Gemcitabine plus sirolimus for relapsed and progressing osteosarcoma patients after standard chemotherapy: a multicenter, single-arm phase II trial of Spanish Group for Research on Sarcoma (GEIS).

BACKGROUND: Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients. PATIENTS AND METHODS: A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5 mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome. RESULTS: Thirty-five patients were enrolled and received at least one cycle. PFSR at 4 months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3-4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival. CONCLUSION: Gemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.

Spatial distribution and risk factors associated with Salmonella enterica in pigs.

The importance of pork in the transmission of Salmonella spp. to humans has led to the development of control programmes worldwide. For this, knowledge on the epidemiology of the infection in the production system is fundamental to the efficacy of the regulations. Our objective was to determine the prevalence and spatial distribution of Salmonella-infected farms in the central region of Argentina, and to identify the predominant serotypes and epidemiological factors associated with an increased risk of infection. Salmonella was isolated from 22 of 52 sampled farms, for a farm prevalence of 42·3% (95% confidence interval 28·4-56·1). The most frequent serotypes isolated were S. Typhimurium and S. Derby, which have often been considered of public health concern in the region. Limited evidences of global and local clustering in the region under study were found, and the type of feed and presence of diarrhoeic pigs were significantly associated with having Salmonella shedders in the farm. This highlights the need to evaluate microbiological controls at the farm level, and demonstrates the usefulness of the spatial tools to identify areas of greatest risk when processing pork at slaughterhouse, which could contribute to increasing the food safety of pork products.

Pharmacologycal activity of peperina (Minthostachys verticillata) on gastrointestinal tract.

ETHNOPHARMACOLOGICAL RELEVANCE: Minthostachys verticillata (Griseb.) Epling (Lamiaceae), known as Peperina is a medicinal native plant, with a traditional use as a digestive, antispasmodic and antidiarrheic. AIM OF THE STUDY: Despite its folkloric use, no scientific evaluation of this plant related to the gastrointestinal inflammatory process has been carried out to date. The present study aims to assess the effects of M. verticillata on gastrointestinal system in experimental models. MATERIALS AND METHODS: M. verticillata (250 and 500 mg/kg) was orally tested in a colitis model induced by acetic acid. Colon weight/length ratio, oxidative stress (oxidized and reduced glutathione), histological changes using Alcian blue and hematoxylin & eosin staining and expression of IL1ß, TNFα, iNOS, COX-2 were evaluated. The effect of the extract in three additional in vivo models were studied: intestinal motility and diarrhea induced by ricin oil, and visceral pain induced by intracolonic administration of capsaicin. Finally, the activity on concentration response curves of acetylcholine, calcium chloride, potassium and serotonin were achieved in isolated rat jejunum. RESULTS: In the colitis model, M. verticillata induced a significant reduction in the colon weight/length ratio, oxidative stress and expression levels of IL-1ß, iNOS and COX-2. Also, the extract diminished the severity of microscopic tissue damage and showed protective effect on goblet cells. Intestinal motility, diarrhea, visceral pain-related behaviors and referred hyperalgesia were significantly reduced when the animals were treated with the extract. Furthermore, in isolated jejunum, M. verticillata significantly reduced the contraction induced by serotonin and acetylcholine. Likewise, the extract non-competitively inhibited the response-concentration induced by CaCl2 and inhibited both low and high K+-induced contractions. CONCLUSIONS: This is the first study to validate traditional use of M. verticillata for digestive disorders and demonstrated that its aqueous extract could represent a promising strategy in targeting the multifactorial pathophysiology of inflammatory bowel disease.

East pacific rise: hot springs and geophysical experiments.

Hydrothermal vents jetting out water at 380 degrees +/- 30 degrees C have been discovered on the axis of the East Pacific Rise. The hottest waters issue from mineralized chimneys and are blackened by sulfide precipitates. These hydrothermal springs are the sites of actively forming massive sulfide mineral deposits. Cooler springs are clear to milky and support exotic benthic communities of giant tube worms, clams, and crabs similar to those found at the Galápagos spreading center. Four prototype geophysical experiments were successfully conducted in and near the vent area: seismic refraction measurements with both source (thumper) and receivers on the sea floor, on-bottom gravity measurements, in situ magnetic gradiometer measurements from the submersible Alvin over a sea-floor magnetic reversal boundary, and an active electrical sounding experiment. These high-resolution determinations of crustal properties along the spreading center were made to gain knowledge of the source of new oceanic crust and marine magnetic anomalies, the nature of the axial magma chamber, and the depth of hydrothermal circulation.

Estimating the short-term prognosis to adjust the transfer of patients with terminal cancer to medium-stay palliative care units. / Estimación de pronóstico a corto plazo para adecuar el traslado de pacientes oncológicos terminales a unidades de cuidados paliativos de media estancia.

