A transcriptomic signature to predict adjuvant gemcitabine sensitivity in pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. PATIENTS AND METHODS: Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated. RESULTS: The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months [95% confidence interval (CI): 61.2-not reached] versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.

Behavior of heptavalent technetium in sulfuric acid under α-irradiation: structural determination of technetium sulfate complexes by X-ray absorption spectroscopy and first principles calculations.

The effect of α-radiolysis on the behavior of heptavalent technetium has been investigated in 13 and 18 M H2SO4. Irradiation experiments were performed using α-particles ((4)He(2+), E = 68 MeV) generated by the ARRONAX cyclotron. UV-visible and X-ray absorption fine structure spectroscopic studies indicate that Tc(VII) is reduced to Tc(V) under α-irradiation. Extended X-ray absorption fine structure (EXAFS) spectroscopy measurements are consistent with the presence of mononuclear technetium sulfate complexes. Experimental results and density functional calculations show the formation of [TcO(HSO4)3(H2O)(OH)](-) and/or [TcO(HSO4)3(H2O)2] and [Tc(HSO4)3(SO4)(H2O)] and/or [Tc(HSO4)3(SO4)(OH)](-) for 13 and 18 M H2SO4, respectively.

Relevance of biopsy-derived pancreatic organoids in the development of efficient transcriptomic signatures to predict adjuvant chemosensitivity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients are frequently treated by chemotherapy. Even if personalized therapy based on molecular analysis can be performed for some tumors, PDAC regimens selection is still mainly based on patients' performance status and expected efficacy. Therefore, the establishment of molecular predictors of chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. We have recently developed an RNA-based signature that predicts the efficacy of adjuvant gemcitabine using 38 PDAC primary cell cultures. While demonstrated its efficiency, a significant association with the classical/basal-like PDAC spectrum was observed. We hypothesized that this flaw was due to the basal-like biased phenotype of cellular models used in our strategy. To overcome this limitation, we generated a prospective cohort of 27 consecutive biopsied derived pancreatic organoids (BDPO) and include them in the signature identification strategy. As BDPO's do not have the same biased phenotype as primary cell cultures we expect they can compensate one with each other and cover a broader range of molecular phenotypes. We then obtained an improved signature predicting gemcitabine sensibility that was validated in a cohort of 300 resected PDAC patients that have or have not received adjuvant gemcitabine. We demonstrated a significant association between the improved signature and the overall and disease-free survival in patients predicted as sensitive and treated with adjuvant gemcitabine. We propose then that including BDPO along primary cell cultures represent a powerful strategy that helps to overcome primary cell cultures limitations producing unbiased RNA-based signatures predictive of adjuvant treatments in PDAC.

Compact sources as the origin of the soft gamma-ray emission of the Milky Way.

The Milky Way is known to be an abundant source of gamma-ray photons, now determined to be mainly diffuse in nature and resulting from interstellar processes. In the soft gamma-ray domain, point sources are expected to dominate, but the lack of sensitive high-resolution observations did not allow for a clear estimate of the contribution from such sources. Even the best imaging experiment revealed only a few point sources, accounting for about 50% of the total Galactic flux. Theoretical studies were unable to explain the remaining intense diffuse emission. Investigating the origin of the soft gamma-rays is therefore necessary to determine the dominant particle acceleration processes and to gain insights into the physical and chemical equilibrium of the interstellar medium. Here we report observations in the soft gamma-ray domain that reveal numerous compact sources. We show that these sources account for the entirety of the Milky Way's emission in soft gamma-rays, leaving at most a minor role for diffuse processes.

[Cholecystolithotomy: first middle-long term results of our series]. / Colecistolitotomía: primeros resultados a medio-largo plazo de nuestra serie.

UNLABELLED: Cholelithiasis in children is an infrequent disease whose incidence has increased over the last few decades. It has its own typical characteristics, different from those present in adults. Laparoscopic cholecystectomy has become the treatment of choice for symptomatic cases, still its connection with right-sided colon cancer and other diseases associated with the procedure has led to recommend it with some reservation. Though several authors adopted cholecystotomy as a therapeutic option in recent years, its use remains controversial. Our indication criteria for this technique are presented herewith, as well as long- and medium-term results (mean follow-up of 10 years) of our series, previously reported in 2003, and a new case added later in 2006. MATERIALS AND METHODS: Since 2003, a prospective study of 15 patients from our previous series and a new patient added afterwards is being carried out, including: 1) Medical history checking for symptoms connected with biliary conditions. 2) DIAGNOSTIC TESTS: laboratory tests and ultrasonography. RESULTS: Out of our 16 patients: A girl relapsed a few months later and underwent cholecystectomy, but whether it was a true relapse or a missed gallstone was not established. A patient with a history of recurrent abdominal pain has shown no improvement in his symptoms even though his tests are normal. Two patients have been lost for our study, but showed normal tests for 5 and 7 years respectively. Our 11 remaining patients show no symptoms as well as normal laboratory and imaging tests. A new patient joined our study in 2006, showing normal tests to date and no postsurgical complications. CONCLUSIONS: Based on our experience, cholecystotomy has proved to be a complication-free, safe and easy procedure with a virtually nonexistent relapse rate in the long and medium term for patients in the pediatric age group presenting with single or double cholelithiasis, unchanged for 1-2 years with no size increase, no apparent etiology, no complications and a normal bile duct.

