Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive basal-like breast cancers.

The discoidin domain receptor 1 (DDR1) is overexpressed in breast carcinoma cells. Low DDR1 expression is associated with worse relapse-free survival, reflecting its controversial role in cancer progression. We detected DDR1 on luminal cells but not on myoepithelial cells of DDR1+/+ mice. We found that DDR1 loss compromises cell adhesion, consistent with data that older DDR1-/- mammary glands had more basal/myoepithelial cells. Basal cells isolated from older mice exerted higher traction forces than the luminal cells, in agreement with increased mammary branches observed in older DDR1-/- mice and higher branching by their isolated organoids. When we crossed DDR1-/- mice with MMTV-PyMT mice, the PyMT/DDR1-/- mammary tumors grew faster and had increased epithelial tension and matricellular fibrosis with a more basal phenotype and increased lung metastases. DDR1 deletion induced basal differentiation of CD90+CD24+ cancer cells, and the increase in basal cells correlated with tumor cell mitoses. K14+ basal cells, including K8+K14+ cells, were increased adjacent to necrotic fields. These data suggest that the absence of DDR1 provides a growth and adhesion advantage that favors the expansion of basal cells, potentiates fibrosis, and enhances necrosis/hypoxia and basal differentiation of transformed cells to increase their aggression and metastatic potential.

Baseline cortisol levels and social behavior differ as a function of handedness in marmosets (Callithrix jacchus).

Population hand preferences are rare in nonhuman primates, but individual hand preferences are consistent over a lifetime and considered to reflect an individual's preference to use a particular hemisphere when engaged in a specific task. Previous findings in marmosets have indicated that left-handed individuals tend to be more fearful than their right-handed counterparts. Based on these findings, we tested the hypotheses that left-handed marmosets are (a) more reactive to a social stressor and (b) are slower than right-handed marmosets in acquiring a reversal learning task. We examined the hand preference of 27 male and female marmosets (ages of 4-7 years old) previously tested in a social separation task and a reversal learning task. Hand preference was determined via a simple reaching task. In the social separation task, monkeys were separated from their partner and the colony for a single 7-hr session. Urinary cortisol levels and behavior were assessed at baseline, during the separation and 24 hr postseparation. Hand preferences were equally distributed between left (n = 10), right-handed (n = 10), and ambidextrous (n = 7) individuals. The separation phase was associated with an increase in cortisol levels and behavioral changes that were similar across handedness groups. However, cortisol levels at baseline were positively correlated with right-handedness, and this relationship was stronger in females than in males. In addition, the occurrence of social behaviors (pre- and postseparation) was positively correlated with right-handedness in both sexes. Baseline cortisol levels did not correlate significantly with social behavior. Acquisition of the reversals was poorer in females than males but did not differ as a function of handedness. We conclude that (a) both stress reactivity and cognitive flexibility are similar across handedness groups and (b) left-handers exhibit less social behavior and have lower basal cortisol levels than ambidextrous and right-handed subjects. The underlying causes for these differences remain to be established.

The Asian Grocery Store-Based Cancer Education Program: Creating New Education Modules.

Operating since 1994, the UCSD Moores Cancer Center's Asian Grocery Store-Based Cancer Education Program (the Program) is a proven and sustainable strategy for disseminating cancer and poison control information to Asian and Pacific Islander (API) communities. This paper describes the process taken to identify health topics that can be readily addressed within the Program's infrastructure and reports results of the pilot testing of the educational module that was developed by following that process. The development of each new module is guided by the Health Belief Model and the Tipping Point Model. The process starts with the selection of a health topic demonstrating pressing need and treatment options in the API community. Then, using the Pareto principle, reasonably modifiable risk factors are chosen to be addressed in the module. "Sticky messaging" for the modifiable risk factors is developed to package the health information as memorable and transmissible calls-to-action. Finally, grocery store outreaches were used to pilot test the new module to assess its effectiveness at facilitating health care information to API community members. By adhering to the steps described in this paper, the authors were able to: (1) select liver cancer as a pressing API health issue that could be positively impacted by the Program; (2) identify reasonably modifiable risk factors for the chosen health issue; (3) generate compelling call-to-action messages to decrease risk of exposure; and (4) demonstrate the cultural and linguistic alignment of the liver cancer control module. The development and testing of new health education modules follow a methodical process guided by scientific principles. Understanding and employing the elements of an existing evidence-based and sustainable health education program can increase the likelihood of success in addressing the health needs of the API community.

