Circulating CD8 lymphocytes predict response to atezolizumab–bevacizumab in hepatocellular carcinoma

Due to the lack of biomarkers predictive of response to atezolizumab-bevacizumab, the standard of care for advanced HCC, we analyzed baseline and early on-treatment variation of peripheral lymphocyte populations of 37 prospective patients treated by atezolizumab-bevacizumab and in 15 prospective patients treated by sorafenib or lenvatinib (TKIs). RNAseq analysis followed by RT-PCR validation on patients-derived PBMC was also performed. At first imaging, re-evaluation 13 patients receiving atezolizumab-bevacizumab, showed an objective response, 17 stable disease, while 7 were nonresponders. Baseline CD8+ and CD8+PD-L1+ peripheral lymphocytes were lower in responders versus nonresponders (T-test, p = 0.012 and 0.004, respectively). At 3 weeks, 28 of 30 responders displayed a rise of CD8+PD1+ lymphocytes with a positive mean fold change of 4.35 (+/- 5.6 SD), whereas 6 of 7 nonresponders displayed a negative fold change of 0.89 (+/- 0.84 SD). These changes were not observed in patients treated by TKIs. TRIM56, TRIM16, TRIM64, and Ki67 mRNAs were validated as upregulated in responders versus nonresponders after 3 weeks after treatment start, providing possible evidence of immune activation. Baseline CD8+ and CD8+PD-L1+ peripheral lymphocytes and early changes in CD8+PD1+ lymphocytes predict response to atezolizumab-bevacizumab providing noninvasive markers to complement clinical practice in the very early phases of treatment of HCC patients.PBMCs represent important elements in assessing the response to immune checkpoint inhibitors. Their analyses through flow cytometry show that baseline CD8+, CD8+PD-L1+, and an early increase in CD8+PD1+ peripheral lymphocytes after the first drug infusion, reliably predict the response to atezolizumab-bevacizumab evaluated by imaging in advanced hepatocellular carcinoma. imag

Online Well-Being Focused Curriculums

Education and health are among the most salient issues facing Americans today. The field of public health has moved away from a physical health medical model to a more well-being focused quality-of-life perspective. K-20 curriculums in the United States need to reflect this ideological shift. In this chapter, content-focused curriculums with process-focused health behavior change-oriented learning are proposed as a strategy to promote well-being. Other issues that need to be addressed in the current education system are that the delivery of health-related curriculums is often inconsistent and taught by untrained personnel. Well-being-focused curriculums delivered online can provide consistency to improve the quality of health courses. This innovative approach has the potential to improve educational and health outcomes for K-20 curriculums while addressing public health issues by promoting well-being and quality-of-life for children and adults throughout the United States. </jats:p

Online Well-Being Focused Curriculums

Education and health are among the most salient issues facing Americans today. The field of public health has moved away from a physical health medical model to a more well-being focused quality-of-life perspective. K-20 curriculums in the United States need to reflect this ideological shift. In this chapter, content-focused curriculums with process-focused health behavior change-oriented learning are proposed as a strategy to promote well-being. Other issues that need to be addressed in the current education system are that the delivery of health-related curriculums is often inconsistent and taught by untrained personnel. Well-being-focused curriculums delivered online can provide consistency to improve the quality of health courses. This innovative approach has the potential to improve educational and health outcomes for K-20 curriculums while addressing public health issues by promoting well-being and quality-of-life for children and adults throughout the United States. </jats:p

Understanding organizational perspectives from clinical research stakeholders involved in recruitment for biopharmaceutical-sponsored clinical trials in the United States: Recommendations for organizational initiatives to improve access and inclusivity in clinical research

Background: Equitable representation of racially and ethnically diverse subpopulations in clinical trials continues to be a problem, and trial participants do not always reflect the demographics of the population that the investigational product will be used to treat. The imperativeness of equitable representation of clinically relevant populations in clinical trials has implications for improving health outcomes, increasing knowledge about the safety and efficacy of new treatments across a wider population, and broadening access to innovative treatment options offered in clinical trials. Methods: The purpose of this study was to understand organizational elements that are involved in the active implementation of racially and ethnically diverse inclusive recruitment practices for biopharmaceutical-funded trials in the United States. Semi-structured, in-depth interviews were used in this qualitative study. The interview guide was designed to explore the perceptions, practices and experiences of 15 clinical research site professionals related to recruiting diverse trial participants. Data analysis utilized an inductive coding process. Results: Five themes were identified pertaining to the actual implementation of inclusive recruitment practices that provided explanations for organizational components: 1) provision of culturally appropriate, general disease and clinical trial education 2) organizational structure tailored for diverse recruitment 3) strong sense of mission related to improving healthcare through clinical research 4) culture of inclusion 5) inclusive recruitment practices evolving based on learning. Conclusion: The findings from this study offer insight into improving access to clinical trials by focusing on organizational change initiatives

