Publications by authors named "Gary Thomas"

137 Publications

Thyroid dysfunction in cerebral venous thrombosis: a retrospective cohort study.

J Neurol 2021 Sep 1. Epub 2021 Sep 1.

Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036, Graz, Austria.

Background: Cerebral venous thrombosis (CVT) is a multifactorial disease with a variety of related conditions and risk factors. Thyroid dysfunction-especially hyperthyroidism-has been linked to CVT, but this is mainly based on case reports ranging back to 1913, while systematic investigations addressing this issue are lacking. Therefore, we investigated the frequency and clinical characteristics of thyroid dysfunction in a large single-center cohort of CVT patients.

Methods: We retrospectively identified all consecutive patients with aseptic CVT treated at our center between 2006 and 2020. Clinical information was extracted from our electronic medical documentation system. Thyroid-stimulating hormone (TSH) had been routinely measured at admission, free thyroid hormones and thyroid autoantibodies were analyzed whenever available.

Results: Of 120 patients with imaging-confirmed CVT, our main analysis included 107 patients (mean age 42 ± 16 years, 74% female) in whom TSH measurements were available. Nineteen patients (17.8%, 95% confidence interval 10-25%) had thyroid dysfunction. Two had newly diagnosed hyperthyroidism (1.9%, 95% confidence interval 0-4%) caused by Graves' disease, but without typical symptoms for this condition. Seventeen patients (15.9%, 95% confidence interval 9-23%) had hypothyroidism (12 previously diagnosed with ongoing thyroid hormone replacement therapy; 5 with newly diagnosed subclinical hypothyroidism). Clinical CVT characteristics were similar comparing patients with versus without thyroid dysfunction.

Conclusion: We observed a remarkably high prevalence of thyroid dysfunction in CVT patients. Whether this finding reflects a causal relationship warrants further studies. Despite that, the frequent coexistence of both diseases argues for TSH screening in CVT patients.
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http://dx.doi.org/10.1007/s00415-021-10776-3DOI Listing
September 2021

Patterns of Thromboembolism in Patients with Advanced Pancreatic Cancer Undergoing First-Line Chemotherapy with FOLFIRINOX or Gemcitabine/nab-Paclitaxel.

Thromb Haemost 2021 Jul 12. Epub 2021 Jul 12.

IIIrd Medical Department of Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectious Disease, Salzburg Cancer Research Institute, Paracelsus Medical University, Salzburg, Austria.

Introduction:  Recent advances in prophylactic anticoagulation and antineoplastic treatment for advanced pancreatic cancer (aPC) warrant an updated reassessment of thromboembolic risk in this population. This multicenter retrospective cohort study aims to comprehensively characterize incidence, risk factors, and outcomes of venous (VTE) and arterial thromboembolism (ATE) in homogenously treated patients with aPC.

Methods:  Four hundred and fifty-five patients with aPC undergoing palliative first-line chemotherapy (Gemcitabine/nab-Paclitaxel (GN) or FOLIRINOX) were included. Primary outcomes were objectively confirmed VTE and/or ATE.

Results:  Over a median follow-up of 26 months, 86 VTE (cumulative incidence: 20.0%; 95% confidence interval [CI]: 16.3-24.0) and 11 ATE events (cumulative incidence: 2.8%; 95% CI: 1.5-4.9) were observed. VTE diagnosis was associated with increased mortality (transition hazard ratio [THR]: 1.59 [95% CI: 1.21-2.09]) and increased risk of cancer progression (THR: 1.47 [95% CI: 1.08-2.01]), while the impact of ATE on mortality was numerically but not statistically significant (THR: 1.85 [95% CI: 0.87-3.94]). The strongest predictor of increased VTE risk was history of cancer-associated VTE (subdistribution hazard ratio [SHR]: 3.29 [95% CI: 2.09-5.18]), while the Khorana score (SHR: 0.78 [0.57-1.06]) failed to predict VTE risk. A history of cerebrovascular disease was associated with markedly increased ATE risk (SHR: 22.05 [95% CI: 6.83-71.22],  < 0.001), especially ischemic stroke. Risk of VTE/ATE did not significantly differ according to type of first-line chemotherapy.

