (MVD) for a period of 6 months. Methods Client-owned dogs with MVD were prospectively recruited for the study. The dogs were allocated into 3 groups (I, II, III) according to the severity of their clinical signs based on the classification suggested by the International Small Animal Cardiac Health Council. During the 6-month study period, serum specimens for biochemical testing were obtained biweekly, clinical progression and response to treatment were also evaluated biweekly, and radiographic reevaluation was performed every 2 months. Results A total of 46 dogs were evaluated. There was a marked decrease in cTnI values during the first 2 weeks after initial diagnosis, more pronounced in group III, and corresponding to the initiation of therapy and clinical stabilization of animals. Serum cTnI was significantly different (P

Background The current gold standard for diagnosing invasive Candida infections is by blood culture, which has low specificity and take up to 2–5 days to grow. T2 magnetic resonance (T2MR) rapidly detects Candida species with high sensitivity/specificity. T2MR identifies five Candida species and reports it in three groups: C. albicans/C. tropicalis, C. parapsilosis, and C. glabrata/C. krusei. Methods This was a retrospective quasi-experimental study at the Augusta University Medical Center. Patients with a positive sterile site culture for Candida species and/or T2MR result were reviewed between April 2014 and March 2016 (pre-T2MR group) and April 2016–May 2017 (T2MR group). Results The pre-T2MR group consisted of 84 patients who had a Candida species isolated from a sterile site culture. The T2MR group consisted of 396 unique patients for whom there were a total of 549 T2MR tests ordered. Of these, 34 were positive, 466 were negative result, and 49 were invalid result (due to malfunctioning of T2MR). Of the 35 tests that were T2MR negative but sterile site culture positive, 27 (77%) of the cultures isolated a Candida sp. that should be detected by the T2MR but did not. The most common site of isolation for these cultures was intraabdominal (41%), followed by blood (33%). For 23% of these results, sterile site cultures grew a Candida that the T2MR does not detect. Table 1: Performance of T2MR Results in Comparison to Sterile Site Cultures T2 + (n = 549) T2 -(n = 466) Sterile site culture + 16 35 Sterile site culture − 18 431 Table 2: Comparison Between Invasive Candidiasis as Detected by Standard Blood Cultures (Pre-T2MR) and T2MR Pre-T2MR T2MR P-value Time to identification of Candida ±SD (hours) ± 210.1 ± 14.4 0.00 All-cause 30-day mortality, n (%) 19 (23%) 7 (23%) 0.56 Conclusion Unfortunately, Candida that grew in sterile site cultures was not always detected by the T2MR, particularly for intraabdominal Candidiasis. T2MR is thought to have high sensitivity and specificity for detecting Candidemia, but in our limited experience, it was found that up to one-third of Candidemias (as diagnosed by blood cultures) were missed by the T2MR. The most common Candida isolate in the T2MR group was C. parapsilosis, which is not typically thought of as a leading cause of invasive candidiasis. Disclosures All authors: No reported disclosures.

Optimal bioreactor harvest time is typically determined based on maximizing product titer without compromising product quality. We suggest that ease of downstream purification should also be considered during harvest. In this view, we studied the effect of antiapoptosis genes on downstream performance. Our hypothesis was that more robust cells would exhibit less cell lysis and thus generate lower levels of cell debris and host-cell contaminants. We focused on the clarification unit operation, measuring postclarification turbidity and host-cell protein (HCP) concentration as a function of bioreactor harvest time/cell viability. In order to mimic primary clarification using disk-stack centrifugation, a scale-down model consisting of a rotating disk (to simulate shear in the inlet feed zone of the centrifuge) and a swinging-bucket lab centrifuge was used. Our data suggest that in the absence of shear during primary clarification (typical of depth filters), a 20-50% reduction in HCP levels and 50-65% lower postcentrifugation turbidity was observed for cells with antiapoptosis genes compared to control cells. However, on exposing the cells to shear levels typical in a disk-stack centrifuge, the reduction in HCP was 10-15% while no difference in postcentrifugation turbidity was observed. The maximum benefit of antiapoptosis genes is, therefore, realized using clarification options that involve low shear

Background Although much health information-seeking behaviour (HISB) research has been reported in patients with good literacy skills, little is known about HISB in patients with limited literacy skills served by under-resourced health-care systems. Objective To investigate medicine information-seeking behaviour and information needs in patients with limited literacy. Methods Using a question guide, four focus group discussions (FGDs) were conducted to explore themes related to information needs, information-seeking practices and awareness of and ability to utilize information sources. Twenty-two isiXhosa-speaking long-term patients with limited formal education were recruited from a primary health-care clinic in South Africa. Discussions were audio-recorded and transcribed verbatim. NVivo® was used for initial coding of transcripts. Codes were analysed, and potential themes and subthemes in the entire data set were identified and refined. Findings The results of this study reflect a passive, disempowered patient. Poor awareness of information sources, lack of health-related knowledge and stigma contributed to a lack of information-seeking practice, thus potentially adversely influencing patient–provider interactions. Patients neither asked questions nor were encouraged to ask questions. All expressed an unmet need for information and a desire for receiving the illustrated written medicines-related information displayed in the FGDs. The main sources of information were health-care professionals, followed by family and friends. Conclusion The significant level of patient disempowerment and passivity reported amongst patients underpinned their inability to actively seek information. Neither sources of information nor types of appropriate medicines information could be identified. Unmet information needs and a desire for information were reported.

