Cultural stress and immigrant well-being: The role of sense of purpose.

OBJECTIVES: Immigrants face multiple forms of cultural stress that hold pernicious influences on their psychological well-being, including everyday discrimination, bicultural stressors, and negative context of reception from others. Research thus is needed to consider potential buffers and mitigating factors that may help immigrant adults in the face of cultural stress. The present studies evaluated a sense of purpose as one potential buffer. METHOD: Study 1 asked immigrant adults in the Unites States to complete measures of the three cultural stress indicators in addition to sense of purpose and measures of well-being (depressive symptoms, anxiety, stress, self-esteem, self-rated health). Multiple regression analyses examined whether sense of purpose moderated the influence of cultural stress on immigrant well-being. Study 2 randomly assigned immigrant participants receive an experimental condition that asked participants to imagine a common cultural stressor faced by immigrants. Multiple regression analyses tested whether sense of purpose operated differently on postscenario affect across the control and experimental conditions. RESULTS: Study 1 found that all cultural stress indicators negatively correlated with psychological well-being and sense of purpose. However, sense of purpose did not significantly moderate these associations. Study 2 found that imagining the cultural stressor led to worse momentary affective well-being, whereas sense of purpose was associated with better well-being. Again, sense of purpose did not interact with the condition to predict the postscenario affect. CONCLUSIONS: Sense of purpose was consistently associated with better psychological well-being. However, little evidence was found that sense of purpose mitigates the ill effects of cultural stress for immigrant adults. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Physiology governing diatom vs. dinoflagellate bloom and decline in coastal Santa Monica Bay.

Algal blooms on the Southern California coast are typically dominated by diatom and dinoflagellate taxa, and are governed by their physiological responses to environmental cues; however, we lack a predictive understanding of the environmental controls underlying the establishment and persistence of these distinct bloom events. In this study, we examined gene expression among the numerically dominant diatom and dinoflagellate taxa during spring upwelling bloom events to compare the physiological underpinnings of diatom vs. dinoflagellate bloom dynamics. Diatoms, which bloomed following upwelling events, expressed genes related to dissolved inorganic nitrogen utilization, and genes related to the catabolism of chitin that may have prolonged their bloom duration following nitrogen depletion. Conversely, dinoflagellates bloomed under depleted inorganic nitrogen conditions, exhibited less variation in transcriptional activity, and expressed few genes associated with dissolved inorganic nutrients during their bloom. Dinoflagellate profiles exhibited evidence of proteolysis and heterotrophy that may have enabled them to bloom to high abundances under depleted inorganic nutrients. Taken together, diatom and dinoflagellate transcriptional profiles illustrated guild-specific physiologies that are tuned to respond to and thrive under distinct environmental "windows of opportunity."

Drosophila as Model System to Study Ras-Mediated Oncogenesis: The Case of the Tensin Family of Proteins.

Oncogenic mutations in the small GTPase Ras contribute to ~30% of human cancers. However, tissue growth induced by oncogenic Ras is restrained by the induction of cellular senescence, and additional mutations are required to induce tumor progression. Therefore, identifying cooperating cancer genes is of paramount importance. Recently, the tensin family of focal adhesion proteins, TNS1-4, have emerged as regulators of carcinogenesis, yet their role in cancer appears somewhat controversial. Around 90% of human cancers are of epithelial origin. We have used the Drosophila wing imaginal disc epithelium as a model system to gain insight into the roles of two orthologs of human TNS2 and 4, blistery (by) and PVRAP, in epithelial cancer progression. We have generated null mutations in PVRAP and found that, as is the case for by and mammalian tensins, PVRAP mutants are viable. We have also found that elimination of either PVRAP or by potentiates RasV12-mediated wing disc hyperplasia. Furthermore, our results have unraveled a mechanism by which tensins may limit Ras oncogenic capacity, the regulation of cell shape and growth. These results demonstrate that Drosophila tensins behave as suppressors of Ras-driven tissue hyperplasia, suggesting that the roles of tensins as modulators of cancer progression might be evolutionarily conserved.

Combined 70- and 80-gene signatures identify tumors with genomically luminal biology responsive to neoadjuvant endocrine therapy and are prognostic of 5-year outcome in early-stage breast cancer.

