Head and Neck Cancer Stem Cells: From Identification to Tumor Immune Network.

Head and neck squamous cell carcinoma (HNSCC) is the most common form of head and neck cancer. Annually, more than half a million individuals are diagnosed with this devastating disease, with increasing incidence in Europe and Southeast Asia. The diagnosis of HNSCC often occurs in late stages of the disease and is characterized by manifestation of a high-grade primary tumor and/or lymph node metastasis, precluding timely management of this deadly cancer. Recently, HNSCC cancer stem cells have emerged as an important factor for cancer initiation and maintenance of tumor bulk. Like normal stem cells, cancer stem cells can undergo self-renewal and differentiation. This unique trait allows for maintenance of the cancer stem cell pool and facilitates differentiation into heterogeneous neoplastic progeny when necessary. Recent studies have suggested coexistence of different cancer stem cell populations within a tumor mass, where the tumor initiation and metastasis properties of these cancer stem cells can be uncoupled. Cancer stem cells also possess resistant phenotypes that evade standard chemotherapy and radiotherapy, resulting in tumor relapse. Therefore, understanding distinctive pathways relating to cancer stem cells will provide insight into early diagnosis and treatment of HNSCC. In this review, we highlight current advances in identifying cancer stem cells, detail the interactions of these cells with the immune system within the tumor niche, and discuss the potential use of immunotherapy in managing HNSCC.

Focusing forward genetics: a tripartite ENU screen for neurodevelopmental mutations in the mouse.

The control of growth, patterning, and differentiation of the mammalian forebrain has a large genetic component, and many human disease loci associated with cortical malformations have been identified. To further understand the genes involved in controlling neural development, we have performed a forward genetic screen in the mouse (Mus musculus) using ENU mutagenesis. We report the results from our ENU screen in which we biased our ascertainment toward mutations affecting neurodevelopment. Our screen had three components: a careful morphological and histological examination of forebrain structure, the inclusion of a retinoic acid response element-lacZ reporter transgene to highlight patterning of the brain, and the use of a genetically sensitizing locus, Lis1/Pafah1b1, to predispose animals to neurodevelopmental defects. We recovered and mapped eight monogenic mutations, seven of which affect neurodevelopment. We have evidence for a causal gene in four of the eight mutations. We describe in detail two of these: a mutation in the planar cell polarity gene scribbled homolog (Drosophila) (Scrib) and a mutation in caspase-3 (Casp3). We find that refining ENU mutagenesis in these ways is an efficient experimental approach and that investigation of the developing mammalian nervous system using forward genetic experiments is highly productive.

The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function.

Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order to understand the relationship of this mutation to AR function, we constructed ARs that varied in the position and size of the polyglutamine tract, and assayed for the abilities of these mutant receptors to bind androgen and to activate transcription of several different AR-responsive reporter genes. Elimination of the tract in both human and rat AR resulted in elevated transcriptional activation activity, strongly suggesting that the presence of the polyglutamine tract is inhibitory to transactivation. Progressive expansion of the CAG repeat in human AR caused a linear decrease of transactivation function. Importantly, expansion of the tract did not completely eliminate AR activity. We postulate that this residual AR activity may be sufficient for development of male primary and secondary sex characteristics, but may fall below a threshold level of activity necessary for normal maintenance of motor neuron function. This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease.

Toxic actions of senaetnine, a new pyrrolizidine-type alkaloid, in rats.

Senaetnine is a new type of Senecio alkaloid with a dihydropyrrolizinone structure. A limited amount of the crude alkaloid was available for preliminary toxicity tests in weanling male rats via i.p., oral and i.v. routes. Single i.p. or p.o. doses up to 280 mg/kg were not acutely toxic, and showed no evidence of hepatotoxicity. The compound or its metabolites appeared to be eliminated rapidly via the kidneys. However, senaetnine had a direct irritant action on tissues near to the site of i.p. administration, and caused damage to pulmonary vascular tissue when given i.v. Senaetnine is closely related to, but less reactive than, dehydrosenecionine, a putative short-lived metabolite of the alkaloid senecionine. It possesses mild alkylating reactivity, and the evidence indicates that it can cause moderate tissue injury without the need for metabolic activation. This suggests the need for testing of this and related compounds for chronic toxicity and carcinogenicity.

