Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging.

L-Lactate is increasingly appreciated as a key metabolite and signaling molecule in mammals. However, investigations of the inter- and intra-cellular dynamics of L-lactate are currently hampered by the limited selection and performance of L-lactate-specific genetically encoded biosensors. Here we now report a spectrally and functionally orthogonal pair of high-performance genetically encoded biosensors: a green fluorescent extracellular L-lactate biosensor, designated eLACCO2.1, and a red fluorescent intracellular L-lactate biosensor, designated R-iLACCO1. eLACCO2.1 exhibits excellent membrane localization and robust fluorescence response. To the best of our knowledge, R-iLACCO1 and its affinity variants exhibit larger fluorescence responses than any previously reported intracellular L-lactate biosensor. We demonstrate spectrally and spatially multiplexed imaging of L-lactate dynamics by coexpression of eLACCO2.1 and R-iLACCO1 in cultured cells, and in vivo imaging of extracellular and intracellular L-lactate dynamics in mice.

Prophylactic Lymphovenous Bypass at the Time of Axillary Lymph Node Dissection Decreases Rates of Lymphedema.

Background: Breast cancer-related lymphedema impacts 30% to 47% of women who undergo axillary lymph node dissection (ALND). Studies evaluating the effectiveness of prophylactic lymphovenous bypass (LVB) at the time of ALND have had small patient populations and/or short follow-up. The aim of this study is to quantitatively and qualitatively evaluate prophylactic LVB in patients with breast cancer. Methods: A retrospective review of patients who underwent ALND from 2018 to 2022 was performed. Patients were divided into cohorts based on whether they underwent prophylactic LVB at the time of ALND. Primary outcomes included 30-day complications and lymphedema. Lymphedema was quantitatively evaluated by bioimpedance analysis, with L-dex scores >7.1 indicating lymphedema. Results: One-hundred five patients were identified. Sixty-four patients (61.0%) underwent ALND and 41 patients (39.0%) underwent ALND+LVB. Postoperative complications were similar between the cohorts. At a median follow-up of 13.3 months, lymphedema occurred significantly higher in the ALND only group compared with ALND+LVB group (50.0% vs 12.2%; P < 0.001). ALND without LVB was an independent risk factor for lymphedema development (odds ratio, 4.82; P = 0.003). Conclusions: Prophylactic LVB decreases lymphedema and is not associated with increased postoperative complications. A multidisciplinary team approach is imperative to decrease lymphedema development in this patient population.

Clinical management of myoid hamartomas of the breast: A case report and literature review.

Background: Myoid Hamartoma of the breast (MHB) is an extremely rare benign breast lesion composed of mammary ducts and lobules, fibrous stroma, adipose tissue, and smooth muscle. Due to its rarity, the clinical management of MHB is not well described. Surgical excision is the most common form of management. This study reviews the current literature on the clinical management of MHB and describes a case report of a young patient presenting with MHB managed with surveillance and shared-decision making. Materials and methods: A healthy 23-year-old female presented with a one-year history of a palpable left breast mass. Her right breast exam was normal. Ultrasound of the left breast revealed a 2.7 cm × 1.4 cm × 2.4 cm lobulated mass at the one o'clock position. The mass caused slight discomfort to palpation but otherwise had no associated skin changes. Ultrasound-guided biopsy revealed a left breast myoid hamartoma. Management options were presented to the patient, and she elected to observe the mass with surveillance imaging. Results: There have been no reported cases in the literature of malignant transformation of MHB. Rather than rely on reflexive surgical excision of MHB, our review suggests that surveillance and routine imaging may be an appropriate form of clinical management in patients who present with a favorable clinical and histopathological profile which includes: a low MIB-1 proliferative index, low breast cancer risk assessment score, lesion size less than 1.2 cm, and radiological-pathological concordance. Conclusion: Further research is needed to determine the clinical significance and threshold levels of these clinical and histopathological factors in patient care. However, given current trends to minimize over treatment in breast pathology, we pose that observation of MHB can be performed when favorable clinical criteria is met.

Postoperative Outcomes following a Multidisciplinary Approach to HIV-positive Breast Cancer Patients.

