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TGFβ/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells
In this study, we have uncovered a novel crosstalk between TGFβ and IGF-1R signaling pathways. We show for the first time that expression and activation of IRS-1, an IGF-1R adaptor protein, is decreased by TGFβ/Smad3 signaling. Loss or attenuation of TGFβ activation leads to elevated expression and phosphorylation of IRS-1 in colon cancer cells, resulting in enhanced cell proliferation, decreased apoptosis and increased tumor growth in vitro and in vivo. Downregulation of IRS-1 expression reversed Smad3 knockdown-mediated oncogenic phenotypes, indicating that TGFβ/Smad3 signaling inhibits cell proliferation and increases apoptosis at least partially through the inhibition of IRS-1 expression and activation. Additionally, the TGFβ/Smad3/IRS-1 signaling axis regulates expression of cyclin D1 and XIAP, which may contribute to TGFβ/Smad3/IRS-1-mediated cell cycle progression and survival. Given that loss of TGFβ signaling occurs frequently in colon cancer, an important implication of our study is that IRS-1 could be a potential therapeutic target for colon cancer treatment.
Journal Article
Porcine pancreatic ductal epithelial cells transformed with KRASG12D and SV40T are tumorigenic
We describe our initial studies in the development of an orthotopic, genetically defined, large animal model of pancreatic cancer. Primary pancreatic epithelial cells were isolated from pancreatic duct of domestic pigs. A transformed cell line was generated from these primary cells with oncogenic KRAS and SV40T. The transformed cell lines outperformed the primary and SV40T immortalized cells in terms of proliferation, population doubling time, soft agar growth, transwell migration and invasion. The transformed cell line grew tumors when injected subcutaneously in nude mice, forming glandular structures and staining for epithelial markers. Future work will include implantation studies of these tumorigenic porcine pancreatic cell lines into the pancreas of allogeneic and autologous pigs. The resultant large animal model of pancreatic cancer could be utilized for preclinical research on diagnostic, interventional, and therapeutic technologies.
Journal Article
Harm reduction services and interventions for People Who Use Drugs (PWUD) in Latin America and the Caribbean (LAC) between 2013–2024: A scoping review protocol
In Latin America and the Caribbean (LAC) the response to substance use has primarily been abstinence-based, acute-care-oriented treatments. While harm reduction services (HRS) and interventions have expanded in LAC over the last decade, the research evidence on such programs has been sparse and disjointed.
This scoping review will map peer-reviewed literature on HRS and interventions in LAC, and synthesize gaps and opportunities for policy, practice, and research.
Studies conducted in LAC. The HRS that will be included in the search are opioid agonist therapy, syringe services programs, drug consumption facilities, safer consumption kits, managed alcohol programs, and drug-checking services. The scoping review will consider peer-reviewed original research, including qualitative, quantitative, and mixed-methods designs. We will exclude studies addressing harms associated with nicotine or tobacco use. We included original research written in English, Spanish, Portuguese, or French published between January 2013 and December 2024.
We will conduct literature searches in English (PubMed, Scopus, Web of Science), Spanish, Portuguese (SciELO and BIREME), and French (BIREME). Two reviewers will independently screen the literature. Extraction of characteristics of the studies using a template in Covidence. Data on the HRS and interventions studied and implemented in LAC will be summarized and presented in tables, graphs, and a narrative summary. We will use a narrative synthesis approach to summarize implications for policy, research, and practice identified in the literature. The review was registered in Open Science Framework (https://osf.io/qya7c/).
The proposed scoping review will provide valuable information regarding the current state of HRS and interventions for PWUD in LAC. This in return can help guide future research for evaluating services that are already being implemented or unveil services needed in the region. To our knowledge, this is the first scoping review to map HRS in LAC using a systematic approach. Furthermore, among the strengths of this review are: the broad number of services, countries, and time, as well as the consultation with experts and knowledge users.