Comparative Lipidomics of Oral Commensal and Opportunistic Bacteria.

The oral cavity contains a vast array of microbes that contribute to the balance between oral health and disease. In addition, oral bacteria can gain access to the circulation and contribute to other diseases and chronic conditions. There are a limited number of publications available regarding the comparative lipidomics of oral bacteria and fungi involved in the construction of oral biofilms, hence our decision to study the lipidomics of representative oral bacteria and a fungus. We performed high-resolution mass spectrometric analyses (<2.0 ppm mass error) of the lipidomes from five Gram-positive commensal bacteria: Streptococcus oralis, Streptococcus intermedius, Streptococcus mitis, Streptococcus sanguinis, and Streptococcus gordonii; five Gram-positive opportunistic bacteria: Streptococcus mutans, Staphylococcus epidermis, Streptococcus acidominimus, Actinomyces viscosus, and Nanosynbacter lyticus; seven Gram-negative opportunistic bacteria: Porphyromonas gingivalis. Prevotella brevis, Proteus vulgaris, Fusobacterium nucleatum, Veillonella parvula, Treponema denticola, and Alkermansia muciniphila; and one fungus: Candida albicans. Our mass spectrometric analytical platform allowed for a detailed evaluation of the many structural modifications made by microbes for the three major lipid scaffolds: glycerol, sphingosine and fatty acyls of hydroxy fatty acids (FAHFAs).

MAP kinase phosphatase-1 deficiency impairs skeletal muscle regeneration and exacerbates muscular dystrophy.

In skeletal muscle, the mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a critical negative regulator of the MAPKs. Since the MAPKs have been reported to be both positive and negative for myogenesis, the physiological role of MKP-1 in skeletal muscle repair and regeneration has remained unclear. Here, we show that MKP-1 plays an essential role in adult regenerative myogenesis. In a cardiotoxin-induced muscle injury model, lack of MKP-1 impaired muscle regeneration. In mdx mice, MKP-1 deficiency reduced body weight, muscle mass, and muscle fiber cross-sectional area. In addition, MKP-1-deficient muscles exhibit exacerbated myopathy accompanied by increased inflammation. Lack of MKP-1 compromised myoblast proliferation and induced precocious differentiation, phenotypes that were rescued by pharmacological inhibition of p38alpha/beta MAPK. MKP-1 coordinates both myoblast proliferation and differentiation. Mechanistically, MyoD bound to the MKP-1 promoter and activated MKP-1 expression in proliferating myoblasts. Later, during myogenesis, MyoD uncoupled from the MKP-1 promoter leading to the down-regulation of MKP-1 and facilitation of promyogenic p38alpha/beta MAPK signaling. Hence, MKP-1 plays a critical role in muscle stem cells and in the immune response to coordinate muscle repair and regeneration.

Regulation of the chondrogenic phenotype in culture.

In recent years, there has been a great deal of interest in the development of regenerative approaches to produce hyaline cartilage ex vivo that can be utilized for the repair or replacement of damaged or diseased tissue. It is clinically imperative that cartilage engineered in vitro mimics the molecular composition and organization of and exhibits biomechanical properties similar to persistent hyaline cartilage in vivo. Experimentally, much of our current knowledge pertaining to the regulation of cartilage formation, or chondrogenesis, has been acquired in vitro utilizing high-density cultures of undifferentiated chondroprogenitor cells stimulated to differentiate into chondrocytes. In this review, we describe the extracellular matrix molecules, nuclear transcription factors, cytoplasmic protein kinases, cytoskeletal components, and plasma membrane receptors that characterize cells undergoing chondrogenesis in vitro and regulate the progression of these cells through the chondrogenic differentiation program. We also provide an extensive list of growth factors and other extracellular signaling molecules, as well as chromatin remodeling proteins such as histone deacetylases, known to regulate chondrogenic differentiation in culture. In addition, we selectively highlight experiments that demonstrate how an understanding of normal hyaline cartilage formation can lead to the development of novel cartilage tissue engineering strategies. Finally, we present directions for future studies that may yield information applicable to the in vitro generation of hyaline cartilage that more closely resembles native tissue.

