Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We ...obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.
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•Patient xenografts are relevant models of pancreatic cancers and of their stroma•Xenografts allow the genomic analysis of unresectable pancreatic cancers•The epigenome, transcriptome, and stroma of pancreatic cancer define two subtypes•Pancreatic cancer is sensitive to inhibition of NPC1L1 by Ezetimibe
Nicolle et al. present a genomic analysis of pancreatic cancer xenografts showing that tumor subtypes are defined by specific epigenetic, transcriptional, and stromal landscapes. They reveal potential therapeutic targets through analysis of signaling cross-talk between tumor and stromal cells.
Purpose
Diagnosis and treatment of AMI are a real issue for implicating physicians. In the literature, only one AMI stroke center has reported its results so far, with increasing survival rates. Our ...aim was to analyze acute mesenteric ischemia (AMI) related mortality and predictive factors, in a single academic center, before creating a dedicated intestinal stroke center.
Methods
All the patients with an AMI, between January 2015 and December 2020, were retrospectively included. They were divided into 2 groups according to the early mortality: death during the first 30 days and alive. The 2 groups were compared.
Results
173 patients (57% of men), were included, with a mean age of 68 ± 16 years. Overall mortality rate was 61%. Mortality occurred within the first 30 days in 78% of dead cases. Dead patients were significantly older, more frequently admitted from intensive care, with more serious clinical, laboratory and radiological characteristics. We have identified 3 protective factors - history of abdominal surgery (Odd Ratio = 0.1; 95%CI = 0.01–0.8, p = 0.03), medical management with curative anticoagulation (OR = 0.09; 95%CI = 0.02–0.5, p = 0.004) and/or antiplatelets (OR = 0.04; 95%CI = 0.006–0.3, p = 0.001)-, and 2 predictive factors of mortality – age > 70 years (OR = 7; 95%CI = 1.4–37, p = 0.02) and previous history of coronaropathy (OR = 13; 95%CI = 1.7–93, p = 0.01).
Conclusions
AMI is a severe disease with high morbidity and mortality rates. Even if its diagnosis is still difficult because of non-specific presentation, its therapeutic management needs to be changed in order to improve survival rates, particularly in patients older than 70 years with history of coronaropathy. Developing a dedicated organization would improve the diagnosis and the management of patients with AMI.
Treating pancreatic cancer is extremely challenging due to multiple factors, including chemoresistance and poor disease prognosis. Chemoresistance can be explained by: the presence of a dense stromal ...barrier leading to a lower vascularized condition, therefore limiting drug delivery; the huge intra-tumoral heterogeneity; and the status of epithelial-to-mesenchymal transition. These factors are highly variable between patients making it difficult to predict responses to chemotherapy. Nicotinamide phosphoribosyl transferase (NAMPT) is the main enzyme responsible for recycling cytosolic NAD+ in hypoxic conditions. FK866 is a noncompetitive specific inhibitor of NAMPT, which has proven anti-tumoral effects, although a clinical advantage has still not been demonstrated. Here, we tested the effect of FK866 on pancreatic cancer-derived primary cell cultures (PCCs), both alone and in combination with three different drugs typically used against this cancer: gemcitabine, 5-Fluorouracil (5FU) and oxaliplatin. The aims of this study were to evaluate the benefit of drug combinations, define groups of sensitivity, and identify a potential biomarker for predicting treatment sensitivity. We performed cell viability tests in the presence of either FK866 alone or in combination with the drugs above-mentioned. We confirmed both inter- and intra-tumoral heterogeneity. Interestingly, only the in vitro effect of gemcitabine was influenced by the addition of FK866. We also found that NAMPT mRNA expression levels can predict the sensitivity of cells to FK866. Overall, our results suggest that patients with tumors sensitive to FK866 can be identified using NAMPT mRNA levels as a biomarker and could therefore benefit from a co-treatment of gemcitabine plus FK866.
