c-Fos regulated by TMPO/ERK axis promotes 5-FU resistance via inducing NANOG transcription in colon cancer.

Acquired drug resistance is one of the most common limitations for the clinical response of colon cancer to 5-Fluorouracil (5-FU)-based chemotherapy. The relevant molecular mechanisms might be diversity, but still not be elucidated clearly. In this study, we aimed to investigate the potential mechanisms of c-Fos, a subfamily of activator protein-1, in 5-FU chemoresistance. We determined that phosphorylated c-Fos promoted colon cancer cells resistance to 5-FU by facilitating the cancer stemness. Mechanically, 5-FU treatment induced autolysosome-dependent degradation of TMPO, which subsequently triggered ERK-mediated phosphorylation of c-Fos. Additionally, c-Fos was found to bind to the promoter of NANOG and phosphorylation of c-Fos at Ser 374 was required for its regulation of NANOG expression. NANOG ablation impaired c-Fos/p-c-Fos induced 5-FU resistance and stemness. Taken together, these findings revealed that TMPO-mediated phosphorylation of c-Fos conferred 5-FU resistance by regulating NANOG expression and promoting cell stemness in colon cancer cells. c-Fos could be as a therapeutic target for colon cancer.

Thymus hormones as prospective anti-inflammatory agents.

IMPORTANCE OF THE FIELD: Inflammatory diseases are characterized by severe immune imbalances, leading to excessive or inappropriate release of mediators, which, in turn, result in massive damage to organs and systems. Effective means to control inappropriate immune reactions are often life-critical needs. Available data on the role of thymus-derived hormones in inflammation show their great potential. AREAS COVERED IN THIS REVIEW: The review aims to systematize information for the last two decades on immune system regulation by thymic peptide hormones, with a primary focus on the role of these hormones in the systemic inflammatory response and inflammatory diseases. Anti-inflammatory potential of three thymic hormones - thymulin, thymosin-alpha, and thymopoietin - is discussed, reviewing recently published clinical and experimental studies. WHAT THE READER WILL GAIN: Our analysis revealed the regulation of inflammatory processes via thymic hormones that could be prospective for therapeutic application. This regulation may be mediated through thymic hormone effects on peripheral immune cell activities and bidirectional coupling between thymic hormones and the hypothalamic-pituitary-adrenal axis. TAKE-HOME MESSAGE: In view of the role of thymic hormones in immune and neuroendocrine systems, they could be suitable as therapeutic agents for inflammation.

TP-3 immunotoxins improve antitumor activity in mice with osteosarcoma.

We measured the antitumor activity of two types of TP-3 immunotoxins that target an antigen expressed in tumors associated with osteosarcoma. Development of novel agents for treatment of patients with osteosarcoma is important. We previously described a monovalent-disulfide-stabilized recombinant immunotoxin made from the TP-3 antibody. This agent is called TP-3(dsFv)-PE38 and is cytotoxic to human osteosarcoma cells in vitro. To improve antigen binding, we designed and produced a bivalent immunotoxin, TP-3(dsFv)2-PE38. We evaluated the activity of both molecules in vitro and in vivo using tumor-bearing mice. Compared with the monovalent TP-3 immunotoxin, the bivalent TP-3 immunotoxin showed an approximately sevenfold increase in cytotoxic activity against three osteosarcoma cell lines which react with the TP-3 monoclonal antibody. The apparent affinity of the bivalent TP-3 immunotoxin was 12-fold greater than that of the monovalent TP-3 immunotoxin. The antitumor activities of both TP-3 immunotoxins were measured using severe combined immunodeficient mice bearing osteosarcoma cell line OHS-M1 tumors. The dose at which the bivalent TP-3 immunotoxin produces complete regressions of tumors is (1/2) that of the monovalent TP-3 immunotoxin. Increasing the avidity of TP-3(dsFv)-PE38 significantly improves its cytotoxic activity in vitro and results in a twofold increase in antitumor activity in vivo. Because TP-3-based immunotoxins have good antitumor activity in mice, these molecules merit additional development for possible treatment of osteosarcoma in humans.

Antitumor activity of TP3(anti-p80)-pokeweed antiviral protein immunotoxin in hamster cheek pouch and severe combined immunodeficient mouse xenograft models of human osteosarcoma.

TP3-pokeweed antiviral protein (PAP) immunotoxin is directed against the p80 antigen on osteosarcoma cells. Previous studies have demonstrated that TP3-PAP kills clonogenic human osteosarcoma cells in vitro and shows significant antitumor activity in a murine soft tissue sarcoma model (P. M. Anderson, et al, Cancer Res., 55: 1321-1327, 1995.) In this study, we demonstrate that TP3-PAP elicits potent in vivo antitumor activity in a hamster cheek pouch model of human osteosarcoma. Furthermore, treatment with TP3-PAP at nontoxic dose levels significantly delayed the emergence and progression of leg tumors and markedly improved tumor-free survival in severe combined immunodeficient mice challenged with OHS human osteosarcoma cells. Thus, TP3-PAP may be useful in the treatment of poor risk osteosarcoma.

Thymopentin and splenopentin as immunomodulators. Current status.

