Background and study aim
Complete esophageal obstruction after (chemo)radiation for head and neck cancers is rare. However, inability to swallow one’s own saliva strongly inflicts upon quality of ...life. Techniques for endoscopic recanalization in complete obstruction are not well established. We assessed the efficacy and safety of rendezvous recanalization.
Patients and methods
We performed a retrospective review of all patients who underwent endoscopic recanalization of complete proximal esophageal obstruction after radiotherapy between January 2009 and June 2016. Technical success was defined as an ability to pass an endoscope across the recanalized lumen, clinical success by changes in the dysphagia score. Adverse events were recorded prospectively.
Results
19 patients with complete obstruction (dysphagia IV°), all of whom had failed at least one trial of conventional dilatation, underwent recanalization by endoscopic rendezvous, a combined approach through a gastrostomy and perorally under fluoroscopic control. Conscious sedation was used in all patients. In 18/19 patients (94.7%), recanalization was technically successful. In 14/18 patients (77.8%), the post-intervention dysphagia score changed to ≤ II. Three patients had their PEG removed. Factors negatively associated with success were obstruction length of 50 mm; and tumor recurrence for long-term success. No severe complications were recorded.
Conclusions
Rendezvous recanalization for complete esophageal obstruction is a reliable and safe method to re-establish luminal patency. Differences between technical and clinical success rates highlight the importance of additional functional factors associated with dysphagia. Given the lack of therapeutic alternatives, rendezvous recanalization is a valid option to improve dysphagia.
Acute liver failure remains a critical clinical condition, with high mortality rates, and increased apoptosis of hepatocytes represents a key event in the cause of liver failure. Alpha‐1‐antitrypsin ...(AAT) is synthesized and secreted mainly by hepatocytes, and plasma purified AAT is used for augmentation therapy in patients with AAT deficiency. Because AAT therapy exerts antiinflammatory and immune modulatory activities in various experimental models, and it was recently suggested that AAT exerts antiapoptotic activities, we aimed to explore whether administration of AAT may represent a therapeutic strategy to treat acute liver failure in mice. Well‐established preclinical models of acute liver failure such as the Jo2 FAS/CD95 activating model and models of acetaminophen and α‐amanitin poisoning were used. Therapeutic effects of AAT were evaluated by monitoring animal survival, histopathological changes, measurement of caspase activity, and serum cytokine levels. Systemic treatment with AAT significantly decreased Jo2‐induced liver cell apoptosis and prolonged survival of mice. Native and oxidized (lacking elastase inhibitory activity) forms of AAT were equally effective in preventing acute liver injury and showed direct inhibition of active caspase‐3 and −8 in liver homogenates and in a cell‐free system in vitro. Concomitantly, mice treated with AAT showed significantly lower serum levels of tumor necrosis factor alpha (TNF‐α), which also paralleled the reduced activity of ADAM17 (TACE). Noticeably, the increased survival and a reduction of apoptotic hepatocytes were also observed in the α‐amanitin and acetaminophen‐induced liver injury mouse models. Conclusion: Our data suggest that systemic administration of AAT can be a promising therapy to treat acute liver failure and clinical studies to explore this treatment in humans should be initiated. (Hepatology 2014;59:2299–2308)
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that the Notch signalling pathway is important in PDAC initiation and ...maintenance, although the specific cell biological roles of the pathway remain to be established. Here we sought to examine this question in established pancreatic cancer cell lines using the γ-secretase inhibitor IX (GSI IX) to inactivate Notch. Based on the known roles of Notch in development and stem cell biology, we focused on effects on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells. We analyzed the effect of the GSI IX on growth and epithelial plasticity of human pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. Notably, apoptosis was induced after GSI IX treatment and EMT markers were selectively targeted. Furthermore, under GSI IX treatment, decline in the growth of pancreatic tumor initiating CD44+/EpCAM+ cells was observed in vitro and in a xenograft mouse model. This study demonstrates a central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit selectively EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
As technical developments in omics and biomedical imaging increase the throughput of data generation in life sciences, the need for information systems capable of managing heterogeneous digital ...assets is increasing. In particular, systems supporting the findability, accessibility, interoperability, and reusability (FAIR) principles of scientific data management.
We propose a Service Oriented Architecture approach for integrated management and analysis of multi-omics and biomedical imaging data. Our architecture introduces an image management system into a FAIR-supporting, web-based platform for omics data management. Interoperable metadata models and middleware components implement the required data management operations. The resulting architecture allows for FAIR management of omics and imaging data, facilitating metadata queries from software applications. The applicability of the proposed architecture is demonstrated using two technical proofs of concept and a use case, aimed at molecular plant biology and clinical liver cancer research, which integrate various imaging and omics modalities.
We describe a data management architecture for integrated, FAIR-supporting management of omics and biomedical imaging data, and exemplify its applicability for basic biology research and clinical studies. We anticipate that FAIR data management systems for multi-modal data repositories will play a pivotal role in data-driven research, including studies which leverage advanced machine learning methods, as the joint analysis of omics and imaging data, in conjunction with phenotypic metadata, becomes not only desirable but necessary to derive novel insights into biological processes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The relative contribution of psychological factors to the onset and course of inflammatory bowel diseases (IBD) is a matter of constant debate since its beginning, as is the clinical need and the ...efficacy of psychotherapeutic interventions. However, the perspective of patients with IBD has largely been ignored in this debate.