BACKGROUND: As more patients with early-stage breast cancer receive neoadjuvant endocrine therapy (NET), there is a need for reliable biomarkers that can identify patients with HR+ HER2- tumors who are likely to benefit from NET. NBRST (NCT01479101) compared the prognostic value of the 70-gene risk classification and 80-gene molecular subtyping signatures with conventional pathological classification methods in response to neoadjuvant therapy. We evaluated the association of these signatures with clinical response and 5-year outcome of patients treated with NET. METHODS: 1091 patients with early-stage breast cancer scheduled to receive neoadjuvant therapy were prospectively enrolled into NBRST, and a sub-analysis of 67 patients treated with NET was performed. Patients received standard of care genomic testing using the 70-gene and 80-gene signatures and were treated with NET, per physician's discretion. The primary endpoint was pathologic partial response (pPR) and secondary endpoints were distant metastasis-free survival (DMFS) and overall survival (OS). Clinical benefit was defined as having a pPR or stable disease (SD) with NET. RESULTS: Overall, 94.4% of patients with genomically (g) Luminal A-Type (50.0% pPR and 44.4% SD) and 95.0% with Luminal B-Type tumors (55.0% pPR and 40.0% SD) exhibited clinical benefit. At 5 years, patients with gLuminal B tumors had significantly worse DMFS (75.6%, 95% CI 50.8-89.1) than patients with gLuminal A (91.1%; 95% CI 74.8-97.1; p = 0.047), with a similar trend for OS, albeit not significant (81.0%, 95% CI 56.9-92.4 and 91.1%, 95% CI 74.8-97.1, respectively; p = 0.13). CONCLUSIONS: Genomic assays offer a broader understanding of the underlying tumor biology, which adds precision to pathology as a preoperative risk classifier. Patients with 70-gene signature Low Risk, gLuminal A tumors treated with endocrine therapy alone have excellent 5-year outcomes. Most patients with genomically-defined Luminal A- and B-Type tumors respond well to NET, suggesting these patients may be safely treated with NET, while those with gLuminal B tumors will also require post-operative chemotherapy or CDK4/6 inhibitors to improve long-term outcomes. Overall, these findings demonstrate that genomic classification, defined by the combined 70- and 80-gene signatures, is associated with tumor response and prognostic of long-term outcomes.

Daily dynamics of contrasting spring algal blooms in Santa Monica Bay (central Southern California Bight).

Protistan algae (phytoplankton) dominate coastal upwelling ecosystems where they form massive blooms that support the world's most important fisheries and constitute an important sink for atmospheric CO2 . Bloom initiation is well understood, but the biotic and abiotic forces that shape short-term dynamics in community composition are still poorly characterized. Here, high-frequency (daily) changes in relative abundance dynamics of the metabolically active protistan community were followed via expressed 18S V4 rRNA genes (RNA) throughout two algal blooms during the spring of 2018 and 2019 in Santa Monica Bay (central Southern California Bight). A diatom bloom formed after wind-driven, nutrient upwelling events in both years, but different taxa dominated each year. Whereas diatoms bloomed following elevated nutrients and declined after depletion each year, a massive dinoflagellate bloom manifested under relatively low inorganic nitrogen conditions following diatom bloom senescence in 2019 but not 2018. Network analysis revealed associations between diatoms and cercozoan putative parasitic taxa and syndinean parasites during 2019 that may have influenced the demise of the diatoms, and the transition to a dinoflagellate-dominated bloom.

EGFRAP encodes a new negative regulator of the EGFR acting in both normal and oncogenic EGFR/Ras-driven tissue morphogenesis.

Activation of Ras signaling occurs in ~30% of human cancers. However, activated Ras alone is insufficient to produce malignancy. Thus, it is imperative to identify those genes cooperating with activated Ras in driving tumoral growth. In this work, we have identified a novel EGFR inhibitor, which we have named EGFRAP, for EGFR adaptor protein. Elimination of EGFRAP potentiates activated Ras-induced overgrowth in the Drosophila wing imaginal disc. We show that EGFRAP interacts physically with the phosphorylated form of EGFR via its SH2 domain. EGFRAP is expressed at high levels in regions of maximal EGFR/Ras pathway activity, such as at the presumptive wing margin. In addition, EGFRAP expression is up-regulated in conditions of oncogenic EGFR/Ras activation. Normal and oncogenic EGFR/Ras-mediated upregulation of EGRAP levels depend on the Notch pathway. We also find that elimination of EGFRAP does not affect overall organogenesis or viability. However, simultaneous downregulation of EGFRAP and its ortholog PVRAP results in defects associated with increased EGFR function. Based on these results, we propose that EGFRAP is a new negative regulator of the EGFR/Ras pathway, which, while being required redundantly for normal morphogenesis, behaves as an important modulator of EGFR/Ras-driven tissue hyperplasia. We suggest that the ability of EGFRAP to functionally inhibit the EGFR pathway in oncogenic cells results from the activation of a feedback loop leading to increase EGFRAP expression. This could act as a surveillance mechanism to prevent excessive EGFR activity and uncontrolled cell growth.