Conclusion:  Patients with aPC undergoing palliative first-line chemotherapy with FOLFIRINOX or GN face a high risk for VTE/ATE and its diagnosis is linked to worse clinical outcomes. VTE-risk prediction models have limited ability to sub-stratify thrombotic events in this high-risk scenario.
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http://dx.doi.org/10.1055/a-1548-4847DOI Listing
July 2021

Rituximab as a Treatment Option after Autologous Hematopoietic Stem Cell Transplantation in a Patient with Systemic Sclerosis.

J Pers Med 2021 Jun 25;11(7). Epub 2021 Jun 25.

Division of Rheumatology and Immunology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

Systemic sclerosis (SSc) is an intractable autoimmune disease characterized by vasculopathy and organ fibrosis. Autologous hematopoietic stem cell transplantation (AHSCT) should be considered for the treatment of selected patients with rapid progressive SSc at high risk of organ failure. It, however, remains elusive whether immunosuppressive therapies such as rituximab (RTX) are still necessary for such patients after AHSCT, especially in those with bad outcomes. In the present report, a 43-year-old man with diffuse cutaneous SSc received AHSCT. Despite AHSCT, SSc further progressed with progressive symptomatic heart failure with newly developed concomitant mitral and tricuspid valve insufficiency, thus the patient started on RTX 8 months after AHSCT. Shortly after initiation of RTX, clinical symptoms and organ functions ameliorated subsequently. Heart valve regurgitations were reversible after initiation of RTX treatment. Currently, the patient remains in a stable condition with significant improvement of clinical symptoms and organ functions. Reporting about therapies after AHSCT in SSc is a very important issue, as randomized controlled trials are lacking, and therefore this report adds to evidence that RTX can be considered as a treatment option in patients with SSc that do not respond to AHSCT.
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http://dx.doi.org/10.3390/jpm11070600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305780PMC
June 2021

Contrasts in Glioblastoma-Venous Thromboembolism versus Bleeding Risk.

Cells 2021 06 7;10(6). Epub 2021 Jun 7.

Division of Internal Medicine, Department of Vascular Medicine, Medical University of Graz, 8036 Graz, Austria.

Glioblastoma is among the tumor entities with an extreme thrombogenic potential and patients are at very high risk of developing a venous thromboembolism (VTE) over the course of the disease, with an incidence of up to 30% per year. Major efforts are currently being made to understand and gain novel insights into the underlying pathomechanisms of the development of VTE in patients with glioblastoma and to find appropriate biomarkers. Yet, patients with glioblastoma not only face a high thromboembolic risk but are also at risk of bleeding events. In the case of VTE, a therapeutic anticoagulation with low molecular weight heparin or, in the case of low bleeding risk, treatment with a direct oral anticoagulant, is recommended, according to recently published guidelines. With respect to an elevated bleeding risk in glioblastoma patients, therapeutic anticoagulation remains challenging in this patient group and prospective data for this vulnerable patient group are scarce, particularly with regard to direct oral anticoagulants.
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http://dx.doi.org/10.3390/cells10061414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228034PMC
June 2021

Is there a hidden blood loss in orthognathic surgery and should it be considered? Results of a prospective cohort study.

J Craniomaxillofac Surg 2021 Jul 2;49(7):545-555. Epub 2020 Aug 2.

Department of Oral and Maxillofacial Surgery, Medical University of Graz, Austria.

