Contemporary Minimally Invasive Surgery for TASC-D Aorto-Iliac Lesions: Analysis of Outcomes and Risk Factors for Primary and Secondary Patency.

BACKGROUND: For complex extensive TASC-II D lesions, the standard of care remains conventional surgery. Nevertheless, guidelines tend to broaden endovascular surgery indications in expert centers for patients at high surgical risk with TASC-II D lesions. Due to the increasing use of endovascular surgery in this setting, we planned to evaluate the patency rate of this approach. METHODS: We conducted a retrospective study in a tertiary center. All patients treated for symptomatic peripheral arterial disease (PAD) with classified D lesions according to the TASC-II classification and requiring management of the aortoiliac bifurcation were retrospectively included between January 1, 2007 and December 31, 2017. The type of surgical approach was classified as a pure percutaneous approach or hybrid surgery. The main objective was to describe long-term patency results. The secondary objectives were to identify risk factors for loss of patency and long-term complications. The primary outcomes were primary patency, primary-assisted patency, and secondary patency at 5 years of follow-up. RESULTS: One hundred and thirty-six patients were included. For the overall population, the primary, primary-assisted, and secondary patency proportions at 5 years were 71.6% (95% confidence interval (CI) 63.2-81%), 82.1% (95% CI 74.9-89.3%), 96.3% (95% CI 92-100%), respectively. For primary patency, there was a significant difference in favor of the covered stent group at 36 months (P < 0.01) and 60 months (P = 0.037). In a multivariate model, only CS and age were associated with a better primary patency (hazard ratio (HR) 0.36, CI 95% [0.15-0.83], P = 0.0193 and an HR 0.07, 95% CI [0.05-0.09], P = 0.005, respectively). The overall rate of perioperative complications was 11%. CONCLUSIONS: We report that endovascular and hybrid surgery are safe and effective in the management of TASC-D complex aortoiliac lesions in mid to long-term follow-up. Short-term and long-term complications were all considered as minor.

A pan-cancer analysis of the human tumor coagulome and its link to the tumor immune microenvironment.

OBJECTIVE: Solid tumors often establish a procoagulable state that can lead to venous thromboembolism (VTE). Although some of the key genes involved in this process are known, no previous study has compared the "coagulome", i.e., the expression of coagulation/fibrinolysis genes, across different primary tumor types. It is also unclear whether the coagulome is associated with specific characteristics of the tumor microenvironment (TME). We aimed to address this question. METHODS: We analyzed the expression of the genes F3, PLAU, PLAT, PLAUR, SERPINB2, and SERPINE1 in 32 cancer types using data from The Cancer Genome Atlas (TCGA) and other freely available resources. RESULTS: We identified specific expression patterns of procoagulant and fibrinolytic genes. The expression of the Tissue Factor (F3) was found to be tumor type dependent, with the highest expression in glioblastoma (GBM), a highly procoagulable tumor type. Conversely, high expression of the fibrinolysis gene cluster PLAU, PLAUR, SERPINE1 was consistently linked to the characteristics of the TME (monocytic infiltration) and high expression of important checkpoints of the immune response, such as PD-L2 and CD276/B7-H3. CONCLUSION: These tumor-specific patterns of expression might partially explain the differences in VTE risk among tumor types. We propose that biomarkers of coagulation fibrinolysis might provide valuable information about the TME in cancer patients.

Contribution of Genomics to the Surgical Management and Study of Oral Cancer.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most frequent type of tumor arising from the oral cavity. Surgery is the cornerstone of the treatment of these cancers. Tumor biology has long been overlooked as an important contributor to the outcome of surgical procedures, but recent studies are challenging this concept. Molecular analyses of tumor DNA or RNA provide a rich source of information about the biology of OSCC. METHODS: We searched for relevant articles using PubMed. We examined in particular the prospect of applying molecular methods for minimally invasive exploration of OSCC biology. RESULTS: We examined five potential applications of genomics to the surgical management and study of OSCC: i) assessing oral potentially malignant lesions; ii) tumor staging prior to surgery; iii) predicting postoperative risk in locally advanced tumors; iv) measuring minimal residual disease and optimizing the longitudinal monitoring of OSCC; and v) predicting the efficacy of medical treatment. CONCLUSIONS: Genomic information can be harnessed in order to identify new biomarkers that could improve the staging, choice of therapy and management of OSCC. The identification of new biomarkers is awaited for better personalization of the surgical treatment of OSCC.

