Signals from the tumor microenvironment trigger cancer cells to adopt an invasive phenotype through epithelial-mesenchymal transition (EMT). Relatively little is known regarding key signal ...transduction pathways that serve as cytosolic bridges between cell surface receptors and nuclear transcription factors to induce EMT. A better understanding of these early EMT events may identify potential targets for the control of metastasis. One rapid intracellular signaling pathway that has not yet been explored during EMT induction is calcium. Here we show that stimuli used to induce EMT produce a transient increase in cytosolic calcium levels in human breast cancer cells. Attenuation of the calcium signal by intracellular calcium chelation significantly reduced epidermal growth factor (EGF)- and hypoxia-induced EMT. Intracellular calcium chelation also inhibited EGF-induced activation of signal transducer and activator of transcription 3 (STAT3), while preserving other signal transduction pathways such as Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. To identify calcium-permeable channels that may regulate EMT induction in breast cancer cells, we performed a targeted siRNA-based screen. We found that transient receptor potential-melastatin-like 7 (TRPM7) channel expression regulated EGF-induced STAT3 phosphorylation and expression of the EMT marker vimentin. Although intracellular calcium chelation almost completely blocked the induction of many EMT markers, including vimentin, Twist and N-cadherin, the effect of TRPM7 silencing was specific for vimentin protein expression and STAT3 phosphorylation. These results indicate that TRPM7 is a partial regulator of EMT in breast cancer cells, and that other calcium-permeable ion channels are also involved in calcium-dependent EMT induction. In summary, this work establishes an important role for the intracellular calcium signal in the induction of EMT in human breast cancer cells. Manipulation of calcium-signaling pathways controlling EMT induction in cancer cells may therefore be an important therapeutic strategy for preventing metastases.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In one comparison from a 2-by-2 factorial trial, 12,705 persons at intermediate cardiovascular risk were assigned to either rosuvastatin or placebo. At 5.6 years, there were significantly fewer ...participants with cardiovascular events in the rosuvastatin group than in the placebo group.
Cardiovascular diseases cause 18 million deaths per year globally and a similar number of nonfatal cardiovascular events.
1
Elevated low-density lipoprotein (LDL) cholesterol levels account for approximately half the population-attributable risk of myocardial infarction
2
and approximately one quarter of the risk of ischemic stroke.
3
In previous trials, lowering LDL cholesterol levels with statins has been shown to reduce the risk of cardiovascular diseases, but most of the patients enrolled in those trials had vascular disease, elevated lipid levels, elevated inflammatory markers, hypertension, or diabetes.
4
,
5
The association between LDL cholesterol level and cardiovascular disease is graded and has no documented threshold. . . .
In this longitudinal study of 1666 persons with diabetes, there was an observed trend toward an increased risk for amputation (χ2 test for trend, 108.0; P < .001), higher-level amputation (χ2 test ...for trend, 113.3; P < .001), and lower extremity—related hospitalization (χ2 test for trend, 118.6; P < .001) with increasing infection severity. The Infectious Diseases Society of America's foot infection classification system may be a useful tool for grading foot infections.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Natural carbon sinks currently absorb approximately half of the anthropogenic CO2 emitted by fossil fuel burning, cement production and land-use change. However, this airborne fraction may change in ...the future depending on the emissions scenario. An important issue in developing carbon budgets to achieve climate stabilisation targets is the behaviour of natural carbon sinks, particularly under low emissions mitigation scenarios as required to meet the goals of the Paris Agreement. A key requirement for low carbon pathways is to quantify the effectiveness of negative emissions technologies which will be strongly affected by carbon cycle feedbacks. Here we find that Earth system models suggest significant weakening, even potential reversal, of the ocean and land sinks under future low emission scenarios. For the RCP2.6 concentration pathway, models project land and ocean sinks to weaken to 0.8 0.9 and 1.1 0.3 GtC yr−1 respectively for the second half of the 21st century and to −0.4 0.4 and 0.1 0.2 GtC yr−1 respectively for the second half of the 23rd century. Weakening of natural carbon sinks will hinder the effectiveness of negative emissions technologies and therefore increase their required deployment to achieve a given climate stabilisation target. We introduce a new metric, the perturbation airborne fraction, to measure and assess the effectiveness of negative emissions.