Salmonid alphavirus subtype 3 (SAV3) causes pancreas disease (PD) and adversely affects salmonid aquaculture in Europe. A better understanding of disease transmission is currently needed in order to manage PD outbreaks. Here, we demonstrate the relationship between viral dose and the outcome of SAV3 infection in Atlantic salmon post-smolts using a bath challenge model. Fish were challenged at 12 °C with 3 different SAV3 doses; 139, 27 and 7 TCID50 L−1 of seawater. A dose of as little as 7 TCID50 L−1 of seawater was able to induce SAV3 infection in the challenged population with a substantial level of variation between replicate tanks and, therefore, likely represents a dose close to the minimum dose required to establish an infection in a population. These data also confirm the highly infectious nature of SAV through horizontal transmission. The outcome of SAV3 infection, evaluated by the prevalence of viraemic fish, SAV3-positive hearts, and the virus shedding rate, was positively correlated to the original SAV3 dose. A maximal shedding rate of 2.4 × 104 TCID50 L−1 of seawater h−1 kg−1 was recorded 10 days post-exposure (dpe) from the highest dose group. The method reported here, for the quantification of infectious SAV3 in seawater, could be useful to monitor PD status or obtain data from SAV3 outbreaks at field locations. This information could be incorporated into pathogen dispersal models to improve risk assessment and to better understand how SAV3 spreads between farms during outbreaks. This information may also provide new insights into the control and mitigation of PD. Electronic supplementary material The online version of this article (doi:10.1186/s13567-016-0385-2) contains supplementary material, which is available to authorized users.

Salmonid alphavirus (SAV) causes pancreatic disease (PD) in salmonids in Northern Europe which results in large economic losses within the aquaculture industry. In order to better understand the underlying immune mechanisms during a SAV3 infection Atlantic salmon post-smolts were infected by either i.m.-injection or bath immersion and their immune responses compared. Analysis of viral loads showed that by 14 dpi i.m.-injected and bath immersion groups had 95.6% and 100% prevalence respectively and that both groups had developed the severe pathology typical of PD. The immune response was evaluated by using RT-qPCR to measure the transcription of innate immune genes involved in the interferon (IFN) response as well as genes associated with inflammation. Our results showed that IFNa transcription was only weakly upregulated, especially in the bath immersion group. Despite this, high levels of the IFN-stimulated genes (ISGs) such as Mx and viperin were observed. The immune response in the i.m.-injected group as measured by immune gene transcription was generally faster, and more pronounced than the response in the bath immersion group, especially at earlier time-points. The response in the bath immersion group started later as expected and appeared to last longer often exceeding the response in the i.m-injected fish at later time-points. High levels of transcription of many genes indicative of an active innate immune response were present in both groups.

Chromatin architecture and dynamics are regulated by various histone and non-histone proteins. The matrix attachment region binding proteins (MARBPs) play a central role in chromatin organization and function through numerous regulatory proteins. In the present study, we demonstrate that nuclear matrix protein SMAR1 orchestrates global gene regulation as determined by massively parallel ChIP-sequencing. The study revealed that SMAR1 binds to T(C/G) repeat and targets genes involved in diverse biological pathways. We observe that SMAR1 binds and targets distinctly different genes based on the availability of p53. Our data suggest that SMAR1 binds and regulates one of the imperative microRNA clusters in cancer and metastasis, miR-371-373. It negatively regulates miR-371-373 transcription as confirmed by SMAR1 overexpression and knockdown studies. Further, deletion studies indicate that a ~200 bp region in the miR-371-373 promoter is necessary for SMAR1 binding and transcriptional repression. Recruitment of HDAC1/mSin3A complex by SMAR1, concomitant with alteration of histone marks results in downregulation of the miRNA cluster. The regulation of miR-371-373 by SMAR1 inhibits breast cancer tumorigenesis and metastasis as determined by in vivo experiments. Overall, our study highlights the binding of SMAR1 to T(C/G) repeat and its role in cancer through miR-371-373.

