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Supplementary Materials and Methods; Supplementary Figure S1. Binding kinetics of hedgehog antibodies to human and mouse hedgehog proteins using surface plasmon resonance. Supplementary Figure S2. Hedgehog ligands stimulate mGLI1 reporter activity and osteoblast differentiation in a dose-dependent manner. Supplementary Figure S3. Selective inhibition of mGLI1 or mPTC1 induction in C3H10T1/2 cells by hedgehog antibodies. Supplementary Figure S4. MEDI-5304 inhibits GLI1 expression in Colo205 xenograft stromal cells but not tumor cells. Supplementary Figure S5. Hedgehog pathway component RNA expression in primary pancreatic tumor explant model P479 and effects of MEDI-5304 on tumorspheres derived from pancreatic explant model 947. Supplementary Figure S6. Pharmacokinetics of MEDI-5304 in rats. Supplementary Figure S7. Exploratory toxicology of MEDI-5304 in rats. Supplementary Figure S8. Pharmacokinetics of MEDI-5304 from preliminary toxicology study in cynomolgus monkeys. Supplementary Figure S9. Pharmacodynamics of MEDI-5304 in cynomolgus monkeys.

PDF file - 153K, Figure to support screening for antibodies

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The Notch signaling pathway has been implicated in cell fate determination and differentiation in many tissues. Accumulating evidence points toward a pivotal role in blood vessel formation, and the importance of the Delta-like ligand (Dll) 4-Notch1 ligand–receptor interaction has been shown in both physiological and tumor angiogenesis. Disruption of this interaction leads to a reduction in tumor growth as a result of an increase in nonfunctional vasculature leading to poor perfusion of the tumor. MEDI0639 is an investigational human therapeutic antibody that targets Dll4 to inhibit the interaction between Dll4 and Notch1. The antibody cross-reacts to cynomolgus monkey but not mouse species orthologues. In vitro MEDI0639 inhibits the binding of Notch1 to Dll4, interacting via a novel epitope that has not been previously described. Binding to this epitope translates into MEDI0639 reversing Notch1-mediated suppression of human umbilical vein endothelial cell growth in vitro. MEDI0639 administration resulted in stimulation of tubule formation in a three-dimensional (3D) endothelial cell outgrowth assay, a phenotype driven by disruption of the Dll4-Notch signaling axis. In contrast, in a two-dimensional endothelial cell–fibroblast coculture model, MEDI0639 is a potent inhibitor of tubule formation. In vivo, MEDI0639 shows activity in a human endothelial cell angiogenesis assay promoting human vessel formation and reducing the number of vessels with smooth muscle actin-positive mural cells coverage. Collectively, the data show that MEDI0639 is a potent modulator of Dll4-Notch signaling pathway. Mol Cancer Ther; 11(8); 1650–60. ©2012 AACR.

Background: There is a paucity of literature regarding rock climbing footwear. Rock climbers anecdotally voice numerous complaints regarding their current footwear. In an effort to improve existing rock-climbing footwear, implementation of a survey tool assessing the attitudes and practices of rock climbers was undertaken. Methods: A Web-based survey was developed to assess the demographics, attitudes, and practices of individuals active in rock climbing, with a focus on footwear. Results: Forty-five of the 417 respondents were male and 55% were female. The average years climbing was 7, with a majority of respondents in the 18- to 34-year-old category. The majority climbed 5 to 10 hours/week. Eighty percent identified as intermediate or advanced climbers. Climbing shoes were an average of 0.83 size smaller than the climber’s street shoes. The more elite the climber, the greater the mismatch. Overall satisfaction with current rock-climbing shoes was 88%; however, as the age of climber and number of years of participation increased, the level of satisfaction decreased. The most frequently reported problems with shoes included inconsistent sizing between brands and poor heel fit. The most commonly reported locations of pain were the toes and heel. Conclusions: The authors concluded the following: 1) a surprisingly high satisfaction with current rock-climbing shoes was reported; 2) the difference in size between climbing shoes and street shoes was less than expected; 3) more shoe fitting problems were experienced by those with the most experience in climbing and those who spend the most time climbing; 4) the most common locations for experiencing pain were the toes and the posterior heel or Achilles tendon; 5) higher than expected satisfaction levels with climbing shoes contrasted with the very high number of specific complaints and recommendations for improvement; and 6) because of the increasing popularity of rock climbing, foot care providers should learn about the various types of climbing and the shoe gear needs that result therefrom.

