Morphological Effects of Lonidamine on Two Human-Tumor Cell Culture Lines

Lonidamine, 1-(2-4-dichlorobenzyl)-1-H-indazol-3-carboxylic acid. is an anticancer drug that has its primary action on cellular metabolism rather than cell division. Since lonidamine is not effective in all tumor cells, we have tested it in two human-tumor cell culture lines: MOLT-4, a T-leukemia and U-87 MG. a glioma. Lonidamine exposure of MOLT-4 cells at 50 μg/mL and pH 6.7 disrupted the mitochondria within 1 h of treatment. The mitochondria were swollen and the cristae were disrupted. When the treated cells were re-incubated in fresh medium at pH 7.4 the mitochondria rapidly returned to their normal morphology. The U-87 MG glioma cells did not show ultrastructural disruption after 1-h treatment with lonidamine at concentrations up to 200 μg/mL at pH 6.7 In the concentration range of 25 μg/mL to 200 μg/mL. lonidamine did not produce any cell killing in MOLT-4 after a 1-h exposure at pH 7.4, although the drug had some limited effectiveness at pH 6.7. Compared to sham-treated controls, long exposures to 100 μg/mL of lonidamine at pH 6.7 reduced survival in MOLT-4 to 92% and 53% after 6-h and 24-h exposures, respectively. Survival of U-87 MG glioma cells was also strongly pH dependent, a 2-h exposure to 50 μg/mL lonidamine at pH 7.4 did not cause cell death; however, survival dropped to 84% of the control at pH 6.65

Relationship between trends, job profiles, skills and training programs in the factory of the future

Industry 4.0 is promoting the digitisation of manufacturing sectors towards smart products, machines, processes and factories. The adoption of disruptive technologies associated to this industrial revolution is re-shaping the manufacturing environment, decreasing low-skilled activities and increasing high-skill activities. These technological trends are affecting the job profiles and the skills required by the workforce, which demand proper training programs to address upskilling and reskilling needs. Having this in mind, this work proposes a model that contributes to understand how technological trends may impact the new job profiles and relevant skills, as well as how these skills may be upskilled by the workforce through available training programs according to their gaps and impact. The applicability of the proposed model was illustrated by considering two trends, the connectivity and the value of the data, and a catalogue of compiled new job profiles and training programs.info:eu-repo/semantics/publishedVersio

Shanghai international consensus on diagnosis and comprehensive treatment of colorectal liver metastases (version 2019)

The liver is the most common anatomical site for hematogenous metastases from colorectal cancer. Therefore effective treatment of liver metastases is one of the most challenging elements in the management of colorectal cancer. However, there is rare available clinical consensus or guideline only focusing on colorectal liver metastases. After six rounds of discussion by 195 clinical experts of the Shanghai International Consensus Expert Group on Colorectal Liver Metastases (SINCE) from 29 countries or regions, the Shanghai Consensus has been finally completed, based on current research and expert experience. The consensus emphasized the principle of multidisciplinary team, provided detailed diagnosis approaches, and guided precise local and systemic treatments. This Shanghai Consensus might be of great significance to standardized diagnosis and treatment of colorectal liver metastases all over the world.status: publishe

Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways

Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies. We demonstrate effectiveness of multiple MEKi against diverse BRAF-fusions with novel N-terminal partners, with trametinib being the most potent. However, resistance to MEKi or PLX8394 develops via increased RTK expression causing activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones. To circumvent acquired resistance, we show potency of combinatorial targeting with trametinib and everolimus, an mTOR inhibitor (mTORi) against multiple BRAF-fusions. While single-agent mTORi and MEKi PLGG clinical trials are underway, our study provides preclinical rationales for using MEKi and mTORi combinatorial therapy to stave off or prevent emergent drug-resistance in BRAF-fusion driven PLGGs

Miocene ocean circulation inferred from marine carbon cycle modeling combined with benthic isotope records

In a modeling sensitivity study we investigate the evolution of the ocean circulation and of marine carbon isotope (δ13C) records during the Miocene (about 23–5 million years ago). For this purpose we ran an ocean-circulation carbon cycle model of intermediate complexity (Large Scale Geostrophic– Hamburg Ocean Carbon Cycle Model, version 2s) exploring various seaway configurations. Our investigations confirm that the Central American Seaway played a decisive role in the history of the Miocene ocean circulation. In simulations with a deep Central American Seaway (depth range 1–3 km), typical for the early to middle Miocene, deep water production in the North Atlantic is absent or weak, while the meridional overturning circulation is dominated by water mass formation in the Southern Ocean. Deep water formation in the North Atlantic begins when the Central American Seaway shoals to a few hundreds of meters, which is typical for the late Miocene. Our results do not support ideas that the mid-Miocene closing of the Eastern Tethys contributed to Antarctic glaciation. On the other hand, we find some water exchange between the Indian Ocean and the Atlantic via the Eastern Tethys during the early Miocene. Our model results for the Atlantic meridional overturning circulation and for Atlantic δ13C during the late Miocene are largely independent from depth variations of the Greenland-Scotland Ridge. To a large extent, the evolution of Miocene deep-sea δ13C records can be explained with large-scale ocean circulation changes. Our model-data comparison for the middle and early Miocene suggests that during the early Neogene the seaway effect on benthic δ13C may have been superimposed by further factors such as climate regime shifts and/or terrestrial carbon cycle changes