SLC7A11 as a biomarker and therapeutic target in HPV-positive head and neck Squamous Cell Carcinoma.

Ferroptosis, a regulated form of cell necrosis was previously reported to be induced upon pharmacological targeting of the cystine transporter SLC7A11 in Head and neck Squamous Cell Carcinoma (HNSCC). Whether tumors arising in a context of chronic infection with Human Papillomavirus (HPV) are sensitive to ferroptosis is unknown. Using RNAseq data (both whole-tumor and single-cell sequencing) we report that HPV positive (HPV+ve) tumors have lower expression levels of SLC7A11 compared to HPV negative (HPV-ve) HNSCC. We examined in vitro the effect of erastin, a specific blocker of SLC7A11, applied on two HNSCC cell lines with stable expression of HPV16 E6 and E7 oncoproteins. We report a decrease in total GSH levels and an increased sensitivity to erastin-induced ferroptosis in E6-E7 cells. Cell sensitivity to ferroptosis was specificaly related to a defect in cystine transport since we found no difference in ferroptosis induced by the direct inhibition of GPX4, and N-Acetyl Cystein abolished the difference between WT and E6-E7-expressing cells. Our findings point to SLC7A11 as an HPV-related biomarker of potential therapeutic relevance in HNSCC. Targeting cystine import to promote ferroptosis might be a promising strategy against HPV+ve HNSCC. (188 words).

Wnt/ß-catenin signaling mediates osteoblast differentiation triggered by peptide-induced α5ß1 integrin priming in mesenchymal skeletal cells.

The α5ß1 integrin is a key fibronectin (FN) receptor that binds to RGD-containing peptides to mediate cell adhesion. We previously reported that α5ß1 integrin promotes osteogenic differentiation in mesenchymal skeletal cells (MSCs), but the underlying mechanisms are not fully understood. In this study, we determined the signaling mechanisms induced by α5ß1 integrin interaction with its high-affinity ligand CRRETAWAC in murine and human MSCs and in vivo. We show that cyclized CRRETAWAC fully displaced MSC adhesion to FN, whereas related peptides lacking the full RRET sequence produced a partial displacement, indicating that RRET acts as an RGD-like sequence that is required to antagonize FN-mediated cell adhesion. However, all peptides increased focal adhesion kinase phosphorylation, OSE2 transcriptional activity, osteoblast gene expression, and matrix mineralization in MSCs, indicating that peptide-induced α5ß1 integrin priming can promote osteogenic differentiation independently of the RRET sequence. Biochemical analyses showed that peptide-induced α5ß1 integrin priming transiently increased PI3K/Akt phosphorylation and promoted Wnt/ß-catenin transcriptional activity independently of RRET. Consistently, pharmacological inhibition of PI3K activity reduced osteoblast differentiation and abolished Wnt regulatory gene expression induced by α5ß1 integrin priming. In vivo, systemic delivery of cyclized GACRETAWACGA linked to (DSS)6 to allow delivery to bone-forming sites for 6 weeks increased serum osteocalcin levels and improved long bone mass and microarchitecture in SAMP-6 senescent osteopenic mice. The results support a mechanism whereby α5ß1 integrin priming by high-affinity ligands integrates Wnt/ß-catenin signaling to promote osteoblast differentiation independently of cell adhesion, which could be used to improve bone mass and microarchitecture in the aging skeleton.

Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib.

