Cancer stem cells in head and neck cancer: A Mini Review.

Head and neck cancer (HNC) is a multifaceted and genomically complex disease and rapidly emerging preclinical and clinical studies have provided a broader landscape of signaling. It is being realized that intra-tumor heterogeneity, genetic and epigenetic mutations considerably challenge wide ranging therapeutics and patients frequently develop locoregional recurrences, second primary tumours and distant metastases. Using high-throughput technologies, it has been revealed that existence of different subpopulations of cells within tumor mass with different phenotypic and functional properties with distinct tumour-initiating potential is responsible to HNC resistance. In light of accumulating evidence reported in recent years, it is now known that different intracellular proteins and cell surface markers have been used to study CSCs. This review provides an overview of CSC biomarkers in HNC treatment and their potential as therapeutic targets in improving the diagnosis, prognosis and treatment of HNC patients for new therapeutic strategies with information about estimation of prognosis and treatment decision. Further studies regarding biomarkers are necessary to determine the specific role of CSCs in HNC which could be useful in development of new therapeutic strategies to eliminate CSCs and maximize clinical outcome. Furthermore, CD44 still need more research in HNC once the studies show contradictions. Studies using lineage tracing and deep sequencing will provide a comprehensive understanding of CSC model and extent to which it is accountable for resistance against therapeutics and carcinogenesis.

Elevated aromatase activity in forebrain synaptic terminals during song.

The enzyme aromatase, which converts androgens into oestrogens, is expressed throughout the brain in zebra finches. Aromatase is enzymatically active in both cell bodies and synaptic terminals of neurones of the songbird brain, particularly within the forebrain motor and auditory networks. Aromatisation within synaptic terminals could thus provide localised and acute modulatory oestrogens within the forebrain during singing and/or audition. In male zebra finches, we tested the hypothesis that forebrain aromatase activity is elevated during singing behaviour and/or hearing male song. The present study reports that aromatase activity is elevated in males that were singing for 30 min compared to nonsinging males, and that this elevation occurs only within the cellular compartment that contains synaptic terminals. In a separate experiment, males that heard acoustic playback of song for 30 min exhibited no differences in aromatase activity or in aromatase mRNA levels, as revealed by quantitative polymerase chain reaction analysis. Therefore, these results indicate that activation of the motor pathway for song production is linked to local elevations in synaptic aromatase activity within the forebrain of male zebra finches. Future experiments could assess whether elevated synaptic aromatase activity during song is dependent on acute regulation of the aromatase protein.

A sex-linked SCAR marker in Bryonia dioica (Cucurbitaceae), a dioecious species with XY sex-determination and homomorphic sex chromosomes.

Genetic crosses between the dioecious Bryonia dioica (Cucurbitaceae) and the monoecious B. alba in 1903 provided the first clear evidence for Mendelian inheritance of dioecy and made B. dioica the first organism for which XY sex-determination was experimentally proven. Applying molecular tools to this system, we developed a sex-linked sequence-characterized amplified region (SCAR) marker for B. dioica and sequenced it for individuals representing the full geographic range of the species from Scotland to North Africa. For comparison, we also sequenced this marker for representatives of the dioecious B. cretica, B. multiflora and B. syriaca, and monoecious B. alba. In no case did any individual, male or female, yield more than two haplotypes. In northern Europe, we found strong linkage between our marker and sex, with all Y-sequences being identical to each other. In southern Europe, however, the linkage between our marker and sex was weak, with recombination detected within both the X- and the Y-homologues. Population genetic analyses suggest that the SCAR marker experienced different evolutionary pressures in northern and southern Europe. These findings fit with phylogenetic evidence that the XY system in Bryonia is labile and suggest that the genus may be a good system in which to study the early steps of sex chromosome evolution.

Phase I/II study of a 3 weekly oral taxane (DJ-927) in patients with recurrent, advanced non-small cell lung cancer.