The aim of this prospective observational study was to investigate the parameter 'hidden blood loss' (HBL) in the context of orthognathic surgery, incorporating undetected bleeding volumes occurring intra- and postoperatively. Orthognathic bleeding volumes were recorded at three different time points. At the end of the operation the visible intraoperative blood loss (VBL) was measured. Additionally, the perioperative blood loss was calculated 24 h and 48 h postoperatively using the 'haemoglobin balance method'. Analysis of the HBL was based on the difference between the visible intraoperative blood loss (VBL) and calculated blood loss (CBL), determined 48 h after surgery. 82 patients (male 33, female 49) were included in this study, of whom 41 underwent bimaxillary surgery and of whom 41 underwent Bilateral Sagittal Split Osteotomy (BSSO). Statistically significant differences with reference to the absolute bleeding volumes were found when comparing the two treatment modalities. In terms of HBL, a bleeding volume of 287.2 ml (±265.9) in the bimaxillary group and 346.9 ml (±271.3) in the BSSO cohort was recorded. This accounted for 32.2% (bimaxillary surgery) and 62.6% (BSSO) of the CBL after 48 h (BIMAX vs. BSSO, p < 0.001). HBL is a valuable adjunct to record within the perioperative management of orthognathic surgery to further improve patient safety and postoperative outcomes.
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http://dx.doi.org/10.1016/j.jcms.2020.07.015DOI Listing
July 2021

Pulmonary embolism and thrombocytopenia following ChAdOx1 vaccination.

Lancet 2021 05 14;397(10287):1842. Epub 2021 Apr 14.

Division of Angiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1016/S0140-6736(21)00871-0DOI Listing
May 2021

β-endorphin and opioid growth factor as biomarkers of physical ability in multiple sclerosis.

Mult Scler Relat Disord 2021 May 27;50:102868. Epub 2021 Feb 27.

Department of Neural and Behavioral Sciences, Hershey, PA 17033, USA. Electronic address:

Background: Multiple sclerosis (MS) is an autoimmune-mediated degenerative disorder with increased peripheral inflammation disrupting the blood brain barrier. With increasing MS-related healthcare costs, the requirement to validate minimally invasive biomarkers has become imperative.

Methods: Relapsing-remitting MS patients on disease modifying therapies were consented at the Penn State Health MS Clinic to provide blood samples for analyses of serum cytokines and endogenous opioid peptides, as well as to complete the MSQOL-54 survey.

Results: Serum OGF levels in MS patients on glatiramer acetate (mean = 326 pg/ml), dimethyl fumarate (mean = 193.3 pg/ml) and natalizumab (mean = 393.4 pg/ml) were significantly elevated (p < 0.01) compared to healthy controls (mean = 98.46 pg/ml). Individuals with elevated OGF levels also had increased levels of TNFα (r = 0.78) and IL-17A (r = 0.81). Only patients treated with glatiramer acetate had significant (p < 0.01) elevations in serum β-endorphin levels. Analyses of MS-QoL 54 data showed no significant differences in physical or mental composite scores between treatment groups. However, serum levels of β-endorphin had a direct correlation with physical health composite score (r = 0.70) in all treatments. Serum vitamin D levels had an indirect relationship with 25-foot walk test times (r = 0.47).

Conclusion: Both regression and cohort data suggest that serum levels of OGF, β-endorphin, and vitamin D are potential biomarkers for physical disease status in MS.
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http://dx.doi.org/10.1016/j.msard.2021.102868DOI Listing
May 2021

Persistierende Beckenvenenthrombose nach Cyanacrylatverschluss der Vena saphena magna.

J Dtsch Dermatol Ges 2020 Nov;18(11):1322-1324

Klinische Abteilung für Angiologie, Universitätsklinik für Innere Medizin, Medizinische Universität Graz, Österreich.

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http://dx.doi.org/10.1111/ddg.14258_gDOI Listing
November 2020

Common APOC3 variants are associated with circulating ApoC-III and VLDL cholesterol but not with total apolipoprotein B and coronary artery disease.

Atherosclerosis 2020 10 5;311:84-90. Epub 2020 Sep 5.

Mannheimer Institute for Public Health, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.

Background And Aims: Very rare loss-of-function mutations in the apolipoprotein C3 (APOC3) gene have been associated with low circulating apoC-III, low triglycerides, and reduced cardiovascular risk. We aimed to analyze the impact of common APOC3 variants on key parameters of lipid metabolism and coronary artery disease in the largest sample so far.