BACKGROUND AND OBJECTIVES: Clinical management for terminal patients should consider various aspects, particularly the patient's functional assessment, which correlates well with the short-term prognosis. The prognosis could improve if the presence of symptoms strongly associated with a poorer progression were included. The study's main objective was to assess whether the prognosis according to the Palliative Performance Scale (PPS) improved with the presence/absence of pain-dyspnoea-delirium symptoms. The secondary objective was to determine caregiver satisfaction with the transfer to medium-stay palliative care units (MSPCUs), which are prepared for medium stays of approximately one month. PATIENTS AND METHOD: We conducted a prospective, observational, multicentre (regional) study that analysed survival in MSPCUs according to the PPS dichotomized to>20% and≤20%. We estimated the mean survival functions using the Kaplan-Meier method and compared them according to the Cox proportional hazards ratios (HR). Caregiver satisfaction was studied using an anonymous self-administered Likert questionnaire. RESULTS: The study included 130 patients. The PPS≤20% and PPS>20% subgroups had a median survival of 6 (3-13) days and 21 (11-42) days, respectively, with an unadjusted mortality HR 3.1-fold greater in the PPS≤20% subgroup. The HR did not change when adjusted for the symptoms. Eighty-three percent of the caregivers found the transfer beneficial, and 40% observed better patient care. CONCLUSIONS: For patients transferred from general hospitals to MSPCUs, PPS scores≤20% were associated with survival shorter than one week, with a 3-fold higher mortality HR than patients with PPS scores>20%, without the analysis adjusted for the presence of pain-dyspnoea-delirium providing greater prognostic accuracy. The caregivers found benefits mainly in the convenience of the facilities and distance.

Association of laboratory and radiologic parameters in the diagnosis of acute cholecystitis. / Asociación de parámetros analíticos y radiológicos en el diagnóstico de la colecistitis aguda.

INTRODUCTION AND OBJECTIVES: There is currently more evidence suggesting that early surgery should be the treatment of choice for acute calculous cholecystitis, although initial conservative treatment is also reported to be safe. Treatment decision depends on the conditions of the patient, surgical experience, and hospital infrastructure, given that early surgery cannot always be carried out. The aim of the present study was to correlate C-reactive protein values with other variables to determine those situations in which surgery cannot be delayed. MATERIALS AND METHODS: A retrospective study was conducted on patients admitted to the hospital from the emergency service with the diagnosis of acute calculous cholecystitis. The patients were divided into 2groups: 1) patients that required urgent cholecystectomy and 2) patients that responded well to conservative medical treatment and later underwent deferred cholecystectomy. RESULTS: A total of 238 patients (♂ 54.6%, ♀ 45.4%) were analyzed. Urgent surgery was performed on 158 patients, whereas the remaining 80 patients were released from the hospital following conservative treatment. The odds ratio of gangrenous cholecystitis presenting in acute cholecystitis for C-reactive protein was calculated in the logistic regression analysis, obtaining an OR of 1.088 and a 95% CI of 1.031-1.121. CONCLUSION: In patients diagnosed with acute calculous cholecystitis, the combination of elevated values of C-reactive protein levels, gallbladder wall thickness, and number of leukocytes was correlated with less favorable clinical and gallbladder histologic states, resulting in a greater need for urgent surgical treatment.

Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke.

Exercise reduces ischemia and reperfusion (I/R) injury in the rat stroke model. We investigated whether pre-ischemic exercise ameliorates blood-brain barrier (BBB) dysfunction in stroke by reducing matrix metalloproteinase (MMP)-9 expression and strengthening basal lamina. Adult male Sprague-Dawley rats were subjected to a 30 min exercise program on a treadmill 5 days a week for 3 weeks. Stroke was induced by a 2-h middle cerebral artery (MCA) occlusion using an intraluminal filament in the exercised and non-exercised groups. Brain infarction was measured and neurological deficits were scored. BBB dysfunction was determined by examining brain edema and Evans Blue extravasation. Expression of collagen IV, the major component of basal lamina essential for maintenance of the endothelial permeability barrier, was quantitatively detected by Western blot and immunocytochemistry. Ex vivo techniques were used to compare collagen IV-labeled vessels in response to ischemic insult. Temporal relationship of expression of MMP-9 and its endogenous inhibitor, the tissue inhibitors of metalloproteinase-1 (TIMP-1), was determined by real-time PCR for mRNA and Western blot for protein during reperfusion. Brain edema and Evans Blue leakage were both significantly (P<0.01) reduced after stroke in the exercised group, in association with reduced brain infarct volume and neurological deficits. Western blot analysis indicated that exercise enhanced collagen IV expression and reduced the collagen loss after stroke. Immunocytochemistry demonstrated that collagen IV-labeled vessels were significantly (P<0.01) increased in exercised rats. In the ex vivo study, after exercised brains were incubated with ischemic brain tissue, a significantly (P<0.01) higher level of collagen IV-labeled vessels was observed as compared with non-exercised brains following the same treatment. The ex vivo study also revealed a key role of MMP-9 in exercise-strengthened collagen IV expression against I/R injury. TIMP-1 protein levels were significantly (P<0.01) increased by exercise. Our results indicate that pre-ischemic exercise reduces brain injury by improving BBB function and enhancing basal lamina integrity in stroke. This study suggests that the neuroprotective effect of physical exercise is associated with an imbalance of MMP-9 and TIMP-1 expression.

