Functions and Metabolism of Amino Acids in the Hair and Skin of Dogs and Cats.

The hair and skin of domestic cats or dogs account for 2% and 12-24% of their body weight, respectively, depending on breed and age. These connective tissues contain protein as the major constituent and provide the first line of defense against external pathogens and toxins. Maintenance of the skin and hair in smooth and elastic states requires special nutritional support, particularly an adequate provision of amino acids (AAs). Keratin (rich in cysteine, serine and glycine) is the major protein both in the epidermis of the skin and in the hair. Filaggrin [rich in some AAs (e.g., serine, glutamate, glutamine, glycine, arginine, and histidine)] is another physiologically important protein in the epidermis of the skin. Collagen and elastin (rich in glycine and proline plus 4-hydroxyproline) are the predominant proteins in the dermis and hypodermis of the skin. Taurine and 4-hydroxyproline are abundant free AAs in the skin of dogs and cats, and 4-hydroxyproline is also an abundant free AA in their hair. The epidermis of the skin synthesizes melanin (the pigment in the skin and hair) from tyrosine and produces trans-urocanate from histidine. Qualitative requirements for proteinogenic AAs are similar between cats and dogs but not identical. Both animal species require the same AAs to nourish the hair and skin but the amounts differ. Other factors (e.g., breeds, coat color, and age) may affect the requirements of cats or dogs for nutrients. The development of a healthy coat, especially a black coat, as well as healthy skin critically depends on AAs [particularly arginine, glycine, histidine, proline, 4-hydroxyproline, and serine, sulfur AAs (methionine, cysteine, and taurine), phenylalanine, and tyrosine] and creatine. Although there are a myriad of studies on AA nutrition in cats and dogs, there is still much to learn about how each AA affects the growth, development and maintenance of the hair and skin. Animal-sourced foodstuffs (e.g., feather meal and poultry by-product meal) are excellent sources of the AAs that are crucial to maintain the normal structure and health of the skin and hair in dogs and cats.

Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node.

Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a CD8+ PD-1+ Tcf-1+ stem-like T cell subset in the tumor-draining lymph node (TdLN). Using murine melanoma models, we found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. Our data indicate that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor.

Alteration of iron responsive gene expression in Arabidopsis glutaredoxin S17 loss of function plants with or without iron stress.

Iron (Fe) is a mineral nutrient and a metal cofactor essential for plants. Iron limitation can have detrimental effects on plant growth and development, while excess iron inside plant cells leads to oxidative damage. As a result, plants have evolved complex regulatory networks to respond to fluctuations in cellular iron concentrations. The mechanisms that regulate these responses however, are not fully understood. Heterologous expression of an Arabidopsis thaliana monothiol glutaredoxin S17 (GRXS17) suppresses the over-accumulation of iron in the Saccharomyces cerevisiae Grx3/Grx4 mutant and disruption of GRXS17 causes plant sensitivity to exogenous oxidants and iron deficiency stress. GRXS17 may act as an important regulator in the plant's ability to respond to iron deficiency stress and maintain redox homeostasis. Here, we extend this investigation by analyzing iron-responsive gene expression of the Fer-like iron deficiency-induced transcription factor (FIT) network (FIT, IRT1, FRO1, and FRO2) and the bHLH transcription factor POPEYE (PYE) network (PYE, ZIF1, FRO3, NAS4, and BTS) in GRXS17 KO plants and wildtype controls grown under iron sufficiency and deficiency conditions. Our findings suggest that GRXS17 is required for tolerance to iron deficiency, and plays a negative regulatory role under conditions of iron sufficiency.

The Mount Sinai Patient-Centered Preoperative Criteria Meant to Optimize Outcomes Are Less of a Barrier to Care Than WPATH SOC 7 Criteria Before Transgender-Specific Surgery.

