Symbiotic Firmicutes establish mutualism with the host via innate tolerance and resistance to control systemic immunity.

The intestinal microbiota regulates immunity across organ systems. Which symbionts control systemic immunity, the mechanisms they use, and how they avoid widespread inflammatory damage are unclear. We uncover host tolerance and resistance mechanisms that allow Firmicutes from the human microbiota to control systemic immunity without inducing immunopathology. Intestinal processing releases Firmicute glycoconjugates that disseminate, resulting in release of cytokine IL-34 that stimulates macrophages and enhances defenses against pneumonia, sepsis, and meningitis. Despite systemic penetration of Firmicutes, immune homeostasis is maintained through feedback control whereby IL-34-mediated mTORC1 activation in macrophages clears polymeric glycoconjugates from peripheral tissues. Smaller glycoconjugates evading this clearance mechanism are tolerated through sequestration by albumin, which acts as an inflammatory buffer constraining their immunological impact. Without these resistance and tolerance mechanisms, Firmicutes drive catastrophic organ damage and cachexia via IL-1ß. This reveals how Firmicutes are safely assimilated into systemic immunity to protect against infection without threatening host viability.

Does large dam removal restore downstream riparian vegetation diversity? Testing predictions on the Elwha River, Washington, USA.

Large dams and their removal can profoundly affect riparian ecosystems by altering flow and sediment regimes, hydrochory, and landform dynamics, yet few studies have documented these effects on downstream plant communities. Ecological theory and empirical results suggest that by altering disturbance regimes, reducing hydrochory, and shifting communities to later successional stages, dams reduce downstream plant diversity. Dam removal could reverse these processes, but the release of large volumes of sediment could have unexpected, transient effects. Two large dams were removed on the Elwha River in Washington State, USA, from 2011 to 2014, representing an unprecedented opportunity to study large dam removal effects on riparian plant communities. Our research objectives were to determine: (1) whether the Elwha River dams were associated with lower downstream plant diversity and altered species composition across riparian landforms pre-dam removal, and (2) whether dam removal has begun to restore downstream diversity and composition. To address these objectives, we compared plant species richness and community composition in river segments above, below, and between the two dams. Plant communities were sampled twice before (2005 and 2010) and four times after (2013, 2014, 2016, and 2017) the start of dam removal, with 2013 and 2014 sampled while the upstream dam removal was ongoing. Prior to dam removal, native species richness was 41% lower below dams compared with the upstream segment; 6 years after dam removal began, it increased ~31% between the dams, whereas nonnative species richness and cover were not apparently affected by dams or their removal. Deposition caused by large volumes of released reservoir sediment had mixed effects on native species richness (increased on floodplains, decreased elsewhere) in the lowest river segment. Plant community composition was also different downstream from dams compared with the upstream reference, and has changed in downstream floodplains and bars since dam removal. In the long term, we expect that diversity will continue to increase in downstream river segments. Our results provide evidence that (1) large dams reduce downstream native plant diversity, (2) dam removal may restore it, and (3) given the natural dynamics of riparian vegetation, long-term, multiyear before-and-after monitoring is essential for understanding dam removal effects.

Immunological design of commensal communities to treat intestinal infection and inflammation.

The immunological impact of individual commensal species within the microbiota is poorly understood limiting the use of commensals to treat disease. Here, we systematically profile the immunological fingerprint of commensals from the major phyla in the human intestine (Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria) to reveal taxonomic patterns in immune activation and use this information to rationally design commensal communities to enhance antibacterial defenses and combat intestinal inflammation. We reveal that Bacteroidetes and Firmicutes have distinct effects on intestinal immunity by differentially inducing primary and secondary response genes. Within these phyla, the immunostimulatory capacity of commensals from the Bacteroidia class (Bacteroidetes phyla) reflects their robustness of TLR4 activation and Bacteroidia communities rely solely on this receptor for their effects on intestinal immunity. By contrast, within the Clostridia class (Firmicutes phyla) it reflects the degree of TLR2 and TLR4 activation, and communities of Clostridia signal via both of these receptors to exert their effects on intestinal immunity. By analyzing the receptors, intracellular signaling components and transcription factors that are engaged by different commensal species, we identify canonical NF-κB signaling as a critical rheostat which grades the degree of immune stimulation commensals elicit. Guided by this immunological analysis, we constructed a cross-phylum consortium of commensals (Bacteroides uniformis, Bacteroides ovatus, Peptostreptococcus anaerobius and Clostridium histolyticum) which enhances innate TLR, IL6 and macrophages-dependent defenses against intestinal colonization by vancomycin resistant Enterococci, and fortifies mucosal barrier function during pathological intestinal inflammation through the same pathway. Critically, the setpoint of intestinal immunity established by this consortium is calibrated by canonical NF-κB signaling. Thus, by profiling the immunological impact of major human commensal species our work paves the way for rational microbiota reengineering to protect against antibiotic resistant infections and to treat intestinal inflammation.

