Publications by authors named "Hoda M"

236 Publications

Telomerase Reverse Transcriptase Promoter Mutations Identify a Genomically Defined and Highly Aggressive Human Pleural Mesothelioma Subgroup.

Clin Cancer Res 2020 07 21;26(14):3819-3830. Epub 2020 Apr 21.

Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Purpose: Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase () gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.

Experimental Design: promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for immortalization. The respective MPM cell models ( = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays.

Results: promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines promoter mutations were associated with enforced promoter activity and mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. promoter-mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While mutations/deletions were exclusive with promoter mutations, homozygous deletions at the and the loci were clearly enriched in mutated cases.

Conclusions: promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3573DOI Listing
July 2020

Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma.

Histopathology 2020 Jul 25;77(1):55-66. Epub 2020 May 25.

2nd Institute of Pathology, Semmelweis University, Budapest, Hungary.

Aims: Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal prognosis. While the epithelioid type is associated with a more favourable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis-necrosis score were investigated in this study.

Methods And Results: Tumour specimens of 192 patients with epithelioid MPM from five European centres were histologically subtyped. Nuclear grading and mitosis-necrosis score were determined and correlated with clinicopathological parameters and overall survival (OS). Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histological subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer OS than the solid/trabecular group (732 days versus 397 days, P = 0.0013). Pleomorphic tumours had the shortest OS (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis-necrosis score. The mitosis-necrosis score was a robust and independent prognostic factor in our patient cohort. The prognostic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumours showed a greater improvement in OS after receiving multimodal therapy than those with solid or trabecular tumours.

Conclusions: Histological subtypes of epithelioid MPM have a prognostic impact, and might help to select patients for intensive multimodal treatment approaches.
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http://dx.doi.org/10.1111/his.14105DOI Listing
July 2020

Attenuation of diabetic retinopathy and neuropathy by resveratrol: Review on its molecular mechanisms of action.

Life Sci 2020 Mar 23;245:117350. Epub 2020 Jan 23.

Department of Biological Sciences, Aliah University, IIA/27-Newtown, Kolkata 700160, India. Electronic address:

Resveratrol is an important phenolic phytochemical from the therapeutic perspective. It has therapeutic impacts over wide range of diseases, especially the ones related to oxidative stress. Resveratrol, being primarily a potent anti-oxidant phytochemical, has significant impact against major diseases as inflammatory disorders, diabetes, and cancer. In the current review article, we intend to highlight the molecular aspects of the mechanism of action of resveratrol against major diabetic implications, namely, retinopathy and neuropathy. Both these diabetic implications are among the first fallouts of chronic hyperglycaemia. Resveratrol, via multiple molecular pathways, tend to attenuate and reverse these deformity and other disease-causing implications.
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http://dx.doi.org/10.1016/j.lfs.2020.117350DOI Listing
March 2020

C3a receptor antagonist therapy is protective with or without thrombolysis in murine thromboembolic stroke.

Br J Pharmacol 2020 06 4;177(11):2466-2477. Epub 2020 Mar 4.

Department of Neurosurgery, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona.

Background And Purpose: Intravenous thrombolysis (IVT) after stroke enhances C3a generation, which may abrogate the benefits of reperfusion. The C3aR antagonist SB290157 is neuroprotective following transient but not permanent middle cerebral artery occlusion (MCAo). SB290157 remains untested in thromboembolic (TE) models, which better approximate human stroke and also facilitate testing in combination with IVT. We hypothesized SB290157 would confer neuroprotection in TE stroke with and without "late" IVT.

Experimental Approach: We used two different models of TE stroke to examine the efficacy of SB290157 alone and in combination with late IVT. We evaluated the benefit of SB290157 in attenuating post-ischaemic behavioural deficits, infarction, brain oedema and haemorrhage.

Key Results: Plasma C3a was elevated 6 hr after TE stroke alongside increased cerebrovascular C3aR expression, which was sustained to 4 weeks. Increased C3aR expression also was visualized in human ischaemic brain. In a photothrombotic (PT) stroke model, which exhibits rapid spontaneous reperfusion, SB290157 given at 1 hr post-PT significantly improved neurofunction and reduced infarction at 48 hr. In an embolic (eMCAo) model, SB290157 administered at 2 hr improved histological and functional outcomes. Conversely, late IVT administered 4.5 hr post-eMCAo was ineffective likely due to increased haemorrhage and brain oedema. However, SB290157 administered prior to late IVT ameliorated haemorrhage and oedema and improved outcomes.

Conclusions And Implications: We conclude that SB290157 is safe and effective with and without late IVT following TE stroke. Therefore, C3a receptor antagonist therapy represents a promising candidate for clinical translation in stroke, particularly as an adjuvant to IVT.
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http://dx.doi.org/10.1111/bph.14989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205805PMC
June 2020

Maxillofacial Fracture Patterns in Road Traffic Accidents.

Ann Maxillofac Surg 2019 Jul-Dec;9(2):345-348

Department of Oral and Maxillofacial Surgery, Vydehi Institute of Dental Sciences, Bengaluru, Karnataka, India.

Objective: The objective of this study is to analyze the maxillofacial fracture pattern from road traffic accidents (RTAs) in cases treated surgically in a tertiary hospital during July 2008-June 2018.

Materials And Method: Data available in the department of oral and maxillofacial surgery of the institution of patients with maxillofacial fractures sustained due to RTAs that were treated in the department between the period July 2008 and June 2018 were collected and analyzed. The variables analyzed for the study were etiology, gender, age, and type of fracture. All cases were treated by open reduction and rigid internal fixation.

