Implication of the β2-microglobulin gene in the generation of tumor escape phenotypes

Classical MHC molecules present processed peptides from endogenous protein antigens on the cell surface, which allows CD8(+) cytotoxic T lymphocytes (CTLs) to recognize and respond to the abnormal antigen repertoire of hazardous cells, including tumor cells. The light chain, β2-microglobulin (β2m), is an essential constant component of all trimeric MHC class I molecules. There is convincing evidence that β2m deficiency generates immune escape phenotypes in different tumor entities, with an exceptionally high frequency in colorectal carcinoma (CRC) and melanoma. Damage of a single β2m gene by LOH on chromosome 15 may be sufficient to generate a tumor cell precommitted to escape. In addition, this genetic lesion is followed in some tumors by a mutation of the second gene (point mutation or insertion/deletion), which produces a tumor cell unable to express any HLA class I molecule. The pattern of mutations found in microsatellite unstable colorectal carcinoma (MSI-H CRC) and melanoma showed a striking similarity, namely the predominance of frameshift mutations in repetitive CT elements. This review emphasizes common but also distinct molecular mechanisms of β2m loss in both tumor types. It also summarizes recent studies that point to an acquired β2m deficiency in response to cancer immunotherapy, a barrier to successful vaccination or adoptive cellular therapy.     

Characterisation of disseminated tumor cells in the bone marrow of breast cancer patients by the Thomsen–Friedenreich tumor antigen

The detection of disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients has proved prognostic significance in all stages of the disease. Further characterisation of those cells could help to improve the biological understanding of metastases, develop targeted therapies and define surface markers for enrichment techniques. The Thomsen–Friedenreich (TF) antigen has been shown to be a tumor specific antigen in breast cancer. The aim of this study was to investigate the expression of TF on DTC-BM in 25 patients. Bone marrow samples were first double-stained by a Cy3 conjugated cytokeratin (CK) antibody (ab) A45 B/B3 (IgG) and anti-TF ab Nemod 2 (IgM), followed by Cy2 conjugated goat anti-mouse IgM ab. For further characterisation samples were also double-stained with anti-TF ab Nemod 2 (IgM), followed by Cy2 conjugated goat anti-mouse IgM ab, and anti MUC1 ab A76-A/C7 IgG, followed by Cy3 conjugated goat anti-mouse IgG. CK positive DTC-BM showed co-expression of TF antigen in 22/23 patients (96%) and 61 of 62 detected cells (98%). Mononuclear BM cells without CK expression were also negative for TF. All of the TF positive cells showed strong MUC1 expression. This is the first study showing co-expression of CK and TF as markers of DTC-BM. Double staining experiments of TF and MUC1 expression showed that MUC1 is the carrier protein of TF in these cells. As TF is a specific marker of DTC-BM, it could be used as a target for antibody based therapy and immunomagnetic enrichment techniques for the isolation of DTC-BM.     

Role of the ubiquitin–proteasome system on macrophages in the tumor microenvironment

Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment, and their different polarization states play multiple roles in tumors by secreting cytokines, chemokines, and so on, which are closely related to tumor development. In addition, the enrichment of TAMs is often associated with poor prognosis of tumors. Thus, targeting TAMs is a potential tumor treatment strategy, in which therapeutic approaches such as reducing TAMs numbers, remodeling TAMs phenotypes, and altering their functions are being extensively investigated. Meanwhile, the ubiquitin–proteasome system (UPS), an important mechanism of protein hydrolysis in eukaryotic cells, participates in cellular processes by regulating the activity and stability of key proteins. Interestingly, UPS plays a dual role in the process of tumor development, and its role in TAMs deserve to be investigated in depth. This review builds on this foundation to further explore the multiple roles of UPS on TAMs and identifies a promising approach to treat tumors by targeting TAMs with UPS.     

The real face of HIF1α in the tumor process

It is well known that the hypoxia-inducible factor 1 α (HIF1α) is detectable as adaptive metabolic response to hypoxia. However, HIF1/HIF1α is detectable even under normoxic conditions, if the metabolism is altered, e.g., high proliferation index. Importantly, both hypoxic metabolism and the Warburg effect have in common a decrease of the intracellular pH value.

In our interpretation, HIF1α is not directly accumulated by hypoxia, but by a process which occurs always under hypoxic conditions, a decrease of the intracellular pH value because of metabolic imbalances. We assume that HIF1α is a sensitive controller of the intracellular pH value independently of the oxygen concentration. Moreover, HIF1α has its major role in activating genes to eliminate toxic metabolic waste products (e.g., NH₃/NH₄+) generated by the tumor-specific metabolism called glutaminolysis, which occur during hypoxia, or the Warburg effect. For that reason, HIF1α appears as a potential target for tumor therapy to disturb the pH balance and to inhibit the elimination of toxic metabolic waste products in the tumor cells.     

