Introduction

American Indian (AI) people experience a disproportionate tobacco and marijuana burden which may have been exacerbated by the COVID-19 pandemic. Little is known about the tobacco and marijuana habits of American Indian individuals during the COVID-19 pandemic. The objective of this study is to examine tobacco and marijuana use as well as change in use during the COVID-19 pandemic among the American Indian community.

Methods

This cross-sectional study analyzes survey data from a convenience sample of American Indian individuals residing in California and Oklahoma and included adults with and without cancer that resided in both rural and urban areas (n=1068).

Results

During October 2020 - January 2021, 36.0% of participants reported current use of tobacco products, 9.9% reported current use of marijuana products, and 23.7% reported increased use of tobacco and/or marijuana in the past 30 days, with no difference between those with cancer and those without cancer. Tobacco use was associated with marital status, age, employment status, COVID-19 exposure, COVID-19 beliefs, and alcohol consumption. Marijuana use was associated with COVID-19 beliefs, alcohol consumption, and income level. Increased tobacco and/or marijuana use was associated with baseline use of those products. Nearly a quarter of participants reported increased use of tobacco and/or marijuana products during the COVID-19 pandemic.

Conclusions

We observed high rates of tobacco use during the COVID-19 pandemic, consistent with other studies. Research is needed to examine whether tobacco and marijuana use will decrease to pre-pandemic levels post-pandemic or if these behaviors will persist post-pandemic. Given these findings, there is a pressing need to increase access to evidence-based tobacco and marijuana treatment services in the AI population post COVID-19 pandemic.

Objective

Little is known about how the COVID-19 pandemic affected cancer screenings among American Indian people residing in California and Oklahoma, 2 states with the largest American Indian populations. We assessed rates and factors associated with cancer screenings among American Indian adults during the pandemic.

Methods

From October 2020 through January 2021, we surveyed 767 American Indian adults residing in California and Oklahoma. We asked participants whether they had planned to obtain screenings for breast cancer, cervical cancer, and colorectal cancer (CRC) from March through December 2020 and whether screening was postponed because of COVID-19. We calculated adjusted odds ratios (AORs) for factors associated with reasons for planned and postponed cancer screening.

Results

Among 395 participants eligible for breast cancer screening, 234 (59.2%) planned to obtain the screening, 127 (54.3%) of whom postponed it. Among 517 participants eligible for cervical cancer screening, 357 (69.1%) planned to obtain the screening, 115 (32.2%) of whom postponed it. Among 454 participants eligible for CRC screening, 282 (62.1%) planned to obtain CRC screening, 80 of whom (28.4%) postponed it. In multivariate analyses, women who lived with a child (vs did not) had lower odds of planning to obtain a breast cancer screening (AOR = 0.6; 95% CI, 0.3-1.0). Adherence to social distancing recommendations was associated with planning to have and postponement of cervical cancer screening (AOR = 7.3; 95% CI, 0.9-58.9). Participants who received (vs did not receive) social or financial support had higher odds of planning to have CRC screening (AOR = 2.0; 95% CI, 1.1-3.9).

Conclusion

The COVID-19 pandemic impeded completion of cancer screenings among American Indian adults. Interventions are needed to increase the intent to receive evidence-based cancer screenings among eligible American Indian adults.

Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol consumption that induce a precancerous field, with phosphoinositide 3-kinase (PI3K) signaling being a common driver. However, the preclinical effectiveness of PI3K inhibitors has not necessarily translated to remarkable benefit in HNSCC patients. Thus, we sought to determine how precancerous keratinocytes influence HNSCC proliferation, cancer stem cell (CSC) maintenance, and response to PI3K inhibitors. We used the NOK keratinocyte cell line as a model of preneoplastic keratinocytes because it harbors two frequent genetic events in HNSCC, CDKN2A promoter methylation and TP53 mutation, but does not form tumors. NOK cell coculture or NOK cell-conditioned media promoted HNSCC proliferation, PI3K inhibitor resistance, and CSC phenotypes. SOMAscan-targeted proteomics determined the relative levels of >1300 analytes in the media conditioned by NOK cells and HNSCC cells ± PI3K inhibitor. These results demonstrated that NOK cells release abundant levels of ligands that activate epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR), two receptor tyrosine kinases with oncogenic activity. Inhibition of EGFR, but not FGFR, blunted PI3K inhibitor resistance and CSC phenotypes induced by NOK cells. Our results demonstrate that precancerous keratinocytes can directly support neighboring HNSCC by activating EGFR. Importantly, PI3K inhibitor sensitivity was not necessarily a cancer cell-intrinsic property, and the tumor microenvironment impacts therapeutic response and supports CSCs. Additionally, combined inhibition of EGFR with PI3K inhibitor diminished EGFR activation induced by PI3K inhibitor and potently inhibited cancer cell proliferation and CSC maintenance.

