Characteristics of tumors that have developed in mice injected with syngenic irradiated mesenchymal stem cells of bone marrow

Mesenchymal stem cells (MSCs) are found in virtually all organs and tissues. These cells can presumably be transformed into tumor stem cells by genotoxic factors and, subsequently, initiate tumor growth. The aim of the present work consisted in analysis of the possibility of malignant transformation of cultured MSCs from the bone marrow (BM) of mice after in vitro exposure to γ-radiation and in the characterization of biochemical and histological features of tumors that developed after the transplantation of BM MSCs to syngenic mice. Two of five mice developed tumors 3 to 4 months after the subcutaneous injection of BM MSCs irradiated at a dose of 1 Gy, five of five animals developed tumors after the administration of BM MSCs irradiated at a dose of 6 Gy, and only one of five mice injected with nonirradiated BM MSCs developed a tumor 6 months after cell transplantation. Telomerase activity in a tumor that developed from BM MSCs irradiated at a dose of 6 Gy was twice as high as that in the tumor that developed from BM MSCs irradiated at a dose of 1 Gy. The histological structure of the neoplasms corresponded to that of multicomponent mesenchymoma, a malignant tumor also termed “a mix of sarcomas.” The tumors consisted of tissue fragments of different histological types. Thus, BM MSCs exposed to 1 or 6 Gy of radiation can be transformed into tumor cells and give rise to multicomponent mesenchymomas, whereas malignant transformation of control BM MSCs occurs much less often.     

Antibiotic therapy of acute dysentery in children with immunologic deficiency conditions

One hundred children with acute Sonnei and flexneri dysentery were followed up with respect to the infection process and main immunity indices. In 32 children the immunity indices were physiological (group 1) and in 68 children secondary immune deficiency was observed (group 2). The children were treated with aminoglycoside antibiotics and prodigiozan and it was stated that the time of recovery in the children with immune deficiency was longer by 5.2 days as compared to that in the children without immune deficiency. In the children with immune deficiency the combined use of one of the aminoglycosides, prodigiozan and lysozyme, led to a reduction of the host immunological reactivity and recovery within the same periods as those recorded for children with the physiological immunity status. It is recommended to use the antibiotic combination with prodigiozan and lysozyme in the treatment of all the forms of dysentery in children with secondary immune deficiency.     

Cause of death and neoplasia in mice continuously exposed to very low dose rates of gamma rays

Four thousand 8-week-old SPF B6C3F1 mice (2000 of each sex) were divided into four groups, one nonirradiated (control) and three irradiated. The irradiated groups were exposed to (137)Cs gamma rays at dose rates of 21, 1.1 and 0.05 mGy day(-1) for approximately 400 days with total doses equivalent to 8000, 400 and 20 mGy, respectively. All mice were kept until natural death, and pathological examination was performed to determine the cause of death. Neoplasms accounted for >86.7% of all deaths. Compared to the nonirradiated controls, the frequency of myeloid leukemia in males, soft tissue neoplasms and malignant granulosa cell tumors in females, and hemangiosarcoma in both sexes exposed to 21 mGy day(-1) were significantly increased. The number of multiple primary neoplasms per mouse was significantly increased in mice irradiated at 21 mGy day(-1). Significant increases in body weights were observed from 32 to 60 weeks of age in males and females exposed to 1.1 mGy day(-1) and 21 mGy day(-1), respectively. Our results suggest that life shortening (Tanaka et al., Radiat. Res. 160, 376-379, 2003) in mice continuously exposed to low-dose-rate gamma rays is due to early death from a variety of neoplasms and not from increased incidence of specific neoplasms.     