INTRODUCTION: A phase I/II study was performed to assess the efficacy and toxicity of a new oral taxane in patients with recurrent, advanced Non-small Cell Lung Cancer. PATIENTS AND METHODS: Patients who were treated with one prior, taxane free chemotherapy regimen, were eligible for this study. A single oral dose of DJ-927 (27 mg/m) was given every 3 weeks. In case of good tolerance, one dose escalation to 35 mg/m was allowed. Response and toxicity were measured and plasma pharmacokinetic analysis was performed during the first course. RESULTS: From October 2004 to September 2005, 36 patients gave informed consent and 34 received medication. The mean age was 58 years (range, 33-75 years). The majority of patients were pretreated with a combination of cisplatin and gemcitabine. Median interval between end of first treatment and the registration of this study was 7 months (range, 0.8-22 months). Twelve patients died on study of which eight due to disease progression. In four patients with preexisting cardiac disease, toxicity led to cardiac worsening and subsequent death. Grade 3 and 4 toxicities according to the National Cancer Institute Common Toxicity Criteria were neutropenia in 18 patients (53%), anemia in six patients (18%), nausea and fatigue in two patients (6%), febrile neutropenia and neurotoxicity in one patient (3%). The overall response rate for all patients was 5.6% (Confidence Interval [CI] 0.7-18.7%). The percentage of patients with stabilization for >6 weeks was 47%. The median time to progression was 97 days (CI: 47-167 days) and the median survival time was 120 days (CI: 68-222 days) for the ITT group. Since only a minority of patients (3) tolerated the higher drug dose we omitted this dose level because of hematological toxicity. Pharmacokinetic analysis showed that the median area under the curve (t = 0-168 hours) was 1752 +/- 1355 ngr/ml/h and the half-life was 167 +/- 77 hours. CONCLUSION: When administered once every 3 weeks, this oral taxane formulation of DJ-927 was well-absorbed with a long terminal half-life of 167 +/- 77 hour. DJ-927 has antitumor activity against Non-small Cell Lung Cancer when given as second-line monotherapy (overall response rate in 5.6%; CI 0.7-18.7%). Ten patients experienced SD for more than 8 weeks. Different types of dose administration (metronomic dosing) or combination with other cytotoxic agents should be considered in future studies.

Effect of whole bone marrow cell infusion in the progression of experimental chronic renal failure.

INTRODUCTION: The therapeutic potential of adult stem cells for the treatment of chronic diseases is becoming increasingly evident over the last few years. In the present study, we sought to assess whether the infusion of bone marrow-derived mononuclear cells (MoSCs) and mesenchymal cells (MSCs) could reduce/stabilize the rate of progression of chronic renal failure (CRF) in rats. METHODS: We used the 5/6 renal mass reduction model to induce chronic renal failure in male Wistar rats. Renal function was assessed by measurements of serum creatinine (sCr), creatinine clearance (Clcr), and 24-hour proteinuria at baseline as well as 60 and 120 days after surgery. MoSCs and MSCs obtained from bone marrow aspirates were separated by the Ficoll-Hypaque method. After a 12- to 14-day culture, 1.5 x 10(6) MSCs and the same number of MoSCs were injected into the renal parenchyma of the remanant kidney of rats with CRF on the day of surgery. RESULTS: Among the control group, at day 120, the results were sCr = 1.31 +/- 0.5 mg/dL, Clcr = 0.64 +/- 0.35 mL/min, and proteinuria = 140.0 +/- 57.7 mg/24 h. Rats treated with MoSCs at day 120 had sCr = 0.81 +/- 0.20 mg/dL, Clcr = 1.05 +/- 0.26 mL/min, and proteinuria = 61 +/- 46.5 mg/24 h, while rats injected with MSCs had sCr = 0.95 +/- 0.1 mg/dL, Clcr = 0.68 +/- 0.24 mL/min, and proteinuria = 119.2 +/- 50.0 mg/24 h. Analysis of the progression to CRF showed that the treatment significantly reduced the rate of decline in Clcr after treatment with MoSc: control: -0.0049 +/- 0.0024 mL/min/d versus MSC: - 0.0013 +/- 0.0017 mL/min/d versus MoSC: +0.0002 +/- 0.0016 mL/min/d (P = .017). Proteinuria tended to be lower among the treated groups. Histological scores of chronic damage were not different, but distinct patterns of chronic lesions were observed among treated rats. CONCLUSION: Our results showed that progression of CRF in rats could be slowed/stabilized by intrarenal parenchymal injection of MoSCs. A trend toward reduction in the progression rate of CRF was also observed with injection of MSCs.

