Les crédits nouveaux à l’habitat des ménages : tendances récentes.

En dépit d’un fléchissement par rapport à ses sommets de la fin de 2010, la distribution de prêts à l’habitat est restée soutenue au 1er semestre 2011 : la remontée des taux de ces derniers mois a peu pesé jusqu’à présent sur la demande des ménages, la production de prêts se maintenant à des niveaux élevés.crédits nouveaux à l’habitat, ancien, neuf, amélioration-entretien, répartition des financements, taux d’intérêt bancaire, prêts relais.

Interactive process mining of cancer treatment sequences with melanoma real-world data.

The growing availability of clinical real-world data (RWD) represents a formidable opportunity to complement evidence from randomized clinical trials and observe how oncological treatments perform in real-life conditions. In particular, RWD can provide insights on questions for which no clinical trials exist, such as comparing outcomes from different sequences of treatments. To this end, process mining is a particularly suitable methodology for analyzing different treatment paths and their associated outcomes. Here, we describe an implementation of process mining algorithms directly within our hospital information system with an interactive application that allows oncologists to compare sequences of treatments in terms of overall survival, progression-free survival and best overall response. As an application example, we first performed a RWD descriptive analysis of 303 patients with advanced melanoma and reproduced findings observed in two notorious clinical trials: CheckMate-067 and DREAMseq. Then, we explored the outcomes of an immune-checkpoint inhibitor rechallenge after a first progression on immunotherapy versus switching to a BRAF targeted treatment. By using interactive process-oriented RWD analysis, we observed that patients still derive long-term survival benefits from immune-checkpoint inhibitors rechallenge, which could have direct implications on treatment guidelines for patients able to carry on immune-checkpoint therapy, if confirmed by external RWD and randomized clinical trials. Overall, our results highlight how an interactive implementation of process mining can lead to clinically relevant insights from RWD with a framework that can be ported to other centers or networks of centers

CT-guided methylene-blue labelling before thoracoscopic resection of pulmonary nodules.

OBJECTIVE: Evaluation of the efficiency of our technique of methylene-blue labelling of pulmonary nodules to facilitate thoracoscopic recognition and excision. DESIGN: Patients with a peripheral pulmonary nodule smaller than 2.5 cm and not in contact with the visceral pleura were included. Under tomodensitometric guidance, the nodules were labelled with methylene-blue within hours before thoracoscopic wedge resection. If frozen section revealed a primary bronchial carcinoma, thoracotomy and classical resection were performed during the same anesthesia. RESULTS: Between July 1992 and August 1996, 54 nodules were removed in 51 patients. Labelling was performed between 75 and 270 min before surgery and was complicated in 13 patients (25.4%) by a small pneumothorax without any clinical consequence. Labelling allowed successful thoracoscopic recognition of 50 nodules (92%) and thoracoscopic wedge resection was possible in all but one cases (91%). Five patients (9%) required thoracotomy. Histology showed a benign lesion in 22 cases, a primary lung carcinoma in 17 and a metastases in 15. Twenty of the 22 benign nodules (91%) were removed without thoracotomy. According to the protocol, 13 patients with a primary lung tumour underwent lobectomy during the same session. There was no mortality nor morbidity amongst patients who had thoracoscopy only. CONCLUSIONS: Our technique of labelling peripheral pulmonary nodules with methylene-blue is very effective and is not associated with any relevant complication. Thoracoscopic excision and diagnosis is possible in more than 90% of the cases. We therefore recommend this simple, low-cost and reliable technique for nodules not in contact with the visceral pleura before thoracoscopic wedge resection

Systematic comparison with autoimmune liver disease identifies specific histological features of immune checkpoint inhibitor-related adverse events.

Immune checkpoint inhibitors (ICIs) have become a mainstay of cancer treatment. Their immune-boosting quality has one major drawback, their proclivity to induce a broad array of immune-related adverse events (irAEs) affecting, among others, the liver and sharing some similarities with classic autoimmune liver diseases (AILD).We aimed to compare clinical, laboratory and histological features of patients with liver-related irAEs and AILD. We systematically compared liver irAEs with AILD, namely autoimmune hepatitis (AIH) and primary biliary cholangitis, regarding their clinical, laboratory, and histological features. Twenty-seven patients with liver irAEs (ICI group) and 14 patients with AILD were identified. We observed three distinct ICI-induced histological liver injury patterns: hepatitic (52%), cholangitic (19%), and mixed (29%). When comparing the ICI and AILD groups, centrilobular injury as well as granuloma formation were more prevalent in the former (p=0.067 and 0.002, respectively). CD4+/CD8+ T cell ratios were heterogeneous between the two groups, without statistically significant difference but with a trend toward increased CD8+ T cells among hepatitic irAEs as compared with AIH. Pattern of liver function test alteration was predictive for the type of irAEs but did not correlate with histological severity. Liver irAEs have broad clinical, laboratory and histological presentations. Histological features of irAEs and AILD are distinct, likely underpinning their different immunological mechanisms