Results: A total of 348 patients with maxillofacial fractures were diagnosed, of which 335 were male and 13 were female. The ages ranged from 7 to 70 years. The maximum cases were in the age group of 16-30 years with 181 fractures followed by 31-45 group with 133 fractures, 45-60 years with 21 fractures, 0-15 years with 8 fractures, and >60 years with five fractures. The maximum incidence of fractures was in the mandible with 168 cases followed by 92 in zygomatic complex, combination of fractures in 53 cases, 13 LeFort I fractures, nine frontal bone fractures, three fractures in other areas, five nasal fractures, and five LeFort II fractures. Males predominated the cases of mandibular fractures involving multiple sites and cases involving multiple bones.

Conclusion: A maximum number of maxillofacial fractures cases were in the second and third decades of life, and the high-speed vehicles and lack of protective safety accessories such as helmets and seatbelts were responsible for the wide variety of pattern fractures of facial bones.
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http://dx.doi.org/10.4103/ams.ams_136_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933960PMC
January 2020

KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy.

Cancers (Basel) 2019 Oct 9;11(10). Epub 2019 Oct 9.

Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, 1122 Budapest, Hungary.

Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking ( = 0.008) and female gender ( = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group ( = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS ( = 0.0255) and OS ( = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; = 0.011) and OS (hazard ratio, 0.645; = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.
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http://dx.doi.org/10.3390/cancers11101514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827133PMC
October 2019

Expression of FGFR1-4 in Malignant Pleural Mesothelioma Tissue and Corresponding Cell Lines and its Relationship to Patient Survival and FGFR Inhibitor Sensitivity.

Cells 2019 09 16;8(9). Epub 2019 Sep 16.

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

Malignant pleural mesothelioma (MPM) is a devastating malignancy with limited therapeutic options. Fibroblast growth factor receptors (FGFR) and their ligands were shown to contribute to MPM aggressiveness and it was suggested that subgroups of MPM patients could benefit from FGFR-targeted inhibitors. In the current investigation, we determined the expression of all four FGFRs (FGFR1-FGFR4) by immunohistochemistry in tissue samples from 94 MPM patients. From 13 of these patients, we were able to establish stable cell lines, which were subjected to FGFR1-4 staining, transcript analysis by quantitative RT-PCR, and treatment with the FGFR inhibitor infigratinib. While FGFR1 and FGFR2 were widely expressed in MPM tissue and cell lines, FGFR3 and FGFR4 showed more restricted expression. FGFR1 and FGFR2 showed no correlation with clinicopathologic data or patient survival, but presence of FGFR3 in 42% and of FGFR4 in 7% of patients correlated with shorter overall survival. Immunostaining in cell lines was more homogenous than in the corresponding tissue samples. Neither transcript nor protein expression of FGFR1-4 correlated with response to infigratinib treatment in MPM cell lines. We conclude that FGFR3 and FGFR4, but not FGFR1 or FGFR2, have prognostic significance in MPM and that FGFR expression is not sufficient to predict FGFR inhibitor response in MPM cell lines.
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http://dx.doi.org/10.3390/cells8091091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769772PMC
September 2019

Development of an unsupervised machine learning algorithm for the prognostication of walking ability in spinal cord injury patients.

Spine J 2020 02 13;20(2):213-224. Epub 2019 Sep 13.

Ottawa Spine Collaborative Analytics Network, The Ottawa Hospital, Ottawa, ON K1Y 4E9, Canada; Division of Orthopaedic Surgery, Department of Surgery, Faculty of Medicine, University of Ottawa, The Ottawa Hospital, 1053 Caroling Ave, Ottawa, ON K1Y 4E9, Canada; Clinical Epidemiology Program, The Ottawa Hospital, Ottawa, ON K1Y 4E9, Canada. Electronic address:

Background Context: Traumatic spinal cord injury can have a dramatic effect on a patient's life. The degree of neurologic recovery greatly influences a patient's treatment and expected quality of life. This has resulted in the development of machine learning algorithms (MLA) that use acute demographic and neurologic information to prognosticate recovery. The van Middendorp et al. (2011) (vM) logistic regression (LR) model has been established as a reference model for the prediction of walking recovery following spinal cord injury as it has been validated within many different countries. However, an examination of the way in which these prediction models are evaluated is warranted. The area under the receiver operators curve (AUROC) has been consistently used when evaluating model performance, but it has been shown that AUROC overemphasizes the most common event resulting in an inaccurate assessment when the data are imbalanced. Furthermore, there is evidence that the use of more advanced MLA, such as an unsupervised k-means model, may show superior performance compared to LR as they can handle a larger number of features.

Purpose: The first objective of the study was to assess the performance of both an unsupervised MLA and LR model with complete admission neurologic information against the vM and Hicks models. Second, a comparison between the accuracy of the AUROC and the F1-score will be made to determine which method is superior for the assessment of diagnostic performance of prediction models on large-scale datasets.

Study Design: Retrospective review of a prospective cohort study.

Patient Sample: The Rick Hansen Spinal Cord Injury Registry (RHSCIR) was used in this study. All patients enrolled between 2004 and 2017 with complete neurologic examination and Functional Independence Measure outcome data at ≥1 year follow-up or who could walk at discharge were included. The prognostic variables included age (dichotomized at ≥65 years old); American Spinal Injury Association Impairment Scale (AIS) grade; and individual motor, light touch, and pinprick score from L2 to S1.