The cytologic diagnosis of malignant neoplasms in pleural and peritoneal effusions

This study presents data on 3,011 pleural and peritoneal effusion specimens that were examined over a three-year period (1982 to 1984). Totals of 812 (44%) of 1,846 pleural and 423 (36%) of 1,165 peritoneal specimens were positive for malignant cells. While 535 patients had malignant pleural effusions, 254 patients had malignant peritoneal effusions, and 57 had both malignant pleural and peritoneal effusions. The most common primary neoplasms causing malignant pleural effusions were carcinomas of breast (24%) and lung (19%) and lymphoreticular neoplasms (16%). The most common primary neoplasms causing malignant peritoneal effusions were carcinomas of ovary (32%) and breast (13%) and lymphoreticular neoplasms (7%). There was an average interval of more than 30 months between the histologic diagnosis of the primary neoplasm and the diagnosis of malignant effusions in patients with carcinoma of breast, lymphoreticular neoplasm and malignant melanoma. The average time until death following the diagnosis of a malignant effusions was five months or less, except for patients with carcinoma of the breast and carcinoma of the ovary. One hundred twenty-five patients (15%) presented with malignant effusions caused by neoplasms of unknown primary sites. The most common primary neoplasms that were later diagnosed were, in decreasing order of frequency, carcinoma of the ovary, carcinoma of the lung and lymphoreticular neoplasms.     

Intraspinal Tumors in Children

Thirty cases of intraspinal neoplasms occurring during the first two decades of life are reviewed. Histologic examination showed 13 of these to be astrocytomas, 6 neuroblastomas, 5 sarcomas, 3 ependymomas, 2 neurofibromas and 1 a schwannoma. Orthopedic deformities developed or worsened in 60 percent of patients surviving longer than a year after diagnosis. In five patients some form of endocrine deficiency developed after irradiation. For treatment of radiosensitive extradural malignant lesions, biopsy followed by irradiation is advocated.     

Induction of tumor immunity by intact irradiated leukemic B cells (BCL1) bearing a tumor-associated cell-surface idiotype and the costimulatory B7 molecule

The idioptypic (Id) determinant of immunoglobulin expressed on the cell surface of malignant B cells represents a prototypical tumor-associated antigen (TAA), which has been used in a purified soluble form for active immunization in experimental tumor models and human hematological malignancies. Using a spontaneous transplantable murine model of B cell leukemia/lymphoma (BCL1), we have demonstrated the expression of the B7 costimulatory molecules in addition to the previously described Id determinant and class II major histocompatibility antigens. Intact irradiated BCL1 cells bearing these distinct determinants induced long lasting antitumor immunity in naive syngeneic mice. Induction was dose-dependent and most effective when three doses of 30×10⁶ intact irradiated BCL 1 cells were given at intervals of 7–10 days. The induced immunity protected 96% of 28 mice inoculated with a lethal dose of 10⁵–10⁶ nonirradiated BCL1 cells and 85% of 27 mice given a second challenge, whereas control mice died on day 20 after inoculation with 10⁶ BCL1 cells. Adoptive transfer of splenocytes derived from immune mice did not induce leukemia in syngeneic recipients. Such splenocytes, harvested more than 365 days following immunization and administered together with fresh BCL1 cells to adoptive recipients, were able to confer protection for 90 days, even following a second challenge given 104 days after the first one. BCL1 immune splenocytes transferred into BCL1-bearing mice exerted a therapeutic effect, preventing leukemia onset for at least 180 days. Our results demonstrate the ability of tumor cells to trigger effective anti-tumor immunity. These findings could ultimately be applied to the prevention of tumor relapse in treatment of hematological and other malignancies expressing TAA, class II MHC antigen and costimulatory molecules.These studies were supported by grant 942010-B from the Israel Cancer Association     

Study on potential effects of "902-MHz GSM-type Wireless Communication Signals" on DMBA-induced mammary tumours in Sprague-Dawley rats

