Background Checkpoint blockade immunotherapy has improved metastatic cancer patient survival, but response rates remain low. There is an unmet need to identify mechanisms and tools to circumvent ...resistance. In human patients, responses to checkpoint blockade therapy correlate with tumor mutation load, and intrinsic resistance associates with pre-treatment signatures of epithelial mesenchymal transition (EMT), immunosuppression, macrophage chemotaxis and TGFbeta signaling. Methods To facilitate studies on mechanisms of squamous cell carcinoma (SCC) evasion of checkpoint blockade immunotherapy, we sought to develop a novel panel of murine syngeneic SCC lines reflecting the heterogeneity of human cancer and its responses to immunotherapy. We characterized six Kras-driven cutaneous SCC lines with a range of mutation loads. Following implantation into syngeneic FVB mice, we examined multiple tumor responses to alpha-PD-1, alpha-TGFbeta or combinatorial therapy, including tumor growth rate and regression, tumor immune cell composition, acquired tumor immunity, and the role of cytotoxic T cells and Tregs in immunotherapy responses. Results We show that alpha-PD-1 therapy is ineffective in establishing complete regression (CR) of tumors in all six SCC lines, but causes partial tumor growth inhibition of two lines with the highest mutations loads, CCK168 and CCK169. alpha-TGFbeta monotherapy results in 20% CR and 10% CR of established CCK168 and CCK169 tumors respectively, together with acquisition of long-term anti-tumor immunity. alpha-PD-1 synergizes with alpha-TGFbeta, increasing CR rates to 60% (CCK168) and 20% (CCK169). alpha-PD-1 therapy enhances CD4 + Treg/CD4 + Th ratios and increases tumor cell pSmad3 expression in CCK168 SCCs, whereas alpha-TGFbeta antibody administration attenuates these effects. We show that alpha-TGFbeta acts in part through suppressing immunosuppressive Tregs induced by alpha-PD-1, that limit the anti-tumor activity of alpha-PD-1 monotherapy. Additionally, in vitro and in vivo, alpha-TGFbeta acts directly on the tumor cell to attenuate EMT, to activate a program of gene expression that stimulates immuno-surveillance, including up regulation of genes encoding the tumor cell antigen presentation machinery. Conclusions We show that alpha-PD-1 not only initiates a tumor rejection program, but can induce a competing TGFbeta-driven immuno-suppressive program. We identify new opportunities for alpha-PD-1/alpha-TGFbeta combinatorial treatment of SCCs especially those with a high mutation load, high CD4+ T cell content and pSmad3 signaling. Our data form the basis for clinical trial of alpha-TGFbeta/alpha-PD-1 combination therapy (NCT02947165). Keywords: Checkpoint blockade, Squamous cell carcinoma, Tumor mutation load, alpha-TGFbeta /alpha-PD-1 combinatorial immunotherapy, Tregs, pSmad signaling, Epithelial mesenchymal transition (EMT)
Checkpoint blockade immunotherapy has improved metastatic cancer patient survival, but response rates remain low. There is an unmet need to identify mechanisms and tools to circumvent resistance. In ...human patients, responses to checkpoint blockade therapy correlate with tumor mutation load, and intrinsic resistance associates with pre-treatment signatures of epithelial mesenchymal transition (EMT), immunosuppression, macrophage chemotaxis and TGFβ signaling.
To facilitate studies on mechanisms of squamous cell carcinoma (SCC) evasion of checkpoint blockade immunotherapy, we sought to develop a novel panel of murine syngeneic SCC lines reflecting the heterogeneity of human cancer and its responses to immunotherapy. We characterized six Kras-driven cutaneous SCC lines with a range of mutation loads. Following implantation into syngeneic FVB mice, we examined multiple tumor responses to α-PD-1, α-TGFβ or combinatorial therapy, including tumor growth rate and regression, tumor immune cell composition, acquired tumor immunity, and the role of cytotoxic T cells and Tregs in immunotherapy responses.