Combining the Love of Art, Science, Business and Medicine to Innovate and Enhance Patient Health. Highlights from the 7th Annual Leaders in Medicine Symposium of the Cummings School of Medicine, Calgary, AB.

The Leader in Medicine (LIM) Program of the Cumming School of Medicine, University of Calgary, hosted its 7th Annual LIM Research Symposium on October 30, 2015 and participation grew once again, with a total of six oral and 99 posters presentations! Over 45 of our Faculty members also participated in the symposium. This year's LIM Symposium theme was "Innovations in Medicine" and the invited guest speaker was our own Dr. Breanne Everett (MD/MBA). She completed her residency in plastic surgery at University of Calgary and holds both a medical degree and an MBA from the University of Calgary. In her inspiring talk, entitled "Marrying Business and Medicine: Toe-ing a Fine Line", she described how she dealt with a clinical problem (diabetic foot ulcers), came up with an innovation that optimized patient care, started her own company and delivered her product to market to enhance the health of the community. She clearly illustrated how to complete the full circle, from identifying a clinical problem to developing and providing a solution that both enhances clinical care and patient health as well as reduces health care costs and hospital admissions. The research symposium was an outstanding success and the abstracts are included in companion article in CIM.

Proceedings from the 7th Annual University of Calgary Leaders in Medicine Research Symposium.

TOn October 30th, 2015, the Leaders in Medicine (LIM) program at the Cumming School of Medicine, University of Calgary hosted its 7th Annual Research Symposium. Dr. Breanne Everett, President and CEO of Orpyx Medical Technologies and holder both of medical and MBA degrees from the University of Calgary, presented a lecture entitled "Marrying Business and Medicine: Toe-ing a Fine Line". The LIM symposium also provides a forum for both LIM and non-LIM medical students to present their research work in oral and poster presentation formats. This year over 100 students submitted their work and six oral presentations and 99 posters were presented. The oral presentations were as follows: Ryan Lewinson, Prediction of wedged insole-induced changes to knee joint moments during walkingLindsey Logan, Robotic measures provide insight on sensorimotor and cognitive impairments following traumatic brain injury Jackie Mann, What medication information do community doctors want to receive in discharge summaries for safer transfers? Ashley Jensen, Increased mortality associated with resident handoff periods at ten veterans administration medical centers Jason Bau, Keratinocyte growth factor protects against C. difficile-induced cell injury and death Michael Keough, A novel drug class promotes regeneration of central nervous system myelin by overcoming inhibitory scar molecules in vitro and in vivo For further details on the University of Calgary Leaders in Medicine Program see "A Prescription that Addresses the Decline of Basic Science Education in Medical School" (Clinical and Investigative Medicine. 2014;37(5):E29). The LIM Symposium has the following objectives: (1) to showcase the variety of projects undertaken by students in the LIM Program as well as University of Calgary medical students; (2) to encourage medical student participation in research and special projects; (3) to inform students and faculty about the diversity of opportunities available for research and special projects during medical school and beyond; and, (4) to enhance student and staff interactions, with the ultimate goal being to enhance translational medicine improve health.

Giardia duodenalis induces pathogenic dysbiosis of human intestinal microbiota biofilms.