Evasion of apoptosis is a hallmark of cancer wherein overexpression and amplification of pro-survival BCL2-family genes like MCL1 is a common observation. MCL1 is frequently amplified in many hematological cancers like Multiple Myeloma (MM) that depend on it for survival. BH3 mimetic drugs, like the BCL2-specific inhibitor Venetoclax, have been successfully used in the clinic to treat certain cancers, and MCL1-selective inhibitors are currently in clinical development. While inhibition of MCL1 displays promising preclinical activity, many cancer models display acquired or intrinsic resistance to MCL1 inhibitors (MCL1i). As MCL1-targeted therapies progress clinically, understanding mechanisms that lead to resistance will be important to not only identify therapeutically-exploitable targets to combat resistance, but to also determine if these biomarkers could stratify patients most likely to respond to an MCL1i. Here, we used a genome-wide CRISPR knock-out screen to identify mechanisms of resistance to MCL1i AZD5991 in two MM cell lines, KMS11 and KMS34. We used a sgRNA library consisting of about 118,000 sgRNAs (~6 sgRNAs/gene), and treated the cells with DMSO or 1uM AZD5991 for 16 days (5 doublings). We identified 316 genes in KMS11 and 184 genes in KMS34 with >4-fold enrichment of sgRNAs; and 221 genes with >2-fold enrichment of sgRNAs in both cell lines. The sgRNAs targeting BAK and BAX were the most enriched overlapping hits. Using GSEA analysis of the 221 common genes with enriched sgRNAs, we discovered that the tRNA wobble uridine modification as the most enriched pathway. The tRNA U34 mcm5s2 modification is catalyzed by the elongator complex ELP1-6 and cytosolic thiouridylase CTU1/2. Each subunit of the elongator complex is essential for its function and loss of any subunit results in destabilization of the complex. By knocking out ELP4 in five MM cell lines (KMS11, KMS34, KMS12-PE, MM.1S, and RPMI-8226), we first validated the destabilization of the complex by showing a robust decrease in the protein levels of ELP1 and ELP3 via western blot. As the elongator complex has additional functions, we also knocked-out tRNA U34 modification pathway specific CTU1 in KMS11, KMS34, and KMS12-PE cells. We showed that genetic knock-out of ELP4 and CTU1 results in increased resistance to MCL1i in all cell lines tested. We observed the highest increase in MCL1i resistance upon ELP4-KO in KMS11 and RPMI-8226 cell lines. To understand the mechanism behind elongator complex mediated regulation of MCL1 dependency, we performed RNAseq and global proteomics in KMS11 cells (Parental, non-targeting control [NTC], ELP4-KO and CTU1-KO) and RPMI-8226 cells (Parental, NTC, and ELP4-KO). We show that the elongator complex is a regulator of IRE1-XBP1 axis of the ER stress response pathway; and knockout of IRE1 also results in MCL1i-resistance in KMS11 and RPMI8226 cell lines. Mechanistically, we show that loss of elongator complex-mediated downregulation of IRE1-XBP1 axis leads to stabilization of MCL1 and upregulation of BCL-XL and NOXA expression. We further show that upon treatment with MCL1i, KMS11-ELP4-KO cells have less disruption of MCL1:Bim complex and an increase in BCL-XL:Bim complex as compared with KMS11-NTC cells. The net increase in pro-survival MCL1 and BCL-XL proteins in ELP4-KO cells resulting in lower levels of unsequestered BIM upon AZD5991 treatment suggests a reduction in apoptotic priming. The mechanistic link between the elongator complex and ER stress response pathway led us to test ER stress inducing drugs in these cell lines. We observed that ELP4-KO results in increased resistance to proteasome inhibitor Bortezomib and other ER stress inducers like Tunicamycin, Thapsigargin, and BrefeldinA as a monotherapy or in combination with AZD5991. These data are consistent with our hypothesis that ELP4-KO cells have reduced apoptotic priming and are thus multi-drug resistant. As bortezomib is used in the clinic to treat MM patients, we asked if an elongator gene signature could be used to predict response to current therapies. We show that the elongator complex components could be used as a gene signature to stratify overall survival in MM patients (MMRF CoMMpass dataset). Moreover, ER stress response gene signature has been shown to be repressed in drug-resistant MM. Taken together, an integrated elongator and IRE-XBP1 gene signature could be a strong predictor of therapy response in MM . Disclosures Aryal: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Sundarrajan: AstraZeneca: Ended employment in the past 24 months. Boiko: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Jenkins: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Liu: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Ahdesmaki: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Bornot: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Jarnuczak: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Miele: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. McDermott: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Fawell: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Drew: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Boise: AbbVie/Genentech: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Research Funding. Cidado: AstraZeneca: Current Employment, Current equity holder in publicly-traded company.