Evaluation of Acellular Dermal Matrix Efficacy in Prosthesis-Based Breast Reconstruction.

BACKGROUND: Although many studies have examined the safety of acellular dermal matrix in immediate prosthetic breast reconstruction, few studies have evaluated efficacy. This study examined initial tissue expander fill volume as a marker of efficacy, comparing patients after staged prosthetic breast reconstruction assisted with acellular dermal matrix versus breast reconstruction not assisted with acellular dermal matrix. Number of fill visits and time interval to implant exchange were examined as secondary endpoints. METHODS: An institutional review board-approved retrospective chart review was conducted to identify consecutive staged prosthetic reconstruction cases over 12 years. RESULTS: Mean initial tissue expander fill volume was significantly higher in the acellular dermal matrix group compared with the non-acellular dermal matrix group (180.8 ± 150.0 versus 45.8 ± 74.4; p = 0.00). Normalizing for final implant size, the acellular dermal matrix group exhibited significantly higher perioperative fill (0.33 ± 0.24 versus 0.11 ± 0.16; p = 0.00). A collinear trend was observed between acellular dermal matrix use and direct-to-implant reconstruction procedures during the study period. CONCLUSIONS: These results suggest that acellular dermal matrix use is more efficacious in achieving greater initial fill volume, fewer visits for expansion, and a shorter time interval to implant exchange compared with non-acellular dermal matrix procedures. The authors also describe a collinear relationship between acellular dermal matrix use and transition to direct-to-implant procedures at their institution. This work serves as a framework for future studies evaluating acellular dermal matrix efficacy, and guides innovation of biomaterials to support breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

The microbiota protects against respiratory infection via GM-CSF signaling.

The microbiota promotes resistance to respiratory infection, but the mechanistic basis for this is poorly defined. Here, we identify members of the microbiota that protect against respiratory infection by the major human pathogens Streptococcus pneumoniae and Klebsiella pneumoniae. We show that the microbiota enhances respiratory defenses via granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which stimulates pathogen killing and clearance by alveolar macrophages through extracellular signal-regulated kinase signaling. Increased pulmonary GM-CSF production in response to infection is primed by the microbiota through interleukin-17A. By combining models of commensal colonization in antibiotic-treated and germ-free mice, using cultured commensals from the Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria phyla, we found that potent Nod-like receptor-stimulating bacteria in the upper airway (Staphylococcus aureus and Staphylococcus epidermidis) and intestinal microbiota (Lactobacillus reuteri, Enterococcus faecalis, Lactobacillus crispatus and Clostridium orbiscindens) promote resistance to lung infection through Nod2 and GM-CSF. Our data reveal the identity, location, and properties of bacteria within the microbiota that regulate lung immunity, and delineate the host signaling axis they activate to protect against respiratory infection.

The regulation of host defences to infection by the microbiota.

The skin and mucosal epithelia of humans and other mammals are permanently colonized by large microbial communities (the microbiota). Due to this life-long association with the microbiota, these microbes have an extensive influence over the physiology of their host organism. It is now becoming apparent that nearly all tissues and organ systems, whether in direct contact with the microbiota or in deeper host sites, are under microbial influence. The immune system is perhaps the most profoundly affected, with the microbiota programming both its innate and adaptive arms. The regulation of immunity by the microbiota helps to protect the host against intestinal and extra-intestinal infection by many classes of pathogen. In this review, we will discuss the experimental evidence supporting a role for the microbiota in regulating host defences to extra-intestinal infection, draw together common mechanistic themes, including the central role of pattern recognition receptors, and outline outstanding questions that need to be answered.

Cabozantinib for the treatment of advanced medullary thyroid cancer.

