PI3K functions as a hub in mechanotransduction.

Mammalian cells integrate different types of stimuli that govern their fate. These stimuli encompass biochemical as well as biomechanical cues (shear, tensile, and compressive stresses) that are usually studied separately. The phosphatidylinositol 3-kinase (PI3K) enzymes, producing signaling phosphoinositides at plasma and intracellular membranes, are key in intracellular signaling and vesicular trafficking pathways. Recent evidence in cancer research demonstrates that these enzymes are essential in mechanotransduction. Despite this, the importance of the integration of biomechanical cues and PI3K-driven biochemical signals is underestimated. In this opinion article, we make the hypothesis that modeling of biomechanical cues is critical to understand PI3K oncogenicity. We also identify known/missing knowledge in terms of isoform specificity and molecular pathways of activation, knowledge that is needed for clinical applications.

Is targeting autophagy a promising lead to unveil the cloak of invisibility in pancreatic cancer?

Pancreatic ductal adenocarcinoma PDAC is considered as one of the less immunogenic solid tumor types. Pancreatic tumors are also known to present a high autophagy flux which supports tumor progression. Autophagy was recently described as a tumor-intrinsic immune escape process during tumor development by sequestration of Major Histocompatibility Complex class I (MHC-I) inside the PDAC cells. We comment this discovery and discuss the implications on how to limit immune escape in patients and how to improve immunotherapy efficiency. Currently, pancreatic adenocarcinoma is the most frequent pancreatic cancer with a poor prognosis, an important lethality, and a 5-year overall survival less than 5%. The development of some therapeutic solutions like targeted therapies are promising [1]. However, it is still important to understand this morbid pathology to improve the treatment, because PDAC is predicted to be the second leading cause of death in Western countries [2].

Rescue transtracheal jet ventilation during difficult intubation in patients with upper airway cancer.

INTRODUCTION: The failure rates of intubation and/or mask ventilation are higher in patients with neck or upper airway disease. To ensure oxygenation, rescue trans-tracheal jet ventilation (RTTJV) may be used. In this critical situation, a high rate of complications has been reported. The aim of this study was to report RTTJV performed by a jet ventilator with an end-expiratory pressure control in an experienced institution. PATIENTS AND METHODS: From a computerised database of 63,905 anaesthesia cases, the anaesthetic reports of patients who underwent emergency RTTJV during intubation were studied retrospectively. The following information were analysed: anaesthetic procedures, data from the monitoring: lowest SpO2, duration of SpO2<90%, and complications. Success of emergency RTTJV was defined when SpO2 was>90% under jet ventilation. RESULTS: RTTJV was used in 31 patients, of whom 26 had upper airway cancer, (pre-treatment, n=9, post-treatment, n=17). Difficult intubation was anticipated in 15 out of 31 cases including six fiber-optic-aided intubations under spontaneous ventilation. RTTJV was effective in all cases with quick restoration of oxygenation (SpO2>90%). During jet ventilation, final airway control was performed either by oral intubation (n=25) or tracheotomy (n=1) in a short delay (mean: 8.1±1.7min). Subcutaneous emphysema was observed in one case without pneumothorax. CONCLUSION: RTTJV with end-expiratory pressure control allowed oxygenation during difficult intubation, with a low rate of complications.

Attenuating PI3K isoforms in pancreatic cancer: Focus on immune PI3Kγ.

Phosphoinositide 3-kinases PI3Ks are major drug targets in oncology. Their role is far from being completely understood in pancreatic ductal adenocarcinoma. Pancreatic cancer is a dismal disease with limited therapeutic options except for surgery. We highlight here two elegant works demonstrating the role of PI3Kγ in cancer-associated macrophages applied in particular to pancreatic tumors. These data open new avenues for the use of PI3K-targetting drugs in cancer as anti-stroma therapies. Amongst the classI PI3K isoforms, PI3Kγ and PI3Kδ, are highly expressed in immune cells. Isoform-specific or pan-class I PI3K inhibitors which target all classI PI3Ks could be used as a targeted therapy towards cancer cell signaling but also as immunotherapies. Research on immunoregulation of human pancreatic cancer by the other ubiquitous α- or ß-isoforms of PI3K needs to be performed.