The aim of the study was to detect whether long-term exposure to "902-MHz GSM-type Wireless Communication Signals" ("radio-frequency (RF)-exposure") would affect 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumours in female Sprague-Dawley rats. Five hundred female rats were each given a single oral dose of 17 mg DMBA per kg body weight (bw) at an age of 46-48 days. Three groups of 100 animals each were RF-exposed (902 MHz; crest factor 8; pulse width=0.57 ms) from the next day onwards to normal whole-body averaged doses (expressed as specific absorption rate, SAR) of 0.4, 1.3 or 4.0 W/kg bw (low/mid/high-dose group) for 4h/d, 5d/week, during 6 months. A sham-exposed and a cage-control group remained without RF-exposure (<0.01 mW/kg). Animals were weekly weighed and palpated for mammary tumours; all mammary glands were examined histopathologically. There were several statistically significant differences between RF-exposed groups and the sham-exposed group, as follows: All RF-exposed groups had, at different times, significantly more palpable tissue masses. There were fewer animals with benign neoplasms, but more with malignant tumours in the high-dose group. In addition, there were more adenocarcinomas in the low-dose group, more malignant neoplasms in the low- and high-dose groups, more animals with adenocarcinomas in the high-dose group, and fewer animals with fibroadenomas in the low- and mid-dose groups. The cage-control group had, when compared with the sham-exposed group, statistically significantly more palpable tissue masses, more benign and also more malignant neoplasms. The cage-control group had in most aspects the highest incidence and malignancy of neoplasms among all groups. None of the above findings in RF-exposed animals produced a clear dose-response relation and the responses of the cage-control group were either similar to or stronger than those of any of the RF-exposed group. The significant differences between the sham-exposed animals and one or more RF-exposed groups may be interpreted as evidence of an effect of RF-exposure. In the context of the results of the cage-control group, in the light of controversial results reported in the literature, and given the fact that the DMBA-mammary tumour model is known to be prone to high variations in the results, it is the authors' opinion that the differences between the groups are rather incidental ones.     

GSM and DCS wireless communication signals: combined chronic toxicity/carcinogenicity study in the Wistar rat

A total of 1170 rats comprised of 65 male and 65 female Han Wistar rats per group were exposed for 2 h/day, 5 days/ week for up to 104 weeks to GSM or DCS wireless communication signals at three nominal SARs of 0.44, 1.33 and 4.0 W/kg. A preliminary study confirmed that the highest exposure level was below that which was capable of causing a measurable increase in the core temperature of the rat. Additional groups for each modulation were sham exposed, and there was also an unrestrained, unexposed (cage) control group. Fifteen male and 15 female rats per group were killed after 52 weeks. From the remaining 50 male and 50 female rats per group, surviving animals were killed after 104 weeks. Evaluations during the study included mortality rate, clinical signs, recording of palpable masses, body weight, food consumption, ophthalmoscopic examination, and clinical pathological investigations. Terminal investigations included organ weight measurement and macroscopic and microscopic pathology examinations. There was no adverse response to the wireless communication signals. In particular, there were no significant differences in the incidence of primary neoplasms, the number of rats with more than one primary neoplasm, the multiplicity and latency of neoplasms, the number of rats with metastases, and the number of benign and malignant neoplasms between the rats exposed to wireless communication signals and rats that were sham exposed.     

Resistance of Calves to Reinfection with Eimeria bovis

SYNOPSIS. An immunity to reinfection with E. bovis was demonstrated in 3 experiments involving 60 calves. This immunity develops rapidly, as indicated by resistance to a challenge given 14 days after the immunizing inoculation. In 3 groups of 3 to 6 young calves each, immunity was still present to a moderate degree 2 to 3 months after inoculation; in one group of 5 animals about a year old there was apparently a high degree of immunity about 7 months after the last inoculation. In one experiment an immunizing inoculum of 10,000 oöcysts did not produce as much immunity as 50,000 oöcysts. In 2 experiments there appeared to be little difference in the immunity produced by a single inoculation of 50,000 as compared with 100,000 oöcysts, but inoculation with 100,000 oöcysts, resulted in substantially longer and more severe illness than 50,000 oöcysts. There appeared to be no appreciable difference in clinical symptoms or development of immunity between calves given a single immunizing inoculum and those given the same number of oöcysts in 5 equal inocula on successive days. Treatment with sulfamethazine and sulfamerazine (Merameth) 13 to 15 days after inoculation alleviated the clinical symptoms of coccidiosis without interfering appreciably with the development of immunity. In one experiment with 7 calves, no beneficial effect was noted from 1 or 2 transfusions of 500 ml. of plasma and leucocytes from immune calves into 4 calves 1 and 12 days or 11 days after a challenge inoculation.     