Urinary tract infection (UTI) is frequently diagnosed in the Emergency Department (ED). Staphylococcus aureus (SA) is an uncommon isolate in urine cultures (0.5-6% of positive urine cultures), except ...in patients with risk factors for urinary tract colonization. In the absence of risk factors, community-acquired SA bacteriuria may be related to deep-seated SA infection including infective endocarditis. We hypothesized that SA bacteriuria could be a warning microbiological marker of unsuspected infective endocarditis in the ED.
This is a retrospective chart review of consecutive adult patients between December 2005 and February 2018. All patients admitted in the ED with both SA bacteriuria (10
CFU/ml SA isolated from a single urine sample) and SA bacteremia, without risk factors for UT colonization (i.e., < 1 month UT surgery, UT catheterization) were analyzed. Diagnosis of infective endocarditis was based on the Duke criteria.
During the study period, 27 patients (18 men; median age: 61 IQR: 52-73 years) were diagnosed with community-acquired SA bacteriuria and had subsequently documented bacteremia and SA infective endocarditis. Only 5 patients (18%) had symptoms related to UT infection. Median delay between ED admission and SA bacteriuria identification was significantly shorter than that between ED admission and the diagnosis of infective endocarditis (1.4 ± 0.8 vs. 4.3 ± 4.2 days: p = 0.01). Mitral and aortic valves were most frequently involved by infective endocarditis (93%). Mortality on day 60 reached 56%.
This study suggests that community-acquired SA bacteriuria should warn the emergency physician about a potentially associated left-sided infective endocarditis in ED patients without risk factors for UT colonization.
Sulfur mustard (SM) is a chemical warfare agent that targets skin where it induces large blisters. DNA alkylation is a critical step to explain SM-induced cutaneous symptoms. We determined the ...kinetics of formation of main SM–DNA adducts and compare it with the development of the SM-induced pathogenesis in skin. SKH-1 mice were exposed to 2, 6 and 60mg/kg of SM and treated skin was biopsied between 6h and 21days. Formation of SM DNA adducts was dose-dependent with a maximum immediately after exposure. However, adducts were persistent and still detectable 21days post-exposure. The time-dependent formation of DNA adducts was also found to be correlated with the appearance of apoptotic cells. This temporal correlation suggests that these two early events are responsible for the severity of the damage to the skin. Besides, SM–DNA adducts were also detected in areas located next to contaminated zone, thus suggesting that SM diffuses in skin. Altogether, this work provides for the first time a clear picture of SM-induced genotoxicity using DNA adducts as a marker.
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•Sulfur mustard adducts are formed in DNA after skin exposure.•DNA damage formation is an early event in the pathological process of skin burn.•The amount of SM–DNA adducts is maximal at the earliest time point investigated.•Adducts are still detected 3weeks after exposure.•Sulfur mustard diffuses in skin especially when large doses are applied.
Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of ...deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti-lewisite (BAL, dimercaprol) but it is not without untoward effects. Analogs of BAL, less toxic, have been developed such as meso-2,3-dimercaptosuccinic acid (DMSA) and have been employed for the treatment of heavy metal poisoning. However, efficacy of DMSA against lewisite-induced skin lesions remains to be determined in comparison with BAL. We have thus evaluated in this study the therapeutic efficacy of BAL and DMSA in two administration modes against skin lesions induced by lewisite vapor on SKH-1 hairless mice. Our data demonstrate a strong protective efficacy of topical application of dimercapto-chelating agents in contrast to a subcutaneous administration 1h after lewisite exposure, with attenuation of wound size, necrosis and impairment of skin barrier function. The histological evaluation also confirms the efficacy of topical application by showing that treatments were effective in reversing lewisite-induced neutrophil infiltration. This protective effect was associated with an epidermal hyperplasia. However, for all the parameters studied, BAL was more effective than DMSA in reducing lewisite-induced skin injury. Together, these findings support the use of a topical form of dimercaprol-chelating agent against lewisite-induced skin lesion within the first hour after exposure to increase the therapeutic management and that BAL, despite its side-effects, should not be abandoned.
