bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved weight management using genetic information to personalize a calorie controlled diet
Authors: Arkadianos Ioannis , Valdes Ana M , Marinos Efstathios , Florou Anna , Gill Rosalynn D , Grimaldi Keith A
Published: October 2007

Background

Gene-environment studies demonstrate variability in nutrient requirements depending upon individual variations in genes affecting nutrient metabolism and transport. This study investigated whether the inclusion of genetic information to personalize a patient's diet (nutrigenetics) could improve long term weight management.

Methods

Patients with a history of failures at weight loss were offered a nutrigenetic test screening 24 variants in 19 genes involved in metabolism. 50 patients were in the nutrigenetic group and 43 patients attending the same clinic were selected for comparison using algorithms to match the characteristics: age, sex, frequency of clinical visits and BMI at initial clinic visit. The second group of 43 patients did not receive a nutrigenetic test. BMI reduction at 100 and > 300 days and blood fasting glucose were measured.

Results

After 300 days of follow-up individuals in the nutrigenetic group were more likely to have maintained some weight loss (73%) than those in the comparison group (32%), resulting in an age and gender adjusted OR of 5.74 (95% CI 1.74–22.52). Average BMI reduction in the nutrigenetic group was 1.93 kg/m2(5.6% loss) vs. an average BMI gain of 0.51 kg/m2(2.2% gain) (p < 0.023). Among patients with a starting blood fasting glucose of > 100 mg/dL, 57% (17/30) of the nutrigenetic group but only 25% (4/16) of the non-tested group had levels reduced to < 100 mg/dL after > 90 days of weight management therapy (OR for lowering glucose to < 100 mg/dL due to diet = 1.98 95%CI 1.01, 3.87, p < 0.046).

Conclusion

Addition of nutrigenetically tailored diets resulted in better compliance, longer-term BMI reduction and improvements in blood glucose levels.
The influence of gender on the effects of aspirin in preventing myocardial infarction
Authors: Yerman Todd , Gan Wen Q , Sin Don D
Published: October 2007

Background

There is considerable variation in the effect of aspirin therapy reducing the risk of myocardial infarction (MI). Gender could be a potential explanatory factor for the variability. We conducted a systematic review and meta-analysis to determine whether gender mix might play a role in explaining the large variation of aspirin efficacy across primary and secondary MI prevention trials.

Methods

Randomized placebo-controlled clinical trials that examined the efficacy of aspirin therapy on MI were identified by using the PUBMED database (1966 to October 2006). Weighted linear regression technique was used to determine the relationship between log-transformed relative risk (RR) of MI and the percentage of male participants in each trial. The reciprocal of the standard error of the RR in each trial (1/SE) was used as the weight.

Results

A total of 23 trials (n = 113 494 participants) were identified. Overall, compared with placebo, aspirin reduced the risk of non-fatal MI (RR = 0.72, 95% confidence interval (CI) 0.64–0.81, p < 0.001) but not of fatal MI (RR = 0.88, 95% CI 0.75–1.03, p = 0.120). A total of 27% of the variation in the non-fatal MI results could be accounted for by considering the gender mix of the trials (p = 0.017). Trials that recruited predominantly men demonstrated the largest risk reduction in non-fatal MI (RR = 0.62, 95% CI 0.54–0.71), while trials that contained predominately women failed to demonstrate a significant risk reduction in non-fatal MI (RR = 0.87, 95% CI 0.71–1.06).

Conclusion

Gender accounts for a substantial proportion of the variability in the efficacy of aspirin in reducing MI rates across these trials, and supports the notion that women might be less responsive to aspirin than men.
Dietary intake and breast density in high-risk women: a cross-sectional study
Authors: Tseng Marilyn , Byrne Celia , Evers Kathryn A , Daly Mary B
Published: October 2007

Background

Women with a family history of breast cancer may be at higher risk for breast cancer, but few previous studies evaluating diet and breast cancer have focused on such women. The objective of the present study was to determine whether diet, a modifiable risk factor, is related to breast density among women at high genetic risk for breast cancer.

Methods

Women with at least one first-degree or second-degree relative with breast cancer or ovarian cancer participating in the Fox Chase Cancer Center Family Risk Assessment Program completed health history and food frequency questionnaires and received standard screening mammograms. Cranial–caudal mammographic images were classified into the four Breast Imaging Reporting and Data System categories ranging from 'entirely fatty' to 'extremely dense'. Logistic regression analysis using proportional odds models for polychotomous outcomes provided estimates of odds ratios for having a higher category versus a lower category of breast density.

Results

Among 157 high-risk women, breast density was inversely associated with vitamin D intake (odds ratio for third tertile versus first tertile, 0.5; 95% confidence interval, 0.2–1.0). In contrast, intakes above the median level for protein (odds ratio, 3.0; 95% confidence interval, 1.3–6.9) and above the median level for animal protein (odds ratio, 4.3; 95% confidence interval, 1.8–10.3) were associated with higher breast density, but only among women whose family history did not reflect a known familial cancer syndrome or a breast cancer predisposition gene.

Conclusion

For women with a strong family history that was not associated with known cancer syndromes, dietary factors may be associated with breast density, a strong predictor of breast cancer risk. Since women with strong family history are often very motivated to change their lifestyle habits, further studies are needed to confirm whether changes in diet will change the breast density and the subsequent onset of breast cancer in these women.
Improved survival of children with sepsis and purpura: effects of age, gender, and era
Authors: Maat Martine , Buysse Corinne MP , Emonts Marieke , Spanjaard Lodewijk , Joosten Koen FM , de Groot Ronald , Hazelzet Jan A
Published: October 2007

Background

To gain insight into factors that might affect results of future case-control studies, we performed an analysis of children with sepsis and purpura admitted to the paediatric intensive care unit (PICU) of Erasmus MC-Sophia Children's Hospital (Rotterdam, The Netherlands).

