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OALib Journal期刊

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C-MET Inhibitors as New Members of the NSCLC Treatment Armamentarium—A Pooled Analysis  [PDF]
Susanne Reuther, Niccolo Bassani, Michael F. Murphy, Wolfram Dempke
Advances in Lung Cancer (ALC) , 2022, DOI: 10.4236/alc.2022.111001
Abstract: Objective: Capmatinib and tepotinib, two recently FDA-approved and highly specific small-molecule inhibitors of c-MET exon 14 skipping mutations are new and important therapeutic options for the treatment of NSCLC patients harbouring c-MET alterations. However, the precise role of these molecules as a new treatment option is still not fully defined. Methods: In an attempt to further evaluate the contributions of c-MET inhibitors to the armamentarium of treatment options for advanced and metastatic NSCLCs, relevant phase II and III studies were retrospectively analyzed in terms of ORR and mPFS (mOS numbers are still not available for current c-MET trials and therefore not considered for statistical purposes). Results: Treatment of advanced and metastatic NSCLC patients harbouring c-MET exon 14 skipping mutations with the novel and highly selective c-MET inhibitors is significantly superior (p < 0.0001) when compared with standard chemotherapy. However, when c-MET inhibitors are compared with immunotherapy or the combination of immunotherapy and chemotherapy, no significant differences in terms of ORR and PFS were found, but treatment with c-MET reported be much more tolerable. Conclusion: The novel and highly selective c-MET inhibitors capmatinib and tepotinib are promising novel treatment options for patients with c-MET-dysregulated NSCLC primarily in the first-line setting, albeit a clear mOS benefit has not yet been established. Since immunotherapy did not appear to be particularly effective in NSCLC patients harbouring c-MET alterations, the vast majority of these patients are treated with immunotherapy plus chemotherapy. C-Met inhibitors appear to be equally effective and thereby sparing patients from the toxic effects of the chemotherapy. The routine testing of c-MET exon 14 skipping mutations should be performed as the GEOMETRY mono-1 data clearly showed higher response rates with capmatinib in treatment-naive than in pretreated patients, indicating that c-MET exon 14 skipping mutations should preferably be molecularly assessed at baseline. C-MET exon 14 skipping mutations are, therefore, clear biomarkers of response to c-MET inhibitors.
Wunderlich Syndrome as the First Manifestation of Renal Cell Carcinoma
Sheng F Oon,Michael Murphy,Stephen S Connolly
Urology Journal , 2010,
Abstract:
Surface-layer protein from Caulobacter crescentus: expression, purification and X-ray crystallographic analysis
Anson C. K. Chan,John F. Nomellini,John Smit,Michael D. Jones,Michael E. P. Murphy
- , 2016, DOI: 10.1107/S2053230X16011638
Abstract:
Developing a Process Driven Morphological Model for Long Term Evolution of a Dynamic Coastal Embayment  [PDF]
Michael O’Shea, Jimmy Murphy
Open Journal of Marine Science (OJMS) , 2020, DOI: 10.4236/ojms.2020.103007
Abstract: Numerical modelling of coastal morphology is a complex and sometimes unrewarding exercise and often not yielding tangible results. Typically, the underlying drivers of morphology are not properly accounted for in numerical models. Such inaccuracies combined with a paucity of validation data create a difficulty for coastal planners/engineers who are required to interpret such morphological models to develop coastal management strategies. This study develops an approach to long term morphological modelling of a barrier beach system that includes the findings of over 10 years of coastal monitoring on a dynamic coastal system. The novel approach to predicting the long term evolution of the area combines a mix of short term hydrodynamic monitoring and long term morphological modelling to predict future changes in a breached barrier system. A coupled wave, wind, hydrodynamic and sediment transport numerical model was used to predict the coastal evolution in the dynamic barrier beach system of Inner Dingle Bay, Co. Kerry, Ireland. The modelling approach utilizes the schematisation of inputs to reflect observed trends. The approach is subject to two stages of validation both quantitative and qualitative. The study highlights the importance of considering all the parameters responsible for driving coastal evolution and the necessity to have long term monitoring results for trend based validation.