•Topically applied dimercapto-chelating agents reduce lewisite-induced skin damage.•One topical application of BAL or DMSA is sufficient to reverse lewisite effects.•Topical BAL is more effective than DMSA to counteract lewisite-induced skin damage.
Data on the toxicity of lewisite (L), a vesicant chemical warfare agent, are scarce and conflicting, and the use of the specific antidote is not without drawbacks. This study was designed to evaluate ...if the SKH‐1 hairless mouse model was suitable to study the L‐induced skin injuries. We studied the progression of lesions following exposure to L vapors for 21 days using paraclinical parameters (color, transepidermal water loss (TEWL), and biomechanical measurements), histological assessments, and biochemical indexes of inflammation. Some data were also obtained over 27 weeks. The development of lesions was similar to that reported in other models. The TEWL parameter appeared to be the most appropriate index to follow their progression. Histological analysis showed inflammatory cell infiltration and microvesications at day 1 and a complete wound closure by day 21. Biochemical studies indicated a deregulation of the levels of several cytokines and receptors involved in inflammation. An increase in the quantity of pro‐matrix metalloproteinases 2 and 9 was shown as observed in other models. This suggests that the SKH‐1 mouse model is relevant for the investigation of the physiopathological process of skin lesions induced by L and to screen new treatment candidates.
•SKH-1 hairless mouse is a suitable model to study the SM-induced skin toxicity.•Time to onset and severity of symptoms are dose-dependent after SM skin exposure.•Degranulation of mast cells is an ...early event of SM skin toxicity.
Sulfur mustard (SM) is a strong bifunctional alkylating agent that produces severe tissue injuries characterized by erythema, edema, subepidermal blisters and a delayed inflammatory response after cutaneous exposure. However, despite its long history, SM remains a threat because of the lack of effective medical countermeasures as the molecular mechanisms of these events remain unclear. This limited number of therapeutic options results in part of an absence of appropriate animal models. We propose here to use SKH-1 hairless mouse as the appropriate model for the design of therapeutic strategies against SM-induced skin toxicity. In the present study particular emphasis was placed on histopathological changes associated with inflammatory responses after topical exposure of dorsal skin to three different doses of SM (0.6, 6 and 60mg/kg) corresponding to a superficial, a second-degree and a third-degree burn. Firstly, clinical evaluation of SM-induced skin lesions using non invasive bioengineering methods showed that erythema and impairment of skin barrier increased in a dose-dependent manner. Histological evaluation of skin sections exposed to SM revealed that the time to onset and the severity of symptoms including disorganization of epidermal basal cells, number of pyknotic nuclei, activation of mast cells and neutrophils dermal invasion were dose-dependent. These histopathological changes were associated with a dose- and time-dependent increase in expression of specific mRNA for inflammatory mediators such as interleukins (IL1β and IL6), tumor necrosis factor (TNF)-α, cycloxygenase-2 (COX-2), macrophage inflammatory proteins (MIP-1α, MIP-2 and MIP-1αR) and keratinocyte chemoattractant (KC also called CXCL1) as well as adhesion molecules (L-selectin and vascular cell adhesion molecule (VCAM)) and growth factor (granulocyte colony-stimulating factor (Csf3)). A dose-dependent increase was also noted after SM exposure for mRNA of matrix metalloproteinases (MMP9) and laminin-γ2 which are associated with SM-induced blisters formation. Taken together, our results show that SM-induced skin histopathological changes related to inflammation is similar in SKH-1 hairless mice and humans. SKH-1 mouse is thus a reliable animal model for investigating the SM-induced skin toxicity and to develop efficient treatment against SM-induced inflammatory skin lesions.
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