Methods

Between 1988 and 2006, all 287 children consecutively admitted with sepsis and purpura were included in various sepsis studies. Data regarding age, gender, ethnicity, serogroup of Neisseria meningitidis, severity, therapy, and survival were collected prospectively. These data were pooled into one database and analyzed retrospectively.

Results

The case fatality rate (CFR) from sepsis and purpura was 15.7%. During the study period, survival improved significantly. Younger age was significantly associated with more severe disease and a higher CFR. Children under the median age of 3.0 years had an increased risk of case fatality (odds ratio 4.3, 95% confidence interval 2.1 to 9.2; p < 0.001). Gender was not associated with CFR. However, males did have higher Paediatric Risk of Mortality scores, fewer PICU-free days, and more presence of shock. The course of sepsis and purpura was not related to ethnic origin. A causative organism was isolated in 84.3% of cases. N. meningitidis was the major organism (97.5%). Although N. meningitidis serogroup B was observed more often in younger children, serogroups were not associated with severity or survival. During the study period, the use of inotropic agents and corticosteroids changed substantially (less dopamine and more dobutamine, norepinephrine, and corticosteroids).

Conclusion

Age and gender are determinants of severity of paediatric sepsis and purpura. Survival rates have improved during the last two decades.
ITIM-dependent endocytosis of CD33-related Siglecs: role of intracellular domain, tyrosine phosphorylation, and the tyrosine phosphatases, Shp1 and Shp2
Authors: Walter Roland B , Raden Brian W , Zeng Rong , Häusermann Peter , Bernstein Irwin D , Cooper Jonathan A
Published: October 2007

The leukocyte CD33-related sialic acid-binding Ig-like lectins (Siglecs) are implicated in glycan recognition and host defense against and pathogenicity of sialylated pathogens. Recent studies have shown endocytosis by CD33-related Siglecs, which is implicated in clearance of sialylated antigens and antigen presentation and makes targeted immunotherapy possible. Using CD33 as a paradigm, we have now investigated the reasons underlying the comparatively slow rate of endocytosis of these receptors. We show that endocytosis is largely limited and determined by the intracellular domain while the extracellular and transmembrane domains play a minor role. Tyrosine phosphorylation, most likely through Src family kinases, increases uptake of CD33 depending on the integrity of the two cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Simultaneous depletion of the protein tyrosine phosphatases, Src homology-2-containing tyrosine phosphatase 1 (Shp1) and Shp2, which bind to phosphorylated CD33, increases internalization of CD33 slightly in some cell lines, whereas depletion of spleen tyrosine kinase (Syk) has no effect, implying that Shp1 and Shp2 can dephosphorylate the ITIMs or mask binding of the phosphorylated ITIMs to an endocytic adaptor. Our studies show that restraint of CD33 internalization through the intracellular domain is relieved partly when the ITIMs are phosphorylated and show that Shp1 and Shp2 can modulate this process.
Thymosin β‐4 Is Essential for Coronary Vessel Development and Promotes Neovascularization via Adult Epicardium
Authors: SMART NICOLA , RISEBRO CATHERINE A. , MELVILLE ATHALIE A. D. , MOSES KELVIN , SCHWARTZ ROBERT J. , CHIEN KENNETH R. , RILEY PAUL R.
Published: October 2007

Abstract:  Ischemic heart disease leading to myocardial infarction causes irreversible cell loss and scarring and is a major cause of morbidity and mortality in humans. Significant effort in the field of cardiovascular medicine has been invested in the search for adult cardiac progenitor cells that may replace damaged muscle cells and/or contribute to new vessel formation (neovascularization) and in the identification of key factors, which may induce such progenitor cells to contribute to myocardial repair and collateral vessel growth. We recently demonstrated that the actin monomer‐binding protein, thymosin β‐4 (Tβ‐4), when secreted from the myocardium provides a paracrine stimulus to the cells of the epicardium‐derived cells (EPDCs) to promote their inward migration and differentiation into endothelial and smooth muscle cells to form the coronary vasculature. Translating this essential role for Tβ‐4 in coronary vessel development to the adult, we found that treatment of cultured adult explants with Tβ‐4 stimulated extensive outgrowth of epicardin‐positive epicardial cells, which, as they migrated away from the explant, differentiated into procollagen type I, SMαA, and Flk1‐positive cells indicative of fibroblasts, smooth muscle, and endothelial cells; thus releasing the adult epicardium from a quiescent state and restoring pluripotency. The ability of Tβ‐4 to promote coronary vessel development and potentially induce new vasculature in the adult is essential for cardiomyocyte survival and could contribute significantly toward the reported Tβ4‐induced cardioprotection and repair in the adult heart. Tβ‐4 is currently subject to multicenter phase 1 clinical trials for treatment of cardiovascular disease (http://www.regenerx.com), therefore, insight into the repair mechanism(s) induced by Tβ‐4 is an essential step toward harnessing therapeutic survival, migration, and repair properties of the peptide in the context of acute myocardial damage.
In Vivo Sampling of Extracellular β‐Thymosin by Ultrafiltration Probes
Authors: LIU YU‐TSUENG , HUANG CHUN‐MING
Published: October 2007

