Radiosensitizing Pancreatic Cancer via Effective Autophagy Inhibition.

Despite aggressive treatments, pancreatic ductal adenocarcinoma (PDAC) remains an intractable disease, largely because it is refractory to therapeutic interventions. To overcome its nutrient-poor microenvironment, PDAC heavily relies on autophagy for metabolic needs to promote tumor growth and survival. Here, we explore autophagy inhibition as a method to enhance the effects of radiotherapy on PDAC tumors. Hydroxychloroquine is an autophagy inhibitor at the focus of many PDAC clinical trials, including in combination with radiotherapy. However, its acid-labile properties likely reduce its intratumoral efficacy. Here, we demonstrate that EAD1, a synthesized analogue of HCQ, is a more effective therapeutic for sensitizing PDAC tumors of various KRAS mutations to radiotherapy. Specifically, in vitro models show that EAD1 is an effective inhibitor of autophagic flux in PDAC cells, accompanied by a potent inhibition of proliferation. When combined with radiotherapy, EAD1 is consistently superior to HCQ not only as a single agent, but also in radiosensitizing PDAC cells, and perhaps most importantly, in decreasing the self-renewal capacity of PDAC cancer stem cells (PCSC). The more pronounced sensitizing effects of autophagy inhibitors on pancreatic stem over differentiated cells points to a new understanding that PCSCs may be more dependent on autophagy to counter the effects of radiation toxicity, a potential mechanism explaining the resistance of PCSCs to radiotherapy. Finally, in vivo subcutaneous tumor models demonstrate that combination of radiotherapy and EAD1 is the most successful at controlling tumor growth. The models also confirmed a similar toxicity profile between EAD1 and Hydroxychloroquine.

A Substantive Narrative Review on the Usage of Lidocaine in Cataract Surgery.

Cataracts are a disease that causes a gradual decrease in visual prowess and requires surgery when the symptoms progress to an abhorrent state. This disease can be treated through surgical procedures that use anesthetics, such as lidocaine. Through inhibiting sensory nerve propagation to the brain, lidocaine plays an invaluable part in reducing pain for patients that undergo cataract surgery. Current clinical practice commonly utilizes 2% lidocaine with fentanyl as a combination agent. However, recent studies have reported that concentrations higher than 1% can cause substantial alteration to corneal epithelium cells. Additionally, fentanyl is cited as an extremely addictive opioid inappropriate for continual use in cataract surgeries. In this review, the authors examine the application and concentration of lidocaine, along with the various combination agents that were reported in several studies that describe the usage of the anesthetic during cataract surgery. Within the review, it was found that most surgeons generally only use lidocaine gel on the corneal epithelium tissue of patients during cataract surgery. Perhaps this standard could change over time as it is generally known that using intracameral injections in conjunction with topical anesthesia produces better patient outcomes. The authors find that although anesthetics and surgical treatment for cataracts are generally beneficial for patients, there are still many adjustments that could be implemented to enhance patient outcomes.

PK-M2-mediated metabolic changes in breast cancer cells induced by ionizing radiation.

