The co-occurrence of substance P-like immunoreactivity and dynorphin-like immunoreactivity in striatopallidal and striatonigral projection neurons in birds and reptiles

Using an immunofluorescence procedure that allows the simultaneous labeling of tissue for two different antigens, substance P-like immunoreactivity (SPLI) and dynorphin-like immunoreactivity (DLI) were observed to co-occur extensively in striatal neurons of the avian and reptilian basal ganglia and in fibers and terminals in the projection targets of the avian and reptilian striata. Thus, SPLI and DLI apparently co-occur extensively in striatopallidal and striatonigral projection neurons of the avian and reptilian basal ganglia. Since basal ganglia organization is fundamentally similar among amniotes, the present results suggest that SPLI and DLI may also co-occur extensively in striatal neurons in mammals.     

A randomized phase II trial of platinum salts in basal-like breast cancer patients in the neoadjuvant setting. Results from the GEICAM/2006-03, multicenter study

Chemotherapy remains as the only systemic treatment option available for basal-like breast cancer (BC) patients. Preclinical models and several phase II studies suggested that platinum salts are active drugs in this BC subtype though there is no randomized study supporting this hypothesis. This study investigates if the addition of carboplatin to a combination of an alkylating agent together with anthracyclines and taxanes is able to increase the efficacy in the neoadjuvant treatment context. Patients with operable breast cancer and immunophenotypically defined basal-like disease (ER-/PR-/HER2- and cytokeratin 5/6+ or EGFR+) were recruited. Patients were randomized to receive EC (epirubicin 90?mg/m² plus cyclophosphamide 600?mg/m² for 4 cycles) followed either by D (docetaxel 100?mg/m²?×?4 cycles; EC?CD) or DCb (docetaxel 75?mg/m² plus carboplatin AUC 6?×?4 cycles; EC?CDCb). The primary end point was pathological complete response (pCR) in the breast following the Miller and Payne criteria. Ninety-four patients were randomized (46 EC?CD, 48 EC?CDCb). pCR rate in the breast was seen in 16 patients (35?%) with EC?CD and 14 patients (30?%) with EC?CDCb (P value?=?0.61). pCR in the breast and axilla was seen in 30?% of patients in both arms. The overall clinical response rate was 70?% (95?% CI 56?C83) in the EC?CD arm and 77?% (95?% CI 65?C87) in the EC?CDCb arm. Grade 3/4 toxicity was similar in both arms. The addition of carboplatin to conventional chemotherapy with EC?CD in basal-like breast cancer patients did not improve the efficacy probably because they had already received an alkylating agent. These findings should be taken into consideration when developing new agents for this disease.     

Neuroblastoma among children in Southern and Eastern European cancer registries: Variations in incidence and temporal trends compared to US

Neuroblastoma comprises the most common neoplasm during infancy (first year of life). Our study describes incidence of neuroblastoma in Southern–Eastern Europe (SEE), including – for the first time – the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM‐ST)/Greece, compared to the US population, while controlling for human development index (HDI). Age‐adjusted incidence rates (AIR) were calculated for 1,859 childhood (0–14 years) neuroblastoma cases, retrieved from 13 collaborating SEE registries (1990–2016), and were compared to those of SEER/US (N = 3,166; 1990–2012); temporal trends were assessed using Poisson regression and Joinpoint analyses. The overall AIR was significantly lower in SEE (10.1/million) compared to SEER (11.7 per million); the difference was maximum during infancy (43.7 vs. 53.3 per million, respectively), when approximately one‐third of cases were diagnosed. Incidence rates of neuroblastoma at ages <1 and 1–4 years were positively associated with HDI, whereas lower median age at diagnosis was correlated with higher overall AIR. Distribution of primary site and histology was similar in SEE and SEER. Neuroblastoma was slightly more common among males compared to females (male‐to‐female ratio: 1.1), mainly among SEE infants. Incidence trends decreased in infants in Slovenia, Cyprus and SEER and increased in Ukraine and Belarus. The lower incidence in SEE compared to SEER, especially in infants living in low HDI countries possibly indicates a lower level of overdiagnosis in SEE. Hence, increases in incidence rates in infancy noted in some subpopulations should be carefully monitored to avoid the unnecessary costs health impacts of tumors that could potentially spontaneously regress.     

Proposed Recommendations for Research on Biochemical Markers for Problematic Drinking

Biochemical markers can serve as valuable tools in screening for problematic drinking, determining whether a health problem is likely alcohol related, and monitoring alcoholics for relapse during and after treatment. Furthermore, biochemical markers can assist in forensic investigations; in identification of public health, safety, and transportation workers who may drink excessively and who, as a result, may put others at risk; in evaluation of efficacy of treatments for alcohol abuse; and in recognition of early phase alcohol-related tissue damage. Within all of these contexts, a biochemical marker or set of markers may corroborate verbal reports or may provide valuable independent information on alcohol use when an individual is unable or unwilling to offer valid data about alcohol consumption.     

Change of phonation control after cochlear implantation.

