The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus.

SIGNIFICANCE: Metabolic syndrome is a frequent precursor of type 2 diabetes mellitus (T2D), a disease that currently affects ∼8% of the adult population worldwide. Pancreatic beta-cell dysfunction and loss are central to the disease process, although understanding of the underlying molecular mechanisms is still fragmentary. RECENT ADVANCES: Oversupply of nutrients, including glucose and fatty acids, and the subsequent overstimulation of beta cells, are believed to be an important contributor to insulin secretory failure in T2D. Hypoxia has also recently been implicated in beta-cell damage. Accumulating evidence points to a role for oxidative stress in both processes. Although the production of reactive oxygen species (ROS) results from enhanced mitochondrial respiration during stimulation with glucose and other fuels, the expression of antioxidant defense genes is unusually low (or disallowed) in beta cells. CRITICAL ISSUES: Not all subjects with metabolic syndrome and hyperglycemia go on to develop full-blown diabetes, implying an important role in disease risk for gene-environment interactions. Possession of common risk alleles at the SLC30A8 locus, encoding the beta-cell granule zinc transporter ZnT8, may affect cytosolic Zn(2+) concentrations and thus susceptibility to hypoxia and oxidative stress. FUTURE DIRECTIONS: Loss of normal beta-cell function, rather than total mass, is increasingly considered to be the major driver for impaired insulin secretion in diabetes. Better understanding of the role of oxidative changes, its modulation by genes involved in disease risk, and effects on beta-cell identity may facilitate the development of new therapeutic strategies to this disease. Antioxid. Redox Signal. 00, 000-000

Solving Problems on Graphs of High Rank-Width

A modulator of a graph G to a specified graph class H is a set of vertices whose deletion puts G into H. The cardinality of a modulator to various tractable graph classes has long been used as a structural parameter which can be exploited to obtain FPT algorithms for a range of hard problems. Here we investigate what happens when a graph contains a modulator which is large but "well-structured" (in the sense of having bounded rank-width). Can such modulators still be exploited to obtain efficient algorithms? And is it even possible to find such modulators efficiently? We first show that the parameters derived from such well-structured modulators are strictly more general than the cardinality of modulators and rank-width itself. Then, we develop an FPT algorithm for finding such well-structured modulators to any graph class which can be characterized by a finite set of forbidden induced subgraphs. We proceed by showing how well-structured modulators can be used to obtain efficient parameterized algorithms for Minimum Vertex Cover and Maximum Clique. Finally, we use well-structured modulators to develop an algorithmic meta-theorem for deciding problems expressible in Monadic Second Order (MSO) logic, and prove that this result is tight in the sense that it cannot be generalized to LinEMSO problems.Comment: Accepted at WADS 201

Current concepts in stereotactic radiosurgery - a neurosurgical and radiooncological point of view

Stereotactic radiosurgery is related to the history of "radiotherapy" and "stereotactic neurosurgery". The concepts for neurosurgeons and radiooncologists have been changed during the last decade and have also transformed neurosurgery. The gamma knife and the stereotactically modified linear accelerator (LINAC) are radiosurgical equipments to treat predetermined intracranial targets through the intact skull without damaging the surrounding normal brain tissue. These technical developments allow a more precise intracranial lesion control and offer even more conformal dose plans for irregularly shaped lesions. Histological determination by stereotactic biopsy remains the basis for any otherwise undefined intracranial lesion. As a minimal approach, it allows functional preservation, low risk and high sensitivity. Long-term results have been published for various indications. The impact of radiosurgery is presented for the management of gliomas, metastases, brain stem lesions, benign tumours and vascular malformations and selected functional disorders such as trigeminal neuralgia. In AVM's it can be performed as part of a multimodality strategy including resection or endovascular embolisation. Finally, the technological advances in radiation oncology as well as stereotactic neurosurgery have led to significant improvements in radiosurgical treatment opportunities. Novel indications are currently under investigation. The combination of both, the neurosurgical and the radiooncological expertise, will help to minimize the risk for the patient while achieving a greater treatment success

Chest wall and intrathoracic desmoid tumors: surgical experience and review of the literature