Early diastolic dysfunction is associated with intensive care unit mortality in cancer patients presenting with septic shock.

BACKGROUND: Cancer patients present a high risk of sepsis and are exposed to cardiotoxic drugs during chemotherapy. Myocardial dysfunction is common during septic shock and can be evaluated at bedside using echocardiography. The aim of this study was to identify early cardiac dysfunctions associated with intensive care unit (ICU) mortality in cancer patients presenting with septic shock. METHODS: Seventy-two cancer patients admitted to the ICU underwent echocardiography within 48 h of developing septic shock. History of malignancies, anticancer treatments, and clinical characteristics were prospectively collected. RESULTS: ICU mortality was 48%. Diastolic dysfunction (e' ≤8 cm s(-1)) was an independent echocardiographic parameter associated with ICU mortality {odds ratio (OR) 7.7 [95% confidence interval (CI), 2.58-23.38]; P<0.001}. Overall, three factors were independently associated with ICU mortality: sepsis-related organ failure assessment score at admission [OR 1.35 ( 95% CI, 1.05-1.74); P=0.017], occurrence of diastolic dysfunction [OR 16.6 (95% CI, 3.28-84.6); P=0.001], and need for conventional mechanical ventilation [OR 16.6 (95% CI, 3.6-77.15); P<0.001]. Diastolic dysfunction was not associated with exposure to cardiotoxic drugs. CONCLUSIONS: Early diastolic dysfunction is a strong and independent predictor of mortality in cancer patients presenting with septic shock. It is not associated with exposure to cardiotoxic drugs. Further studies incorporating monitoring of diastolic function and therapeutic interventions improving cardiac relaxation need to be evaluated in cancer patients presenting with septic shock.

[Inadvertent peripheral nerve catheter shearing occurring during ultrasound guidance]. / Cisaillements accidentels de cathéters périnerveux lors de poses échoguidées.

We report two cases of inadvertent peripheral nerve catheter (PNC) shearing that occurred during placement under ultrasound guidance. Same PNC kits were used in two different hospitals. The possible causes of PNC shearing are exposed. Differences and mechanical properties of different PNC kits are discussed. The management of retained PNC carried out in these cases is presented.

[Institutional review board of the French college of obstetricians and gynecologists (CEROG).]. / Le Comité d'éthique de la recherche en obstétrique et gynécologie (CEROG).

OBJECTIVE: To report the rules and the activity of the institutional review board of the French college of obstetricians and gynecologists (Comité d'éthique de la recherche en obstétrique et gynécologie [CEROG]) created in 2008. The submission requirements are also described. METHODS: Retrospective study. RESULTS: The Ethical Review Committee [institutional review board of the French college of obstetricians and gynecologists (CNGOF)] CEROG have examined 65 project studies in 2008. The median number of submitted studies was 5.5 per month (IQR: 3.75-6.25). The origins of the submission were as follows: tertiary care university hospitals (n=63, 97 %), Inserm (n=1), INRA (n=1). Researches were found to be in conformity with the French laws and regulations, to conform to generally accepted scientific principles and medical research ethical standards in 44 cases (68 %). In 13 cases (20 %), the study has been forwarded to the Persons Protection Committee (PPC) since it concerned biomedical research or "usual care research" (soin courant). In six cases (9 %), the investigators have not responded to IRB suggestions. In two cases (3 %), the information form has been judged unsatisfactory. CONCLUSION: The CEROG is the first national IRB in obstetrics and gynecology. This new committee clarifies IRB submission procedure in France concerning non-interventional studies in the field of obstetrics and gynecology.