Pioglitazone and losartan modify hemodynamic and metabolic parameters and vascular prostanoids in fructose-overloaded rats.

This study analyzes the effects of losartan (AT1 blocker) and pioglitazone (insulin sensitizer), alone and in combination, in the fructose-overloaded rat, a model of metabolic syndrome. All treatments (nine weeks) reduced blood pressure and triglyceridemia and also restored the diminished release of vasodilator prostaglandins (prostacyclin in aorta and mesenteric vascular bed and prostaglandin E(2) in the latter). Pioglitazone, alone and in combination with losartan, reduced the release of the vasoconstrictor thromboxane in controls and fructose rats in both vascular preparations. In conclusion, although combination therapy and single treatments exerted similar effects, there may still be some advantage to the combined treatment.

[Chromophobe renal cell carcinoma, an exceptional entity in childhood: a case report]. / Carcinoma renal de células cromófobas, una entidad excepcional en la infancia: caso clínico.

Chromophobe renal cell carcinoma (CRCC) is a rare variant of renal carcinomas arising from the intercalated cells of the distal renal tubule and representing 5% among all renal tumors. Its biological behaviour is variable, less aggresive than clear cell renal carcinoma. Histochemical, ultrastructural and molecular genetic characteristics are different from other renal carcinomas. Age at presentation is about the 6th decade of life. We report an exceptional 10 year-old boy case with a CRCC. Diagnostic and therapeutic aspects for the management of this tumor are reviewed.

Correction: Porous monoliths synthesized via polymerization of styrene and divinyl benzene in nonaqueous deep-eutectic solvent-based HIPEs.

[This corrects the article DOI: 10.1039/C5RA02374B.].

Two new records of Pycnogonids on the Uruguayan coast.

The Pycnogonida from Uruguayan waters are scarcely known, and their reports are markedly discontinuous. In this paper, several individuals of two previously unrecorded Pycnogonids at the shallow rocky subtidal and lower intertidal fringes of Cerro Verde (Rocha, Uruguay) are reported. The specimens were assigned to Pycnogonum pamphorum Marcus, 1940 and Anoplodactylus petiolatus (Kroyer, 1844). This is the first record of these species on the Uruguayan coast and the southernmost record of P. pamphorum, previously recorded only in Santos, Brazil (type locality).

Failure of a single dose of medroxyprogesterone acetate to induce uterine infertility in postnatally treated domestic cats.

In mice and sheep, neonatal administration of progesterone or progestins inhibited development of uterine glands. The aims of the present study were (1) to describe uterine gland development on postnatal Days 6 to 8 and (2) to evaluate the effects of a single postnatal administration of a progestin on reproduction and adult uterine glands morphology and function in domestic cats. Necropsy was performed on three 1-week-old female cats which had died unrelated to this study. Ten female kittens were randomly assigned within the first 24 hours of birth to: medroxyprogesterone acetate 10 mg/animal subcutaneously (MPA; n = 6) or placebo (PLC; n = 4) and followed up until puberty when they were mated. Twenty-four days after the end of estrus, ovulation and pregnancy were diagnosed by serum progesterone measurement and ultrasonography, respectively. Then, all the cats were ovariohysterectomized. After necropsy or surgery, the excised organs were histologically evaluated. Seven queens ovulated (4 of 6 MPA and 3 of 4 PLC; P > 0.1) and were pregnant (P > 0.1). Four MPA cats presented endometrial hyperplasia and one of them developed a pyometra. The 1-week-old females presented uterine glands in the stage of budding and incipient penetration of the glandular epithelium into the underlying stroma. The MPA-treated queens revealed that the area occupied by uterine glands per square-micrometer (0.55 ± 0.2 vs. 0.49 ± 0.2; P > 0.1) and the height of the glandular epithelium (µm; 24.5 ± 6.7 vs. 24.4 ± 7.2; P > 0.1) did not differ from those of the PLC group. Neither significant gross nor microscopical differences were also found for ovaries (P > 0.1). It is concluded that 1-week-old kittens had an incipient stage of uterine gland development and that a single postnatal supraphysiological dose of MPA did not alter uterine adenogenesis in this species. Furthermore, this treatment seemed to predispose to uterine disease without prevention of fertility.