Objectives: With expanding coverage of gender-affirming care in the United States, many insurers default to the World Professional Association for Transgender Health (WPATH) Standards of Care 7 (SOC 7) to establish eligibility requirements for surgery coverage. Informed by bariatric and transplant surgery evaluation models, the Mount Sinai Center for Transgender Medicine and Surgery (CTMS) developed patient-centered criteria to assess readiness for surgery, focusing on concerns that could impair recovery. To make recommendations for the next version of the WPATH SOC, SOC 8, we compared Mount Sinai patient-centered surgical readiness criteria with the WPATH SOC 7 criteria. Methods: Data were extracted from a deidentified data set developed as part the quality dashboard for CTMS. The data set included all patients seeking vaginoplasty who were evaluated by a single mental health provider, from July 2016 through August 2018, and who completed the full CTMS assessment. The number of patients eligible for surgery based on the Mount Sinai CTMS criteria was compared with the number of patients eligible for surgery according to WPATH SOC 7 criteria. Results: Of 139 patients identified, 63 (45%) were ready for surgery immediately based on the Mount Sinai patient-centered model. By contrast, only 21 (15%) out of the 139 met criteria for surgery based on WPATH SOC 7. Fifty patients (40%) were ready for surgery as per Mount Sinai patient-centered readiness review but not WPATH criteria. Conclusion: An assessment designed to better prepare patients for surgery may also result in fewer barriers to care than existing criteria used by insurance companies in the United States.

Mitochondrial Iron Transporters (MIT1 and MIT2) Are Essential for Iron Homeostasis and Embryogenesis in Arabidopsis thaliana.

Iron (Fe) is an essential nutrient for virtually all organisms, where it functions in critical electron transfer processes, like those involved in respiration. Photosynthetic organisms have special requirements for Fe due to its importance in photosynthesis. While the importance of Fe for mitochondria- and chloroplast-localized processes is clear, our understanding of the molecular mechanisms that underlie the trafficking of Fe to these compartments is not complete. Here, we describe the Arabidopsis mitochondrial iron transporters, MIT1 and MIT2, that belong to the mitochondrial carrier family (MCF) of transport proteins. MIT1 and MIT2 display considerable homology with known mitochondrial Fe transporters of other organisms. Expression of MIT1 or MIT2 rescues the phenotype of the yeast mrs3mrs4 mutant, which is defective in mitochondrial iron transport. Although the Arabidopsis mit1 and mit2 single mutants do not show any significant visible phenotypes, the double mutant mit1mit2 displays embryo lethality. Analysis of a mit1 -- /mit2 + - line revealed that MIT1 and MIT2 are essential for iron acquisition by mitochondria and proper mitochondrial function. In addition, loss of MIT function results in mislocalization of Fe, which in turn causes upregulation of the root high affinity Fe uptake pathway. Thus, MIT1 and MIT2 are required for the maintenance of both mitochondrial and whole plant Fe homeostasis, which, in turn, is important for the proper growth and development of the plant.

Anti-CTLA-4 based therapy elicits humoral immunity to galectin-3 in patients with metastatic melanoma.

The combination of CTLA-4 blockade ipilimumab (Ipi) with VEGF-A blocking antibody bevacizumab (Bev) has demonstrated favorable clinical outcomes in patients with advanced melanoma. Galectin-3 (Gal-3) plays a prominent role in tumor growth, metastasis, angiogenesis, and immune evasion. Here we report that Ipi plus Bev (Ipi-Bev) therapy increased Gal-3 antibody titers by 50% or more in approximately one third of treated patients. Antibody responses to Gal-3 were associated with higher complete and partial responses and better overall survival. Ipi alone also elicited antibody responses to Gal-3 at a frequency comparable to the Ipi-Bev combination. However, an association of elicited antibody responses to Gal-3 with clinical outcomes was not observed in Ipi alone treated patients. In contrast to being neutralized in Ipi-Bev treated patients, circulating VEGF-A increased by 100% or more in a subset of patients after Ipi treatment, with most having progressive disease. Among the Ipi treated patients with therapy-induced Gal-3 antibody increases, circulating VEGF-A was increased in 3 of 6 nonresponders but in none of 4 responders as a result of treatment. Gal-3 antibody responses occurred significantly less frequently (3.2%) in a cohort of patients receiving PD-1 blockade where high pre-treatment serum Gal-3 was associated with reduced OS and response rates. Our findings suggest that anti-CTLA-4 elicited humoral immune responses to Gal-3 in melanoma patients which may contribute to the antitumor effect in the presence of an anti-VEGF-A combination. Furthermore, pre-treatment circulating Gal-3 may potentially have prognostic and predictive value for immune checkpoint therapy.