Methods: Common variants in APOC3 were tested for associations with circulating apoC-III, lipids, and apolipoprotein B (apoB) in 3041 participants of the LUdwigshafen RIsk and Cardiovascular health study (LURIC). These variants were then tested for associations with coronary artery disease in a meta-analysis comprising up to 332,389 participants of the CARDIOGRAMplusC4D consortium and the UK Biobank.

Results: The mean (standard deviation) apoC-III concentration was 14.6 (5.1) mg/dl. Seven common variants in APOC3 (rs734104, rs4520, rs5142, rs5141, rs5130, rs5128, and rs4225) were associated with circulating apoC-III (all p < 0.05). The alleles that modestly raised apoC-III were also associated with markedly higher total triglycerides and very low density lipoprotein (VLDL) triglycerides and cholesterol (all p < 0.05), but not with low density lipoprotein (LDL) cholesterol and total apoB (all p > 0.05). These variants were not associated with coronary artery disease in the CARDIOGRAMplusC4D consortium and the UK Biobank (all p > 0.1).

Conclusions: Modest, genetically caused elevations of apoC-III are associated with a marked increase of triglyceride-rich lipoproteins but not with an increase of LDL cholesterol, total apoB, and coronary artery disease. Whether effective inhibition of apoC-III production with antisense oligomers will be instrumental to reduce cardiovascular risk remains to be demonstrated.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.08.017DOI Listing
October 2020

Persistent iliac vein thrombosis after cyanoacrylate closure of the great saphenous vein.

J Dtsch Dermatol Ges 2020 Nov 2;18(11):1322-1324. Epub 2020 Sep 2.

Division of Angiology, Department of Internal Medicine, Medical University of Graz, Austria.

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http://dx.doi.org/10.1111/ddg.14258DOI Listing
November 2020

Platelet-rich Plasma for Androgenetic Alopecia Treatment: A Randomized Placebo-controlled Pilot Study.

Acta Derm Venereol 2020 Aug 18;100(15):adv00247. Epub 2020 Aug 18.

Department of Dermatology, Medical University of Graz, AT-8036 Graz, Austria.

Platelet-rich plasma injections have been presented as an effective treatment for androgenetic alopecia; however, reliable study data concerning this therapy are lacking. The current randomized, placebo-controlled pilot study explored this novel therapy in 30 healthy male subjects with androgenetic alopecia. Five platelet-rich plasma treatments, at intervals of 4-6 weeks, and 2 follow-up examinations were performed. Twenty subjects were injected intracutaneously with platelet-rich plasma and 10 with physiological saline. Treatment efficacy was assessed by changes in hair number and diameter, measured with the TrichoScan system. A secondary objective was to assess clinical improvement, which was evaluated by an independent reviewer using patient photographs and a 5-point Likert scale. In addition, subject satisfaction was assessed by survey. No improvements were seen over the course of the trial, using TrichoScan measurements or visual assessment. In conclusion, these results suggest that treatment with platelet-rich plasma as a monotherapy does not improve hair growth in men with androgenetic alopecia.
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http://dx.doi.org/10.2340/00015555-3609DOI Listing
August 2020

Incidence, Therapy, and Bleeding Risk-Cancer- Associated Thrombosis in Patients with Glioblastoma.

Cancers (Basel) 2020 May 26;12(6). Epub 2020 May 26.

Division of Vascular Medicine, Department of Internal Medicine, Medical University of Graz, Graz 8036, Austria.

Cancer is an independent risk factor for the development of venous thromboembolism (VTE). Glioblastomas are amongst cancer types with the most thrombogenic potential and patients are at a particularly high risk of VTE with an incidence up to 20-30% per year. Currently, major efforts are underway to gain novel insights into risk factors and pathomechanisms to provide a better understanding of development of VTE in patients with primary brain tumors. Treatment of VTE requires therapeutic anticoagulation, which accordingly to recently-published guidelines should be performed using low molecular weight heparin or, in case of low bleeding risk, using a direct oral anticoagulant. However, this can be very challenging due to an increased risk of intracranial hemorrhage in this patient group. Furthermore, limited data are available on the subgroup of patients with primary brain tumors.
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http://dx.doi.org/10.3390/cancers12061354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353056PMC
May 2020

The multifunctional protein PACS-1 is required for HDAC2- and HDAC3-dependent chromatin maturation and genomic stability.

