The European Union has set out to reduce the carbon intensity of its electricity generation substantially, as defined in the European Roadmap 2050. This paper analyses the impact of foresight towards ...decarbonization targets on the investment decisions in the European electricity sector using a specific model developed by the authors called dynELMOD. Incorporating the climate targets makes the investment into any additional fossil capacity uneconomic from 2025 onwards, resulting in a coal and natural gas phase-out in the 2040s. Limited foresight thus results in stranded investments of fossil capacities in the 2020s. Using a CO2 budgetary approach, on the other hand, leads to an even sharper emission reduction in the early periods before 2030, reducing overall costs. We also find that renewables carry the major burden of decarbonization; nuclear power (3rd or 4th generation) is unable to compete with other fuels and will, therefore, be phased out over time.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The proliferative activity of aging hematopoietic stem cells (HSCs) is controversially discussed. Inducible fluorescent histone 2B fusion protein (H2B-FP) transgenic mice are important tools for ...tracking the mitotic history of murine HSCs in label dilution experiments. A recent study proposed that primitive HSCs symmetrically divide only four times to then enter permanent quiescence. We observed that background fluorescence due to leaky H2B-FP expression, occurring in all H2B-FP transgenes independent of label induction, accumulated with age in HSCs with high repopulation potential. We argue that this background had been misinterpreted as stable retention of induced label. We found cell division-independent half-lives of H2B-FPs to be short, which had led to overestimation of HSC divisional activity. Our data do not support abrupt entry of HSCs into permanent quiescence or sudden loss of regeneration potential after four divisions, but show that primitive HSCs of adult mice continue to cycle rarely.
Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, little is known regarding brain functional processes mediating ECT effects.
In a non-randomized ...prospective study, functional magnetic resonance imaging data during the automatic processing of subliminally presented emotional faces were obtained twice, about 6 weeks apart, in patients with major depressive disorder (MDD) before and after treatment with ECT (ECT, n = 24). Additionally, a control sample of MDD patients treated solely with pharmacotherapy (MED, n = 23) and a healthy control sample (HC, n = 22) were obtained.
Before therapy, both patient groups equally showed elevated amygdala reactivity to sad faces compared with HC. After treatment, a decrease in amygdala activity to negative stimuli was discerned in both patient samples indicating a normalization of amygdala function, suggesting mechanisms potentially unspecific for ECT. Moreover, a decrease in amygdala activity to sad faces was associated with symptomatic improvements in the ECT sample (r spearman = -0.48, p = 0.044), and by tendency also for the MED sample (r spearman = -0.38, p = 0.098). However, we did not find any significant association between pre-treatment amygdala function to emotional stimuli and individual symptom improvement, neither for the ECT sample, nor for the MED sample.
In sum, the present study provides first results regarding functional changes in emotion processing due to ECT treatment using a longitudinal design, thus validating and extending our knowledge gained from previous treatment studies. A limitation was that ECT patients received concurrent medication treatment.
Long-term survival of adoptively transferred chimeric Ag receptor (CAR) T cells is often limited. Transplantation of hematopoietic stem cells (HSCs) transduced to express CARs could help to overcome ...this problem as CAR-armed HSCs can continuously deliver CAR
multicell lineages (e.g., T cells, NK cells). In dependence on the CAR construct, a variable extent of tonic signaling in CAR T cells was reported; thus, effects of CAR-mediated tonic signaling on the hematopoiesis of CAR-armed HSCs is unclear. To assess the effects of tonic signaling, two CAR constructs were established and analyzed 1) a signaling CAR inducing a solid Ag-independent tonic signaling termed CAR-28/ζ and 2) a nonstimulating control CAR construct lacking intracellular signaling domains termed CAR-Stop. Bone marrow cells from immunocompetent mice were isolated, purified for HSC-containing Lin
cKit
cells or the Lin
cKit
Sca-1
subpopulation (Lin
Sca-1
cKit
), and transduced with both CAR constructs. Subsequently, modified bone marrow cells were transferred into irradiated mice, in which they successfully engrafted and differentiated into hematopoietic progenitors. HSCs expressing the CAR-Stop sustained normal hematopoiesis. In contrast, expression of the CAR-28/ζ led to elimination of mature CAR
T and B cells, suggesting that the CAR-mediated tonic signaling mimics autorecognition via the newly recombined immune receptors in the developing lymphocytes.
