The Economics of 1.5°C Climate Change

The economic case for limiting warming to 1.5°C is unclear, due to manifold uncertainties. However, it cannot be ruled out that the 1.5°C target passes a cost-benefit test. Costs are almost certainly high: The median global carbon price in 1.5°C scenarios implemented by various energy models is more than US$100 per metric ton of CO2 in 2020, for example. Benefits estimates range from much lower than this to much higher. Some of these uncertainties may reduce in the future, raising the question of how to hedge in the near term. Maintaining an option on limiting warming to 1.5°C means targeting it now. Setting off with higher emissions will make 1.5°C unattainable quickly without recourse to expensive large-scale carbon dioxide removal (CDR), or solar radiation management (SRM), which can be cheap but poses ambiguous risks society seems unwilling to take. Carbon pricing could reduce mitigation costs substantially compared with ramping up the current patchwork of regulatory instruments. Nonetheless, a mix of policies is justified and technology-specific approaches may be required. It is particularly important to step up mitigation finance to developing countries, where emissions abatement is relatively cheap

TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM) on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta) signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited.</p> <p>Methods</p> <p>Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF-beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4) in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2) vs. high-grade (i.e. grade 3 and 4)), lymph node metastasis, distant metastasis, 5 year cancer related survival) using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed.</p> <p>Results</p> <p>High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and shorter survival. Stromal TGF-beta receptor 2 expression was an independent prognostic factor for cancer related survival.</p> <p>Conclusion</p> <p>Histological phenotype and clinical behaviour of colon cancer is not only influenced by mutational incidents in tumour cells but also affected by interaction of tumour tissue with inflammatory cells like macrophages and associated stroma and TGF-beta signalling is one important part of this crosstalk. Further studies are needed to elucidate the exact mechanisms.</p

Transforming growth factor-β and breast cancer: Tumor promoting effects of transforming growth factor-β

The transforming growth factor (TGF)-βs are potent growth inhibitors of normal epithelial cells. In established tumor cell systems, however, the preponderant experimental evidence suggests that TGF-βs can foster tumor-host interactions that indirectly support the viability and/or progression of cancer cells. The timing of this 'TGF-β switch' during the progressive transformation of epithelial cells is not clear. More recent evidence also suggests that autocrine TGF-β signaling is operative in some tumor cells, and can also contribute to tumor invasiveness and metastases independent of an effect on nontumor cells. The dissociation of antiproliferative and matrix associated effects of autocrine TGF-β signaling at a transcriptional level provides for a mechanism(s) by which cancer cells can selectively use this signaling pathway for tumor progression. Data in support of the cellular and molecular mechanisms by which TGF-β signaling can accelerate the natural history of tumors will be reviewed in this section

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial

BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.clinicaltrials.gov as NCT03676504

Strategies in the use of light energy by Genipa spruceana Steyerm seedlings subjected to flooding

In an attempt to elucidate strategies in the use of light energy by G. spruceana seedlings subjected to flooding, we investigated the capacity of light capture and use of light energy by G. spruceana in three growing conditions: 1- absence of flooding (SA), 2- partially flooded (PA) and 3- totally flooded (TA). Destructive and non-destructive measurements, such as specific leaf area, chloroplast pigment (chlorophyll and carotenoids) content and fluorescence analyses, were made at regular intervals over a period of 90 days. All parameters decreased in seedlings subjected to flooding. Plants of treatment TA dropped all of their leaves after 30 days of complete submergence. Chloroplast pigment content differed between treatments SA and TA after 30 days from the start of the experiment; whereas SA and PA plants only differed for this variable after 90 days. Plants subjected to flooding (PA and TA) exhibited high dissipation of photochemical de-excitation (DIo/ABS), indicating a limited efficiency of light energy use. This fact was proven by the performance index (PI ABS) only in analyses after 90 days, and no significant difference was verified for PI ABS among treatments up to 30 days. Therefore, considering that G. spruceana seedlings subjected to flooding reduced the chloroplast pigment content more quickly than PI ABS, we suggest that the light energetic flux in G. spruceana seedlings subjected to flooding, in the beginning, is more restricted to a decrease in the structures that captures light (reduction chlorophyll pigment content) than how the photosynthetic apparatus functions (alterations in photochemical efficiency of photosystem II).Na tentativa de elucidar estratégias de utilização da energia luminosa em plantas jovens de Genipa spruceana Steyerm submetidas ao alagamento, nós investigamos a capacidade de captura e uso de energia luminosa em G. spruceana sob três condições de crescimento1- ausência de alagamento (SA), 2- plantas parcialmente alagadas (PA) e 3- plantas totalmente alagadas (TA). Medidas de área foliar específica, teores de pigmentos cloroplastídicos e fluorescência da clorofila a foram feitas em intervalos regulares no período de 90 dias. Todos os parâmetros analisados diminuíram em condições de alagamento (PA e TA). Aos 30 dias, as plantas no tratamento TA sofreram abscisão foliar. Os teores dos pigmentos cloroplastídicos (clorofilas e carotenóides) entre os tratamentos SA e TA diferiram aos 30 dias. Ao passo que, somente foi possível verificar diferenças entre os tratamentos SA e PA aos 90 dias. As plantas submetidas ao alagamento (PA e TA) exibiram alta dissipação de energia de excitação (DIo/ABS) indicando limitada eficiência na utilização da energia luminosa. Este fato foi comprovado pelos resultados do índice de desempenho (PI ABS) somente ao fim do período experimental (90 dias). Mas, não foi verificado diferença para PI ABS entre os tratamentos aos 30 dias. Portanto, considerando que G. spruceana submetidas ao tratamento TA reduziram seus teores de clorofilas mais rapidamente do que decrescem seus PI ABS, sugere-se que o fluxo de energia luminosa em plântulas de G. spruceana sob alagamento total, no início, é mais restringido pelo decréscimo na estrutura de captura de luz (diminuição dos pigmentos cloroplastídicos) do que no funcionamento do aparato fotossintético (alterações na eficiência fotoquímica do fotossistema II)