Persons with diabetes might experience significant benefits through regular exercise. Not unlike the general population, those with diabetes could also lack motivation to participate in an exercise program. Often, those treating persons with diabetes lack training and/or interest in exercise prescription and are therefore unable to provide the needed information and encouragement. In many cases, reluctance to exercise could result from an inability to find an enjoyable exercise activity. Attempts to find activities that, not only provide effective aerobic challenges, but are also enjoyable to participate in are fraught with difficulty. Three electronic databases were searched in January 2017. Evidence for the merits of exercise for those with diabetes was robust. Numerous reports have addressed the degree of noncompliance to exercise recommendations and the barriers reported for this nonadherence. Additional studies concluded that most medical providers are deficient in formal training in the prescription of an exercise program. Newer studies are evaluating the effects of exercise and vitamin D supplementation and their interplay with diabetic peripheral neuropathy and ulceration. Exercise confers remarkable benefits to those with diabetes; however, the challenges to compelling patients with diabetes to exercise are formidable. An improved focus on exercise prescription and related motivation during provider training must be undertaken.

Background Persons with intellectual disabilities frequently have podiatric conditions. Limited information exists on their prevalence in international cohorts of Special Olympics (SO) athletes. Findings from multiple United States (US) venues are compared to those from athletes screened at the 2011 Special Olympics World Summer Games in Athens, Greece (ATHENS). Methods Data from Fit Feet screenings from 2096 ATHENS participants was compared to 7192 US participants. Results Frequently noted in the ATHENS population were motion restriction in both the ankle and the first metatarsal phalangeal joint (1st MTPJ), pes planus, metatarsus adductus, brachymetatarsia, hallux abducto valgus (HAV), onychomycosis, onychocryptosis, and tinea pedis. ATHENS differed from the US cohort as HAV and restricted ankle joint and 1st MTPJ joint motion was less frequent. Significantly more tinea pedis, xerosis, and hyperhidrosis were present in the ATHENS population. Discussion/Conclusion SO athletes have a higher prevalence of podiatric structural conditions compared to the general population, and some vary between ATHENS versus US. Less prevalent in ATHENS was HAV, and restricted motion in both the ankle and 1st MTPJ. This may reflect differences due to varied clinical observers. The higher rates of several dermatological conditions in ATHENS may reflect venue seasonal climate, or social factors.

Background:Exercise is highly beneficial for persons with diabetes. Similar to many other patients, those with diabetes may be reluctant to exercise given a lack of motivation and proper instruction regarding an exercise prescription. In general, medical providers are poorly equipped to develop an exercise prescription and furnish motivation. Attempts to find activities that not only provide effective aerobic challenges but also are enjoyable to participate in are fraught with difficulty. Hiking as a potential option for a safe and enjoyable activity is discussed, including the possible downsides.Methods:Multiple publications were reviewed using key words.Results:A review of the literature uncovered limited publications or controlled trials that discussed the use of hiking per se as an activity for the management of diabetes. Newer studies reviewing weightbearing exercise and diabetic polyneuropathy and those discussing the advantages of trekking poles for balance and proprioception are cited in support of the recommendation for hiking as an activity for those with diabetes.Conclusions:Exercise has been shown to substantially benefit individuals with diabetes, but convincing patients with diabetes to exercise is daunting. Hiking, unlike other, more tedious exercise programs, may be an exercise option that persons with diabetes might find enjoyable. Hiking may encourage balance training and reduced ground reaction forces. These benefits may be augmented by trekking poles, which may likewise counter the concerns of the uneven surfaces that present challenges to the hiker with diabetes.

In the last five plus years, many of us have been queried, “What’s the deal with barefoot running?” “Is it good or bad?” or other similar questions. Because of the keen interest and/or curiosity, it is essential that health care providers involved in the care of athletes need to be cognizant of the current trends in the world of training, whether they be long-lasting movements or short-lived fads.

Commissioned to host the 2014 FIFA (Federation Internationale de Football Association) World CupTM tournament, Brazil was given access to a global platform which holds the power to stimulate considerable levels of tourism value. However, tourist anxiety surrounding safety and security raised questions as to whether the event could successfully achieve the host nation's diverse set of underpinned socioeconomic objectives. As a benchmark of success in this regard, Brazil was first set to host the 2013 FIFA Confederations CupTM, a prelude to the 2014 FIFA World CupTM tournament. This article investigates the constructs found to manage sport tourists' safety-risk perceptions; and examines how the interrelationships amongst these constructs can positively influence sport tourists' repeat visitation intentions as a practice that drives tourism growth. First, a mediation model regarding the interrelationships between safety-risk perception, satisfaction, and repeat visitation was synthesised from sport tourism l...