Outcome Measures: The Functional Independence Measure locomotor score was used to assess independent walking ability at discharge or 1-year follow-up.

Methods: An unsupervised MLA with k=2 was chosen in order to identify a "walk" cluster and a "not walk" cluster. Model performance was assessed through the development of a receiver operating characteristic curve with associated AUROC and a precision-recall curve with associated F1-score. The study and the RHSCIR are supported by funding from Health Canada, Western Economic Diversification Canada, and the Governments of Alberta, British Columbia, Manitoba, and Ontario. These funders had no role in the study or study reporting and the authors have no conflicts of interest to report.

Results: No clinically relevant differences were found between with the use of an unsupervised MLA with a greater amount of initial neurologic information compared to the established standards for any AIS classification. Although demonstrated for all separate AIS classifications, most notably, the AUROC for the vM (0.78) and Hicks models (0.76) were found to be superior to that of the new LR model (0.72); however, the vM and Hicks models had more than double the amount of false negative classifications compared to the LR. The F1-scores between these three models were also found to be different but with the vM and Hicks models being lower than the LR (0.85, 0.81, and 0.89, respectively).

Conclusions: No clinically relevant differences were found between the use of an unsupervised MLA with complete admission neurologic information compared to the previously validated standards; however, when comparing the performance of the AUROC and F1-score, the AUROC showed inaccurate prognostic performance when there was an imbalance toward a greater amount of false negatives. Importantly, the F1-score did not succumb to this imbalance. As AUROC has been used as the standard when evaluating performance of prediction models, consideration as to whether this is the most appropriate method is warranted. Future work should focus on comparing AUROC and F1-scores with other previously validated models.
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http://dx.doi.org/10.1016/j.spinee.2019.09.007DOI Listing
February 2020

Acetyl-11-keto-β-boswellic acid (AKBA) Attenuates Oxidative Stress, Inflammation, Complement Activation and Cell Death in Brain Endothelial Cells Following OGD/Reperfusion.

Neuromolecular Med 2019 12 12;21(4):505-516. Epub 2019 Sep 12.

Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center (SJHMC), Dignity Health, 350 W Thomas Rd, Phoenix, AZ, 85013, USA.

Brain endothelial cells play an important role in maintaining blood flow homeostasis in the brain. Cerebral ischemia is a major cause of endothelial dysfunction which can disrupt the blood-brain barrier (BBB). Oxygen-glucose deprivation (OGD)/reperfusion promote cell death and BBB breakdown in brain endothelial cells. Acetyl-11-keto-β-boswellic acid (AKBA), a biologically active phytoconstituent of the medicinal plant Boswellia serrata, has been shown to be protective against various inflammatory diseases as well as ischemic brain injury. The molecular mechanisms underlying these beneficial characteristics of AKBA are poorly understood. We subjected bEND.3 cells to OGD/reperfusion to investigate the protective role of AKBA in this model. We found that AKBA treatment attenuated endothelial cell death and oxidative stress assessed by means of TUNEL assay, cleaved-caspase-3, and dihydroethidium (DHE) staining. Furthermore, OGD downregulated tight junction proteins ZO-1 and Occludin levels, and increased the expressions of inflammatory cytokines TNF-α, ICAM-1, and complement C3a receptor (C3aR). We also noticed the increased phosphorylation of ERK 1/2 in bEND.3 cells in OGD group. AKBA treatment significantly attenuated expression levels of these inflammatory proteins and prevented the degradation of ZO-1 and Occludin following OGD. In conclusion, AKBA treatment provides protection against endothelial cell dysfunction following OGD by attenuating oxidative stress and inflammation.
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http://dx.doi.org/10.1007/s12017-019-08569-zDOI Listing
December 2019

Prognostic assessment in patients with newly diagnosed small cell lung cancer brain metastases: results from a real-life cohort.

J Neurooncol 2019 Oct 27;145(1):85-95. Epub 2019 Aug 27.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Purposes: Brain metastases (BM) are a frequent complication in small cell lung cancer (SCLC), resulting in a reduced survival prognosis. Precise prognostic assessment is an important foundation for treatment decisions and clinical trial planning.

Methods: Patients with newly diagnosed SCLC BM were identified from the Vienna Brain Metastasis Registry and evaluated concerning prognostic factors.

Results: 489 patients (male 62.2%, female 37.8%; median age 61 years) were included. Neurological symptoms were present in 297/489 (60.7%) patients. A- to oligosymptomatic patients (5 vs. 9 months, p = 0.030) as well as patients with synchronous diagnosis of BM and primary tumor (5 vs. 9 months, p = 0.008) presented with improved overall survival (OS) prognosis. RPA (HR 1.66; 95% CI 1.44-1.91; p < 0.001), GPA (HR 1.65; p < 0.001), DS-GPA (HR 1.60; p < 0.001) and LabBM score (HR 1.69; p < 0.001) were statistically significantly associated with OS. In multivariate analysis, DS-GPA (HR 1.59; p < 0.001), neurological deficits (HR 1.26; p = 0.021) and LabBM score (HR 1.57; p < 0.001) presented with statistical independent association with OS.

Conclusion: A- to oligosymptomatic BM as well as synchronous diagnosis of SCLC and BM were associated with improved OS. Established prognostic scores could be validated in this large SCLC BM real-life cohort.
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http://dx.doi.org/10.1007/s11060-019-03269-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775039PMC
October 2019

Ameloblastoma Management: "Horses for Courses" Protocol.