Myeloablative busulfan/cytoxan conditioning versus reduced-intensity fludarabine/melphalan conditioning for allogeneic hematopoietic stem cell transplant in patients with acute myelogenous leukemia.

Fludarabine and melphalan (Flu/Mel) has emerged as a more tolerable chemotherapy-based conditioning regimen compared with busulfan and cyclophosphamide (Bu/Cy) for allogeneic stem cell transplant (allo-hematopoietic stem cell transplantation (HSCT)) patients with acute myelogenous leukemia (AML). We conducted a retrospective review of a single-institution database including patients with AML who received allo-HSCT following conditioning with Mel/Flu or Bu/Cy-based regimens. We performed descriptive statistical analysis to examine patient demographics and clinical outcomes. We identified 156 patients meeting criteria between 2005 and 2014. Overall, patients conditioned with Bu/Cy were significantly younger, but more likely to be treated in an earlier era than those receiving Flu/Mel. Regimen choice was not associated with relapse rates (RR), relapse-free survival (RFS), or overall survival (OS) on both univariate and multivariable analyses. Bu/Cy was associated with increased non-relapse mortality (NRM) on multivariable analysis. These findings demonstrate that Flu/Mel provides non-inferior disease control and could be an appropriate regimen for selected patients.

SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination.

DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.

Arabidopsis Glutaredoxin S17 Contributes to Vegetative Growth, Mineral Accumulation, and Redox Balance during Iron Deficiency.

Iron (Fe) is an essential mineral nutrient and a metal cofactor required for many proteins and enzymes involved in the processes of DNA synthesis, respiration, and photosynthesis. Iron limitation can have detrimental effects on plant growth and development. Such effects are mediated, at least in part, through the generation of reactive oxygen species (ROS). Thus, plants have evolved a complex regulatory network to respond to conditions of iron limitations. However, the mechanisms that couple iron deficiency and oxidative stress responses are not fully understood. Here, we report the discovery that an Arabidopsis thaliana monothiol glutaredoxin S17 (AtGRXS17) plays a critical role in the plants ability to respond to iron deficiency stress and maintain redox homeostasis. In a yeast expression assay, AtGRXS17 was able to suppress the iron accumulation in yeast ScGrx3/ScGrx4 mutant cells. Genetic analysis indicated that plants with reduced AtGRXS17 expression were hypersensitive to iron deficiency and showed increased iron concentrations in mature seeds. Disruption of AtGRXS17 caused plant sensitivity to exogenous oxidants and increased ROS production under iron deficiency. Addition of reduced glutathione rescued the growth and alleviates the sensitivity of atgrxs17 mutants to iron deficiency. These findings suggest AtGRXS17 helps integrate redox homeostasis and iron deficiency responses.

Directing iron transport in dicots: regulation of iron acquisition and translocation.

Iron is essential for plant growth and development, but excess iron is cytotoxic. While iron is abundant in soil, it is often a limiting nutrient for plant growth. Consequentially, plants have evolved mechanisms to tightly regulate iron uptake, trafficking and storage. Recent work has contributed to a more comprehensive picture of iron uptake, further elucidating molecular and physiological processes that aid in solubilization of iron and modulation of the root system architecture in response to iron availability. Recent progress in understanding the regulators of the iron deficiency response and iron translocation from root to shoots, and especially to seeds are noteworthy. The molecular bases of iron sensing and signaling are gradually emerging, as well.

Combined Anti-VEGF and Anti-CTLA-4 Therapy Elicits Humoral Immunity to Galectin-1 Which Is Associated with Favorable Clinical Outcomes.