Rectal metastasis from lobular breast carcinoma 15 years after primary diagnosis

Lobular breast carcinoma represents 2-20% of infiltrative carcinomas of the breast. The incidence of extrahepatic gastrointestinal (GI) tract metastases observed in necropsy studies varies from 6% to 18% and the most commonly affected organ is the stomach, followed by colon and rectum [1-4]. Reported herein is the case of a 67-year-old woman who was primarily diagnosed and surgically treated for a lobular carcinoma of the breast 15 years ago and is now referred with back pain and right hydronephrosis caused by a metastasis in rectum. Frequently, the absence of specific symptoms of digestive metastases of breast cancer leads to a misdiagnosis of this pathology [5-7]. The treatment will be based on a detailed clinical history and histopathological findings. Metastases from breast cancer in GI tract tumours must be excluded in a patient with previous history of breast carcinoma, as in the case reported herein (AU)

[Effect of women's weight on the success rate of in vitro fertilization]. / Influence du poids sur les taux de succès en fécondation in vitro.

OBJECTIVE: To examine the effect of women's weight on the success rate of in vitro fertilization. PATIENTS AND METHODS: Single centre retrospective study of a continuous series of 846 patients who underwent 1444 in vitro fertilization or ICSI cycles. The outcomes of each cycle was analysed as a function of the woman's body mass index (BMI). Three groups were defined: (1) underweight (BMI<18 kg/m2, n=68 cycles, 43 women), (2) normal BMI (18 < or =BMI<25, n=1045 cycles, 607 women), (3) overweight or obese women (IMC > or =25, n=331 cycles, 196 women). MAIN OUTCOME MEASUREMENT: Live birth rate per cycle. RESULTS: In group 3, the live birth rate per cycle (10,6% [95% confidence interval: 7,3-13,9]) was significantly lower than in group 2 (16,6% [14,3-18,8]). There was a non-significant trend towards a decreased live birth rate in group I (11,8% [4,1-19,4]). In group 3, the cancellation rate (30,8% [25,8-35,8]) was significantly greater than in group 2 (19,6% [17,2-22]), the pregnancy per oocyte pick-up rate was lower (19,9% versus 24,6%) and the early miscarriage rate was increased (26,9% versus 15,7%) without reaching statistical significance. DISCUSSION AND CONCLUSION: The live birth rate was decreased among overweight or obese women. This could be mediated by impairment of response to ovarian stimulation, oocyte quality, or implantation abnomalies.

Lack of risk of transmission of caprine arthritis-encephalitis virus (CAEV) after an appropriate embryo transfer procedure.

The aim of this study was to demonstrate that embryo transfer can be used to produce CAEV-free kids from CAEV-infected biological mothers when appropriate procedure is implemented. Twenty-eight goats that had tested positive for CAEV using PCR on vaginal secretions were used as embryo donors. Embryos with intact-ZP were selected and washed 10 times; they were then frozen and used for transfer into CAEV-free recipient goats. Nineteen of the 49 recipient goats gave birth, producing a total of 23 kids. Three blood samples were taken from each recipient goat, 10 days before, during, and 10 days after parturition; these were tested for CAEV antibodies using ELISA and for CAEV proviral DNA using PCR. The mothers were then euthanized. Tissue samples were taken from the lungs, udder, and retromammary and prescapular lymph nodes. The kids were separated from their mothers at birth. Seven of them died. At 4 months of age, 16 kids were subjected to drug-induced immunosuppression. Blood samples were taken every month from birth to 4 months of age; samples were then taken on days 15, 21, and 28 after the start of the immunosuppressive treatment. The kids were then euthanized and tissue samples taken from the carpal synovial membrane, lung tissue, prescapular lymph nodes, inguinal and retromammary lymph nodes, and uterus. All samples from the 19 recipient goats and 23 kids were found to be negative for CAEV antibodies and/or CAEV proviral DNA. Under acute conditions for infection this study clearly demonstrates that embryo transfer can be safely used to produce CAEV-free neonates from infected CAEV donors.

Estimating the success of an in vitro fertilization programme using multiple imputation.