Giardia duodenalis is a prevalent cause of acute diarrheal disease worldwide. However, recent outbreaks in Italy and Norway have revealed a link between giardiasis and the subsequent development of chronic post-infectious irritable bowel syndrome. While the mechanisms underlying the causation of post-infectious irritable bowel syndrome remain obscure, recent findings suggest that alterations in gut microbiota communities are linked to the pathophysiology of irritable bowel syndrome. In the present study, we use a laboratory biofilm system to culture and enrich mucosal microbiota from human intestinal biopsies. Subsequently, we show that co-culture with Giardia induces disturbances in biofilm species composition and biofilm structure resulting in microbiota communities that are intrinsically dysbiotic - even after the clearance of Giardia. These microbiota abnormalities were mediated in part by secretory-excretory Giardia cysteine proteases. Using in vitro cell culture and germ-free murine infection models, we show that Giardia-induced disruptions of microbiota promote bacterial invasion, resulting in epithelial apoptosis, tight junctional disruption, and bacterial translocation across an intestinal epithelial barrier. Additionally, these dysbiotic microbiota communities resulted in increased activation of the Toll-like receptor 4 signalling pathway, and overproduction of the pro-inflammatory cytokine IL-1beta in humanized germ-free mice. Previous studies that have sought explanations and risk factors for the development of post-infectious irritable bowel syndrome have focused on features of enteropathogens and attributes of the infected host. We propose that polymicrobial interactions involving Giardia and gut microbiota may cause persistent dysbiosis, offering a new interpretation of the reasons why those afflicted with giardiasis are predisposed to gastrointestinal disorders post-infection.

Chemosensitivity and Endocrine Sensitivity in Clinical Luminal Breast Cancer Patients in the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST) Predicted by Molecular Subtyping.

PURPOSE: Hormone receptor-positive (HR+) tumors have heterogeneous biology and present a challenge for determining optimal treatment. In the Neoadjuvant Breast Registry Symphony Trial (NBRST) patients were classified according to MammaPrint/BluePrint subtyping to provide insight into the response to neoadjuvant endocrine therapy (NET) or neoadjuvant chemotherapy (NCT). OBJECTIVE: The purpose of this predefined substudy was to compare MammaPrint/BluePrint with conventional 'clinical' immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) subtyping in 'clinical luminal' [HR+/human epidermal growth factor receptor 2-negative (HER2-)] breast cancer patients to predict treatment sensitivity. METHODS: NBRST IHC/FISH HR+/HER2- breast cancer patients (n = 474) were classified into four molecular subgroups by MammaPrint/BluePrint subtyping: Luminal A, Luminal B, HER2, and Basal type. Pathological complete response (pCR) rates were compared with conventional IHC/FISH subtype. RESULTS: The overall pCR rate for 'clinical luminal' patients to NCT was 11 %; however, 87 of these 474 patients were reclassified as Basal type by BluePrint, with a high pCR rate of 32 %. The MammaPrint index was highly associated with the likelihood of pCR (p < 0.001). Fifty-three patients with BluePrint Luminal tumors received NET with an aromatase inhibitor and 36 (68 %) had a clinical response. CONCLUSIONS: With BluePrint subtyping, 18 % of clinical 'luminal' patients are classified in a different subgroup, compared with conventional assessment, and these patients have a significantly higher response rate to NCT compared with BluePrint Luminal patients. MammaPrint/BluePrint subtyping can help allocate effective treatment to appropriate patients. In addition, accurate identification of subtype biology is important in the interpretation of neoadjuvant treatment response since lack of pCR in luminal patients does not portend the worse prognosis associated with residual disease in Basal and HER2 subtypes.

A TASER conducted electrical weapon with cardiac biomonitoring capability: Proof of concept and initial human trial.

INTRODUCTION: Despite research demonstrating the overall safety of Conducted Electrical Weapons (CEWs), commonly known by the brand name TASER(®), concerns remain regarding cardiac safety. The addition of cardiac biomonitoring capability to a CEW could prove useful and even lifesaving in the rare event of a medical crisis by detecting and analyzing cardiac rhythms during the period immediately after CEW discharge. OBJECTIVE: To combine an electrocardiogram (ECG) device with a CEW to detect and store ECG signals while still allowing the CEW to perform its primary function of delivering an incapacitating electrical discharge. METHODS: This work was performed in three phases. In Phase 1 standard law enforcement issue CEW cartridges were modified to demonstrate transmission of ECG signals. In Phase 2, a miniaturized ECG recorder was combined with a standard issue CEW and tested. In Phase 3, a prototype CEW with on-board cardiac biomonitoring was tested on human volunteers to assess its ability to perform its primary function of electrical incapacitation. RESULTS: Bench testing demonstrated that slightly modified CEW cartridge wires transmitted simulated ECG signals produced by an ECG rhythm generator and from a human volunteer. Ultimately, a modified CEW incorporating ECG monitoring successfully delivered incapacitating current to human volunteers and successfully recorded ECG signals from subcutaneous CEW probes after firing. CONCLUSION: An ECG recording device was successfully incorporated into a standard issue CEW without impeding the functioning of the device. This serves as proof-of-concept that safety measures such as cardiac biomonitoring can be incorporated into CEWs and possibly other law enforcement devices.