Splenopentin (SP-5, Arg-Lys-Glu-Val-Tyr) and thymopentin (TP-5, Arg-Lys-Asp-Val-Tyr) are synthetic immunomodulating peptides corresponding to the region 32-34 of a splenic product called splenin (SP) and the thymic hormone thymopoietin (TP), respectively. TP was originally isolated as a 5-kDa (49-amino acids) protein from bovine thymus while studying effects of the thymic extracts on neuromuscular transmission and was subsequently observed to affect T cell differentiation and function. TP I and II are two closely related polypeptides isolated from bovine thymus. A radioimmunoassay for TP revealed a crossreaction with a product found in spleen and lymph node. This product, named splenin, differs from TP only in position 34, aspartic acid for bovine TP and glutamic acid for bovine splenin and it was called TP III as well. Synthetic pentapeptides (TP-5) and (SP-5), reproduce the biological activities of TP and SP, respectively. It is now evident that various forms of TPs were created by proteolytic cleavage of larger proteins during isolation. cDNA clones have been isolated for three alternatively spliced mRNAs that encodes three distinct human T cell TPs. The immunomodulatory properties of TP, SP, TP-5, SP-5 and some of their synthetic analogs reported in the literature have been briefly reviewed.

[The immune response to brain contusion with hematoma-induced compression]. / Immunnyi otvet na ushib mozga s sdavleniem gematomoi.

Non-specific immune responses, cell-mediated immunity, and humoral immunity were analyzed in 35 patients with acute subdural hematomas vs. 55 healthy controls. The importance of prophylactic immunomodulation in prevention of infections and other clinically significant long-term complications after head trauma was demonstrated.

[The efficacy of immunomodulating therapy in patients with chronic cholestatic liver diseases]. / Effektivnost' immunomoduliruiushchei terapii bol'nykh s khronicheskimi kholestaticheskimi zabolevaniiami pecheni.

The use is studied of the immunomodulating agents splenin and vilosen in a combined therapy of 93 patients with chronic cholestatic disorders of the liver. The above drug combination was found to have a positive effect on both the immune status and condition of microhemodynamics, with the clinical parameters getting improved, duration of remission lengthened.

[Incidence of SLE in a patient thymectomized for myasthenia gravis]. / SLE fellépése myasthenia gravis miatt thymectomizált betegen.

The appearance of systemic lupus erythematosus (SLE) as well as thymopoietin (TP3) treatment in a patient who has undergone thymectomy because of myasthenia gravis (MG) is described. To the authors' knowledge this is the first case of this treatment upon the diagnoses above. The therapy was performed for 12 weeks by the Hungarian Thymotrinan (TP3) preparate according to a previous protocol worked out for Hodgkin's disease. At the beginning and during therapy, cellular and humoral immune parameters were monitored. Twenty months after the therapy the patient has remained in clinical remission for both diseases, MG and SLE, respectively. There is a brief survey of the biochemistry of thymic hormones as well as their clinical use, especially in the treatment of autoimmune disorders. The relative rarity of SLE after operative treatment of MG is under discussion together with the effectiveness of substitutional thymic hormone therapy.

[The immunomodulating effect of vilozen and splenin in the treatment of patients with acute and chronic toxic-allergic hepatitis]. / Immunomoduliruiushchii èffekt vilozena i splenina pri lechenii bol'nykh ostrym i khronicheskim toksiko-allergicheskim gepatitom.

65 patients with acute hepatitis and 116 patients with chronic hepatitis of toxico-allergic nature were examined. 20 patients with acute hepatitis and 40 patients with chronic form of the disease were prescribed in addition to conventional treatment 2-4 ml i.m. of splenin daily, 20 mg of vilosen daily in 3-4 divided doses in the form of 1% solution intranasally and the same quantity--sublingually. The drugs were administered for 10-15 days. Co-administration of splenin and vilosen was established to hasten normalization of clinical indices and immune homeostasis restitution thus advocating the use of the drugs as a part of therapeutic complex in the treatment of acute and chronic toxico-allergic hepatitis.

[The immunomodulating action of vilozen and splenin in angina patients against a background of chronic bronchitis]. / Immunomoduliruiushchee deistvie vilozena i splenina u bol'nykh anginoi, protekaiushchei na fone khronicheskogo bronkhita.

Immunological indices were compared in 138 patients with angina and concomitant bronchitis; 86 of them received antibiotics, splenin and vylosen; 52 received routine treatment. It was established that use of a combination of splenin and vylosen produces a pronounced immunodulating effect in primary immunodeficiency states due to recurrences of angina and concomitant pathology of the bronchopulmonary in workers of a large industrial enterprise. Immunomodulators are indicated in the treatment of repeat and relapsing angina, especially in the presence of concomitant bronchitis.

[Effect of pretreatment with immunomodulating agents on the outcome of lymphocytic choriomeningitis virus infection in athymic (nude) and euthymic mice]. / Lymphocytas choriomeningitis (LCM) vírusfertözés lefolyása immunmodulánsokkal elökezelt genetikailag thymus-hiányos (nude) és normál immunrendszerü egerekben.

