Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin)

Abstract Heat shock protein 90 (Hsp90) and its co-chaperones promote cancer, and targeting Hsp90 holds promise for cancer treatment. Most of the efforts to harness this potential have focused on targeting the Hsp90 N-terminus ATP binding site. Although newer-generation inhibitors have shown improved efficacy in aggressive cancers, induction of the cellular heat shock response (HSR) by these inhibitors is thought to limit their clinical efficacy. Therefore, Hsp90 inhibitors with novel mechanisms of action and that do not trigger the HSR would be advantageous. Here, we investigated the mechanism by which capsaicin inhibits Hsp90. Through mutagenesis, chemical modifications, and proteomic studies, we show that capsaicin binds to the N-terminus of Hsp90 and inhibits its ATPase activity. Consequently, capsaicin and its analogs inhibit Hsp90 ATPase-dependent progesterone receptor reconstitution in vitro. Capsaicin did not induce the HSR, instead, it promoted the degradation of Hsp70 through the lysosome-autophagy pathway. Remarkably, capsaicin did not induce degradation of the constitutively expressed cognate Hsc70, indicating selectivity for Hsp70. Combined treatments of capsaicin and the Hsp90 inhibitor 17-AAG improved the anti-tumor efficacy of 17-AAG in cell culture and tridimensional tumor spheroid growth assays using breast and prostate cancer models. Consistent with this, in silico docking studies revealed that capsaicin binding to the ATP binding site of Hsp90 was distinct from classical N-terminus Hsp90 inhibitors, indicating a novel mechanism of action. Collectively, these findings support the use of capsaicin as a chemical scaffold to develop novel Hsp90 N-terminus inhibitors as well as its ability to be a potential cancer co-therapeutic

Life-Cycle Environmental Impact of High-Speed Rail System in the I-45 Corridor [Supporting Dataset]

69A3551747106National Transportation Library (NTL) Curation Note: As this dataset is preserved in a repository outside U.S. DOT control, as allowed by the U.S. DOT's Public Access Plan (https://doi.org/10.21949/1503647) Section 7.4.2 Data, the NTL staff has performed NO additional curation actions on this dataset. The current level of dataset documentation is the responsibility of the dataset creator. NTL staff last accessed this dataset at its repository URL on 2022-11-11. If, in the future, you have trouble accessing this dataset at the host repository, please email [email protected] describing your problem. NTL staff will do its best to assist you at that time.The Houston-Dallas (I-45) corridor is the busiest route among 18 traffic corridors in Texas. The expected population growth and the surge in passenger mobility could result in a significant impact on the regional environment. This study uses a life cycle framework to estimate the net change in environmental impact with the development of a high speed rail system (HSR) along the I-45 corridor. The study follows ISO 14040 principles and standards of life cycle assessment and uses SimaPro 8.5\uae software and the Ecoinvent 3.3 inventory database. Infrastructure construction, vehicle manufacturing, system operation, and end of life phases are included in the life cycle assessment. The energy and emissions of the system are evaluated per vehicle/passenger-kilometers traveled and compared with the existing transportation modes. The vehicle component accounts for 14.50 kgCO2eq/VKT, of which fossil-fuel usage during operation is the primary contributor with 98% of the greenhouse gas (GHG) emissions. For the infrastructure component, 56.76% of GHG emissions result from the material extraction and processing phase (23.75kgCO2eq/VKT). Life cycle CO2 emissions of this system are 40% lower than comparable systems in Europe, Asia, and North America. The minimum ridership levels required to offset the environmental impact from conventional modes of transport are around 12% and 27% for GHG emissions and NOx emissions respectively. For the stakeholders, policymakers, and community leaders, this study recommends the construction of HSR system between Dallas-Houston, since it does not only save time, reduces traffic jam, and improve passengers\u2019 mobility, but it also saves energy, which benefits the regional environment. The total size of the described zip file is 4.38 MB. Files with the .xlsx extension are Microsoft Excel spreadsheet files. These can be opened in Excel or open-source spreadsheet programs. Docx files are document files created in Microsoft Word. These files can be opened using Microsoft Word or with an open source text viewer such as Apache OpenOffice. PDFs are used to display text and images and can be opened with any PDF reader or editor

Quality of life in caregivers of patients receiving chimeric antigen receptor T-cell therapy

Objective Informal family caregivers provide critical support for patients receiving chimeric antigen receptor (CAR) T-cell therapy. However, caregivers' experiences are largely unstudied. This study examined quality of life (QOL; physical functioning, pain, fatigue, anxiety, and depression), caregiving burden, and treatment-related distress in caregivers in the first 6 months after CAR T-cell therapy, when caregivers were expected to be most involved in providing care. Relationships between patients' clinical course and caregiver outcomes were also explored. Methods Caregivers completed measures examining QOL and burden before patients' CAR T-cell therapy and at days 90 and 180. Treatment-related distress was assessed at days 90 and 180. Patients' clinical variables were extracted from medical charts. Change in outcomes was assessed using means and 99% confidence intervals. Association of change in outcomes with patient clinical variables was assessed with backward elimination analysis. Results A total of 99 caregivers (mean age 59, 73% female) provided data. Regarding QOL, pain was significantly higher than population norms at baseline but improved by day 180 (p < .01). Conversely, anxiety worsened over time (p < .01). Caregiver burden and treatment-related distress did not change over time. Worsening caregiver depression by day 180 was associated with lower patient baseline performance status (p < .01). Worse caregiver treatment-related distress at day 180 was associated with lower performance status, intensive care unit admission, and lack of disease response at day 90 (ps < 0.01). Conclusions Some CAR T-cell therapy caregivers experience pain, anxiety, and burden, which may be associated patients' health status. Further research is warranted regarding the experience of CAR T-cell therapy caregivers