The Larynx is Protected from Secondary and Vertical Papillomavirus Infection in Immunocompetent Mice.

OBJECTIVE: Mouse papillomavirus MmuPV1 causes both primary and secondary infections of the larynx in immunocompromised mice. Understanding lateral and vertical transmission of papillomavirus to the larynx would benefit patients with recurrent respiratory papillomatosis (RRP). To test the hypothesis that the larynx is uniquely vulnerable to papillomavirus infection, and to further develop a mouse model of RRP, we assessed whether immunocompetent mice were vulnerable to secondary or vertical laryngeal infection with MmuPV1. METHODS: Larynges were collected from 405 immunocompetent adult mice that were infected with MmuPV1 in the oropharynx, oral cavity, or anus, and 31 mouse pups born to immunocompetent females infected in the cervicovaginal tract. Larynges were analyzed via polymerase chain reaction (PCR) of lavage fluid or whole tissues for viral DNA, histopathology, and/or in situ hybridization for MmuPV1 transcripts. RESULTS: Despite some positive laryngeal lavage PCR screens, all laryngeal tissue PCR and histopathology results were negative for MmuPV1 DNA, transcripts, and disease. There was no evidence for lateral spread of MmuPV1 to the larynges of immunocompetent mice that were infected in the oral cavity, oropharynx, or anus. Pups born to infected mothers were negative for laryngeal MmuPV1 infection from birth through weaning age. CONCLUSION: Secondary and vertical laryngeal MmuPV1 infections were not found in immunocompetent mice. Further work is necessary to explore immunologic control of laryngeal papillomavirus infection in a mouse model and to improve preclinical models of RRP. LEVEL OF EVIDENCE: NA Laryngoscope, 134:2322-2330, 2024.

Participant experiences in HIV cure-directed trial with an extended analytical treatment interruption in Philadelphia, United States.

BACKGROUND: A feature of HIV cure trials is the need to interrupt treatment to test the efficacy of experimental interventions-a process known as analytical treatment interruptions (ATIs). OBJECTIVES: We report the experiences of participants after they completed an extended ATI. METHODS: From April to November 2022, we conducted post-ATI in-depth interviews with BEAT2 clinical trial (NCT03588715) participants who stopped ART while receiving an immunotherapy regimen. We used conventional content analysis to code the data. RESULTS: We conducted interviews with 11 Black/African American and three White/Caucasian participants (11 males, two females, and one transgender woman). The mean ATI was 38 weeks. Participants noted several significant experiences surrounding the interventions' side effects, ATI, and returning to medication. Some participants had positive experiences with their ATI. Other participants were nervous during the ATI. Rising viral loads led some to feel a sense of failure. Although trial experiences were heterogeneous, participants unanimously had positive interactions with the clinical trial staff which facilitated their retention in the trial. Participants shared their experiences with the trial, including changes in expectations, experiences with experimental interventions and procedures, compensation as a measure of respect, effort, transportation, and effects of COVID-19 during the trial. Based on these results, we provide considerations for the conduct of future HIV cure-directed clinical trials involving ATIs. CONCLUSIONS: Managing expectations, focusing on participants' contributions, and providing support to reduce feelings of having failed the research team and/or the HIV community following viral rebound should be part of HIV cure trial design. Discussing the mental health impact of rebound during consent, distinct from risk, is needed. Continued efforts to understand how people with HIV experience ATIs will improve future designs of HIV cure clinical trials.

Preclinical Models of Laryngeal Papillomavirus Infection: A Scoping Review.

OBJECTIVE: Laryngeal human papillomavirus (HPV) infection causes recurrent respiratory papillomatosis (RRP) and accounts for up to 25% of laryngeal cancers. Lack of satisfactory preclinical models is one reason that treatments for these diseases are limited. We sought to assess the literature describing preclinical models of laryngeal papillomavirus infection. DATA SOURCES: PubMed, Web of Science, and Scopus were searched from the inception of database through October 2022. REVIEW METHODS: Studies searched were screened by two investigators. Eligible studies were peer-reviewed, published in English, presented original data, and described attempted models of laryngeal papillomavirus infection. Data examined included type of papillomavirus, infection model, and results including success rate, disease phenotype, and viral retention. RESULTS: After screening 440 citations and 138 full-text studies, 77 studies published between 1923 and 2022 were included. Models used low-risk HPV or RRP (n = 51 studies), high-risk HPV or laryngeal cancer (n = 16), both low- and high-risk HPV (n = 1), and animal papillomaviruses (n = 9). For RRP, 2D and 3D cell culture models and xenografts retained disease phenotypes and HPV DNA in the short term. Two laryngeal cancer cell lines were consistently HPV-positive in multiple studies. Animal laryngeal infections with animal papillomaviruses resulted in disease and long-term retention of viral DNA. CONCLUSIONS: Laryngeal papillomavirus infection models have been researched for 100 years and primarily involve low-risk HPV. Most models lose viral DNA after a short duration. Future work is needed to model persistent and recurrent diseases, consistent with RRP and HPV-positive laryngeal cancer. LEVEL OF EVIDENCE: NA Laryngoscope, 133:3256-3268, 2023.

