In vivo and in vitro growth-inhibitory effect of bovine seminal ribonuclease on a system of rat thyroid epithelial transformed cells and tumors.

We investigated the antitumoral effect of bovine seminal RNase (BS-RNase) in vivo and in vitro on a model system of epithelial tumor- and metastasis-derived cells as well as on epithelial tumors derived from the same system. We found that while BS-RNase significantly inhibited the growth in vitro of the epithelial tumor-derived cells, its inhibitory effect was even more dramatic on the growth of metastasis-derived cells. BS-RNase exerted no appreciable growth inhibition on normal thyroid epithelial cells. When administered in vivo to rats bearing solid carcinomas, having the same thyroid origin, BS-RNase induced a drastic reduction in the tumor weight, with no detectable toxic effects on the treated animals. These data show, for the first time on a system of neoplastically transformed epithelial cells, that BS-RNase has a potent specific antitumoral activity.     

Up‐regulation of pro‐inflammatory genes as adaptation to hypoxia in MCF‐7 cells and in human mammary invasive carcinoma microenvironment

The role of tumor cells in synthesizing pro‐inflammatory molecules is still controversial. Here we report that hypoxic treatment of the MCF‐7 human mammary adenocarcinoma cell line induced activation of hypoxia‐inducible factor 1α (HIF‐1α) and nuclear factor‐kappa B (NF‐κB). Importantly, hypoxia regulated expression of alarmin receptors such as the receptor for advanced glycation end products (RAGE) and the purinoreceptor (P2X7R), and up‐regulated inflammatory response (IR) genes such as the inducible enzymes nitric oxide synthase (NOS2), cycloxygenase (COX2), and the acute‐phase protein pentraxin‐3 (PTX3). Hypoxia also stimulated chemokine (C‐X‐C motif) receptor 4 (CXCR4) mRNA synthesis. In fact, the CXCR4 ligand stromal‐derived factor‐1α (SDF‐1α) increased invasion and migration of hypoxic MCF‐7 cells. Inhibition of HIF‐1α by chetomin and NF‐κB by parthenolide reduced mRNA and protein expression of the studied molecules and prevented invasion of hypoxic MCF‐7 cells. Moreover, solid invasive mammary tumor microenvironment was analyzed after laser‐capture microdissection (LCMD) comparing tumor versus host normal tissue. Nuclear translocation of HIF‐1α and NF‐κB and up‐regulation of IR, CXCR4, estrogen receptor α (ERα), and epithelial growth factor receptor (EGFR) was observed in tumor but not in host normal tissue in the absence of a local inflammatory leukocyte infiltrate. We conclude that under hypoxic conditions MCF‐7 cells acquire a pro‐inflammatory phenotype, and that solid human mammary carcinoma evidenced a similar activation of HIF‐1α, NF‐κB, and IR genes in malignant tumor cells as compared to the normal host tissues. We suggest a role for IR activation in the malignant progression of transformed cells. (Cancer Sci 2010; 101: 1014–1023)     

Objects are highlighted by spatial attention

Selective attention may be focused upon a region of interest within the visual surroundings, thereby improving the perceptual quality of stimuli at that location. It has been debated whether this spatially selective mechanism plays a role in the attentive selection of whole objects in a visual scene. The relationship between spatial and object-selective attention was investigated here through recordings of event-related brain potentials (ERPs) supplemented with functional magnetic brain imaging (fMRI). Subjects viewed a display consisting of two bar-shaped objects and directed attention to sequences of stimuli (brief corner offsets) at one end of one of the bars. Unattended stimuli belonging to the same object as the attended stimuli elicited spatiotemporal patterns of neural activity in the visual cortex closely resembling those elicited by the attended stimuli themselves, albeit smaller in amplitude. This enhanced neural activity associated with object-selective attention was localized by use of ERP dipole modeling and fMRI to the lateral occipital extrastriate cortex. We conclude that object-selective attention shares a common neural mechanism with spatial attention that entails the facilitation of sensory processing of stimuli within the boundaries of an attended object.     

Ceftolozane/tazobactam for the treatment of serious Pseudomonas aeruginosa infections: a multicentre nationwide clinical experience

This study describes the largest clinical experience using ceftolozane/tazobactam (C/T) for different Pseudomonas aeruginosa infections. A retrospective study was performed at 22 hospitals in Italy (June 2016–March 2018). All adult patients treated with ≥4 days of C/T were enrolled. Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to P. aeruginosa infection and lack of microbiological evidence of infection. C/T treatment was documented in 101 patients with diverse infections, including nosocomial pneumonia (31.7%), acute bacterial skin and skin-structure infection (20.8%), complicated UTI (13.9%), complicated IAI (12.9%), bone infection (8.9%) and primary bacteraemia (5.9%). Over one-half of P. aeruginosa strains were XDR (50.5%), with 78.2% of isolates resistant to at least one carbapenem. C/T was used as first-line therapy in 39 patients (38.6%). When used as second-line or later, the most common reasons for discontinuation of previous antibiotics were in vitro resistance of P. aeruginosa and clinical failure of previous therapy. Concomitant antibiotics were reported in 35.6% of patients. C/T doses were 1.5 g q8h in 70 patients (69.3%) and 3 g q8h in 31 patients (30.7%); median duration of C/T therapy was 14 days. Overall clinical success was 83.2%. Significant lower success rates were observed in patients with sepsis or receiving continuous renal replacement therapy (CRRT). Mild adverse events were reported in only three patients. C/T demonstrated a favourable safety and tolerability profile regardless of the infection type. Clinicians should be aware of the risk of clinical failure with C/T therapy in septic patients receiving CRRT.     

