Astragaloside IV enhances the sensitivity of breast cancer stem cells to paclitaxel by inhibiting stemness

Background: Chemotherapy is one of the common treatments for breast cancer. The induction of cancer stem cells (CSCs) is an important reason for chemotherapy failure and breast cancer recurrence. Astragaloside IV (ASIV) is one of the effective components of the traditional Chinese medicine (TCM) Astragalus membranaceus, which can improve the sensitivity of various tumors to chemotherapy drugs. Here, we explored the sensitization effect of ASIV to chemotherapy drug paclitaxel (PTX) in breast cancer from the perspective of CSCs. Methods: The study included both in vitro and in vivo experiments. CSCs from the breast cancer cell line MCF7 with stem cell characteristics were successfully induced in vitro. Cell viability and proliferation were detected using the Cell Counting Kit-8 (CCK-8) and colony formation assays, and flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) methods were performed to detect cell apoptosis. Stemness-related protein expression was determined by western blotting (WB) and immunohistochemistry (IHC). Body weight, histopathology, and visceral organ damage of mice were used to monitor drug toxicity. Results: The expression of stemness markers including Sox2, Nanog, and ALDHA1 was stronger in MCF7-CSCs than in MCF7. PTX treatment inhibited the proliferation of tumor cells by promoting cell apoptosis, whereas the stemness of breast cancer stem cells (BCSCs) resisted the effects of PTX. ASIV decreased the stemness of BCSCs, increased the sensitivity of BCSCs to PTX, and synergistically promoted PTX-induced apoptosis of breast cancer cells. Our results showed that the total cell apoptosis rate increased by about 25% after adding ASIV compared with BCSCs treated with PTX alone. The in vivo experiments demonstrated that ASIV enhanced the ability of PTX to inhibit the growth of breast cancer. WB and IHC showed that ASIV reduced the stemness of CSCs. Conclusions: In this study, the resistance of breast cancer to PTX was attributed to the existence of CSCs; ASIV weakened the resistance of MCF7-CSCs to PTX by significantly attenuating the hallmarks of breast cancer stemness and improved the efficacy of PTX. Keywords: Breast cancer; cancer stem cells (CSCs); astragaloside IV (ASIV); paclitaxel (PTX); chemotherap

Astragaloside IV enhances the sensitivity of breast cancer stem cells to paclitaxel by inhibiting stemness.

Chemotherapy is one of the common treatments for breast cancer. The induction of cancer stem cells (CSCs) is an important reason for chemotherapy failure and breast cancer recurrence. Astragaloside IV (ASIV) is one of the effective components of the traditional Chinese medicine (TCM) , which can improve the sensitivity of various tumors to chemotherapy drugs. Here, we explored the sensitization effect of ASIV to chemotherapy drug paclitaxel (PTX) in breast cancer from the perspective of CSCs. The study included both and experiments. CSCs from the breast cancer cell line MCF7 with stem cell characteristics were successfully induced . Cell viability and proliferation were detected using the Cell Counting Kit-8 (CCK-8) and colony formation assays, and flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) methods were performed to detect cell apoptosis. Stemness-related protein expression was determined by western blotting (WB) and immunohistochemistry (IHC). Body weight, histopathology, and visceral organ damage of mice were used to monitor drug toxicity. The expression of stemness markers including Sox2, Nanog, and ALDHA1 was stronger in MCF7-CSCs than in MCF7. PTX treatment inhibited the proliferation of tumor cells by promoting cell apoptosis, whereas the stemness of breast cancer stem cells (BCSCs) resisted the effects of PTX. ASIV decreased the stemness of BCSCs, increased the sensitivity of BCSCs to PTX, and synergistically promoted PTX-induced apoptosis of breast cancer cells. Our results showed that the total cell apoptosis rate increased by about 25% after adding ASIV compared with BCSCs treated with PTX alone. The experiments demonstrated that ASIV enhanced the ability of PTX to inhibit the growth of breast cancer. WB and IHC showed that ASIV reduced the stemness of CSCs. In this study, the resistance of breast cancer to PTX was attributed to the existence of CSCs; ASIV weakened the resistance of MCF7-CSCs to PTX by significantly attenuating the hallmarks of breast cancer stemness and improved the efficacy of PTX. [Abstract copyright: 2023 Translational Cancer Research. All rights reserved.

A Multicenter Evaluation of Different Chemotherapy Regimens in Older Adults With Head and Neck Squamous Cell Carcinoma Undergoing Definitive Chemoradiation