BACKGROUND: Sorafenib, a kinase inhibitor active against various solid tumours, induces oxidative stress and ferroptosis, a new form of oxidative necrosis, in some cancer cells. Clinically-applicable biomarkers that reflect the impact of sorafenib on the redox metabolism of cancer cells are lacking. METHODS: We used gene expression microarrays, real-time PCR, immunoblot, protein-specific ELISA, and gene reporter constructs encoding the enzyme luciferase to study the response of a panel of cancer cells to sorafenib. Tumour explants prepared from surgical hepatocellular carcinoma (HCC) samples and serum samples obtained from HCC patients receiving sorafenib were also used. RESULTS: We observed that genes of the metallothionein-1 (MT1) family are induced in the HCC cell line Huh7 exposed to sorafenib. Sorafenib increased the expression of MT1G mRNA in a panel of human cancer cells, an effect that was not observed with eight other clinically-approved kinase inhibitors. We identified the minimal region of the MT1G promoter that confers inducibility by sorafenib to a 133 base pair region containing an Anti-oxidant Response Element (ARE) and showed the essential role of the transcription factor NRF2 (Nuclear factor erythroid 2-Related Factor 2). We examined the clinical relevance of our findings by analysing the regulation of MT1G in five tumour explants prepared from surgical HCC samples. Finally, we showed that the protein levels of MT1 increase in the serum of some HCC patients receiving sorafenib, and found an association with reduced overall survival. CONCLUSION: These findings indicate that MT1 constitute a biomarker adapted for exploring the impact of sorafenib on the redox metabolism of cancer cells.

Short-term culture of tumour slices reveals the heterogeneous sensitivity of human head and neck squamous cell carcinoma to targeted therapies.

BACKGROUND: Despite recent progress, investigating the impact of targeted therapies on Head and Neck Squamous Cell Carcinoma (HNSCC) remains a challenge. We investigated whether short-term culture of tumour fragments would permit the evaluation of tumour sensitivity to targeted therapies at the individual level. METHODS: We cultivated tumour slices prepared from 18 HNSCC tumour samples obtained during surgical resection. The samples were treated for 48 h with a panel of 8 targeted therapies directed against selected oncogenic transduction pathways. We analysed the cell proliferation index (CPI) of tumour cells using Ki67 labelling and the activation status of the RAF-MEK-ERK cascade through ERK phosphorylation analysis. RESULTS: Fourteen tumours were successfully analysed after short-term culture of tumour samples, revealing a striking individual heterogeneity of HNSCC in terms of tumour cell sensitivity to targeted therapies. Using 50% inhibition of CPI as threshold, sorafenib was shown to be active in 5/14 tumours. Cetuximab, the only approved targeted drug against HNSCC, was active in only 2/14 tumours. A more than 50% inhibition was observed with at least one drug out of the eight tested in 10/14 tumours. Cluster analysis was carried out in order to examine the effect of the drugs on cell proliferation and the RAF-MEK-ERK cascade. CONCLUSIONS: In vitro culture of tumour fragments allows for the evaluation of the effects of targeted therapies on freshly resected human tumours, and might be of value as a possible guide for the design of clinical trials and for the personalization of the medical treatment of HNSCC.

N-cadherin/wnt interaction controls bone marrow mesenchymal cell fate and bone mass during aging.

Age-related bone loss is characterized by reduced osteoblastogenesis and excessive bone marrow adipogenesis. The mechanisms governing bone marrow mesenchymal stromal cell (BMSC) differentiation into adipocytes or osteoblasts during aging are unknown. We show here that overexpressing N-cadherin (Cadh2) in osteoblasts increased BMSC adipocyte differentiation and reduced osteoblast differentiation in young transgenic (Tg) mice whereas this phenotype was fully reversed with aging. The reversed phenotype with age was associated with enhanced Wnt5a and Wnt10b expression in osteoblasts and a concomitant increase in BMSC osteogenic differentiation. Consistent with this mechanism, conditioned media from young wild type osteoblasts inhibited adipogenesis and promoted osteoblast differentiation in BMSC from old Cadh2 Tg mice, and this response was abolished by Wnt5a and Wnt10b silencing. Transplantation of BMSC from old Cadh2 Tg mice into young Tg recipients increased Wnt5a and Wnt10b expression and rescued BMSC osteogenic differentiation. In senescent osteopenic mice, blocking the CADH2-Wnt interaction using an antagonist peptide increased Wnt5a and Wnt10b expression, bone formation, and bone mass. The data indicate that Cadh2/Wnt interaction in osteoblasts regulates BMSC lineage determination, bone formation, and bone mass and suggest a therapeutic target for promoting bone formation in the aging skeleton.

