Author
Pavlos Msaouel
Other affiliations: University of Texas Health Science Center at Houston, National and Kapodistrian University of Athens, Baylor College of Medicine ...read more
Bio: Pavlos Msaouel is an academic researcher from University of Texas MD Anderson Cancer Center. The author has contributed to research in topics: Medicine & Renal cell carcinoma. The author has an hindex of 31, co-authored 159 publications receiving 2648 citations. Previous affiliations of Pavlos Msaouel include University of Texas Health Science Center at Houston & National and Kapodistrian University of Athens.
Topics: Medicine, Renal cell carcinoma, Nivolumab, Cancer, Internal medicine
Papers published on a yearly basis
Papers
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TL;DR: An overview and concise update on the function and regulation of IGF-1 as well as the role it plays in breast malignancies is provided.
Abstract: IGF-1 is a potent mitogen of major importance in the mammary gland. IGF-1 binding to the cognate receptor, IGF-1R, triggers a signaling cascade leading to proliferative and anti-apoptotic events. Although many of the relevant molecular pathways and intracellular cascades remain to be elucidated, a growing body of evidence points to the important role of the IGF-1 system in breast cancer development, progression and metastasis. IGF-1 is a point of convergence for major signaling pathways implicated in breast cancer growth. In this review, we provide an overview and concise update on the function and regulation of IGF-1 as well as the role it plays in breast malignancies.
282 citations
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TL;DR: Initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4 warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadJuvant treatment.
Abstract: Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma1,2, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy2. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%2. Here we report on the first pilot combination neoadjuvant trial (
NCT02812420
) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease3–5. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment. Neoadjuvant combination of immune checkpoint therapy in patients with cisplatin-ineligible bladder cancer achieves clinical efficacy and uncovers immune features as potential predictive biomarkers of treatment response.
152 citations
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TL;DR: Preclinical efficacy and safety data for engineered oncolytic MV-Edm derivatives that led to their clinical translation are discussed, and an overview of the early experience in three ongoing clinical trials of patients with ovarian cancer, glioblastoma multiforme and multiple myeloma is provided.
Abstract: Viruses have adapted through millennia of evolution to effectively invade and lyse cells through diverse mechanisms. Strains of the attenuated measles virus Edmonston (MV-Edm) vaccine lineage can preferentially infect and destroy cancerous cells while sparing the surrounding tissues. This specificity is predominantly due to overexpression of the measles virus receptor CD46 in tumor cells. To facilitate in vivo monitoring of viral gene expression and replication, these oncolytic strains have been engineered to either express soluble marker peptides, such as the human carcinoembryonic antigen (CEA; MV-CEA virus), or genes that facilitate imaging and therapy, such as the human thyroidal sodium iodide symporter (NIS) gene (MV-NIS). Preclinical efficacy and safety data for engineered oncolytic MV-Edm derivatives that led to their clinical translation are discussed in this review, and an overview of the early experience in three ongoing clinical trials of patients with ovarian cancer, glioblastoma multiforme and multiple myeloma is provided. The information obtained from these ongoing trials will guide the future clinical application and further development of MV strains as anticancer agents.
123 citations
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TL;DR: The aim of this study was to determine the relative accuracy of TEE in the detection of PFO.
Abstract: Background
Patent foramen ovale (PFO) is a remnant of the fetal circulation present in 20% of the population Right-to-left shunting (RLS) through a PFO has been linked to the pathophysiology of stroke, migraine with aura, and hypoxemia While different imaging modalities including transcranial Doppler, intra-cardiac echo, and transthoracic echo (TTE) have often been used to detect RLS, transesophageal echo (TEE) bubble study remains the gold standard for diagnosing PFO The aim of this study was to determine the relative accuracy of TEE in the detection of PFO
Methods and Results
A systematic review of Medline, using a standard approach for meta-analysis, was performed for all prospective studies assessing accuracy of TEE in the detection of PFO using confirmation by autopsy, cardiac surgery, and/or catheterization as the reference Search results revealed 3105 studies; 4 met inclusion criteria A total of 164 patients were included TEE had a weighted sensitivity of 892% (95% CI: 811–947%) and specificity of 914% (95% CI: 823–968%) to detect PFO The overall positive likelihood ratio (LR+) was 593 (95% CI: 130–2709) and the overall negative likelihood ratio (LR−) was 022 (95% CI: 008–056)
Conclusion
While TEE bubble study is considered to be the gold standard modality for diagnosing PFO, some PFOs may still be missed or misdiagnosed It is important to understand the limitations of TEE and perhaps use other highly sensitive screening tests, such as transcranial doppler (TCD), in conjunction with TEE before scheduling a patient for transcatheter PFO closure
105 citations
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TL;DR: Emmphasis is given to the detection and treatment of the micrometastatic stage of prostate cancer, as well as recent attempts to target the bone metastasis microenvironment-related survival factors using an anti-survival factor manipulation.
