Background Eosinophilic esophagitis (EoE) is a chronic allergic disease with limited treatment options. Objective We evaluated QAX576, an mAb against IL-13, in the treatment of patients with EoE. ...Methods Patients (18-50 years) with proton pump inhibitor–resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1) at weeks 0, 4, and 8 and were followed for 6 months. The primary end point was the responder rate for a greater than 75% decrease in peak eosinophil counts at week 12. Efficacy was to be declared if the lower 90% confidence limit for the proportion of responders on QAX576 was 35% or greater. Secondary end points included changes in esophageal eosinophil counts, symptoms assessed by questionnaire scores, and quantification of a series of biomarkers. Results Twenty-three patients completed the study up to week 12, and 18 continued to the end of the study. For the proximal and distal esophageal biopsies combined, the responder rate was 12.5% (90% confidence limit, 1% to 43%) with placebo, compared to 40.0% (90% confidence limit, 22% to 61%) with QAX576. Although the primary end point was not met, the mean esophageal eosinophil count decreased by 60% with QAX576 versus an increase of 23% with placebo ( P = .004), and the decrease was sustained up to 6 months. There was a trend for improved symptoms, particularly dysphagia. QAX576 improved expression of EoE-relevant esophageal transcripts, including eotaxin-3, periostin, and markers of mast cells and barrier function, for up to 6 months after treatment. QAX576 was well tolerated. Conclusions QAX576 significantly improved intraepithelial esophageal eosinophil counts and dysregulated esophageal disease–related transcripts in adults with EoE in a sustained manner.
Cite this article as: Kaiser SE. Lipid-lowering therapy seen through the lens of experts: Expectations thwarted by reality. Turk Kardiyol Dern Ars. 2022;50(8):550-553.
Objective
To test whether long‐term antihypertensive treatment with metoprolol succinate (a β1‐adrenoceptor blocker) or olmesartan medoxomil (an angiotensin II AT1‐receptor blocker) reverses ...microvascular dysfunction in hypertensive patients.
Methods
This study included 44 hypertensive outpatients and 20 age and sex‐matched healthy controls. We used skin capillaroscopy to measure capillary density and recruitment at rest and during PORH. Endothelium‐dependent vasodilation of skin microcirculation was evaluated with a LDPM system in combination with ACh iontophoresis, PORH, and LTH.
Results
Pretreatment capillary density in hypertensive patients was significantly reduced compared with controls (71.3 ± 1.5 vs. 80.6 ± 1.8 cap/mm2; p < 0.001), as was PORH (71.7 ± 1.5 vs. 79.5 ± 2.6 cap/mm2; p < 0.05). After treatment for six months, capillary density increased to 75.4 ± 1.1 cap/mm2 (p < 0.01) at rest and 76.8 ± 1.1 cap/mm2 during PORH. During LTH, CVC in perfusion units (PU)/mmHg was similar in patients (1.71 1.31–2.12) and controls (1.60 1.12–1.91) and increased significantly (1.82 1.30–2.20) after treatment. Maximal CVC during PORH was reduced in hypertensive patients (0.30 0.22–0.39) compared to controls (0.39 0.31–0.49, p < 0.001) and increased (0.41 0.29–0.51, p < 0.001) after treatment.
Conclusions
Capillary rarefaction and microvascular endothelial dysfunction in hypertensive patients responded favorably to long‐term pharmacological treatment.
Despite the noteworthy advancements and the introduction of new technologies in diagnostic tools for cardiovascular disorders, the electrocardiogram (ECG) remains a reliable, easily accessible, and ...affordable tool to use. In addition to its crucial role in cardiac emergencies, ECG can be considered a very useful ancillary tool for the diagnosis of many non-cardiac diseases as well. In this narrative review, we aimed to explore the potential contributions of ECG for the diagnosis of non-cardiac diseases such as stroke, migraine, pancreatitis, Kounis syndrome, hypothermia, esophageal disorders, pulmonary embolism, pulmonary diseases, electrolyte disturbances, anemia, coronavirus disease 2019, different intoxications and pregnancy.
The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may ...represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5.
We report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear beta-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF).
Cross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and between-modules for next-generation combinatorial therapeutics and improved mouse models.
The pathogenesis and clinical heterogeneity of Parkinson's disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of ...cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into "endotypes". The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.