Two series of homoleptic phenolate complexes with fluorinated aryloxide ligands A2[M(OAr)4] with M = Co2+ or Cu 2+, OAr- = (OC6F5)- (OArF) or {3,5-OC6H3(CF3) 2}- (OAr′), A+ = K (18-crown-6) +, Tl+, Ph4P+, Et3HN +, or Me4N+ have been synthesized. Two related complexes with nonfluorinated phenoxide ligands have been synthesized and studied in comparison to the fluorinated aryloxides demonstrating the dramatic structural changes effected by modification of OPh to OArF. The compounds {K(18-crown-6)}2[Cu(OArF)4], 1a; {K(18-crown-6)}2[Cu(OAr′)4], 1b; [Tl 2Cu(OArF)4], 2a; [Tl2Cu(OAr′) 4], 2b; (Ph4P)2[Cu(OArF) 4], 3; (nBu4N)2[Cu(OAr F)4], 4; (HEt3N)2[Cu(OAr F)4], 5; {K(18-crown-6)}2[Cu 2(μ2-OC6H5)2(OC 6H5)4], 6; {K(18-crown-6)} 2[Co(OArF)4], 7a; {K(18-crown-6)} 2[Co(OAr′)4], 7b; [Tl2Co(OAr F)4], 8a; [Tl2Co(OAr′)4], 8b; (Me4N)2[Co(OArF)4], 9; [Cp 2Co]2[Co(OAr′)4], 10; and {K(18-crown-6)}2[Co2(μ2-OC6H 5)2(OC6H5)4], 11, have been characterized with UV-vis and multinuclear NMR spectroscopy and solution magnetic moment studies. Cyclic voltammetry was used to study 1a, 1b, 7a, and 7b, X-ray crystallography was used to characterize 1b, 3, 4, 5, 6, 7a, 7b; 10, and 11. The related [MX4]2- compound (Ph 4P)2[Co(OArF)2Cl2], 12, has also been synthesized and characterized spectroscopically, as well as with conductivity and single-crystal X-ray diffraction. Use of fluorinated aryloxides permits synthesis and isolation of the mononuclear, homoleptic phenolate anions in good yield without oligomerized side products. The reaction conditions that result in homoleptic 1a and 7a with OArF upon changing the ligand to OPh result in μ2-OPh bridging phenoxides and the dimeric complexes 6 and 11. The [M(OArF)4]2- and [M(OAr′)4]2- anions in 1a, 1b, 3, 4, 5, 7a, 7b, 9, and 10 demonstrate that stable, isolable homoleptic phenolate anions do not need to be coordinatively or sterically saturated and can be achieved by increasing the electronegativity of the ligand.

Cell signaling initiated at the epidermal growth factor receptor (EGFR), RAS oncoproteins, or PI3K contributes to a common pathway that promotes tumor survival after radiation-induced DNA damage. Inhibition of signaling at the level of EGFR, RAS, and PI3K has been tested, but clinical applicability has been shown only at the level of the EGFR or by inhibiting RAS indirectly with prenyltransferase inhibitors. Inhibition of PI3K with LY294002 or wortmannin lacks specificity and has shown unacceptable toxicity in preclinical studies. We previously showed that inhibiting class I PI3K expression with siRNA resulted in enhanced radiation killing of tumor cells. Here, we tested the possibility of achieving specific tumor cell radiosensitization with a pharmacologic inhibitor of class I PI3K, the pyridinylfuranopyrimidine inhibitor PI-103. Our results show that inhibiting PI3K activity reduces phosphorylation of AKT at serine 473. Reduced survival is seen in cells with AKT activation and seems preferential for tumor cells over cells in which AKT activity is not elevated. Reduced survival is accompanied by persistence of DNA damage as evidenced by persistence of γH2AX and Rad 51 foci after irradiation in the presence of the inhibitor. Reduced survival does not result from cell cycle redistribution during the PI-103 treatment intervals tested, although combining PI-103 treatment with radiation enhances the G2-M delay observed after irradiation. These results indicate that pharmacologic inhibitors with enhanced specificity for class I PI3K may be of benefit when combined with radiotherapy. [Cancer Res 2008;68(14):5915–23]

The aim of this study was to evaluate survival and success rates following autotransplantation of permanent maxillary canine teeth. Sixty-three cases of maxillary canine autotransplantation from 49 subjects (mean age at transplantation 21.8 years, range 13-42.1 years) undertaken between 1977 and 2003 were collected as part of an audit project of transplantation success. All maxillary canines had complete root development at the time of transplantation. The sample was divided into two groups, a matched case-control study to compare 27 unilateral transplanted canines with the non-transplanted canine on the contralateral side, and all 63 transplanted canines with no controls. Teeth were assessed clinically using established criteria for success: tooth presence for survival and resorption, mobility, probing pocket depth (PPD), gingival bleeding, vitality, and colour. Radiographic investigation for success assessed internal and external inflammatory resorption (including the amount) bone levels and any signs of pathology. Data were described with descriptive statistics and analytical tests were used to assess frequencies of occurrence.The survival rate was 83 per cent with an average duration of 14.5 years in situ. Thirty-eight per cent of the transplants were deemed successful. There were statistically significant associations between the transplanted and non-transplanted teeth in PPD (P = 0.006), gingival bleeding (P = 0.006), vitality (P = 0.004), and colour (P = 0.002). Autotransplantation of impacted maxillary canines can be successful in the long term and may be indicated in selected cases. Although the rate for complete success in this study was low (no signs of resorption, mobility, and sound periodontal tissues), the survival rate can be considered favourable when evaluating autotransplantation as a treatment option for grossly malpositioned canines with little scope for orthodontic alignment. © 2010 The Author.