The transcriptional landscape of the mammalian genome.

This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.

Phase II study of exatecan mesylate (DX-8951f) as first line therapy for advanced non-small cell lung cancer.

BACKGROUND: Exatecan mesylate (DX-8951f) is a water soluble analogue of camptothecin that inhibits topoisomerase I. This multi-centre phase II study evaluated the activity of single agent exatecan in previously untreated patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with histologically or cytologically proven stage IIIb or IV NSCLC were treated with exatecan 0.5 mg/m(2) per day by 30 min intra-venous (i.v.) infusion for 5 days every 3 weeks to a maximum of six cycles. Measurable disease was documented prior to study entry and patients were re-staged every two cycles. Pharmacokinetic (PK) sampling was performed during cycle one. RESULTS: 39 patients (32 patients ECOG performance status 0 or 1; 29 male and ten female; mean age 63 years) were entered into the study. Thirty-three completed at least two cycles of exatecan and 11 completed six cycles. Two patients (5.1%, 95% C.I. 0.3-21.3%) had a partial response, 7 (18.0%) minor response and 8 (20.5%) stable disease. Median time to tumour progression (TTP) was 88 days and median overall survival 262 days. The main toxicity was reversible neutropenia. PK analysis of exatecan demonstrated a mean clearance of 2.28 l/h per m(2), volume of distribution 18.2 l/m(2) and mean elimination half-life of 7.9 h. CONCLUSIONS: Exatecan mesylate has limited activity in advanced NSCLC and is not recommended for further evaluation as a single agent in this tumour type. PK data from this trial supports results established in phase I studies.

Phage typing of Salmonella enteritidis from different sources in Brazil.

The occurrence of Salmonella Enteritidis (SE) phage types (PTs) in samples collected from healthy and diseased chickens, in outbreaks of human gastroenteritis related to the consumption of egg products, in samples of poultry meat, in pipped embryos of broiler chickens, in meat meal, in poultry-rearing environments, and in many foods (cheese, mayonnaise, cake, and bacon) is described for strains isolated from 1995 to 1997 in Brazil. SE strains were isolated, and the most common PT was found to be PT 4, followed by PTs 7, 21, 35, 6, 4a, 8, 30, 6a, 5a, 1, and 1b. Fourteen strains were classified as react-but-do-not-conform strains, and one strain was not typeable. The results of this study demonstrate that PT 4 has a wider distribution among the sources studied than do any other SE phage types and is the most important phage type in human salmonellosis.

A unique early gastric tubular adenocarcinoma arising from a pre-existent carcinoid tumor in a patient with a more than 20-year history of type A gastritis: an immunohistochemical and ultrastructural study.

A unique early gastric tubular adenocarcinoma developed from a pre-existent carcinoid tumor in a patient with a more than 20-year history of type A gastritis, multiple endocrine cell micronests, hypergastrinemia, and a high level of serum antiparietal cell autoantibody. The patient was a 60-year-old Japanese man. The background gastric mucosa around the tumor showed marked atrophy with intestinal metaplasia, in which endocrine cell micronests were frequently observed, and was consistent with type A gastritis. The mass was composed of both adenocarcinoma and carcinoid tumor. The adenocarcinoma was restricted to the lamina mucosa and submucosal area, and constituted a minor component of the tumor mass. The carcinoid tumor was the dominant constituent of the tumor, that invaded continuously the subserosa and muscularis propria. Based on this examination together with the detailed immunohistochemical and ultrastructural studies, the adenocarcinoma was presumed to have developed from the pre-existent carcinoid tumor. Ultrastructurally there were no amphicrine cells in the tumor, containing both endocrine granules and mucin droplets.