Desmoid tumors are fibroblastic/myofibroblastic neoplasms, which originate from musculo-aponeurotic structures and are classified as deep fibromatoses. Despite their benign histologic appearance and lack of metastatic potential, desmoid tumors may cause aggressive local infiltrations and compression of surrounding structures. They are often associated with female gender, familial adenomatous polyposis (FAP) and sporadically may occur at sites of previous trauma, scars or irradiation. Molecular studies have demonstrated that these patients are associated with a bi-allelic APC mutation in the affected tissue. Radical tumor resection with free margins remains the first therapy of choice. In cases with anatomical or technical limitations for a wide excision, radiation therapy represents a proven and effective alternative or supplementary treatment

Sunitinib induced pyoderma gangrenosum-like ulcerations

Pyoderma gangrenosum is a non-infectious neutrophilic skin disease commonly associated with underlying systemic diseases. Histopathological and laboratory diagnostics are unspecific in the majority of the cases and the diagnosis is made in accordance with the clinical picture. Here, we report the case of a 69-year old man with progredient pyoderma gangrenosum-like ulcerations under treatment with sunitinib due to hepatocellular carcinoma. A conventional ulcer therapy did not lead to a regression of the lesions. Solely cessation of sunitinib therapy resulted in an improvement of the ulcerations. Sunitinib is a multikinase inhibitor that targets the PDGF-α - and -β-, VEGF-1-3-, KIT-, FLT3-, CSF-1- and RET-receptor, thereby impairing tumour proliferation, pathological angiogenesis and metastasation. Here, we demonstrate that pyoderma gangrenosum-like ulcers may represent a serious side effect of sunitinib-based anti-cancer treatment

Gene expression of circulating tumour cells and its correlation with tumour stage in breast cancer patients

<p>Abstract</p> <p>Background</p> <p>Breast cancer (BC) represents one of the leading causes of cancer related deaths worldwide. New tools for diagnostic staging and therapeutic monitoring are needed to improve individualized therapies and improve clinical outcome. The analyses of circulating tumour cells may provide important prognostic information in the clinical setting.</p> <p>Materials and methods</p> <p>Circulating tumour cells (CTC) of 63 BC patients were isolated from peripheral blood (PB) through immunomagnetic separation. Subsequently, RT-PCR or mPCR for the genes <it>ga733.2</it>, <it>muc-1</it>, <it>c-erbB2</it>, <it>mgb-1</it>, <it>spdef </it>and <it>c-erbB2 </it>were performed. Subsequently, expression data were correlated with the tumour stages. Fourteen healthy individuals served as controls.</p> <p>Results</p> <p>Significant correlations with tumour stages were found in single gene analyses of <it>ga733.2</it>, <it>muc-1 </it>and in multi-gene analyses of <it>ga733.2</it>/<it>muc-1</it>/<it>mgb1</it>/<it>spdef</it>. Furthermore, a significant correlation of <it>Ca 15-3 </it>and all studied genes was also observed.</p> <p>Conclusion</p> <p>Herein, we demonstrated a positive correlation of a gene signature consisting of <it>ga733.2</it>, <it>muc-1</it>, <it>mgb1 </it>and <it>spdef </it>and advanced stages of BC. Moreover, all studied genes and gene patterns revealed a significant correlation with <it>Ca 15-3 </it>positive cases.</p

The role of neoadjuvant and adjuvant treatment for adenocarcinoma of the upper gastrointestinal tract

Both locally advanced adenocarcinoma of the stomach and gastro-esophageal junction are associated with poor prognosis due to the lack of effective treatment. Recently multimodal treatment consisting of neoadjuvant chemotherapy in combination with radiotherapy is reported to improve survival when compared to surgery alone. Neoadjuvant therapy in these locally advanced tumors allows for early tumor responses and the extent of tumor regression that can be achieved is considered a significant prognostic factor. This, in turn, increases the resectability of these tumors. Also due to the high frequency of lymph node metastasis, patients with locally advanced adenocarcinoma should undergo a D2 lymphadenectomy. Postoperative chemoradiation and perioperative chemotherapy have been studied in gastric adenocarcinomas and showed a survival benefit. However, the surgical techniques used in these trials are no longer considered to be standard by today's surgical practice. In addition, there are no standard recommendations for adjuvant chemotherapy or chemoradiation after R0 resection and adequate lymph node dissection