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International journal of molecular sciences 2020 Oct 23
Authors:
Shnaider PV
Abstract
The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.
PMID:
33114182
[PubMed - as supplied by publisher]
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Authors:
Simon KC, Tideman S, Hillman L, Lai R, Jathar R, Ji Y, Bergman-Bock S, Castle J, Franada T, Freedom T, Marcus R, Mark A, Meyers S, Rubin S, Semenov I, Yucus C, Pham A, Garduno L, Szela M, Frigerio R, Maraganore DM
Abstract
To demonstrate the feasibility of pragmatic clinical trials comparing the effectiveness of treatments using the electronic medical record (EMR) and an adaptive assignment design.
We have designed and are implementing pragmatic trials at the point-of-care using custom-designed structured clinical documentation support and clinical decision support tools within our physician's typical EMR workflow. We are applying a subgroup based adaptive design (SUBA) that enriches treatment assignments based on baseline characteristics and prior outcomes. SUBA uses information from a randomization phase (phase 1, equal randomization, 120 patients), to adaptively assign treatments to the remaining participants (at least 300 additional patients total) based on a Bayesian hierarchical model. Enrollment in phase 1 is underway in our neurology clinical practices for 2 separate trials using this method, for migraine and mild cognitive impairment (MCI).
We are successfully collecting structured data, in the context of the providers' clinical workflow, necessary to conduct our trials. We are currently enrolling patients in 2 point-of-care trials of non-inferior treatments. As of March 1, 2018, we have enrolled 36% of eligible patients into our migraine study and 63% of eligible patients into our MCI study. Enrollment is ongoing and validation of outcomes has begun.
This proof of concept article demonstrates the feasibility of conducting pragmatic trials using the EMR and an adaptive design.
The demonstration of successful pragmatic clinical trials based on a customized EMR and adaptive design is an important next step in achieving personalized medicine and provides a framework for future studies of comparative effectiveness.
PMID:
30386852
[PubMed - as supplied by publisher]
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Authors:
Meyers S, Claire Simon K, Bergman-Bock S, Campanella F, Marcus R, Mark A, Freedom T, Rubin S, Semenov I, Lai R, Hillman L, Tideman S, Pham A, Frigerio R, Maraganore DM
Abstract
To use the electronic medical record (EMR) to optimize patient care, facilitate documentation, and support quality improvement and practice-based research, in a headache specialty clinic.
Many physicians enter data into the EMR as unstructured free text and not as discrete data. This makes it challenging to use data for quality improvement or research initiatives.
We describe the process of building a customized structured clinical documentation support toolkit, specific for patients seen in a headache specialty clinic. The content was developed through frequent physician meetings to reach consensus on elements that define clinical Best Practices. Tasks were assigned to the care team and data mapped to the progress note.
The toolkit collects hundreds of fields of discrete, standardized data. Auto scored and interpreted score tests include the Generalized Anxiety Disorder 7-item, Center for Epidemiology Studies Depression Scale, Migraine Disability Assessment questionnaire, Insomnia Sleep Index, and Migraine-Specific Quality of Life. We have developed Best Practice Advisories (BPA) and other clinical documentation support tools that alert physicians, when appropriate. As of April 1, 2018, we have used the toolkits at 4346 initial patient visits. We provide screenshots of our toolkits, details of data fields collected, and diagnoses of patients at the initial visit.
The EMR can be used to effectively structure and standardize headache clinic visits for quality improvement and practice-based research. We are sharing our proprietary toolkit with other clinics as part of the Neurology Practice-Based Research Network. These tools are also facilitating clinical research enrollment and a pragmatic trial of comparative effectiveness at the point-of-care among migraine patients.