The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint anti-CTLA-4 blockade (ipilimumab) in a phase I study showed tumor endothelial activation and immune cell infiltration that were associated with favorable clinical outcomes in patients with metastatic melanoma. To identify potential immune targets responsible for these observations, posttreatment plasma from long-term responding patients were used to screen human protein arrays. We reported that ipilimumab plus bevacizumab therapy elicited humoral immune responses to galectin-1 (Gal-1), which exhibits protumor, proangiogenesis, and immunosuppressive activities in 37.2% of treated patients. Gal-1 antibodies purified from posttreatment plasma suppressed the binding of Gal-1 to CD45, a T-cell surface receptor that transduces apoptotic signals upon binding to extracellular Gal-1. Antibody responses to Gal-1 were found more frequently in the group of patients with therapeutic responses and correlated with improved overall survival. In contrast, another subgroup of treated patients had increased circulating Gal-1 protein instead, and they had reduced overall survival. Our findings suggest that humoral immunity to Gal-1 may contribute to the efficacy of anti-VEGF and anti-CTLA-4 combination therapy. Gal-1 may offer an additional therapeutic target linking anti-angiogenesis and immune checkpoint blockade. Cancer Immunol Res; 5(6); 446-54. ©2017 AACR.

Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.

Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in cancer treatment. However, the identification of biomarkers for predicting clinical outcomes and mechanisms to overcome resistance remain as critical needs. Angiogenesis is increasingly appreciated as an immune modulator with potential for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an immune target in patients and is involved in resistance to anti-VEGF treatment with the monoclonal antibody bevacizumab. We investigated the predictive and prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with reduced overall survival in CTLA-4 and PD-1 blockade-treated patients. These treatments also increased serum ANGPT2 in many patients early after treatment initiation, whereas ipilimumab plus bevacizumab treatment decreased serum concentrations. ANGPT2 increases were associated with reduced response and/or overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab decreased, tumor vascular ANGPT2 expression in a subset of patients, which was associated with increased and decreased tumor infiltration by CD68+ and CD163+ macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting and functional antibody responses to ANGPT2 in a subset of patients receiving clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a predictive and prognostic biomarker for immune checkpoint therapy and may contribute to treatment resistance via increasing proangiogenic and immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2 provides a rational combinatorial approach to improve the efficacy of immune therapy. Cancer Immunol Res; 5(1); 17-28. ©2016 AACR.

Outcomes of magnetic sphincter augmentation - A community hospital perspective.

BACKGROUND: Magnetic sphincter augmentation (MSA) is FDA approved for the surgical treatment of GERD. While multiple reports from academic settings exist, we report the early experience from two community-based health systems. METHODS: The first 102 post-trial cases of MSA were reviewed. Outcomes were compared to those in the initial clinical trial. RESULTS: Mean follow-up duration was 7.6 months. GERD medication use decreased from 98% preoperative to 8% postoperative (P<0.001). Median GERD health-related quality of life (HRQL) improved from 27 preoperative to 5 postoperative (P<0.001). Patient satisfaction increased from 8% preoperative to 84% postoperative (P<0.001). Results were similar to the trial data. CONCLUSIONS: MSA is a safe and effective treatment for GERD, with significant improvement in quality of life. GERD-HRQL, medication reduction, operative times, and dysphagia rates were similar to other reports, demonstrating the reproducibility of MSA. Lower dilation rates may be due to refinements in technique and postoperative dietary management.

Resolution of Fundic Gland Polyposis following Laparoscopic Magnetic Sphincter Augmentation and Subsequent Cessation of Proton Pump Inhibitors.

Gastric polyps occur from a variety of sources and are found commonly on upper endoscopy. We present the case of a 49-year-old female who presented for evaluation for antireflux surgery with a history of fundic gland polyposis who required twice-daily proton pump inhibitors (PPIs) for control of her gastric reflux. After verifying that she met criteria for surgery, she underwent an uncomplicated laparoscopic magnetic sphincter augmentation placement. With the cessation of PPIs following surgery, the fundic gland polyposis resolved. Fundic gland polyps may occur sporadically or within certain syndromes, such as familial adenomatous polyposis. Multiple possible inciting factors exist, including the use of PPIs. This is the first reported case of the resolution of numerous fundic gland polyps following the completion of laparoscopic magnetic sphincter augmentation.