Journal Article
Motivational interviewing to increase drug checking and reduce overdose rates among people who use drugs: protocol for a hybrid type 1 effectiveness–implementation trial of an adjunctive intervention
Background
The unpredictable and toxic nature of the unregulated drug supply poses overdose and other health risks for people who use drugs (PWUD). Drug checking services can reduce risks by identifying adulterants in individuals’ drug supplies. In the United States (U.S.), DCS are increasingly offered through community harm reduction services that provide evidence-based risk reduction services for PWUD, such as syringe services programs (SSPs). However, PWUD face several multi-level barriers to consistently utilizing DCS and engaging in post-DCS safer drug use behaviors (e.g., discard, use less, avoid using alone, etc.). Staff from a San Diego-based mobile SSP and researchers drew from Social Cognitive Theory and the Social Ecological Model to develop a motivational-interviewing adjunctive intervention (MI-CHANCE) led by peers with lived substance use experience to address multi-level barriers and promote DCS engagement and adoption of post-DCS safer drug use behaviors among PWUD.
Methods
We employ a hybrid type-1 effectiveness–implementation trial with a primary goal of determining effectiveness of the MI-CHANCE adjunctive intervention in increasing DCS utilization (primary behavioral outcome) and safer drug use behaviors (secondary behavioral outcome), leading to reduced overdose risk (primary health outcome) and HIV/HCV incidence (secondary health outcome). We will recruit, consent, conduct a baseline interview, and randomize 588 PWUD who used opioids or stimulants within the week prior to receive either MI-CHANCE or an attention-control standard-of-care condition. All participants will be offered DCS following exposure to the intervention or control condition. We will conduct six-month follow-up with participants over a 30-month period to collect outcomes and hypothesized predictors, mediators and potential confounders. Our secondary goal is to assess MI-CHANCE implementation considerations guided by the RE-AIM/PRISM framework via annual in-depth interviews over the course of the trial with SSP staff (
N
= 5) and participants (
N
= 20), focusing on acceptability and feasibility, and the potential for scalability via interviews with a broad sample of diverse U.S. SSPs (
N
= 20).
Discussion
This hybrid trial will advance crucial knowledge on the effectiveness and implementation of an adjunctive intervention to promote DCS engagement and safer drug use behaviors to reduce overdose risk among PWUD.
Trial registration
ClinicalTrials.gov, NCT06855836. Registered February 28, 2025.
https://clinicaltrials.gov/study/NCT06855836?term=NCT06855836/rank=1
.
Journal Article
Induction of pancreatic neoplasia in the KRAS / TP53 Oncopig
The 5-year survival of pancreatic cancer (PC) remains low. Murine models may not adequately mimic human PC and can be too small for medical device development. A large-animal PC model could address these issues. We induced and characterized pancreatic tumors in Oncopigs (transgenic swine containing KRASG12D and TP53R167H). The oncopigs underwent injection of adenovirus expressing Cre recombinase (AdCre) into one of the main pancreatic ducts. Resultant tumors were characterized by histology, cytokine expression, exome sequencing and transcriptome analysis. Ten of 14 Oncopigs (71%) had gross tumor within 3 weeks. At necropsy, all of these subjects had gastric outlet obstruction secondary to pancreatic tumor and phlegmon. Oncopigs with injections without Cre recombinase and wild-type pigs with AdCre injection did not show notable effect. Exome and transcriptome analysis of the porcine pancreatic tumors revealed similarity to the molecular signatures and pathways of human PC. Although further optimization and validation of this porcine PC model would be beneficial, it is anticipated that this model will be useful for focused research and development of diagnostic and therapeutic technologies for PC. This article has an associated First Person interview with the joint first authors of the paper.