Background:Barefoot running is slowly gaining a dedicated following. Proponents of barefoot running claim many benefits, such as improved performance and reduced injuries, whereas detractors warn of the imminent risks involved.Methods:Multiple publications were reviewed using key words.Results:A review of the literature uncovered many studies that have looked at the barefoot condition and found notable differences in gait and other parameters. These findings, along with much anecdotal information, can lead one to extrapolate that barefoot runners should have fewer injuries, better performance, or both. Several athletic shoe companies have designed running shoes that attempt to mimic the barefoot condition and, thus, garner the purported benefits of barefoot running.Conclusions:Although there is no evidence that either confirms or refutes improved performance and reduced injuries in barefoot runners, many of the claimed disadvantages to barefoot running are not supported by the literature. Nonetheless, it seems that barefoot running may be an acceptable training method for athletes and coaches who understand and can minimize the risks. (J Am Podiatr Med Assoc 101(3): 231–246, 2011)

Background Podiatric conditions are frequently seen in persons with intellectual disabilities. Unfortunately, many are not detected or addressed. This study attempts to determine the prevalence of a variety of selected podiatric conditions in Special Olympics athletes and compare the findings to studies of a similarly matched general population. Methods Screenings from 1580 Special Olympics athletes participating in a sampling of United States competitions in 2004–2006 were used for the analysis. The athletes voluntarily underwent a foot screening which followed the standardized Special Olympics Fit Feet protocol. Results The most commonly identified conditions included overpronated gait, abducted gait, restriction in both the ankle and the first metatarsal phalangeal joint, pes planus, metatarsus adductus, brachymetatarsia, hallux abducto valgus, onychomycosis, onychocryptosis and tinea pedis. Discussion/Conclusion The prevalence of all the structural conditions was notably higher than a similarly matched general population and both conditions and biomechanical/gait findings associated with ligamentous laxity like pes planus and hallux abducto valgus had especially high prevalence rates. Restricted motion in the ankle and first metatarsal phalangeal joint was surprising and may indicate some athletes have intellectual disabilities with contractures. The higher rates of dermatophyte related conditions may reflect increased exposure from the athletic competition environment, immunocompromise, issues with hygiene or both. Higher rates of onychocryptosis in the athletes may be due to ill fitting shoes and/or hygiene issues.

This article reviews the history of sports medicine highlighting the "jogging boom" of the 1970s and the advocacy of Dr George Sheehan, which boosted the position of podiatry in sports medicine. Significant events in mainstream sports medicine that promoted the rise of podiatric medicine are discussed. Reasons as to why podiatric medicine should be a member of the sports medicine team are outlined, and lastly, examples that highlight podiatric medicine as participants alongside other specialties in the evaluation and care of athletes are given.

While immunotherapies directed against PD-1 and PD-L1 have proven effective across multiple indications, there is still a large unmet medical need for therapies for patients who do not respond or who develop acquired resistance during the course of treatment. There are several emerging hypotheses to explain the lack of response, including the overall presence and localization of immune cells, as well as the up-regulation of additional T-cell checkpoints, including TIM-3 in tumor infiltrating lymphocytes. To investigate the potential role of TIM-3, we set out to evaluate the expression and function of TIM-3 and the relationship to PD-1 in several systems. Firstly, we developed a flow cytometry methodology to enumerate T-cell, including CD4 and CD8 positive cells, as well as other immune cell populations in a panel of human tumor samples, including non-small cell lung cancer (NSCLC). In these samples, we investigated the expression profiles of TIM-3 and PD-1 in both T-cell and non-T-cell populations. In addition, we performed complementary genomic studies to explore gene expression profiles of not only the bulk tumor samples but also of isolated PD1 positive/TIM-3 negative versus PD1 and TIM-3 double positive cell populations. The profiling identified tumors with a range of tumor infiltrating lymphocyte content and also differences in PD1 and TIM-3 expression. It was found that in addition to T-cells, TIM-3 was expressed on myeloid cell populations and furthermore, that there were distinct differences in the gene expression profiles of PD1 single positive versus PD1 and TIM-3 double positive cells. Building on the expression studies, the functional role of Tim-3 in T-cells and also on myeloid-derived cells was explored. Taken together, these studies provide further evidence for TIM-3 as an important immunological checkpoint and as a relevant therapeutic target for the treatment of cancer with the potential for biological effects in both the T-cell and myeloid compartments of the tumor microenvironment. Citation Format: Kristen McEachern, Srimoyee Ghosh, Yonghong Zhao, Qiyao Zhang, Norman Zhang, David W. Jenkins. Evaluation of the expression and function of TIM-3 relative to PD-1 in human tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 651. doi:10.1158/1538-7445.AM2017-651

A symptomatic foreign body embedded in the human body can be a frustrating problem for physician and patient alike. A unique case of a retained foreign object resulting from a pellet gun injury has been presented. Although the course of treatment in this case was uncomplicated, it is important to understand the complexities of the human body's response to foreign bodies.

