Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation

Abstract Maximum likelihood methodology was applied to determine the mode of inheritance of rare binary traits with data structures typical for swine populations. The genetic models considered included a monogenic, a digenic, a polygenic, and three mixed polygenic and major gene models. The main emphasis was on the detection of major genes acting on a polygenic background. Deterministic algorithms were employed to integrate and maximize likelihoods. A simulation study was conducted to evaluate model selection and parameter estimation. Three designs were simulated that differed in the number of sires/number of dams within sires (10/10, 30/30, 100/30). Major gene effects of at least one SD of the liability were detected with satisfactory power under the mixed model of inheritance, except for the smallest design. Parameter estimates were empirically unbiased with acceptable standard errors, except for the smallest design, and allowed to distinguish clearly between the genetic models. Distributions of the likelihood ratio statistic were evaluated empirically, because asymptotic theory did not hold. For each simulation model, the Average Information Criterion was computed for all models of analysis. The model with the smallest value was chosen as the best model and was equal to the true model in almost every case studied.

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Intrabodies targeting human papillomavirus 16 E6 and E7 oncoproteins for therapy of established HPV-associated tumors

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01841-w ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Francesca Paolini ◽

Carla Amici ◽

Mariantonia Carosi ◽

Claudia Bonomo ◽

Paola Di Bonito ◽

...

Keyword(s):

Human Papillomavirus ◽

Antitumor Activity ◽

Tumor Growth ◽

Tumor Progression ◽

Cellular Transformation ◽

Neoplastic Progression ◽

Single Chain ◽

Hpv16 E6 ◽

Associated Lesions ◽

E6 And E7

Abstract Background The oncogenic activity of the high risk human papillomavirus type 16 (HPV16) is fully dependent on the E6 and E7 viral oncoproteins produced during viral infection. The oncoproteins interfere with cellular homeostasis by promoting proliferation, inhibiting apoptosis and blocking epithelial differentiation, driving the infected cells towards neoplastic progression. The causal relationship between expression of E6/E7 and cellular transformation allows inhibiting the oncogenic process by hindering the activity of the two oncoproteins. We previously developed and characterized some antibodies in single-chain format (scFvs) against the HPV16 E6 and E7 proteins, and demonstrated both in vitro and in vivo their antitumor activity consisting of protective efficacy against tumor progression of HPV16-positive cells. Methods Envisioning clinical application of the best characterized anti-HPV16 E6 and –HPV16 E7 scFvs, we verified their activity in the therapeutic setting, on already implanted tumors. Recombinant plasmids expressing the anti-HPV16 E6 scFvI7 with nuclear targeting sequence, or the anti-HPV16 E7 scFv43M2 with endoplasmic reticulum targeting sequence were delivered by injection followed by electroporation to three different preclinical models using C57/BL6 mice, and their effect on tumor growth was investigated. In the first model, the HPV16+ TC-1 Luc cells were used to implant tumors in mice, and tumor growth was measured by luciferase activity; in the second model, a fourfold number of TC-1 cells was used to obtain more aggressively growing tumors; in the third model, the HPV16+ C3 cells where used to rise tumors in mice. To highlight the scFv possible mechanism of action, H&E and caspase-3 staining of tumor section were performed. Results We showed that both the anti-HPV16 E6 and HPV16 E7 scFvs tested were efficacious in delaying tumor progression in the three experimental models and that their antitumor activity seems to rely on driving tumor cells towards the apoptotic pathway. Conclusion Based on our study, two scFvs have been identified that could represent a safe and effective treatment for the therapy of HPV16-associated lesions. The mechanism underlying the scFv effectiveness appears to be leading cells towards death by apoptosis. Furthermore, the validity of electroporation, a methodology allowed for human treatment, to deliver scFvs to tumors was confirmed.

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Irradiation of Nf1 mutant mouse models of spinal plexiform neurofibromas drives pathologic progression and decreases survival

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab063 ◽

2021 ◽

Author(s):

Danny Laurent ◽

Abbi E Smith ◽

Waylan K Bessler ◽

Marc Mendonca ◽

Helen Chin-Sinex ◽

...