Changes in the content of ascorbic acid in the crown-gall tumor tissue ofNicotiana tabacum under the influence of Co60γ-rays

Jednorázové ozá?ení γ-paprsky Co⁶⁰ zp?sobuje u izolovaného nádorového pletiva tabáku (Nicotiana tabacum) in vitro pr?kazné zvý?ení obsahu kyseliny askorbové. Zdá se, ?e toto zvý?ení je trvalého charakteru, nebot se udr?uje po dobu jednoho roku. P?idání extraktu v?elí ka?i?ky k ?ivnému mediu zvy?uje rezistenei pletiva k ozá?ení γ-paprsky a sou?asně u pletiva je?tě více zvy?uje obsah kyseliny askorbové.     

Studies of the mechanisms of toxicity of the administration of recombinant tumor necrosis factor α in normal and tumor-bearing mice

Summary Tumor-bearing mice have a greater sensitivity to the acute lethal effects of the administration of high-dose recombinant human tumor necrosis factor (rhTNF-) compared to normal, non-tumor-bearing mice. We studied whether or not the presence of tumor per se was responsible for the enhanced rhTNF- toxicity. Tumor-bearing mice underwent tumor excision or sham operation before the systemic administration of rhTNF at staged times (0.5–24 h) following surgery. There was little survival difference between sham-operated tumor-bearing mice and tumor-bearing mice undergoing tumor excision (at 24 h, treatment with 12 µg rhTNF-, survival:sham-operated tumor bearers = 0/12, excised tumor-bearers = 0/12;P ² <0.01 compared to non-tumor-bearers). Mice without tumors receiving sham operation, had minimal toxicity (10 of 12 mice surviving). The injection of 3 ml Ringer's lactate i.p. before i.v. rhTNF- therapy increased survival in tumor-bearing animals; following pretreatment with Ringer's lactate 30/42 mice survived 12 µg rhTNF- compared to 6/42 surviving a similar rhTNF- dose without hydration (P ² <0.001). Since the production of oxygen free-radical metabolites has been postulated to play a role in the acute toxicity of rhTNF-, bismuth subnitrate was used to induce the enzyme metallothionein to act as a natural scavenger for these metabolites. Daily oral bismuth subnitrate treatments improved survival of mice with MCA-106 or MCA-102 sarcoma and of mice without tumors, with higher rhTNF- doses (12–20 µg), without reducing the therapeutic effect of rhTNF- against the weakly immunogenic MCA-106 sarcoma. These studies suggest methods for reducing the toxicity of rhTNF- administration in clinical trials.     

Genetics of esterases in Drosophila. V. Characteristics of the “pupal” esterase in D. virilis

From analysis of the properties of the pupal esterase (p-esterase) in Drosophila virilis, it is concluded that it is heat stable, its electrophoretic detection depends on culture density, its expression is stage specific, and it is not a variant of esterase 2. It was also demonstrated that p-esterase, like esterase 6, is activated by injections of the juvenile hormone into larvae. Heat treatment of heat-resistant D. virilis stocks led to decreased activities of the juvenile hormone dependent esterases but did not affect those of the heat-sensitive stocks. It is suggested that heat resistance in D. virilis is related to some functional features of the system of modifier genes controlling the phenotypic expression of esterases.     

The therapeutic potential of interleukin-1β in the treatment of chemotherapy or radiation-induced myelosuppression and in tumor therapy

In vivo administration of rHuIL-l selectively enhanced the recovery from granulocytopenia and thrombocytopenia caused by sublethal irradiation or 5-FU treatment. Granulopoiesis and thrombopoiesis were stimulated by rHuIL-l in a dose-dependent manner at doses ranging from 0.1 to 100 g/kg. In this study, we have observed IL-1 to induce at least two distinct types of hematopoietic growth factorsin vivo, namely GM-CSF and a thrombopoiessn-like factor. Various kinds of CSFs alone did not stimulate colony formation of primitive hematopoietic progenitor cells obtained from 5-FU treated mice. However, the pretreatment of primitive hematopoietic progenitor cells with IL-1in vitro orin vivo for 5 days accelerated the recovery of a cell population which respond to several types of CSFs. These data suggest that IL-1 may be useful clinically to enhance the recovery of granulocytes and platelets in myelosuppressed patients. In addition, we observed that rHuIL-1 is directly cytostatic for certain tumor cellsin vitro. Intratumoral or subcutaneous injection of rHuIL-l caused regression of a subcutaneous murine sarcoma by augmenting host antitumor responses. Together with the profound effects on hematopoiesis, these results point to potentially important uses of IL-l in treatment of disease.     