BACKGROUND: The outcome of in vitro fertilization (IVF) has been widely investigated over the last 30 years, but evaluation was mostly based on pregnancy rate per oocyte retrieval. Our objective was to estimate the cumulative live birth rate after four IVF aspirations, using multiple imputation that takes into account treatment interruptions. METHODS: We analysed data from 3037 couples beginning IVF treatment between 1998 and 2002 in two French IVF units. Multiple imputations were used at each aspiration to impute the IVF outcome (delivery or not) for couples who interrupted treatment. The global success rate after four aspirations was then computed. RESULTS: At the first aspiration, 21% of couples obtained a live birth and 24% discontinued treatment. The multiple imputation method provided an estimated cumulative live birth rate at each aspiration as if no couple discontinued treatment: 35% at the second aspiration and 41% at the third. The cumulative success rate after four aspirations was estimated at 46% (95% CI: 44-48%). CONCLUSIONS: Multiple imputation is a promising method for estimating the cumulative success rate of IVF. It could provide new insight on IVF evaluation and should be tested in further studies.

[Anonymous gamete donation: what to protect and does it violate the human rights?]. / Anonymat du don de gamètes: protection d'un modèle social ou atteinte aux droits de l'homme?

The French legislation about gamete donation imposes anonymity between the donor and the demanders, in reference to the principles of protection of the human dignity that are applied in other fields of biomedicine. We are here wondering about this choice: does this obligation really protect the human rights that are one of the ethical bases of law? At the time the French law was written, anonymity in gamete donation was inherited from the practice of the French CECOS but it has now become controversial. Many European countries have opened the access to the genetic origins. There is no evidence for this practice to be an efficient protection of the respect of human body and the disinterested nature of donation. Concerning gametes, it seems that it protects a social object, the parental project, but that it has no influence on the protection of parenthood, filiation, and the concept that humankind is not only biological. At last, we analyse the most important human rights documents to assume the hypothesis that anonymous gamete donation, although not violating the human rights, is an implement for Foucault's biopower, far from protecting the ethical foundations of human dignity.

Novel synergistic mechanism for sst2 somatostatin and TNFalpha receptors to induce apoptosis: crosstalk between NF-kappaB and JNK pathways.

Somatostatin is a multifunctional hormone that modulates cell proliferation, differentiation and apoptosis. Mechanisms for somatostatin-induced apoptosis are at present mostly unsolved. Therefore, we investigated whether somatostatin receptor subtype 2 (sst2) induces apoptosis in the nontransformed murine fibroblastic NIH3T3 cells. Somatostatin receptor subtype 2 expression induced an executioner caspase-mediated apoptosis through a tyrosine phosphatase SHP-1 (Src homology domain phosphatase-1)-dependent stimulation of nuclear factor kappa B (NF-kappaB) activity and subsequent inhibition of the mitogen-activated protein kinase JNK. Tumor necrosis factor alpha (TNFalpha) stimulated both NF-kappaB and c-Jun NH2-terminal kinase (JNK) activities, which had opposite action on cell survival. Importantly, sst2 sensitized NIH3T3 cells to TNFalpha-induced apoptosis by (1) upregulating TNFalpha receptor protein expression, and sensitizing to TNFalpha-induced caspase-8 activation; (2) enhancing TNFalpha-mediated activation of NF-kappaB, resulting in JNK inhibition and subsequent executioner caspase activation and cell death. We have here unraveled a novel signaling mechanism for a G protein-coupled receptor, which directly triggers apoptosis and crosstalks with a death receptor to enhance death ligand-induced apoptosis.

Detection of ovine lentivirus in the cumulus cells, but not in the oocytes or follicular fluid, of naturally infected sheep.

The aim of this study was to examine the Maedi-Visna virus (MVV) infection status of oocytes, cumulus cells, and follicular fluid taken from 140 ewes from breeding flocks. MVV proviral-DNA and MVV RNA were detected using nested-PCR and RT-PCR MVV gene amplification, respectively in the gag gene. Nested-PCR analysis for MVV proviral-DNA was positive in peripheral blood mononuclear cells in 37.1% (52/140) of ewes and in 44.6% (125/280) of ovarian cortex samples. The examination of samples taken from ovarian follicles demonstrated that 8/280 batches of cumulus cells contained MVV proviral-DNA, whereas none of the 280 batches of oocytes taken from the same ovaries and whose cumulus cells has been removed, was found to be PCR positive. This was confirmed by RT-PCR analysis showing no MVV-viral RNA detection in all batches of oocytes without cumulus cells (0/280) and follicular fluid samples taken from the last 88 ovaries (0/88). The purity of the oocyte fraction and the efficacy of cumulus cell removal from oocytes was proved by absence of granulosa cell-specific mRNA in all batches of oocytes lacking the cumulus cells, using RT-PCR. This is the first demonstration that ewe cumulus cells harbor MVV genome and despite being in contact with these infected-cumulus cells, the oocytes and follicular fluid remain free from infection. In addition, the enzymatic and mechanical procedures we used to remove infected-cumulus cells surrounding the oocytes, are effective to generate MVV free-oocytes from MVV-infected ewes.