Journal Article
Arm-Swinging in the Red-Shanked Douc (Pygathrix nemaeus): Implications of Body Mass
Across the primates, larger body mass often necessitates below-branch locomotion (such as arm-swinging or brachiation). While colobines are typically considered arboreal quadrupeds, Pygathrix exhibits a high degree of arm-swinging behavior in captivity (ca. 50% of locomotion time). However, little is known about their behavior in the wild. We examined two questions about the locomotion of Pygathrix nemaeus in the wild: 1) What is the proportion of arm-swinging in the locomotor repertoire? 2) Given the difference in sizes between the sexes and age categories in this species, do adult males, adult females, subadults, and juveniles differ in arm-swinging frequency? Based on the hypothesis that increased body mass is typically associated with below-branch locomotion, we predict adult males will arm-swing the most, followed by adult females with a ventral infant, adult females without an infant, subadults, and then juveniles. We recorded data between November 2016 and April 2017 in Son Tra Nature Reserve, Da Nang, Vietnam. This time frame encompasses the wet and dry seasons. We video-recorded P. nemaeus between dawn and dusk, 5 days a week, and recorded behavioral data from the footage. We found that juveniles used arm-swinging the most (34.3%), followed by subadults (21.7%), adult females (17.6%), adult females carrying infants (15.5%), and then adult males (9.8%). These results do not support the hypothesis that larger bodied individuals engage more in below-branch locomotion. It is not uncommon for colobine juveniles to show higher proportions of arm-swinging than adults, but more research is needed to understand the relatively high proportions of arm-swinging in adult P. nemaeus.
Journal Article
Barriers and facilitators to implementing an urban co-responding police-mental health team
BackgroundIn an effort to reduce the increasing number of persons with mental illness (PMI) experiencing incarceration, co-responding police-mental health teams are being utilized as a way to divert PMI from the criminal justice system. Co-response teams are typically an inter-agency collaboration between police and mental health professionals, and in some cases include emergency medical personnel. These teams are intended to facilitate emergency response by linking patients to mental health resources rather than the criminal justice system, thus reducing burdens on both the criminal justice systems as well as local healthcare systems. The current study examines the barriers and facilitators of successfully implementing the Mobile Crisis Assistance Team model, a first-responder co-response team consisting of police officers, mental health professionals, and paramedics. Through content analysis of qualitative focus groups with team members and interviews with program stakeholders, this study expands previous findings by identifying additional professional cultural barriers and facilitators to program implementation while also exploring the role of clear, systematic policies and guidelines in program success.ResultsFindings demonstrate the value of having both flexible and formal policies and procedures to help guide program implementation; ample community resources and treatment services in order to successfully refer clients to needed services; and streamlined communication among participating agencies and the local healthcare community. A significant barrier to successful program implementation is that of role conflict and stigma. Indeed, members of the co-response teams experienced difficulty transitioning into their new roles and reported negative feedback from other first responders as well as from within their own agency. Initial agency collaboration, information sharing between agencies, and team building were also identified as facilitators to program implementation.ConclusionThe current study provides a critical foundation for the implementation of first-responder police-mental health co-response teams. Cultural and systematic barriers to co-response team success should be understood prior to program creation and used to guide implementation. Furthermore, attention must be directed to cultivating community and professional support for co-response teams. Findings from this study can be used to guide future efforts to implement first-response co-response teams in order to positively engage PMI and divert PMI from the criminal justice system.
Journal Article
TGFbeta/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells
In this study, we have uncovered a novel crosstalk between TGF[beta] and IGF-1R signaling pathways. We show for the first time that expression and activation of IRS-1, an IGF-1R adaptor protein, is decreased by TGF[beta]/Smad3 signaling. Loss or attenuation of TGF[beta] activation leads to elevated expression and phosphorylation of IRS-1 in colon cancer cells, resulting in enhanced cell proliferation, decreased apoptosis and increased tumor growth in vitro and in vivo. Downregulation of IRS-1 expression reversed Smad3 knockdown-mediated oncogenic phenotypes, indicating that TGF[beta]/Smad3 signaling inhibits cell proliferation and increases apoptosis at least partially through the inhibition of IRS-1 expression and activation. Additionally, the TGF[beta]/Smad3/IRS-1 signaling axis regulates expression of cyclin D1 and XIAP, which may contribute to TGF[beta]/Smad3/IRS-1-mediated cell cycle progression and survival. Given that loss of TGF[beta] signaling occurs frequently in colon cancer, an important implication of our study is that IRS-1 could be a potential therapeutic target for colon cancer treatment.
Journal Article