We show that α-PD-1 therapy is ineffective in establishing complete regression (CR) of tumors in all six SCC lines, but causes partial tumor growth inhibition of two lines with the highest mutations loads, CCK168 and CCK169. α-TGFβ monotherapy results in 20% CR and 10% CR of established CCK168 and CCK169 tumors respectively, together with acquisition of long-term anti-tumor immunity. α-PD-1 synergizes with α-TGFβ, increasing CR rates to 60% (CCK168) and 20% (CCK169). α-PD-1 therapy enhances CD4 + Treg/CD4 + Th ratios and increases tumor cell pSmad3 expression in CCK168 SCCs, whereas α-TGFβ antibody administration attenuates these effects. We show that α-TGFβ acts in part through suppressing immunosuppressive Tregs induced by α-PD-1, that limit the anti-tumor activity of α-PD-1 monotherapy. Additionally, in vitro and in vivo, α-TGFβ acts directly on the tumor cell to attenuate EMT, to activate a program of gene expression that stimulates immuno-surveillance, including up regulation of genes encoding the tumor cell antigen presentation machinery.
We show that α-PD-1 not only initiates a tumor rejection program, but can induce a competing TGFβ-driven immuno-suppressive program. We identify new opportunities for α-PD-1/α-TGFβ combinatorial treatment of SCCs especially those with a high mutation load, high CD4+ T cell content and pSmad3 signaling. Our data form the basis for clinical trial of α-TGFβ/α-PD-1 combination therapy (NCT02947165).
Although the healthy pancreas consists mostly of epithelial cells, pancreatic cancer and the precursor lesions known as pancreatic intraepithelial neoplasia, are characterized by an extensive ...accumulation of fibroinflammatory stroma that includes a substantial and heterogeneous fibroblast population. The cellular origin of fibroblasts within the stroma has not been determined. Here, we show that the Gli1 and Hoxb6 markers label distinct fibroblast populations in the healthy mouse pancreas. We then set out to determine whether these distinct fibroblast populations expanded during carcinogenesis.
We developed genetically engineered models using a dual-recombinase approach that allowed us to induce pancreatic cancer formation through codon-optimized Flp recombinase-driven epithelial recombination of Kirsten rat sarcoma viral oncogene homolog while labeling Gli1+ or Hoxb6+ fibroblasts in an inducible manner. By using these models, we lineage-traced these 2 fibroblast populations during the process of carcinogenesis.
Although in the healthy pancreas Gli1+ fibroblasts and Hoxb6+ fibroblasts are present in similar numbers, they contribute differently to the stroma in carcinogenesis. Namely, Gli1+ fibroblasts expand dramatically, whereas Hoxb6+ cells do not.
Fibroblasts present in the healthy pancreas expand during carcinogenesis, but with a different prevalence for different subtypes. Here, we compared Gli1+ and Hoxb6+ fibroblasts and found only Gli1+ expanded to contribute to the stroma during pancreatic carcinogenesis.
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•SARS-CoV-2 positivity has led to cancelation and delay of elective pediatric surgical procedures.•It is not understood how these delays and cancelations affect outcomes.•Our study found a low rate ...of postoperative respiratory complications in asymptomatic SARS-CoV-2 positive patients.•Moving forward, hospitals should consider these data when making policies regarding case cancelation and rescheduling.
Data examining rates of postoperative complications among SARS-CoV-2 positive children are limited. The purpose of this study was to evaluate the impact of symptomatic and asymptomatic SARS-CoV-2 positive status on postoperative respiratory outcomes for children.
This retrospective cohort study included SARS-CoV-2 positive pediatric patients across 20 hospitals who underwent general anesthesia from March to October 2020. The primary outcome was frequency of postoperative respiratory complications, including: high-flow nasal cannula/non invasive ventilation, reintubation, pneumonia, Extracorporeal Membrane Oxygenation (ECMO), and 30-day respiratory-related readmissions or emergency department (ED) visits. Univariate analyses were used to evaluate associations between patient and procedure characteristics and stratified analyses by symptoms were performed examining incidence of complications.