Inhibiting the oncogenic mir-221 by microRNA sponge: Toward microRNA-based therapeutics for hepatocellular carcinoma

Aim: We evaluated the capability of "microRNA sponges" in sequestering and inhibiting the over-expressed miR-221 in HCC cell lines. Background: Advanced hepatocellular carcinoma (HCC) is a serious public health problem, with no effective cure at present. It has been demonstrated that the deregulation of microRNAs expression contributes to tumorigenesis. In HCC, miR-221 was shown to be up-regulated in more than 70% of the cases and was associated with higher tumor stage, metastasis and a shorter time to recurrence after surgery, suggesting an important pathogenic role. A tumor promoting function of miR-221 was proved in a transgenic mouse model, which was predisposed to the development of liver cancers. These findings suggested that miR-221 could represent a potential target for anti-tumor approaches. Material and Methods: Novel adeno and adeno-associated viral vectors (AAVs) were developed: they were genetically modified to drive the expression of multiple binding sites for miR-221, the "miR-221 sponge", which was designed to sequester miR-221 cellular molecules. Results: Analysis of viral vectors activity in HCC cells revealed their capability to reduce miR-221 endogenous levels, which was accompanied by the increase in CDKN1B/p27 protein, a known target of miR-221. An increase in apoptosis was also measured in Hep3B cells after infection with any of the two viral vectors in comparison with control vectors, with stronger effects induced by adenovirus compared to AAV vectors. Conclusion: The depletion of oncogenic microRNAs represents a potential anti-cancer approach that needs to be tested for safety and efficacy. Here, we describe the development of novel "miR-221 sponge" vectors, which can reduce miR-221 activity in vitro and may be used for in vivo delivery

Erratum: miR-199a-3p increases the anti-tumor activity of palbociclib in liver cancer models (Molecular Therapy - Nucleic Acids (2022) 29 (538–549), (S2162253122001846), (10.1016/j.omtn.2022.07.015))

: [This corrects the article DOI: 10.1016/j.omtn.2022.07.015.]

TCL1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human B-cell chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy with a mature phenotype. In spite of its relatively indolent nature, no radical cure is as yet available. CLL is not associated with either a unique cytogenetic or a molecular defect, which might have been a potential therapeutic target. Instead, several factors are involved in disease development, such as environmental signals which interact with genetic abnormalities to promote survival, proliferation and an immune surveillance escape. Among these, PI3-Kinase signal pathway alterations are nowadays considered to be clearly important. The TCL1 gene, an AKT co-activator, is the cause of a mature T-cell leukemia, as well as being highly expressed in all B-CLL. A TCL1 transgenic mouse which reproduces leukemia with a distinct immunophenotype and similar to the course of the human B-CLL was developed several years ago and is widely used by many groups. This is a review of the CLL biology arising from work of many independent investigators who have used TCL1 transgenic mouse model focusing on pathogenetic, microenviroment and therapeutic targets

Anti-Tumor Activity of a miR-199-dependent Oncolytic Adenovirus

The down-regulation of miR-199 occurs in nearly all primary hepatocellular carcinomas (HCCs) and HCC cell lines in comparison with normal liver. We exploited this miR-199 differential expression to develop a conditionally replication-competent oncolytic adenovirus, Ad-199T, and achieve tumor-specific viral expression and replication. To this aim, we introduced four copies of miR-199 target sites within the 3’UTR of E1A gene, essential for viral replication. As consequence, E1A expression from Ad-199T virus was tightly regulated both at RNA and protein levels in HCC derived cell lines, and replication controlled by the level of miR-199 expression. Various approaches were used to asses in vivo properties of Ad-199T. Ad-199T replication was inhibited in normal, miR-199 positive, liver parenchyma, thus resulting in reduced hepatotoxicity. Conversely, the intrahepatic delivery of Ad-199T in newborn mice led to virus replication and fast removal of implanted HepG2 liver cancer cells. The ability of Ad-199T to control tumor growth was also shown in a subcutaneous xenograft model in nude mice and in HCCs arising in immune-competent mice. In summary, we developed a novel oncolytic adenovirus, Ad-199T, which could demonstrate a therapeutic potential against liver cancer without causing significant hepatotoxicity