Oncogene 2020 03 27;39(12):2583-2596. Epub 2020 Jan 27.

Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Centre, Lubbock, TX, 79430, USA.

Phosphofurin acidic cluster sorting protein-1 (PACS-1) is a multifunctional membrane traffic regulator that plays important roles in organ homeostasis and disease. In this study, we elucidate a novel nuclear function for PACS-1 in maintaining chromosomal integrity. PACS-1 progressively accumulates in the nucleus during cell cycle progression, where it interacts with class I histone deacetylases 2 and 3 (HDAC2 and HDAC3) to regulate chromatin dynamics by maintaining the acetylation status of histones. PACS-1 knockdown results in the proteasome-mediated degradation of HDAC2 and HDAC3, compromised chromatin maturation, as indicated by elevated levels of histones H3K9 and H4K16 acetylation, and, consequently, increased replication stress-induced DNA damage and genomic instability.
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http://dx.doi.org/10.1038/s41388-020-1167-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085454PMC
March 2020

A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin Alfa for Chemotherapy-Induced Anemia in Patients With Advanced NSCLC.

J Thorac Oncol 2020 02 16;15(2):190-202. Epub 2019 Oct 16.

Amgen Inc., Thousand Oaks, California.

Introduction: This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin (Hb) ceiling.

Methods: Adults with stage IV NSCLC expected to receive two or more cycles of myelosuppressive chemotherapy and Hb less than or equal to 11.0 g/dL were randomized 2:1 to blinded 500 μg darbepoetin alfa or placebo every 3 weeks. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] < 1.15). Secondary endpoints were PFS and incidence of transfusions or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period.

Results: The primary analysis set included 2516 patients: 1680 were randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR = 0.92; 95% confidence interval [CI]: 0.83‒1.01) and PFS (stratified HR = 0.95; 95% CI: 0.87‒1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period (stratified odds ratio = 0.70; 95% CI: 0.57‒0.86; p < 0.001). Objective tumor response was similar between the groups (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events was 31.1% in both groups. No unexpected adverse events were observed.

Conclusions: Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb less than or equal to 8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.
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http://dx.doi.org/10.1016/j.jtho.2019.10.005DOI Listing
February 2020

The White Blood Cell Count to Mean Platelet Volume Ratio for the Prediction of Chronic Limb-Threatening Ischemia in Lower Extremity Artery Disease.

J Clin Med 2019 Oct 2;8(10). Epub 2019 Oct 2.

Division of Vascular Medicine, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

Background: The white blood cell count to mean platelet volume ratio (WMR) is increasingly gaining importance as a promising prognostic marker in atherosclerotic disease, but data on lower extremity artery disease (LEAD) are not yet available. The principle aim of this study was to assess the association of the WMR with the occurrence of CLTI (chronic limb-threatening ischemia) as the most advanced stage of disease.

Methods: This study was performed as a retrospective analysis on 2121 patients with a diagnosis of LEAD. Patients were admitted to the hospital for the reason of LEAD and received conservative or endovascular treatment. Blood sampling, in order to obtain the required values for this analysis, was implemented at admission. Statistical analysis was conducted by univariate regression in a first step and, in case of significance, by multivariate regression additionally.

Results: Multivariate regression revealed an increased WMR ( < 0.001, OR (95%CI) 2.258 (1.460-3.492)), but also advanced age ( < 0.001, OR (95%CI) 1.050 (1.040-1.061)), increased CRP ( < 0.001, OR (95%CI) 1.010 (1.007-1.014)), and diabetes ( < 0.001, OR (95%CI) 2.386 (1.933-2.946)) as independent predictors for CLTI.

Conclusions: The WMR presents an easily obtainable and cost-effective parameter to identify LEAD patients at high risk for CLTI.
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http://dx.doi.org/10.3390/jcm8101593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832925PMC
October 2019

Chemical Strike against a Dominant-Inherited MUC1-Frameshifted Protein Associated with Progressive Kidney Disease.