Objectives

Assess the percentage of cancer-related appointment delays, cancelations, and the unavailability of medications experienced by American Indian participants during the COVID-19 pandemic.

Methods

This cross-sectional survey study was completed between October 2020 and July 2021 by 360 individuals with cancer who lived in California and Oklahoma. Binary and multivariate logistic regression analysis was completed in SAS 9.4.

Results

During the initial Covid-19 pandemic, almost one-third (30%) of respondents delayed cancer-related appointments, 42% canceled cancer-related appointments, and one-quarter (24%) were unable to access prescription medications or over-the-counter medications (27%) due to COVID-19. People who underwent testing for COVID-19 were five times more likely to delay a medical appointment [adjusted odds ratio (aOR) = 5.3, 95% CI:2.4, 11.7] and people who followed three or more social distancing measures were more than six times more likely to cancel medical appointments (aOR:6.3, 95% CI:2.9, 13.9).

Conclusion

This study identifies delays, cancelations, and medication inaccessibility people identifying as American Indian faced during the coronavirus pandemic. Disparities in healthcare delivery could contribute to increased morbidity and mortality rates of cancer.

The ocean is the linchpin supporting life on Earth, but it is in declining health due to an increasing footprint of human use and climate change. Despite notable successes in helping to protect the ocean, the scale of actions is simply not now meeting the overriding scale and nature of the ocean's problems that confront us.Moving into a post-COVID-19 world, new policy decisions will need to be made. Some, especially those developed prior to the pandemic, will require changes to their trajectories; others will emerge as a response to this global event. Reconnecting with nature, and specifically with the ocean, will take more than good intent and wishful thinking. Words, and how we express our connection to the ocean, clearly matter now more than ever before.The evolution of the ocean narrative, aimed at preserving and expanding options and opportunities for future generations and a healthier planet, is articulated around six themes: (1) all life is dependent on the ocean; (2) by harming the ocean, we harm ourselves; (3) by protecting the ocean, we protect ourselves; (4) humans, the ocean, biodiversity, and climate are inextricably linked; (5) ocean and climate action must be undertaken together; and (6) reversing ocean change needs action now.This narrative adopts a 'One Health' approach to protecting the ocean, addressing the whole Earth ocean system for better and more equitable social, cultural, economic, and environmental outcomes at its core. Speaking with one voice through a narrative that captures the latest science, concerns, and linkages to humanity is a precondition to action, by elevating humankind's understanding of our relationship with 'planet Ocean' and why it needs to become a central theme to everyone's lives. We have only one ocean, we must protect it, now. There is no 'Ocean B'.

Cancer-associated fibroblasts (CAFs) have been shown to enhance squamous cell carcinoma (SCC) growth, but it is unclear whether they promote SCC lung metastasis. We generated CAFs from K15.KrasG12D.Smad4-/- mouse SCCs. RNA expression analyses demonstrated that CAFs had enriched transforming growth factor-beta (TGFβ) signaling compared to normal tissue-associated fibroblasts (NAFs), therefore we assessed how TGFβ-enriched CAFs impact SCC metastasis. We co-injected SCC cells with CAFs to the skin, tail vein, or the lung to mimic sequential steps of lung metastasis. CAFs increased SCC volume only in lung co-transplantations, characterized with increased proliferation and angiogenesis and decreased apoptosis compared to NAF co-transplanted SCCs. These CAF effects were attenuated by a clinically relevant TGFβ receptor inhibitor, suggesting that CAFs facilitated TGFβ-dependent SCC cell seeding and survival in the lung. CAFs also increased tumor volume when co-transplanted to the lung with limiting numbers of SCC cancer stem cells (CSCs). In vitro, CSC sphere formation and invasion were increased either with co-cultured CAFs or with CAF conditioned media (which contains the highest TGFβ1 concentration) and these CAF effects were blocked by TGFβ inhibition. Further, TGFβ activation was higher in primary human oral SCCs with lung metastasis than SCCs without lung metastasis. Similarly, TGFβ activation was detected in the lungs of mice with micrometastasis. Our data suggest that TGFβ-enriched CAFs play a causal role in CSC seeding and expansion in the lung during SCC metastasis, providing a prognostic marker and therapeutic target for SCC lung metastasis.