In ovarian cancer, two of the most important prognostic factors for survival are completeness of staging and completeness of cytoreductive surgery. Therefore, intra-operative visualization of tumor ...lesions is of great importance. Preclinical data already demonstrated tumor visualization in a mouse-model using near-infrared (NIR) fluorescence imaging and indocyanine green (ICG) as a result of enhanced permeability and retention (EPR). The aim of this study was to determine feasibility of intraoperative ovarian cancer metastases imaging using NIR fluorescence imaging and ICG in a clinical setting.
Ten patients suspected of ovarian cancer scheduled for staging or cytoreductive surgery were included. Patients received 20 mg ICG intravenously after opening the abdominal cavity. The mini-FLARE NIR fluorescence imaging system was used to detect NIR fluorescent lesions.
6 out of 10 patients had malignant disease of the ovary or fallopian tube, of which 2 had metastatic disease outside the pelvis. Eight metastatic lesions were detected in these 2 patients, which were all NIR fluorescent. However, 13 non-malignant lesions were also NIR fluorescent, resulting in a false-positive rate of 62%. There was no significant difference in tumor-to-background ratio between malignant and benign lesions (2.0 vs 2.0; P=0.99).
This is the first clinical trial demonstrating intraoperative detection of ovarian cancer metastases using NIR fluorescence imaging and ICG. Despite detection of all malignant lesions, a high false-positive rate was observed. Therefore, NIR fluorescence imaging using ICG based on the EPR effect is not satisfactory for the detection of ovarian cancer metastases. The need for tumor-specific intraoperative agents remains.
ISRCTN Registry ISRCTN16945066.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The microbiome of diabetic foot osteomyelitis van Asten, S. A. V.; La Fontaine, J.; Peters, E. J. G. ...
European journal of clinical microbiology & infectious diseases,
02/2016, Volume:
35, Issue:
2
Journal Article
Peer reviewed
Open access
The purpose of this investigation was to evaluate the diversity of bacteria in diabetic foot osteomyelitis using a 16S rRNA sequencing approach and to compare the results with conventional culture ...techniques. In this prospective observational study, we obtained 34 bone samples from patients admitted to our hospital with a moderate–severe diabetic foot infection. We analysed the distribution of the 16S rRNA gene sequences in the bone samples, using an Illumina MiSeq Personal Sequencer. We compared the genera that were detected with the cultured pathogens in the bone samples with conventional techniques. In the 23 samples that had positive results with both techniques,
Staphylococcus
,
Corynebacterium
,
Streptococcus
and
Propionibacterium
spp. were detected in 20, 18, 13 and 11 samples, respectively. Significantly more anaerobes were detected with 16S rRNA sequencing compared to conventional techniques (86.9 % vs. 23.1 %,
p
= 0.001) and more Gram-positive bacilli were present (78.3 % vs. 3.8 %,
p
< 0.001).
Staphylococcus
spp. were identified in all of the sequenced bone samples that were negative with conventional techniques. Mixed genera were present in 83.3 % (5 of 6) of the negative samples. Anaerobic and fastidious organisms may play a more significant role in osteomyelitis than previously reported. Further studies with larger populations are needed in order to fully understand the clinical importance of the microbial diversity of diabetic foot osteomyelitis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background Endoscopic resection (ER) is an important treatment for high-grade intraepithelial neoplasia and early cancer in Barrett's esophagus. ER-cap requires submucosal lifting and positioning of ...a snare in the cap, making it technically demanding and laborious. Multiband mucosectomy (MBM) uses a modified variceal band ligator and requires no submucosal lifting or positioning of a snare. Objective To compare ER-cap and MBM for piecemeal ER of early Barrett's neoplasia. Design Randomized, controlled trial. Setting Tertiary-care and community-care centers. Patients This study involved 84 patients (64 men; median age 70 years) undergoing piecemeal ER of Barrett's neoplasia. Intervention Piecemeal ER was performed by using ER-cap (n = 42) or MBM (n = 42). Main Outcome Measurements Safety, efficacy, procedure time, costs. Results Procedure time (34 vs 50 minutes; P = .02) and costs (€240 vs €322; P < .01) were significantly less with MBM compared with ER-cap. MBM resulted in smaller resection specimens than ER-cap (18 ×13 mm vs 20 × 15 mm; P < .01). Maximum thicknesses of specimens and resected submucosa were not significantly different. There were no clinically relevant bleeding episodes. Four perforations occurred, 3 with ER-cap, 1 with MBM ( P = not significant). Limitations Potential bias because of different levels of experience among participating endoscopists. Conclusion Piecemeal ER with MBM is faster and cheaper than with ER-cap. Despite the lack of submucosal lifting, MBM appears not to be associated with more perforations. Although MBM results in slightly smaller specimens, the clinical relevance of this may be limited because depth of resections does not differ between both techniques. MBM may thus be preferred for piecemeal ER of early Barrett's neoplasia. (Clinical trial registration number: NTR1435.)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background
The optimal treatment sequence for patients with rectal cancer and synchronous liver metastases remains unclear. The aim of this study was to evaluate the feasibility and effectiveness of ...short‐course pelvic radiotherapy (5 × 5 Gy) followed by systemic therapy and local treatment of all tumour sites in patients with potentially curable stage IV rectal cancer in daily practice.