High risk for unbalanced segregation of some reciprocal translocations: a large pedigree containing distal 4q trisomy from t(4;7)(q28;p22).

We report on a familial t(4;7)(q28;p22) with 2:2 adjacent-1 unbalanced segregation producing duplication of 4q28-->qter in multiple offspring. Within the large four-generation pedigree, a carrier had a reproductive outcome that was approximately equal for 1) the balanced translocation, 2) normal chromosomes, and 3) viable 4q trisomy or pregnancy loss. The three individuals with chromosomal confirmation of trisomy 4q28-->qter (comprising approximately 1.8% of the haploid autosomal length) had similar mental and developmental retardation, hypotonia, restricted speech, seizures, and facial anomalies but no cardiac, renal, or skeletal anomalies. It is suggested that these latter severe malformations, associated with the classic 4q2 to 3 group of anomalies, were from an imbalance outside 4q28-->qter and were not necessarily related to the relatively large size of the trisomic segment. Multiple different chromosomes are reported to be rearranged with 4q in the production of distal 4q trisomy. The incidence of 4q rearrangement remains unexplained, but once it is present in a family, viability of a large trisomy in 4q seems to explain the number of affected individuals reported.

The relationship between the level of expression of intercellular adhesion molecule-1 in placenta and onset of preeclampsia.

OBJECTIVE: To investigate the differences in the expression of intercellular adhesion molecule-1 (ICAM-1) in the placenta and the concentration of soluble ICAM-1 between early-onset and late-onset preeclampsia. METHODS: Preeclampsia was divided into early-onset type (EO: 20 to 31 weeks gestation) and late-onset type (LO: > or = 32 weeks gestation). Post delivery, placentas were obtained from 19 control pregnant women and from 9 EO and 8 LO preeclamptic women. The expression of ICAM-1 in placenta was determined by immunohistochemical staining. Blood samples were taken from 21 non-pregnant women, 16 control pregnant women, 13 EO and 8 LO preeclamptic women, and umbilical cord blood samples from 38 control pregnancies and from 16 EO and 14 LO preeclampsia. The concentration of ICAM-1 was measured by enzyme-linked immunosorbent assays. RESULTS: The expression of ICAM-1 in placenta was higher in LO than in EO preeclampsia (48.2 +/- 8.2% vs 17.9 +/- 5.0%) (p < 0.05). ICAM-1 concentration in umbilical cord blood was higher in EO than in LO preeclampsia (umbilical artery, 150.6 +/- 34.0 ng/ml vs 90.3 +/- 9.4 ng/ ml) (umbilical vein, 128.3 +/- 31.2 ng/ml vs 91.3 +/- 10.2 ng/ml) (p < 0.05). CONCLUSIONS: Significant differences were noted in the expression of ICAM-1 between patients with EO and LO preeclampsia, which suggest that the possibility that EO and LO preeclampsia may have different onset mechanisms.

Characterization of the oxidized beta-Si3N4 whisker surface layer using XPS and TOF-SIMS.

The change in composition of the surface layer of beta-Si3N4 whiskers was examined after heat treatment in atmosphere. At 873 K, the beta-Si3N4 whisker was barely oxidized. At 1273 K, the oxidation of the surface layers of the whisker occurred easily. With the beta-Si3N4 oxidation, the Si-N bond gradually changed into the Si-N-O bond, and finally became the oxidized layer (amorphous layer) of the whisker surface. It was assumed that the whisker surface has a gradient interface structure which gradually changes from the oxide layer of the whisker's outer surface to the nitride crystal of the inside layer. It was confirmed that impurity elements such as Y and Ca existed mainly in the amorphous region near the interface between the amorphous layer and the crystal layer.