Drugs That Mimic Hypoxia Selectively Target EBV-Positive Gastric Cancer Cells.

Latent infection of Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cell cancers, including 10% of gastric carcinomas. We previously reported that hypoxia inducible factor-1α (HIF-1α) induces EBV's latent-to-lytic switch and identified several HIF-1α-stabilizing drugs that induce this viral reactivation. Here, we tested three classes of these drugs for preferential killing of the EBV-positive gastric cancer AGS-Akata cell line compared to its matched EBV-negative AGS control. We observed preferential killing with iron chelators [Deferoxamine (DFO); Deferasirox (DFX)] and a prolyl hydroxylase inhibitor (BAY 85-3934 (Molidustat)), but not with a neddylation inhibitor [MLN4924 (Pevonedistat)]. DFO and DFX also induced preferential killing of the EBV-positive gastric cancer AGS-BDneo and SNU-719 cell lines. Preferential killing was enhanced when low-dose DFX (10 µM) was combined with the antiviral prodrug ganciclovir. DFO and DFX induced lytic EBV reactivation in approximately 10% of SNU-719 and 20-30% of AGS-Akata and AGS-BDneo cells. However, neither DFO nor DFX significantly induced synthesis of lytic EBV proteins in xenografts grown in NSG mice from AGS-Akata cells above the level observed in control-treated mice. Therefore, these FDA-approved iron chelators are less effective than gemcitabine at promoting EBV reactivation in vivo despite their high specificity and efficiency in vitro.

Impact of Stigma on Clinician Training for Opioid Use Disorder Care: A Qualitative Study in a Primary Care Learning Collaborative.

PURPOSE: We undertook a study to examine how stigma influences the uptake of training on medication for opioid use disorder (MOUD) in primary care academic programs. METHODS: We conducted a qualitative study of 23 key stakeholders responsible for implementing MOUD training in their academic primary care training programs that were participants in a learning collaborative in 2018. We assessed barriers to and facilitators of successful program implementation and used an integrated approach to develop a codebook and analyze the data. RESULTS: Participants represented the family medicine, internal medicine, and physician assistant fields, and they included trainees. Most participants described clinician and institutional attitudes, misperceptions, and biases that enabled or hindered MOUD training. Perceptions included concerns that patients with OUD are "manipulative" or "drug seeking." Elements of stigma in the origin domain (ie, beliefs by primary care clinicians or the community that OUD is a choice and not a disease), the enacted domain (eg, hospital bylaws banning MOUD and clinicians declining to obtain an X-Waiver to prescribe MOUD), and the intersectional domain (eg, inadequate attention to patient needs) were perceived as major barriers to MOUD training by most respondents. Participants described strategies that improved the uptake of training, including giving attention to clinician concerns, clarifying the biology of OUD, and ameliorating clinician fears of being ill equipped to provide care for patients. CONCLUSIONS: OUD-related stigma was commonly reported in training programs and impeded the uptake of MOUD training. Potential strategies to address stigma in the training context, beyond providing content on effective evidence-based treatments, include addressing the concerns of primary care clinicians and incorporating the chronic care framework into OUD treatment.

The use of a topical protease inhibitor, Saquinavir, to alleviate mouse papillomavirus-mediated anal disease.

Select protease inhibitors (PI) have been found to be effective in decreasing human papillomavirus oncoprotein expression. This study evaluated whether the topical PI, Saquinavir (SQV), promotes viral clearance in an infectious mouse model with Mus musculus papillomavirus 1 (MmuPV1). NOD scid gamma (NSG) mice were anally infected with ∼4 × 108 viral genome equivalents of MmuPV1 and 120 days post-infection (when majority have high-grade anal dysplasia), began topical treatments: control (mock), 7,12-dimethylbenz(a)anthracene (DMBA) only, once weekly to promote carcinogenesis, 1% SQV only, daily (Monday - Friday), and SQV + DMBA. Viral MmuPV1 load was analyzed from anal lavages pre and post-treatment. Anal tissue was harvested, processed, and evaluated for drug absorption, grade of anal disease, and anal viral RNA. Results suggest that topical SQV promotes decreased viral shedding in female mice treated with SQV.