J Maxillofac Oral Surg 2019 Sep 23;18(3):400-404. Epub 2019 Jan 23.

Department of Oral and Maxillofacial Surgery, Vydehi Institute of Dental Sciences, Bangalore, 560043 India.

Purpose: The purpose of the article is to review 45 cases of ameloblastoma treated in a tertiary care centre depending on the extent of the pathology, in terms of recurrence and morbidity of the patients.

Materials And Method: This was a retrospective study of patients who underwent treatment for ameloblastoma between 2009 and 2018 at Vydehi Institute of Dental Sciences, Bangalore. During the first phase of 4 years, the focus of the treatment was on avoiding any recurrence, and therefore, resection followed by reconstruction with reconstruction plates was the only modality used in ten patients. However, from 2014, it was decided to treat each patient based on the extent of the lesion and decide on either conservative management in the form of enucleation followed by peripheral ostectomy and chemical cauterisation or resection with safe margins and reconstruction with reconstruction plates.

Results: The study sample consisted of 45 patients, and the ages ranged from 12 to 65 years with an average of 36. There were 30 males and 15 females. In the first phase of treatment protocol adopted, ten patients underwent resection. In the later period, 18 patients were treated by conservative methods and 16 patients were treated by radical management. There were only three recurrences over a period of 3-year follow-up in the group treated conservatively.

Conclusion: Considering the benign nature of the tumour and the morbidity after resection, patients, most of whom are in the younger age group, can still be subjected to conservative treatment provided they are followed up for a long period thus assuring them of a better quality of life.
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http://dx.doi.org/10.1007/s12663-019-01189-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639525PMC
September 2019

Impact of resident involvement on cervical and lumbar spine surgery outcomes.

Spine J 2019 12 16;19(12):1905-1910. Epub 2019 Jul 16.

Division of Orthopaedic Surgery, Department of Surgery, University of Ottawa, The Ottawa Hospital, Ottawa, Ontario, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Electronic address:

Background Context: Resident involvement in the operating room is a vital component of their medical education. Conflicting and limited research exists regarding the effects of surgical resident participation on spine surgery patient outcomes.

Purpose: To determine the effect of resident involvement on surgery duration, length of hospital stay and 30-day postoperative complication rates in common spinal surgery using the American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) database.

Study Design: Multicenter retrospective cohort study.

Patient Sample: A total of 1,441 patients met the inclusion criteria: 1,142 patients had surgeries with an attending physician alone and 299 patients had surgeries with trainee involvement. All anterior cervical or posterior lumbar surgery patients were identified. Patients who had missing trainee involvement information, surgery for cancer, preoperative infection or dirty wound classification, spine fractures, traumatic spinal cord injury, intradural surgery, thoracic surgery, and emergency surgery were excluded.

Outcome Measures: The main outcomes of interest analyzed from the ACS-NSQIP database included surgical complications, medical complications, length of hospital stay, and surgery duration.

Methods: Propensity score for risk of any complication was calculated to account for baseline characteristic differences between the attending alone and trainee present group. Multivariate logistic regression was used to investigate the impact of resident involvement on surgery duration, length of hospital stay, and 30-day postoperative complication rates.

Results: After adjusting using the calculated propensity score, the multivariate analysis demonstrated that there was no significant difference in any complication rates between surgeries involving trainees compared to surgeries with attending surgeons alone. Surgery times were found to be significantly longer for surgeries involving trainees. To further explore this relationship, separate analyses were performed for tertiles of predicted surgery duration, cervical or lumbar surgery, fusion or nonfusion, and inpatient or outpatient surgery. The effect of trainee involvement on increasing surgery time remained significant for medium predicted surgery duration, longer predicted surgery duration, cervical surgery, lumbar surgery, fusion surgery, and inpatient surgery. There were no significant differences reported for any other factors.

Conclusions: After adjusting for confounding, we demonstrated in a national database that resident involvement in surgeries did not increase complication rates. We demonstrated that surgeries with more complex features may lead to an increase in operative time when trainees are involved. Further study is required to determine how to efficiently integrate resident involvement in surgeries without affecting their medical education.
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http://dx.doi.org/10.1016/j.spinee.2019.07.006DOI Listing
December 2019

C3a Receptor Inhibition Protects Brain Endothelial Cells Against Oxygen-glucose Deprivation/Reperfusion.

Exp Neurobiol 2019 Apr 30;28(2):216-228. Epub 2019 Apr 30.

Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Dignity Health, Phoenix, Arizona 85013, USA.

The complement cascade is a central component of innate immunity which plays a critical role in brain inflammation. Complement C3a receptor (C3aR) is a key mediator of post-ischemic cerebral injury, and pharmacological antagonism of the C3a receptor is neuroprotective in stroke. Cerebral ischemia injures brain endothelial cells, causing blood brain barrier (BBB) disruption which further exacerbates ischemic neuronal injury. In this study, we used an model of ischemia (oxygen glucose deprivation; OGD) to investigate the protective effect of a C3aR antagonist (C3aRA, SB290157) on brain endothelial cells (bEnd.3). Following 24 hours of reperfusion, OGD-induced cell death was assessed by TUNEL and Caspase-3 staining. Western blot and immunocytochemistry were utilized to demonstrate that OGD upregulates inflammatory, oxidative stress and antioxidant markers (ICAM-1, Cox-2, Nox-2 and MnSOD) in endothelial cells and that C3aRA treatment significantly attenuate these markers. We also found that C3aRA administration restored the expression level of the tight junction protein occludin in endothelial cells following OGD. Interestingly, OGD/reperfusion injury increased the phosphorylation of ERK1/2 and C3aR inhibition significantly reduced the activation of ERK suggesting that endothelial C3aR may act via ERK signaling. Furthermore, exogenous C3a administration stimulates these same inflammatory mechanisms both with and without OGD, and C3aRA suppresses these C3a-mediated responses, supporting an antagonist role for C3aRA. Based on these results, we conclude that C3aRA administration attenuates inflammation, oxidative stress, ERK activation, and protects brain endothelial cells following experimental brain ischemia.
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http://dx.doi.org/10.5607/en.2019.28.2.216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526115PMC
April 2019

