Nilotinib combined with interleukin-2 mediates antitumor and immunological effects in a B16 melanoma model.

The immune system contributes to tumor cell killing which can be enhanced by cancer chemotherapeutics and immune modulatory pharmaceuticals such as tyrosine kinase inhibitors (TKIs). Recently, the beneficial effect of natural killer (NK) cells was demonstrated when combining interleukin-2 (IL-2) with the TKI imatinib. The aim of the present study was to address the antitumor and immunological effects of recently approved TKIs. Therefore, we focused on the comparison of the efficacy between imatinib and nilotinib in combination with IL-2 in a murine B16F10 melanoma model. Both TKIs possessed antitumor activity in vivo. However, the combination of nilotinib and IL-2 showed a superior outcome. Importantly, both the use of immunodeficient Rag2γc-/- mice, which lack T-lymphocytes, B-lymphocytes and NK cells, as well as NK cell-depletion in C57Bl/6 mice reduced the therapeutic effect of nilotinib. Flow cytometry revealed a significant increase in the IFN-γ-producing CD27+ NK cell subpopulation following treatment with nilotinib and IL-2. Furthermore, the therapeutic antitumor effect of nilotinib/IL-2 was completely lost in IFN-γ-/- mice. In summary, we suggest that nilotinib combined with IL-2 confers high antitumor activity involving the subset of IFN-γ-producing CD27+ NK cells. These new insights are of high importance for the understanding and development of immunotherapeutic protocols using TKIs.

Microsatellite instability in Bulgarian patients with endometrial cancer.

PURPOSE: Microsatellite instability (MSI) is a frequent event in different types of cancer. In several studies MSI was shown to have both clinical and prognostic value. The aim of our study was to determine the frequency of MSI in Bulgarian patients with endometrial cancer (EC) and the possible relation of this phenomenon to their clinicopathological characteristics. PATIENTS AND METHODS: A total of 33 histologically confirmed EC patients were analyzed for tumor MSI using a panel of 6 microsatellite markers. RESULTS: We identified MSI in 30% of endometrial cancer cases. Six of them had high degree of MSI (MSI-H), and 4 displayed low degree of MSI (MSI-L). CONCLUSION: The frequency of MSI in Bulgarian EC patients does not differ significantly from that reported in other European studies.

A method for estimating underutilization of mental health services by ethnic groups.

Most studies of utilization of mental health services by ethnic groups have used parity as a measure of whether members of ethnic groups are receiving a fair share of services. The level of services is assumed to be adequate if the percentage of ethnic group members in the treatment population is the same as the group's percentage in the general population. However, service planning based on achieving parity fails to consider whether some groups have higher levels of need than others. The authors describe a method for more accurately projecting service needs of minority groups based on population data and on sample surveys of needs. The results help define more equitable service goals for all population groups.

The correspondence of health complaints and depressive symptoms among Anglos and Mexican-Americans.

This study examines the relationship between depressive symptoms and somatic complaints and/or disorders in two ethnic groups. Data reported herein are from an epidemiological field survey of a disproportionate stratified sample of Anglos (N = 637) and two Mexican-American subsamples, United States-born (N = 342) and Mexican-born (N = 201), all living in Santa Clara County, California. The covariation between depressive symptoms and a severity of somatic complaints/disorders scale derived from collapsing International Classification of Diseases categories was compared among the three ethnic subsamples with control on age, sex, education, and marital status. A significant, direct linear correlation was found between depressive symptomatology and severity of somatic complaints/disorders for each ethnic group and was found in multivariate analyses not to change significantly with the introduction of controls. Partial correlations pointed to a stronger association for Mexican-Americans than for Anglos.

The mental health needs of Mexican-American agricultural workers.

