Lymphosarcoma with lymphoblastic leukemia in a New Zealand white rabbit.

An 8 to 10-week-old female New Zealand white rabbit, Oryctolagus cuniculus, which exhibited clinical signs of anorexia, depression, and torticollis was found to have lymphosarcoma with lymphoblastic leukemia. The multiple visceral involvement with neoplastic lymphoid cells observed in this animal was similar to previously reprted cases of lymphosarcoma in the rabbit. An unusual finding was the occurrence of lymphoblastic leukemia since lymphosarcoma in the rabbit has previously been reported as aleukemic.     

Increased interleukin-10 mRNA expression in tumor-bearing or persistently lymphocytotic animals infected with bovine leukemia virus.

Interleukin-10 (IL-10), produced by Th2 helper T cells, B cells, and macrophages, can inhibit cytokine production by Th1 cells and enhance B-cell proliferation and differentiation. Here, we show that peripheral blood mononuclear cells (PBMCs) from bovine leukemia virus-infected animals with late-stage disease express considerably more IL-10 mRNA than animals that are not infected or that are in the early stages of disease. In contrast, the quantities of type 1 cytokines, IL-2 and gamma interferon, decrease with disease progression. In addition, we observed that IL-10 is expressed principally by monocytes/macrophages, not B lymphocytes, in persistently lymphocytotic animals. This observation supports a role for monocytes/macrophages in progression of bovine leukemia virus infection and, of importance, indicates that proliferating B cells are not the source of IL-10 expression. These findings suggest that IL-10 produced by monocytes/macrophages may influence the progression of bovine leukosis in animals that develop persistent lymphocytosis of B cells or B-cell lymphosarcoma.     

New perspectives on hereditary influences in metastatic progression

Metastasis, the process by which cancer cells spread to distant sites and form secondary tumors, depends upon the ability of cells to escape the primary tumor, and colonize and proliferate in a novel microenvironment. Many mechanisms have been proposed to explain this phenomenon although no theory has comprehensively explained all biological observations. There is growing evidence that host hereditary factors modulate the ability of tumor cells to form metastatic lesions, and host genetic polymorphism could be a significant variable in this process. This review is intended to illustrate the role of hereditary variation in metastatic progression, how this integrates with currently proposed metastatic mechanisms, and the potential clinical impact on this frequently fatal consequence of cancer.     

CAR T cells transform to trucks: chimeric antigen receptor–redirected T cells engineered to deliver inducible IL-12 modulate the tumour stroma to combat cancer

Adoptive T cell therapy recently achieved impressive efficacy in early-phase clinical trials; this significantly raises the profile of immunotherapy in the fight against cancer. A broad variety of tumour cells can specifically be targeted by patients' T cells, which are redirected in an antibody-defined, major histocompatibility complex-unrestricted fashion by endowing them with a chimeric antigen receptor (CAR). Despite promising results for some haematologic malignancies, the stroma of large, established tumours, the broad plethora of infiltrating repressor cells, and cancer cell variants that had lost the target antigen limit their therapeutic efficacy in the long term. This article reviews a newly described strategy for overcoming some of these shortcomings by engineering CAR T cells with inducible or constitutive release of IL-12. Once redirected, these T cells are activated, and released IL-12 accumulates in the tumour lesion where it promotes tumour destruction by at least two mechanisms: (1) induction of an innate immune cell response towards those cancer cells which are invisible to redirected T cells and (2) triggering programmatic changes in immune-suppressive cells. Given the enormous complexity of both tumour progression and immune attack, the upcoming strategies using CAR-redirected T cells for local delivery of immune-modulating payloads exhibited remarkable efficacy in pre-clinical models, suggesting their evaluation in clinical trials.     