The diverse roles of FRO family metalloreductases in iron and copper homeostasis.

Iron and copper are essential for plants and are important for the function of a number of protein complexes involved in photosynthesis and respiration. As the molecular mechanisms that control uptake, trafficking and storage of these nutrients emerge, the importance of metalloreductase-catalyzed reactions in iron and copper metabolism has become clear. This review focuses on the ferric reductase oxidase (FRO) family of metalloreductases in plants and highlights new insights into the roles of FRO family members in metal homeostasis. Arabidopsis FRO2 was first identified as the ferric chelate reductase that reduces ferric iron-chelates at the root surface-rhizosphere interface. The resulting ferrous iron is subsequently transported across the plasma membrane of root epidermal cells by the ferrous iron transporter, IRT1. Recent work has shown that two other members of the FRO family (FRO4 and FRO5) function redundantly to reduce copper to facilitate its uptake from the soil. In addition, FROs appear to play important roles in subcellular compartmentalization of iron as FRO7 is known to contribute to delivery of iron to chloroplasts while mitochondrial family members FRO3 and FRO8 are hypothesized to influence mitochondrial metal ion homeostasis. Finally, recent studies have underscored the importance of plasma membrane-localized ferric reductase activity in leaves for photosynthetic efficiency. Taken together, these studies highlight a number of diverse roles for FROs in both iron and copper metabolism in plants.

Mitochondrial iron transport and homeostasis in plants.

Iron (Fe) is an essential nutrient for plants and although the mechanisms controlling iron uptake from the soil are relatively well understood, comparatively little is known about subcellular trafficking of iron in plant cells. Mitochondria represent a significant iron sink within cells, as iron is required for the proper functioning of respiratory chain protein complexes. Mitochondria are a site of Fe-S cluster synthesis, and possibly heme synthesis as well. Here we review recent insights into the molecular mechanisms controlling mitochondrial iron transport and homeostasis. We focus on the recent identification of a mitochondrial iron uptake transporter in rice and a possible role for metalloreductases in iron uptake by mitochondria. In addition, we highlight recent advances in mitochondrial iron homeostasis with an emphasis on the roles of frataxin and ferritin in iron trafficking and storage within mitochondria.

Complexities of TGF-ß targeted cancer therapy.

Many advanced tumors produce excessive amounts of Transforming Growth Factor-ß (TGF-ß) which, in normal epithelial cells, is a potent growth inhibitor. However, in oncogenically activated cells, the homeostatic action of TGF-ß is often diverted along alternative pathways. Hence, TGF-ß signaling elicits protective or tumor suppressive effects during the early growth-sensitive stages of tumorigenesis. However, later in tumor development when carcinoma cells become refractory to TGF-ß-mediated growth inhibition, the tumor cell responds by stimulating pathways with tumor progressing effects. At late stages of malignancy, tumor progression is driven by TGF-ß overload. The tumor microenvironment is a target of TGF-ß action that stimulates tumor progression via pro-tumorigenic effects on vascular, immune, and fibroblastic cells. Bone is one of the richest sources of TGF-ß in the body and a common site for dissemination of breast cancer metastases. Osteoclastic degradation of bone matrix, which accompanies establishment and growth of metastases, triggers further release of bone-derived TGF-ß. This leads to a vicious positive feedback of tumor progression, driven by ever increasing levels of TGF-ß released from both the tumor and bone matrix. It is for this reason, that pharmaceutical companies have developed therapeutic agents that block TGF-ß signaling. Nonetheless, the choice of drug design and dosing strategy can affect the efficacy of TGF-ß therapeutics. This review will describe pre-clinical and clinical data of four major classes of TGF-ß inhibitor, namely i) ligand traps, ii) antisense oligonucleotides, iii) receptor kinase inhibitors and iv) peptide aptamers. Long term dosing strategies with TGF-ß inhibitors may be ill-advised, since this class of drug has potentially highly pleiotropic activity, and development of drug resistance might potentiate tumor progression. Current paradigms for the use of TGF-ß inhibitors in oncology have therefore moved towards the use of combinatorial therapies and short term dosing, with considerable promise for the clinic.