Comparative behavior of britholites and monazite/brabantite solid solutions during leaching tests: a combined experimental and DFT approach.

In the field of the specific immobilization of actinides, several phosphate-based ceramics have already been proposed as suitable candidates. Among them, britholite and monazite/brabantite (now called monazite/cheralite) solid solutions have been considered as serious candidates on the basis of several properties of interest. Although both matrices appear almost similar from a chemical point of view, their chemical behavior during leaching tests appear to be strongly different with normalized dissolution rates of typically (2.1 +/- 0.2) g.m(-2).day(-1) for Th-britholites (10(-1)M HNO(3), theta = 25 degrees C, dynamic conditions) and (2.2 +/- 0.2) 10(-5) g.m(-2).day(-1) for Th-brabantites (10(-1)M HNO(3), theta = 90 degrees C, dynamic conditions). To understand such difference from a crystallographic point of view, comparative leaching tests have been performed using either high or low renewal of the leachate. The results obtained clearly revealed a lower chemical durability of An-britholites compared to that of (Ln, Ca, An)-monazite/brabantite solid solutions. As a confirmation of this point, density functional theory calculations clearly showed some great differences in the cohesive energy of calcium in both crystal structures, which can explain this strong difference in the chemical durability of both materials.

New insight into the ternary complexes of uranyl carbonate in seawater.

Uranium is naturally present in seawater at trace levels and may in some cases be present at higher concentrations, due to anthropogenic nuclear activities. Understanding uranium speciation in seawater is thus essential for predicting and controlling its behavior in this specific environmental compartment and consequently, its possible impact on living organisms. The carbonato calcic complex Ca2UO2(CO3)3 was previously identified as the main uranium species in natural seawater, together with CaUO2(CO3)32-. In this work, we further investigate the role of the alkaline earth cation in the structure of the ternary uranyl-carbonate complexes. For this purpose, artificial seawater, free of Mg2+ and Ca2+, using Sr2+ as a spectroscopic probe was prepared. Combining TRLIF and EXAFS spectroscopy, together with DFT and theoretical thermodynamic calculations, evidence for the presence of Sr alkaline earth counter ion in the complex structure can be asserted. Furthermore, data suggest that when Ca2+ is replaced by Sr2+, SrUO2(CO3)32- is the main complex in solution and it occurs with the presence of at least one monodentate carbonate in the uranyl coordination sphere.

Preventing long-lasting fear recovery using bilateral alternating sensory stimulation: A translational study.

Posttraumatic stress disorder (PTSD) is a highly debilitating and prevalent psychological disorder. It is characterized by highly distressing intrusive trauma memories that are partly explained by fear conditioning. Despite efficient therapeutic approaches, a subset of PTSD patients displays spontaneous recurrence of traumatic memories after successful treatment. The development of animal behavioral models mimicking the individual variability in treatment outcome for PTSD patients represent therefore an important challenge as it allows for the identification of predicting factors of resilience or susceptibility to relapse. However, to date, only few animal behavioral models of long-lasting fear recovery have been developed and their predictive validity has not been tested directly. The objectives of this study were twofold. First we aimed to develop a simple animal behavioral model of long-lasting fear recovery based on auditory cued fear conditioning and extinction learning, which recapitulates the heterogeneity of fear responses observed in PTSD patients after successful treatment. Second we aimed at testing the predictive validity of our behavioral model and used to this purpose a translational approach based (i) on the demonstration of the efficiency of Eye Movement Desensitization and Reprocessing (EMDR) therapy to reduce conditioned fear responses in PTSD patients and (ii) on the implementation in our behavioral model of an electrical bilateral alternating stimulation of the eyelid which mimics the core feature of EMDR. Our data indicate that electrical bilateral alternating stimulation of the eyelid during extinction learning alleviates long-lasting fear recovery of conditioned fear responses and dramatically reduces inter-individual variability. These results demonstrate the face and predictive validity of our animal behavioral model and provide an interesting tool to understand the neurobiological underpinnings of long-lasting fear recovery.