How can chiropractic become a respected mainstream profession? The example of podiatry
Donald R Murphy, Michael J Schneider, David R Seaman, Stephen M Perle, Craig F Nelson
Chiropractic & Manual Therapies , 2008, DOI: 10.1186/1746-1340-16-10
Abstract: To present a perspective on the current state of the chiropractic profession and to make recommendations as to how the profession can look to the podiatric medical profession as a model for how a non-allopathic healthcare profession can establish mainstream integration and cultural authority.There are several key areas in which the podiatric medical profession has succeeded and in which the chiropractic profession has not. The authors contend that it is in these key areas that changes must be made in order for our profession to overcome its shrinking market share and its present low status amongst healthcare professions. These areas include public health, education, identity and professionalism.The chiropractic profession has great promise in terms of its potential contribution to society and the potential for its members to realize the benefits that come from being involved in a mainstream, respected and highly utilized professional group. However, there are several changes that must be made within the profession if it is going to fulfill this promise. Several lessons can be learned from the podiatric medical profession in this effort.The chiropractic profession has been in existence for over 110 years. In that time it has overcome a variety of hardships and adversities, including practitioners being jailed for practicing medicine without a license, attempts by the American Medical Association to contain and eliminate the profession, and general ostracism by many within and outside health care [1]. It has made some remarkable advances in recent years including substantial Federal funding of chiropractic research by the National Institutes of Health and the inclusion of chiropractic physicians in the Veterans Administration healthcare system. However, in spite of this, the profession has not gained a level credibility and cultural authority in mainstream society that is required to establish itself on equal ground with other healthcare professions. The profession st
CD8 T Cell Memory to a Viral Pathogen Requires Trans Cosignaling between HVEM and BTLA
Rachel Flynn, Tarun Hutchinson, Kenneth M. Murphy, Carl F. Ware, Michael Croft, Shahram Salek-Ardakani
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077991
Abstract: Defining the molecular interactions required to program activated CD8 T cells to survive and become memory cells may allow us to understand how to augment anti-viral immunity. HVEM (herpes virus entry mediator) is a member of the tumor necrosis factor receptor (TNFR) family that interacts with ligands in the TNF family, LIGHT and Lymphotoxin-α, and in the Ig family, B and T lymphocyte attenuator (BTLA) and CD160. The Ig family members initiate inhibitory signaling when engaged with HVEM, but may also activate survival gene expression. Using a model of vaccinia virus infection, we made the unexpected finding that deficiency in HVEM or BTLA profoundly impaired effector CD8 T cell survival and development of protective immune memory. Mixed adoptive transfer experiments indicated that BTLA expressed in CD8α+ dendritic cells functions as a trans-activating ligand that delivers positive co-signals through HVEM expressed in T cells. Our data demonstrate a critical role of HVEM-BTLA bidirectional cosignaling system in antiviral defenses by driving the differentiation of memory CD8 T cells.
The Magellan Uniform Survey of Damped Lyman alpha Systems II: Paucity of Strong Molecular Hydrogen Absorption
Regina A. Jorgenson,Michael T. Murphy,Rodger Thompson,Robert F. Carswell
Physics , 2014, DOI: 10.1093/mnras/stu1314
Abstract: We present the first large, blind and uniformly selected survey for molecular hydrogen (H_2) in damped Lyman alpha systems (DLAs) with moderate-to-high resolution spectra. 86 DLAs were searched for absorption in the many Lyman and Werner H_2 transitions, with approximately 79% completeness for H_2 column densities above N(H_2)=10^17.5 cm^-2 for an assumed Doppler broadening parameter b=2 km s^-1. Only a single strong H_2 absorber was found -- a system detected previously in VLT/UVES spectra. Given our distribution of N(H_2) upper limits, this ~1% detection rate is smaller than expected from previous surveys at 99.8% confidence. Assuming the N(H_2) distribution shape from previous surveys, our detection rate implies a covering factor of ~1% for N(H_2) >= 10^17.5 cm^-2 gas in DLAs (<6% at 95% confidence). We obtained new Magellan/MagE spectra for 53 DLAs; 8 km s^-1 -resolution spectra were available for 27 DLAs. MagE's moderate resolution (~71 km s^-1) yields weaker N(H_2) upper limits and makes them dependent on the assumed Doppler parameter. For example, half the (relevant) previous H_2 detections have N(H_2) >= 10^18.1 cm^-2, a factor of just 3 higher than our median upper limit. Nevertheless, several tests suggest our upper limits are accurate, and they would need to be increased by 1.8 dex to bring our detection rate within 95% confidence of previous surveys.