Impact of Tumor Size on Probability of Pathologic Complete Response After Neoadjuvant Chemotherapy.

BACKGROUND: The prospective Neoadjuvant Breast Symphony Trial (NBRST) study found that MammaPrint/BluePrint functional molecular subtype is superior to conventional immunohistochemistry/fluorescence in situ hybridization subtyping for predicting pathologic complete response (pCR) to neoadjuvant chemotherapy. The purpose of this substudy was to determine if the rate of pCR is affected by tumor size. METHODS: The NBRST study includes breast cancer patients who received neoadjuvant chemotherapy. MammaPrint/BluePrint subtyping classified patients into four molecular subgroups: Luminal A, Luminal B, HER2 (human epidermal growth factor receptor 2), and Basal type. Probability of pCR (ypT0/isN0) as a function of tumor size and molecular subgroup was evaluated. RESULTS: A total of 608 patients were evaluable with overall pCR rates of 28.5 %. Luminal A and B patients had significantly lower rates of pCR (6.1 and 8.7 %, respectively) than either basal (37.1 %) or HER2 (55.0 %) patients (p < 0.001). The probability of pCR significantly decreased with tumor size >5 cm [p = 0.022, odds ratio (OR) 0.58, 95 % confidence interval (CI) 0.36, 0.93]. This relationship was statistically significant in the Basal (p = 0.026, OR 0.46, 95 % CI 0.23, 0.91) and HER2 (p = 0.039, OR 0.36, 95 % CI 0.14, 0.95) subgroups. In multivariate logistic regression analyses, the dichotomized tumor size variable was not significant in any of the molecular subgroups. DISCUSSION: Even though tumor size would intuitively be a clinical determinant of pCR, the current analysis showed that the adjusted OR for tumor size was not statistically significant in any of the molecular subgroups. Factors significantly associated with pCR were PR status, grade, lymph node status, and BluePrint molecular subtyping, which had the strongest correlation.

Highlights from the 6th Annual University of Calgary Leaders in Medicine Research Symposium and the Keynote Address by Dr. Danuta Skowronski.

The Leaders in Medicine (LIM) Program at the University of Calgary hosted its 6th Annual Research Symposium on November 14, 2014, showcasing the quality and breadth of work performed by students at the Cumming School of Medicine. Participation at this year's event was our most successful to date, with a total of six oral and 77 poster presentations during the afternoon symposium. For a detailed description of the work presented at the symposium, please see the Proceedings from the 6th Annual University of Calgary Leaders in Medicine Research Symposium published in this issue of Clinical and Investigative Medicine.

Proceedings from the 6th Annual University of Calgary Leaders in Medicine Research Symposium.

On November 14, 2014, the Leaders in Medicine (LIM) program at the Cumming School of Medicine, University of Calgary hosted its 6th Annual Research Symposium. Dr. Danuta Skowronski, Epidemiology Lead for Influenza and Emerging Respiratory Pathogens at the British Columbia Centre for Disease Control (BCCDC), was the keynote speaker and presented a lecture entitled "Rapid response research during emerging public health crises: influenza and reflections from the five year anniversary of the 2009 pandemic". The LIM symposium provides a forum for both LIM and non-LIM medical students to present their research work, either as an oral or poster presentation. There were a total of six oral presentations and 77 posters presented. The oral presentations included: Swathi Damaraju, "The role of cell communication and 3D Cell-Matrix environment in a stem cell-based tissue engineering strategy for bone repair"; Menglin Yang, "The proteolytic activity of Nepenthes pitcher fluid as a therapeutic for the treatment of celiac disease"; Amelia Kellar, "Monitoring pediatric inflammatory bowel disease - a retrospective analysis of transabdominal ultrasound"; Monica M. Faria-Crowder, "The design and application of a molecular profiling strategy to identify polymicrobial acute sepsis infections"; Waleed Rahmani, "Hair follicle dermal stem cells regenerate the dermal sheath, repopulate the dermal papilla and modulate hair type"; and, Laura Palmer, "A novel role for amyloid beta protein during hypoxia/ischemia". The article on the University of Calgary Leaders in Medicine Program, "A Prescription that Addresses the Decline of Basic Science Education in Medical School," in a previous issue of CIM (2014 37(5):E292) provides more details on the program. Briefly, the LIM Research Symposium has the following objectives: (1) to showcase the impressive variety of projects undertaken by students in the LIM Program as well as University of Calgary medical students; (2) to encourage medical student participation in research and special projects; and, (3) to inform students and faculty about the diversity of opportunities available for research and special projects during medical school and beyond.The following abstracts were submitted for publication.