105 citations
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TL;DR: Recent advances in the understanding of miRNAs in cancer and in other diseases are described and the challenge of identifying the most efficacious therapeutic candidates is discussed and a perspective on achieving safe and targeted delivery of miRNA therapeutics is provided.
Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic. In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.
3,210 citations
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TL;DR: This comprehensive meta-regression analysis reports a significant decline in sperm counts between 1973 and 2011, driven by a 50-60% decline among men unselected by fertility from North America, Europe, Australia and New Zealand.
Abstract: BACKGROUND Reported declines in sperm counts remain controversial today and recent trends are unknown. A definitive meta-analysis is critical given the predictive value of sperm count for fertility, morbidity and mortality. OBJECTIVE AND RATIONALE To provide a systematic review and meta-regression analysis of recent trends in sperm counts as measured by sperm concentration (SC) and total sperm count (TSC), and their modification by fertility and geographic group. SEARCH METHODS PubMed/MEDLINE and EMBASE were searched for English language studies of human SC published in 1981-2013. Following a predefined protocol 7518 abstracts were screened and 2510 full articles reporting primary data on SC were reviewed. A total of 244 estimates of SC and TSC from 185 studies of 42 935 men who provided semen samples in 1973-2011 were extracted for meta-regression analysis, as well as information on years of sample collection and covariates [fertility group ('Unselected by fertility' versus 'Fertile'), geographic group ('Western', including North America, Europe Australia and New Zealand versus 'Other', including South America, Asia and Africa), age, ejaculation abstinence time, semen collection method, method of measuring SC and semen volume, exclusion criteria and indicators of completeness of covariate data]. The slopes of SC and TSC were estimated as functions of sample collection year using both simple linear regression and weighted meta-regression models and the latter were adjusted for pre-determined covariates and modification by fertility and geographic group. Assumptions were examined using multiple sensitivity analyses and nonlinear models. OUTCOMES SC declined significantly between 1973 and 2011 (slope in unadjusted simple regression models -0.70 million/ml/year; 95% CI: -0.72 to -0.69; P < 0.001; slope in adjusted meta-regression models = -0.64; -1.06 to -0.22; P = 0.003). The slopes in the meta-regression model were modified by fertility (P for interaction = 0.064) and geographic group (P for interaction = 0.027). There was a significant decline in SC between 1973 and 2011 among Unselected Western (-1.38; -2.02 to -0.74; P < 0.001) and among Fertile Western (-0.68; -1.31 to -0.05; P = 0.033), while no significant trends were seen among Unselected Other and Fertile Other. Among Unselected Western studies, the mean SC declined, on average, 1.4% per year with an overall decline of 52.4% between 1973 and 2011. Trends for TSC and SC were similar, with a steep decline among Unselected Western (-5.33 million/year, -7.56 to -3.11; P < 0.001), corresponding to an average decline in mean TSC of 1.6% per year and overall decline of 59.3%. Results changed minimally in multiple sensitivity analyses, and there was no statistical support for the use of a nonlinear model. In a model restricted to data post-1995, the slope both for SC and TSC among Unselected Western was similar to that for the entire period (-2.06 million/ml, -3.38 to -0.74; P = 0.004 and -8.12 million, -13.73 to -2.51, P = 0.006, respectively). WIDER IMPLICATIONS This comprehensive meta-regression analysis reports a significant decline in sperm counts (as measured by SC and TSC) between 1973 and 2011, driven by a 50-60% decline among men unselected by fertility from North America, Europe, Australia and New Zealand. Because of the significant public health implications of these results, research on the causes of this continuing decline is urgently needed.
794 citations
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TL;DR: The aim of this article is to provide general information about RDW and its routine assessment, to review the most relevant implications in health and disease and give some insights about its potential clinical applications.