Psychometric tests including the Short-Form IBD Questionnaire (SIBDQ), the ADAP test measuring demand for psychotherapy, and the Fear-of-Progression Questionnaire Short Form as well as disease-related questions were positioned on the internet between December 2014 and January 2016. The study was advertised through DCCV (German branch of the European Federation of Crohn's and Ulcerative Colitis Associations).
n = 631 patients responded, and complete data from n = 578 (356 Crohn's disease, 219 ulcerative colitis, 3 unclear) were available for analysis. n = 296 had previous experiences with psychotherapy, whereas n = 282 had not. This distribution clearly determined the factor "demand for psychotherapy" (chi-square = 23.7, P < 0.001). When all available data were entered into a (stepwise-forward) regression model, psychotherapy demand was dependent on previous experience (P < 0.001), fear of progression (P < 0.001), quality of life (P = 0.001), smoking (P = 0.003), and previous surgery (P = 0.005) with the total model explaining 29.7% of the variance. The total explained variance of this model was higher in ulcerative colitis (37.6%) than in Crohn's disease alone (25.4%).
The demand for psychotherapy as additional therapy in IBD depends on previous experience with psychotherapy, fear for disease progression but also other disease or social characteristics and quality of life.
The Hedgehog signaling pathway plays a pivotal role during embryonic development, stem cell maintenance, and wound healing. Hedgehog signaling also is deregulated in many cancers. However, the role ...of this signaling pathway in the carcinogenesis of cholangiocarcinoma (CCC) is still unknown. In this study, we investigated the effects of Hedgehog inhibition by cyclopamine and 5E1 in cultured human CCC cell lines and in vivo using a xenograft mouse model. We also investigated the involvement of Hedgehog in epithelial to mesenchymal transition (EMT), migration, and CCC tumor growth. Sonic hedgehog (Shh) ligand was highly expressed in 89% of human CCC tissues and in CCC cell lines. Cyclopamine and 5E1 treatments effectively inhibited cell proliferation, migration, and invasion by down‐regulating the Hedgehog target genes glioblastoma 1 and glioblastoma 2. In vitro and in vivo, we detected an increase in epithelial marker, E‐cadherin, after Hedgehog inhibition. In addition, we saw an increase in necrotic areas and a decrease in mitotic figures in cyclopamine and 5E1‐treated CCC xenograft tumors. Conclusion: This study supports the presence of autocrine Hedgehog signaling in human CCC, where CCC cells produce and respond to Shh ligand. Blocking the Hedgehog pathway inhibited EMT and decreased the viability of CCC cells. In addition, cyclopamine and 5E1 inhibited the growth of CCC xenograft tumors. (HEPATOLOGY 2013)
The occurrence and spread of multidrug-resistant bacteria is a prominent health concern. To curb this urgent threat, new innovative strategies pursuing novel antimicrobial agents are of the utmost ...importance. Here, we unleashed the antimicrobial activity of human neutrophil peptide-4 (HNP-4) by tryptic digestion. We identified a single 11 amino acid long fragment (HNP-4
1
–
11
) with remarkable antimicrobial potential, exceeding that of the full length peptide on both mass and molar levels. Importantly, HNP-4
1
–
11
was equally bactericidal against multidrug-resistant and non-resistant strains; a potency that was further enhanced by N- and C-terminus modifications (acetylation and amidation, respectively). These observations, combined with negligible cytotoxicity not exceeding that of the full length peptide, presents proteolytic digestion of innate host-defense-peptides as a novel strategy to overcome the current health crisis related to antibiotic-resistant bacteria.
Comorbidities are risk factors for development of severe coronavirus disease 2019 (COVID-19). However, the extent to which an underlying comorbidity influences the immune response to severe acute ...respiratory syndrome coronavirus 2 remains unknown.
Our aim was to investigate the complex interrelations of comorbidities, the immune response, and patient outcome in COVID-19.
We used high-throughput, high-dimensional, single-cell mapping of peripheral blood leukocytes and algorithm-guided analysis.
We discovered characteristic immune signatures associated not only with severe COVID-19 but also with the underlying medical condition. Different factors of the metabolic syndrome (obesity, hypertension, and diabetes) affected distinct immune populations, thereby additively increasing the immunodysregulatory effect when present in a single patient. Patients with disorders affecting the lung or heart, together with factors of metabolic syndrome, were clustered together, whereas immune disorder and chronic kidney disease displayed a distinct immune profile in COVID-19. In particular, severe acute respiratory syndrome coronavirus 2–infected patients with preexisting chronic kidney disease were characterized by the highest number of altered immune signatures of both lymphoid and myeloid immune branches. This overall major immune dysregulation could be the underlying mechanism for the estimated odds ratio of 16.3 for development of severe COVID-19 in this burdened cohort.
The combinatorial systematic analysis of the immune signatures, comorbidities, and outcomes of patients with COVID-19 has provided the mechanistic immunologic underpinnings of comorbidity-driven patient risk and uncovered comorbidity-driven immune signatures.
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Polo-like kinases (Plks) perform crucial functions during mitosis, cytokinesis and centriole duplication. Plk2 is activated in early G1 phase and is involved in the reproduction of centrosomes. ...However, the mechanisms underlying Plk2-induced centriole duplication are incompletely understood. Here, we show that Plk2 directly targets the F-box protein F-box/WD repeat-containing protein 7 (Fbxw7), which is a regulator of the ubiquitin-mediated degradation of cyclin E. Plk2 phosphorylates Fbxw7 on serine 176 and the two proteins form a complex in vitro and in vivo. Phosphorylation of Fbxw7 by Plk2 induces destabilization of the F-box protein resulting in accumulation of cyclin E and increased potential for centriole reproduction. In addition, loss of Fbxw7 in human cells leads to uncontrolled centriole duplication, highlighting the importance of Fbxw7 regulation by Plk2. These findings define a previously unknown Plk2-dependent pathway involved at the onset of S phase and in centrosome duplication.
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