Hydrogen sulfide protects from colitis and restores intestinal microbiota biofilm and mucus production.

BACKGROUND: Microbiota dysbiosis and impaired barrier function are among the most prominent features of inflammatory bowel disease. In the gastrointestinal tract, hydrogen sulfide (H(2)S) is an important regulator of mucosal homeostasis. We hypothesized that H(2)S promotes resolution of colonic inflammation through actions on microbiota biofilm and the mucus barrier. METHODS: We used mice genetically deficient for a key enzyme for H(2)S production (cystathionine γ-lyase) and pharmacologically inhibited that enzyme during colitis in wild-type mice. We tested the effects of administering an H(2)S donor (diallyl disulfide) to rodents during hapten-induced colitis. Colonic microbiota biofilm was visualized by fluorescent in situ hybridization, and mucus granules were quantified with periodic acid-alcian blue staining. We exposed human microbiota biofilms and planktonic bacteria to H(2)S donors ex vivo to determine changes in their growth, viability, and biomass. RESULTS: Intestinal microbiota formed linear biofilms in the colon of healthy rodents. During colitis, microbiota biofilms were fragmented and mucus granule production decreased. Endogenous production of H(2)S had beneficial effects on establishment of microbiota biofilms and colonic mucus production. Therapeutic delivery of H(2)S into the colon reduced inflammation, restored the microbiota biofilm, and increased the production of mucus granules. In ex vivo human microbiota, H(2)S not only promoted biofilm formation but also reduced growth of planktonic bacteria. CONCLUSIONS: Our results suggest that H(2)S donors could be used therapeutically during colitis, facilitating correction of microbiota biofilm dysbiosis and mucus layer reconstitution.

Chemosensitivity predicted by BluePrint 80-gene functional subtype and MammaPrint in the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST).

PURPOSE: The purpose of the NBRST study is to compare a multigene classifier to conventional immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) subtyping to predict chemosensitivity as defined by pathological complete response (pCR) or endocrine sensitivity as defined by partial response. METHODS: The study includes women with histologically proven breast cancer, who will receive neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy. BluePrint in combination with MammaPrint classifies patients into four molecular subgroups: Luminal A, Luminal B, HER2, and Basal. RESULTS: A total of 426 patients had definitive surgery. Thirty-seven of 211 (18 %) IHC/FISH hormone receptor (HR)+/HER2- patients were reclassified by Blueprint as Basal (n = 35) or HER2 (n = 2). Fifty-three of 123 (43 %) IHC/FISH HER2+ patients were reclassified as Luminal (n = 36) or Basal (n = 17). Four of 92 (4 %) IHC/FISH triple-negative (TN) patients were reclassified as Luminal (n = 2) or HER2 (n = 2). NCT pCR rates were 2 % in Luminal A and 7 % Luminal B patients versus 10 % pCR in IHC/FISH HR+/HER2- patients. The NCT pCR rate was 53 % in BluePrint HER2 patients. This is significantly superior (p = 0.047) to the pCR rate in IHC/FISH HER2+ patients (38 %). The pCR rate of 36 of 75 IHC/FISH HER2+/HR+ patients reclassified as BPLuminal is 3 %. NCT pCR for BluePrint Basal patients was 49 of 140 (35 %), comparable to the 34 of 92 pCR rate (37 %) in IHC/FISH TN patients. CONCLUSIONS: BluePrint molecular subtyping reclassifies 22 % (94/426) of tumors, reassigning more responsive patients to the HER2 and Basal categories while reassigning less responsive patients to the Luminal category. These findings suggest that compared with IHC/FISH, BluePrint more accurately identifies patients likely to respond (or not respond) to NCT.

Post-infectious irritable bowel syndrome: mechanistic insights into chronic disturbances following enteric infection.