A Novel In Vivo Model of Laryngeal Papillomavirus-Associated Disease Using Mus musculus Papillomavirus.

Recurrent respiratory papillomatosis (RRP), caused by laryngeal infection with low-risk human papillomaviruses, has devastating effects on vocal communication and quality of life. Factors in RRP onset, other than viral presence in the airway, are poorly understood. RRP research has been stalled by limited preclinical models. The only known papillomavirus able to infect laboratory mice, Mus musculus papillomavirus (MmuPV1), induces disease in a variety of tissues. We hypothesized that MmuPV1 could infect the larynx as a foundation for a preclinical model of RRP. We further hypothesized that epithelial injury would enhance the ability of MmuPV1 to cause laryngeal disease, because injury is a potential factor in RRP and promotes MmuPV1 infection in other tissues. In this report, we infected larynges of NOD scid gamma mice with MmuPV1 with and without vocal fold abrasion and measured infection and disease pathogenesis over 12 weeks. Laryngeal disease incidence and severity increased earlier in mice that underwent injury in addition to infection. However, laryngeal disease emerged in all infected mice by week 12, with or without injury. Secondary laryngeal infections and disease arose in nude mice after MmuPV1 skin infections, confirming that experimentally induced injury is dispensable for laryngeal MmuPV1 infection and disease in immunocompromised mice. Unlike RRP, lesions were relatively flat dysplasias and they could progress to cancer. Similar to RRP, MmuPV1 transcript was detected in all laryngeal disease and in clinically normal larynges. MmuPV1 capsid protein was largely absent from the larynx, but productive infection arose in a case of squamous metaplasia at the level of the cricoid cartilage. Similar to RRP, disease spread beyond the larynx to the trachea and bronchi. This first report of laryngeal MmuPV1 infection provides a foundation for a preclinical model of RRP.

"A Catch-22": A Firsthand Account of Barriers and Facilitators to Accessing Health Care During Reentry.

Although a history of incarceration is associated with poor long-term health status, the experience of seeking health care access during reentry is complex. Semistructured open-ended interviews were conducted among individuals with a recent history of incarceration (N = 20). The majority of participants were male (90%) and African American (80%). The majority (55%) had one or more chronic medical conditions, 40% reported active substance addiction, and 75% reported having a chronic psychiatric condition. In qualitative analysis, participants described the three biggest facilitators to accessing health care as eligibility for Medicaid, support through reentry organizations, and online resources. Participants said the major barriers to accessing health care were multiple and competing priorities, limitations of Medicaid, and lack of access to health records. Ensuring individuals with a history of incarceration are connected to the public assistance programs for which they are eligible is an important public health initiative and may facilitate successful reintegration.

Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression.

Estrogen protects females from hepatocellular carcinoma (HCC). To determine whether this protection is mediated by classic estrogen receptors, we tested HCC susceptibility in estrogen receptor-deficient mice. In contrast to a previous study, we found that diethylnitrosamine induces hepatocarcinogenesis to a significantly greater extent when females lack Esr1, which encodes Estrogen Receptor-α. Relative to wild-type littermates, Esr1 knockout females developed 9-fold more tumors. Deficiency of Esr2, which encodes Estrogen Receptor-ß, did not affect liver carcinogenesis in females. Using microarrays and QPCR to examine estrogen receptor effects on hepatic gene expression patterns, we found that germline Esr1 deficiency resulted in the masculinization of gene expression in the female liver. Six of the most dysregulated genes have previously been implicated in HCC. In contrast, Esr1 deletion specifically in hepatocytes of Esr1 conditional null female mice (in which Cre was expressed from the albumin promoter) resulted in the maintenance of female-specific liver gene expression. Wild-type adult females lacking ovarian estrogen due to ovariectomy, which is known to make females susceptible to HCC, also maintained female-specific expression in the liver of females. These studies indicate that Esr1 mediates liver cancer risk, and its control of sex-specific liver gene expression involves cells other than hepatocytes.

