Extraordinary Response Research Articles

Whole exome sequencing (WES) in HER2+ metastatic breast cancer (MBC) patients (pts) with extraordinary responses to trastuzumab (T).

611 Background: While 50-70% of pts with HER2+ MBC treated with T respond to therapy, the vast majority eventually develop resistance, after a median duration of 1 year. In rare cases, pts have exc...

Tunable near-infrared plasmonic perfect absorber based on phase-change materials

A tunable plasmonic perfect absorber with a tuning range of similar to 650 nm is realized by introducing a 20 nm thick phase-change material Ge2Sb2Te5 layer into the metal-dielectric-metal configuration. The absorption at the plasmonic resonance is kept above 0.96 across the whole tuning range. In this work we study this extraordinary optical response numerically and reveal the geometric conditions which support this phenomenon. This work shows a promising route to achieve tunable plasmonic devices for multi-band optical modulation, communication, and thermal imaging. (C) 2015 Chinese Laser Press

N of 1 case reports of exceptional responders accrued from pancreatic cancer patients enrolled in first-in-man studies from 2002 through 2012.

To identify exceptional responders among patients with advanced pancreatic cancer enrolled in first-in-man (FIM) studies. A Scopus search identified 66 FIM studies that enrolled at least one patient with advanced pancreatic cancer between 2002-2012. Descriptive statistics were used to summarize categorical variables. We also screened CRKL amplifications in the FoundationOne™ pancreatic cancer database. Most FIM studies included targeted therapies (76 vs. 24%). The most common targeted therapy involved cell cycle inhibitors (24%). Pharmacodynamic analyses were more frequently done in trials with targeted therapies (70 vs. 31%, p=0.006). Response rates were similar. Treatment-related death was 0.5%. Skin, cardiovascular and metabolic grade 3-4 toxicities were more frequent with targeted therapies. Four exceptional responses were identified including a complete response to bosutinib (Src Inhibitor) and partial responses to trametinib (MEK inhibitor) (2 patients) and CHR-3996 (histone deacetylase inhibitor). We found that CRKL amplifications, a potential biomarker for Src inhibitors, are present in 1% of PDA. We retrospectively identified extraordinary responses among patients with advanced PDA enrolled in FIM studies with Src, HDAC and MEK inhibitors. We identified CRKL amplifications are present in 1% of PDA and need to be evaluated as predictive biomarker for Src inhibitors.

Co-Movement Puzzle and the Overlapping Roles of Consumer Durables and Capital

This paper develops an alternative new Keynesian dynamic stochastic general equilibrium model that assumes, as a new feature, overlapping roles for capital and consumer durables. The model is able to generate co-movement responses of durable spending and non-durable spending to monetary policy shocks, consistently with the empirical evidence. Additionally, in contrast with the standard theory that finds a counter-factual extraordinary sensitive responses of consumer durables and capital to monetary policy shocks, the model yields responses more in tune with actual observation.

Investigation of ion induced damage in KBr, YAG:Ce, CaF2:Eu and CsI:Tl irradiated by various-energy protons

New experimental results on the scintillation processes for KBr, YAG:Ce, CaF2:Eu and CsI:Tl crystals under H2+ irradiation for the energy range of 600-2150 keV/u are systematically reported. The scintillation light yield was measured as a function of accumulated particle fluence at the rare isotope ReAccelerator (ReA) facility of the National Superconducting Cyclotron Laboratory (NSCL). The data indicates that YAG:Ce and CsI:Tl can maintain stable luminescence under continuous ion bombardment for at least a total fluence of 1.8×1012 ions/mm2 in the energy range used for this experiment. On the other hand, the luminescence of CaF2:Eu shows a rapid initial decay but then maintains a nearly constant luminescence yield. The extraordinary scintillation response of KBr is initially enhanced under ion bombardment, approaches a maximum, and then eventually decays. The scintillation efficiency of the CsI:Tl scintillator is superior to the other materials. The stability of the measured beam profile width deducted from the different scintillator materials in static beam conditions was also investigated as a function of irradiation time. We observed that the low-energy H2+ bombardment (25 keV/u) on the YAG:Ce scintillator can lead to the significant degradation of the scintillation yields. Different scintillation degradation responses for the low- and high-energy bombardments can be attributed to the transmission loss of the emitted light inside the crystal caused by displacement damages.