Irritable bowel syndrome (IBS) is a commonly encountered chronic functional gastrointestinal (GI) disorder. Approximately 10% of IBS patients can trace the onset of their symptoms to a previous a bout of infectious dysentery. The appearance of new IBS symptoms following an infectious event is defined as post-infectious-IBS. Indeed, with the World Health Organization estimating between 2 and 4 billion cases annually, infectious diarrheal disease represents an incredible international healthcare burden. Additionally, compounding evidence suggests many commonly encountered enteropathogens as unique triggers behind IBS symptom generation and underlying pathophysiological features. A growing body of work provides evidence supporting a role for pathogen-mediated modifications in the resident intestinal microbiota, epithelial barrier integrity, effector cell functions, and innate and adaptive immune features, all proposed physiological manifestations that can underlie GI abnormalities in IBS. Enteric pathogens must employ a vast array of machinery to evade host protective immune mechanisms, and illicit successful infections. Consequently, the impact of infectious events on host physiology can be multidimensional in terms of anatomical location, functional scope, and duration. This review offers a unique discussion of the mechanisms employed by many commonly encountered enteric pathogens that cause acute disease, but may also lead to the establishment of chronic GI dysfunction compatible with IBS.

Direct and indirect anti-inflammatory effects of tulathromycin in bovine macrophages: inhibition of CXCL-8 secretion, induction of apoptosis, and promotion of efferocytosis.

Recent evidence indicates that immunomodulation by antibiotics may enhance their clinical efficacy. Specifically, drug-induced leukocyte apoptosis and macrophage efferocytosis have been shown to promote the resolution of inflammation in a variety of disease settings. Tulathromycin is a new macrolide antibiotic for the treatment of bovine respiratory disease. The direct antimicrobial effects of the drug alone do not fully justify its superior clinical efficacy, and we hypothesize that tulathromycin may have immunomodulating properties. We recently reported that tulathromycin promotes apoptosis and inhibits proinflammatory NF-κB signaling in bovine neutrophils. In this study, we investigated the direct and indirect anti-inflammatory effects of tulathromycin in bovine macrophages. The findings indicate that bovine monocyte-derived macrophages and alveolar macrophages readily phagocytose tulathromycin-induced apoptotic neutrophils both in vitro and in the airways of Mannheimia haemolytica-infected calves. Moreover, tulathromycin promotes delayed, concentration-dependent apoptosis, but not necrosis, in bovine macrophages in vitro. Activation of caspase-3 and detection of mono- and oligonucleosomes in bovine monocyte-derived macrophages treated with tulathromycin was observed 12 h posttreatment; pretreatment with a pan-caspase inhibitor (ZVAD) blocked the proapoptotic effects of the drug. Lastly, tulathromycin inhibited the secretion of proinflammatory CXCL-8 in lipopolysaccharide (LPS)-stimulated bovine macrophages; this effect was independent of caspase activation or programmed cell death. Taken together, these immunomodulating effects observed in bovine macrophages help further elucidate the mechanisms through which tulathromycin confers anti-inflammatory and proresolution benefits. Furthermore, these findings offer novel insights on how antibiotics may offer anti-inflammatory benefits by modulating macrophage-mediated events that play a key role in inflammation.

Host parasite interactions and pathophysiology in Giardia infections.

Giardia is a protozoan parasite of the small intestine, and a leading cause of diarrhoeal disease worldwide in a variety of animals, including humans. The host-parasite interaction and pathophysiological processes of giardiasis remain incompletely understood. Current research suggests that Giardia-induced diarrhoeal disease is mediated by small intestinal malabsorption and maldigestion, chloride hypersecretion and increased rates of small intestinal transit. Small intestinal malabsorption and maldigestion results from the CD8+ lymphocyte-induced diffuse shortening of brush border microvilli. Activation of CD8+ lymphocytes occurs secondary to small intestinal barrier dysfunction, which results from heightened rates of enterocyte apoptosis and disruption of epithelial tight junctions. Both host and parasite factors contribute to the pathogenesis of giardiasis and ongoing research in this field may elucidate genotype/assemblage-specific pathogenic mechanisms. Giardia infections can result in chronic gastrointestinal disorders such as post-infectious Irritable Bowel Syndrome and symptoms may manifest at extra-intestinal sites, even though the parasite does not disseminate beyond the gastrointestinal tract. The infection can cause failure to thrive in children. Furthermore, there is now evidence suggesting that Giardia symptoms may vary between industrialised and developing areas of the world, for reasons that remain obscure. More research is needed to improve our understanding of this parasitic infection which was recently included in the World Health Organisation "Neglected Disease Initiative".