A Digital Photographic Technique for Knee Range of Motion Measurement: Performance in a Total Knee Arthroplasty Clinical Population  [PDF]
Michael Murphy, Julie Hides, Trevor Russell
Open Journal of Orthopedics (OJO) , 2013, DOI: 10.4236/ojo.2013.31002
Abstract: Background: Knee range of motion is an essential outcome measure following total knee arthroplasty and it is important to measure this outcome with a simple and accurate tool. Measurement from digital photographs could provide a superior clinical alternative to the common goniometer as devices for capturing digital photographs are becoming more accessible, measurement accuracy is assisted with the associated software and images can be saved and stored for later reference. This ability to store images with measurements could be particularly useful in research involving knee range of motion. This study evaluated the validity and reliability of a simple photographic measurement technique to measure knee flexion and extension of patients following knee arthroplasty.Methods: Knee flexion and extension of 38 subjects who had undergone total knee arthroplasty were assessed at the one year post-operative review with the digital technique and a universal goniometer as the criterion reference. Digital measurements were repeated one month later by the first assessor (intra-tester reliability) and another independent assessor (inter-tester reliability).Results: Validity: the digital technique was found to have a high level of agreement with the universal goniometer measurements (all MAD < 2.35°). Reliability: small differences were observed in intra and intertester measurements for both flexion and extension with almost perfect Intra-Class Correlations (Intra-tester; flexion 0.99, extension 0.96; inter-tester; flexion 0.97, extension 0.93).Conclusion:
Validating New Technologies to Treat Depression, Pain and the Feeling of Sentient Beings: A Reply to “Neuroscience for the Soul”  [PDF]
Michael A. Persinger, Todd R. Murphy
Neuroscience & Medicine (NM) , 2016, DOI: 10.4236/nm.2016.71004
Abstract: The primary assumption of Neuroscience is that all experiences are strongly correlated with or caused by the specifics of brain structures and their particular dynamics. The profound experiences attributed to the “sensed presence” and their cultural anthropomorphisms such as deities and gods are persistent reports in human populations that are frequently associated with permanent changes in behavior, reduced depression and alleviation of pain. The majority of traditional clinical observations and modern imaging techniques have emphasized the central role of right temporal lobe structures and their directly related networks. The experimental simulation of sensed presences which can result in attributions to spiritual, deity-based or mystical sources within the clinical laboratory by the application of physiologically-patterned magnetic fields across the temporal lobes through our God Helmet requires the same precision of technology that is essential for synthesizing molecular treatments for modifying anomalous behavior, depression and pain. Despite the clinical utility of these simulated conditions within Neuroscience and Medicine, misinformation concerning the bases and efficacy of this new technology persist. Here we present detailed technical clarifications and rebuttals to refute these misconceptions. A Hegelian approach to this delay of development and impedance provides a context through which the ultimate synthesis and application of this technology may be accommodated in the near future.
Spatial variation in the fine-structure constant -- new results from VLT/UVES
Julian A. King,John K. Webb,Michael T. Murphy,Victor V. Flambaum,Robert F. Carswell,Matthew B. Bainbridge,Michael R. Wilczynska,F. Elliot Koch
Physics , 2012, DOI: 10.1111/j.1365-2966.2012.20852.x
Abstract: (abridged) We present a new analysis of a large sample of quasar absorption-line spectra obtained using UVES (the Ultraviolet and Visual Echelle Spectrograph) on the VLT (Very Large Telescope) in Chile. In the VLT sample (154 absorbers), we find evidence that alpha increases with increasing cosmological distance from Earth. However, as previously shown, the Keck sample (141 absorbers) provided evidence for a smaller alpha in the distant absorption clouds. Upon combining the samples an apparent variation of alpha across the sky emerges which is well represented by an angular dipole model pointing in the direction RA=(17.3 +/- 1.0) hr, dec. = (-61 +/- 10) deg, with amplitude (0.97 +0.22/-0.20) x 10^(-5). The dipole model is required at the 4.1 sigma statistical significance level over a simple monopole model where alpha is the same across the sky (but possibly different to the current laboratory value). The data sets reveal a number of remarkable consistencies: various data cuts are consistent and there is consistency in the overlap region of the Keck and VLT samples. Assuming a dipole-only (i.e. no-monopole) model whose amplitude grows proportionally with `lookback-time distance' (r=ct, where t is the lookback time), the amplitude is (1.1 +/- 0.2) x 10^(-6) GLyr^(-1) and the model is significant at the 4.2 sigma confidence level over the null model [Delta alpha]/alpha = 0). We apply robustness checks and demonstrate that the dipole effect does not originate from a small subset of the absorbers or spectra. We present an analysis of systematic effects, and are unable to identify any single systematic effect which can emulate the observed variation in alpha.
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