Keyword(s):

Overall Survival ◽

Mouse Models ◽

Conditional Knockout ◽

Benign Neoplasms ◽

Neoplastic Progression ◽

Plexiform Neurofibromas ◽

Normal Tissues ◽

Peripheral Nerve Sheath Tumors ◽

Conditional Knockout Mouse ◽

Therapeutic Irradiation

Abstract Background Genetically susceptible individuals can develop malignancies after irradiation of normal tissues. In the context of therapeutic irradiation, it is not known whether irradiating benign neoplasms in susceptible individuals promotes neoplastic transformation and worse clinical outcomes. Individuals with Neurofibromatosis 1 (NF1) are susceptible to both radiation-induced second malignancies and spontaneous progression of plexiform neurofibromas (PNs) to malignant peripheral nerve sheath tumors (MPNSTs). The role of radiotherapy in the treatment of benign neoplasms such as PNs is unclear. Methods To test whether radiotherapy promotes neoplastic progression of PNs and reduces overall survival, we administered spinal irradiation (SI) to conditional knockout mouse models of NF1-associated PNs in two germline contexts: Nf1 fllfl; PostnCre + and Nf1 fl/-; PostnCre +. Both genotypes develop extensive Nf1 null spinal PNs, modeling PNs in NF1 patients. A total of 101 mice were randomized to 0 Gy, 15 Gy (3 Gy x 5), or 30 Gy (3 Gy x 10) of spine-focused, fractionated SI and aged until signs of illness. Results SI decreased survival in both Nf1 fllfl mice and Nf1 fl/- mice, with the worst overall survival occurring in Nf1 fl/- mice receiving 30 Gy. SI was also associated with increasing worrisome histologic features along the PN-MPNST continuum in PNs irradiated to higher radiation doses. Conclusions This pre-clinical study provides experimental evidence that irradiation of pre-existing PNs reduces survival and may shift PNs to higher grade neoplasms.

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TAMI-06. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.895 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii214-ii214

Author(s):

Jenna Minami ◽

Nicholas Bayley ◽

Christopher Tse ◽

Henan Zhu ◽

Danielle Morrow ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cultured Cells ◽

Tumor Biology ◽

Metabolic Reprogramming ◽

Neoplastic Progression ◽

Extracellular Milieu ◽

Metabolic Defects ◽

Metabolic Heterogeneity

Abstract Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM, and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.

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Predictive Factors for Pancreatic Cancer and Its Early Detection Using Special Pancreatic Ultrasonography in High-Risk Individuals

Cancers ◽

10.3390/cancers13030502 ◽

2021 ◽

Vol 13 (3) ◽

pp. 502

Author(s):

Junko Fukuda ◽

Kenji Ikezawa ◽

Miho Nakao ◽

Suetsumi Okagaki ◽

Reiko Ashida ◽

...

Keyword(s):

Pancreatic Cancer ◽

High Risk ◽

Predictive Factors ◽

Survival Duration ◽

Pancreatic Cysts ◽

Neoplastic Progression ◽

Dismal Prognosis ◽

Independent Risk Factors ◽

Cyst Growth

Because pancreatic cancer has a dismal prognosis, a strategy for early diagnosis is required. This study aimed to identify predictive factors of neoplastic progression in patients at high risk for pancreatic cancer and examined the efficiency of surveillance using transabdominal special ultrasonography focusing on the pancreas (special pancreatic US). Patients with slight main pancreatic duct (MPD) dilatation (≥2.5 mm) and/or pancreatic cysts (≥5 mm) were enrolled in a prospective surveillance study with special pancreatic US in a Japanese cancer referral center. A total of 498 patients undergoing surveillance for ≥3 years were included. During the median follow-up of 5.9 years, neoplastic progression developed in 11 patients (2.2%), including 9 patients who underwent pancreatectomy. Eight patients (72.7%) were diagnosed with stage 0/I disease, with an overall survival duration of 8.8 years. Findings of both MPD dilatation and pancreatic cysts at initial surveillance, MPD growth (≥0.2 mm/year) and cyst growth (≥2 mm/year) during surveillance were identified as independent risk factors for neoplastic progression. In summary, surveillance with special pancreatic US for high-risk individuals contributed to earlier detection of neoplastic progression, leading to a favorable prognosis. During surveillance, attention should be paid to MPD growth as well as to cyst growth.

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