Trends Mol Med 2019 10 11;25(10):821-823. Epub 2019 Sep 11.

Department of Genetics and HHMI, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address:

In a recent paper by Dvela-Levitt et al., chemical screening using an immunofluorescent assay identified a compound that caused removal of a dominant-inherited misfolded secretory protein, mucin1-frameshifted, from an intracellular location in immortalized renal epithelial cells of a patient affected with progressive medullary cystic kidney disease. This illustrates the power of chemical screening at the cellular level to address specific proteinopathies and the utility of such compounds to illuminate novel cellular pathways that can clear toxic proteins.
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http://dx.doi.org/10.1016/j.molmed.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405134PMC
October 2019

Extending the SBUV PMC Data Record with OMPS NP.

Atmos Chem Phys 2019 14;19(11):7913-7925. Epub 2019 Jun 14.

Laboratory for Atmospheric and Space Physics (LASP)/University of Colorado, Boulder, Colorado 80303 USA.

We have utilized Solar Backscatter Ultraviolet (SBUV) instrument measurements of atmospheric radiance to create a 40-year record of polar mesospheric cloud (PMC) behavior. While this series of measurements is nearing its end, we show in this paper that Ozone Mapping and Profiling Suite (OMPS) Nadir Profiler (NP) instruments can be added to the merged SBUV PMC data record. Regression analysis of this extended record shows smaller trends in PMC ice water content (IWC) since approximately 1998, consistent with previous work. Current trends are significant at the 95% confidence level in the Northern Hemisphere, but not in the Southern Hemisphere. The PMC IWC response to solar activity has decreased in the Northern Hemisphere since 1998, but has apparently increased in the Southern Hemisphere.
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http://dx.doi.org/10.5194/acp-19-7913-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687313PMC
June 2019

The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites.

Cells 2019 06 25;8(6). Epub 2019 Jun 25.

INSERM, UMR 1048, Institute of Metabolic and Cardiovascular Diseases/I2MC, F-31342 Toulouse, France.

Mitochondria-associated ER membranes (MAMs) are crucial for lipid transport and synthesis, calcium exchange, and mitochondrial functions, and they also act as signaling platforms. These contact sites also play a critical role in the decision between autophagy and apoptosis with far reaching implications for cell fate. Vascular smooth muscle cell (VSMC) apoptosis accelerates atherogenesis and the progression of advanced lesions, leading to atherosclerotic plaque vulnerability and medial degeneration. Though the successful autophagy of damaged mitochondria promotes VSMC survival against pro-apoptotic atherogenic stressors, it is unknown whether MAMs are involved in VSMC mitophagy processes. Here, we investigated the role of the multifunctional MAM protein phosphofurin acidic cluster sorting protein 2 (PACS-2) in regulating VSMC survival following a challenge by atherogenic lipids. Using high-resolution confocal microscopy and proximity ligation assays, we found an increase in MAM contacts as in PACS-2-associated MAMs upon stimulation with atherogenic lipids. Correspondingly, the disruption of MAM contacts by PACS-2 knockdown impaired mitophagosome formation and mitophagy, thus potentiating VSMC apoptosis. In conclusion, our data shed new light on the significance of the MAM modulatory protein PACS-2 in vascular cell physiopathology and suggest MAMs may be a new target to modulate VSMC fate and favor atherosclerotic plaque stability.
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http://dx.doi.org/10.3390/cells8060638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627983PMC
June 2019

Evaluation of Space Traffic Effects in SBUV Polar Mesospheric Cloud Data.

J Geophys Res Atmos 2019 Apr 14;124(7):4203-4221. Epub 2019 Mar 14.

Laboratory for Atmospheric and Space Physics, University of Colorado, Boulder, CO, USA.