Glutamine synthetase, hemoglobin alpha-chain, and macrophage migration inhibitory factor binding to amyloid beta-protein: their identification in rat brain by a novel affinity chromatography and in Alzheimer's disease brain by immunoprecipitation.

Proteins binding to amyloid beta-protein (Abeta) may modulate the accumulation of Abeta in Alzheimer's disease (AD) brain. We developed a monomeric Abeta column for isolation of the proteins binding to Abeta from rat brain. By amino acid sequence analysis and immunoreactivity with specific antibodies, we identified three new Abeta-binding proteins, glutamine synthetase, hemoglobin alpha-chain, and macrophage migration inhibitory factor as well as serum albumin, beta-tubulin, and glyceraldehyde-3-phosphate dehydrogenase already identified as proteins bound to amyloid beta-protein precursor. In addition, the retained fraction contained both apolipoprotein E and alpha(1)-antichymotrypsin already known as Abeta binding proteins. Furthermore, we detected the complexes of these new binding proteins with Abeta in a soluble fraction of the cerebral cortex of AD brain by immunoprecipitation. Our results suggest that these binding proteins also associate with Abeta, leading to the clearance or the accumulation of Abeta and the neuronal cell damage in human brain.

Identification and characterization of the point mutation which affects the transcription level of the chromosomal 3-N-acetyltransferase gene of Streptomyces griseus SS-1198.

We determined the molecular basis for the enhanced expression of the aac(3)-Xa gene encoding an aminoglycoside 3-N-acetyltransferase in Streptomyces griseus. A C-->T substitution was identified at the putative promoter of the mutant gene. RNA analyses demonstrated that the substitution caused a marked increase in the production of the gene-specific transcripts. Therefore, it seemed very likely that the aac(3)-Xa gene was activated by the substitution resulting in the emergence of a stronger promoter.

[Methods and clinical significance of an oral tolerance test of essential trace element, especially an oral zinc tolerance test].

Oral administration of zinc (zinc tolerance test) was performed in 6 healthy adults, 11 patients with chronic hepatitis and 17 patients with liver cirrhosis to evaluate the ability of the digestive organs in patients with chronic hepatic diseases to absorb zinc. That is 300 mg of zinc sulfate powder (ZnSO4 7H2O)--equivalent to 68 mg of zinc--was dissolved in 200 ml of physiological saline solution, and the subjects received oral administration of the solution in a fasting condition during the early morning. The mean levels of serum Zn (ppm) at 0, 1, 2, and 3 hours after the test dose of ZnSO4 were 0.8 +/- 0.06, 1.66 +/- 0.21, 2.73 +/- 0.22 and 2.53 +/- 0.33 in cirrhotic patients, respectively. In most subjects, serum Zn levels peaked at 2 or 3 ours. The increase in serum Zn at 60 minutes during the base line Zn tolerance test was similar in patients and controls. The area under the curve was also significantly decreased in cirrhotic patients. These results will confirm the presence of diminished absorption by the intestinal tract in patients with liver cirrhosis.

[Liver diseases and essential trace elements].

The significance of the biochemical and nutritional roles of trace elements is widely recognized, since metals are found as constituent components of many metalloproteins and metalloenzymes. Some trace elements such as copper act as cofactors against hepatic fibrosis in chronic liver diseases, particularly in the biosynthesis of collagen. As the disease progress from chronic hepatitis to liver cirrhosis, serum calcium, magnesium, phosphorus and zinc concentrations decrease, while the copper concentration increases. In the patients with hepatocellular carcinoma, serum concentrations of trace elements are similar to those of liver cirrhosis. In the patients with acute hepatitis, serum calcium, magnesium and zinc concentrations decrease, while phosphorus, iron and copper concentrations decrease. These trace element abnormalities may reflect such pathological conditions as liver dysfunction, cholestasis, hepatic fibrosis or liver regeneration.