IMP1/IGF2BP1 in human colorectal cancer extracellular vesicles.

Colorectal cancer (CRC) is a leading cause of cancer-related death. There is an urgent need for new methods of early CRC detection and monitoring to improve patient outcomes. Extracellular vesicles (EVs) are secreted, lipid-bilayer bound, nanoparticles that carry biological cargo throughout the body and in turn exhibit cancer-related biomarker potential. RNA binding proteins (RBPs) are posttranscriptional regulators of gene expression that may provide a link between host cell gene expression and EV phenotypes. Insulin-like growth factor 2 RNA binding protein 1 (IGF2BP1/IMP1) is an RBP that is highly expressed in CRC with higher levels of expression correlating with poor prognosis. IMP1 binds and potently regulates tumor-associated transcripts that may impact CRC EV phenotypes. Our objective was to test whether IMP1 expression levels impact EV secretion and/or cargo. We used RNA sequencing, in vitro CRC cell lines, ex vivo colonoid models, and xenograft mice to test the hypothesis that IMP1 influences EV secretion and/or cargo in human CRC. Our data demonstrate that IMP1 modulates the RNA expression of transcripts associated with extracellular vesicle pathway regulation, but it has no effect on EV secretion levels in vitro or in vivo. Rather, IMP1 appears to affect EV regulation by directly entering EVs in a transformation-dependent manner. These findings suggest that IMP1 has the ability to shape EV cargo in human CRC, which could serve as a diagnostic/prognostic circulating tumor biomarker.NEW & NOTEWORTHY This work demonstrates that the RNA binding protein IGF2BP1/IMP1 alters the transcript profile of colorectal cancer cell (CRC) mRNAs from extracellular vesicle (EV) pathways. IMP1 does not alter EV production or secretion in vitro or in vivo, but rather enters CRC cells where it may further impact EV cargo. Our work shows that IMP1 has the ability to shape EV cargo in human CRC, which could serve as a diagnostic/prognostic circulating tumor biomarker.

IMP1 3' UTR shortening enhances metastatic burden in colorectal cancer.

The RNA-binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) is overexpressed in colorectal cancer (CRC); however, evidence for a direct role for IMP1 in CRC metastasis is lacking. IMP1 is regulated by let-7 microRNA, which binds in the 3' untranslated region (UTR) of the transcript. The availability of binding sites is in part controlled by alternative polyadenylation, which determines 3' UTR length. Expression of the short 3' UTR transcript (lacking all microRNA sites) results in higher protein levels and is correlated with increased proliferation. We used in vitro and in vivo model systems to test the hypothesis that the short 3' UTR isoform of IMP1 promotes CRC metastasis. Herein we demonstrate that 3' UTR shortening increases IMP1 protein expression and that this in turn enhances the metastatic burden to the liver, whereas expression of the long isoform (full length 3' UTR) does not. Increased tumor burden results from elevated tumor surface area driven by cell proliferation and cell survival mechanisms. These processes are independent of classical apoptosis pathways. Moreover, we demonstrate the shifts toward the short isoform are associated with metastasis in patient populations where IMP1-long expression predominates. Overall, our work demonstrates that different IMP1 expression levels result in different functional outcomes in CRC metastasis and that targeting IMP1 may reduce tumor progression in some patients.

The Molecular Basis of Metastatic Colorectal Cancer.

PURPOSE OF REVIEW: Metastatic colorectal cancer (CRC) is a vexing clinical problem. In contrast to early stage disease, once CRC metastasizes to other organs, long-term survival is compromised. We seek to review the molecular pathogenesis, animal models, and functional genomics for an enhanced understanding of how CRC metastasizes and how this can be exploited therapeutically. RECENT FINDINGS: Mouse models may recapitulate certain aspects of metastatic human CRC and allow for studies to identify regulators of metastasis. Modulation of transcription factors, onco-proteins, or tumor suppressors have been identified to activate known metastatic pathways. CD44 variants, microRNAs and RNA binding proteins are emerging as metastatic modulators. SUMMARY: CRC metastasis is a multi-faceted and heterogeneous disease. Despite common pathways contributing to metastatic development, there are numerous variables that modulate metastatic signals in subsets of patients. It is paramount that studies continue to investigate metastatic drivers, enhancers and inhibitors in CRC to develop therapeutic targets and improve disease outcomes.

DNA/MVA Vaccination of HIV-1 Infected Participants with Viral Suppression on Antiretroviral Therapy, followed by Treatment Interruption: Elicitation of Immune Responses without Control of Re-Emergent Virus.

GV-TH-01, a Phase 1 open-label trial of a DNA prime­Modified Vaccinia Ankara (MVA) boost vaccine (GOVX-B11), was undertaken in HIV infected participants on antiretroviral treatment (ART) to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI). Nine men who began antiretroviral therapy (ART) within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/µl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine. TRIAL REGISTRATION: clinicaltrials.gov NCT01378156.

The "10 keys" to healthy aging: 24-month follow-up results from an innovative community-based prevention program.

The purpose of this report was to evaluate a prevention program to reduce risk factors for common diseases among older individuals in a lower income community. This randomized community-based study enrolled older adults into a Brief Education and Counseling Intervention or a Brief Education and Counseling Intervention plus a physical activity and (for those with hypertension) a dietary sodium intervention. Outcomes were collected on 389 adults with a mean age of 73.9 years over 24 months. Adherence to the "10 Keys" improved significantly in the proportion meeting goals for low-density lipoprotein cholesterol (+14%), bone mineral density testing (+11%), pneumonia vaccination (+11%), colonoscopy (+14%), and adherence to antihypertensive medication (+9%). This program resulted in significant reductions in key risk factors, increases in immunizations, and adherence to established prevention guidelines over 2 years. Further research is needed to refine the use of community health counselors for translating prevention knowledge into community settings. A major limitation of these studies is the low participation percentage.

The 10 keys to healthy aging: findings from an innovative prevention program in the community.

OBJECTIVE: To develop and evaluate a novel, comprehensive prevention program for older adults designed to assess and improve adherence to preventive health care goals. METHOD: In McKeesport, Pennsylvania, 389 men and women aged 65 and older were enrolled. We assessed adherence to 10 preventive health goals, provided education and counseling, and reevaluated after 12 months. RESULTS: At baseline, adherence varied. After 12 months, proportions of participants meeting goals were improved for several areas. Overall, improvements were seen for the proportion of participants meeting goals for low-density lipoprotein (LDL) cholesterol (+43%), blood pressure control in hypertensives (+17%), blood glucose control in diabetics (+50%), and colon cancer screening (+13%). Among those without prior vaccination, influenza vaccine increased by 25% and pneumonia vaccine by 20%. DISCUSSION: This comprehensive prevention program had short-term benefits for improving adherence to established prevention guidelines in older adults. This low-cost effective program could be disseminated nationwide.