Expression of miR-200c in claudin-low breast cancer alters stem cell functionality, enhances chemosensitivity and reduces metastatic potential.

Claudin-low tumors are a highly aggressive breast cancer subtype with no targeted treatments and a clinically documented resistance to chemotherapy. They are significantly enriched in cancer stem cells (CSCs), which makes claudin-low tumor models particularly attractive for studying CSC behavior and developing novel approaches to minimize CSC therapy resistance. One proposed mechanism by which CSCs arise is via an epithelial-mesenchymal transition (EMT), and reversal of this process may provide a potential therapeutic approach for increasing tumor chemosensitivity. Therefore, we investigated the role of known EMT regulators, miR-200 family of microRNAs in controlling the epithelial state, stem-like properties and therapeutic response in an in vivo primary, syngeneic p53(null) claudin-low tumor model that is normally deficient in miR-200 expression. Using an inducible lentiviral approach, we expressed the miR-200c cluster in this model and found that it changed the epithelial state, and consequently, impeded CSC behavior in these mesenchymal tumors. Moreover, these state changes were accompanied by a decrease in proliferation and an increase in the differentiation status. miR-200c expression also forced a significant reorganization of tumor architecture, affecting important cellular processes involved in cell-cell contact, cell adhesion and motility. Accordingly, induced miR200c expression significantly enhanced the chemosensitivity and decreased the metastatic potential of this p53(null) claudin-low tumor model. Collectively, our data suggest that miR-200c expression in claudin-low tumors offers a potential therapeutic application to disrupt the EMT program on multiple fronts in this mesenchymal tumor subtype, by altering tumor growth, chemosensitivity and metastatic potential in vivo.

Pronoun resolution without pronouns: some consequences of memory-based text processing.

A memory-based processing approach to discourse comprehension emphasizes the rapid deployment of information in memory to facilitate understanding of the text that is currently being read. S. B. Greene, R. J. Gerrig, G. McKoon, and R. Ratcliff (1994) demonstrated that when a text described the reunion of 2 characters who had previously discussed a 3rd character, the accessibility of the 3rd character increased, and the use of an unheralded pronoun (R. J. Gerrig, 1986) to refer to that character was felicitous. In experiments in this article, the authors demonstrate that concepts related to the unheralded pronoun also increase in accessibility and that those concepts form associations in memory with concepts present in the discourse at the time the pronoun is used. The authors also show that the increase in accessibility for the referent of the pronoun, as well as the appropriate long-term memory associations, occurs even in the absence of the pronoun.

Discourse models, pronoun resolution, and the implicit causality of verbs.

Some interpersonal verbs, such as admire and amaze, describe an action or property of one person (the reactor) that is necessarily a response to an action or property of another (the initiator). We hypothesized that these verbs make the initiator relatively more accessible in a comprehender's discourse model and that this change in relative accessibility aids identification of the referent of a pronoun in a subsequent because clause. We predicted that, as a result, subjects would be faster to recognize a character's name after a because clause that uses a pronoun to refer to that character than after one that refers to some other character. Four experiments confirmed this prediction. Three further experiments demonstrated the importance of the verb's causal structure and of the presence of the connective because to this result.

Effects of unilateral hypothalamic manipulations on the sexual behaviors of rats.

Four experiments that assessed the contributions of each side of the hypothalamus to the control of sexual behavior found the following. (a) Exposing the left, but not the right, ventromedial nucleus to estrogen neonatally defeminized sexual behavior in female rats. This asymmetry did not reverse as sexual differentiation progressed. (b) Unilateral cuts lateral to the medial preoptic area disrupted mounting in females that had mounted regularly before surgery, when given testosterone. The deficits were greater when the cuts were on the left side, but a third of the females with unilateral cuts showed severe deficits regardless of the side. (c) Comparable cuts did not impair masculine sexual behavior in gonadally intact males. In fact, left-side cuts seemed to accelerate copulation in males. (d) Unilateral lesions of the ventromedial nucleus disrupted lordosis in female rats in an essentially all-or-none fashion. This effect did not vary with side.

Pronoun resolution and discourse models.

Psychological investigations of pronoun resolution have implicitly assumed that the processes involved automatically provide a unique referent for every pronoun. We challenge this assumption and propose a new framework for studying pronoun resolution. Drawing on advances in discourse representation and global memory modeling, this framework suggests that automatic processes may not always identify a unique referent for a pronoun. In 9 experiments, we demonstrate that, unlike noun anaphors, pronouns sometimes do not produce relative facilitation of their referents in comparison with nonreferents. We argue that research on pronoun resolution must consider the discourse contexts in which pronouns are likely to occur.

Multiple explanations for multiply quantified sentences: are multiple models necessary?

Johnson-Laird, Byrne, and Tabossi (1989) presented a theory of deductive reasoning for inference problems using multiply quantified premises (e.g., "All of the squares are connected to some of the circles"). Their theory classifies such problems into those that require subjects to construct only 1 mental model and those that require multiple models. They presented data that corroborate the theory. This article shows that Johnson-Laird et al.'s major results can be explained without invoking mental models or, in fact, deductive reasoning at all. Furthermore, it is demonstrated that, contrary to the assumption of these authors, reversing the order of the quantifiers in a multiply quantified sentence may produce a sentence that is both more difficult to comprehend and more ambiguous. Finally, some implications for theories of how people understand multiply quantified sentences are noted.