Abstract: 
In vivo detection and monitoring of extracellular β‐thymosin will facilitate the understanding of their biological function and association with disease progression.  A novel technique using capillary ultrafiltration (CUF) probes linked to mass spectrometry is capable of sensing extracellular thymosin β‐4 and/or thymosin β‐10 in vivo in wounded skin and other tissue microenvironments. In this review, we highlight the association of extracellular β‐thymosin with skin wound healing and the potential adjuvant effects on vaccination. The fabrication and biological application of CUF probes are also described. Data from CUF probe‐captured β‐thymosin may guide future exploration of extracellular β‐thymosin.
Thymosin α1
Authors: ROMANI LUIGINA , BISTONI FRANCESCO , MONTAGNOLI CLAUDIA , GAZIANO ROBERTA , BOZZA SILVIA , BONIFAZI PIERLUIGI , ZELANTE TERESA , MORETTI SILVIA , RASI GUIDO , GARACI ENRICO , PUCCETTI PAOLO
Published: October 2007

Abstract:  Thymosin α1 (Tα1), first described and characterized by Allan Goldstein in 1972, is used worldwide for the treatment of some immunodeficiencies, malignancies, and infections. Although Tα1 has shown a variety of effects on cells and pathways of the immune system, its central role in modulating dendritic cell (DC) function has only recently been appreciated. As DCs have the ability to sense infection and tissue stress and to translate collectively this information into an appropriate immune response, an action on DCs would predict a central role for Tα1 in inducing different forms of immunity and tolerance. Recent results have shown that Tα1: (a) primed DCs for antifungal Th1 resistance through Toll‐like receptor (TLR)/MyD88‐dependent signaling and this translated in vivo in protection against aspergillosis; (b) activated plasmacytoid DCs (pDC) via the TLR9/MyD88‐dependent viral recognition, thus leading to the activation of interferon regulatory factor 7 and the promotion of the IFN‐α/IFN‐γ−dependent effector pathway, which resulted in vivo in protection against primary murine cytomegalovirus infection; (c) induced indoleamine 2,3‐dioxygenase activity in DCs, thus affecting tolerization toward self as well as microbial non‐self‐antigens, and this resulted in vivo in transplantation tolerance and protection from inflammatory allergy. Tα1 is produced in vivo by cleavage of prothymosin α in diverse mammalian tissues. Our data qualify Tα1 as an endogenous regulator of immune homeostasis and suggest that instructive immunotherapy with Tα1, via DCs and tryptophan catabolism, could be at work to control inflammation, immunity, and tolerance in a variety of clinical settings.
Localization of Thymosin β‐4 in Tumors
Authors: LARSSON LARS‐INGE , HOLCK SUSANNE
Published: October 2007

Abstract:  Overexpression of thymosin β‐4 has been linked to malignant progression but the localization of this polypeptide within tumors is incompletely known. We therefore examined breast cancers for thymosin β‐4 using immunofluorescence. Reactive cells were identified with monoclonal cell marker antibodies. A very heterogeneous staining pattern for thymosin β‐4 was observed. Thus, while leukocytes and macrophages showed intense reactivity for this polypeptide, cancer cells, and endothelial cells showed a much more variable reactivity. A similar heterogeneous staining was observed also in colorectal carcinomas. The degree of staining of breast cancer cells for thymosin β‐4 correlated neither to histological grade nor to endothelial cell staining. However, there was a tendency toward correlation (P= 0.07) between staining of endothelial cells and histological grade. Treatment of cultured breast cancer cells (SK‐BR‐3) with 1–4 μg thymosin β‐4/mL significantly increased cell numbers, as determined by MTT‐assays. These data reveal an unexpected cellular heterogeneity of thymosin β‐4 expression in breast and colonic carcinomas and suggest that local release of this polypeptide in the tumor microenvironment may modulate tumor behavior.
The Role of DNA and Actin Polymers on the Polymer Structure and Rheology of Cystic Fibrosis Sputum and Depolymerization by Gelsolin or Thymosin Beta 4
Authors: KATER ARNON , HENKE MARKUS O. , RUBIN BRUCE K.
Published: October 2007

Abstract:  Mucus clearance is the first line of pulmonary defense against inhaled irritants, microorganisms, and allergens. In health, the gel‐forming mucins are the principal polymeric components of airway mucus but in cystic fibrosis (CF), the necrotic death of inflammatory and epithelial cells releases a network of copolymerized extracellular DNA and filamentous (F‐) actin‐producing secretions that are similar to pus and difficult to clear by cilia or airflow. The large amounts of F‐actin in CF sputum suggested that thymosin β4 (Tβ4) or gelsolin could depolymerize the secondary polymer network of CF sputum. Dose‐dependent CF sputum rheology and polymer structure were measured before and after the addition of excipient, dornase alfa, Tβ4, gelsolin, and Tβ4 or gelsolin with dornase for 30 min. Sputum was also incubated with Tβ4 30 μg/mL, gelsolin 10 μg/mL or excipient for 0, 5, 10, 15, 20, or 60 min. There was a dose‐dependent decrease in cohesivity with Tβ4 and a time‐dependent decrease in cohesivity at 30 μg/mL. With the combination of dornase alfa and Tβ4 at 1.5 μg/mL, there was a 65% decrease in elasticity (P= 0.013). There was a time‐dependent decrease in cohesivity (P= 0.0004) and elasticity (P= 0.047) with gelsolin and a dose‐dependent fall in cohesivity (P= 0.0008). An apparent synergy of Tβ4 or gelsolin on actin and dornase on DNA may be explained by the combined effect of actin depolymerization and DNA filament severing or by virtue of actin depolymerization increasing the effectiveness of dornase alfa.
Thymosin β4
Authors: YARMOLA ELENA G. , KLIMENKO EVGUENIA S. , FUJITA GO , BUBB MICHAEL R.
Published: October 2007