Balb/c (euthymic) and nu/nu (athymic) mice were treated intraperitoneally with TP-4 (a synthetic tetrapeptide, thymopoietin sequence analog, Pharmaceutical Product's Factory Gedeon Richter, Budapest, Hungary) or with Mannozym (0.1% zymosan suspension, Institute for Serobacterological Production and Research, HUMAN, Budapest, Hungary), and were infected intracerebrally with LCM virus. Both of the agents contributed to the development of fatal choriomeningitis, consequently they stimulated the cellular immune response in euthymic mice, but the athymic mice, either treated or not, survived the infection, consequently the agents had no effect on the course of LCM virus infection. The results showed that the cellular immune response stimulating effect by both agents was thymus-dependent. Using these agents immunostimulatory effect can be realized only in the presence of the thymus or the T-dependent lymphoid system, respectively.

[The tocopherol acetate and splenin correction of the immunological disorders in patients with viral hepatitis B]. / Korrektsiia tokoferola atsetatom i spleninom immunologicheskikh narushenii u bol'nykh virusnym gepatitom B.

Inclusion of tocopherol acetate and splenin into complex treatment of viral hepatitis B (VHB) ensures a marked immunomodulating effect consisting in control of T-lymphopenia, normalization of helper-suppressor ratio, reduction of circulating immune complexes and a tendency to restoration of normal ratio between separate fractions of immune complexes, stimulation of phagocytic activity of monocytes of the peripheral blood. Splenin and tocopherol acetate are recommended in the complex treatment of hepatitis B.

Effects of the immunomodulator diacetyl-splenopentin on antigen-induced arthritis in rabbits.

Long-term treatment with the immunomodulator diacetyl-splenopentin reduces the severity of chronic joint inflammation and cartilage destruction in rabbits with antigen-induced arthritis. The level of specific antibodies as well as specific and non-specific cell-mediated immune reactivities including the proliferative response of spleen lymphocytes to cartilage proteoglycans in treated animals are lower than in untreated arthritic rabbits. Moreover, suppressor cell activity, which normally decreases during the early phase of inflammation, is enhanced and hyperreactive helper cell potential is reduced. These findings suggest that treatment with diacetyl-splenopentin normalizes the immune regulation, which is disturbed in the early phase of inflammation. This might result in a depression of the hyperreactive immune system including the autoimmunity developed against cartilage. Lowered immune reactivity in the joint in turn reduces the severity of chronic joint inflammation.

[Long-term results of therapy of primary hypothyroidism in relation to immune status]. / Otdalennye rezultaty terapii pervichnogo gipotireoza v zavisimosti ot immunnogo statusa.

Disorders in the immune status of patients with hypothyroidism (idiopathic and postoperative) produce a negative effect on a course of disease. Periods of decompensation (exacerbation) develop in such patients more frequently than in patients suffering from hypothyroidism with the normally or moderately changed immune status.

[Splenopentin--modulator of immunological and behavioral reactions in secondary immunodeficiency state induced by experimental alcoholism]. / Splenopentin--moduliator immunnykh i povedencheskikh reaktsii pri vtorichnom immunodefitsitnom sostoianii, vyzvannom éksperimental'nym alkogolizmom.

Effect of splenopentin on some patterns of immunity was studied in mice with chronic alcoholic intoxication. Splenopentin was administrated into animals once intraperitoneally (250 micrograms/kg). Administration of splenopentin was found to normalize several immunological patterns in animals with chronic alcoholic intoxication: the immune response to the thymus-dependent antigen sheep red blood cells and phagocytic activity of peritoneal macrophages. Also observations over C57B1/6 mice characterized by high level of alcoholic motivation showed that alcohol consumption in mice decreased after administration of splenopentin at a dose of 250 micrograms/kg during two weeks.

[The treatment of protracted forms of Flexner dysentery]. / Lechenie zatiazhnykh form dizenterii Fleksnera.

The clinical efficacy of sodium nucleinate (SN) combined with splenin and quercetin given for lingering Flexner's dysentery in a group of 43 patients was compared with that of routine therapy used in a group of the same number of patients. It has been established that the above drug combination favours the elimination of the pathological symptoms of dyspepsia, the arrest of bacterial isolation and normalization of the immune status. Provided the effect of the combined drug treatment is insufficient, the method of choice is the administration of gene engineering alpha 2-interferon (reaferon) in combination with tocopherol acetate and rectal suppositories containing methyluracil.

[Immunoactive drugs in the combined modality therapy of patients with hypothyroidism]. / Immunoaktivnye preparaty v kompleksnom lechenii bol'nykh gipotireozom.

Comparative studies into the clinico-immunologic status of patient with primary hypothyrosis have shown that the multimodality treatment including differentiated administration of immunoactive agents (glucocorticoids, splenin) promoted more well-defined normalization of cellular, humoral immunity and nonspecific defence as well as reduction or disappearance of the clinical disease manifestations as compared to patients who did not receive those drugs as part of the multimodality therapy. The use of glucocorticoids and splenin may be recommended as part of the multimodality treatment of patients suffering from primary hypothyrosis marked by pronounced disorders in the immune system.