Of 266 SARS-CoV-2 positive patients, 163 (61.7%) were male, and the median age was 10 years (interquartile range 4–14). The majority of procedures were emergent or urgent (n = 214, 80.5%). The most common procedures were appendectomies (n = 78, 29.3%) and fracture repairs (n = 40,15.0%). 13 patients (4.9%) had preoperative symptoms including cough or dyspnea. 26 patients (9.8%) had postoperative respiratory complications, including 15 requiring high-flow oxygen, 8 with pneumonia, 4 requiring non invasive ventilation, 3 respiratory ED visits, and 2 respiratory readmissions. Respiratory complications were more common among symptomatic patients than asymptomatic patients (30.8% vs. 8.7%, p = 0.01). Higher ASA class and comorbidities were also associated with postoperative respiratory complications.
Postoperative respiratory complications are less common in asymptomatic versus symptomatic SARS-COV-2 positive children. Relaxation of COVID-19-related restrictions for time-sensitive, non urgent procedures in selected asymptomatic patients may be reasonably considered. Additionally, further research is needed to evaluate the costs and benefits of routine testing for asymptomatic patients.
Iii, Respiratory complications
Background & Aims: Although the healthy pancreas consists mostly of epithelial cells, pancreatic cancer and the precursor lesions known as pancreatic intraepithelial neoplasia, are characterized by ...an extensive accumulation of fibroinflammatory stroma that includes a substantial and heterogeneous fibroblast population. The cellular origin of fibroblasts within the stroma has not been determined. Here, we show that the Gli1 and Hoxb6 markers label distinct fibroblast populations in the healthy mouse pancreas. We then set out to determine whether these distinct fibroblast populations expanded during carcinogenesis. Methods: We developed genetically engineered models using a dual-recombinase approach that allowed us to induce pancreatic cancer formation through codon-optimized Flp recombinase-driven epithelial recombination of Kirsten rat sarcoma viral oncogene homolog while labeling Gli1+ or Hoxb6+ fibroblasts in an inducible manner. By using these models, we lineage-traced these 2 fibroblast populations during the process of carcinogenesis. Results: Although in the healthy pancreas Gli1+ fibroblasts and Hoxb6+ fibroblasts are present in similar numbers, they contribute differently to the stroma in carcinogenesis. Namely, Gli1+ fibroblasts expand dramatically, whereas Hoxb6+ cells do not. Conclusions: Fibroblasts present in the healthy pancreas expand during carcinogenesis, but with a different prevalence for different subtypes. Here, we compared Gli1+ and Hoxb6+ fibroblasts and found only Gli1+ expanded to contribute to the stroma during pancreatic carcinogenesis.
Adoumié Vincent. Le réveil religieux landais au XXe siècle. In: Annales du Midi : revue archéologique, historique et philologique de la France méridionale, Tome 108, N°215, 1996. Vie politique et ...histoire économique XIXe-XXe siècles. pp. 377-394.
L'affaire Paul Touvier a remis en lumière une série de polémiques concernant le rôle de l'Église durant la Seconde Guerre mondiale. Si l'attitude de l'Institution a été bien analysée dans son ...engagement pétainiste, le refus de la collaboration d'une partie des fidèles et des clercs n'a pas donné lieu à une véritable approche socioculturelle exhaustive. Peut-on comparer le cheminement des quelques prélats ou prêtres qui s'engagèrent dans La Résistance ? Ont- ils eu la même formation spirituell...
Lung transplantation has emerged as an acceptable option for the management of cystic fibrosis patients with endstage lung disease. Heart-lung transplantation and, more recently, double lung ...transplantation have been successfully performed in this group of patients. The choice of operation, so far, has been based on the surgeon's preference and experience as well as the cardiac function of the patient. Each of the procedures has advantages and disadvantages. This article reviews the current worldwide experience in lung transplantation for patients with cystic fibrosis and highlights the controversies involved in the selection of patients and procedure.
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