Views From Patients With Cancer in the Setting of Unplanned Acute Care: Informing Approaches to Reduce Health Care Utilization.

PURPOSE: New oncology care delivery models that avoid preventable acute care are needed, yet it is unclear which interventions best meet the needs of patients and caregivers. Perspectives from patients who experienced unplanned acute care events may inform the successful development and implementation of care delivery models. METHODS: We performed a qualitative interview study of patients with solid tumors on active treatment who experienced the following 3 types of unplanned acute care events: emergency department visits, first hospitalizations, and multiple hospitalizations. Patients were prospectively recruited within a large academic health system from August 2018 to January 2019. Interviews followed a semi-structured guide developed from the Consolidated Framework for Implementation Research. The constant comparative approach was used to identify themes. RESULTS: Forty-nine patients were interviewed; 51% were men, 75% were non-Hispanic White, and the mean age was 57.4 years (standard deviation, 1.9 years). Fifty-five percent of patients had metastatic disease, and 33% had an Eastern Cooperative Oncology Group performance status of 3-4. We identified the following key themes: drivers of the decision to seek acute care, patients' emotional concerns that influence interactions with the oncology team, and strategies used to avoid acute care. Patients' recommendations for interventions included anticipatory guidance, peer support, improved triage methods, and enhanced symptom management. Patients preferred options for virtual and home-based outpatient care. CONCLUSION: Patient-centered care models should focus on early delivery of supportive interventions that help patients and caregivers navigate the unexpected issues that come with cancer treatment. Patients advocate for proactive, multidisciplinary supportive interventions that enable home-based care and are led by the primary oncology team.

A Mouse Model of Oropharyngeal Papillomavirus-Induced Neoplasia Using Novel Tools for Infection and Nasal Anesthesia.

Human head and neck cancers that develop from the squamous cells of the oropharynx (Oropharyngeal Squamous Cell Carcinomas or OPSCC) are commonly associated with the papillomavirus infection. A papillomavirus infection-based mouse model of oropharyngeal tumorigenesis would be valuable for studying the development and treatment of these tumors. We have developed an efficient system using the mouse papillomavirus (MmuPV1) to generate dysplastic oropharyngeal lesions, including tumors, in the soft palate and the base of the tongue of two immune-deficient strains of mice. To maximize efficiency and safety during infection and endoscopy, we have designed a nose cone for isoflurane-induced anesthesia that takes advantage of a mouse's need to breathe nasally and has a large window for oral manipulations. To reach and infect the oropharynx efficiently, we have repurposed the Greer Pick allergy testing device as a virus delivery tool. We show that the Pick can be used to infect the epithelium of the soft palate and the base of the tongue of mice directly, without prior scarification. The ability to induce and track oropharyngeal papillomavirus-induced tumors in the mouse, easily and robustly, will facilitate the study of oropharyngeal tumorigenesis and potential treatments.

Treatment for Opioid Use Disorder in Primary Care: Opportunities and Challenges for Sustainable Training Programs.

Drug overdose death rates from opioid use have risen steadily since 1999 and reached epidemic levels, slowing for the first time in 2018, though not for many forms of opioid use. Yet evidence-based approaches to combating OUD, such as medication-assisted treatment for OUD (MT-OUD), are still inaccessible to many. Primary care providers are well-positioned to offer these services; however, training and education in OUD care remains inadequate. The National Center for Integrated Behavioral Health interviewed the Health Resources Service Administration (HRSA) awardees of federal funding to implement an MT-OUD curriculum in their primary care residency training programs to identify barriers and facilitators to implementation. Awardees were interviewed at program launch and one year later. Results showed the importance of leadership willingness to participate, effective treatment integration into existing workflow, curriculum and clinical flexibility, and supportive interdisciplinary and community partnerships. Recommendations for best practices of MT-OUD training in primary care are identified.

The human papillomavirus 16 E5 gene potentiates MmuPV1-Dependent pathogenesis.

The papillomavirus E5 gene contributes to transformation and tumorigenesis; however, its exact function in these processes and viral pathogenesis is unclear. While E5 is present in high-risk mucosotropic HPVs that cause anogenital and head and neck cancers, it is absent in cutaneous HPVs and the recently discovered mouse papillomavirus (MmuPV1), which causes papillomas and squamous cell carcinomas of the skin and mucosal epithelia in laboratory mice. We infected K14E5 transgenic mice, which express the high-risk mucosotropic HPV16 E5 gene in stratified epithelia, with MmuPV1 to investigate the effects of E5 on papillomavirus-induced pathogenesis. Skin lesions in MmuPV1-infected K14E5 mice had earlier onset, higher incidence, and reduced frequency of spontaneous regression compared to those in non-transgenic mice. K14E5 mice were also more susceptible to cervicovaginal cancers when infected with MmuPV1 and treated with estrogen compared to non-transgenic mice. Our studies support the hypothesis that E5 contributes to papillomavirus-induced pathogenesis.