Cost sharing and its effects on hospital utilization. The Blue Cross and Blue Shield of North Carolina experience.

A natural movement away from traditional first-dollar health care benefits to coverage with cost-sharing features was studied among employer groups covered by Blue Cross and Blue Shield of North Carolina. The groups choosing the new benefits were atypical: they had a record of high rates of hospitalization. The new benefits were successful in shifting part of the financial burden away from the employer and, additionally, the groups collectively experienced a decline in inpatient utilization in excess of the decrease noted among controls. Despite the overall decline in utilization, their days/1000 remained in excess of the control groups in the year following the benefit change. Not every group experienced a utilization decline. Participants in counties with traditionally low levels of utilization did not experience a further decline.

Behavioral effects of pergolide mesylate on food intake and body weight.

In a crossover design experiment, pergolide mesylate significantly suppressed food intake and body weight in spayed female rats. Inhibition of food intake by a constant dose of pergolide progressively diminished with repeated administrations. Pergolide continued to suppress body weight with no indications of tolerance. When pergolide was discontinued, body weight increased sufficiently to compensate for the loss and failure to gain during drug treatment. A second experiment investigated the observation that animals injected first with vehicle showed greater anorexia when subsequently injected with pergolide than did animals injected first with pergolide. In addition, tolerance was further assessed by administering on two occasions a higher dose of pergolide. Following chronic pergolide treatment, this dose was insufficient to reinstate anorexia; however, after a period of abstinence, this dose produced anorexia comparable to that observed at the beginning of pergolide treatment. Due to pergolide mesylate's action as a postsynaptic dopamine agonist, a dopaminergic neural system is implicated in pergolide induced anorexia.

The conversion of claims files to an episode data base: a tool for management and research.

The construction of an episode-of-care file based on utilization data from the insurance claims system of Blue Cross and Blue Shield of North Carolina was undertaken for its subscribers and Medicare beneficiaries, a data base that includes 60% of the hospital days in North Carolina. The conversion was accomplished without interfering with the integrity of the accounting system, and the resulting file provides essential data for management decisions and epidemiological research. Among the uses to which the information in the file can be put are the promotion of ambulatory surgery, the redesign of group insurance benefits by employers, and the support of statewide health planning programs.

VMN lesion deficits in lordosis: partial reversal with pergolide mesylate.

Bilateral lesions of the VMN virtually eliminate estrogen-progesterone stimulated lordosis in the spayed female rat. The present paper demonstrates that some recovery in lordosis is possible following treatment with pergolide mesylate, a potent long acting dopamine agonist. Chronic administration of pergolide mesylate in combination with estrogen and progesterone resulted in significant recovery of lordosis in VMN lesioned female rats. The magnitude of recovery was related to the duration and/or dose of pergolide.

Should extended care following hospitalization be encouraged?

The use of extended care facilities following acute care hospitalization has been suggested as a way to reduce the use of the more expensive acute care facilities. Data from 1979 and 1980 on hospitalizations of the North Carolina Medicare aged population were analyzed to study the impact of the use of extended care facilities on the length of the preceding acute care hospitalizations. Contrary to what might be expected, it was found that the use of extended care facilities was related to longer, rather than shorter, stays in acute care facilities.

Frequency of hospitalization among hospital employees and their families.

Using claims data from 443 employee groups in North Carolina, this study examines the acute care hospital utilization rates of hospital employees and their dependents and compares them to employee groups in non-hospital settings. Results show that hospital employee groups account for 28 per cent more hospital days than non-hospital employee groups. The significantly higher rates are due primarily to employee utilization, although hospital employee dependents also showed higher rates of use than would be expected. We hypothesize that the high utilization rates of the hospital employee groups is due to the unusual availability and accessibility of hospital services and an atypical doctor-patient relationship.

Racial differences in medical care expenditures.

Out of pocket medical expenditures made by families for physician services, dental visits, medications, hospitalizations and insurance premiums are examined in a southern rural community using household survey interview data. White families paid an average out of pocket amount for total medical services of $709 as compared with $383 for black families over a 12-month period, 1974-75. Correlates of expenditure differences between blacks and whites are explored with respect to family characteristics (race, education of household head, family income, family size and family composition), illness levels (number of family members with perceived fair or poor health status and number of family members reporting chronic conditions), and use of services (number of doctor visits and type of usual source of care). We find that whites consistently report greater expenditures than blacks, regardless of the variables controlled for. We consider that expenditure differences are in part due to a mix of three factors: variations in the cost of doctor visits to whites and blacks; a lower level of use of services by blacks; and the differential availability and use of third party payors.

Distribution of illnesses and its implications in a rural community.

This study is a continuation of a series of reports on the utilization of health care services in a southern rural community. In this investigation the distribution of the utilization of medical care services is assessed with respect to reported illnesses and related disabilities. It is found that whites report significantly more illnesses, disabilities and physicians visits than blacks. Furthermore, even when controlling for disability and illness, whites use more physician services than blacks. The differential in utilization may be due to varying interpretations of the survey questions possibly reflecting different cultures and lifestyles and/or dissimilar expectations of the health care system in blacks having experienced greater barriers to access in the past.