Transcriptional Induction of SERPINE1 and Fibrinolysis Inhibition as Predominant Effects of Glucocorticoids on the Cancer Coagulome.

BACKGROUND/AIM: How tumors regulate the genes of the coagulome is crucial for cancer-associated thrombosis and the occurrence of venous thromboembolic complications in patients with cancer. We have previously reported potent yet complex effects of glucocorticoids (GC) on the expression of three genes that play a key role in the regulation of thrombin/plasmin activation (F3, PLAU, and SERPINE1). This study aimed to extend the investigation of GC effects to the whole tumor coagulome and assess the resulting impact on the ability of cancer cells to activate thrombin and plasmin. MATERIALS AND METHODS: Cancer RNA expression data were retrieved from various sources. Additionally, oral squamous cell carcinoma (OSCC) cells exposed to GC in vitro were analyzed using QPCR, enzymatic assays measuring thrombin and urokinase-type Plasminogen Activator (uPA) activity, and D-dimer concentrations. RESULTS: Our findings highlight the potent and specific stimulatory effect of GC on SERPINE1 expression across different types of cancer. Consistently, GC were found to inhibit uPA proteolytic activity and reduce the concentrations of D-dimers in OSCC in vitro. CONCLUSION: Fibrinolysis inhibition is a key consequence of cancer cell exposure to GC, possibly leading to the stabilization of the fibrin clot in cancer.

An MRI Radiomics Approach to Predict the Hypercoagulable Status of Gliomas.

Venous thromboembolic events are frequent complications of Glioblastoma Multiforme (GBM) and low-grade gliomas (LGGs). The overexpression of tissue factor (TF) plays an essential role in the local hypercoagulable phenotype that underlies these complications. Our aim was to build an MRI radiomics model for the non-invasive exploration of the hypercoagulable status of LGG/GBM. Radiogenomics data from The Cancer Genome Atlas (TCGA) and REMBRANDT (Repository for molecular BRAin Neoplasia DaTa) cohorts were used. A logistic regression model (Radscore) was built in order to identify the top 20% TF-expressing tumors, considered to be at high thromboembolic risk. The most contributive MRI radiomics features from LGG/GBM linked to high TF were identified in TCGA using Least Absolute Shrinkage and Selection Operator (LASSO) regression. A logistic regression model was built, whose performance was analyzed with ROC in the TCGA/training and REMBRANDT/validation cohorts: AUC = 0.87 [CI95: 0.81-0.94, p < 0.0001] and AUC = 0.78 [CI95: 0.56-1.00, p = 0.02], respectively. In agreement with the key role of the coagulation cascade in gliomas, LGG patients with a high Radscore had lower overall and disease-free survival. The Radscore was linked to the presence of specific genomic alterations, the composition of the tumor coagulome and the tumor immune infiltrate. Our findings suggest that a non-invasive assessment of the hypercoagulable status of LGG/GBM is possible with MRI radiomics.

The coagulome of oral squamous cell carcinoma: examining the role and regulation of coagulation in oral cancers using a systems approach.

