Evidence for Msh2 haploinsufficiency in mice revealed by MNU-induced sister-chromatid exchange analysis

The role of Msh2 in chromosome stability has been investigated in a targeted mouse model for HNPCC Msh2Δ7N. Chromosome aberration frequencies were similar in bone marrow of Msh2+/+Msh2+/–and Msh2–/–mice and no differential effects of in vivo X-irradiation were noted. By contrast, the induction of sister-chromatid exchanges (SCEs) by methyl nitrosourea (MNU) was reduced in Msh2–/–and Msh2+/–cells to ~20% and ~45% wild-type levels respectively indicating a phenotypic effect of haploinsufficiency of the mouse Msh2 gene. © 2000 CancerResearch Campaig

Midgut neuroendocrine tumor patients have a depleted gut microbiome with a discriminative signature

Rationale: When compared to other types of cancer, the prevalence of midgut neuroendocrine tumors (NET) has disproportionally increased over the past decades. To date, there has been very little progress in discovering (epi)genetic drivers and treatment options for these tumors. Recent microbiome research has revealed that enteroendocrine cells communicate with the intestinal microbiome and has provided novel treatment targets for various other cancer types. Hence, our aim was to analyze the role of the gut microbiome in midgut NET patients. Methods: Fecal samples, prospectively collected from patients and control subjects, were analyzed with next generation 16S sequencing. Patients with neuroendocrine carcinomas and recent antibiotics use were excluded. Relevant variables were extracted from questionnaires and electronic health records. Microbial composition was compared between patients and controls as well as between groups within the patient cohort. Results: 87 midgut NET patients and 95 controls were included. Midgut NET patients had a less rich and diverse gut microbiome than controls (p &lt; 0.001). Moreover, we identified 31 differentially abundant species and a gut microbial signature consisting of 17 species that was predictive of midgut NET presence with an area under the receiver operating characteristic curve of 0.863. Gut microbial composition was not directly associated with the presence of the carcinoid syndrome, tumor grade or multifocality. Nonetheless, we did observe a potential link between microbial diversity and the presence of carcinoid syndrome symptoms within the subset of patients with elevated 5-hydroxyindolacetic acid levels. Conclusion: Midgut NET patients have an altered gut microbiome which suggests a role in NET development and could provide novel targets for microbiome-based diagnostics and therapeutics.</p

Toepasssing van Aquanox in de glastuinbouw

Wageningen UR Glastuinbouw heeft samen met Reinders Vernevelings- en Ontsmettingstechniek het project uitgevoerd naar Toepassingen van Aquanox in de glastuinbouw. Gefinancierd door Productschap Tuinbouw en Ministerie EL&I. Screeningstesten onder laboratoriumcondities geven aan dat er een brede werking is tegen schimmels en bacteriën. Virusdeeltjes in plantensap werden echter nog onvoldoende gedood door geactiveerd water. Screening van het gedrag van insecten op overleving na 24 uur in een vernevelingsbehandeling met Aquanox gaf geen doding op natuurlijke plaagbestrijders. Een lichte bestrijdende werking werd gevonden op witte vlieg, spintmijt en Californische trips. De proeven met tomaat, komkommer, roos, Poinsettia en gerbera geven aan dat er een bestrijdend effect is van geactiveerd water tegen echte meeldauw en Botrytis. Het vervolgonderzoek zal gericht zijn op vermindering van corrosierisico’s en vermindering van risico op gewasschade binnen diverse toepassingen in de teel

Role of the mTOR pathway in normal and tumoral adrenal cells

The mammalian target of rapamycin (mTOR) is a kinase of the phosphoinositide 3-kinase (PI3Ks)/protein kinase B (PKB or AKT) signaling pathway, which is one of the most important intracellular mediators of the activity of growth factors receptors, including vascular endothelial growth factor (VEGF) and insulin-like growth factors (IGFs). Dysregulation of the mTOR pathway has been found in many human tumors. Therefore, the mTOR pathway is considered as a target for antineoplastic therapy in several malignancies. Presently, the role and functions of mTOR and its signaling pathway in the normal and pathological adrenal gland has not been clarified yet. However, many growth factors and growth factor receptors, which are considered to play a role in the pathogenesis of adrenal tumors, can at least in part exert their effects through the activation of PI3K/AKT/mTOR pathway. Dysregulation of AKT has been reported in adrenocortical carcinomas and adrenomedullary tumors, named pheochromocytomas. Adrenocortical carcinomas and malignant pheochromocytomas are aggressive tumors with poor prognosis and scant treatment options. Therefore, new treatment options are warranted for these malignancies. On the basis of the current knowledge, mTOR could play a role in the pathogenesis of both adrenocortical carcinomas and pheochromocytomas. Moreover, mTOR inhibitors, interfering with the activation of several mitogenic and angiogenic factors, could be considered as a novel treatment opportunity for the management of malignant adrenal tumors