Inactivation of endothelial adenosine A receptors protects mice from cerebral ischaemia-induced brain injury.

Br J Pharmacol 2019 07 21;176(13):2250-2263. Epub 2019 May 21.

Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA.

Background And Purpose: Inactivation of the gene for adenosine A receptors (ADORA2A for humans and Adora2a for rodents) protects against brain injury in experimental stroke. However, the cell-specific pathogenic effects of A receptors in thromboembolic stroke and the underlying mechanisms remain undefined. Here, we tested the hypothesis that inhibition of endothelial A receptors after thromboembolic stroke improves post-stroke outcomes via down-regulation of inflammation.

Experimental Approach: Thromboembolic stroke was induced by embolic middle cerebral artery occlusion in mice. Post-stroke outcomes were determined with neurological deficit scoring, infarct volume, inflammatory marker expression, brain leukocyte infiltration, blood-brain barrier (BBB) leakage, and oedema assessment. Anti-inflammatory effects of silencing the gene for A receptors or pharmacological antagonism of these receptors were assessed in vitro.

Key Results: Thromboembolic stroke induced Adora2a expression in the brain. Mice globally deficient in Adora2a (Adora2a ) were resistant to stroke injury. Mice specifically deficient in endothelial Adora2a (Adora2a ) showed reduced leukocyte infiltration, BBB leakage, and oedema after stroke, along with attenuated downstream proinflammatory markers, both in vivo and in vitro. The A receptor antagonist, KW 6002, also reduced brain injury and inflammation after stroke. Inactivation of ADORA2A inhibited endothelial inflammation via suppression of the NLRP3 inflammasome, down-regulating cleaved caspase 1 and IL-1β expression.

Conclusions And Implications: Specific inactivation of endothelial A receptors mitigated ischaemic brain injury and improved post-stroke outcomes, at least partly, through anti-inflammatory effects via blockade of NLRP3 inflammasome activity. Our findings may open new approaches to vascular protection after ischaemic stroke.
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http://dx.doi.org/10.1111/bph.14673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555863PMC
July 2019

Results of the extended analysis for cancer treatment (EXACT) trial: a prospective translational study evaluating individualized treatment regimens in oncology.

Oncotarget 2019 Jan 29;10(9):942-952. Epub 2019 Jan 29.

Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.

Background: The concept of personalized medicine defines a promising approach in cancer care. High-throughput genomic profiling of tumor specimens allows the identification of actionable mutations that potentially lead to tailored treatment for individuals' benefit. The aim of this study was to prove efficacy of a personalized treatment option in solid tumor patients after failure of standard treatment concepts.

Results: Final analysis demonstrates that 34 patients (62%) had a longer PFS upon experimental treatment (PFS1) when compared to previous therapy (PFS0); PFS ratio > 1.0 ( = 0.002). The median PFS under targeted therapy based on molecular profiling (PFS1) was 112 days (quartiles 66/201) and PFS0 = 61 days (quartiles 51/92; = 0.002). Of the 55 patients, 31 (56%) showed disease control (DCR), consisting of 2 (4%) patients which achieved a complete remission, 14 (25%) patients with a partial remission and 15 (27%) patients who had a stabilization of disease. Median OS from start of experimental therapy was 348 days (quartiles 177/664).

Conclusion: The prospective trial EXACT suggests that treatment based on real-time molecular tumor profiling leads to superior clinical benefit.

Materials And Methods: In this prospective clinical phase II trial, 55 cancer patients, after failure of standard treatment options, aimed to achieve a longer progression-free survival on the experimental treatment based on the individual's molecular profile (PFS1) when compared to the last treatment given before (PFS0). The personalized medicine approach was conceived to be clinical beneficial for patients who show a PFS ratio (PFS 1/PFS0) of > 1.0.
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http://dx.doi.org/10.18632/oncotarget.26604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398177PMC
January 2019

Solid predominant subtype in lung adenocarcinoma is related to poor prognosis after surgical resection: A systematic review and meta-analysis.

Eur J Surg Oncol 2019 Jul 4;45(7):1156-1162. Epub 2019 Feb 4.

Division of Thoracic Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. Electronic address:

Background: Recent studies have indicated that solid predominant (SP) subtype of lung adenocarcinoma (LADC) may be associated with early recurrence and worse prognosis. Hence, a systematic review and meta-analysis were performed to evaluate the association between LADC subtype and survival.

Methods: The MEDLINE, SCOPUS, Web of Science and Cochrane Libraries were reviewed for eligible studies in December 2017. Studies were included if they compared outcomes of patients with and without SP subtype in resection specimens of LADC patients after surgical treatment by using multivariate Cox regression analysis. A meta-analysis for overall survival (OS) and disease-free survival (DFS) was performed. The hazard ratios (HR) or odds ratios with 95% confidence intervals (CIs) from each study were used to calculate pooled HRs. Statistical analyses were performed using Review Manager 5.3.

