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Each cytokine which utilizes the Jak-Stat signal transduction pathway activates a distinct combination of members of the Jak and Stat families. Thus, either the Jaks, the Stats, or both could contribute to the specificity of ligand action. With the use of chimeric receptors involving the interferon ␥ receptor (IFN-␥R) complex as a model system, we demonstrate that Jak2 activation is not an absolute requirement for IFN-␥ signaling. Other members of the Jak family can functionally substitute for Jak2. IFN-␥ can signal through the activation of Jak family members other than Jak2 as measured by Statl␣ homodimerization and major histocompatibility complex class I antigen expression. This indicates that Jaks are interchangeable and indiscriminative in the JakStat signal transduction pathway. The necessity for the activation of one particular kinase during signaling can be overcome by recruiting another kinase to the receptor complex. The results may suggest that the Jaks do not contribute to the specificity of signal transduction in the Jak-Stat pathway to the same degree as Stats.The Jak-Stat signal transduction pathway was first discovered for interferon ␣ (IFN-␣) 1 and interferon ␥ (IFN-␥) by the complementation of mutant cell lines defective in response to IFN-␥ and/or IFN-␣ (Velazquez et al., 1992;Watling et al., 1993;Mü ller et al., 1993aMü ller et al., , 1993bDarnell et al., 1994;Leung et al., 1995). It has subsequently been shown that the same general pathway is activated by most cytokines and some growth factors (for review, see Ihle and Kerr (1995) and Taniguchi (1995)). This pathway is activated predominantly through receptors which do not possess intrinsic intracellular kinase domains and belong to the class I or class II cytokine receptor superfamily. The lack of inherent catalytic activity in these receptors is overcome through the use of receptor-associated kinases of the Janus kinase (Jak) family. Upon ligand binding, the receptor chains oligomerize allowing the associated kinases to interact and likely cross-activate each other by tyrosine phosphorylation. Subsequently, the activated Jaks directly phosphorylate the intracellular domains of the receptors on specific tyrosine residues. This phosphorylation allows the selective recruitment of SH2-domain containing proteins, particularly Stats (signal transducers and activators of transcription), through a specific interaction between the Stat SH2 domains and the phosphotyrosines within the Stat recruitment sites of the intracellular domains of the receptor chains. These receptor-associated Stats are then rapidly phosphorylated, likely by the activated Jaks . The phosphorylation of the Stats is followed by Stat dimerization, translocation to the nucleus, and activation of cytokine inducible genes.The Jak and Stat families are growing rapidly. The Jak family consists of four members so far: Jak1, Jak2, Jak3, and Tyk2 (Wilks et al., 1991;

Background: Prodigiosin produced by Serratia marcescens is a promising drug owing to its reported characteristics of having antifungal, immunosuppressive and antiproliferative activity. From an industrial point of view the necessity to obtain a suitable medium to simultaneously enhance the growth of Serratia marcescens and the pigment production was the aim of this work. The usage of individual fatty acid as substrate in industries would be cost-effective in the long run and this paved the way for us to try the effect of different fatty acid-containing seeds and oils of peanut, sesame and coconut as source of substrate.

Stevia rebaudiana is an introduced crop in India. The leaf and its extract although sweet have a bitter after taste that precludes commercial acceptability. The composition of the leaf refl ected a high nutritive value and polyphenol concentration averaging 4.15% by weight of dried leaf. Variably processed extracts enriched with polyphenols, pigments and a mixture of both were evaluated for sensory attributes by a semi trained panel when added to cofee and lime juice. Presence of polyphenols infl uenced the acceptability of the sweeteners marginally, while chlorophyll was found unacceptable in any of the extracts. The antioxidant activity of the extracts was synergistic when it was mixed with coffee and lime juice. Complete purifi cation of stevia leaf extracts to obtain pure glycosides is not necessary for it to become a commercially acceptable sweetener.

Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 ϫ 10 5 ) were injected subcutaneously into the scruff of 6-to 8-wk-old male C57BL/6 mice (n ϭ 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/ wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) ϩ vehicle, 2) SED ϩ DOX, 3) EX ϩ vehicle, and 4) EX ϩ DOX. Tumor volume was attenuated in DOX and lowest in EX ϩ DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, ␤-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOXinduced cardiotoxicity in a murine model of melanoma. neoplasm; drug therapy; cardiotoxicity; heart DOXORUBICIN (DOX) is an anthracycline with broad clinical application across the cancer spectrum as an effective antineoplastic agent (14, 30). However, progressive and dose-dependent early and late-onset cardiotoxicity limits the clinical efficacy of DOX (9). Acute cardiotoxicity is associated with arrhythmias and transient left ventricular (LV) dysfunction, whereas late-onset cardiomyopathy, which can occur up to 15 years after DOX administration, can manifest with overt LV dysfunction and heart failure (35). This is a significant clinical issue given cancer survivors already face a 15-fold increased rate of heart failure (27).There are numerous transcriptional and posttranslational pathophysiological mechanisms associated with DOX-induced cardiotoxicity, including increased generation of reactive oxygen species and lipid peroxidation, mitochondrial damage, DNA damage, reduction in protein synthesis, increased apoptosis, and alterations in ␤-adrenergic signaling and Ca 2ϩ handling (28). A recent study also showed that DOX caused nearly full extinction of competent cardiac progenitor cells. Subsequent intramyocardial injections of syngeneic cardiac progenitors rescued the heart from DOX-induced cardiotoxicity (7). These data suggest that a reduction in cardiomyocyte cell number...