Management of mass casualty in Rana Plaza tragedy, the worst industrial disaster in Bangladesh

Introduction: On April 24, 2013, Rana Plaza, an 8 storied building accommodating 5 garment factories, a bank, a number of commercial shops and offices collapsed at Savar, Dhaka, Bangladesh, while more than 4 thousand people were working inside. A massive rescue operation was carried out in following 21 days by the Government of Bangladesh involving all of her associated organs with a key role played by the Armed Forces. A total of 2438 injured victims were rescued between 24 Apr 2013 and 10 May 2013 including a female garment worker who was rescued after 17 days of the building collapse. The death toll finally reached to 1132 including 2 rescue workers. This unprecedented disaster was mitigated by extraordinary responses from almost all the organs of government and also from non-government bodies. All available medical resources were utilized for immediate, short term and long term management of the injured victims. Objective: This study is aimed to find out the pattern of injuries in the victims of this catastrophe and also the management of mass casualty in Rana Plaza tragedy which occurred due to the multistoried commercial building collapse. Methods: This observational study was conducted on pre-hospital, in-hospital and post-hospital management of the victims of the disaster. Each of the injured individuals was tracked for a period of more than 3 months. Data were collected from interviews, observation and by studying the records of field medical units, secondary and tertiary hospitals and rehabilitation centres. Results: This was the deadliest garments factory accident in the history causing 1132 deaths and 2438 injured cases. The rescue operation was carried out upto 14 May 2013. Removal of the whole collapsed building rubbles took 21 days and 1127 dead bodies had been recovered. Two rescuers died during rescue operation. Out of 2438 casualties 407 were brought to SMH Savar, 28 victims of serious injury were evacuated to CMH Dhaka where only one patient died. One thousand and seven hundred casualties were taken to Enam Medical College and Hospital, Savar and 105 patients were taken to National Institute of Traumatology and Rehabilitation (NITOR). Two hundred and twenty six patients received management in the other private clinics. Out of 2438 patients, 951 received prolonged hospital treatment of which blunt trauma was found in 225(23.66%) cases, soft tissue injuries in 149(15.67%) cases, fractures in 137(14.41%) cases, crush syndrome in 46(4.84%), head injuries in 40(4.20%), limb loss in 33(3.47%) and other non lethal injuries were observed in 321(33.75) cases. Three patients expired during treatment due to complications like acute renal failure, ARDS and complication of head injury. Up to 26 Jul 2013, 36 cases were found disabled to sequelae of head injury, spinal injury, fracture of long bones of limbs and injury of peripheral nerves. Among the patients of mass casualty commonest complication or presentation was acute stress reaction in 44.92 percent of patients. Conclusion: Management of mass casualty in this building collapse provides us with a valuable experience which may be utilized in dealing with similar disasters that might take place in any densely populated city in an earthquake prone country like Bangladesh. DOI: http://dx.doi.org/10.3329/jafmc.v9i2.21819 Journal of Armed Forces Medical College Bangladesh Vol.9(2) 2013

MTOR Inhibitors in Cancer: What Can We Learn from Exceptional Responses?

mTOR Inhibitors in Cancer: What Can We Learn from Exceptional Responses?

An Integrated Chronic Disease Management Model- A diagonal approach to health system strengthening