Results: In total, 14 eligible studies including 12,137 LADC patients were identified, which assessed the impact of SP subtype on OS and DFS in patients treated with pulmonary resection. SP subtype was reported in 1246 (10.2%) patients and was associated with significantly worse OS (pooled HR, 1.51; 1.29-1.75) and DFS (pooled HR, 1.26; 1.14-1.40).

Conclusions: SP subtype is associated with significantly worse OS and DFS in patients with LADC after pulmonary resection. These data provide evidence for the integration of the distinct histological LADC subtyping into prognostic tools and guidelines for adjuvant treatment after complete surgical resection.
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http://dx.doi.org/10.1016/j.ejso.2019.01.220DOI Listing
July 2019

Fly control to prevent diarrhoea in children.

Cochrane Database Syst Rev 2018 12 17;12:CD011654. Epub 2018 Dec 17.

Division of Women and Child Health, Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi, Sind, Pakistan.

Background: Diarrhoeal disease accounts for millions of child deaths every year. Although the role of flies as vectors of infectious diarrhoea has been established, fly control is not often mentioned as an approach to decrease childhood diarrhoea. Theoretically, fly control for decreasing diarrhoea incidence can be achieved by intervening at four different levels: reduction or elimination of fly breeding sites; reduction of sources that attract houseflies; prevention of contact between flies and disease-causing organisms; and protection of people, food, and food utensils from contact with flies.

Objectives: To assess the impact of various housefly control measures on the incidence of diarrhoea and its related morbidity and mortality in children under five years of age.

Search Methods: We searched electronic databases including the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, CINAHL, and LILACS, from database inception to 24 May 2018. We also searched trial registries for relevant grey literature and ongoing trials. We checked the references of the identified studies and reviews. We did not apply any filters for language, publication status (published, unpublished, in press, and ongoing), or publication date.

Selection Criteria: We planned to include randomized controlled trials (RCTs), quasi-RCTs, and controlled before-and-after studies that studied the effect of fly control on diarrhoea in children under five years of age.

Data Collection And Analysis: Two review authors extracted the data and independently assessed the risk of bias in the included study. We planned to contact study authors for additional information, where necessary. We assessed the certainty of the evidence using the GRADE approach.

Main Results: We included one cluster-RCT (491 participants) conducted in Pakistan that evaluated insecticide spraying in the first two years and baited fly traps in the third year. Insecticide spraying reduced the fly population (house index) in the intervention group during the four months of the year when both flies and cases of diarrhoea were more common, but not at other times. On average, this was associated with a reduction in the incidence of diarrhoea in the first year (illustrative mean episodes per child-year in the intervention group was 6.3 while in the control group was 7.1) and second year of the intervention (illustrative mean episodes per child‒year in the intervention group was 4.4 while in the control group was 6.5; rate ratio (RaR) 0.77, 95% confidence interval (CI) 0.67 to 0.89, low-certainty evidence). In the third year of the intervention, the baited fly traps did not demonstrate an effect on the fly population or on diarrhoea incidence (RaR 1.15, 95% CI 0.90 to 1.47, low-certainty evidence).

Authors' Conclusions: The trial, conducted in a setting where there were clear seasonal peaks in fly numbers and associated diarrhoea, shows insecticide spraying may reduce diarrhoea in children. Further research on whether this finding is applicable to other setting is required, as well as work on other fly control methods, their effects, feasibility, costs, and acceptability.
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http://dx.doi.org/10.1002/14651858.CD011654.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302900PMC
December 2018

The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma.

J Mol Med (Berl) 2019 02 11;97(2):231-242. Epub 2018 Dec 11.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria.

No tyrosine kinase inhibitors are approved for malignant pleural mesothelioma (MPM). Preclinical studies identified focal adhesion kinase (FAK) as a target in MPM. Accordingly, we assessed the novel, highly selective FAK inhibitor (BI 853520) in 2D and 3D cultures and in vivo. IC values were measured by adherent cell viability assay. Cell migration and 3D growth were quantified by video microscopy and spheroid formation, respectively. Phosphorylation of FAK, Akt, S6, and Erk was measured by immunoblot. The mRNA expression of the putative tumor stem cell markers SOX2, Nanog, CD44, ALDH1, c-myc, and Oct4 was analyzed by qPCR. Cell proliferation, apoptosis, and tumor tissue microvessel density (MVD) were investigated in orthotopic MPM xenografts. In all 12 MPM cell lines, IC exceeded 5 μM and loss of NF2 did not correlate with sensitivity. No synergism was found with cisplatin in adherent cells. BI 853520 decreased migration in 3 out of 4 cell lines. FAK phosphorylation was reduced upon treatment but activation of Erk, Akt, or S6 remained unaffected. Nevertheless, BI 853520 inhibited spheroid growth and significantly reduced tumor weight, cell proliferation, and MVD in vivo. BI 853520 has limited effect in adherent cultures but demonstrates potent activity in spheroids and in orthotopic tumors in vivo. Based on our findings, further studies are warranted to explore the clinical utility of BI 853520 in human MPM. KEY MESSAGES: Response to FAK inhibition in MPM is independent of NF2 expression or histotype. FAK inhibition strongly interfered with MPM spheroid formation. BI 853520 has been shown to exert anti-tumor effect in MPM.
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http://dx.doi.org/10.1007/s00109-018-1725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348072PMC
February 2019

New insights into the impact of primary lung adenocarcinoma location on metastatic sites and sequence: A multicenter cohort study.