Water-rich rocket exhaust plumes, in particular those emitted by the National Aeronautics and Space Administration Space Shuttle, have been suggested to make a significant contribution to long-term trends in polar mesospheric cloud (PMC) ice water content. We investigate this claim using the combined Solar Backscatter Ultraviolet (SBUV) PMC data record from eight separate instruments, which includes 60 Shuttle launches during PMC seasons between 1985 and 2011. No statistically significant postlaunch signal in PMC total ice is observed based on superposed epoch analysis of the SBUV record. Only a few launches show individual peaks in total ice anomaly above the seasonal background that exceed an empirical threshold, and the maximum cumulative signature from these infrequent cases is typically less than 5% of the season total in ice mass. Other non-Shuttle launches show circumstantial evidence of possible PMC effects, although supporting evidence for plume transport is not available. We conclude that space traffic effects have been a negligible component of long-term PMC behavior.
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http://dx.doi.org/10.1029/2018JD029756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362299PMC
April 2019

Increased Bleeding Risk in a Patient with Oral Anticoagulant Therapy and Concomitant Herbal Intake - A Case Report.

EJIFCC 2019 Mar 1;30(1):95-98. Epub 2019 Mar 1.

Division of Angiology, Department of Internal Medicine, Medical University of Graz, Austria.

We report the case of a 36-year old male, under stable rivaroxaban therapy for 18 months, who was admitted to our emergency room with sudden onset of hemoptysis. Anticoagulant therapy was given after recurrent spontaneous deep vein thrombosis (DVT) and a heterozygous Factor-V-Leiden mutation was present. There was no co-medication reported, however, the patient reported a constant intake of three liters of home-brewn ginger tea per day in the last month. The patient was hospitalized to further investigate the reason of hemoptysis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416813PMC
March 2019

A Phase 2 Study of PCI-27483, a Factor VIIa Inhibitor in Combination with Gemcitabine for Advanced Pancreatic Cancer.

Oncology 2019 7;96(4):217-222. Epub 2019 Mar 7.

Gabrail Cancer Center, Canton, Ohio, USA.

Objectives: Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor.

Methods: This was an open-label, multicenter phase 2 trial of patients with advanced pancreatic cancer. Part A of the study was an intrapatient dose escalation lead-in portion in patients concurrently receiving gemcitabine, and in part B, patients were randomized 1: 1 to the recommended phase 2 dose combination PCI-27483-gemcitabine versus gemcitabine alone.

Results: Target international normalized ratio (between 2.0-3.0) was achieved following PCI-27483 treatment. Overall safety of PCI-27483-gemcitabine (n = 26) was similar to gemcitabine alone (n = 16), with a higher incidence of mostly low-grade bleeding events (65% vs. 19%). Progression-free survival (PFS) and overall survival (OS) were not significantly different between patients treated with PCI-27483-gemcitabine (PFS: 3.7 months, OS: 5.7 months) and those treated with gemcitabine alone (PFS: 1.9 months, OS: 5.6 months).

Conclusions: Targeted inhibition of the coagulation cascade was achieved by administering PCI-27483. PCI-27483-gemcitabine was well tolerated, but superiority to single agent gemcitabine was not demonstrated.
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http://dx.doi.org/10.1159/000495988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492608PMC
May 2019

Preserved Left Atrial Mechanics Following a 5-h Laboratory Triathlon in Euhydrated Athletes.

Int J Sports Med 2019 Feb 3;40(2):88-94. Epub 2019 Jan 3.

Division of Sports and Rehabilitation Medicine, University Hospital Ulm, Ulm, Germany.

