Increasing pH in cancer: enabling a new therapeutic paradigm using novel carbonate nanoparticles

Enormous progress has been made to treat cancer, and yet the mortality rate of cancer remains unacceptably high. High clinical resistance to molecularly targeted therapeutics has pushed interest again towards inhibiting universal biochemical hallmarks of cancer. Recent evidence suggests that malignant tumors acidify the local extracellular environment to activate proteases for degrading the tumor matrix, which facilitates metastasis, and explains why more aggressive tumors are more acidic. Current therapies have only focused on using the low pH for enhancing drug release in tumors, thereby still relying on the traditional paradigm of intracellular inhibition of pathways, a method that continues to have mixed results. In this dissertation we explore the development of a novel platform that can be made to monitor and modify the critical tumor extracellular environment. The platform enables a shift in the paradigm of current cancer therapy from a predominantly intracellular approach to an extracellular synergistic method of targeting cancer. In the process, we demonstrate the synthesis of a novel type of CaCO3 nanoparticle, its stabilization, the increase of pH in vivo, a mathematical justification and simulation, and the subsequent inhibition of tumor growth and metastasis. By neutralizing the tumor extracellular microenvironment, the platform aims to prevent tumor progression and metastasis as well as minimize the traditional intracellular based pathways of resistance. Because of the broad universal aspect of low extracellular pH in cancer, particularly in the more malignant tumors, we expect this platform will also have wide applicability, with particular potency on the most aggressive of cancers

Acidic extracellular pH of tumors induces octamer-binding transcription factor 4 expression in murine fibroblasts in vitro and in vivo

Octamer-binding transcription factor 4 (OCT-4) is an important marker of cellular de-differentiation that can be induced by environmental stressors, such as acidity. Here we demonstrate that chronic acidic stress in solid tumors induced OCT-4 expression in fibroblasts and other stromal cells in four tumor models. The results have implications for how tumors utilize pH modulation to recruit associated stromal cells, induce partial reprogramming of tumor-associated stromal cells, and respond to therapy

A novel patient engagement platform using accessible text messages and calls (Epharmix): Feasibility study

BACKGROUND: Patient noncompliance with therapy, treatments, and appointments represents a significant barrier to improving health care delivery and reducing the cost of care. One method to improve therapeutic adherence is to improve feedback loops in getting clinically acute events and issues to the relevant clinical providers as necessary (ranging from detecting hypoglycemic events for patients with diabetes to notifying the provider when patients are out of medications). Patients often don\u27t know which information should prompt a call to their physician and proactive checks by the clinics themselves can be very resource intensive. We hypothesized that a two-way SMS system combined with a platform web service for providers would enable both high patient engagement but also the ability to detect relevant clinical alerts. OBJECTIVE: The objectives of this study are to develop a feasible two-way automated SMS/phone call + web service platform for patient-provider communication, and then study the feasibility and acceptability of the Epharmix platform. First, we report utilization rates over the course of the first 18 months of operation including total identified clinically significant events, and second, review results of patient user-satisfaction surveys for interventions for patients with diabetes, COPD, congestive heart failure, hypertension, surgical site infections, and breastfeeding difficulties. METHODS: To test this question, we developed a web service + SMS/phone infrastructure ( Epharmix ). Utilization results were measured based on the total number of text messages or calls sent and received, with percentage engagement defined as a patient responding to a text message at least once in a given week, including the number of clinically significant alerts generated. User satisfaction surveys were sent once per month over the 18 months to measure satisfaction with the system, frequency and degree of communication. Descriptive statistics were used to describe the above information. RESULTS: In total, 28,386 text messages and 24,017 calls were sent to 929 patients over 9 months. Patients responded to 80% to 90% of messages allowing the system to detect 1164 clinically significant events. Patients reported increased satisfaction and communication with their provider. Epharmix increased the number of patient-provider interactions to over 10 on average in any given month for patients with diabetes, COPD, congestive heart failure, hypertension, surgical site infections, and breastfeeding difficulties. CONCLUSIONS: Engaging high-risk patients remains a difficult process that may be improved through novel, digital health interventions. The Epharmix platform enables increased patient engagement with very low risk to improve clinical outcomes. We demonstrated that engagement among high-risk populations is possible when health care comes conveniently to where they are

Binocular Goggle Augmented Imaging and Navigation System provides real-time fluorescence image guidance for tumor resection and sentinel lymph node mapping

The inability to identify microscopic tumors and assess surgical margins in real-time during oncologic surgery leads to incomplete tumor removal, increases the chances of tumor recurrence, and necessitates costly repeat surgery. To overcome these challenges, we have developed a wearable goggle augmented imaging and navigation system (GAINS) that can provide accurate intraoperative visualization of tumors and sentinel lymph nodes in real-time without disrupting normal surgical workflow. GAINS projects both near-infrared fluorescence from tumors and the natural color images of tissue onto a head-mounted display without latency. Aided by tumor-targeted contrast agents, the system detected tumors in subcutaneous and metastatic mouse models with high accuracy (sensitivity = 100%, specificity = 98% ± 5% standard deviation). Human pilot studies in breast cancer and melanoma patients using a near-infrared dye show that the GAINS detected sentinel lymph nodes with 100% sensitivity. Clinical use of the GAINS to guide tumor resection and sentinel lymph node mapping promises to improve surgical outcomes, reduce rates of repeat surgery, and improve the accuracy of cancer staging

Evaluation of paravertebral blocks in improving post-procedural pain and decreasing hospital admission after microwave ablation of liver tumors