Perspectives and Practice in the Identification and Treatment of Opioid Use, Alcohol Use, and Depressive Disorders.

OBJECTIVE: Little research has focused on the treatment of adults with substance use disorders in primary care despite the high occurrence, morbidity, and mortality associated with these disorders. METHODS: An electronic survey was administered to primary care providers in a large health system to assess screening and treatment practices and comfort managing opioid use, alcohol use, and depressive disorders. A total of 146 providers completed the survey (32%). RESULTS: Providers were significantly less likely to screen for or treat opioid use disorders and alcohol use disorders, compared with depression. Providers reported feeling significantly less confident, less prepared, less expected to treat, less sure of the appropriateness of treating, and less able to navigate community resources in the treatment of opioid and alcohol use disorders, compared with depression. CONCLUSIONS: Given the preponderance of substance use disorders in primary care, increased attention to equipping primary care providers to treat these conditions is warranted.

Conceptualizing restorative justice for people with mental illnesses leaving prison or jail.

Individuals with psychiatric disabilities who are involved in the criminal justice system face a number of challenges to community integration upon release. There is a critical need to develop and evaluate interventions for these individuals that connect them to the community by enhancing naturalistic social connections and helping them to participate meaningfully in valued roles. The purposes of this article are to describe, provide a theoretical rationale, and propose a conceptual model for the use of a particular restorative justice model, circles of support and accountability, to meet this need. We describe the principles of restorative justice (repairing harm, stakeholder involvement, and the transformation of community and governmental roles and relationships) and how these map on to elements of the circles intervention. These elements include a focus on community participation, positive social support, democratic decision making, collective ownership of crime problems, and connection to community-based resources. We then suggest how changes in identity transformation, moral development and motivation, and collective efficacy might mediate relationships between these intervention elements and community integration outcomes. Finally, we encourage the systematic evaluation of the circles intervention for people with mental health conditions leaving custody and provide recommendations for policy and practice. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Activating Mutations in Pik3ca Contribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes.

PURPOSE: Over 95% of human anal cancers are etiologically associated with high-risk HPVs, with HPV type 16 (HPV16) the genotype most commonly found. Activating mutations in the catalytic subunit of Phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), encoded by the Pik3ca gene, are detected in approximately 20% of human anal cancers.Experimental Design: We asked if common activating mutations in Pik3ca contribute to anal carcinogenesis using an established mouse model for anal carcinogenesis in which mice are topically treated with the chemical carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA). Mice expressing in their anal epithelium one of two activating mutations in Pik3ca genes, Pik3caH1047R or Pik3caE545K , were monitored for anal carcinogenesis in the presence or absence of transgenes expressing the HPV16 E6 and E7 oncogenes. RESULTS: Both mutant forms of Pik3ca increased susceptibility to anal carcinogenesis in the absence of HPV16 oncogenes, and cooperated with HPV16 oncogenes to induce the highest level and earliest onset of anal cancers. The combination of HPV16 oncogenes and Pik3ca mutations led to anal cancers even in the absence of treatment with DMBA. We further observed that the investigational mTOR1/2 dual inhibitor, TAK-228, significantly reduced the size of anal cancer-derived tumor spheroids in vitro and reduced the growth rates of anal cancer-derived tumor grafts in vivo. CONCLUSIONS: These data demonstrate that activating mutations in Pik3ca drive anal carcinogenesis together with HPV16 oncogenes, and that the PI3K/mTOR pathway is a relevant target for therapeutic intervention.

Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication.

EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both "on target" and "off target" mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.

Exploring Personal Medicine as Part of Self-Directed Care: Expanding Perspectives on Medical Necessity.