Hematological and blood chemical values of mallard, Anas p. platyrhynchos, drakes before, during and after remige moult.

Hematological and blood chemical values were determined for wild and captive mallards, Anas p. platyrhynchos, for the late spring period prior to remige moult through early fall migration. Hemoglobin, packed cell volume, erythrocyte and total leukocyte counts, as well as the number of heterophils and lymphocytes, declined significantly during and after remige moult compared to values recorded prior to remige moult. During fall migration mallard drakes had elevated levels of glucose and uric acid. No significant changes were observed in total protein, alkaline phosphatase, glutamic oxaloacetic transaminase or creatine phosphokinase in pre- or post-moult periods. The hematological and biochemical values should prove useful in providing background information on mallard drakes, and documenting baseline data for intra and interspecies comparisons with diseased birds.

Social class and fertility in metropolitan Madras.

PIP: The relationship between social class and fertility in Madras, India, is described by comparing the prevalence of sterility and duration of marriage among women in different classes. Differences between social classes in generational replacement is also explored. 463 families were selected from 3 city districts, yielding a satisfactorily representative sample. Complete data were available for 402 families in unbroken marriages. The number of children ever born ranged from 0-19, with a mean of 3.5 births. For the lower class (determined by the respondent's self assessment) the mean is 4.04 births, for the middle class, 3.19, and 3.29 for the upper class. Fertility of the lower class is significantly higher than that for the other 2 classes. When fertility is standardized by age, the total fertility of lower class women is 46% higher than that of upper class women and 26% higher than that of the middle class. The effect of sterility on fertility seems to be minor. After age adjustments, 8% of lower class women, 15% of middle class women, and 15% of upper class women are sterile. However, fertility of the middle class is 16% higher than that of the upper class, and in older age groupings where sterility differences are imperceptible, fertility of the lower class exceeds that of the middle class by 10% and the upper class by 50%. Marriage duration differs by social class: the median for the lower class is 13.8 years, 12.5 years for the middle class, and 18 years for the upper class. Controlling for differences in duration, fertility is inversely related to social class, with the exception of durations of 5 years or less. Total child mortality is inversely associated with social class: the standardized mean is 1.15 for the lower class, .82 for the middle class and .32 for the upper class. Equal mortality rates are observed for boys and girls. Forwomen of all ages, the standardized average number of surviving children is 3.21 for the lower class, 2.73 for the middle class, and 2.55 for the upper class. The number of surviving girls is inversely associated with social class. The general inverse correlations between social class and both fertility and child mortality seem to cooperate to keep the reproduction of the social classes in balance with their number in the contemporary generation.^ieng

Mercury levels in waterfowl from Manitoba, Canada, 1971-72.

From two locations in Manitoba suspected of mercury pollution, waterfowl were collected during 1971 and 1972 to determine the incidence and nature of the contamination. Total mercury concentrations averaged 0.18 ppm and 0.22 ppm in breast muscle of 169 adult dabbling (Anatini) and 77 adult diving ducks (Aythyini, Mergini, and Oxyurini), respectively. Mercury concentrations in breast muscles of immature ducks of these tribes averaged 0.15 ppm total mercury for 70 dabblers and 0.16 ppm for 40 divers. Mean mercury residues in livers were 0.54 ppm and 0.31 ppm, respectively, in 60 adults and 30 immature dabblers and 0.93 ppm and 0.29 ppm, respectively, in 31 adults and 15 immature divers. Primary feathers of 20 adult and 12 immature dabblers collected in the Saskatchewan River Delta averaged 2.67 ppm and 1.34 ppm, while 10 adult and 7 immature divers averaged 1.48 ppm and 1.11 ppm, respectively. Only in 20 ducks, 10 dabblers and 10 divers, did mercury concentrations in the breast muscle exceed 0.50 ppm. Statistically significant relationships for the concentration of mercury in feathers to breast muscle, feathers to liver, and breast muscle to liver were found for spring adults and for immature dabbling ducks. The only significant relationship for divers was feather to liver concentrations for immature ducks and breast muscle to liver concentrations of spring adults in 1972 in the Saskatchewan River Delta.