Abstract: The red blood cell distribution width (RDW) is a simple and inexpensive parameter, which reflects the degree of heterogeneity of erythrocyte volume (conventionally known as anisocytosis), and is traditionally used in laboratory hematology for differential diagnosis of anemias. Nonetheless, recent evidence attests that anisocytosis is commonplace in human disorders such as cardiovascular disease, venous thromboembolism, cancer, diabetes, community-acquired pneumonia, chronic obstructive pulmonary disease, liver and kidney failure, as well as in other acute or chronic conditions. Despite some demographic and analytical issues related to the routine assessment that may impair its clinical usefulness, an increased RDW has a high negative predictive value for diagnosing a variety of disorders, but also conveys important information for short- and long-term prognosis. Even more importantly, the value of RDW is now being regarded as a strong and independent risk factor for death in the general population. Although it has not been definitely established whether an increased value of RDW is a risk factor or should only be considered an epiphenomenon of an underlying biological and metabolic imbalance, it seems reasonable to suggest that the assessment of this parameter should be broadened far beyond the differential diagnosis of anemias. An increased RDW mirrors a profound deregulation of erythrocyte homeostasis involving both impaired erythropoiesis and abnormal red blood cell survival, which may be attributed to a variety of underlying metabolic abnormalities such as shortening of telomere length, oxidative stress, inflammation, poor nutritional status, dyslipidemia, hypertension, erythrocyte fragmentation and alteration of erythropoietin function. As such, the aim of this article is to provide general information about RDW and its routine assessment, to review the most relevant implications in health and disease and give some insights about its potential clinical applications.
657 citations
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TL;DR: Overconfidence, the anchoring effect, information and availability bias, and tolerance to risk may be associated with diagnostic inaccuracies or suboptimal management.
Abstract: Cognitive biases and personality traits (aversion to risk or ambiguity) may lead to diagnostic inaccuracies and medical errors resulting in mismanagement or inadequate utilization of resources. We conducted a systematic review with four objectives: 1) to identify the most common cognitive biases, 2) to evaluate the influence of cognitive biases on diagnostic accuracy or management errors, 3) to determine their impact on patient outcomes, and 4) to identify literature gaps. We searched MEDLINE and the Cochrane Library databases for relevant articles on cognitive biases from 1980 to May 2015. We included studies conducted in physicians that evaluated at least one cognitive factor using case-vignettes or real scenarios and reported an associated outcome written in English. Data quality was assessed by the Newcastle-Ottawa scale. Among 114 publications, 20 studies comprising 6810 physicians met the inclusion criteria. Nineteen cognitive biases were identified. All studies found at least one cognitive bias or personality trait to affect physicians. Overconfidence, lower tolerance to risk, the anchoring effect, and information and availability biases were associated with diagnostic inaccuracies in 36.5 to 77 % of case-scenarios. Five out of seven (71.4 %) studies showed an association between cognitive biases and therapeutic or management errors. Of two (10 %) studies evaluating the impact of cognitive biases or personality traits on patient outcomes, only one showed that higher tolerance to ambiguity was associated with increased medical complications (9.7 % vs 6.5 %; p = .004). Most studies (60 %) targeted cognitive biases in diagnostic tasks, fewer focused on treatment or management (35 %) and on prognosis (10 %). Literature gaps include potentially relevant biases (e.g. aggregate bias, feedback sanction, hindsight bias) not investigated in the included studies. Moreover, only five (25 %) studies used clinical guidelines as the framework to determine diagnostic or treatment errors. Most studies (n = 12, 60 %) were classified as low quality. Overconfidence, the anchoring effect, information and availability bias, and tolerance to risk may be associated with diagnostic inaccuracies or suboptimal management. More comprehensive studies are needed to determine the prevalence of cognitive biases and personality traits and their potential impact on physicians’ decisions, medical errors, and patient outcomes.
561 citations
01 Jan 1998
TL;DR: In this paper, phenylalkylamine com-pounds, typified by NPS R-568 and its deschloro derivative NPSR-467, increased the concentration of cytoplasmic Ca 2 1 ([Ca 2 1 ] i ) in bovine parathyroid cells and inhibited PTH secretion at nanomolar concentrations.
Abstract: Parathyroid hormone (PTH) secretion is reg-ulated by a cell surface Ca 2 1 receptor that detects small changesin the level of plasma Ca 2 1 . Because this G protein-coupledreceptor conceivably provides a distinct molecular target fordrugs useful in treating bone and mineral-related disorders, wesought to design small organic molecules that act on the Ca 2 1 receptor. We discovered that certain phenylalkylamine com-pounds, typified by NPS R-568 and its deschloro derivative NPSR-467, increased the concentration of cytoplasmic Ca 2 1 ([Ca 2 1 ] i ) in bovine parathyroid cells and inhibited PTH secre-tion at nanomolar concentrations. These effects were stereose-lective and the R enantiomers were 10- to 100-fold more potentthan the S enantiomers. NPS R-568 potentiated the effects ofextracellular Ca 2 1 on [Ca 2 1 ] i and PTH secretion but waswithout effect in the absence of extracellular Ca 2 1 . Both com-pounds shifted the concentration–response curves for extracel-lular Ca 2 1 to the left. Presumably, these compounds act aspositive allosteric modulators to increase the sensitivity of theCa
542 citations