Abstract:  The intracellular function of thymosin β4 is not limited to simple sequestration of globular actin. Our recent studies revealed that thymosin β4 affects actin critical concentration and forms a ternary complex with actin and profilin. The consequences of this complex formation can be very significant. Our new data demonstrate that it is likely that profilin affects binding of thymosin β4 to actin in the ternary complex through allosteric changes in actin rather than through competition for the binding site. The N‐ and C‐terminal thymosin β4 helices are known to be unstructured in aqueous solution and to adopt helical conformation in organic solvents or upon binding to actin. Osmolytes stabilize protein structure, and TMAO (trimethylamine N‐oxide) specifically stabilizes hydrogen bonds. This increases affinity of intact thymosin β4 to actin significantly, but the increase is much less for thymosin β4 sulfoxide. Our data show that oxidation does not alter binding of profilin to form a ternary complex, and therefore it is very likely that there is no direct steric interference by methionine 6 of thymosin β4. Rather, since TMAO has little effect on thymosin β4 sulfoxide, this observation is consistent with the hypothesis that methionine oxidation prevents helix transition. The experiment with truncated versions of thymosin β4 also supports this hypothesis. Oxidation and formation of the helices are important for both intra‐ and extracellular properties of thymosin β4. We found that actin and, in lesser extent, profilin–actin complex protect thymosin β4 from oxidation.
Thymosin Beta 4 Induces Hair Growth via Stem Cell Migration and Differentiation
Authors: PHILP DEBORAH , ST‐SURIN SHARLEEN , CHA HEE‐JAE , MOON HYE‐SUNG , KLEINMAN HYNDA K. , ELKIN MICHAEL
Published: October 2007

Abstract:  Thymosin beta 4 is a small 43‐amino‐acid molecule that has multiple biological activities, including promotion of cell migration angiogenesis, cell survival, protease production, and wound healing. We have found that thymosin beta 4 promotes hair growth in various rat and mice models including a transgenic thymosin beta 4 overexpressing mouse. We have also determined the mechanism by which thymosin beta 4 acts to promote hair growth by examining its effects on follicle stem cell growth, migration, differentiation, and protease production.
Models of the Actin‐Bound Forms of the β‐Thymosins
Authors: XUE BO , AGUDA ADELEKE HALILU , ROBINSON ROBERT CHARLES
Published: October 2007

Abstract:  In recent years two structures have been reported that demonstrate how the two halves of a β‐thymosin repeat bind to actin monomers. Here we assess the validity of these structures and construct minimally biased models of the β‐thymosin:actin complexes. The models reveal that the β‐thymosins interact with actin throughout their length and that all the conserved residues are functional in this interface. These models are judged to be in excellent agreement with published biochemical and functional data. In particular, the models are consistent with the actin monomer sequestering and actin filament binding properties of β‐thymosins. The models also correctly predict competition between thymosin‐β4 with DNase I or profilin in binding actin while allowing ternary complexes at higher concentrations.
Contributions from All Over
Authors: AU JOSHUA K. , CRUZ ENRIQUE M. DE LA , SAFER DANIEL
Published: October 2007

Abstract:  We have used site‐directed mutagenesis to investigate the contributions of widely distributed residues in the thymosin beta‐4 (Tβ4) sequence to the formation and stability of the actin–Tβ4 complex. Equilibrium and kinetic studies of actin binding were performed by monitoring the change in fluorescence of an N‐iodoacetyl‐N9‐(5‐sulfo‐1‐naphthyl)ethylenediamine (Aedans) fluorophore on actin cysteine‐374. We evaluated the contributions of hydrophobic residues throughout Tβ4, the conserved and variable proline residues, and the conserved lysine residues to the kinetics and thermodynamics of Tβ4 binding to MgATP‐actin monomers. Pro4, Lys18, Lys19, Pro27, Leu28, Pro29, and Ile34 were substituted by alanine residues. All these mutations weaken the affinity of the actin–Tβ4 complex, but the kinetic basis of the lower stability of the complex varies among the mutants. Our results support a model in which Tβ4 initially binds actin through an electrostatic interaction, followed by the formation of widely distributed hydrophobic contacts. Several mutants, particularly at proline residues, dissociate much more rapidly than the wild‐type complex, but also show small increases in the rate of association. This seeming paradox suggests that conformational searching of Tβ4, and particularly cis–trans isomerization of proline residues, contributes to the slow association rate constant of Tβ4, and to the stability of the hydrophobic contacts associated with strong actin binding.
Epidermolysis Bullosa
Authors: FINE JO‐DAVID
Published: October 2007

Abstract:  Inherited epidermolysis bullosa (EB), having an overall incidence of only about 19 in every 1 million live births, encompasses many phenotypically and genotypically distinct diseases characterized by the presence of recurrent blisters, mechanical fragility of the skin and other epithelial structures (most notably the cornea and gastrointestinal tract), and scar formation. Each disease is the result of mutations within any of 10 specific structural proteins (keratins, laminins, collagens, integrins) within the basilar keratinocyte or the skin basement membrane zone. Two of the more severe subtypes, junctional and dystrophic EB, often involve many extracutaneous tissues. If severe, these conditions may be life threatening. Recent studies in wounds that had been artificially induced on normal skin, both in rodents and in human volunteers, have suggested that thymosin β4 may be effective in promoting epithelial migration across the wounds. A randomized double‐blind clinical trial has been recently organized to determine whether this novel biologic agent may be beneficial in promoting wound healing in patients with junctional and dystrophic EB. To do so, a solitary noninfected cutaneous wound of standardized size will be treated topically on a daily basis with either one of three concentrations of thymosin β4 or a placebo control. Serial wound healing will be quantitated by computerized digital‐imaging technique. At the same time, the occurrence of adverse effects will be sought, so as to confirm the safety of thymosin β4 when applied to EB skin, both in children and in adults. Although as yet unproven, topically applied thymosin β4 may prove to be an extremely important addition to the overall management of patients with this potentially devastating disease.
β‐Thymosins
Authors: HANNAPPEL E.
Published: October 2007