The neutrophil enzyme myeloperoxidase (MPO) promotes oxidative stress in numerous inflammatory pathologies by producing hypohalous acids. Its inadvertent activity is a prime target for pharmacological control. Previously, salicylhydroxamic acid was reported to be a weak reversible inhibitor of MPO. We aimed to identify related hydroxamates that are good inhibitors of the enzyme. We report on three hydroxamates as the first potent reversible inhibitors of MPO. The chlorination activity of purified MPO was inhibited by 50% by a 5 nm concentration of a trifluoromethyl-substituted aromatic hydroxamate, HX1. The hydroxamates were specific for MPO in neutrophils and more potent toward MPO compared with a broad range of redox enzymes and alternative targets. Surface plasmon resonance measurements showed that the strength of binding of hydroxamates to MPO correlated with the degree of enzyme inhibition. The crystal structure of MPO-HX1 revealed that the inhibitor was bound within the active site cavity above the heme and blocked the substrate channel. HX1 was a mixed-type inhibitor of the halogenation activity of MPO with respect to both hydrogen peroxide and halide. Spectral analyses demonstrated that hydroxamates can act variably as substrates for MPO and convert the enzyme to a nitrosyl ferrous intermediate. This property was unrelated to their ability to inhibit MPO. We propose that aromatic hydroxamates bind tightly to the active site of MPO and prevent it from producing hypohalous acids. This mode of reversible inhibition has potential for blocking the activity of MPO and limiting oxidative stress during inflammation.

(1996). How Should Feedback be Delivered? Journal of Physical Education, Recreation & Dance: Vol. 67, No. 1, pp. 18-22.

Background:Improperly fitted shoes are frequently seen in athletes participating in Special Olympics competitions. This foot-to-shoe mismatch may result in deformities as well as discomfort and reduced performance or injuries in competitions. A primary purpose for providing medical screenings is to identify conditions unknown and to promptly refer to an appropriate provider for evaluation and care. This study attempts to determine the prevalence of improperly fitted shoes and the rate of referral for Special Olympics athletes screened at Fit Feet venues.Methods:To evaluate the foot-to-shoe mismatch and rate of referral, 4,094 Fit Feet screenings of Special Olympics athletes participating in US competitions in 2005 to 2009 were analyzed. The participants were 58.5% male and 41.5% female, with a median age of 25.6 years. A power analysis and the χ2test were used. The athletes voluntarily underwent a foot screening that followed the standardized Special Olympics Fit Feet protocol. The Brannock Device for measuring feet was used to assess proper fit.Results:A proper fit was found in 58.56% of the athletes, with 28.60% wearing shoes too big and 12.84% wearing shoes too small. Unrelated to shoe fit, 20% of the athletes required referrals for professional follow-up based on abnormal clinical findings.Conclusions:There is a significant (41.44%) mismatch of foot to shoe in Special Olympics athletes. The most common mismatch is a shoe too big, with a much smaller number of athletes having shoes too small. Awareness of this foot-to-shoe incompatibility may be useful for the development of shoes better designed for athletes with a foot structure not consistent with conventional shoes. Because 20% of the athletes required a referral for professional follow-up, Fit Feet examinations are important for identifying athletes with conditions that can be more readily evaluated and treated, thus improving the athletes’ comfort and performance. Beyond knowing the rate of referral, future studies can determine the conditions or findings that necessitate a referral and the ultimate outcome of that referral. (J Am Podiatr Med Assoc 102(3): 187–197, 2012)

Predictions of deep levels associated with N vacancies in AlxGa1−xN as functions of alloy composition x explain both (i) the dramatic change from naturally n‐type to semi‐insulating behavior (for x=xc≂0.5) in terms of a shallow‐deep transition for the vacancy’s T2 level, and (ii) the major photoluminescence feature in terms of recombination from the vacancy’s A1 deep level. Extrinisic photoluminescence data for Zn‐doped AlxGa1−xN are interpreted in terms of a transition from the conduction band to a T2‐symmetric deep level in the lower part of the gap. This level is associated with antisite Zn on a N site, ZnN.