South Africa is facing a complex burden of disease arising from a combination of rapidly growing chronic infectious illness (driven by HIV/AIDS) and non-communicable diseases (NCDs). The extent of this burden has few global parallels and demands an extraordinary response (1). A recent publication of a multi-centre prospective cross-sectional survey of consultations in primary care in four provinces of South Africa: Western Cape, Limpopo, Northern Cape and North West indicated that Hypertension, HIV/AIDS, Type 2 Diabetes and Tuberculosis (TB) were the most common conditions in terms of chronic care visits (2) The unprecedented roll out of antiretroviral treatment (ART) has transformed HIV / AIDS into a chronic disease, as people with HIV are living longer andageing, and are developing non-HIVrelated chronic conditions similar to the rest of the population. Some NCDs are related to HIV infection itself and to the side effects of some of the medicines used to treat HIV infection (3). Providing affordable and effective care to the often large and increasing numbers of people is already an immense challenge but as the burden of chronic diseases both (communicable and NCDs) increases, this will become an even bigger problem requiring a different and innovative approach. Whilst chronic disease management of NCDS and mental health within primary care is and has been provided in primary care for many years, in many instances the health system has put greater emphasis on the relief of acute symptoms to the detriment of prevention and optimal care of chronic conditions. Moreover chronic disease services are primarily run as disease specific entities and hence programmes treat specific diseases rather than the whole person. Where an individual has more than one condition they often need to attend on different days of the week and be seen by a different practitioner with consequences not only for patient care but costs to patient in terms of time and transport. The successful management of chronic diseases requires coordination of services for individuals over an extended time period and across disciplines and is dependent on a strong health system and innovative, robustly supported service delivery models that promote patient empowerment (4). Leveraging on the innovations of the HIV program and utilising South Africa’s recently adopted policy for re-engineering primary health care an integrated chronic disease management (ICDM) World Congress on Integrated Care 2014, Sydney, November 23-26, 2014. International Journal of Integrated Care – Volume 14, 8 December – URN:NBN:NL:UI:10-1-116681– http://www.ijic.org/ model, based on the WHO health system building blocks was proposed as a vehicle to improve the management of chronic conditions. The aim of the ICDM is to achieve optimal clinical outcomes for patients with chronic communicable and non-communicable diseases in order to respond to the growing burden in an efficient and cost effective manner (5). The ICDM is designed using a Public Health approach to empower the individual to take responsibility for their own health whilst simultaneously intervening at a community/population and health service level. The model was developed through a combination of initial theoretical and academic considerations over a two year period. The ICDM consists of four inter-related phases that are dependent on overarching strong stewardship and ownership at all levels of the health system l The four inter-related phases include: • Facility re-organisation to improve service efficiency. • Clinical supportive management to improve quality of clinical care. • “Assisted “self-support and management of patients through the ward based outreach teams (WBOT) to empower individuals to take responsibility for managing their own conditions and increasing awareness of chronic diseases at the population level • Strengthening of support systems and structures outside the facility to ensure a fully functional and responsive health system. Achieving an integrated chronic care disease management model requires a new way of thinking and acting. It is imperative that this model is piloted at a limited number of sites to assess the feasibility and sustainability whilst simultaneously evaluating the outcomes of chronic patients managed within the model. The lessons gained from the pilot sites can be used to further develop the model and scale up the implementation to saturate all districts in the country.

From Plato to Erikson: How the war on ‘bad play’ has impoverished higher education

For centuries, the titans of educational reform—Plato, Rousseau, Dewey, Piaget, Erikson, Csikszentmihalyi and others—have championed the educational benefits of play. Yet many professors and administrators are boggled by the idea of playing academic games in college. They instantly dismiss faculty initiatives like ‘Reacting to the Past’, where students play complex role-playing games set in the past, their roles informed by classic texts. This article maintains that skepticism towards such forms of play derives from the ideas of the chief proponents of educational play: their endorsement of play has also included a powerful denunciation of competitive role-playing games. This centuries-old philosophical predisposition against such modes of play has impeded pedagogical innovation at the college level. That such games can revitalize higher education is demonstrated by the extraordinary response at the over 350 colleges and universities where faculty have adopted ‘Reacting’ during the past decade.

Exceptional Responders: The “N of 1” Paradigm

Clinical OMICsVol. 1, No. 13 Exceptional Responders: The “N of 1” ParadigmHope for Better Cancer Treatments May Lie in Those Patients Who Respond Exceptionally WellPatricia Fitzpatrick DimondPatricia Fitzpatrick DimondPATRICIA FITZPATRICK DIMOND, Ph.D. has been a long-time contributor to GEN and currently serves as the publication's Technical Editor. She is also president of BioInsight Communications. During her career in the biotechnology industry, she was VP of strategic development and corporate communications at Coley Pharmaceutical Group (now Pfizer), where she developed and managed the company's investor relations and communications programs. (E-mail Address: pdimond@liebertpub.com)Search for more papers by this authorPublished Online:25 Nov 2015https://doi.org/10.1089/clinomi.01.13.05AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited bySLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma22 April 2015 | Oncotarget, Vol. 6, No. 18 Volume 1Issue 13Nov 2014 InformationCopyright © GEN PublishingTo cite this article:Patricia Fitzpatrick Dimond.Exceptional Responders: The “N of 1” Paradigm.Clinical OMICs.Nov 2014.6-8, 20.http://doi.org/10.1089/clinomi.01.13.05Published in Volume: 1 Issue 13: November 25, 2015PDF download

Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.

Engineered photoelectrochemical platform for rational global antioxidant capacity evaluation based on ultrasensitive sulfonated graphene-TiO2 nanohybrid.