Abstract:  The development of thymosin β4 from a thymic hormone to an actin‐sequestering peptide and back to a cytokine supporting wound healing will be outlined. Thymosin fraction 5 consists of a mixture of polypeptides and improves immune response. Starting with fraction 5, several main peptides (thymosin α1, polypeptide β1, and thymosin β4) were isolated and tested for biological activity. However, none of the isolated peptides were really thymic hormones. They are all biological important peptides with diverse functions. Polypeptide β1 is identical to ubiquitin truncated by two C‐terminal glycine residues. Several peptides related to thymosin β4 were isolated and sequenced from various species. Large amounts of thymosin β4 were found in many cells. It was postulated that the β‐thymosins might have a general function. The identification of a biological function of thymosin β4 was tedious. In 1990, Dan Safer and his colleagues recognized that thymosin β4 sequesters G‐actin. The dissociation constant of the complex in the micromolar range allows for fast binding and release of G‐actin. β‐Thymosins are the main intracellular G‐actin‐sequestering peptides in most vertebrate cells. Thymosin β4 is unstructured but folds into a stable conformation on binding to G‐actin. It is present in the nucleus as well as the cytoplasm and might be responsible for sequestering nuclear actin. Several biological effects are attributed to thymosin β4, oxidized thymosin β4, or to ac‐SDKP possibly generated from thymosin β4. However, very little is known about molecular mechanisms mediating the effects attributed to extracellular β‐thymosins.
The β‐Thymosin Enigma
Authors: SUN HUI QIAO , YIN HELEN L.
Published: October 2007

Abstract:  Actin dynamics in nonmuscle cells is controlled by the availability of actin nucleating sites and actin monomers. Thymosin β‐4 (Tβ‐4) has been implicated in modulating the availability of actin monomers in a large variety of cells. It together with actin nucleating, severing, and uncapping proteins, harnesses the intrinsic dynamic properties of actin to regulate the actin polymerization response in cells. Overexpression or addition of exogenous Tβ‐4 or its homolog, Tβ‐10, alters the actin cytoskeleton, and has multiple effects on cellular functions related to motility. Some of these effects are consistent with β‐thymosins functioning exclusively as monomer‐binding proteins, while others are not. Therefore, the complex pleiotropic effects of β‐thymosin in cells may be due to direct and indirect effects on the actin cytoskeleton, as well as modulation of signaling pathways that will impact the cytoskeleton and a variety of cell functions.
Thymosin Fraction‐5 Possesses Antiproliferative Properties in HL‐60 Human Promyelocytic Leukemia Cells
Authors: SPANGELO BRYAN L. , ROACH JOSEPH D. , HADI FREIDUN , DAMAVANDY ALI A. , PLIESKATT JORDAN , BADAMCHIAN MAHNAZ
Published: October 2007

Abstract:  Thymosin fraction‐5 (TF5) is a protein preparation of the bovine thymus. TF5 stimulates many assays of T cell—mediated immunity. We found that TF5 substantially suppressed proliferation of the rat C6 glioma and MMQ pituitary adenoma cell lines. Our current research using the promyelocytic cell line HL‐60 suggests that TF5 also prevents proliferation of human myeloid leukemia cells. Our objective is the purification and chemical characterization of TF5 peptide components responsible for inhibition of HL‐60 proliferative capacity. Using the inhibition of HL‐60 cell proliferation, we have chemically characterized TF5 using fast protein liquid chromatography (FPLC), reversed‐phase high‐performance liquid chromatography (RP‐HPLC), and high‐performance capillary electrophoresis (HPCE). Vital dye‐exclusion, oxidative metabolism of chromogenic dyes, and clonogenic growth profiles were used to determine rates of HL‐60 proliferation. Our results identified an ∼6000 Da component of TF5 capable of inducing HL‐60 growth arrest. Synchronized HL‐60 cells exposed to TF5 and its various constituents were subjected to cytometric analysis by flow cytometry. TF5‐treated HL‐60 cells had an increased subdiploid faction (i.e., sub‐G1) compared to control cells. TF5 also increased Annexin V staining in randomly cycling HL‐60 cells. Thus, a TF5 subfraction possesses growth‐suppressive activity for human myeloid neoplasms. Our results indicate that this effect is characterized by at least one hallmark of apoptosis. Future clinical management strategies for certain leukemias may involve the use of thymic peptides.
Thymosin β‐NB Is the Human Isoform of Rat Thymosin β15
Authors: BANYARD JACQUELINE , HUTCHINSON LLOYD M. , ZETTER BRUCE R.
Published: October 2007