Studies on the metabolism of steroids in the foetus. Biosynthesis of 6α-hydroxytestosterone in the human foetal liver

After incubation of testosterone with 105000g microsomes of human foetal liver, 6alpha-hydroxytestosterone was isolated and identified by t.l.c. and g.l.c.-mass spectrometry. This is the first example of 6alpha-hydroxylation of C(19) steroids in the human liver, and the finding is discussed in relation to earlier reports of 6-oxygenated C(19) and C(18) steroids in pregnant women.     

14. Are the impacts of events in the earth's history discernable in the current distributions of freshwater algae?

Freshwater microalgae, lacking a fossil record, have contributed little to the study of historical biogeography. Some of the innate difficulties are discussed, as well as some of the more hopeful possibilities, if distribution records, morphology and DNA sequence analysis are combined with knowledge of the earth's history. Examples of species within the same family showing quite different distributions are given, along with suggested explanations. These include possible examples of the role played by waterfowl in dissemination of freshwater algae.     

Plasma membrane heterogeneity in ascites tumor cells. Isolation of a light and a heavy membrane fraction of the glycogen-free Ehrlich-Lettré substrain

In this work we report on the isolation of two plasma membrane fractions of a glycogen-free substrain of Ehrlich-Lettré ascites cells, a light fraction sedimenting in a sucrose gradient at 1.10 g/ml, and a heavy fraction sedimenting at nuclei by a combination of short-term swelling and mild Dounce homogenization. A 12 000 X g postnuclear pellet (PII) containing major portions of the plasma membrane marker enymes, 5'-nucleotidase, ouabain-sensitive (Na+ + K+)-ATPase and the alkaline phosphatase, was prepared by differential centrifugation. The two plasma membrane fractions were obtained by centrifugation on a discontinuous sucrose gradient, from which they were further purified on a linear sucrose gradient applying sedimentation velocity conditions only. Enrichment factors for the three marker enzymes were between 5- and 14-fold for the light fraction and between 3- and 7-fold for the heavy fraction with an overall yield of 1--4% and 0.5--1.7%, respectively, of cellular protein. Contamination of both fractions with nuclear material was minor. Mitochondrial contamination was about 8% for the light material and somewhat higher for the heavy material. In the light fraction, co-sedimentation of lysosomal and Golgi marker enzymes was detected. The presence of membrane structures of these organelles could not be confirmed definitely by electron microscopy. Differences in sialic acid content and phospholipid composition within the two fractions, especially in the relative proportion of lecithin to sphingomyelin, suggests differences in membrane fluidity. The light material showed mostly unit membrane vesicles in thin-section and freeze-etch electron microscopy, whereas the heavy fraction mainly consisted of sheet-like membrane fragments.     

Innatism in the Anthropology of A. L. Kroeber: A Critique of ‘the Boasian Paradigm’

Basing his analysis on Kroeber's ‘The superorganic’ (1917 Kroeber, A. L. 1917. The superorganic.. American Anthropologist, 19: 163–213. [Crossref] [Google Scholar]) and ‘Eighteen professions’ (1915 Kroeber, A. L. 1915. Eighteen professions.. American Anthropologist, 17: 283–88. [Crossref] [Google Scholar]), Derek Freeman has put forward the notion of a ‘Boasian paradigm’, whereby Kroeber is alleged to have perpetuated the biology/culture split suggested by Boas. I argue, instead, that there is a strong innatist element in Kroeber's writings throughout his long career; and that the articles noted above need to be placed in the social and intellectual contexts of their time, particularly the encroachment of the eugenics movement on social theory and its application to immigration restriction.     

Characteristics of β-galactosidase in the mucosa of the small intestine of infant rats. Physicochemical properties

1. The characteristics of acid and neutral beta-galactosidases isolated chromatographically from homogenates of the mucosa of the jejunum and ileum of suckling rats were studied. 2. The minimal molecular weight of the acid beta-galactosidase, as estimated by gel filtration on Sephadex G-200, was in the range 83000-105000, whereas for the neutral beta-galactosidase the estimated molecular weight was in the range 360000-510000. 3. The acid and neutral beta-galactosidases were inhibited competitively by galactono-(1-->4)-lactone, with respective K(i) values of 0.15mm and 1.1mm. Only the acid beta-galactosidase was inhibited competitively by sodium galactonate (K(i) 0.17mm). 4. Heat inactivation of both beta-galactosidases occurred according to first-order kinetics. The neutral enzyme was more labile, but bovine serum albumin protected acid enzyme only. 5. Urea treatment inactivated both beta-galactosidases, the neutral beta-galactosidase being more sensitive than the acid beta-galactosidase. 6. No differences were found between preparations from the jejunum and ileum.     