Data on polyphenols and biological activity analyses of an Andean tomato collection and their relationships with tomato traits and geographical origin.

Data provide information about a tomato collection composed of accessions from the Andean Valley, commercial accessions and wild species. Antioxidant metabolites were measured in mature fruits of this collection, and their biological activities were assessed by both in vitro and in vivo methods. In this work, the parameters used to identify and quantify polyphenols compounds in tomato fruit by liquid chromatography coupled to diode array detector and quadrupole time of flight mass spectrometer are described. Moreover, data supporting a procedure to characterize the properties of tomato fruits to revert death by thermal stress in Caenorhabditis elegans are explained in detail. Lastly, principal component analysis and hierarchical cluster analysis of metabolites composition, antioxidant activities (in vivo and in vitro), tomato traits and geographical origin of the tomatoes collection are shown. The data presented here are related to the research article entitled "Hydrophilic antioxidants from Andean Tomato Landraces assessed by their bioactivities in vitro and in vivo" [1].

[Age's influence in superficial bladder cancer's behaviour]. / Influencia de la edad en el comportamiento de los carcinomas uroteliales superficiales.

INTRODUCTION: Transitional bladder cancer is infrequent in younger people. The tumor's aggressiveness in this population is subject of discussion. We present our experience. MATERIAL & METHOD: 551 primary tumors, with at least one year of follow-up. Group A (less than 41 years old), Group B (bigger than 40 years old). We compare, stage, grade, lymphatic permeation, multiplicity, recurrence, progression, sex, T.L.E. (time free of disease), volume. We do uni and multivariate analysis. RESULTS: 17 tumors in younger than 41 years (2.1%). The recurrence rate is 11.8% in Group A and 36% in Group B (p .041). Progression rate: 0% in A and 4.1% in B (p .253). In Group A, T1 tumors (13.3% vs. 39%), G2 tumors (0% vs. 36.7%); withouts in lymphatic permeation (0% vs. 35%) and solitary tumors (13.3% vs. 35.3%) have statistically less recurrence. In univariate analysis we appreciate statistical differences in relation with grade (p .002) and sex (p .011). In multivariate analysis, stage, "group of age" and prophylactic treatment are independent variables for recurrence, and grade for progression. CONCLUSIONS: In younger than 41 years old: Less pathologic aggressivity (0% G3); Group of age is independent prognostic variable for recurrence, but not p for progression, despite a "less aggressive behaviour": 11.8% recurrence, 0% progression; T.L.E. bigger (one year more); Higher incidence in women (41% vs. 11%); Less recurrence in T1 tumors (13.3% vs. 39%), G2 tumors (0% vs. 36.7%) and solitary tumors (13.3% vs. 35.32%).

Histologic effect of a postnatal slow-release GnRH agonist on feline gonads.

In postnatal domestic cats, GnRH agonists suppressed fecal concentrations of sexual steroids and delayed puberty. The aim of this study was to describe the gross and microscopic morphometric effects of a single administration of the GnRH agonist, deslorelin acetate, on the gonads of postnatally treated cats. Twenty-seven postnatal male (n = 14) and female (n = 13) kittens were randomly assigned to one of the following treatment groups within the first 24 hours of birth: deslorelin acetate (1.6 mg, subcutaneous; DA, n = 16) or control that remained untreated (CO, n = 11) and spayed or castrated immediately after the onset of puberty. After surgical removal, the gonads were gross and histologically assessed. Sertoli cells also were examined immunohistochemically. Comparisons between the treatments were carried out by the Student t test. Gross gonadal wet weight and volume as well as gonadosomatic index were significantly lower in the DA than those in the CO males; these same parameters were not different in females. Primordial (461.4 + 3.0 vs. 1074.3 + 117.5; P < 0.01), primary (59.1 + 13.5 vs. 165.4 + 24.6; P < 0.01), and secondary (17.5 + 2.6 vs. 31.17 + 8.1; P < 0.05) follicles per mm(2) were decreased in DA than in CO gonads. Epididymal sperm motility and morphology were normal in all but two DA cats that had too few sperm to be evaluated. Germinal epithelial height (µm; 39.68 + 0.92 vs. 72.7 + 1.2; P < 0.01) and most of their cellular components as well as the Sertoli (cm(3); 0.1 + 0.02 vs. 0.24 + 0.05; P < 0.01) cells were diminished in the DA cats. Gonadotropin-releasing hormone agonist endocrine disruption during the neonatal critical reproductive time window may have a potential as a contraceptive agent in domestic felids.