The purpose of this study was to investigate echocardiographic changes in left ventricular (LV) diastolic filling and left atrial (LA) strain mechanics following prolonged exercise. Ten male triathletes completed a 60-min swim, 180-min bike exercise, and a 60-min all-out run in a laboratory environment. Special attention was paid to prevent dehydration and energy deficit during the exercise protocol. All participants underwent comprehensive echocardiographic analyses of Doppler- and volumetric-derived LV diastolic filling indices and novel speckle-tracking echocardiography (STE)-derived LA strain indices. LV stroke volume (pre: 108.0±15.9 vs. post: 88.8±19.0 mL; p=0.03) and LA passive emptying volume (pre: 31.2±7.5 vs. post: 22.4±9.8 mL; p=0.05) were significantly reduced following the exercise protocol. Of the STE-derived indices of LA function, reservoir and conduit strain did not change significantly, while there was a trend towards enhanced contraction strain (pre: 15.1±3.8 vs. post: 19.4±4.8%; p=0.07). Resting heart rate was significantly higher post-exercise (53.1±5.0 vs. 81.9±16.9 bpm; p<0.001) and its change correlated strongly with depression of Doppler-derived ratio of early to late ventricular filling velocities (r=0.74, p=0.01) and reduction of LA passive emptying volume (r=0.86, p=0.01). Following prolonged exercise, LV stroke volume was reduced due to heart rate related reduction in LA passive emptying volume whereas global LA strain mechanics were not compromised in this study.
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http://dx.doi.org/10.1055/a-0750-5780DOI Listing
February 2019

An Insulin-Responsive Sensor in the SIRT1 Disordered Region Binds DBC1 and PACS-2 to Control Enzyme Activity.

Mol Cell 2018 12 8;72(6):985-998.e7. Epub 2018 Nov 8.

Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address:

Current models of SIRT1 enzymatic regulation primarily consider the effects of fluctuating levels of its co-substrate NAD, which binds to the stably folded catalytic domain. By contrast, the roles of the sizeable disordered N- and C-terminal regions of SIRT1 are largely unexplored. Here we identify an insulin-responsive sensor in the SIRT1 N-terminal region (NTR), comprising an acidic cluster (AC) and a 3-helix bundle (3HB), controlling deacetylase activity. The allosteric assistor DBC1 removes a distal N-terminal shield from the 3-helix bundle, permitting PACS-2 to engage the acidic cluster and the transiently exposed helix 3 of the 3-helix bundle, disrupting its structure and inhibiting catalysis. The SIRT1 activator (STAC) SRT1720 binds and stabilizes the 3-helix bundle, protecting SIRT1 from inhibition by PACS-2. Identification of the SIRT1 insulin-responsive sensor and its engagement by the DBC1 and PACS-2 regulatory hub provides important insight into the roles of disordered regions in enzyme regulation and the mode by which STACs promote metabolic fitness.
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http://dx.doi.org/10.1016/j.molcel.2018.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309500PMC
December 2018

What does the research say about androgen use and cerebrovascular events?

Ther Adv Drug Saf 2018 Aug 8;9(8):439-455. Epub 2018 May 8.

Penn State Hershey Neurology, Penn State University, PA, USA.

Many studies have investigated the benefits of androgen therapy and neurosteroids in aging men, while concerns remain about the potential associations of exogenous steroids and incidents of cerebrovascular events and ischemic stroke (IS). Testosterone is neuroprotective, neurotrophic and a potent stimulator of neuroplasticity. These benefits are mediated primarily through conversion of a small amount of testosterone to estradiol by the catalytic activity of estrogen synthetase (aromatase cytochrome P450 enzyme). New studies suggest that abnormal serum levels of the nonaromatized potent metabolite of testosterone, either high or low dihydrotestosterone (DHT), is a risk factor for stroke. Associations between pharmacologic androgen use and the incidence of IS are questionable, because a significant portion of testosterone is converted to DHT. There is also insufficient evidence to reject a causal relationship between the pro-testosterone adrenal androgens and incidence of IS. Moreover, vascular intima-media thickness, which is a predictor of stroke and myocardial symptoms, has correlations with sex hormones. Current diagnostic and treatment criteria for androgen therapy for cerebrovascular complications are unclear. Confounding variables, including genetic and metabolic alterations of the key enzymes of steroidogenesis, ought to be considered. Information extracted from pharmacogenetic testing may aid in expounding the protective-destructive properties of neurosteroids, as well as the prognosis of androgen therapy, in particular their cerebrovascular outcomes. This investigative review article addresses relevant findings of the clinical and experimental investigations of androgen therapy, emphasizes the significance of genetic testing of androgen responsiveness towards individualized therapy in post-IS injuries as well as identifying pertinent questions.
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http://dx.doi.org/10.1177/2042098618773318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199678PMC
August 2018
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