Hepatectomy with initial suprahilar control of intrahepatic portal pedicles.

In 1985 Couinaud described an original technique for left hepatectomy. This technique is based on initial control of the left intrahepatic portal pedicle after wedge incision of the hepatic capsule is made and the hilar plate is lowered before the hepatic parenchyma is opened. The vascular and biliary pedicular elements are dissected concomitantly at a point where they are protected by and contained within a sheath emanating from the hepatic capsule. After elective clamping of the pedicle at this level is done, the territory to be removed becomes obvious by the change of color produced by ischemia, and bleeding is minimized preventively. Although Couinaud's technique concerned only one case of left hepatectomy, we confirmed the ease, safety, and reproducibility afforded by this technique in four left hepatectomies. Based on the same principles, this technique may be used for other types of hepatic resections, notably, left hepatectomy extended to segments 5 and 8 (trisegmentectomies). We report our experience with this technique in 15 cases of major hepatic resections.

The Clock Drawing Test: utility for dementia detection in multiethnic elders.

BACKGROUND: Disproportionate increases in dementia morbidity in ethnic minorities challenge established screening methodologies because of language and culture barriers, varying access to health services, and a relative paucity of cross-cultural data validating their use. Simple screening techniques adapted to a range of health and social service settings would accelerate dementia detection and social and health services planning for demented minority elders. METHODS: The effectiveness of the Clock Drawing Test (CDT) for dementia detection was compared with that of the Mini-Mental State Examination (MMSE) and the Cognitive Abilities Screening Instrument (CASI) in community-dwelling elders of diverse linguistic, ethnic, and educational backgrounds. Subjects (N = 295) were tested at home in their native languages (English, n = 141; another language, n = 154). An informant-based clinical dementia history and functional severity index derived from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) protocols were used to classify subjects as probably demented (n = 170), and probably not demented (n = 125). RESULTS: All tests were significantly affected by education (p < .001) but not by primary language (p > .05). Sensitivities and specificities for probable dementia were 82% and 92%, respectively, for the CDT; 92% and 92% for the MMSE; and 93% and 97% for the CASI for subjects completing each test. However, in poorly educated non-English speakers, the CDT detected demented subjects with higher sensitivity than the two longer instruments (sensitivity and specificity 85% and 94% for the CDT, 46% and 100% for the MMSE, and 75% and 95% for the CASI). Moreover less information was lost due to noncompletion of the CDT than the MMSE or CASI (severe dementia or refusal: CDT 8%, MMSE 12%, and CASI 16%). CONCLUSIONS: Overall, the CDT may be as effective as the MMSE or CASI as a first-level dementia screen for clinical use in multiethnic, multilingual samples of older adults. Its brevity (1-5 minutes), minimal language requirements, high acceptability, and lack of dependence on specialized testing materials are well adapted for screening of non-English-speaking elderly persons in settings where bilingual interpreters are not readily available and screening time is at a premium.

[Cancer of the rectum: distal intramural spread is correlated with lymph node involvement]. / Cancer du rectum: l'extension intra-pariétale distale est corrélée à l'envahissement ganglionnaire.

Cancers of the rectum are only rarely associated with distal intraparietal microscopic extension situated below the apparent pole of the tumour. When such extension exists, it may be either limited to several millimetres and is generally continuous with the tumour, or it may be extensive and composed of tumour lesions separated from the principal lesion by healthy tissue. On 119 rectal resection specimens for cancer, distal intraparietal extension was found to be significantly correlated with the degree and multiplicity of lymph node involvement. Tumours without distal intramural extension were associated with lymph node invasion in only 20% of cases and half of them were multiple involvements. In contrast, the frequency of lymph node invasion in cases of distal intramural extension was 80% with multiple node involvement in every case. In cases of distal intraparietal invasion, immuno-histochemical techniques demonstrated tumour emboli in the vessels and lymphatics. In cases of the rectum, lymph node invasion and its multiplicity are directly related to the presence of distal intraparietal invasion.

[Results of reoperation for under correction of radial keratotomies. Apropos of 25 cases]. / Résultats des réinterventions pour sous correction des kératotomies radiaires. A propos de 25 cas.

Twenty-two under corrected patients (25 eyes) after radial keratotomy, were reoperated according to the Stan Franks surgical technique. The results and the possible factors of predictability of this method of reoperation were evaluated. The residual myopia was less than one diopter in 88% of cases (20% before reoperation). The non corrected visual acuity was superior or equal to 20/40 in 88% of cases (32% before reoperation). The mean dioptrie gain after reoperation was 1.30 diopters. Statistical analysis showed that the refractive gain significantly increased with: the initial residual myopia, the delay between the first radial keratotomy and the reoperation, the number of incisions concerned. Age, sex, corneal thickness, initial protocol and presumed cause of undercorrection were not correlated to the refractive gain. (concerning the mean dioptrie gain). The comparison between data derived from different studies, showed no significant differences between the techniques of reoperation. Induced astigmatism with loss of best corrected visual acuity in 12% of cases was the main complication. The causes of under correction after radial keratotomy, and the effectiveness of the Stan Franks method of reoperation are discussed. The authors emphasize the interindividual corneal reaction to radial keratotomy.