INTRODUCTION: Patients with advanced medullary thyroid cancer (MTC) have poor prognoses and limited treatment options. Improved knowledge about molecular aberrations associated with MTC and the availability of novel targeted tyrosine kinase inhibitors (TKIs) have led to new potential treatment modalities. Cabozantinib is an oral multitargeted TKI with activity against multiple receptors including RET, vascular endothelial growth factor receptor type 2 (VEGFR2), and MET that has been evaluated in MTC in the preclinical and clinical arenas. METHODS: This article reviews unmet clinical needs in advanced MTC. The authors consider novel agents that have been studied in MTC, with a focus on the investigational agent cabozantinib. Up-to-date clinical data of cabozantinib in MTC are discussed. RESULTS: Recent clinical evaluation suggests that cabozantinib is the first agent to prolong progression-free survival in patients with progressive MTC. These findings indicate that cabozantinib may be an effective therapy in advanced MTC. No improvement in overall survival has been demonstrated but data are not mature. CONCLUSION: Cabozantinib may be an effective treatment option for patients with advanced MTC and is worthy of further evaluation.

Clinical use of U-500 regular insulin: review and meta-analysis.

The use of U-500 regular insulin (U-500R) to treat diabetic patients with severe insulin resistance has increased. In this review, we performed a meta-analysis of PubMed studies reporting the use of U-500R to evaluate the effects of U-500R on hemoglobin A1c (HbA1c), body weight, and total daily insulin dose (TDD). These studies included 310 patients using U-500R as multiple daily injections (MDI) and 55 patients using U-500R via continuous subcutaneous insulin infusion (CSII). Overall, the use of U-500R as MDI resulted in a significant HbA1c reduction of 1.59%, a significant weight gain of 4.38 kg, and a significant increase in TDD by 51.9 units. The use of U-500R via CSII resulted in a similarly significant HbA1c reduction of 1.64% but a nonsignificant weight gain and a nonsignificant change in TDD. The use of U-500 regular insulin both as MDI and via CSII was not reported to be associated with severe hypoglycemia but was associated with an increase in patient satisfaction as well as in cost savings. Suggestions in initiating U-500R in the outpatient setting using U-500R in hospitalized patients are reviewed. In addition, precautions for avoiding prescription and patient errors are discussed.

Tyrosine kinase inhibitor-induced hypothyroidism: incidence, etiology, and management.

In recent years, tyrosine kinase inhibitors (TKIs) have emerged as a new class of anti-cancer therapy with proven efficacy in several types of carcinoma. Although generally considered less toxic than cytotoxic chemotherapy, TKIs do have significant side effects including fatigue and hypertension. In addition, TKI-induced thyroid dysfunction is now recognized as a common toxicity that is associated with some TKI inhibitors. Detection of TKI-induced thyroid dysfunction requires routine monitoring of thyroid function and, in some cases, may require treatment. This review provides a comprehensive assessment of literature evaluating TKI-induced thyroid dysfunction, focusing on the potential mechanisms that result in this toxicity, whether the development of thyroid dysfunction is clinically meaningful, and controversies regarding treatment with thyroid hormone therapy.

Thyroid cancer: burden of illness and management of disease.

OBJECTIVE: The incidence of thyroid cancer, the most common endocrine malignancy, has increased dramatically in the last fifty years. This article will review the standard approach to thyroid cancer treatment as well as novel therapies under investigation. We will also address potential cost considerations in the management of thyroid cancer. STUDY DESIGN: A comprehensive literature search was performed. METHODS: Review article. RESULTS: The high prevalence of thyroid cancer and the availability of novel therapies for patients with metastatic disease have potential economic implications that have not been well-studied. Because many patients likely have very low morbidity from their cancers, better tools to identify the lowest risk patients are needed in order to prevent overtreatment. Improved risk stratification should include recognizing patients who are unlikely to benefit from radioactive iodine therapy after initial surgery and identifying those with indolent and asymptomatic metastatic disease that are unlikely to benefit from novel therapies. In patients with advanced incurable disease, randomized-controlled studies to assess the efficacy of novel agents are needed to determine if the costs associated with new agents are warranted. CONCLUSIONS: Health care costs associated with the increased diagnosis of thyroid cancer remain unknown but are worthy of further research.

The role of hydrochory in structuring riparian and wetland vegetation.