Methods
This was a retrospective study performed in eight tertiary referral centres in the Netherlands. Patients aged 18 years or above with rectal cancer and potentially resectable liver ± extrahepatic metastases, treated between 2010 and 2015, were eligible. Main outcomes included full completion of treatment schedule, symptom control and survival.
Results
In total, 169 patients were included with a median follow‐up of 49·5 (95 pr cent c.i. 43·6 to 55·6) months. The completion rate for the entire treatment schedule was 65·7 per cent. Three‐year progression‐free survival and overall survival (OS) rates were 24·2 (95 per cent c.i. 16·6 to 31·6) and 48·8 (40·4 to 57·2) per cent respectively. Median OS of patients who responded well and completed the treatment schedule was 51·5 months, compared with 15·1 months for patients who did not complete the treatment (P < 0·001). Adequate symptom control of the primary tumour was achieved in 87·0 per cent of all patients.
Conclusion
Multimodal treatment leads to relief of symptoms in most patients, and is associated with good survival rates in those able to complete the schedule. Correction added on 12 February 2020, after first online publication: the Conclusion has been reworded for clarity
Antecedentes
La secuencia óptima de tratamiento en pacientes con cáncer de recto y metástasis hepáticas sincrónicas sigue sin estar clara. El objetivo de este estudio fue evaluar en la práctica diaria la viabilidad y efectividad de la radioterapia pélvica de ciclo corto (5 x 5 Gy) seguida de tratamiento sistémico y tratamiento local de todas las localizaciones del tumor primario en pacientes con cáncer de recto estadio IV potencialmente curables.
Métodos
Estudio retrospectivo realizado en ocho centros terciarios de referencia en Holanda. Se consideró elegibles a los pacientes mayores de 18 años con cáncer de recto y metástasis hepáticas ± extrahepáticas potencialmente resecables, que fueron tratados entre 2010 y 2015. Los criterios de valoración principales incluyeron la finalización completa del programa de tratamiento, el control de los síntomas y la supervivencia.
Resultados
En total se incluyeron 169 pacientes con una mediana de seguimiento de 50 meses (rango 2‐89 meses). La tasa de finalización del programa de tratamiento completo fue del 65,7%. Las tasas de supervivencia libre de progresión a 3 años y supervivencia global (overall survival, OS) fueron 24,2% (i.c. del 95% 16,6‐31,6) y 48,8% (i.c. del 95% 40,4‐57,2), respectivamente. La mediana de OS de los pacientes que respondieron bien y completaron el programa de tratamiento fue de 51,5 meses, en comparación con 15,1 meses en pacientes que no completaron el tratamiento (P < 0,001). Se logró un control adecuado de los síntomas del tumor primario en el 87,0% de todos los pacientes.
Conclusión
El tratamiento multimodal consigue paliar los síntomas en la mayoría de los pacientes y se asocia con buenas tasas de supervivencia en aquellos pacientes que pueden completar el programa.
Treatment of patients with potentially curable stage IV rectal cancer with short‐course pelvic radiotherapy followed by systemic therapy and local treatment of all tumour sites is a feasible and effective schedule. Long‐term survival was accomplished in one‐third of patients, while providing adequate symptom relief in the majority of the other patients.
Good results
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In a randomized trial involving patients who had a first stroke from an embolus of unknown source, rivaroxaban at a daily dose of 15 mg did not result in a lower incidence of recurrent stroke than ...aspirin at a dose of 100 mg. Bleeding rates were higher with rivaroxaban.
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