The unconventional myosin CRINKLED and its mammalian orthologue MYO7A regulate caspases in their signalling roles

Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration. How caspases are activated under non-apoptotic conditions and process a selective set of substrates without killing the cell remain enigmatic. Here we find that the Drosophila unconventional myosin CRINKLED (CK) selectively interacts with the initiator caspase DRONC and regulates some of its non-apoptotic functions. Loss of CK in the arista, border cells or proneural clusters of the wing imaginal discs affects DRONC-dependent patterning. Our data indicate that CK acts as substrate adaptor, recruiting SHAGGY46/GSK3-β to DRONC, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity. Similarly, the mammalian CK counterpart, MYO7A, binds to and impinges on CASPASE-8, revealing a new regulatory axis affecting receptor interacting protein kinase-1 (RIPK1)>CASPASE-8 signalling. Together, our results expose a conserved role for unconventional myosins in transducing caspase-dependent regulation of kinases, allowing them to take part in specific signalling events

Thoracoscopic detection of occult indeterminate pulmonary nodules using bronchoscopic pleural dye marking

Background: The annual incidence of a small indeterminate pulmonary nodule (IPN) on computed tomography (CT) scan remains high. While traditional paradigms exist, the integration of new technologies into these diagnostic and treatment algorithms can result in alternative, potentially more efficient methods of managing these findings. Methods: We report on an alternative diagnostic and therapeutic strategy for the management of an IPN. This approach combines electromagnetic navigational bronchoscopy (ENB) with an updated approach to placement of a pleural dye marker. This technique lends itself to a minimally invasive wedge resection via either video-assisted thoracoscopic surgery (VATS) or a robotic approach. Results: Subsequent to alterations in the procedure, a cohort of 22 patients with an IPN was reviewed. Navigation was possible in 21 out of 22 patients with one patient excluded based on airway anatomy. The remaining 21 patients underwent ENB with pleural dye marking followed by minimally invasive wedge resection. The median size of the nodules was 13.4 mm (range: 7–29). There were no complications from the ENB procedure. Indigo carmine dye was used in ten patients. Methylene blue was used in the remaining 11 patients. In 81% of cases, the visceral pleural marker was visible at the time of surgery. In one patient, there was diffuse staining of the parietal pleura. In three additional patients, no dye was identified within the hemithorax. In all cases where dye marker was present on the visceral pleural surface, it was in proximity to the IPN and part of the excised specimen. Conclusions: ENB with pleural dye marking can provide a safe and effective method to localize an IPN and can allow for subsequent minimally invasive resection. Depending on the characteristics and location of the nodule, this method may allow more rapid identification intraoperatively

A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis

Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations in thirteen CLN genes. Mutations in one CLN gene, CLN5, cause variant late-infantile NCL, with an age of onset between 4 and 7 years. The CLN5 protein is ubiquitously expressed in the majority of tissues studied and in the brain, CLN5 shows both neuronal and glial cell expression. Mutations in CLN5 are associated with the accumulation of autofluorescent storage material in lysosomes, the recycling units of the cell, in the brain and peripheral tissues. CLN5 resides in the lysosome and its function is still elusive. Initial studies suggested CLN5 was a transmembrane protein, which was later revealed to be processed into a soluble form. Multiple glycosylation sites have been reported, which may dictate its localisation and function. CLN5 interacts with several CLN proteins, and other lysosomal proteins, making it an important candidate to understand lysosomal biology. The existing knowledge on CLN5 biology stems from studies using several model organisms, including mice, sheep, cattle, dogs, social amoeba and cell cultures. Each model organism has its advantages and limitations, making it crucial to adopt a combinatorial approach, using both human cells and model organisms, to understand CLN5 pathologies and design drug therapies. In this comprehensive review, we have summarised and critiqued existing literature on CLN5 and have discussed the missing pieces of the puzzle that need to be addressed to develop an efficient therapy for CLN5 Batten disease

De novo design of protein logic gates

The design of modular protein logic for regulating protein function at the posttranscriptional level is a challenge for synthetic biology. Here, we describe the design of two-input AND, OR, NAND, NOR, XNOR, and NOT gates built from de novo–designed proteins. These gates regulate the association of arbitrary protein units ranging from split enzymes to transcriptional machinery in vitro, in yeast and in primary human T cells, where they control the expression of the TIM3 gene related to T cell exhaustion. Designed binding interaction cooperativity, confirmed by native mass spectrometry, makes the gates largely insensitive to stoichiometric imbalances in the inputs, and the modularity of the approach enables ready extension to three-input OR, AND, and disjunctive normal form gates. The modularity and cooperativity of the control elements, coupled with the ability to de novo design an essentially unlimited number of protein components, should enable the design of sophisticated posttranslational control logic over a wide range of biological functions