Abstract:  Thymosin β15 is a small actin‐binding protein upregulated in highly metastatic rat prostate cancer cells, relative to low metastatic cells. We have previously established an important role for thymosin β15 as a diagnostic marker in human prostate cancer, with potential as a prognostic indicator. We here review the data supporting increased thymosin β15 expression in other cancer types, including breast, brain, and lung. Human NB thymosin β is a β‐thymosin originally found in neuroblastoma. New data demonstrate that NB thymosin β represents the human homolog of rat thymosin β15; thus we suggest classification as human thymosin β15. In addition to the previously described gene, thymosin β15a, we report the discovery of a new isoform of human thymosin β15, thymosin β15b, which is transcribed from an independent gene on human chromosome X. The gene structure of thymosin β15a and β15b is conserved and the isoforms show 87% identity across the nucleotide sequence. Across the coding sequence the nucleotide differences are silent, resulting in identical proteins. Other thymosin family members have recently been shown to exert potent clinical effects. The functional data available for thymosin β15, combined with the tumor expression pattern, suggest that thymosin β15 may play an important role in tumor development and progression in addition to its value as a biomarker in prostate cancer.
Influence of the N Terminus and the Actin‐Binding Motif of Thymosin β4 on Its Interaction with G‐Actin
Authors: ZOUBEK ROBERT E. , HANNAPPEL EWALD
Published: October 2007

Abstract:  Thymosin β4 binds G‐actin in a 1:1 ratio and prevents its aggregation to F‐actin by sequestration. Substitution or modification of single amino acid residues within the N‐terminal sequence 1 to 22 of thymosin β4 alters its interaction with G‐actin.We generated thymosin β4 variants with amino acid substitutions within the N‐terminal α‐helix and the putative actin‐binding motif. None of the E. coli‐generated thymosin β4 variants was modified or acetylated at its N terminus. The stability of the complex of G‐actin with nonacetylated thymosin β4 or β4A7V is higher than the one with naturally occurring thymosin β4, which is always acetylated. The complex of G‐actin with nonacetylated thymosin β4A7V,K18,19A and β4K14,16,18,19A is 15 times less stable compared to the complex with thymosin β4. The G‐actin sequestering activities of all thymosin β4 variants correspond to their complex stabilities with G‐actin, except for nonacetylated thymosin β4A7V, where it is attenuated. Thymosin β4Δ17–23 missing the putative actin‐binding motif shows no interaction with G‐actin.
Subcellular Distribution of Thymosin β4
Authors: ZOUBEK ROBERT E. , HANNAPPEL EWALD
Published: October 2007

Abstract:  The localization of Oregon Green cadaverine‐labeled thymosin β4, its fragments, and variants was investigated in cytoplasm‐depleted A431 cells and in microinjected cells without and with fixation. The studied thymosin β4 variants included substitutions of the lysine residues within the basic cluster (14‐KSKLKK‐19) and the actin‐binding motif (17‐LKKTETQ‐23). In contrast to Oregon Green cadaverine, none of the variants or fragments of thymosin β4 could pass the intact nuclear pore of cytoplasm‐depleted cells and were hence excluded from the nucleus. However, an equal distribution of all thymosin β4 variants was observed in living cells. The nuclear localization is neither dependent on the actin‐binding ability of thymosin β4 nor on its basic lysine cluster. The equal distribution of the β‐thymosins, the ability of the fragments thymosin β41 − 26 and β427 − 43 to enter the nucleus in intact cells immediately after injection, and their exclusion from cytoplasm‐depleted nuclei make it unlikely that they are transported by a single transport protein. A passive but regulated diffusion could explain the described ability of thymosin β4 to shuttle into the nucleus.
IRX‐2 and Thymosin α1 (Zadaxin) Increase T Lymphocytes in T Lymphocytopenic Mice and Humans
Authors: HADDEN J. W. , VERASTEGUI E. , HADDEN E.
Published: October 2007

Abstract:  Mouse studies showed a synergy of thymosin α1 (Tα1) and a natural cytokine mixture (IRX‐2) in increasing T lymphocyte number and responses. Clinical studies with IRX‐2 showed increases of T lymphocytes in lymphocytopenic cancer patients but relatively little effect on irradiated, lymphocytopenic patients. The present phase 1 and 2 study shows that Tα1 enhances the effect of IRX‐2 in these lymphocytopenic patients. Patients (seven) were treated with subcutaneously injected IRX‐2 (200 units IL‐2 equivalence), Tα1 (1.6 mg/day) (four patients), or the combination of IRX‐2 and Tα1 (seven patients) daily for 10 days. Peripheral blood lymphocytes (T, B, NK) and subsets (CD4, CD8) were measured at the start of treatment and on day 11. IRX‐2 and Tα1 had little or no significant effect. The combination markedly increased various lymphocyte populations (>350 cells/μL). Four patients followed for 6 weeks displayed sustained increases involving both naïve and memory T cells. Responses to persistent infections were observed in three of the four patients and no significant toxicity was observed. Tα1 and IRX‐2 synergize to increase safely T cells in lymphocytopenic patients.
Thymalfasin for the Treatment of Chronic Hepatitis C Infection
Authors: RUSTGI VINOD K.
Published: October 2007

Abstract:  The purpose of this review article is to examine previous and ongoing studies of thymalfasin in combination with peginterferon‐α2a and peginterferon‐α2a plus ribavirin in difficult‐to‐treat hepatitis C virus (HCV) patients. The following studies will be reviewed in detail: (1) Sherman and colleagues conducted a study in 109 HCV RNA positive HVC patients comparing the combination of thymalfasin + IFN versus IFN alone versus placebo. (2) Rustgi et al. evaluated the efficacy and safety of thymalfasin and peg‐IFN‐α2a in 31 genotype 1, high viral load, HCV nonresponders in a 12‐week viral kinetic study. (3) Di Bisceglie, Sherman et al. performed a study of previous HCV nonresponders being retreated with either peginterferon‐α2a plus thymalfasin or peginterferon‐α2a plus placebo. (4) Poo and colleagues in Mexico evaluated triple combination therapy using thymalfasin, peginterferon‐α2a, and ribavirin for the treatment of Hispanic HCV nonresponders.
Thymosin β4 Upregulates the Expression of Hepatocyte Growth Factor and Downregulates the Expression of PDGF‐β Receptor in Human Hepatic Stellate Cells
Authors: BARNAEVA ELENA , NADEZHDA AGLADZE , HANNAPPEL EWALD , SJOGREN MARIA H. , ROJKIND MARCOS
Published: October 2007