PMID:
30066412
[PubMed - as supplied by publisher]
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Disease-a-month : DM 2015 Jun
Authors:
Semenov IA
PMID:
25911064
[PubMed - as supplied by publisher]
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Disease-a-month : DM 2015 Jun
Authors:
Semenov IA
PMID:
25911063
[PubMed - as supplied by publisher]
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Disease-a-month : DM 2015 Jun
Authors:
Semenov IA
Abstract
TTH are very common in general population and may be under diagnosed. They are more common in patients suffering from migraine headaches. In general underlying psychiatric conditions, such as anxiety and depression, are prevalent in TTH sufferers. For acute therapy NSAIDs are the main treatment option. Tricyclic antidepressant, SSRI, and cognitive behavioral therapy have been proven to be effective for prophylactic purposes.
PMID:
25882693
[PubMed - as supplied by publisher]
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Authors:
Borsody M, Semenov I, Carroll K, Kessler A, Dubow J, Olson E, Stern J, Barion A, Hammond C, Van Stavern G, Raizer J, White R, Leenen F
Abstract
To determine the relationship between levels of ouabain-like compounds (OLC) in the cerebrospinal fluid (CSF) and the occurence of idiopathic intracranial hypertension (IIH).
OLC are naturally occurring inhibitors of the sodium-potassium ATPase that are found in the CSF of mammals. Since the production of CSF is dependent upon sodium-potassium ATPase activity, and since there is evidence that the increased intracranial pressure found in the condition of IIH may be the result of increased CSF production, we hypothesized that the level of endogenous OLC would be reduced in the CSF of patients with IIH.
CSF samples were obtained from n = 7 patients with IIH and n = 31 patients with neurological disorders other than IIH ("control" patients) who had lumbar puncture as part of their routine evaluation or treatment. The concentration of OLC in the CSF samples was measured using an established ELISA.
Patients with IIH exhibited a concentration of OLC in the CSF of 0.11 +/- 0.03 ng/mL. In comparison, the concentration of OLC in CSF samples from non-IIH control patients was 0.12 +/- 0.01 ng/mL. These values were not statistically different when compared with a t-test (P= 0.31). However, the concentration of OLC did negatively correlate to the opening pressure on lumbar puncture, but only in the IIH group (r=-0.80, P= .03). Furthermore, IIH patients who were newly diagnosed or who were unsuccessfully treated (n = 5 of 7 IIH patients) exhibited OLC concentrations of 0.06 +/- 0.1 ng/mL, which is nearly lower than that of the control group (P= .06).
The average concentration of OLC in IIH patients (treated and untreated) is unlikely to be distinguishable from that in non-IIH control patients with other neurological conditions. However, the concentration of OLC may be inversely related to the intracranial pressure in patients with IIH, and it may prove to be lower in the subgroup of untreated and unsuccessfully treated IIH patients.
PMID:
16942469
[PubMed - as supplied by publisher]
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Journal of the neurological sciences 2005 Jul 15
Authors:
Bhangoo S, Chua R, Hammond C, Kimmel Z, Semenov I, Videnovic A, Kessler J, Borsody M
Abstract
Limited evidence suggests that focal neurological injury (e.g., acute flaccid paralysis) caused by infection with the West Nile virus (WNV) is more common in older patients. We re-evaluate this association in a series of patients who were infected with the WNV during the 2002 epidemic.
We performed a retrospective chart review of 34 patients who were hospitalized for treatment of serologically confirmed WNV infection. Measurements included the patient's demographic characteristics, baseline medical diagnoses, the occurrence of symptoms and exam findings, the results of various diagnostic tests, and the patient's clinical outcome.
Patients infected with the WNV who developed focal neurological injury were found to be comparable to patients who did not develop focal neurological injury both in terms of patient age and the number of medical conditions the patient had prior to infection. This is in contrast to WNV-infected patients who developed an encephalitis-like clinical course, or who died or were institutionalized after their hospitalization; such patients tended to be older and-in cases with a poor outcome-have more medical conditions prior to WNV infection.
In our patient group, focal neurological injury caused by WNV infection was not related to advanced patient age or to the number of medical conditions the patient had prior to infection. Our findings bring into question commonly held views about the development of focal neurological injury caused by WNV infection, and they raise concerns about the management of future WNV epidemics and the testing and use of potential antiviral treatments against this infection.
PMID:
15958267
[PubMed - as supplied by publisher]