Abstract Although ablations are performed with conscious sedation or general anesthesia, microwave ablations can be painful post procedure. Newer analgesic modalities, including regional blocks, have promoted the proliferation of less invasive anesthesia care for ablative procedures. This study evaluates whether bilateral paravertebral blocks reduce the need for additional analgesics in comparison to unilateral blocks in microwave ablations. In this retrospective study, individuals undergoing microwave ablation who underwent unilateral versus bilateral nerve blocks at a single institution from 2017 to 2019 were compared. Categorical variables were analyzed using Pearson’s chi-squared tests. Comparisons of means were completed using multiple T-tests corrected using the Holm-Sidak method with $$\alpha$$ α = 0.05. Regression modeling was used to identify factors related to increased MME (milligram morphine equivalent) usage and post-procedure admission rates. A total of 106 patients undergoing 112 liver MWA procedures were included in this analysis, with patients receiving either a bilateral or unilateral block. Pre-procedural characteristics demonstrated no significant differences in age or gender. Bilateral blocks were associated with decreased usage of gabapentin (14% vs. 0%, p = 0.01) and a lower rate of post-procedure admissions (OR 0.23, p = 0.003). Therefore, when using paravertebral blocks, bilateral blocks are superior to unilateral blocks, as demonstrated by decreased rates of hospital admission and reduced use of systemic neuropathic pain medication. Additionally, reducing post-procedural MME may reduce the rate of admission to the hospital

Assessing Public Interest in Elective Surgery During the COVID-19 Pandemic

Objective:. To determine trends in internet search volume for elective surgery terms during the first peak of the coronavirus disease 2019 (COVID-19) pandemic using Google Trends data. Background:. Postponement of much-needed elective and urgent oncologic surgeries takes a toll on patients and the health care system. The COVID-19 pandemic has led to a decline in elective surgery volume, partially due to the cancellation of elective surgeries at the start of the pandemic. Methods:. We performed a cross-sectional analysis of internet search volume trends for elective surgery terms during the first peak of the COVID-19 pandemic using Google Trends data and compared to a control group of terms representing common urgent and oncologic surgeries. Results:. Search volume for elective surgery terms (“knee replacement,” “spinal fusion,” “hip replacement,” “laminectomy,” “cataract surgery”) revealed a decrease of up to 54% compared to the prepandemic period, a significantly greater decrease than search volume for urgent and oncologic surgery terms (“C-section,” “cholecystectomy,” “CABG,” “colectomy,” “lobectomy,” and “mastectomy”). Conclusions:. The first phase of the COVID-19 pandemic led to sharp declines in search volume for essential elective surgical procedures, which may have been partially due to the cancellation of elective surgeries, but patient factors such as a temporary decline in interest in elective surgery might have also played a role. Attention to internet search volume may be used during future public health crises to monitor public engagement and interest in important health topics, including preventive health measures such as cancer screening

Ethnic preparation and quality assessment of Chhurpi, a home-made cheese of Ladakh, India

Chhurpi is a traditional cottage cheese found in different hilly regions of India including Sikkim, Darjeeling, Ladakh, etc. The main aim of this study was to explore the preparation process, microbial, and chemical compositions of chhurpi in Ladakh. There are mainly two types of chhurpi found in Ladakh: soft and hard (sun dried). Results showed that yeast, mold, lactic acid bacteria, and Bifidobacterium sp. were the major participating microbes in Ladakhi chhupri. The amount of riboflavin (162.71 μg/g), thiamine (64.48 μg/g), and vitamin C (23.53 μg/g) were higher in soft chhurpi than the hard chhurpi. However, lactic acid and acetic acid contents in hard chhurpi (0.23 mg/g and 0.16 mg/g, respectively) were higher than the soft chhurpi (0.12 mg/g and 0.06 mg/g, respectively). It also contains a very good amount of protein (60–63%) and carbohydrates (23–24%); and a low amount of fat (7–8%). Very low amounts of ethanol and methanol were also detected. This study clearly demonstrated that microbial interaction during fermentation of milk makes it more nutritious as it enriches the fermented material with vitamins and organic acids

Extracellular pH Modulates Neuroendocrine Prostate Cancer Cell Metabolism and Susceptibility to the Mitochondrial Inhibitor Niclosamide.

Neuroendocrine prostate cancer is a lethal variant of prostate cancer that is associated with castrate-resistant growth, metastasis, and mortality. The tumor environment of neuroendocrine prostate cancer is heterogeneous and characterized by hypoxia, necrosis, and numerous mitoses. Although acidic extracellular pH has been implicated in aggressive cancer features including metastasis and therapeutic resistance, its role in neuroendocrine prostate cancer physiology and metabolism has not yet been explored. We used the well-characterized PNEC cell line as a model to establish the effects of extracellular pH (pH 6.5, 7.4, and 8.5) on neuroendocrine prostate cancer cell metabolism. We discovered that alkalinization of extracellular pH converted cellular metabolism to a nutrient consumption-dependent state that was susceptible to glucose deprivation, glutamine deprivation, and 2-deoxyglucose (2-DG) mediated inhibition of glycolysis. Conversely, acidic pH shifted cellular metabolism toward an oxidative phosphorylation (OXPHOS)-dependent state that was susceptible to OXPHOS inhibition. Based upon this mechanistic knowledge of pH-dependent metabolism, we identified that the FDA-approved anti-helminthic niclosamide depolarized mitochondrial potential and depleted ATP levels in PNEC cells whose effects were enhanced in acidic pH. To further establish relevance of these findings, we tested the effects of extracellular pH on susceptibility to nutrient deprivation and OXPHOS inhibition in a cohort of castrate-resistant prostate cancer cell lines C4-2B, PC-3, and PC-3M. We discovered similar pH-dependent toxicity profiles among all cell lines with these treatments. These findings underscore a potential importance to acidic extracellular pH in the modulation of cell metabolism in tumors and development of an emerging paradigm that exploits the synergy of environment and therapeutic efficacy in cancer