Dietary antioxidants as health promoters for human beings have attracted much attention and triggered tremendous efforts in evaluation of the antioxidant capacity. Unfortunately, no versatile detection system has been designed to date. Due to the possible synergistic effect among antioxidant components in a diversified system, to isolate and quantify an individual antioxidant via a chromatography approach limits the scope for global antioxidant activity assay. Quality inspections with a spectroscopy strategy to any colored food are far from satisfactory. Herein, a photoelectrochemical (PEC) platform with an ultrasensitive titanium dioxide decorated sulfonated graphene (SGE-TiO2) based transducer was introduced for antioxidant monitoring. Under an open circuit potential (zero potential), with extraordinary response, excellent reproducibility and stability, this PEC sensor could be successfully applied for rational analysis of the global antioxidant capacity. Such a highly efficient strategy showed advantages such as simplicity, convenience, high sensitivity and universality, which were also applicable to the detection of colored system. Moreover, the PEC sensor could be employed for practical evaluation of antioxidant capacity of teas. The concerned mechanism was further proposed and adequately discussed. This straightforward yet powerful approach provides a general format for dietary antioxidant assessment in foodstuff industries.

The Conflict of Love and Islam: The Main Ingredients in the Popular Islamic Novels of Malaysia

This study arises from a recent development in Malaysia – the emergence of what is commonly known as the phenomenon of ‘popular Islamic novels’. The phenomenon is characterized by overwhelmingly positive public reception of novels overtly displaying Islamic external features in their titles, covers and blurbs. The development is particularly interesting because the novels that previously dominated the general literary market in Malaysia were teenage romance novels with erotic nuances. Thus there has been a marked shift in the popular literary tastes of the public. This shift invites a number of questions: are the stories in the popular Islamic novels of Malaysia actually Islamic, as suggested by their external features? If so, just how is Islam represented in these novels? And in relation to that question, what narrative strategies have the writers of these novels employed to garner such an extraordinary response from the public? To answer these questions, the present study analyses two popular Islamic novels, Salju Sakinah by Zaid Akhtar and Hidayah Cinta by Ilham Hamdani. The aim of the analysis is to identify the representations of Islam contained within these books, and subsequently to summarize the narrative strategies in both novels. The author finds that romantic conflicts are the overriding theme in the two novels, with Islam being employed as the moral scheme according to which these romantic conflicts are evaluated. It is also noted that romantic conflicts and Islam are the two main ingredients that are exploited as narrative strategies to appeal to the popular literary tastes of the Malaysian reading public.

The extraordinary magnetoelectric response in silicene doped with Fe and Cr atoms

We have investigated the magnetic properties of the silicene doped with Fe and Cr metal atoms under external electric field by the first-principles calculations. We find that the doped systems show a variety of interesting magnetoelectric (ME) behaviors: (1) The magnetic moment of Fe doped silicene show a sharp jump at a threshold electric field, which indicates a good switching effect; (2) For the low concentrations of Fe or Cr doped silicene, there are two structures in which the changes of magnetism are significantly different under external electric field; (3) The magnetic moment of the doped systems has a nearly linear region with the electric field. We find that the changes of magnetic moment strongly depend on the direction of the electric field. In particular, one structure of Fe doped silicene shows an interesting ME response which can be considered as a magnetoelectric diode. With the electric field, the good controllability and sharp switching of the magnetism may offer a potential applications in the ME devices.

Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib

Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or "personalized") medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.

Extraordinary Dynamic Mechanical Response of Vanadium Dioxide Nanowires around the Insulator to Metal Phase Transition

Nanomechanical resonators provide a compelling platform to investigate and exploit phase transitions coupled to mechanical degrees of freedom because resonator frequencies and quality factors are exquisitely sensitive to changes in state, particularly for discontinuous changes accompanying a first-order phase transition. Correlated scanning fiber-optic interferometry and dual-beam Raman spectroscopy were used to investigate mechanical fluctuations of vanadium dioxide (VO2) nanowires across the first order insulator to metal transition. Unusually large and controllable changes in resonator frequency were observed due to the influences of domain wall motion and anomalous phonon softening on the effective modulus. In addition, extraordinary static and dynamic displacements were generated by local strain gradients, suggesting new classes of sensors and nanoelectromechanical devices with programmable discrete outputs as a function of continuous inputs.