Future treatment strategies of aggressive pituitary tumors

While surgery remains the first-line treatment of most aggressive pituitary adenomas, medical therapy is important as second-line or adjunctive therapy in a large proportion of patients. Dopamine agonists (DAs) are the best treatment for prolactinomas, but when DAs are not tolerated, new somatostatin receptor subtype 5 (SSTR5) inhibitors may offer an alternative in the future. Unfortunately, these are unlikely to be effective in DA-resistant prolactinomas. In acromegaly, the existing somatostatin analogs, octreotide and lanreotide, will remain the medical treatment of choice for the foreseeable future. There is an urgent need for medical therapies in Cushing’s disease, and the SSTR5 analogs could offer an effective treatment in a proportion of patients within the next few years. Finally, the medical management options for non-functioning pituitary adenomas are also very limited, and a new chimeric agent with activity towards dopamine receptors, SSTR5 and SSTR2 may help reduce adenoma recurrence in the future

Physiological and pathophysiological role of somatostatin receptors in the human thymus

This is a review summarizing the physiological and pathophysiological role of somatostatin receptors in the human thymus

The medical treatment of Cushing's disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery

BACKGROUND: The role of dopamine agonists in the treatment of Cushing's disease (CD) has been previously debated. AIM: The aim of this study was to evaluate the effectiveness of short-term (3 months) and long-term (12-24 months) treatment with cabergoline in patients with CD. Patients and Methods: 20 patients with CD unsuccessfully treated by surgery entered the study. Cabergoline was administered at an initial dose of 1 mg/wk, with a monthly increase of 1 mg, until urinary cortisol levels normalized or the maximal dose of 7 mg/wk was achieved. The responsiveness to treatment was evaluated according to changes in urinary cortisol excretion. A decrease greater than 25% was considered as a partial response, whereas complete normalization was considered as a full response at short-term evaluation; persistence of normal cortisol excretion was the only criterion to evaluate the response at long-term evaluation. RESULTS: After short-term treatment, 15 (75%) patients were responsive to cabergoline treatment. Among these, normalization of cortisol excretion was maintained in 10, whereas treatment escape was observed in five patients after 6-18 months. Among the 10 long-term responsive patients, eight were followed for 24 months, whereas the remaining two were followed for 12-18 months, due to cabergoline withdrawal for intolerance. A sustained control of cortisol secretion for 24 month cabergoline treatment at the maximal dose ranging from 1-7 mg/wk (median: 3.5) without significant side effects, was obtained in eight of 20 (40%) patients. CONCLUSIONS: The results of this study demonstrated that cabergoline treatment is effective in controlling cortisol secretion for at least 1-2 yr in more than one third of a limited population of patients with CD. If this evidence is confirmed by additional studies, this agent may be considered as a useful treatment option in patients with CD who are unsuccessfully treated by neurosurgery

Onderzoek naar de oorzaak van 'zwarte vaten in radijs'

Op één Nederlands radijsbedrijf treedt vanaf de herfst van 2007 een verschijnsel op, waarbij radijsknollen bruine tot zwarte vaatbundels vertonen. De radijsplantjes blijven veelal achter in groei of gaan dood. Uitwendig is de verkleuring niet altijd waarneembaar, waardoor deze knollen toch in het handelskanaal terecht kunnen komen. Sinds het voorjaar van 2008 is het verschijnsel ook op een ander bedrijf opgetreden. Op de betreffende bedrijven breidt het verschijnsel zich elk jaar uit en leidt tot veel schade in het winterhalfjaar. Een bekende ziekteverwekker is in voorgaande onderzoeken niet geïsoleerd, daarom is er in dit onderzoek verder gezocht om een onbekende ziekteverwekker te kunnen identificeren. Gedurende dit onderzoek is er vastgesteld dat de ziekte overdraagbaar is via grond en wordt veroorzaakt door de bacterie Stenotrophomonas spp. De bacterie is geïsoleerd uit geïnfecteerde knollen, er is een moleculaire analyse gemaakt van de isolaten en de postulaten van Koch zijn toegepast. Op basis van de analyse en het terug toetsen van het pathogeen kan worden geconcludeerd dat Stenotrophomonas spp. verantwoordelijk is voor de symptomen in het gewas