Hydrochory, or the passive dispersal of organisms by water, is an important means of propagule transport, especially for plants. During recent years, knowledge about hydrochory and its ecological consequences has increased considerably and a substantial body of literature has been produced. Here, we review this literature and define the state of the art of the discipline. A substantial proportion of species growing in or near water have propagules (fruits, seeds or vegetative units) able to disperse by water, either floating, submerged in flowing water, or with the help of floating vessels. Hydrochory can enable plants to colonize sites out of reach with other dispersal vectors, but the timing of dispersal and mechanisms of establishment are important for successful establishment. At the population level, hydrochory may increase the effective size and longevity of populations, and control their spatial configuration. Hydrochory is also an important source of species colonizing recruitment-limited riparian and wetland communities, contributing to maintenance of community species richness. Dispersal by water may even influence community composition in different landscape elements, resulting in landscape-level patterns. Genetically, hydrochory may reduce spatial aggregation of genetically related individuals, lead to high gene flow among populations, and increase genetic diversity in populations receiving many propagules. Humans have impacted hydrochory in many ways. For example, dams affect hydrochory by reducing peak flows and hence dispersal capacity, altering the timing of dispersal, and by presenting physical barriers to dispersal, with consequences for riverine plant communities. Hydrochory has been inferred to be an important vector for the spread of many invasive species, but there is also the potential for enhancing ecosystem restoration by improving or restoring water dispersal pathways. Climate change may alter the role of hydrochory by modifying the hydrology of water-bodies as well as conditions for propagule release and plant colonization.

Standard and emerging therapeutic approaches for thyroid malignancies.

Differentiated thyroid cancer (DTC) is the most common endocrine malignancy. The standard treatment for DTC includes surgery, radioiodine ablation, and thyroid hormone-suppressive therapy. With this approach, overall survival is excellent. Still, controversy exists when tailoring therapy according to an individual's chance of developing metastases. Patients with genetic and environmental risk factors, those at the extremes of age, and those with comorbid conditions require special consideration. The most effective method to monitor patients for disease recurrence and the most optimal treatment for those who recur are debated. New understandings about the genetic aberrations underlying thyroid cancer have led to novel therapeutic options for patients with metastatic disease. The traditional approach to DTC treatment with an emphasis on topics of continued uncertainty will be discussed. In addition, emerging therapies for DTC will be reviewed.

Transformation of a pituitary macroadenoma into to a corticotropin-secreting carcinoma over 16 years.

OBJECTIVE: To describe a case of a pituitary macroadenoma that differentiated into a corticotropin (ACTH)-secreting carcinoma with metastasis to the thigh. METHODS: We present a case report with a 16-year follow-up that includes anatomic and endocrine documentation of the history of an ACTH-secreting carcinoma. RESULTS: A 32-year-old woman presented for evaluation in 1989 because of visual field defects. Magnetic resonance imaging revealed a locally invasive 3-cm macroadenoma. She had no clinical signs of cortisol excess. The patient underwent surgical debulking followed by a course of radiation directed to the pituitary. Results from retrospective immunohistochemical staining with antibodies against ACTH, prolactin, and MIB-1 were negative. Postoperatively, she could not be weaned from exogenous steroids without developing symptoms of adrenal insufficiency. In 1995, she developed left facial palsy and diplopia caused by tumor growth. In 1997, the patient developed progressive symptoms of cortisol excess, which continued after exogenous steroid replacement was discontinued. The patient's clinical status continued to deteriorate because of local mass effect from tumor growth and uncontrolled hypercortisolism. She underwent bilateral adrenalectomy in 2003. The patient remained debilitated in a long-term care facility for 2 years when she was found to have a mass on her left hip. Biopsy results of the obturator muscle revealed metastatic tumor of neuroendocrine origin with strong reactivity to ACTH antibodies and MIB-1 labeling in 8% of tumor cell nuclei. CONCLUSION: A pituitary tumor can transform into an ACTH-secreting carcinoma in an indolent manner. Patients with invasive pituitary adenomas require long-term surveillance to monitor for differentiation into pituitary carcinoma.

An approach to the evaluation and treatment of Cushing's disease.

Cushing's syndrome is an uncommon disorder involving dysregulation of the hypothalamic-pituitary-adrenal axis resulting in endogenous hypercortisolemia. It has multiple causes, but most commonly is due to hypersecretion of corticotropin from the pituitary gland, called Cushing's disease. The diagnosis of Cushing's syndrome remains a challenge to clinicians because routine hormonal assays can have significant overlap in pathological and normal states. We will review an approach to evaluating patients with suspected cortisol excess. We will also discuss treatment options and post-surgical assessment for those diagnosed with Cushing's disease.