Abstract:  Hepatic stellate cells (HSCs) are the main producers of type I collagen in the liver, and therefore are responsible, in part, for the fibrous scar observed in cirrhotic livers. Although there is no approved treatment for this deadly disease, drugs inducing HSC apoptosis in animals (gliotoxin) and hepatocyte regeneration in man (hepatocyte growth factor [HGF]), have been used successfully in ameliorating liver fibrosis. In this communication we investigated whether thymosin β4 (Tβ4), an actin‐sequestering peptide that prevents scarring of the heart after a myocardial infarction and that prevents kidney fibrosis in animals, has the potential to be used to treat liver fibrosis. To this end we studied whether the administration of Tβ4 to HSCs could alter the expression of genes encoding for extracellular matrix components, as well as those required for differentiation of HSCs. Our preliminary findings show that Tβ4 had no effect on the expression of α2 (I) collagen, tissue inhibitor of metalloproteinases‐1, and matrix metalloproteinase‐2 mRNAs. However, it upregulated the expression of HGF and downregulated the expression of platelet‐derived growth factor‐β receptor mRNAs in these cells. Overall, these findings suggest that Tβ4 has antifibrogenic potential.
Thymosin α1
Authors: GARACI ENRICO
Published: October 2007

Abstract:  Thymosin α 1 (Tα1), initially isolated from thymus, was characterized by Allan Goldstein in 1977. Since the beginning, our studies were aimed at evaluating its immunomodulating effects when used in combination with cytokines and chemotherapy. Combination therapies have now proved to be effective in inhibiting tumoral growth and in controlling infective diseases especially in the immunocompromised host. More recent studies showed that Tα1 molecule increased major histocompatibility complex (MHC) class‐1 and Toll‐like receptor expression as well as cytokine production, suggesting its immunoregulatory role. Overall these results led us to start pilot clinical trials on patients with hepatitis C and cancer.
Thymosin α1 as a Chemopreventive Agent in Lung and Breast Cancer
Authors: MOODY TERRY W.
Published: October 2007

Abstract:  The ability of thymosin α1 (Tα1) to prevent lung and breast cancer was investigated. Lung adenomas developed in A/J mice injected with carcinogens, such as urethane. The lung adenoma number was reduced by 15–45% if animals were daily treated subcutaneously (s.c.) with Tα1 (0.4 mg/kg). Tα1 (1 μM) directly inhibited the growth of mouse lung cell lines. These results suggest that Tα1 may prevent mouse lung carcinogenesis because it directly inhibits the growth of lung cancer cells. Tα1 prevented mammary carcinogenesis in two animal models. In the Fisher rat, an animal model of mammary cancer that is estrogen receptor dependent, tumors were initiated by the injection of N‐methylurea (NMU). The rat survival was significantly increased by the daily injection of Tα1. In the SV40T antigen mouse, a transgenic female mouse that spontaneously gets mammary cancer in an estrogen receptor‐independent manner, survival was increased and tumor burden was significantly decreased by daily injection of Tα1. These results indicate that Tα1 is a chemopreventive agent in animal models for lung and breast carcinogenesis.
History of the Discovery of the Thymosins
Authors: GOLDSTEIN ALLAN L.
Published: October 2007

Abstract:  From a historical perspective, the studies that led to the isolation and characterization of the thymosins began in earnest in the early 1960s in the laboratory of Abraham White at the Albert Einstein College of Medicine in New York. In a 1966 paper in the Proceedings of the National Academy of Sciences, U.S., we first named these thymic‐derived factors “Thymosins.” By 1972, the thymosin team had moved to the University of Texas Medical Branch in Galveston (UTMB) where an extremely talented group of young scientists and students succeeded over the next 6 years in preparing and testing a highly active partially purified calf thymus preparation, termed thymosin fraction‐5 (TF5), which was amenable for scale‐up and suitable for clinical use. In 1974, we received the first IND for a thymic hormone preparation from the FDA to begin a phase‐I study with TF5 in children with primary immunodeficiency diseases at the University of California Medical Center in San Francisco. The immunorestorative and potentially life‐saving properties of TF5 in clinical medicine were first documented in a landmark paper in 1975 by Drs. Arthur Ammann and Diane Wara in the New England Journal of Medicine. TF5 consists of a family of at least 40 mostly small acidic polypeptides, with molecular weights ranging from 1000 to 15,000 Da. This article will identify the key scientists and the milestones involved in the initial studies with TF5 that have led to the chemical characterization of the thymosins and to translational studies from the lab bench to the clinic.
Studies of Therapy with Thymosin α1 in Combination with Pegylated Interferon α2a and Ribavirin in Nonresponder Patients with Chronic Hepatitis C
Authors: CAMERINI ROBERTO , CIANCIO ALESSIA , DE ROSA ALFONSO , RIZZETTO MARIO
Published: October 2007