Iron and neoplasia

Normal and neoplastic cells (like nonpathogenic and pathogenic microorganisms) apparently have similar needs and tolerances for iron, but neoplastic cells (like pathogenic microorganisms) may exhibit altered mechanisms of iron acquisition that permit continued growth in host iron-restricted tissues. Excess iron tends to interfere with host defense against malignant cells (as well as against microbial invaders); severe iron deficiency may likewise be detrimental. Elevated temperature is more toxic towards neoplastic than to normal host cells; it is not yet known whether the site of action of heat might be associated with iron acquisition (as has been demonstrated for gram negative bacteria). Persons or animals with iron overload tend to be at greater risk than normal hosts in the development of neoplasms. Construction of animal models of iron overload, although difficult, is strongly indicated at this time. Based on such models, decisions then can be made about the extent to which (a) nutritional immunity against neoplastic cells is practiced by vertebrate hosts and (b) clinical procedures could be employed to strengthen such immunity as an adjunct to radiotherapy, chemotherapy, and surgery.     

Suppression of delayed-type hypersensitivity to oxazolone in whole-body-irradiated mice and protection by WR-2721

The effect of whole-body irradiation on cellular immunity, as measured in vivo by delayed-type hypersensitivity (DTH) to oxazolone (4- ethoxymethylene -2-phenyl- oxazol -5-one), was determined in CD2F1 mice. DTH, determined by changes in ear swelling after challenge with oxazolone, was significantly depressed in irradiated mice (500-900 rad of 60Co) in a dose-dependent fashion when animals were irradiated after sensitization and before challenge with oxazolone. Administration of WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid] 30 min before irradiation (2 days after sensitization) resulted in protection against suppression of DTH, which was dependent on drug and radiation dose. An effective dose of WR-2721 (200 mg/kg body wt) provided an approximate dose-modifying factor of 1.3. The data suggest that WR-2721 interacts with cells involved in that DTH response (lymphocytes and/or macrophages) and that WR-2721 may be useful in protecting against radiation-induced decrements in cell-mediated immunity.     

Mechanism of the protective immunity against murine typhoid: persistence of salmonella L forms in the liver after immunization with live-cell vaccines

Abstract Live-cell vaccines of Salmonella typhimurium , either a sub-lethal dose of a wild-type (strain LT2) or a high dose of its two-heptose Rd₁ mutant (strain SL1004), induced acquired resistance to murine typhoid, which remained 180 days after immunozation. Growth of S. typhimurium as a bacillary form ceased between days 30 and 60 of immunization, but L forms of this bacterium colonized the liver (the mean number of L forms in the liver: 600 L-forming units) even at 180 days post-immunization. In contrast, a high inoculum of either a Ra mutant (strain TV148) of strain LT2 or S. schottmülleri 8006 sharing the same O antigenic components with those of S. typhimurium induced only a short-lived protection in proportion to the number of L forms in the liver, and the protective immunity was lost before day 180. However, there was no significant difference in the salmonella-specific T-cell responses among groups of immunized mice on day 180 of immunization. A lethal infection with strain LT2 in mice which had been immunized 75 days previously with living cells of strain SL1004 resulted in a rapid clearance of the challenge inoculum, together with a rapid elevation of anti- S. typhimurium antibody responses. Thus, the present data suggest that the long-lived immunity conferred upon live S. typhimurium vaccines is attributable to the colonization of this bacterium in the liver as L forms and the ability to colonize the liver as L forms is independent of the brain length of salmonella O-antigens.     

The recovery of humoral immunity after the long-term action of tritium oxide at different irradiation levels

Dynamics of recovery of humoral immunity of CBA mice was studied 1, 3, 6 and 12 months after termination of long-term exposure to tritium oxide at various levels of absorbed doses (3, 5 and 9 Gy) and dose rates (3.3, 4.9 and 9.2 cGy.day-1). A severer and more stable residual radiation damage was observed in the department of lymphocyte precursors. A considerable decrease in the content of antibody producers was due to the lymphoid tissue hypoplasia. There was a direct relationship between the immunodeficiency and dose rate and total absorbed dose of beta radiation.     