OBJECTIVE: Self-directed care (SDC) offers flexibility in and control over mental health services. This study examined the types of goods and services that individuals with serious mental illness request in an SDC intervention. METHODS: Data were from a randomized controlled trial that enrolled adult participants receiving Medicaid-reimbursed services, with two years of expenditures at the 50%-90% level of all Medicaid enrollees in the county and no hospitalizations within six months of the study. Data were analyzed for 60 participants randomly assigned to an SDC intervention, who were allowed to make requests for and purchase nontraditional goods and services through a noncapitated fund. Requests were coded by using the section on activities and participation of the World Health Organization's International Classification of Function, Disability, and Health (ICF) model. Descriptive statistics are presented for the categories of requests made by participants. RESULTS: The 60 participants made a total of 507 requests, representing 621 ICF codes. Requests ranged from 0 to 37 requests per person, with a mean of 8.45 requests. The average time to first request was 95.5 days. Most codes were in the area of self-care (19%) and general tasks and demands (19%). Among the 52 participants who made requests, the mean was 11.94 requests, which addressed an average of 5.60 unique needs. CONCLUSIONS: Individuals with serious mental illness identified personal-medicine strategies to address needs that are currently unmet by traditional mental health services. Self-directed care may be a service delivery option that allows consumers to access their own personal medicine and better address their needs.

Genetic background determines if Stat5b suppresses or enhances murine hepatocarcinogenesis.

Murine hepatocarcinogenesis requires growth hormone (GH). To determine if the GH-responsive transcription factor STAT5b (signal transducer and activator of transcription 5b) is also required, we compared the hepatic gene expression profiles of global Stat5b null mice to cancer-resistant mice mutant in the GH pathway-GH-deficient little and androgen receptor-null Tfm males. We found a high degree of overlap among Tfm, little, and Stat5b null males. The liver cancer susceptibility of global Stat5b null mice was assessed on three distinct genetic backgrounds: BALB/cJ (BALB), C57BL/6J (B6), and C3H/HeJ (C3H). The effect of Stat5b on hepatocarcinogenesis depended on the genetic background. B6 Stat5b null congenic males and females developed 2.4 times as many tumors as wild-type (WT) controls (P < 0.002) and the tumors were larger (P < 0.003). In BALB/c congenics, loss of STAT5b had no effect on either sex. C3H Stat5b null congenic males and females were resistant to liver cancer, developing 2.7- and 6-fold fewer tumors, respectively (P < 0.02, 0.01). These results provide the first example of a single gene behaving as both oncogene and tumor suppressor in a given tissue, depending only on the endogenous modifier alleles carried by different genetic backgrounds.

Identification of susceptibility loci in a mouse model of KRASG12D-driven pancreatic cancer.

Genetic background affects susceptibility to pancreatic ductal adenocarcinoma in the Ela-KRAS(G12D) mouse model. In this model, KRAS oncogene expression is driven by an elastase promoter in acinar cells of the pancreas on an FVB/NTac (FVB) background [FVB-Tg(Ela-KRAS(G12D))] with the transgene carried on the Y chromosome. Through linkage analysis of crosses between the C57BL/6J (B6), BALB/cJ (BALB), and DBA/2J (D2) inbred strains of mice and resistant FVB-Tg(Ela-KRAS(G12D)), we have identified six susceptibility loci that affect mean preinvasive lesion multiplicity. Markers on chromosome 2 segregated with high tumor multiplicity in all three strains; these loci were designated Prsq1-3 (pancreatic ras susceptibility quantitative trait loci 1-3; combined F2 and N2 LOD(W), 6.0, 4.1, and 2.7, respectively). Susceptibility loci on chromosome 4, designated Prsq4 and Prsq5, were identified in crosses between FVB transgenic mice and B6 or BALB mice (combined F2 and N2 LOD(W), 3.6 and 2.9, respectively). A marker on chromosome 12 segregated with tumor multiplicity in a BALB × FVB-Tg(Ela-KRAS(G12D)) cross and was designated Prsq6 (LOD(W), ∼2.5). B6-Chr Y(FVB-Tg(Ela-KRASG12D)) and BALB-Chr Y(FVB-Tg(Ela-KRASG12D)) consomics, which carry the KRAS transgene on the FVB Y chromosome on an otherwise inbred B6 or BALB background, developed ∼4-fold (B6) and ∼10-fold (BALB) more lesions than FVB-Tg(Ela-KRAS(G12D)) mice. By 12 months of age, 10% of BALB-Chr Y(FVB-Tg(Ela-KRASG12D)) mice developed invasive carcinomas. Our findings provide evidence that regions of chromosomes 2, 4, and 12 influence the development and progression of pancreatic neoplasms initiated by an oncogenic allele of KRAS in mice.