[Values and complications of peripheral deepenings in radial keratotomies]. / Intérêts et complications des approfondissements périphériques lors des kératotomies radiaires.

Single and double peripheral deepenings were used to increase the refractive effect of radial keratotomy (RK). The objective of this study was to statistically evaluate the effect and the complications of these surgical techniques. Simple and double peripheral deepenings were performed in 36 patients (52 eyes) and 14 patients (19 eyes) respectively. The functional results and the complications in these two groups were statistically compared with those of a control group which was comparable according to criteria of size, age, sex and preoperative myopia. The standard RK surgical technique was used in this control group. The difference of mean gain between the control group, and the single and double peripheral deepening groups, was 0.53 and 0.47 diopter, respectively. This difference was statistically significant. On the other hand there was no significant difference diopter gain between the single and the double peripheral deepening groups. There was a significant difference concerning spherical equivalent. The non corrected visual acuity was significantly higher in the peripheral deepenings groups, probably due to corneal topographic alterations generating multifocal corneas. The complication rate (micro-perforations, induced astigmatism, loss of best corrected visual acuity) was higher in the peripheral deepenings groups. The limited diopter gain (about 0.50 diopter) compared with the standard radial keratotomy surgical technique, the lack of decreased, reoperation rate and the increased rate complication justified peripheral deepenings surgery technique discussed by the authors.

[Combined cataract-glaucoma operations. Extracapsular extraction and trabeculectomy versus phacoemulsification and trabeculectomy]. / Interventions combinées cataracte-glaucome. ECCE et trabéculectomie versus phacoémulsification et trabéculectomie.

This retrospective study was conducted to evaluate the results of Combined Surgery of Cataract and Glaucoma (triple procedure). The procedure of combined surgery were trabeculectomy and extracapsular extraction (14 eyes) versus trabeculectomy and phacoemulsification (15 eyes). The follow-up of both groups was at least 9 months and up to 16 months (mean: 12 months). The mean decrease of IOP was 12.4 mmHg and 8.9 mm Hg in the first and second group respectively. Instillation of Beta-blockers twelve months after surgery were more frequent in the first group (64.3%) than in the second (26.7%). Finally, the IOP values one year after surgery were equivalent in both groups (less than 19 mmHg in 93% of cases). The mean features to emphasize the delay of recuperation of the best corrected visual acuity: one month for phacotrabeculectomy, and three months for extracapsular with trabeculectomy. The frequency of complications was low in both groups. We observed more hyphemas but less secondary cataracts in the phacotrabeculectomy group. Phacotrabeculectomy could become a reference procedure for combined glaucoma and cataract surgery.

Dermatitis digital en novillos de feedlot: Descripción de 2 brotes en el Noroeste Argentino

La Dermatitis Digital (DD) es una afección podal de distribución mundial. Al igual que otras enfermedades que afectan al pie bovino induce evidentes cojeras, con las consecuentes pérdidas productivas y económicas. Comúnmente se la describe en el ganado lechero y raramente en ganado de carne. En este trabajo se presentan dos brotes de DD en novillos de feedlot del Noroeste Argentino. Se destacan aspectos clínicos, epidemiológicos, patológicos y de diagnóstico. La incidencia fue de 5 y 35 %. Las lesiones se identificaron típicamente en el área palmar de los miembros posteriores e histopatológicamente se observó una dermatitis necrotizante con infiltrado neutrofílico. Mediante la tinción Warthin-Starry se identificaron espiroquetas intralesionales en el 50% (4/8) de las muestras colectadas.

Digital Dermatitis (DD) is a podal condition of worldwide distribution. Like other diseases that affect the bovine foot, it induces obvious lameness, with consequent productive and economic losses. It is commonly described in dairy cattle and descriptions in beef cattle are scarce. In this paper, two DD outbreaks are described in steers from feed-lot in the Argentine Northwest. Emphasis is given to more relevant aspects of clinical, epidemiological, pathological and diagnostic findings. The incidence was 5 and 35%. Lesions are typically identified in the palmar area of the hind limbs, and a necrotizing dermatitis with neutrophil infiltrate was observed histopathologically. By Warthin-Starry staining was identified an intralesional spirochetes in 50% (4/8) of collected samples.