Should patients with chronic hepatitis c who have normal alt levels be treated?

Up to 25% of patients with chronic hepatitis C have persistently normal serum alanine aminotransferase (ALT) levels. Reports from some studies indicate that patients with normal ALT levels are more likely to be female and nondrinkers. Patients with persistently normal aminotransferase levels often have mild disease on liver biopsy with little or no fibrosis, but a small number of patients may have substantial fibrosis or cirrhosis. Treatment with interferon monotherapy has been disappointing. Combination therapy with interferon and ribavirin is controversial, but early clinical results have shown good response rates. Currently, therapy for chronic HCV patients with normal ALT levels should be based upon results from liver biopsy and preferably be done in the context of a clinical trial.     

The clinical utility of the dementia rating scale for assessing Alzheimer patients

Community residing patients with mild (n = 18) or moderately severe (n = 16) Alzheimer's disease and controls (n = 23) were given Mattis' Dementia Rating Scale (DRS) and a brief measure of confrontation naming selected from the Boston Naming Test (BNT). The DRS was shown to be a reliable and clinically useful measure of mental status in patients with Alzheimer's disease. The DRS subscales and the BNT had excellent internal consistency reliabilities and the total DRS score (TDRS) was shown to be generally unrelated to gender and education. Among the dementia patients, performance on the TDRS was significantly associated with functional competence. The two dementia samples had similar profiles on the DRS and BNT, with the mild subjects performing significantly better than the moderately severe subjects on each measure. Extending the range of DRS subscales would improve this measure's utility as an evaluation instrument.     

Tandem high-dose chemotherapy and autologous stem cell transplantation in refractory/relapsed Hodgkin's lymphoma: a monocenter prospective study

We designed a prospective study to evaluate the feasibility and efficacy of tandem high-dose chemotherapy (HDCT) in the treatment of refractory or relapsed Hodgkin's lymphoma (HL). Thirty-two patients were treated with salvage chemotherapy (IGEV, ifosfamide, gemcitabine, and vinorelbine) and chemo-sensitive patients received a first HDCT course with melphalan 200 mg/m(2) (MEL200) and a second BEAM course. The median time interval between the two HDCT courses was 66 days. The median number of reinfused CD34(+) cells was 4.7 x 10(6)/kg after MEL200 and 5.8 x 10(6)/kg after BEAM. The hematological reconstitution after both HDCT courses did not differ. No grade III or IV renal, hepatic, lung, cardiac, and neurological toxicity was observed. Severe (grade III and IV) oral mucositis was the most prominent complication affecting 60 and 50% of patients after MEL200 and BEAM, respectively. Fever of unknown origin occurred in 65 and 70% of patients after MEL200 and BEAM, respectively. One patient died from septic shock during the aplasia period following BEAM. In an intention-to-treat analysis, the overall response rate increased after each stage of protocol, ranging from 47% to 65% and 75% after IGEV, MEL200, and BEAM, respectively. Tandem HDCT is feasible and effective in patients with relapsed or refractory HL.     

Germline mutations and new copy number variants among 40 pediatric cancer patients suspected for genetic predisposition

Cancer predisposition syndromes (CPS) result from germline pathogenic variants, and they are increasingly recognized in the etiology of many pediatric cancers. Herein, we report the genetic/genomic analysis of 40 pediatric patients enrolled from 2016 to 2018. Our diagnostic workflow was successful in 50% of screened cases. Overall, the proportion of CPS in our case series is 10.9% (20/184) of enrolled patients. Interestingly, 12.5% of patients achieved a conclusive diagnosis through the analysis of chromosomal imbalance. Indeed, we observed germline microdeletions/duplications of regions encompassing cancer-related genes in 50% of patients undergoing array-CGH: EIF3H duplication in a patient with infantile desmoplastic astrocytoma and low-grade Glioma; SLFN11 deletion, SOX4 duplication, and PARK2 partial deletion in three neuroblastoma patients; a PTPRD partial deletion in a child diagnosed with glioblastoma multiforme. Finally, we identified two cases due to DICER1 germline mutations.     

Validity of a short insomnia questionnaire: the SDQ

The SDQ is a brief self-report insomnia questionnaire, which permits the rapid evaluation of insomnia based on the DSM-IV and ICSD-R criteria. The SDQ was developed to provide a fast and valid instrument both for the pre-screening of subjects who complain of insomnia and for epidemiological studies based on standardized definitions of this sleep disorder. Two studies were carried out in order to assess the validity of the SDQ as a self-report measure of insomnia. In the first study the convergent validity of the SDQ was assessed with respect to the global score of the Pittsburgh Sleep Quality Index (PSQI) in a sample of general practitioners' patients. The second study assessed the sensitivity and the specificity of the SDQ in discriminating between insomniacs or normal sleepers in a sample of college students who were given an extensive sleep evaluation within an insomnia counseling program. The SDQ classifications have a good convergent validity with the global sleep quality scores of the PSQI and its classifications of students who complain of or who do not complain of problems of insomnia have a sensitivity of 95% and a specificity of 87%. Results indicate that the SDQ is a valid paper and pencil instrument to screen insomnia.