Biomarkers in rare neuromuscular diseases

Neuromuscular diseases (NMDs) comprise a range of rare disorders that include both hereditary peripheral neuropathies and myopathies. The heterogeneity and rarity of neuromuscular disorders are challenges for researchers seeking to develop effective diagnosis and treatment strategies. In particular, clinical trials of new therapies are made more difficult due to lack of reliable and monitorable clinical outcome measures. Biomarkers could be a way to speed up research in this field, shedding light on the pathophysiological mechanisms behind such diseases and providing invaluable tools for monitoring their progression, prognosis and response to drug treatment. Furthermore, biomarkers could represent a surrogate endpoint for clinical trials, enabling better stratification of patient cohorts through more accurate diagnosis and prognosis prediction.     

Tumor progression as a factor of variability of diurnal rhythm of phosphorus metabolism in a tumor

In a transplanted lymphosarcoma of rats by means of Cosinor method we discovered rhythm of P32 inclusions with ultradian and circadian periods. In the course of tumor growth changes of spectrum of periods, amplitudes and acrophases of rhythms take place. These shifts are explained by the progression and clonal structure of neoplasms.     

The Relation Between Lymphosarcoma and Leukemia

Of 283 cases of lymphocytic disease, 81% fell within three distinct categories: lymphocytic and lymphoblastic lymphosarcoma and lymphocytic leukemia. The remaining 19% showed transitions from more mature to less mature cell types or from local to general anatomic distribution. The clinical course was related to the cell type and the extent of disease rather than to the presence of blood stream invasion. Survival of patients with lymphocytic leukemia and of those with lymphocytic lymphosarcoma was the same, while that of patients with lymphoblastic lymphosarcoma was much shorter. Survival curves are simple exponentials and do not suggest two populations, one with disease less malignant than the other.     

Intercellular information flow in the process of immunogenesis. VII. The effect of low- and high-polymer immune nuclear RNA on antibody synthesis by the cells of rat transplantable]U

Rats were immunized with sheep red cells. From their spleen tissue 4S and 26S electrophoretically homogenous RNA fractions were extracted. Effects of these RNA fractions on the hemolysin synthesis were studied in cells of rat transplantable lymphosarcoma in the presense of actinomycin D (AD). The time intervals between the introduction if RNA into the lymphosarcoma cells suspension and the addition of AD were different. The duration of the period within which no synthesis of antibodies occurred was determined, this period being termed the AD-dependent period in induction of antibody synthesis. AD being introduced later (after the end of this period) failed to exert its inhibiting action. With highmolecular (26S) RNA, the AD-dependent period was somewhat shorter as compared with the lowmolecular (4S) RNA. This difference is suggested to be due, presumably, to different mechanism of action of both the RNA fractions on recipient cells.     

Genetics of colorectal cancer

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. As such, it assumes a significant role in both health policy decision-making and scientific research. CRC has been a model for investigating the molecular genetics of cancer development and progression; this is in part due to the easily detectable, sequential transition of cells from normal colonic epithelium to adenoma and then to adenocarcinoma. In addition, familial syndromes that predispose to CRC, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), have significantly contributed to our understanding of the genetic mechanisms underlying CRC formation. It is now well recognized that hereditary CRC syndromes are due to germline mutations of genes that function as tumor suppressors or, less frequently, oncogenes. Accumulation of subsequent mutations in other genes with related functions results in the stepwise progression to carcinoma. It is important to note that somatic changes in similar genes are involved in the formation of sporadic CRC. The identification of these important CRC-related genes may help facilitate the early diagnosis, prevention, and treatment of CRC. This article reviews the various familial CRC syndromes along with their genetic etiology, as well as discusses the principle of genetic testing for these conditions.     

Intercellular information transfer in the process of immunogenesis. VI. The induction of antiphage antibody synthesis in the cells of rat transplantable lymphosarcoma under the influence of splenic RNA from rats and mice immunized with phage T2]

It has been proved that nuclear and cytoplasmic RNAs, isolated from spleens of T2 phage immunized rats and mice, can induce T2 phage antibodies in cells of the transplantable rat lymphosarcoma. With the nuclear RNA from rat spleens, the effect is persisting in a number of subsequent cell generations. The data presented are principally in accord with results of the authors' previous studies in which lymphosarcoma cells were treated with RNA extracted from spleens of rat immunized with sheep red cells. These results well compare with the authors' earlier advanced hypothesis suggesting a possible involvement of RNA in deblockation of genes responsible for the synthesis of the antibodies in question.     