Unusual Response to Bromocriptine of a Giant Pituitary Adenoma and Fertility Restoration: a Record of a Pregnancy

A 23-year-old woman presented to clinic with a large pituitary adenoma and coexisting hyperprolactinaemia. Diagnoses, initially considered, included two possibilities: prolactinoma or nonfunctioning tumour with a pituitary stalk disconnection. Diagnosis of prolactinoma was considered as the first possibility. Therefore, a trial with the dopamine agonist Bromocriptine was decided. Serum prolactin levels decreased and significant tumour shrinkage was obtained. Bromocriptine was discontinued when the patient became pregnant. Surprisingly, tumour enlargement did not occur. The residual adenoma remained stable for six years after delivery. Surgical intervention was neither needed during pregnancy nor after a long follow-up period. This clinical presentation was consistent with a final diagnosis of nonfunctioning pituitary macroadenoma with an extraordinary response to Bromocriptine treatment.

Disaster and Strategy to Respond

According to WHO, any occurrence, that causes damage, ecological disruption, loss of human life, deterioration of health and health services, on a scale sufficient to warrant an extraordinary response from outside the affected community or area can be defined as disaster. Any organization or business can experience the effect of disaster in some way or other, so it is recommended to be prepared for its effects and consequences in all the possible ways.

Growth and Yield Response of Mungbean (Vigna radiata L. Wilczek) Genotypes to Wet Puddling, Flooding and Saturated Soil Culture

Anoxia and hypoxia, caused by excessive rainfall and inadequate drainage are the most common environmental stresses in upland crops after wetland rice in many regions of Asia. Such stresses and/or puddling of soil in rice culture often reduce the growth and yield of post-rice upland crops. This study examined the growth and yield responses of three mungbean genotypes viz. VC3950-88, VC6173A and BARI Mung-5 to three different environmental stresses viz. wet puddling, soil flooding and saturated soil culture. Wet puddling significantly reduced the field emergence and vigor index of seedlings. Height of plants was also adversely affected due to the stresses, although recovery was comparatively better in flooded situation. Irrespective of growing conditions, leaf chlorophyll index reduced significantly and recovered almost completely. The extraordinary responses of plants to all the stresses were the damaging of roots and/or impairing of root and shoot growth. The subsequent recovery of root and shoot growth significantly varied depending on the types of stresses. The development of numerous adventitious roots and the production of greater amount of root nodules were the most important recovery mechanisms of plants to withstand flooding situation and saturated soil culture, respectively. As a result, seed production was less affected under these two conditions. In contrast, wet puddling situation performed the worst, showing depressed plant growth throughout the growing period and thus seed production was affected the most. Among the genotypes, VC6173A was best adapted under the three stresses, giving the highest seed yield by producing higher amount of pods, increased seed size and longer pod.

The Law of Deliberative Democracy: Seeding the Field

Two basic expectations of public governance appear to lie in sharp tension. One is that public decision making should involve democratic participation by citizens, through voting or other means. The other is that decision making should be deliberative—for example, informed, cooperative, reflective, and capable of issuing sound policy and law. Classically, governance was understood as either democratic or deliberative, but seldom both at once. Observers from Aristotle to Mill noted this deliberative tension.1 Yet in recent decades it has seemed to grow more acute. Runaway policy complexity—in economics, the environment, international affairs, etc.—coexists uneasily with the global rise of direct lay-citizen input into lawmaking.2 Moreover, timeworn models of representative government, beset by polarization and other problems, often fail to meet the deliberative demands of contemporary lawmaking. One extraordinary response to the deliberative tension has been a partial reorientation of political theory over two decades or more. In that time, the burgeoning literature of deliberative democracy has solidified a number of central questions and propositions. A particular concern in the field is whether the tension is to some extent illusory, and whether in fact particular governance models can sometimes robustly encourage democratic participation and deliberation at once.3 Some authors in the field's sizeable normative strand of research even stress that only governance able to achieve this goal qualifies as legitimate.4 To be sure, the task of accommodating both deliberation and democracy is profoundly vexed. Yet to many deliberativists, the status quo in governance is more problematic still, and perhaps even untenable. For instance, the deliberative tension is one likely cause of the long crisis of legitimacy afflicting developed democracies since the 1960s, reflected in largely unbroken trends of declining public trust.5 Unable or unwilling to meet both deliberative and democratic demands, a government's perceived legitimacy may weaken—along with its capacity to respond to pressing challenges facing the polity.