Calcium-Binding Proteins in the Turtle Thalamus. Analysis in the Light of Hypothesis of the “Core-Matrix” Thalamic Organization in Relation to the Problem of Homology of Thalamic Nuclei among Amniotes

Distribution of immunoreactivity (IR) to Ca-binding proteins (CaBPr) (calbindin, Calb, parvalbumin, Parv., and calretinin, Calr) was studied in the thalamus of the Central Asian terrestrial turtles (Testudo horsfieldi) and fresh water turtles (Emys orbicularis). There has been established a wide spread of these proteins, which combines overlapping and a relative alternation of distribution of different CaBPr in individual nuclei. A comparison of IR was made in two relay nuclei of the visual system, GLd and Rot. Both nuclei had IR to all CaBPr, but with different degree of intensity. In the terrestrial turtles, the amounts of Calb-, Parv-, and Calr-IR neurons in the cellular plate of the GLd were close. In this plate and in the neuropil part of this nucleus there was observed CaBPr-innervation of various density. Calr-IR neurons in the GLd of the fresh water turtles dominated over Parv- and Calb-IR neurons, whose detection varied significantly. In Rot, a clear predominance of Calb-IR neurons was shown over Parv- and Calr-IR cells by constancy of their detection, the number (1.5–2-fold higher), and intensity of the immune label, as well as the highest density of Calb and Parv innervation. The character of IR in the Rot was similar in the both turtle species. In the auditory and somatic relay thalamic nuclei and in the non-sensory anterior thalamic nuclei (Dma, Dla) there were present neurons and terminals with IR to all CaBPr without any predominance of Parv-IR in the relay nuclei and Calb-IR in the anterior thalamic nuclei. The constant and characteristic feature of Enta in the turtles of both species is a dense population of Parv-IR neurons, whose topography and cellular composition coincide with those of population of GABA-IR neurons in this nucleus. The data obtained have shown that the alternative presence of different CaBPr in the relay sensory and non-sensory thalamic nuclei, which has been established as a characteristic feature of the mammalian thalamus, is not characteristic at all of turtles. It seems that in the course of evolution there occurred a reorganization of distribution of different CaBPr in thalamic nuclei of amniotes due to changes of their functional loading. The reptilian thalamic sensory relay nuclei are likely to be represented mainly by less specific parts comparable with Calb-IR matrix of specific nuclei in the higher amniotes (mammals), while their more specialized (core) Parv-IR regions are formed later in evolution. Therefore, the distribution of Parv- and Calb-IR neurons in the turtle thalamic nuclei cannot be a criterion at evaluation of homology of thalamic nuclei in amniotes, but permits judging about the degree of their specialization.     

Misunderstanding in the classification of diabetes mellitus. What's in a name?

To assess whether physicians, residents, medical students, hospital diagnosis coders, and patients properly use the designations insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) that were established by criteria of the National Diabetes Data Group, we reviewed clinic and hospital records and administered questionnaires. Although essentially all cases of true IDDM were identified as such and most cases of NIDDM not requiring insulin therapy were correctly identified by all groups, patients with NIDDM on insulin therapy were misidentified as having IDDM by 38% of residents in internal medicine clinics and 68% of primary care and surgical subspecialty residents. On a survey, of 22 patients with NIDDM on insulin therapy, 17 (77%) considered themselves to have IDDM. Thus, patients who have NIDDM by the established criteria who are on insulin therapy are commonly mislabeled as having IDDM. We present an approach for dealing with this problem by adapting nomenclature focusing on insulin deficiency and resistance. It would probably also be helpful to separately identify the subset of patients with "insulin-deficient diabetes" who are ketosis-prone. It is important to use immunologic profiling (islet cell antibody testing) and insulin sensitivity or deficiency testing (C-peptide levels).     

Variation in the timing of river entry of Atlantic salmon （Salmo salar L. ） in the Baltic

The timing of river entry in the Atlantic salmon is known to depend on genetic, demographic and environmental factors, but little is known about the relative magnitude of among population and among year variation and covariation in this respect in natural state Atlantic salmon rives. To investigate this, variability in the timing of river entry in three historical Finnish Atlantic salmon populations were analyzed using salmon trap data collected during 1870- 1902. The analyses reveled that 1 ） the timing of river entry differed substantially and consistently among the rivers, and that 2） variation among the rivers was much larger than variation among years. Annual variations were not explained by regional environmental conditions, whereas in one river the timing of the local flood peak was a significant predictor of the timing of river entry. Differences in the timing of salmon entry to geographically closely situated rivers suggests that a regionally fixed opening date for coastal fisheries might not be the best management strategy as it may lead to uneven exploitation of salmon populations from different rivers [ Current Zoology 55 （5） ： 342 - 349, 2009] .