Overuse knee joint injuries are the primary injuries to cyclists. Overuse injuries have been intuitively linked to the anatomic structure of the foot because external loads are applied to the foot in cycling. Thus, the structure and function of the foot should dictate in part how the loads are transmitted to the knee joint. Therefore, it was hypothesized that patterns in knee loads are related to the anatomic structure of the foot. To test this hypothesis, peak knee loads (dependent variables) were related to anatomical variables (independent variables) through statistical analyses. This required first the detailed evaluation (i.e. measurement) of the anatomical structure of the foot and leg for 23 subjects. Next, three-dimensional knee joint loads were determined for a standardized riding condition. The results of the statistical analyses indicated that a group of cyclists with the most extreme inversion of the forefoot relative to the transverse plane developed significantly greater average posterior knee force and extensive knee moment. In addition, a number of anatomical variables significantly accounted for the variability in peak values of the posterior force, the extensive moment, the varus/valgus moment and the external axial moment. Based on these results, the hypothesis is accepted.

The most cost effective transport for high bandwidth metro networks uses ROADM enabled DWDM technology, with ring based protection. With appropriate engineering early on, such networks can gracefully and cost effectively evolve to optical meshes.

A simple, analytical, semiempirical model is presented for the optical constants of AlxGa1−xAs including the index of refraction. The model is tailored to the energy range of 1.0–3.0 eV, the operating range for many AlxGa1−xAs‐based devices and incorporates the important electronic transitions in the solid which affect light propagation and absorption. The parameters of the model are simple functions of composition allowing for ready computation of any of the optical constants, n, k, α, e1, or e2, for any energy E (or wavelength λ) of light between 1.0 and 3.0 eV (400–1200 nm) and any composition x.

Bradykinin and prostaglandins are both local mediators strongly implicated in pain and inflammation. Here, we have investigated the effects of bradykinin on the release of prostaglandin E(2) from cultured neurones derived from adult rat trigeminal ganglia. Bradykinin was a potent inducer of prostaglandin E(2) release, an effect that was likely mediated by bradykinin B(2) receptors, as the bradykinin-induced prostaglandin E(2) release was attenuated by the bradykinin B(2) receptor-selective antagonist, arginyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl-3-(2-thienyl)-L-alanyl-L-seryl-D-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-L-(2 alpha, 3 beta, 7a beta)-octahydro-1H-indole-2-carbonyl-L-arginine (HOE 140), but not by the bradykinin B(1) receptor-selective antagonist, des-Arg(9),[Leu(8)]-bradykinin. Furthermore, bradykinin-induced prostaglandin E(2) release was inhibited following treatment with the phospholipase A(2) inhibitor, arachidonyltrifluoromethyl ketone (AACOCF(3)), the nonselective cyclooxygenase inhibitor, piroxicam, the mitogen-activated protein kinase kinase-1 (MEK1) inhibitor, 2'-amino-3'-methoxyflavone (PD98059), and the protein kinase C inhibitor, bisindolylmaleimide XI (Ro320432). Taken together, these data suggest that bradykinin, acting via bradykinin B(2) receptors, induces prostaglandin E(2) release from trigeminal neurones through the protein kinase C and mitogen-activated protein kinase-dependent activation of phospholipase A(2) and consequent stimulation of cyclooxygenases.

Delta-like ligand 4 (DLL4) is a membrane bound ligand for Notch receptors essential for functional vessel formation during development and angiogenesis. We have shown previously that MEDI0639, a human anti-DLL4 antibody, has potent in vitro and in vivo activity in blocking DLL4-Notch interaction. However, because MEDI0639 has low binding affinity to mouse DLL4, to enable in vivo pharmacology studies using xenograft tumor models in mice, MEDI0639 was engineered to bind more strongly to mouse DLL4. The resulting affinity-optimized variant antibody (anti-mDLL4 mAb) bound with high affinity to both human and mouse DLL4 and maintained binding specificity to DLL4. In a number of human cancer xenograft models in nude mice, the MEDI0639 variant antibody markedly inhibited the growth of tumors. qRT-PCR analysis using the Fluidigm platform showed decreases in mouse genes downstream of the Notch signaling pathway at efficacious doses, indicating on-target antibody effect on tumor vasculature. In addition, IHC and imaging analysis of xenograft tumors from the anti-DLL4 mAb dosed animals showed a dose-dependent increase in microvessel density and decrease in tumor perfusion compared to the control groups. In summary, we describe here the generation of mouse and human DLL4 cross-reactive antibody and the utilization of this antibody in demonstrating a positive correlation between the anticipated mechanism of action of DLL4 blockade on vasculature and inhibition of tumor growth. Citation Format: Song H. Cho, David W. Jenkins, Patrick Strout, Martin Korade, Haihong Zhong, Ching Ching Leow, Shannon Breen, Jon Chesebrough, Nicholas Holoweckyj, Ivan Inigo, Gennady Gololobov, Ping Tsui, Kimberly Cook, Melissa Damschroder, Meggan Czapiga, Philip Brohawn, Jiaqi Huang, Sally-Ann Ricketts, Juliana Maynard, Adeela Kamal. A mouse DLL4 cross-reactive variant of MEDI0639 disrupts functional vessel formation and inhibits tumor growth in preclinical models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5098. doi:10.1158/1538-7445.AM2013-5098