A pituitary carcinoma secreting TSH and prolactin: a non-secreting adenoma gone awry.

To our knowledge, only one case of a TSH-secreting carcinoma has previously been reported. We describe here a second patient with a pituitary carcinoma producing TSH and prolactin (PRL). A 37-year-old male underwent a left frontotemporal craniotomy in 1996 for a sellar mass. Except for mildly increased PRL and elevated alpha-subunit, hormone evaluation was normal. Pathologic examination revealed a chromophobe adenoma with increased mitotic forms. The patient completed a course of external beam radiation to the pituitary and was prescribed l-thyroxine, bromocriptine, and hydrocortisone. He was lost to follow-up but did well for 6 years, until 2002, when he presented with TSH-dependent thyrotoxicosis and hyperprolactinemia. The patient was started on bromocriptine and propylthiouracil and was, again, lost to follow-up. In 2004, 9 years after his initial presentation, he presented after falling. Magnetic resonance imaging showed two brain masses with associated midline shift. Emergent resection of the larger mass revealed a pituitary cancer with positive staining for PRL, but not for TSH. Nine months later, the patient underwent further debulking of metastatic disease. Although development of a carcinoma from a pituitary adenoma is very rare (<0.5%), macroadenomas that become hormonally active should be suspect for transformation into pituitary cancer.

A role for the GCC-box in jasmonate-mediated activation of the PDF1.2 gene of Arabidopsis.

The PDF1.2 gene of Arabidopsis encoding a plant defensin is commonly used as a marker for characterization of the jasmonate-dependent defense responses. Here, using PDF1.2 promoter-deletion lines linked to the beta-glucoronidase-reporter gene, we examined putative promoter elements associated with jasmonate-responsive expression of this gene. Using stably transformed plants, we first characterized the extended promoter region that positively regulates basal expression from the PDF1.2 promoter. Second, using promoter deletion constructs including one from which the GCC-box region was deleted, we observed a substantially lower response to jasmonate than lines carrying this motif. In addition, point mutations introduced into the core GCC-box sequence substantially reduced jasmonate responsiveness, whereas addition of a 20-nucleotide-long promoter element carrying the core GCC-box and flanking nucleotides provided jasmonate responsiveness to a 35S minimal promoter. Taken together, these results indicated that the GCC-box plays a key role in conferring jasmonate responsiveness to the PDF1.2 promoter. However, deletion or specific mutations introduced into the core GCC-box did not completely abolish the jasmonate responsiveness of the promoter, suggesting that the other promoter elements lying downstream from the GCC-box region may also contribute to jasmonate responsiveness. In other experiments, we identified a jasmonate- and pathogen-responsive ethylene response factor transcription factor, AtERF2, which when overexpressed in transgenic Arabidopsis plants activated transcription from the PDF1.2, Thi2.1, and PR4 (basic chitinase) genes, all of which contain a GCC-box sequence in their promoters. Our results suggest that in addition to their roles in regulating ethylene-mediated gene expression, ethylene response factors also appear to play important roles in regulating jasmonate-responsive gene expression, possibly via interaction with the GCC-box.

AKAP7gamma is a nuclear RI-binding AKAP.

Spatial regulation of protein kinase A (PKA) is accomplished by its sequestration via A-kinase anchor proteins (AKAPs). PKA activity is critical for mammalian oocyte development, suggesting that PKA must be appropriately positioned in these large cells. A screen for AKAPs in oocytes identified AKAP7gamma, an AKAP originally found in pancreas. Yeast two-hybrid analysis and co-immunoprecipitation studies showed that AKAP7gamma bound the type I PKA regulatory subunit (RI) and that the RI-binding domain overlapped the previously identified type II PKA regulatory subunit (RII) binding domain. Overexpressed AKAP7gamma localized to the nuclei of HEK 293 cells via a nuclear localization signal. In addition, endogenous AKAP7gamma protein was found in both the nucleus and cytoplasm of oocytes. This work identifies AKAP7gamma as the first nuclear AKAP to bind RI and suggests that AKAP7gamma may be responsible for positioning PKA via RI and/or RII to regulate PKA-mediated gene transcription in both somatic cells and oocytes.