A Comparison of Positron Emission Tomography and Colonoscopy for the Detection of Advanced Colorectal Neoplasms in Subjects Undergoing a Health Check-Up

Background & Aims

There is no agreement as to whether F-18 fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) screening for advanced colorectal neoplasms is meaningful. This retrospective study was undertaken to determine whether FDG PET/CT may be a valuable screening tool for the detection of advanced colorectal neoplasms.

Methods

A retrospective review of the records of 1,109 FDG PET/CT scans acquired from January 2007 to December 2011 was performed. Colonoscopy and FDG PET/CT imaging were performed within two days of each other. The results of colonoscopy were taken as the gold standard, either with or without the results of the histopathological examination. An advanced neoplasm was defined as the presence of a malignant tumor, an adenoma ≥1 cm, or histological evidence of high-grade dysplasia or significant villous components.

Results

A total of 36 subjects had advanced colorectal neoplasms detected by colonoscopy (totaling 38 neoplasms). Six of the 38 neoplasms were also detected by FDG PET/CT. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of FDG PET/CT in the detection of advanced colorectal neoplasms were 15.8% (6/38), 99.1% (1063/1073), 37.5% (6/16), 97.1% (1063/1095), and 96.2% (1069/1111) respectively. The presence of lesions with an endoscopic size ≤1.5 cm (P<0.001) and low-grade dysplasia (P<0.001) were the main predictors of false-negative FDG PET/CT findings.

Conclusions

We conclude that FDG PET/CT screening of advanced colorectal neoplasms is unwarranted, especially in the presence of lesions with an endoscopic size ≤1.5 cm or low-grade dysplasia.     

Microscopic distribution of iodine radioisotopes in the thyroid of the iodine deficient new-born rat: insight concerning the Chernobyl accident.

Thyroid cancer markedly increased in children exposed to iodine radioisotopes following the Chernobyl accident. This increase exceeded predictions based on dose estimates to the whole organ. We sought to investigate whether iodine deficiency may have influenced the pattern of microscopic distribution of radioiodines, which may be important to interpretation of the observed effects. Iodine-deficient new-born rats were injected with iodine-129 (129I) and the microscopic distribution in the thyroid tissue was studied at 24 hr and at one week after administration, using secondary ion mass spectrometry (SIMS). Twenty-four hr after administration, SIMS images showed large differences in 129I uptake among thyroid follicles, with more than a factor ten variation in the local concentration. In addition, the distribution of 129I inside follicles varied with time. At 24 hr, the highest concentration was found at the periphery of the colloid, close to the thyroid cells. There also was enhanced concentration of 129I at one pole of follicles. Distribution inside follicles was homogeneous at 7 days. Conclusions: 1/Dosimetric models, which assume uniform iodine uptake by thyroid follicles, give an oversimplified picture of radiation dosimetry in cases involving iodine deficiency, which induces patchy tissue irradiation. 2/The dynamic pattern of iodine distribution within thyroid follicles suggests that decay events from short-lived iodines will occur closer to thyroid cells than events resulting from iodine-131.     

Live virulent Rhodococcus equi, rather than killed or avirulent, elicits protective immunity to R. equi infection in mice