Abstract:  Despite the use of combination therapy with pegylated interferon α2a (peg‐IFN‐α2a) + Ribavirin, a large proportion of patients with chronic hepatitis C (CHC) remain unresponsive to treatment. Thymosin alpha 1 (Tα1) is an immunomodulator, which displays immunological and antiviral activities against hepatitis C virus (HCV) in preclinical clinical settings. The purpose of this study was to evaluate the efficacy and safety of a triple combination therapy with peg‐IFN‐α2a + Ribavirin + Tα1 in CHC patients who were nonresponders to a previous course with peg‐IFN‐α2a + Ribavarin. The primary endpoint is the rate of sustained virological response (SVR). We designed a phase 3, randomized, double‐blind, multicenter, prospective, placebo controlled study. Patients meeting selection criteria were randomized centrally (through IVR system) to receive either peg‐IFN‐α2a 180 mcg s.c. once weekly + Ribavirin 1000–1200 mg p.o. daily + Tα1 1.6 mg s.c. twice weekly for 24 weeks. Patients who remained HCV‐RNA positive after 24 weeks stopped treatment and were considered nonresponders. HCV‐RNA negative patients continued treatment up to week 48. All patients were followed up for 24 additional weeks after the end of treatment for the evaluation of the SVR. From December 2004 to November 2006, 638 patients were screened in 52 European sites. Preliminary blinded safety analysis suggests that both regimens are well tolerated. Efficacy evaluation will be available after the opening of this blinded phase 3 trial, planned for May 2008.
Thymosin β4 Is Cardioprotective after Myocardial Infarction
Authors: SRIVASTAVA DEEPAK , SAXENA ANKUR , MICHAEL DIMAIO J. , BOCK‐MARQUETTE ILDIKO
Published: October 2007

Abstract:  Heart disease is a leading cause of death in newborns and in adults. Efforts to promote cardiac repair by introduction or recruitment of exogenous stem cells hold promise but typically involve isolation and introduction of autologous or donor progenitor cells. We have found that the G‐actin‐sequestering peptide thymosin β4 promotes myocardial and endothelial cell migration in the embryonic heart and retains this property in postnatal cardiomyocytes. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin β4. We found that thymosin β4 formed a functional complex with PINCH and integrin‐linked kinase (ILK), resulting in activation of the survival kinase Akt/PKB, which was necessary for thymosin β4's effects on cardiomyocytes. After coronary artery ligation in mice, thymosin β4 treatment resulted in upregulation of ILK and Akt activity in the heart, enhanced early myocyte survival, and improved cardiac function. These findings suggest that thymosin β4 promotes cardiomyocyte and endothelial migration, survival, and repair and may be a novel therapeutic target in the setting of acute myocardial damage.
Thymosin Alpha 1 as an Adjunct to Influenza Vaccination in the Elderly
Authors: ERSHLER WILLIAM B. , GRAVENSTEIN STEFAN , GELOO ZEBA S.
Published: October 2007

Abstract:  From a clinical perspective, the immune deficiency of aging (immune senescence) is not profound. In fact, it may be of little clinical consequence. However, older people are prone to chronic and debilitating disorders which alone, or in concert with the medications used in their treatment, may add to the age effect and create a more clinically relevant immune deficiency. As a result, many older people are susceptible to infection. Furthermore, it is now well recognized that older people respond less well to immunization protocols. Protection against influenza by vaccination with hemagluttinin is the prototype example. Despite programs that have raised vaccination rates dramatically over the past three decades, influenza remains a major cause of morbidity and mortality in the elderly. This, in part, is due to the fact that vaccine responses are reduced in older recipients. Strategies are under development to enhance vaccine efficacy in this population and one such strategy is the adjuvant use of thymosin alpha 1 (Tα1). In both animal experiments and human trials, there has been demonstrated enhancement of vaccine responses. The findings to date warrant additional efforts to further examine the role of Tα1 in augmenting specific vaccine responses both in the elderly or in younger subjects in situations in which there are suboptimal quantities of immunizing antigen available.
Rational Selection of Patients for Antibacterial Prophylaxis After Chemotherapy
Authors: Cullen Michael H. , Billingham Lucinda J. , Gaunt Claire H. , Steven Neil M.
Published: October 2007

Purpose

The SIGNIFICANT (Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy ± Antibiotic in a Number of Tumours) trial reported a reduction in febrile episodes (FEs) among 1,565 patients with solid cancers and lymphomas receiving cyclical, myelosuppressive chemotherapy (causing grade 4 neutropenia) in a randomized, placebo-controlled, double-blind trial of levofloxacin (P = .01). In response to concerns that increased antibacterial prescribing selects for microbial resistance, we examined our data to explore the rationale for more limited prophylaxis.

Patients and Methods

The risk of FE was calculated for control patients on first versus nonfirst cycles, with or without first-cycle FE, and within subgroups defined by cancer type, performance status (PS), age, and treatment context (adjuvant v nonadjuvant). Using the randomized trial data, the prophylactic efficacy of levofloxacin was examined for the same subgroups.

Results

The per-cycle FE incidence was much lower on nonfirst (3.3%) versus first cycles (8.0%). Prophylaxis was less effective for nonfirst (odds ratio [OR] = 0.78; P = .16) compared with first cycles (OR = 0.42; P < .001). However, FE on cycle 1 predicted a much higher risk of FE and a trend to continued prophylactic efficacy on subsequent cycles. FE rate was greatest for testicular cancer (27.9%), then small-cell lung cancer (17.3%), and lowest for breast cancer (11.5%). Prophylactic efficacy was consistent across age, sex, PS, treatment context, and disease type (except possibly non-Hodgkin's lymphoma).

Conclusion

Under pressure to limit antibacterial use, these exploratory data support offering prophylactic levofloxacin on cycle 1 only of myelosuppressive cancer chemotherapy and on subsequent cycles after a cycle-1 fever. Prophylactic levofloxacin is effective regardless of age, PS, or tumor type.