Lung Cancer 2018 12 5;126:139-148. Epub 2018 Nov 5.

National Korányi Institute of Pulmonology, Budapest, Hungary. Electronic address:

Introduction: The presence of organ metastases is a major factor for unfavorable prognosis in lung adenocarcinoma (LADC). However, the influence of primary tumor location on metastatic sites and sequence has not been extensively analyzed.

Methods: We performed a multicenter cohort study, evaluating clinicopathological data of 1126 Caucasian LADC patients, focusing on the distinct location of primary tumors and metastatic sites during disease progression.

Results: Metastases to the lung (p < 0.001), pleura (p < 0.001) and adrenal glands (p < 0.001) occurred earlier during disease progression and central primary tumors were associated with early metastases (OR 1.43, p = 0.02). In secondary exploratory analysis we found that bone metastases were more frequent in patients with central tumors (OR 1.86, p = 0.017), whereas lung metastases in those with peripheral tumors (OR 1.35, p = 0.015). Central primary LADCs were associated with decreased median overall survival (vs. peripheral tumors, 10.2 vs. 22 months) both in univariate (HR 2.075, p = 0.001) and in multivariate (HR 1.558, p < 0.001) analyses and independent from stage and T factor. By subsequent analysis, we found that bone metastases tend to appear together with adrenal and liver metastases, and adrenal with skin, and pleural with pericardial metastases more frequently than expected if metastatic events occurred independently.

Conclusion: This comprehensive large cohort analysis demonstrates metastatic site- and sequence-specific variations in patients with LADC. Central LADC is associated with early metastatic disease, bone involvement and, consequently, decreased survival.
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http://dx.doi.org/10.1016/j.lungcan.2018.11.004DOI Listing
December 2018

A Controlled Impact of Optic Nerve as a New Model of Traumatic Optic Neuropathy in Mouse.

Invest Ophthalmol Vis Sci 2018 11;59(13):5548-5557

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, United States.

Purpose: Traumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma. In this study, we modified the model of controlled cortical impact and adapted it for studying TON.

Methods: We defined new standardized procedures to induce TON in mice, wherein the optic nerve is reproducibly exposed to a graded controlled impact of known velocity to produce a graded deficit in retinal ganglion cell (RGC) electrophysiological functions.

Results: The key results of validating this newly modified model, "controlled orbital impact (COI)," included (1) the injury parameters (velocity as well as contusion depth and time), which were quantifiable and manageable to generate a wide range of TON severities; (2) a reproducible endpoint of diminished positive scotopic threshold response (pSTR) has been achieved without the interference of surgical variability and destruction of surrounding tissues; (3) the contralateral eyes showed no significant difference to the eyes of naïve mice, allowing them to be used as an internal control to minimize interindividual variability among mice; and (4) the occurrence of injury-associated mortality and/or ocular comorbidity was rare.

Conclusions: Taken together, this model overcomes some limitations of prior TON mouse models and provides an innovative platform to identify therapeutic targets for neuroprotection and/or neurorestoration following traumatic ocular injury.
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http://dx.doi.org/10.1167/iovs.18-24773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262644PMC
November 2018

Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation.

J Exp Med 2018 10 6;215(10):2636-2654. Epub 2018 Sep 6.

Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA

Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation-deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism. Whereas RIC increased anti-inflammatory macrophage activation, myeloid cell depletion eliminated the beneficial effects of RIC after ICH. Myeloid-specific inactivation of the metabolic regulator, AMPKα1, attenuated RIC-induced anti-inflammatory macrophage polarization and delayed hematoma resolution, providing a molecular link between RIC and immune activation. Finally, chimera studies implicated myeloid CD36 expression in RIC-mediated neurological recovery after ICH. Thus, RIC, a clinically well-tolerated therapy, noninvasively modulates innate immune responses to improve ICH outcomes. Moreover, immunometabolic changes may provide pharmacodynamic blood biomarkers to clinically monitor the therapeutic efficacy of RIC.
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http://dx.doi.org/10.1084/jem.20171905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170180PMC
October 2018

Current status of G-protein coupled receptors as potential targets against type 2 diabetes mellitus.

Int J Biol Macromol 2018 Oct 17;118(Pt B):2237-2244. Epub 2018 Jul 17.

Department of Biological Sciences, Aliah University, Kolkata 700 160, India. Electronic address:

GPCRs are among the most abundant surface receptors that play diverse roles including cell signalling and molecular transportation. They are major therapeutic receptor targets against various diseases like cancer and diabetes. A number of new GPCRs are being consistently being identified and deorphanised. Among them, some GPCRs are constitutively expressed while others are down-regulated. New therapeutic agents in the form of small molecule, synthetic peptides, and recombinant nucleic acids and proteins act as antagonists and agonists against various GPCR targets that potentially regulate glucose homeostasis. In the current review, we intend to summarize the various categories of GPCRs. At the same time, we intend to highlight the major GPCRs that have been targeted by various pharmaceutical companies against diabetes mellitus. In addition, we intended to summarize the most recently identified orphan GPCRs and their therapeutic potential against diabetes.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.07.091DOI Listing
October 2018

The BET-inhibitor PFI-1 diminishes AR/AR-V7 signaling in prostate cancer cells.

World J Urol 2019 Feb 22;37(2):343-349. Epub 2018 Jun 22.

Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.

Objective: The bromodomain and extra-terminal (BET) family of proteins provides a scaffolding platform for the recruitment and tethering of transcription factors to acetylated chromatin, thereby modulating gene expression. In this study, we evaluated the efficacy of the BET-inhibitor PFI-1 to diminish AR/AR-V7 signaling and proliferation in castration-resistant prostate cancer cells.

Methods: Prostate-specific antigen and androgen receptor (AR) protein were quantified by means of two commercial ELISAs. Transactivation of the AR, AR-V7 and Q641X was determined by reporter gene assays. Cell proliferation was measured using a colorimetric MTT-assay.

Results: PFI-1 dose-dependently inhibited transactivation of full-length AR (non- mutated, i.e., wild-type or point-mutated/promiscuous forms) without affecting their cellular protein levels. Moreover, PFI-1 was active against C-terminally truncated constitutively active ARs like AR-V7 and Q641X. Prostate cancer cells exhibiting a transcriptionally active AR-signaling complex (LNCaP, 22Rv1) were more susceptible to the growth-inhibitory effects than the AR-negative PC-3 cells.

Conclusion: The quinazolinone PFI-1 is a highly efficient inhibitor of AR-signaling-competent prostate cancer cells in vitro. PFI-1 could serve as a lead compound for the development of new therapeutics able to block AR/AR-V7 signaling in advanced prostate cancer.
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http://dx.doi.org/10.1007/s00345-018-2382-8DOI Listing
February 2019

Nintedanib Is Active in Malignant Pleural Mesothelioma Cell Models and Inhibits Angiogenesis and Tumor Growth .

Clin Cancer Res 2018 08 3;24(15):3729-3740. Epub 2018 May 3.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Centre Vienna, Medical University Vienna, Austria.

Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase II MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase III trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting. We have examined the antineoplastic activity of nintedanib in various and models of human MPM. Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant antivascular and antitumor potential independently of baseline VEGF-A levels. Nintedanib exerts significant antitumor activity in MPM both and These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1507DOI Listing
August 2018

Controversies in oncology: surgery for small cell lung cancer? It's time to rethink the case.

ESMO Open 2018 27;3(3):e000366. Epub 2018 Apr 27.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1136/esmoopen-2018-000366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926649PMC
April 2018

FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal.

Carcinogenesis 2018 04;39(4):534-545

Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna.

Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGFβ or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma.
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http://dx.doi.org/10.1093/carcin/bgy018DOI Listing
April 2018

Malignant pleural mesothelioma-the impact of globalization on rare diseases.

J Thorac Dis 2018 Feb;10(2):638-640

Mesothelioma Program, Department of Thoracic Surgery and Thoracic Endoscopy, University Medicine Essen-Ruhrlandklinik, Essen, Germany.

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http://dx.doi.org/10.21037/jtd.2017.12.139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864653PMC
February 2018

Author Correction: Down-regulated GATA-1 up-regulates interferon regulatory factor 3 in lung adenocarcinoma.

Sci Rep 2018 Mar 6;8(1):4299. Epub 2018 Mar 6.

Dpartment of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-22517-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840352PMC
March 2018

Bladder Distension as a Cause of Abdominal Compartment Syndrome.

J Coll Physicians Surg Pak 2018 Feb;28(2):155-156

Department of Anaesthetic, Manchester Royal Infirmary Hospital, Oxford Road, Manchester.

Abdominal compartment syndrome (ACS) is increasingly identified in critically ill patient and its harmful effects are well documented. The disparity among the pressure, volume in abdominal cavity and its contents, results in ACS. The actual incidence of ACS is not known. However, it has been observed predominantly in patients with severe blunt and penetrating abdominal trauma, ruptured abdominal aortic aneurysms, retro- and intra-peritoneal hemorrhage, pneumoperitoneum, neoplasm, pancreatitis, ascites and multiple bone fracture. We present a case of 40-year female who underwent emergency cesarean section and developed abdominal compartment syndrome due to urinary bladder distension secondary to blockade of urinary catheter with blood clots. This is a very unusual cause of ACS.
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http://dx.doi.org/10.29271/jcpsp.2018.02.155DOI Listing
February 2018

Stabilizers influence drug-polymer interactions and physicochemical properties of disulfiram-loaded poly-lactide-co-glycolide nanoparticles.

Future Sci OA 2018 Feb 13;4(2):FSO263. Epub 2017 Dec 13.

Department of Biochemistry & Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, 605 014, India.

Aim: Stabilizers are known to be an integral component of polymeric nanostructures. Ideally, they manipulate physicochemical properties of nanoparticles. Based on this hypothesis, we demonstrated that disulfiram (drug) and Poly-lactide-co-glycolide (polymer) interactions and physicochemical properties of their nanoparticles formulations are significantly influenced by the choice of stabilizers.

Methodology: Electron microscopy, differential scanning calorimetry, x-ray diffraction, Raman spectrum analysis, isothermal titration calorimetry and docking studies were performed.

Results & Discussion: Polysorbate 80 imparted highest crystallinity while Triton-X 100 imparted highest rigidity, possibly influencing drug bioavailability, blood-retention time, cellular uptake and sustained drug release. All the molecular interactions were hydrophobic in nature and entropy driven. Therefore, polymeric nanoparticles may be critically manipulated to streamline the passive targeting of drug-loaded nanoparticles.
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http://dx.doi.org/10.4155/fsoa-2017-0091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778387PMC
February 2018
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