PURPOSE OF REVIEW: Solid tumors often establish a locally hypercoagulant state that promotes vascular complications, such as venous thromboembolism (VTE). Oral squamous cell carcinoma (OSCC) is associated with a broad range of hemostatic complications. Although VTE rarely occurs in ambulatory patients with OSCC, the coagulation cascade is typically activated by surgical resection and local hemorrhage. We present the recent progress in the understanding of the role and regulation of coagulation in OSCC. RECENT FINDINGS: Application of systems biology, using bulk tumor and single cell genomic analyses, unveiled the landscape of the tumor coagulome. Of all tumor types, OSCC express the highest mRNA levels of F3 and PLAU, the genes that encode the tissue factor (TF) and urokinase-type plasminogen activator (uPA), the key regulators of coagulation and fibrinolysis, respectively. It also brought to light the intimate and reciprocal regulation between coagulation/fibrinolysis and the tumor microenvironment (TME). SUMMARY: OSCC have a specific coagulome, with consequences that likely extend beyond the vascular risk. We discuss the attractive possibility that biomarkers of the coagulation cascade might reflect some important characteristics of the TME, offering new opportunities to better understand the impact of surgical procedures, better predict their oncological outcome and improve current therapeutic approaches.

The Tumor Coagulome as a Transcriptional Target and a Potential Effector of Glucocorticoids in Human Cancers.

BACKGROUND: The coagulome, defined as the repertoire of genes that locally regulate coagulation and fibrinolysis, is a key determinant of vascular thromboembolic complications of cancer. In addition to vascular complications, the coagulome may also regulate the tumor microenvironment (TME). Glucocorticoids are key hormones that mediate cellular responses to various stresses and exert anti-inflammatory effects. We addressed the effects of glucocorticoids on the coagulome of human tumors by investigating interactions with Oral Squamous Cell Carcinoma, Lung Adenocarcinoma, and Pancreatic Adenocarcinoma tumor types. METHODS: We analyzed the regulation of three essential coagulome components, i.e., the tissue factor (TF), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) in cancer cell lines exposed to specific agonists of the glucocorticoid receptor (GR) (dexamethasone and hydrocortisone). We used QPCR, immunoblots, small-interfering RNA, Chromatin immunoprecipitation sequencing (ChIPseq) and genomic data from whole tumor and single-cell analyses. RESULTS: Glucocorticoids modulate the coagulome of cancer cells through a combination of indirect and direct transcriptional effects. Dexamethasone directly increased PAI-1 expression in a GR-dependent manner. We confirmed the relevance of these findings in human tumors, where high GR activity/high SERPINE1 expression corresponded to a TME enriched in active fibroblasts and with a high TGF-ß response. CONCLUSION: The transcriptional regulation of the coagulome by glucocorticoids that we report may have vascular consequences and account for some of the effects of glucocorticoids on the TME.

Coagulome and the tumor microenvironment: an actionable interplay.

Human tumors often trigger a hypercoagulable state that promotes hemostatic complications, including venous thromboembolism. The recent application of systems biology to the study of the coagulome highlighted its link to shaping the tumor microenvironment (TME), both within and outside of the vascular space. Addressing this link provides the opportunity to revisit the significance of biomarkers of hemostasis and assess the communication between vasculature and tumor parenchyma, an important topic considering the advent of immune checkpoint inhibitors and vascular normalization strategies. Understanding how the coagulome and TME influence each other offers exciting new prospects for predicting hemostatic complications and boosting the effectiveness of cancer treatment.

Targeting coagulation to unlock antitumor immunity?

Besides a number of physical consequences (reduced blood supply, stabilization of circulating tumor microemboli, shielding from the attack of immune cells), the coagulation cascade may specifically regulate antitumor immunity. We recently applied systems biology and genomics to explore the regulation of the tumor immune microenvironment by coagulation.

[Toward precision surgery for Head and Neck tumors]. / Principe et applicabilité de la chirurgie de précision aux cancers de la tête et du cou.

Surgical resection is the most frequent curative treatment proposed to patients with head and neck cancers. It is currently integrated into specific therapeutic schemes and therapeutic stratification, but the surgical procedure itself as well as its evaluation do not rely on tumor biology. Here, we present a number of recent studies, mostly based on system analyses and genomics, that show how tumor analyses could help to: i) define the indications and the extent of surgical resections; ii) personalize the perioperative management; iii) facilitate the detection of post-surgical tumor recurrence. Overall, these studies provide a proof of principle that precision surgery, i.e. based on tumor biology, similarly to precision medicine, is applicable to head and neck cancers.