We used three measurement procedures to produce a comprehensive profile of the mental health needs of Mexican-American farmworkers and to determine what kinds of mental health services were required to meet those needs. These measurement procedures were a field survey, a key informant survey, and a nominal group process. The results of the field survey indicated that rural Mexican Americans are not being served by mental health providers, despite their having higher symptom levels than would be expected in the general population and their substantial use of rural primary health clinics and private physicians. The key informant survey included mental health providers, health providers, and community agency personnel. According to these informants, the mental health sector is unable to provide services for the farmworkers; and the ability of other providers to reach them depends on a number of factors, including the nature of the services offered and the socioeconomic characteristics of the farmworkers themselves. Key informants identified the environmental conditions implicated in the farmworkers' psychosocial problems and recommended types of services, sites, and key personnel. Key informants concurred that general health settings and multiservice agencies were the most appropriate for reaching Mexican Americans, and that mental health services must include bilingual and bicultural staff members. Key informants disagreed, however, about the relative value of certain kinds of mental health services. The nominal group process identified 32 design criteria that could be used to improve mental health services for farmworkers.(ABSTRACT TRUNCATED AT 250 WORDS)

The prevalence of depressive symptoms among Mexican Americans and Anglos.

The study reports epidemiologic field survey data on the distribution of depressive symptoms among Anglos (n = 637) and two Mexican-American subsamples (n = 551) living in Santa Clara County, California. One of the Mexican-American subsamples was interviewed in English (n = 330) and the other in Spanish (n = 221). Analysis of variance indicated that those with low educational achievement, females, those in disrupted marital statuses, and those under 30 years of age had significantly higher levels of depressive symptoms than their counterparts. The prevalence of depressive symptoms for the Anglo and Mexican-American English-speaking samples was very similar and much lower than that reported by the Spanish-speaking Mexican-American subsample. Differences in educational levels appear to be accounting for many of the variations in depressive symptoms between the Anglo and English-speaking subsamples and the Spanish-speaking one. The authors suggest that the lack of language skills along with low educational achievement may be indicating a relative lack of acculturation and societal integration which in turn may be accounting for some of the increased symptoms among the Spanish-speaking subsample. The results of multiple stepwise regression analyses indicate that age, sex, marital status, and educational attainment explain relatively low and fluctuating amounts of the total variance. These analyses also indicate that social and demographic factors are differentially related to depressive symptoms for each of the subsamples. The variables education, female, and separated were significant in all of the equations, but their order of entrance and the amount of variance explained by them varied.

Clonal growth of human tumor xenografts. First experiences in drug testing.

Human tumors growing as nude mice xenografts were investigated for growth in a clonogenic assay. Colony formation of more than 30 colonies per plate was obtained in 47 of 63 tumors examined (74.6%). The growth rate was enhanced by raising the concentration of fetal calf serum in the culture medium. Plating efficiency ranged from 0.0003% to 5.5%. To study the applicability of this model for screening new anticancer drugs, preliminary studies in drug sensitivity were conducted with continuous incubation of different anticancer drugs in a dose range of 1/10 to 10 times the maximum achievable plasma level. The highest concentration almost always led to a complete suppression of colony growth. In our opinion the procedure described may be a useful combination of two methods in predictive drug testing, provided drug concentration and mode of drug incubation are adequately considered.

Mental health expenditures in California counties.

In 1957 California began placing responsibility for public mental health services on county programs still vary widely in emphasis and size. The authors explored determinants of counties' unequal program developments using per capita expenditures as the measure of county services. Sociodemographic variables that help explain states' social program expenditures correlate weakly or not at all with county mental health expenditures. The most powerful predictor of these expenditures is number of psychiatrists per 10,000 population. Equal per capita expenditures, however, are not a reasonable goal; these can mask wide variations in program content, efficiency, and quality of care.

Nonhospital alternatives for acute psychiatric care in California.