PURPOSE: Radiotherapy (RT) constitutes an important part of breast cancer treatment. However, triple negative breast cancers (TNBC) exhibit remarkable resistance to most therapies, including RT. Developing new ways to radiosensitize TNBC cells could result in improved patient outcomes. The M2 isoform of pyruvate kinase (PK-M2) is believed to be responsible for the re-wiring of cancer cell metabolism after oxidative stress. The aim of the study was to determine the effect of ionizing radiation (IR) on PK-M2-mediated metabolic changes in TNBC cells, and their survival. In addition, we determine the effect of PK-M2 activators on breast cancer stem cells, a radioresistant subpopulation of breast cancer stem cells. METHODS: Glucose uptake, lactate production, and glutamine consumption were assessed. The cellular localization of PK-M2 was evaluated by western blot and confocal microscopy. The small molecule activator of PK-M2, TEPP46, was used to promote its pyruvate kinase function. Finally, effects on cancer stem cell were evaluated via sphere forming capacity. RESULTS: Exposure of TNBC cells to IR increased their glucose uptake and lactate production. As expected, PK-M2 expression levels also increased, especially in the nucleus, although overall pyruvate kinase activity was decreased. PK-M2 nuclear localization was shown to be associated with breast cancer stem cells, and activation of PK-M2 by TEPP46 depleted this population. CONCLUSIONS: Radiotherapy can induce metabolic changes in TNBC cells, and these changes seem to be mediated, at least in part by PK-M2. Importantly, our results show that activators of PK-M2 can deplete breast cancer stem cells in vitro. This study supports the idea of combining PK-M2 activators with radiation to enhance the effect of radiotherapy in resistant cancers, such as TNBC.

Mebendazole Potentiates Radiation Therapy in Triple-Negative Breast Cancer.

PURPOSE: The lack of a molecular target in triple-negative breast cancer (TNBC) makes it one of the most challenging breast cancers to treat. Radiation therapy (RT) is an important treatment modality for managing breast cancer; however, we previously showed that RT can also reprogram a fraction of the surviving breast cancer cells into breast cancer-initiating cells (BCICs), which are thought to contribute to disease recurrence. In this study, we characterize mebendazole (MBZ) as a drug with potential to prevent the occurrence of radiation-induced reprogramming and improve the effect of RT in patients with TNBC. METHODS AND MATERIALS: A high-throughput screen was used to identify drugs that prevented radiation-induced conversion of TNBC cells into cells with a cancer-initiating phenotype and exhibited significant toxicity toward TNBC cells. MBZ was one of the drug hits that fulfilled these criteria. In additional studies, we used BCIC markers and mammosphere-forming assays to investigate the effect of MBZ on the BCIC population. Staining with propidium iodide, annexin-V, and γ-H2AX was used to determine the effect of MBZ on cell cycle, apoptosis, and double-strand breaks. Finally, the potential for MBZ to enhance the effect of RT in TNBC was evaluated in vitro and in vivo. RESULTS: MBZ efficiently depletes the BCIC pool and prevents the ionizing radiation-induced conversion of breast cancer cells into therapy-resistant BCICs. In addition, MBZ arrests cells in the G2/M phase of the cell cycle and causes double-strand breaks and apoptosis. MBZ sensitizes TNBC cells to ionizing radiation in vitro and in vivo, resulting in improved tumor control in a human xenograft model of TNBC. CONCLUSIONS: The data presented in this study support the repurposing of MBZ as a combination treatment with RT in patients with TNBC.

Socioeconomic inequalities in self-reported chronic non-communicable diseases in urban Hanoi, Vietnam.

This study measures and decomposes socioeconomic inequalities in the prevalence of self-reported chronic non-communicable diseases (NCDs) in urban Hanoi, Vietnam. A cross-sectional survey of 1211 selected households was carried out in four urban districts in both slum and non-slum areas of Hanoi city in 2013. The respondents were asked if a doctor or health worker had diagnosed any household members with an NCD, such as cardiovascular diseases, chronic respiratory, diabetes or cancer, during last 12 months. Information from 3736 individuals, aged 15 years and over, was used for the analysis. The concentration index (CI) was used to measure inequalities in self-reported NCD prevalence, and it was also decomposed into contributing factors. The prevalence of chronic NCDs in the slum and non-slum areas was 7.9% and 11.6%, respectively. The CIs show gradients disadvantageous to both the slum (CI = -0.103) and non-slum (CI = -0.165) areas. Lower socioeconomic status and aging significantly contributed to inequalities in the self-reported NCDs, particularly for those living in the slum areas. The findings confirm the existence of substantial socioeconomic inequalities linked to NCDs in urban Vietnam. Future policies should target these vulnerable areas.