Mice inoculated intravenously with a sublethal dose of live virulent Rhodococcus equi ATCC 33701 that contained an 85-kb virulence plasmid were immune to a lethal intravenous challenge of ATCC 33701. This immunity depended upon the dose of immunization and developed rapidly: mice primed with 10(5) live ATCC 33701 eliminated the challenged bacteria more rapidly than mice primed with doses ranging from 10(2) to 10(4) bacteria, and mice given 10(5) live ATCC 33701 intravenously withstood the lethal challenge as early as 5 days after the initial inoculation. However, this protective immunity did not develop in mice immunized with doses of heat-killed ATCC 33701 ranging from 10(6) to 10(8), or in mice immunized with doses of live ATCC 33701P-, a plasmid-cured derivative (avirulent), in doses ranging from 10(5) to 10(7). These mice had positive antibody titers against R. equi at the challenge (14 days after priming). Adoptive transfer of resistance to virulent R equi was obtained with spleen cells from mice immunized with live ATCC 33701, but not monoclonal antibody to 15- to 17-kDa virulence-associated antigens. These results revealed that live ATCC 33701P-, a plasmid-cured derivative of virulent R equi, could not elicit protective immunity, and are consistent with previous observations that protective immunity was induced by live virulent, but not killed organisms.     

Vitamin A Deficiency Impairs Mucin Expression and Suppresses the Mucosal Immune Function of the Respiratory Tract in Chicks

The chicken immune system is immature at the time of hatching. The development of the respiratory immune system after hatching is vital to young chicks. The aim of this study was to investigate the effect of dietary vitamin A supplement levels on respiratory mucin and IgA production in chicks. In this study, 120 one-day-old broiler chicks were randomly divided into 4 groups consisting of three replicates of 10 broilers and subjected to dietary vitamin A supplement levels of 0, 1,500, 6,000, or 12,000 IU/kg for seven days. Compared with control birds, vitamin A supplementation significantly increased the mucin and IgA levels in the bronchoalveolar lavage fluid (BALF) as well as the IgA level in serum. In the lungs, vitamin A supplementation downregulated TNF-α and EGFR mRNA expression. The TGF-β and MUC5AC mRNA expression levels were upregulated by vitamin A supplementation at a dose of 6,000 IU/kg, and the IL-13 mRNA expression level was increased at the 12,000 IU/kg supplement level. Vitamin A deficiency (control) significantly decreased the mRNA expression levels of MUC2, IgA, EGFR, IL-13 and TGF-β in trachea tissue. Histological section analysis revealed that the number of goblet cells in the tracheal epithelium was less in the 0 and 12,000 IU/kg vitamin A supplement groups than in the other groups. In conclusion, vitamin A deficiency suppressed the immunity of the airway by decreasing the IgA and mucin concentrations in neonatal chicks. This study suggested that a suitable level of vitamin A is essential for the secretion of IgA and mucin in the respiratory tract by regulating the gene expression of cytokines and epithelial growth factors.     

Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia

Although the immune system has long been implicated in the control of cancer, evidence for specific and efficacious immune responses in human cancer has been lacking. In the case of chronic myelogenous leukemia (CML), either allogeneic bone marrow transplant (BMT) or interferon-alpha2b (IFN-alpha2b) therapy can result in complete remission, but the mechanism for prolonged disease control is unknown and may involve immune anti-leukemic responses. We previously demonstrated that PR1, a peptide derived from proteinase 3, is a potential target for CML-specific T cells. Here we studied 38 CML patients treated with allogeneic BMT, IFN- alpha2b or chemotherapy to look for PR1-specific T cells using PR1/HLA-A*0201 tetrameric complexes. There was a strong correlation between the presence of PR1-specific T cells and clinical responses after IFN-alpha and allogeneic BMT. This provides for the first time direct evidence of a role for T-cell immunity in clearing malignant cells.     

Dose and time dependence of chromosomal aberration yields of bone marrow cells in male Chinese hamsters after a single i.p. injection of aflatoxin B1

The frequency of chromosomal aberrations in bone marrow cells, after a single i.p. aflatoxin B1 (AFB1) dose, was examined in male Chinese hamsters (Cricetulus griseus). There was a significant increase in aberrant cells within 5 days of administration of a dose of 0.1 micrograms-5 mg AFB1/kg, and on the 36th day. After a single dose of 5 mg AFB1/kg the enhanced frequency of aberrant cells was monitored up to day 104 with no sign of a decrease to control level. The results indicate that the minimum mutagenic effect of an AFB1 dose in this system is 0.1 micrograms/kg. Attention is drawn to the long-term presence of chromosomal aberrations even after a single i.p. exposure to AFB1.