TGF-ß-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion.

In cancer progression, carcinoma cells gain invasive behavior through a loss of epithelial characteristics and acquisition of mesenchymal properties, a process that can lead to epithelial-mesenchymal transition (EMT). TGF-ß is a potent inducer of EMT, and increased TGF-ß signaling in cancer cells is thought to drive cancer-associated EMT. Here, we examine the physiological requirement for mTOR complex 2 (mTORC2) in cells undergoing EMT. TGF-ß rapidly induces mTORC2 kinase activity in cells undergoing EMT, and controls epithelial cell progression through EMT. By regulating EMT-associated cytoskeletal changes and gene expression, mTORC2 is required for cell migration and invasion. Furthermore, inactivation of mTORC2 prevents cancer cell dissemination in vivo. Our results suggest that the mTORC2 pathway is an essential downstream branch of TGF-ß signaling, and represents a responsive target to inhibit EMT and prevent cancer cell invasion and metastasis.

Transcriptome sequencing identifies SPL7-regulated copper acquisition genes FRO4/FRO5 and the copper dependence of iron homeostasis in Arabidopsis.

The transition metal copper (Cu) is essential for all living organisms but is toxic when present in excess. To identify Cu deficiency responses comprehensively, we conducted genome-wide sequencing-based transcript profiling of Arabidopsis thaliana wild-type plants and of a mutant defective in the gene encoding SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7 (SPL7), which acts as a transcriptional regulator of Cu deficiency responses. In response to Cu deficiency, FERRIC REDUCTASE OXIDASE5 (FRO5) and FRO4 transcript levels increased strongly, in an SPL7-dependent manner. Biochemical assays and confocal imaging of a Cu-specific fluorophore showed that high-affinity root Cu uptake requires prior FRO5/FRO4-dependent Cu(II)-specific reduction to Cu(I) and SPL7 function. Plant iron (Fe) deficiency markers were activated in Cu-deficient media, in which reduced growth of the spl7 mutant was partially rescued by Fe supplementation. Cultivation in Cu-deficient media caused a defect in root-to-shoot Fe translocation, which was exacerbated in spl7 and associated with a lack of ferroxidase activity. This is consistent with a possible role for a multicopper oxidase in Arabidopsis Fe homeostasis, as previously described in yeast, humans, and green algae. These insights into root Cu uptake and the interaction between Cu and Fe homeostasis will advance plant nutrition, crop breeding, and biogeochemical research.

The complexities of TGF-ß action during mammary and squamous cell carcinogenesis.

Many advanced tumors produce excess amounts of Transforming Growth Factor-ß (TGF-ß), which is a potent growth inhibitor of normal epithelial cells. However, in tumors its homeostatic action on cells can be diverted along several alternative pathways. Thus, TGF-ß signaling has been reported to elicit a preventative or tumor suppressive effect during the earlier stages of tumorigenesis, but later in tumor development, when carcinoma cells become refractory to TGF-ß-mediated growth inhibition, response to TGF-ß signaling elicits predominantly tumor progressing effects. This is not a simple switch from suppression to progression, but more like a rheostat, involving multiple complementary and antagonizing activities that slowly tip the balance from one to the other. This review will focus on the multiple activities of TGF-ß in regulation of two epithelial tumor types, namely squamous cell carcinoma and breast cancer. Basic findings in current mouse models of cancer are presented, as well as a discussion of the complicating issue of outcome of altered TGFß signaling depending on genetic variability between mouse strains. This review also discusses the role TGF-ß within the tumor microenvironment particularly its ability to polarize the microenvironment towards a pro-tumorigenic milieu.