Summary Until theory and experiment reach new levels of precision, the physics of semiconductor alloys, whether superlattices or not, appears to be adequately treated by the recursion method and a Born-von Karman model such as those described here. But light-scattering studies such as resonant Raman scattering spectroscopy are beginning to provide new and precise information about vibrations in alloys, and, when analyzed with improved models of long-ranged forces, will no doubt allow very detailed comparisons of theory with data. A better understanding of correlations in alloys should follow, and will involve the theory of phase transitions as well. In summary, the recursion method provides a very good way to understand the phonon spectra of the semiconductor alloys discussed here, as well as the spectra of other III-V and II-VI alloys (Amirthara et al. 1985; Fu and Dow 1987; Lucovsky et al. 1975, 1976). While this method provides a satisfactory description of the density of states per squared frequency in an alloy, its primary limitation is that it normally does not provide matrix elements (which can be calculated for large clusters (Ren and Dow 1992), but not for clusters so large as those amenable to treatment with the recursion method). The discussion of one-mode versus two-mode k = 0 optical phonon behavior is seen to be largely moot: unless the masses of the atoms are virtually equal, one invariably finds two-mode behavior, but one of the modes may be resonant with a phonon continuum, and therefore may not be visible. The phonon spectra of the substitutional crystalline semiconducting alloys are nearly “persistent”, but the deviations from this persistent behavior are the alloy modes, and those modes are the subject of investigations of alloy physics. (One should not claim success for an elegant theory that does little more than reproduce the persistent limit!) The advantage of the recursion method as applied to the alloy physics of the semiconductor alloys is that it can be dissected to associate specific features of a spectrum with particular local configurations. With the Redfield method of generating correlated clusters, and with the separation of the alloy problem into the following parts: (i) determination of the cluster (correlated or not), (ii) evaluation of the forces, and (iii) computation of the density of states, it is now possible to predict the main properties of the substitutional crystalline alloy semiconductors. The present work assumed that all of the atoms of the alloy occupied crystalline sites on a zinc-blende lattice. Of course, with strains in the materials, and with diffusion at finite temperatures, this assumption will not be 100% valid. Therefore, one of the next major problems to be addressed is the physics of substitutional nearly-crystalline alloys whose crystal structures deviate from the perfect geometry of the zinc-blende structure, due to strain, for example. This will be interesting from the viewpoint of pure physics, and it has important technological implications: interfaces between alloy semiconductors exhibit interdiffusion, and this interdiffusion is one of the elements scattering electrons and limiting the electronic mobility - and hence limiting the performance of high-speed optoelectronic devices based on these materials.

Zincblende-to-diamond-lattice structural phase transitions should occur in metastable (III–V)1−xIV2x alloys at a transition composition xc that is controllable by growth conditions. The effect of this transition should be visible both in the electronic as well as the vibrational properties of these alloys. For example, in the prototypical (III–V)1−xIV2x alloy, (GaAs)1−xGe2x, the observed anomalous V-shaped bowing of the direct gap is explained in terms of the phase transition, which occurs at the minimum of the “V.” Predictions are made for the band gaps of new metastable alloys, such as (GaSb)1−xSn2x. Consequences of this transition for (III–V)-IV superlattices are also discussed.