Purpose
To evaluate an alternative dose point, so-called ALG (for Alain Gerbaulet), for the bladder in comparison to the International Commission on Radiation Units and Measurements (ICRU) point and ...D2cm
3
(minimal dose to maximally exposed 2 cm
3
) in a large cohort of patients with locally advanced cervical cancer treated with external beam radiotherapy followed by image-guided pulsed dose rate brachytherapy.
Methods and materials
For each patient, the ALG point was constructed 1.5 cm above the ICRU bladder, parallel to the tandem (coronal and sagittal planes). The dosimetric data from 162 patients were reviewed.
Results
Average doses to ALG and bladder points were 19.40 Gy ± 7.93 and 17.14 ± 8.70, respectively (p = 0.01). The 2 cm
3
bladder dose averaged 24.40 ± 6.77 Gy. Ratios between D2cm
3
and dose points were 1.37 ± 0.46 and 1.68 ± 0.74 (p < 0.001) for ALG and ICRU points, respectively. Both dose points appeared correlated with D2cm
3
(p < 0.001) with coefficients of determination (R
2
) of 0.331 and 0.399 respectively. The estimated dose to the ICRU point of the rectum was 12.77 ± 4.21 and 15.76 ± 5.94 for D2cm
3
(p < 0.0001). Both values were significantly correlated (p < 0.0001, R
2
= 0.485).
Conclusion
The ALG point underestimates the D2cm
3
, but its mean on a large cohort is closer to D2cm
3
than the dose to ICRU point. However, it shows great variability between cases and the weak strength of its correlation to D2cm
3
indicates that it is not a good surrogate for individual volumetric evaluation of the dose D2cm
3
.
Abstract Aims To assess the efficacy of pulse dose rate (PDR) interstitial brachytherapy in the treatment of carcinoma of the penis and to compare with historical data of low dose rate (LDR) ...brachytherapy. Materials and methods We reviewed the clinical records of 27 consecutive patients treated in our institution with exclusive PDR brachytherapy for a squamous cell carcinoma of the penis. The median tumour greatest diameter was 20 mm (range: 10–50 mm). Twenty-three patients (85%) had tumours limited to the glans and/or prepuce and four patients (15%) also had inguinal lymph node metastases. Implantations were carried out according to the Paris system and treatments were delivered with PDR brachytherapy. Results The median brachytherapy dose was 60 Gy (range: 60–70 Gy). The median treated volume was 28 cm3 (range: 8–62 cm3 ). The median reference isodose rate was 0.4 Gy/pulse/h (range: 0.4–0.5 Gy/pulse/h). The median number of pulses was 150 (range: 120–175 pulses). With a median follow-up of 33 months (range: 6–64 months), tumour relapses in the penis were reported in four patients (15%). All patients with only local relapse ( n = 3) were successfully salvaged with partial amputation. The estimated overall survival rate at 3 years was 95% (95% confidence interval: 83–100%). No grade 3 or more acute reaction was observed. Delayed ulcerations and stenoses requiring at least one meatal dilatation were reported in two (9%) and five (22%) patients without local relapse. The treated volume was significantly correlated to the risk of clinically relevant delayed toxicity. Conclusions The efficacy/toxicity results of PDR brachytherapy for the treatment of penile carcinoma are comparable with those obtained with LDR brachytherapy in historical cohorts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background: The objective of this study was to evaluate the clinical outcomes and to discuss the management of women presenting with an invasive cervical cancer during pregnancy. Patients and ...methods: We retrospectively reviewed patients treated for an invasive cervical cancer diagnosed during pregnancy between 1985 and 2000 in our institution. Results: Twenty-one pregnant patients among a total of 487 women were treated. Thirteen, five, two and one, respectively, were diagnosed during the first, second and third pregnancy trimester and post-partum. The FIGO stage was IB in 15 cases, IIB in five cases and IVA in one case. Mean follow-up was 64 months (range 2–165). Overall and disease-free survival at 5 years were 82% and 79%, respectively. All five patients diagnosed in the second trimester were alive. Two of the 13 patients and one of the two patients diagnosed during the first trimester and the third trimester, respectively, died of their disease. No difference was observed between the nine patients whose treatment was delayed or not. Conclusions: Invasive cervical cancer during pregnancy is rare but is a dilemma for women and their physicians. The present study and review of the literature suggest that pregnancy does not seem to influence the prognosis of cervical cancer. Delayed treatment could be proposed to selected patients diagnosed at the end of the second trimester or at the beginning of the third trimester, with a small tumor (<2 cm) and negative nodes, after a multidisciplinary approach.