OBJECTIVE: To assess the influence of acquired auditory control on some voice parameters in deaf children and adults after cochlear implantation. STUDY DESIGN: Prospective clinical study. SETTING: Tertiary referral center. PATIENTS: Twenty-nine prelingually deafened children and 11 postlingually deafened adults. INTERVENTIONS: The samples of a vowel /a/ were analyzed with an Multi-Dimensional Voice Program (Kay Elemetrics Corporation, Lincoln Park, NJ) before and 6 to 12 months after the cochlear implantation. MAIN OUTCOME MEASURES: The average fundamental frequency (F0), the short-term variation of F0 (JIT) and the amplitude (SH), the very long-term variation of F0 (vF0) and the amplitude (vAm), and the noise-to-harmonic ratio (NHR) were determined and compared for both age groups. The results of the acoustic analysis performed before the implantation were compared with the results after the implantation for children and adults. RESULTS: Significantly greater JIT, SH, vF0, and vAm were detected in the children than in the adults before and after the implantation. The prelingually deafened children significantly improved the control of their phonation after 6 to 12 months' use of the cochlear implant (JIT: p=0.014, SH: p=0.011, vF0: p=0.014, vAm: p=0.031). In the postlingually deafened adults, no significant improvement was found in any of the studied voice parameters after the implantation. F0 showed little or no change after the implantation in children and adults. CONCLUSION: As expected, the voice quality of the prelingually deafened children was significantly worse than that of the postlingually deafened adults. After cochlear implantation, the children significantly improved their short-term and long-term F0 and amplitude variability. In adults, no significant improvement was detected. We suppose that the improvement is a consequence not only of the acquired hearing control but also of the adaptation ability of neuromuscular phonation control and the maturing of these control mechanisms in children. In adults, better phonation quality in general and lesser improvement after the implantation can be the results of well-developed and stable phonation patterns.     

Targeting CD137 enhances the efficacy of cetuximab

Treatment with cetuximab, an EGFR-targeting IgG1 mAb, results in beneficial, yet limited, clinical improvement for patients with head and neck (HN) cancer as well as colorectal cancer (CRC) patients with WT KRAS tumors. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the efficacy of cetuximab. The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. Furthermore, activation of CD137 with an agonistic mAb enhanced NK cell degranulation and cytotoxicity. In multiple murine xenograft models, including EGFR-expressing cancer cells, HN cells, and KRAS-WT and KRAS-mutant CRC, combined cetuximab and anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving cetuximab, the level of CD137 on circulating and intratumoral NK cells was dependent on postcetuximab time and host FcyRIIIa polymorphism. Interestingly, the increase in CD137-expressing NK cells directly correlated to an increase in EGFR-specific CD8⁺ T cells. These results support development of a sequential antibody approach against EGFR-expressing malignancies that first targets the tumor and then the host immune system.     

Initial report of the use of an injectable porcine collagen-derived matrix to stimulate healing of diabetic foot wounds in humans

A novel injectable scaffolding matrix (E-Matrix) has been developed to accelerate wound healing in diabetic foot ulcers. This porcine collagen-derived matrix is designed to mimic tertiary embryonic connective tissue and to stimulate fetal wound repair mechanisms including angiogenesis. In vitro and animal studies have indicated a beneficial effect on tissue growth and an acceptable safety profile. In this report, we describe the initial use of this product in a pilot study of six humans with chronic nonhealing diabetic foot ulcers. A dramatic initial response to injection was seen, with an average wound size reduction of 72% 2 weeks after injection. Randomized trials are underway to define the potential benefit of this new treatment modality for diabetic foot ulcers.     

High frequency recombination betweenloxP sites in human chromosomes mediated by an adenovirus vector expressing Cre recombinase

An adenovirus vector (AdCre1) expressing Cre recombinase has been used to induce recombination betweenloxP sites in human chromosomes. G418 resistant cells with oneloxP site, generated by transfection with a plasmid containingloxP between the SV40 promoter and the G418 resistance (neo) gene, were infected with AdCre1 and transfected with a plasmid containingloxP adjacent to a promoterless hisD gene. This resulted in integration of hisD downstream of the SV40 promoter with gain of histidinol and loss of G418 resistance. Since AdCre1 is non-replicating and Cre expression transient, histidinol resistant cells containing the hisD gene flanked byloxP sites were stable. Reinfection of these cells with AdCre1 induced excision of hisD in over 90% of infected cells. This high efficiency of site-specific recombination suggests that AdCre1 may be exploited for temporal and tissue-specific regulation of gene expression and for chromosome engineering in vitro and in animals.     

Simultaneous mapping of human papillomavirus integration sites and molecular karyotyping in short-term cultures of cervical carcinomas by using 49-color combined binary ratio labeling fluorescence in situ hybridization

Infection with high-risk type human papillomavirus (HPV) is a necessary causal factor in the pathogenesis of cervical carcinoma. In most invasive cervical cancers, HPV is integrated in the host cell genome, and additional genetic aberrations are observed among which are chromosomal aberrations. To analyze in detail such often complex chromosomal changes and simultaneously map HPV integration sites, we extended the multiplicity of the combined binary ratio labeling fluorescence in situ hybridization (COBRA-FISH) technique to 49 by inclusion of a large Stokes' shift fluorochrome as the third binary label. The technique allows mapping of the integrated HPV genome in the context of p- and q-arm COBRA-FISH, with a sensitivity of one copy of the HPV genome as tested for HPV 16 in SiHa cells. We investigated the molecular karyotypes and integration patterns of HPV types 16 and 18 in metaphase spreads from short-term cultures of primary cervical carcinomas (n=5). Of the tested cervical carcinomas, two contained integrated HPV at 8q24, one of which in addition harbored the integrated virus near a translocation breakpoint. Two carcinomas had integrated HPV at 17q21 through 23 in a morphologically normal chromosome 17. One carcinoma contained HPV at 1q42 in a morphologically normal chromosome 1. Our data illustrate the efficacy of 49-color COBRA-FISH to resolve complex karyotypes and simultaneously map specific sequences in metaphases obtained from short-term solid tumor cultures.