In California multiple social forces and financial constraints are leading to the rapid development of local alternatives not only to state hospitals but to general hospital psychiatric units as well. Two dissimilar patterns of acute-care services are emerging: the use of skilled nursing facilities with additional staff to provide mental health services and the development of a wide range of primarily nonmedical facilities under the licensing category of "residential care facility." The author summarizes characteristics of both kinds of programs and describes how they draw on all available sources of revenue before using state and county mental health funds. He also describes Santa Clara County's plan for local acute-care services in which a 54-bed residential building and a 15-bed psychiatric unit in a county hospital will replace two county-hospital psychiatric wards.

Adaptive changes of rat liver cells induced by repeated intraperitoneal injections of d-galactosamine. III-Light- and electron-microscopic investigations of hepatocellular cytoplasmic changes.

In rats hepatocellular cytoplasmic changes after daily repeated D-galactosamine (GalN) intoxication--i.e. subacute GalN intoxication--were studied by light and electron microscopy. The number of GalN injections--and thus the days of survival--was between one and 30. The rats were killed six hours after the last GalN injection. Less degenerative changes were found after repeated GalN injections. An increased formation of atypical dense bodies (ADB), a temporary pronounced lipid accumulation and changes of the rough and smooth endoplasmic reticulum were prominent features of subacute GalN intoxication. The implications with respect to a modified GalN action in subacute GalN intoxication are discussed with special reference to biochemical data obtained in the same experimental model (Schuchhardt et al., 1977).

Adaptive changes of the rat liver cells induced by repeated intraperitoneal injections of d-galactosamine. II. Light and electron microscopic investigations of hepatocellular nucleolar alterations.

The effects of repeated d-galactosamine (GalN) administration - i.e. subacute GalN intoxication - on rat liver cell nucleoli were examined. After an initial intraperitoneal injection of 375 mg GalN/kg body weight the rats were treated with 250 mg GalN/kg body weight daily at intervals between 24 h and 30 days. The rats were sacrificed six h after the last injection by decapitation. Specimens of liver were studied by light and electron microscopy. According to the nucleolar size three stages were to be distinguished. Stage I: decreased nucleolar size after one injection, stage II: increased and maximal nucleolar size after two to five injections, stage III: slightly increased relatively stable nucleolar size after six and more injections. Fine structural observations suggest a nucleolar hyperfunction in subacute GalN intoxication as well as a minor disturbance of the transcription and the transfer of the nucleolar RNA.

The appearance and degradation of specific hepatocellular cytoplasmic inclusion bodies in rat liver due to D-galactosamine. I. The relation between the amount of liver glycogen and the appearance of the atypical dense bodies in the liver cell.

One of the most sensitive and specific signs of the galactosamine effect upon the rat liver cell is the appearance of PAS-positive and diastase-resistant granules within the cytoplasm of hepatocytes. Light-microscopic, histochemical, biochemical, and electron-microscopic findings reveal that the appearance of these ADB (= atypical dense bodies) depends upon a working glycogen metabolism at the time of GalN treatment. The ADB are composed of particles resembling, due to shape and size, ribosomes and beta particles of glycogen. Most of them are surrounded by the rER, but they are never enclosed by a limiting membrane. Due to sequential changes they can be generally classified into three types; the early, the intermediate, and the late type. In seven experiments it can be shown, that the appearance of the ADB depends upon the time and dosage after GalN treatment. They occur even if an additional treatment with galactose or uridine prevents the liver from the features of a hepatitis, as also shown in the livers of newborn animals up to 3 weeks of age. The histochemical response against various glucosidases, hexosaminidases, pronase, and RNAse as well as against various fixatives indicates that ADB are composed of, at least, two different constituents, the former RNAse-sensitive and visible with routine light-microscopic staining procedures, the latter RNA-resistant, PAS-positive, and invisible after staining with H & E or toluidine blue. The latter is diastase-resistant, suggesting that this portion of ADB does not represent the usual glycoproteins but some abnormal metabolite of glycogen. The ADB can be detected with maximal accumulation in the cytoplasm of hepatocytes at that time when the glycogen content determined in the liver homogenate by biochemical methods is greatly reduced.