Title: Principe et applicabilité de la chirurgie de précision aux cancers de la tête et du cou. Abstract: La chirurgie est la modalité de traitement curatif la plus fréquemment utilisée dans les cancers de la tête et du cou. Elle est intégrée dans des schémas de stratification thérapeutique précis, mais la conduite de l'acte chirurgical et son évaluation ne tiennent, la plupart du temps, pas compte de la biologie tumorale. Nous présentons dans cette revue plusieurs études qui montrent comment les analyses de la biologie tumorale pourraient préciser les indications et le contour d'une résection chirurgicale, personnaliser la prise en charge péri-opératoire du patient, et faciliter la détection des récurrences tumorales. Ces études apportent ainsi une preuve de principe qu'une chirurgie de précision, c'est-à-dire adossée à la biologie tumorale, à la façon de la médecine de précision pour d'autres cancers, est applicable aux cancers de la tête et du cou.

Utility of assessing CD3+ cell chimerism within the first months after allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia.

After allogeneic hematopoietic stem-cell transplantation (alloHSCT), the chimerism assay is used to monitor cell engraftment and quantify the respective proportions of donor/recipient cells in blood or bone-marrow samples. Here, we aimed to better assess the utility of determining CD3+ cell chimerism within the first 6 months post alloHSCT. One hundred and thirty five patients diagnosed with acute myeloid leukemia were enrolled in this study. We observed significantly lower overall survival and relapse free survival for patients without full donor chimerism (<95%, <98%, <99%) in whole blood at Day 30, as well as at Day 90 after alloHSCT, than for patients with full donor chimerism. This outcome was not observed when assessing selected CD3+ cells. However, at Day 90, patients with discordant whole blood versus selected CD3+ cell chimerism showed both significantly lower overall survival and relapse free survival, giving an interest to assess selected cells chimerism.

Molecular Landscape of the Coagulome of Oral Squamous Cell Carcinoma.

BACKGROUND: Hemostatic complications, ranging from thromboembolism to bleeding, are a significant source of morbidity and mortality in cancer patients. The tumor coagulome represents the multiple genes and proteins that locally contribute to the equilibrium between coagulation and fibrinolysis. We aimed to study the coagulome of Oral Squamous Cell Carcinoma (OSCC) and examine its link to the tumor microenvironment (TME). METHODS: We used data from bulk tumor DNA/RNA-seq (The Cancer Genome Atlas), single-cell RNA-seq data and OSCC cells in culture. RESULTS: Among all tumor types, OSCC was identified as the tumor with the highest mRNA expression levels of F3 (Tissue Factor, TF) and PLAU (urokinase type-plasminogen activator, uPA). Great inter- and intra-tumor heterogeneity were observed. Single-cell analyses showed the coexistence of subpopulations of pro-coagulant and pro-fibrinolytic cancer cells within individual tumors. Interestingly, OSCC with high F3 expressed higher levels of the key immune checkpoint molecules CD274/PD-L1, PDCD1LG2/PD-L2 and CD80, especially in tumor dendritic cells. In vitro studies confirmed the particularity of the OSCC coagulome and suggested that thrombin exerts indirect effects on OSCC cells. CONCLUSIONS: OSCC presents a specific coagulome. Further studies examining a possible negative modulation of the tumor's adaptive immune response by the coagulation process are warranted.

Evaluation of Proton MR Spectroscopy for the Study of the Tongue Tissue in Healthy Subjects and Patients With Tongue Squamous Cell Carcinoma: Preliminary Findings.