The electronic structures of InN, ${\mathrm{In}}_{\mathrm{x}}$${\mathrm{Ga}}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$N, and ${\mathrm{In}}_{\mathrm{x}}$${\mathrm{Al}}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$N are predicted and these materials are found to be direct-band-gap semiconductors with fundamental band gaps ranging from orange through the blue-green to the ultraviolet. The deep levels associated with substitutional s- and p-bonded impurities are predicted, and, for InN we find (i) that the native defect responsible for naturally occurring n-type InN is a nitrogen vacancy (not ${\mathrm{N}}_{\mathrm{In}}$); (ii) that the nitrogen vacancy also produces a deep level just below the conduction-band edge, which is responsible for an observed 0.2-eV optical-absorption feature; (iii) that p-type doping should be achievable by inserting column-II impurities on In sites; (iv) that n-type conductivity should result from oxygen atoms on N sites; (v) that ${\mathrm{In}}_{\mathrm{N}}$ produces s- and p-like deep levels near midgap that are responsible for an optical-absorption feature near 1 eV; (vi) that column-IV impurities on either anion or cation sites will tend to make the material semi-insulating, and (vii) that an isoelectronic electron trap should be produced by ${\mathrm{B}}_{\mathrm{In}}$, whereas column-V impurities on the N site should produce deep isoelectronic hole traps. Similar results hold for the alloys ${\mathrm{In}}_{\mathrm{x}}$${\mathrm{Ga}}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$N and ${\mathrm{In}}_{\mathrm{x}}$${\mathrm{Al}}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$N. Some impurities undergo shallow-deep transitions in the alloys, as functions of alloy composition.

The energy band gaps and substitutional deep impurity levels of metastable alloys ${\mathrm{Ge}}_{\mathrm{x}}$${\mathrm{Sn}}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$ are predicted. As a function of decreasing alloy composition x the indirect band structure of semiconducting Ge first becomes direct (indicating that ${\mathrm{Ge}}_{\mathrm{x}}$${\mathrm{Sn}}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$ may have applications as an infrared detector) and then metallic. Doping anomalies commonly occur as x decreases. Between x\ensuremath{\simeq}0.4 and x\ensuremath{\simeq}0.8, the Gunn effect should occur.

The energy band structure of wurtzite-structure semiconductive InN is predicted using empirical nearest-neighbor tight-binding theory. The tight-binding parameters are extrapolated from those of zincblende InP, InAs, and InSb by using empirical rules for the dependences of the parameters on bond length and on row of the Periodic Table. The predicted band gap is direct and agrees well with the data for this potential orange light-emitter. It is suggested that zincblende InN, if it can be grown, also will have a band-gap near 2 eV.

Predictions of the energy band gaps as functions of alloy composition are given for the Greene alloys, which are metastable, crystalline, substitutional alloys of III-V compounds and group-IV elemental materials. All possible combinations of these alloys involving Al, Ga, In, P, As, Sb, Si, Ge, and Sn are considered. The \ensuremath{\Gamma} and L conduction-band minima, relative to the valence-band maxima, exhibit characteristic V-shaped bowing and kinks as functions of composition x; the band edges at point X bifurcate at critical compositions corresponding to the order-disorder transition of Newman et al. The V-shaped bowing due to the transition offers the possibility of band gaps significantly smaller than expected on the basis of the conventional virtual-crystal approximation. Alloys with modest lattice mismatches that are predicted to have especially interesting band gaps include (InP${)}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$${\mathrm{Ge}}_{2\mathrm{x}}$, (AlSb${)}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$${\mathrm{Sn}}_{2\mathrm{x}}$, (GaSb${)}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$${\mathrm{Sn}}_{2\mathrm{x}}$, and (InAs${)}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$${\mathrm{Sn}}_{2\mathrm{x}}$, which are alloys with potentially small band gaps, and (AlAs${)}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$${\mathrm{Ge}}_{2\mathrm{x}}$ and (GaAs${)}_{1\mathrm{\ensuremath{-}}\mathrm{x}}$${\mathrm{Si}}_{2\mathrm{x}}$, which are alloys with larger gaps and several interesting band-edge crossings as functions of composition.

The energy-band structure of InN is predicted using the pseudofunction method (a first-principles, self-consistent local-density scheme). Some significant differences exist between this electronic structure and extrapolated empirical tight-binding theory for InN.

We report theoretical calculations of deep levels in GaAs/AlxGa1−xAs superlattices under hydrostatic pressure. We predict phase diagrams for DX centers: for a given composition x there is a function p(a), which relates pressure p and GaAs quantum-well width a, and defines a phase boundary between two regions: one in which DX is a deep trap in the fundamental band gap and another in which the DX deep level lies in the conduction band.

Based on the idea of a zincblende‐diamond structural phase transition, we predict that metastable, crystalline, substitutional alloys of (InP)1−xGe2x should exhibit significantly smaller fundamental band gaps than has been expected for random alloys of InP and Ge, and hence may be candidates for materials with gaps ≂10 μm.

Corrosive burns of the stomach often go undetected until serious, life-threatening complications occur. Early diagnosis and prompt surgical intervention may avoid these complications. Gastroscopic diagnosis of a lye burn of the stomach led to early and curative surgery in the case herein reported. In selected cases, gastroscopy appears to be a useful tool and may either establish the need for surgery or avoid a diagnostic laparotomy in suspected gastric injury.