PURPOSE: The number of older adults with head-and-neck squamous cell carcinoma (HNSCC) is increasing, and treatment of these patients is challenging. Although cisplatin-based chemotherapy concomitantly with radiotherapy is considered standard regimen for patients with locoregionally advanced HNSCC, there is substantial real-world heterogeneity regarding concomitant chemotherapy in older HNSCC patients. METHODS: The XXX study is an international multicenter cohort study including older (≥65 years) HNSCC patients treated with definitive radiotherapy at 13 academic centers in the United States and Europe. Here, patients with concomitant chemoradiation were analyzed regarding overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analyses, while Fine-Gray competing risks regressions were performed regarding the incidence of locoregional failures (LRFs) and distant metastases (DMs). RESULTS: Six hundred ninety-seven patients with a median age of 71 years were included in this analysis. Single-agent cisplatin was the most common chemotherapy regimen (n=310; 44%), followed by cisplatin plus 5-fluorouracil (n=137; 20%), carboplatin (n=73; 10%), and mitomycin c plus 5-fluorouracil (n=64; 9%). Carboplatin-based regimens were associated with diminished PFS (HR=1.39 [1.03-1.89], p.05). Median cumulative dose of cisplatin was 180 mg/m2 (IQR, 120-200 mg/m2). Cumulative cisplatin doses ≥200 mg/m2 were associated with increased OS (HR=0.71 [0.53-0.95], p=.02), PFS (HR=0.66 [0.51-0.87], p=.003), and lower incidence of LRFs (SHR=0.50 [0.31-0.80], p=.004). Higher cumulative cisplatin doses remained an independent prognostic variable in the multivariate regression analysis for OS (HR=0.996 [0.993-0.999], p=.009). CONCLUSIONS: Single-agent cisplatin can be considered as the standard chemotherapy regimen for older HNSCC patients who can tolerate cisplatin. Cumulative cisplatin doses are prognostically relevant also in older HNSCC patients

Clinical Characteristics, Racial Inequities, and Outcomes in Patients with Breast Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Cohort Study

BACKGROUND: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. METHODS: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. RESULTS: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. CONCLUSIONS: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. FUNDING: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. CLINICAL TRIAL NUMBER: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The Prognostic and Predictive Value of Genomic Assays in Guiding Adjuvant Breast Radiation Therapy

Many patients with non-metastatic breast cancer benefit from adjuvant radiation therapy after lumpectomy or mastectomy on the basis of many randomized trials. However, there are many patients that have such low risks of recurrence after surgery that de-intensification of therapy by either reducing the treatment volume or omitting radiation altogether may be appropriate options. On the other hand, dose intensification may be necessary for more aggressive breast cancers. Until recently, these treatment decisions were based solely on clinicopathologic factors. Here, we review the current literature on the role of genomic assays as prognostic and/or predictive biomarkers to help guide adjuvant radiation therapy decision-making

Oncolytic Viruses—Natural and Genetically Engineered Cancer Immunotherapies

There has long been interest in innovating an approach by which tumor cells can be selectively and specifically targeted and destroyed. The discovery of viruses that lyse tumor cells, termed oncolytic viruses (OVs), has led to a revolution in the treatment of cancer. The potential of OVs to improve the therapeutic ratio is derived from their ability to preferentially infect and replicate in cancer cells while avoiding destruction of normal cells surrounding the tumor. Two main mechanisms exist through which these viruses are reported to improve outcomes: direct lysis of tumor cells and indirect augmentation of host anti-tumor immunity. With these factors in mind, viruses are chosen or modified to selectively target tumor cells, decrease pathogenicity to normal cells, decrease the antiviral immune response (to prevent viral clearance), and increase the antitumor immune response. While only one OV has been approved for the treatment of cancer in the United States, and only two other OVs have been approved worldwide, a wide spectrum of OVs are in various stages of preclinical development and in clinical trials. These viruses are being studied as alternatives and adjuncts to more traditional cancer therapies including surgical resection, chemotherapy, radiation, hormonal therapies, targeted therapies, and other immunotherapies. Here, we review the natural characteristics and genetically engineered modifications that enhance the effectiveness of OVs for the treatment of cancer

General acts passed by the General Court of Massachusetts

Imprint varies.Vols. for 1915-19 published in 2 v.: General acts; Special acts.Vols. for some years issued in parts.Separate vols. issued for extra session, 1916, and for extra session, 1933.Vol. 12 (May 1831-Mar. 1833) in Jan. session, 1833; Jan. 1834-Apr. 1836 in vol. for extra session 1835/Jan. session 1836; May 1824-Mar. 1828; June 1828-June 1831, Jan. 1832-Apr. 1834, Jan. 1835-Apr. 1838, each bound with corresponding vol.Resolves issued separately, 1780-1838

Oncolytic viruses-natural and genetically engineered cancer immunotherapies

© 2017 Jhawar, Thandoni, Bommareddy, Hassan, Kohlhapp, Goyal, Schenkel, Silk and Zloza. There has long been interest in innovating an approach by which tumor cells can be selectively and specifically targeted and destroyed. The discovery of viruses that lyse tumor cells, termed oncolytic viruses (OVs), has led to a revolution in the treatment of cancer. The potential of OVs to improve the therapeutic ratio is derived from their ability to preferentially infect and replicate in cancer cells while avoiding destruction of normal cells surrounding the tumor. Two main mechanisms exist through which these viruses are reported to improve outcomes: direct lysis of tumor cells and indirect augmentation of host anti-tumor immunity. With these factors in mind, viruses are chosen or modified to selectively target tumor cells, decrease pathogenicity to normal cells, decrease the antiviral immune response (to prevent viral clearance), and increase the antitumor immune response. While only one OV has been approved for the treatment of cancer in the United States, and only two other OVs have been approved worldwide, a wide spectrum of OVs are in various stages of preclinical development and in clinical trials. These viruses are being studied as alternatives and adjuncts to more traditional cancer therapies including surgical resection, chemotherapy, radiation, hormonal therapies, targeted therapies, and other immunotherapies. Here, we review the natural characteristics and genetically engineered modifications that enhance the effectiveness of OVs for the treatment of cancer