From Particularities to Context: Refining Our Thinking on Illness Narratives.

This paper examines how illness narratives are used in medical education and their implications for clinicians' thinking and care of patients. Ideally, collecting and reading illness narratives can enhance clinicians' sensitivity and contextual thinking. And yet these narratives have become part of institutionalizing cultural competency requirements in ways that tend to favor standardization. Stereotyping and reductionistic thinking can result from these pedagogic approaches and obscure structural inequities. We end by asking how we might best teach and read illness narratives to fulfill the ethical obligations of listening and asking more informative clinical interview questions that can better meet the needs of patients and the community.

The Difficult-to-Control Asthmatic: A Systematic Approach.

With the judicious use of inhaled corticosteroids, beta2 agonists, and leukotriene modifiers, most patients with asthma are easily controlled and managed. However, approximately 5% of asthmatics do not respond to standard therapy and are classified as "difficult to control." 1 Typically, these are patients who complain of symptoms interfering with daily living despite long-term treatment with inhaled corticosteroids in doses up to 2,000 mug daily. Many factors can contribute to poor response to conventional therapy, and especially for these patients, a systematic approach is needed to identify the underlying causes. First, the diagnosis of asthma and adherence to the medication regimen should be confirmed. Next, potential persisting exacerbating triggers need to be identified and addressed. Concomitant disorders should be discovered and treated. Lastly, the impact and implications of socioeconomic and psychological factors on disease control can be significant and should be acknowledged and discussed with the individual patient. Less conventional and novel strategies for treating corticosteroid-resistant asthma do exist. However, their use is based on small studies that do not meet evidence-based criteria; therefore, it is essential to sort through and address the above issues before reverting to other therapy.

Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer.

Increased collagen expression in tumors is associated with increased risk of metastasis, and triple-negative breast cancer (TNBC) has the highest propensity to develop distant metastases when there is evidence of central fibrosis. Transforming growth factor-ß (TGF-ß) ligands regulated by cancer-associated fibroblasts (CAFs) promote accumulation of fibrosis and cancer progression. In the present study, we have evaluated TNBC tumors with enhanced collagen to determine whether we can reduce metastasis by targeting the CAFs with Pirfenidone (PFD), an anti-fibrotic agent as well as a TGF-ß antagonist. In patient-derived xenograft models, TNBC tumors exhibited accumulated collagen and activated TGF-ß signaling, and developed lung metastasis. Next, primary CAFs were established from 4T1 TNBC homograft tumors, TNBC xenograft tumors and tumor specimens of breast cancer patients. CAFs promoted primary tumor growth with more fibrosis and TGF-ß activation and lung metastasis in 4T1 mouse model. We then examined the effects of PFD in vitro and in vivo. We found that PFD had inhibitory effects on cell viability and collagen production of CAFs in 2D culture. Furthermore, CAFs enhanced tumor growth and PFD inhibited the tumor growth induced by CAFs by causing apoptosis in the 3D co-culture assay of 4T1 tumor cells and CAFs. In vivo, PFD alone inhibited tumor fibrosis and TGF-ß signaling but did not inhibit tumor growth and lung metastasis. However, PFD inhibited tumor growth and lung metastasis synergistically in combination with doxorubicin. Thus, PFD has great potential for a novel clinically applicable TNBC therapy that targets tumor-stromal interaction.

MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice.