Lymphoblastomas in childhood; cutaneous manifestations

The lymphoblastomas occurring in childhood are divided for purposes of discussion into lymphocytoma cutis, mycosis fungoides, lymphosarcoma, Hodgkin's disease, and leukemia. The cutaneous lesions may be either specific (as a result of the infiltration of the skin with specific cells of the conditions) or toxic (non-specific). With the possible exception of mycosis fungoides, the cutaneous manifestations are not diagnostic. The final diagnosis depends upon microscopic examination of the specific tissue involved and the coordination of the clinical and microscopic findings.     

Suspension cultures of human malignant lymphoma in the leukocyte migration test

The effects of supernatants of primary and secondary malignant human lymphoma cell cultures were analyzed as parameters of spontaneous secretion of factors by these cells using the leukocyte migration test (LMT). Spontaneous cultivation for up to five weeks was successful in four cases. The postulated production of mediators, i.e. the inhibitory and stimulating effects on leukocyte migration were characterized by testing the influence of (a) concentration, (b) temperature and (c) absorption with normal blood leukocytes on the effect. Reproducible stimulatory and inhibitory effects on the migration of normal leukocytes were dependent on concentration and temperature and were apparently mediated by one or more factors. The supernatants of a lymphoblastic lymphosarcoma of the T-cell type and of a lymphoblastic lymphosarcoma clearly revealed congruous and reproducible inhibitory effects. A further case of lymphoblastic lymphosarcoma that could not exactly be defined with immunological methods either and a case of centroblastic/centrocytic lymphosarcoma exhibited stimulating effects which could be reduced in a time-dependent manner through preincubation with blood leukocytes. The results of these studies support the assumption that malignant lymphoma cells are capable not only of secreting immunoglobulin, but also of other biologically effective secretion. The effects of such secretion are differentiated into stimulating and inhibitory ones. They might be important for the spreading of a tumor or for resistance of the organism to the disease.     

Cells containing Epstein--Barr nuclear antigen (EBNA) in peripheral blood.

The anti-complement immunofluorescence (ACIF) method was used to demonstrate EBNA in B lymphocytes separated from the peripheral blood of patients with infectious mononucleosis (IM) or other diseases. In the acute phase of IM of Epstein-Barr virus (EBV) origin, 0.5--1% of the B lymphocytes proved to be positive in 6 of the 8 patients tested. In two of the positive cases the test was repeated 20 and 26 days, respectively, after clinical symptoms had appeared; the result was negative in both cases. No EBNA-positive cells were found in the peripheral blood of 17 patients with Hodgkin disease, 3 with systemic lupus erythematosus and 2 with lymphosarcoma. It is supposed that EBNA-positive cells appear in detectable amount exclusively in the acute phase of EBV infection.     

Anti-tumor effects of allogeneic bone marrow transplantation in (NZB X NZW)F1 hybrids with spontaneous lymphosarcoma