The recent announcement of the first FDA-approved therapeutic vaccine for prostate cancer, Sipuleucel-T, is a watershed moment for the field of tumor immunotherapy. However, while Sipuleucel-T provides a powerful tool to clinicians for the most prevalent form of cancer in men, there remains an unmet need for a similar therapeutic strategy against breast cancer, the most prevalent cancer in women. While current breast cancer vaccines in development target several antigens, the most prevalent is the tumor-associated antigen, HER2. Initial results with HER2 vaccines appear promising in terms of efficacy; however, the lack of HER2 overexpression by a majority of breast tumors and the safety concerns associated with current HER2-targeted immunotherapy suggest that additional therapeutic strategies would be beneficial. Recently, several studies have identified ISG15 as a molecule highly expressed in numerous malignancies. ISG15 is a small ubiquitin-like protein regulated by type-I interferon and classically associated with viral defense. Elevated ISG15 expression in breast cancer is especially well documented and is independent of HER2, progesterone receptor, and estrogen receptor status. Additionally, high ISG15 expression in breast cancer correlates with an unfavorable prognosis and poor responses to traditional treatment strategies such as chemotherapy and radiation. To overcome these challenges, we employ a novel strategy to specifically target tumor-associated ISG15 expression with immunotherapy. We demonstrate that vaccination against ISG15 results in significant CD8-mediated reductions in both primary and metastatic mammary tumor burden. These results validate ISG15 as a tumor-associated antigen for cancer immunotherapy.

The receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor implicated in multiple disease states. Although RAGE is expressed on systemic vascular endothelium, the expression and function of RAGE on lung endothelium has not been studied. Utilizing in vitro (human) and in vivo (mouse) models, we established the presence of RAGE on lung endothelium. Because RAGE ligands can induce the expression of RAGE and stored red blood cells express the RAGE ligand N ε -carboxymethyl lysine, we investigated whether red blood cell (RBC) transfusion would augment RAGE expression on endothelium utilizing a syngeneic model of RBC transfusion. RBC transfusion not only increased lung endothelial RAGE expression but enhanced lung inflammation and endothelial activation, since lung high mobility group box 1 and vascular cell adhesion molecule 1 expression was elevated following transfusion. These effects were mediated by RAGE, since endothelial activation was absent in RBCtransfused RAGE knockout mice. Thus, RAGE is inducibly expressed on lung endothelium, and one functional consequence of RBC transfusion is increased RAGE expression and endothelial activation. receptor for advanced glycation end products; red blood cell transfusion; endothelial cell; lung inflammation; red blood cells THE RECEPTOR FOR ADVANCED glycation end products (RAGE) is widely expressed on systemic endothelium and functions as a pattern recognition receptor for multiple ligands, including advanced glycation end products (AGEs), high mobility group box 1 (HMGB1), calgranulins (s100A12 and s100B), amyloid ␤-proteins, Mac-1, phosphotidylserine, and lipopolysaccharide (10,24,26,35). AGEs, a heterogenous group of adducts formed during pathological states, hyperglycemia, and periods of increased oxidative stress, lead to increased generation of reactive oxygen species (ROS) and inflammatory cytokines following ligation of RAGE expressed on vascular endothelium (25,31,32). We have previously shown that stored red blood cells (RBCs) that express the RAGE ligand N ε -carboxymethyl lysine (N ε -CML) trigger lung endothelial ROS generation that was attenuated by soluble receptor for advanced glycation end products (sRAGE), the extracellular ligandbinding domain of the receptor that acts as a decoy by binding RAGE ligands (19). This finding supports the hypothesis that RAGE ligands on the surface of stored RBCs promote activation of lung endothelium, thus contributing to the pathogenesis of lung injury in susceptible transfusion recipients.Because RAGE is abundantly expressed on alveolar epithelium, particularly type I epithelial cells, and is utilized as a specific marker of alveolar epithelial injury, the existence of RAGE on pulmonary endothelium has come into question (9,28,30). Indeed, prior studies failed to detect RAGE in lung endothelium (9, 28). However, the complexities of RAGE biology render it a difficult molecule to study, since RAGE is known to exist in several different isoforms, subject to cleavage by proteases, ra...