Oxidative myofibers, also known as slow-twitch myofibers, help maintain the metabolic health of mammals, and it has been proposed that decreased numbers correlate with increased risk of obesity. The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1alpha) plays a central role in maintaining levels of oxidative myofibers in skeletal muscle. Indeed, loss of PGC-1alpha expression has been linked to a reduction in the proportion of oxidative myofibers in the skeletal muscle of obese mice. MAPK phosphatase-1 (MKP-1) is encoded by mkp-1, a stress-responsive immediate-early gene that dephosphorylates MAPKs in the nucleus. Previously we showed that mice deficient in MKP-1 have enhanced energy expenditure and are resistant to diet-induced obesity. Here we show in mice that excess dietary fat induced MKP-1 overexpression in skeletal muscle, and that this resulted in reduced p38 MAPK-mediated phosphorylation of PGC-1alpha on sites that promoted its stability. Consistent with this, MKP-1-deficient mice expressed higher levels of PGC-1alpha in skeletal muscle than did wild-type mice and were refractory to the loss of oxidative myofibers when fed a high-fat diet. Collectively, these data demonstrate an essential role for MKP-1 as a regulator of the myofiber composition of skeletal muscle and suggest a potential role for MKP-1 in metabolic syndrome.

Inhibition of allergen-induced airway remodeling in Smad 3-deficient mice.

Intracellular signaling pathways that converge on Smad 3 are used by both TGF-beta and activin A, key cytokines implicated in the process of fibrogenesis. To determine the role of Smad 3 in allergen-induced airway remodeling, Smad 3-deficient and wild-type (WT) mice were sensitized to OVA and challenged by repetitive administration of OVA for 1 mo. Increased levels of activin A and increased numbers of peribronchial TGF-beta1(+) cells were detected in WT and Smad 3-deficient mice following repetitive OVA challenge. Smad 3-deficient mice challenged with OVA had significantly less peribronchial fibrosis (total lung collagen content and trichrome staining), reduced thickness of the peribronchial smooth muscle layer, and reduced epithelial mucus production compared with WT mice. As TGF-beta and Smad 3 signaling are hypothesized to mediate differentiation of fibroblasts to myofibroblasts in vivo, we determined the number of peribronchial myofibroblasts (Col-1(+) and alpha-smooth muscle actin(+)) as assessed by double-label immunofluorescence microscopy. Although the number of peribronchial myofibroblasts increased significantly in WT mice following OVA challenge, there was a significant reduction in the number of peribronchial myofibroblasts in OVA-challenged Smad 3-deficient mice. There was no difference in levels of eosinophilic airway inflammation or airway responsiveness in Smad 3-deficient compared with WT mice. These results suggest that Smad 3 signaling is required for allergen-induced airway remodeling, as well as allergen-induced accumulation of myofibroblasts in the airway. However, Smad 3 signaling does not contribute significantly to airway responsiveness.

Indoleamine-2,3-dioxygenase modulation of allergic immune responses.

Induction of immunologic tolerance is highly desirable in the treatment and prevention of allergy and other immune disease states in which the immune response to foreign or self antigens has become overactive. Indoleamine-2,3-dioxygenase (IDO), an enzyme classically known for its role in the tryptophan degradation pathway, has recently emerged as an important immunomodulator of T-cell function and inducer of tolerance. The induced expression of IDO by dendritic cells may suppress T-cell responses and promote tolerance either through direct effects on T cells (mediated by tryptophan depletion or tryptophan metabolites) or through effects of IDO on the dendritic cell. In addition to the potential role of IDO in promoting tolerance in pregnancy, transplantation, and autoimmunity, its role in modulating allergic responses has more recently been investigated, raising the possibility that IDO and its metabolites may be novel targets for immunomodulation in allergy and asthma.

Making the call: the diagnosis of acute community-acquired bacterial sinusitis.

BACKGROUND: Although one of the most common illnesses encountered in the primary care setting, acute community-acquired bacterial sinusitis (ACABS) can be a challenge to diagnose. METHODS: Existing diagnostic modalities ranging from clinical history to imaging studies used to diagnose ACABS are discussed. RESULTS: Numerous methods exist but they do not distinguish well between viral and bacterial illness. CONCLUSION: Diagnosis of ACABS should primarily be made based on the clinical history. Other modalities provide useful information in select cases.