ICSI outcomes in obstructive azoospermia: influence of the origin of surgically retrieved spermatozoa and the cause of obstruction.

BACKGROUND: Spermatozoa can be retrieved from the testis and epididymis of men with obstructive azoospermia (OA) and used for ICSI. However, it is unknown whether the outcome of ICSI depends on the cause of obstruction or the origin of surgically retrieved spermatozoa. METHODS: A cohort of 171 men with OA and normal spermatogenesis were included in this retrospective study. They were divided into three groups according to the site and origin of obstruction: 83 men had congenital bilateral absence of vas deferens; 55 and 33 had acquired epididymal and deferent duct obstructions, respectively. The outcome of 368 ICSI cycles was determined and compared according to the origin of spermatozoa: epididymal (n = 253) or testicular (n = 115). RESULTS: Fertilization and clinical pregnancy rates did not differ between spermatozoa of different origin (58.9% versus 51.9% and 22.1% versus 24.3% with epididymal and testicular spermatozoa, respectively). However, the miscarriage rate was significantly higher for testicular spermatozoa (35.7% versus. 12.5% P < 0.05, chi2 test). Findings were similar whatever the aetiology of the OA. CONCLUSION: This study suggests that the use of testicular spermatozoa, even those generated during normal spermatogenesis, alters embryonic development and that epididymal spermatozoa should be preferentially used, irrespective of the aetiology of OA.

Nasal carriage of Staphylococcus aureus in dairy sheep.

The purpose of this study was to assess the prevalence of Staphylococcus aureus nasal carriage of dairy sheep in farms producing cheeses manufactured with raw ewe's milk. The study showed that 29% of ewes carried S. aureus in their nares. The genetic diversity of the 136 isolates recovered from the anterior nares of the ewes, from the ambient air of the milking parlour and from cheeses was investigated using pulsed-field gel electrophoresis (PFGE) of DNA SmaI digests. The genotyping results showed that 75 out of 106 isolates recovered from nasal carriage in dairy sheep belonged to a dominant pattern (previously named OV) and a genetically related pattern (named OV'). The same profile (OV or OV') was found in the ambient air and cheeses, suggesting a continuum between isolates within these different compartments.

Physiology of somatostatin receptors.

Since its discovery three decades ago as an inhibitor of GH release from the pituitary gland, somatostatin has attracted much attention because of its functional role in the regulation of a wide variety of physiological functions in the brain, pituitary, pancreas, gastrointestinal tract, adrenals, thyroid, kidney and immune system. Its actions include inhibition of endocrine and exocrine secretions, modulation of neurotransmission, motor and cognitive functions, inhibition of intestinal motility, absorption of nutrients and ions and vascular contractility. In addition, the peptide controls the proliferation of normal and tumor cells. Its action is mediated by a family of G protein-coupled receptors [somatostatin receptor (SSTR)1-SSTR5] that are widely distributed in normal and cancer cells. Direct antitumor activities, mediated through SSTR expressed in tumor cells, include blockade of autocrine/paracrine growth-promoting hormone and growth factor production, inhibition of growth factor-mediated mitogenic signals and induction of apoptosis. Indirect antitumor effects include inhibition of growth-promoting hormone and growth factor secretion, and antiangiogenic actions. Many human tumors express more than one SSTR subtype, with SSTR2 being predominant. These receptors represent the molecular basis for the clinical use of somatostatin analogs in the treatment of endocrine tumors and their in vivo localization. This review covers the present knowledge in SSTR biology and signaling.