Purpose: To noninvasively assess spectroscopic and metabolic profiles of healthy tongue tissue and in an exploratory objective in nontreated and treated patients with tongue squamous cell carcinoma (SCC). Methods: Fourteen healthy subjects (HSs), one patient with nontreated tongue SCC (NT-SCC), and two patients with treated tongue SCC (T-SCC) underwent MRI and single-voxel proton magnetic resonance spectroscopy (1H-MRS) evaluations (3 and 1.5T). Multi-echo-times 1H-MRS was performed at the medial superior part (MSP) and the anterior inferior part (AIP) of the tongue in HS, while 1H-MRS voxel was placed at the most aggressive part of the tumor for patients with tongue SCC. 1H-MRS data analysis yielded spectroscopic metabolite ratios quantified to total creatine. Results: In HS, compared to MSP and AIP, 1H-MRS spectra revealed higher levels of creatine, a more prominent and well-identified trimethylamine-choline (TMA-Cho) peak. However, larger prominent lipid peaks were better differentiated in the tongue MSP. Compared to HS, patients with NT-SCC exhibited very high levels of lipids and relatively higher values of TMA-Cho peak. Interestingly, patients with T-SCC showed almost nonproliferation activity. However, high lipids levels were measured, although they were relatively lower than lipids levels measured in patients with NT-SCC. Conclusion: The present study demonstrated the potential use of in-vivo 1H-MRS to noninvasively assess spectroscopic and metabolic profiles of the healthy tongue tissue in a spatial location-dependent manner. Preliminary results revealed differences between HS and patients with tongue NT-SCC as well as tongue T-SCC, which should be confirmed with more patients. 1H-MRS could be included, in the future, in the arsenal of tools for treatment response evaluation and noninvasive monitoring of patients with tongue SCC.

The Bcl-2 homology domain 3 (BH3) mimetic ABT-737 reveals the dynamic regulation of bad, a proapoptotic protein of the Bcl-2 family, by Bcl-xL.

The proteins of the B-cell lymphoma 2 (Bcl-2) family are important regulators of apoptosis under normal and pathological conditions. Chemical compounds that block the antiapoptotic proteins of this family have been introduced, such as 4-[4-[(4'-Chloro[1,1'-biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]benzamide (ABT-737), a BH3-mimetic that neutralizes Bcl-2 and Bcl-xL. In this study, we used ABT-737 to explore the dynamic regulation of Bcl-2 proteins in living cells of different origins. Using ABT-737 as well as RNA interference or the application of growth factors, we examined the impact of the functional availability of the antiapoptotic proteins Bcl-2 and Bcl-2-extra large (Bcl-xL) on the Bcl-2 network. We report that ABT-737 increases the expression of Bcl-2-associated death promoter (Bad), a proapoptotic partner of the proteins Bcl-2 and Bcl-xL. Our observations indicate that Bad overexpression induced by ABT-737 results from the control of its normally rapid protein turnover, leading to the stabilization of this protein. We demonstrate the relevance of Bad post-translational regulation by Bcl-xL to the physiological setting using RNA interference against Bcl-xL as well as the application of epidermal growth factor, a growth factor that promotes the dissociation of Bad from Bcl-xL. Our results highlight a new facet of the mode of action of the antiapoptotic proteins Bcl-2 and Bcl-xL consisting of the regulation of the stability of the protein Bad. Finally, our results shed light on the mode of action of ABT-737, currently the best characterized inhibitor of the antiapoptotic proteins of the Bcl-2 family, and bear important implications regarding its use as an anticancer drug.

Therapeutic Perspectives for the Perioperative Period in Oral Squamous Cell Carcinoma (OSCC).

The perioperative period is the relatively short window of time, usually measured in days or weeks, around the surgical procedure. Despite its short duration, this time period is of great importance for cancer patients. From a biological point of view, the perioperative period is complex. Synchronous with primary tumor removal, surgery has local and distant consequences, including systemic and local inflammation, coagulation and sympathetic activation. Furthermore, the patients often present comorbidities and receive several medical prescriptions (hypnotics, pain killers, anti-emetics, hemostatics, inotropes, antibiotics). Because of the complex nature of the perioperative period, it is often difficult to predict the oncological outcome of tumor resection. Here, we review the biological consequences of surgery of Oral Squamous Cell Carcinoma (OSCC), the most frequent form of primary head and neck tumors. We briefly address the specificities and the challenges of the surgical care of these tumors and highlight the biological and clinical studies that offer insight into the perioperative period. The recent trials examining neoadjuvant immunotherapy for OSCC illustrate the therapeutic opportunities offered by the perioperative period.