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Intracavitary brachytherapy is an effective treatment for gynecologic cancers. Twelve magnetic resonance (MR) imaging studies were performed during intracavitary brachytherapy (10 initial studies and ...two during repeat brachytherapy) in 10 patients with clear cell adenocarcinoma (n = 9) or epithelioma (n = 1). Fifty percent of the vaginal lesions did not demonstrate high signal intensity on T2-weighted images. Individually tailored molded applicators allowed easy detection of abnormal vaginal parietal thickening on T1-weighted images: Results in seven cases were concordant with results of clinical examination, and there were no false-negative results. MR imaging was useful in controlling the relationships between the tumor and the applicator and facilitated treatment planning, since the radiation dose to the tumor volume and adjacent critical organs could be calculated accurately. Limitations of MR imaging were underestimation of superficial vaginal tumors and the inability to differentiate between tumor and inflammation after recent surgery or repeat intracavitary brachytherapy. MR imaging during intracavitary brachytherapy appears to be a useful adjunct to clinical examination.
Frameshift mutations in
(calreticulin) are associated with essential thrombocythemia (ET), but the stages at and mechanisms by which mutant CALR drives transformation remain incompletely defined. ...Here, we use single-cell approaches to examine the hematopoietic stem/progenitor cell landscape in a mouse model of mutant CALR-driven ET. We identify a trajectory linking hematopoietic stem cells (HSCs) with megakaryocytes and prospectively identify a previously unknown intermediate population that is overrepresented in the disease state. We also show that mutant CALR drives transformation primarily from the earliest stem cell compartment, with some contribution from megakaryocyte progenitors. Last, relative to wild-type HSCs, mutant CALR HSCs show increases in JAK-STAT signaling, the unfolded protein response, cell cycle, and a previously undescribed up-regulation of cholesterol biosynthesis. Overall, we have identified a novel megakaryocyte-biased cell population that is increased in a mouse model of ET and described transcriptomic changes linking
mutations to increased HSC proliferation and megakaryopoiesis.
Basal cell carcinomas (BCCs) are very frequent cutaneous cancers, often located on the face. Cure rates with surgery and radiotherapy are high, but these treatments have never been compared ...prospectively. A randomized trial was initiated in 1982 to compare surgery and radiotherapy in the treatment of primary BCC of the face measuring less than 4 cm. The primary end point was the failure rate (persistent or recurrent disease) after 4 years of follow-up. The secondary end point was the cosmetic results assessed by the patient, the dermatologist and three persons not involved in the trial. In the course of the trial, 347 patients were treated. Of the 174 patients in the surgery group, 71% had local anaesthesia and 91% frozen section examination. Of the 173 patients in the radiotherapy group, 55% were treated with interstitial brachytherapy, 33% with contactherapy and 12% with conventional radiotherapy. The 4-year actuarial failure rate (95% CI) was 0.7% (0.1-3.9%) in the surgery group compared with 7.5% (4.2-13.1%) in the radiotherapy group (log-rank P = 0.003). The cosmetic results assessed by four of the five judges were significantly better after surgery than after radiotherapy. Eighty-seven per cent of the surgery-treated patients and 69% of the radiation-treated patients considered the cosmetic result as good (P < 0.01). Thus, in the treatment of BCC of the face of less than 4 cm in diameter, surgery should be preferred to radiotherapy.
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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
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