Novel low-avidity glypican-3 specific CARTs resist exhaustion and mediate durable antitumor effects against HCC.

BACKGROUND AND AIMS: Chimeric antigen receptor engineered T cells (CARTs) for HCC and other solid tumors are not as effective as they are for blood cancers. CARTs may lose function inside tumors due to persistent antigen engagement. The aims of this study are to develop low-affinity monoclonal antibodies (mAbs) and low-avidity CARTs for HCC and to test the hypothesis that low-avidity CARTs can resist exhaustion and maintain functions in solid tumors, generating durable antitumor effects. METHODS AND RESULTS: New human glypican-3 (hGPC3) mAbs were developed from immunized mice. We obtained three hGPC3-specific mAbs that stained HCC tumors, but not the adjacent normal liver tissues. One of them, 8F8, bound an epitope close to that of GC33, the frequently used high-affinity mAb, but with approximately 17-fold lower affinity. We then compared the 8F8 CARTs to GC33 CARTs for their in vitro function and in vivo antitumor effects. In vitro, low-avidity 8F8 CARTs killed both hGPC3high and hGPC3low HCC tumor cells to the same extent as high-avidity GC33 CARTs. 8F8 CARTs expanded and persisted to a greater extent than GC33 CARTs, resulting in durable responses against HCC xenografts. Importantly, compared with GC33 CARTs, there were 5-fold more of 8F8-BBz CARTs in the tumor mass for a longer period of time. Remarkably, the tumor-infiltrating 8F8 CARTs were less exhausted and apoptotic, and more functional than GC33 CARTs. CONCLUSION: The low-avidity 8F8-BBz CART resists exhaustion and apoptosis inside tumor lesions, demonstrating a greater therapeutic potential than high-avidity CARTs.

Evaluating the Quality, Readability, and Activity of Online Information on Brain Arteriovenous Malformations.

Introduction Brain arteriovenous malformations (AVMs) are vascular deformities created by improper connections between arteries and veins, most commonly in the brain and spinal cord. The management is complex and patient-dependent; further understanding of patient education activities is imperative. Internet access has become more ubiquitous, allowing patients to utilize a large database of medical information online. Using Google Trends (GT) (Google LLC, Mountain View, CA, USA), one can see the public interest in a particular topic over time. Further, when presented with numerous search results, patients may not be able to identify the highest-yielding resources, making objective measures of information quality and readability imperative. Methods A GT analysis was conducted for "hereditary hemorrhagic telangiectasia," "cerebral aneurysm," and "arteriovenous malformation". These relative search volumes (RSV) were compared with the 2017 to 2019 annual USA AVM diagnosis quantity for correlation. These RSVs were also compared with the 2017 to 2019 annual USA deaths due to cerebral hemorrhagic conditions. One search was conducted for "brain arteriovenous malformation". Since most users looking for health information online use only the first page of sources, the quality and readability analyses were limited to the first page of results on Google search. Five quality tools and six readability formulas were used. Results Pearson's correlation coefficients showed positive correlations between USA AVM RSVs and annual AVM deaths per capita from 2017 to 2019 (R2=0.932). The AVM annual diagnosis quantity and AVM RSVs showed a strong positive correlation as well (R2=0.998). Hereditary hemorrhagic telangiectasia and cerebral aneurysms had strong positive correlations between their RSVs and their corresponding annual diagnoses in the 2017 to 2019 time period (R2=0.982, R2=0.709). One-way ANOVA, for USA's 2004 to 2021 AVM RSVs and 2004 to 2019 deaths per capita, displayed no month-specific statistically significant repeating pattern (all p>0.483). The DISCERN tool had four websites that qualified as "poor" and five as "good." The average score for the tool was "good." The Journal of the American Medical Association (JAMA) benchmark scores were very low on average, as four websites achieved zero points. There was a wide variance in the currency, relevance, authority, accuracy, and purpose (CRAAP) scores, indicating an inconsistent level of webpage reliability across results. The patient education materials assessment tool (PEMAT) understandability (86.6%) showed much higher scores than the PEMAT actionability (54.6%). No readability score averaged at or below the American Medical Association (AMA)-recommended sixth-grade reading level. Conclusion These GT correlations may be due to patients and families with new diagnoses researching those same conditions online. The seasonality results reflect that no prior research has detected seasonality for AVM diagnosis or presentation. The quality study showed a wide variance in website ethics, treatment information quality, website/author qualifications, and actionable next steps regarding AVMs. Overall, this study showed that patients are routinely attempting to access information regarding these intracranial conditions, but the information available, specifically regarding AVMs, is not routinely reliable and the reading level required to understand them is too high.

Assessing Patterns in Childhood Obesity Patient Education: A Quality of Online Health Information and Google Trends Analysis.