Transforming growth factor beta (TGFβ) and programmed death-ligand 1 (PD-L1) are often overproduced in refractory squamous cell carcinoma (SCC). We examined spatial patterns of PD-L1⁺ cells in mouse and human SCCs and found that PD-L1 was primarily expressed on infiltrating leukocytes. Although combined TGFβ and PD-L1 blockade are undergoing cancer clinical trials, there are no predictive markers for therapeutic responders. To address this, we used both a small molecule TGFβ inhibitor in combination with anti-PD-L1 and a bifunctional fusion protein targeting both TGFβ and PD-L1 to treat mouse SCCs and found TGFβ inhibition enhanced PD-L1 blockade-induced tumor eradication in multiple tumor models. Furthermore, we identified distinct cell populations of responders and non-responders to bintrafusp alfa, with responders showing a shift toward a more immune-permissive microenvironment. The cellular and molecular signatures of responders versus non-responders to combined TGFβ and PD-L1 blockade provide important insights into future personalized immunotherapy in SCC.

Transforming growth factor beta (TGFβ) activity is linked to metastasis in many cancer types, but whether TGFβ activity is necessary for squamous cell carcinoma (SCC) lung metastasis has not been studied. Here we used a lung metastatic SCC model derived from keratin 15 (K15). Kras^G12D.Smad4^-/- SCC and human SCC specimens to identify metastasis drivers and test therapeutic interventions. We demonstrated that a TGFβ receptor (TGFβR) inhibitor reduced lung metastasis in mouse SCC correlating with reduced CD11b⁺/Ly6G⁺ myeloid cells positive for inducible nitric oxide synthase (iNOS). Further, TGFβ activity and iNOS were higher in primary human oral SCCs with metastasis than SCCs without metastasis. Consistently, either depleting myeloid cells with anti-Gr1 antibody or inhibiting iNOS with L-N6-(1-iminoethyl)-l-lysine (L-NIL) reduced SCC lung metastasis. L-NIL treated tumor-bearing mice exhibited reductions in tumor-infiltrating myeloid cells and in plasma Cxcl5 levels, and attenuated primary tumor growth with increased apoptosis and decreased proliferation. Blocking Cxcl5 with an antagonist of its receptor Cxcr2, SB225002, also reduced SCC lung metastasis.

PURPOSE: Recent studies reported therapeutic effects of Smad7 on oral mucositis in mice without compromising radiation therapy-induced cancer cell killing in neighboring oral cancer. This study aims to assess whether a Smad7-based biologic can treat oral mucositis in a clinically relevant setting by establishing an oral mucositis model in dogs and analyzing molecular targets. METHODS AND MATERIALS: We created a truncated human Smad7 protein fused with the cell-penetrating Tat tag (Tat-PYC-Smad7). We used intensity modulated radiation therapy to induce oral mucositis in dogs and applied Tat-PYC-Smad7 to the oral mucosa in dose-finding studies after intensity modulated radiation therapy. Clinical outcomes were evaluated. Molecular targets were analyzed in biopsies and serum samples. RESULTS: Tat-PYC-Smad7 treatment significantly shortened the duration of grade 3 oral mucositis based on double-blinded Veterinary Radiation Therapy Oncology Group scores and histopathology evaluations. Topically applied Tat-PYC-Smad7 primarily penetrated epithelial cells and was undetectable in serum. NanoString nCounter Canine IO Panel identified that, compared to the vehicle samples, top molecular changes in Tat-PYC-Smad7 treated samples include reductions in inflammation and cell death and increases in cell growth and DNA repair. Consistently, immunostaining shows that Tat-PYC-Smad7 reduced DNA damage and neutrophil infiltration with attenuated TGF-β and NFκB signaling. Furthermore, IL-1β and TNF-α were lower in Tat-PYC-Smad7 treated mucosa and serum samples compared to those in vehicle controls. CONCLUSIONS: Topical Tat-PYC-Smad7 application demonstrated therapeutic effects on oral mucositis induced by intensity modulated radiation therapy in dogs. The local effects of Tat-PYC-Smad7 targeted molecules involved in oral mucositis pathogenesis as well as reduced systemic inflammatory cytokines.