Malignant peripheral nerve sheath tumors (MPNST) are highly invasive soft tissue sarcomas that arise within the peripheral nerve and frequently metastasize. To identify molecular events contributing ...to malignant transformation in peripheral nerve, we compared eight cell lines derived from MPNSTs and seven normal human Schwann cell samples. We found that MPNST lines are heterogeneous in their in vitro growth rates and exhibit diverse alterations in expression of pRb, p53, p14(Arf), and p16(INK4a) proteins. All MPNST cell lines express the epidermal growth factor receptor and lack S100beta protein. Global gene expression profiling using Affymetrix oligonucleotide microarrays identified a 159-gene molecular signature distinguishing MPNST cell lines from normal Schwann cells, which was validated in Affymetrix microarray data generated from 45 primary MPNSTs. Expression of Schwann cell differentiation markers (SOX10, CNP, PMP22, and NGFR) was down-regulated in MPNSTs whereas neural crest stem cell markers, SOX9 and TWIST1, were overexpressed in MPNSTs. Previous studies have implicated TWIST1 in apoptosis inhibition, resistance to chemotherapy, and metastasis. Reducing TWIST1 expression in MPNST cells using small interfering RNA did not affect apoptosis or chemoresistance but inhibited cell chemotaxis. Our results highlight the use of gene expression profiling in identifying genes and molecular pathways that are potential biomarkers and/or therapeutic targets for treatment of MPNST and support the use of the MPNST cell lines as a primary analytic tool.
Global gene expression analysis provides a comprehensive molecular characterization of non-small cell lung cancer (NSCLC).
To evaluate the feasibility of integrating expression profiling into routine ...clinical work-up by including both surgical and minute bronchoscopic biopsies and to develop a robust prognostic gene expression signature.
Tissue samples from 41 chemotherapy-naive patients with NSCLC and 15 control patients with inflammatory lung diseases were obtained during routine clinical work-up and gene expression profiles were gained using an oligonucleotide array platform (NovaChip; 34'207 transcripts). Gene expression signatures were analyzed for correlation with histological and clinical parameters and validated on independent published data sets and immunohistochemistry.
Diagnostic signatures for adenocarcinoma and squamous cell carcinoma reached a sensitivity of 80%/80% and a specificity of 83%/94%, respectively, dependent on the proportion of tumor cells. Sixty-seven of the 100 most discriminating genes were validated with independent observations from the literature. A 13-gene metagene refined on four external data sets was built and validated on an independent data set. The metagene was a strong predictor of survival in our data set (hazard ratio = 7.7, 95% CI 2.8-21.2) and in the independent data set (hazard ratio = 1.6, 95% CI 1.2-2.2) and in both cases independent of the International Union against Cancer staging. Vascular endothelial growth factor-beta, one of the key prognostic genes, was further validated by immunohistochemistry on 508 independent tumor samples.
Integration of functional genomics from small bronchoscopic biopsies allows molecular tumor classification and prediction of survival in NSCLC and might become a powerful adjunct for the daily clinical practice.
Optimal risk assessment for primary prevention remains highly challenging. Recent registries have highlighted major discrepancies between guidelines and daily practice. Although guidelines have ...improved over time and provide updated risk scores, they still fail to identify a significant proportion of at-risk individuals, who then miss out on effective prevention measures until their initial ischemic events. Cardiovascular imaging is progressively assuming an increasingly pivotal role, playing a crucial part in enhancing the meticulous categorization of individuals according to their risk profiles, thus enabling the customization of precise therapeutic strategies for patients with increased cardiovascular risks. For the most part, the current approach to patients with atherosclerotic cardiovascular disease (ASCVD) is homogeneous. However, data from registries (e.g., REACH, CORONOR) and randomized clinical trials (e.g., COMPASS, FOURIER, and ODYSSEY outcomes) highlight heterogeneity in the risks of recurrent ischemic events, which are especially higher in patients with poly-vascular disease and/or multivessel coronary disease. This indicates the need for a more individualized strategy and further research to improve definitions of individual residual risk, with a view of intensifying treatments in the subgroups with very high residual risk. In this narrative review, we discuss advances in cardiovascular imaging, its current place in the guidelines, the gaps in evidence, and perspectives for primary and secondary prevention to improve risk assessment and therapeutic strategies using cardiovascular imaging.
The modulation of striatal dopamine release by presynaptic nicotinic acetylcholine receptors is well documented for both synaptosomes and slices. Because the latter retain local anatomical integrity, ...we have compared
3Hdopamine release evoked by the nicotinic receptor agonists (−)-nicotine and (±)-anatoxin-a from striatal synaptosome and slice preparations in parallel. At higher agonist concentrations, mecamylamine-sensitive
3Hdopamine release was greater from slices, indicative of an additional component, and this increase was abolished by glutamate receptor antagonists. To begin to examine the localisation of specific nicotinic acetylcholine receptor subtypes in the striatum, immunogold electron microscopy was undertaken with the β2-specific monoclonal antibody 270. In striatal sections, gold particles were associated with symmetric synapses (dopaminergic) but were absent from asymmetric synapses (glutamatergic). Surface labelling of striatal synaptosomes with gold particles was also demonstrated. Taken together, these results are consistent with dopamine release mediated by β2-containing nicotinic acetylcholine receptors on dopamine terminals, while non-β2-containing nicotinic acetylcholine receptors may enhance dopamine release indirectly by releasing glutamate from neighbouring terminals.
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