Background: Childhood obesity (CO) is rapidly increasing in prevalence and developing into a health crisis of developed nations. The condition is associated with increased risk of developing various comorbidities later in life. Current treatment algorithms primarily target family education. Thus, this study aims to understand the quality of information online regarding CO and common comorbidities, determine the readability of online information, and report patterns in public interest over time using Google Trends. Methods: Four validated quality of information tools and 6 readability tools were implemented across 36 websites derived from 4 Google searches. Pearson's correlation coefficient was used to determine the associations between Google Trends' relative search volumes (RSVs) and biennial BMI-based cumulative proportion of CO. Results: Results showed variable information quality among the websites as scores ranged from "fair" to "very poor." Using six readability formulas, no website scored at or below the sixth grade reading level recommended by the American Medical Association. Google Trends' RSVs for the term "Childhood Obesity" were repeatedly increased in the months that fall in the US academic school year (October-November and February-May), and decreased within months in the US vacation periods (December-January and June-September). Search volumes were also negatively correlated with CO and pediatric type 2 diabetes prevalence. Conclusions: In summary, while Google Trends analysis showed that schools may play a role in increasing interest and awareness online, quality of information and readability analysis displayed that the information and its accessibility are far too variable to be reliable.

Google Trends™ and Quality of Information Analyses of Google™ Searches Pertaining to Concussion.

Sports-related concussions occur with high incidence in the United States. Google Trends™ (GT) analyses indicate changes of public interest in a topic over time, and can be correlated with incidence of health events such as concussion. Internet searches represent a primary means of patient education for many health topics, including concussion; however, the quality of medical information yielded by internet searches is variable and frequently of an inappropriate reading level. This study therefore aims to describe GT over time and evaluate the quality and readability of information produced by Google™ searches of the term "concussion." We identified a strong negative correlation from 2009 to 2016 between GT scores and total number of American high school football participants (R 2 = 0.8553) and participants per school (R 2 = 0.9533). Between 2004 and 2020, the monthly GT popularity score were variable (p = 3.193E-08), with September having the greatest scores, correlating with the height of American tackle football season. Applying five validated quality assessment scoring systems at two time points, it was confirmed that different sources yielded varying quality of information. Academic and non-profit healthcare sources demonstrated the highest quality metrics across two time points. There was significant variability of scores among the different scoring systems, however. The majority of searches at both time points yielded information that was rated as "fair" to "poor" in quality. Applying six readability tests, we revealed that only a single commercial website offered information written at or below the American Medical Association- recommended 6th-grade level for healthcare information. In summary, GT data analyses suggest that searches correlate with the American tackle football season and increased between 2009 and 2016, given that public interest in concussion increased and annual participation in football decreased. The quality of information yielded by Google™ searches and readability are inadequate, indicating the need for significant improvement.

Employing Google Trends to Assess Concussion Search Popularity, Seasonality, and Association With High School Sports Participation.

OBJECTIVE: This investigation employs 2004-2020 Google Trends data to correlate concussion search popularity and high school sports participation while assessing search seasonality and factors associated with search escalation. BACKGROUND: Events linked to concussions, from news to entertainment, altered public perception of concussions and discouraged high-risk activities. Such sentiment likely promoted high school football's 2004-2018 8% decrease in participation, despite simultaneous 8% increase for sports overall. Google Trends (GT) analysis calculates distinct subjects' popularity scores (0-100) by normalizing Google search frequency with other subjects in the same topic. With 35% of patients researching their conditions using Google, tracking concussion popularity scores allows robust analysis of event-driven fluctuation, seasonal variation, and sports impact. DESIGN/METHODS: Worldwide GT analysis was conducted for the disease topic "Concussion" with the categorical filter "Health" from 2004 to 2020. This period's monthly popularity scores with annual averages and annual high school sports participation data were subsequently obtained from Google Trends and the National Federation of State High School Associations, respectively. RESULTS: Concurrence of significant score changes with CTE studies' publication, release of 2015 film Concussion, and the COVID-19 pandemic validates GT's measurement of public interest. From 2006 to 2016, Pearson's correlation coefficients demonstrated strong negative correlation between GT popularity scores for "Concussion" with total number of high school football participants overall (R2 = 0.8553) and participants per school (R2 = 0.9533). Confirming football-related seasonality, one-way ANOVA regression analysis concluded 2004-2020's mean change in month-specific popularity score is not the same (p = 3.193E-08), and months during football season had statistically significant variability (September: p = 4.389E-05) with elevated average z-scores. CONCLUSIONS: Coupled with ANOVA regression and normalized analyses, strong negative correlations between concussion popularity score and high school football participation produce quantitative measures of a long-suspected relationship. Tracking concussion popularity and seasonality with Google Trends provides insight into how, when, and why patients are educating themselves online.