Untreated female (NZB X NZW)F1 hybrid mice (B/W F1) were found to develop lymphosarcoma spontaneously as they aged. Tumor incidence was evaluated in B/W F1 mice immunosuppressed with total lymphoid irradiation (TLI) and in TLI-conditioned B/W F1 mice reconstituted with 3 X 10(7) BALB/c bone marrow (BM) cells. BALB/C leads to B/W F1 chimerism (79 to 89% BALB/c-type cells) was confirmed by typing peripheral blood lymphocytes with specific alloantisera and complement by using a microcytotoxicity assay. Chimeras showed no clinical signs of graft-vs-host disease (GVHD). TLI-treated mice seemed to show a slightly accelerated onset of lymphosarcoma as compared with untreated controls, but the difference was not significant (p = 0.08). BALB/c leads to B/W F1 chimeras reconstituted at 1 to 3 mo of age (25 mice) developed no tumors for an observation period of 18 mo after transplantation. In contrast, tumors developed in 24/130 of age-matched controls, and in 13/57 of TLI-treated nonreconstituted age-matched B/W F1 mice. Tumor incidence in BALB/c leads to B/W F1 chimeras transplanted at an older age (9 to 11 mo) was similar to that observed in age-matched TLI-treated B/W F1 mice and age-matched untreated controls. The data suggests that the high naturally occurring incidence of lymphosarcoma could be reversed by reconstituting TLI-treated mice with BM cells (p = 0.027). Thus, allogeneic BM transplantation may exert potent graft-vs-tumor effects (GVT) when tumor susceptible hosts are reconstituted at an early age, whereas GVT is relatively ineffective at an advanced age, which probably correlates with an advanced stage of tumor development. Allogeneic BM transplantation should be additionally explored as a potential clinical tool for eradication of certain solid tumors in adjunct to high-dose radiochemotherapy, inasmuch as GVT seems to be independent of GVHD.     

The effects of radiation and alkylating agents on chromatin degradation in normal and tumour lymphoid cells.

The dynamic of chromatin degradation was studied in thymocytes and LS/BL tumour cells. In permeabilised LS/BL cells, the rate of DNA degradation induced by endogenous calcium and magnesium-dependent endonuclease was approx. 25 times slower than in thymocytes. In LS/BL cells irradiation does not induce chromatin degradation. The alkylating agent TS 160 induced chromatin degradation in both LS/BL lymphosarcoma cells and thymocytes.     

LYMPHOBLASTOMAS IN CHILDHOOD—Cutaneous Manifestations

The lymphoblastomas occurring in childhood are divided for purposes of discussion into lymphocytoma cutis, mycosis fungoides, lymphosarcoma, Hodgkin''s disease, and leukemia. The cutaneous lesions may be either specific (as a result of the infiltration of the skin with specific cells of the conditions) or toxic (non-specific). With the possible exception of mycosis fungoides, the cutaneous manifestations are not diagnostic. The final diagnosis depends upon microscopic examination of the specific tissue involved and the coordination of the clinical and microscopic findings.     

Marker chromosome 14q+ in two non-Burkitt lymphomas.

Marker chromosome 14q+, similar to the specific marker of the Burkitt lymphoma, was revealed in all malignant blood cells of a patient with generalized lymphosarcoma, in all lymph node cells, and in a part of the blood cells of a patient with chronic lymphocytic leukaemia. Possible causes of this similarity are discussed.     

Mutation in HSF4 associated with early but not late-onset hereditary cataract in the Boston Terrier

Primary hereditary cataract (HC) is one of the most common disorders in purebred dogs and is a leading cause of blindness. Boston Terriers suffer from 2 distinct forms of HC which occur at different ages and which are different in their appearance and progression. Early-onset hereditary cataract (EHC) affects dogs within the first few months of life, is always progressive and bilateral, and results in total blindness, whereas late-onset hereditary cataract (LHC) in general affects dogs over the age of 3 and is more variable in its clinical phenotype, age of onset, progression, and the degree to which vision is impaired. A mutation in HSF4 has recently been reported in a small number of Boston Terriers affected with EHC. In this study, we analyzed 22 additional Boston Terriers affected with early-onset cataract to confirm that the HSF4 mutation is causative for this form of cataract in this breed. In addition, we analyzed 40 Boston Terriers that were either clinically clear or affected with LHC for the presence or absence of the HSF4 mutation. By also sequencing HSF4 in dogs affected with LHC, we conclude that HSF4 is not associated with the development of the late-onset form of cataract and that the 2 forms of cataract in this breed are therefore genetically discrete conditions.