Improvements in human immunodeficiency virus (HIV) treatment resulted in drastic increases in the lifespan of HIV-positive individuals, resulting in higher rates of non-AIDS-defining cancers. We describe our postoperative outcomes in HIV+ breast cancer (BC) patients, highlighting our multidisciplinary experience with this high-risk population. Methods: A 7-year multi-institutional retrospective review of all HIV+ BC patients who underwent surgical intervention was performed. Patient demographics, therapeutic interventions, and treatment outcomes were collected. Results: Twenty-four patients were identified, including one male patient (4.2%). Most patients were African American (83.3%). Mean age was 52.1 + 9.7 years at the time of diagnosis in HIV+ BC patients. Surgical interventions included lumpectomy (n = 16, 66.7%), simple mastectomy (n = 3, 12.5%), and skin-sparing mastectomy (n = 5. 20.8%). All patients were on antiretroviral therapy, and 81.3% had undetectable viral loads at the time of operation. Seventeen patients (70.8%) underwent breast reconstruction, with three (17.7%) undergoing delayed reconstruction. Thirty-day postoperative complications occurred in three patients (17.6%), including flap necrosis (11.8%), infection (11.8%), dehiscence (5.9%), and return to OR (11.8%). Three patients (12.5%) experienced recurrence at a median of 18 months since operation. Mean follow-up was 51.4 + 33.3 months since BC diagnosis. Conclusions: While postoperative complication rates in HIV+ patients trended higher (17.6%) compared with the existing data on breast reconstruction patients overall (10.1%), HIV+ patients did not exhibit increased risk of BC recurrence (12.5%) compared with BC patients overall (12-27%). This highlights the importance of a combined multidisciplinary approach involving infectious disease, breast surgery, and plastic and reconstructive surgery to optimize surgical and oncologic outcomes in these high-risk patients.

A comparative analysis of males and females with breast cancer undergoing mastectomy using the American College of Surgeon's National Surgical Quality Improvement Project (NSQIP).

INTRODUCTION: There is a paucity of literature comparing the postoperative outcomes of males and females with breast cancer who undergo mastectomy. The aim of this study is to evaluate the comorbidities and 30-day post-mastectomy complication rates among males and females. METHODS: We performed a retrospective analysis of breast cancer patients who underwent mastectomy from 2014 to 2016 using the American College of Surgeon's National Surgical Quality Improvement Project database. Data including patient demographics, comorbidities, and 30-day surgical and medical complications were collected. Statistical analysis included Chi-square and Fisher's exact tests for categorical variables and Student T-tests for continuous variables. Statistical significance was defined as p < 0.05. RESULTS: A total of 15,167 patients were identified. There were 497 males (3.3%) and 14,670 females (96.7%). Age was significantly higher in females compared to males (63.5 vs. 57.6 years, p < 0.001). Body mass index (BMI) at time of surgery was also higher in males (30.0 vs. 29.3 kg/m2, p = 0.011). There was a higher prevalence of diabetes in males (20.1 vs. 16.5%, p = 0.032). Operative duration was significantly longer in females (114.9 vs. 95.0 min, p < 0.001). Median postoperative length of stay was also longer in females (1.2 vs. 0.8 days, p < 0.001). There were no significant differences in 30-day medical or surgical complication rates between the two sexes. CONCLUSION: Our findings suggest that differences in age, BMI, and comorbidities between males and females do not significantly impact 30-day medical or surgical complications following total mastectomy for breast cancer. Further research is warranted to identify perioperative risk factors that influence post-mastectomy complication rates. LEVEL OF EVIDENCE: 3 (Retrospective cohort study).

Risk-reducing surgery in PALB2 mutations carriers with breast cancer: a case series and literature review.

Background: Inherited germline mutations in PALB2 are known to predispose patients to a higher risk of breast, ovarian and pancreatic cancer with an estimated risk of developing breast cancer in over half of all affected women by age 80 years. Current guidelines for screening patients with PALB2 mutations include annual mammograms beginning at age 30 years and consideration of breast magnetic resonance imaging (MRI) and tomosynthesis. Existing evidence regarding risk-reducing surgery with mastectomy is insufficient to make a definitive recommendation to patients. In this case series, we describe the presentation and management of 5 patients with unilateral breast cancer and PALB2 mutations. To our knowledge, this is the first reported case series discussing the role of contralateral risk-reducing mastectomy (CRRM) in breast cancer patients with PALB2 mutations. The aim of our study was to evaluate the challenges in managing breast cancer risk in patients with PALB2 pathogenic variants with illustration through real-world clinical cases and a review of the literature. Methods: In this retrospective observational study, we present 5 patients with PALB2 mutations between the ages of 29 and 61 years who were diagnosed with breast cancer and underwent surgical management of their breast cancer at our institution between November 2020 and March 2022. Through their clinical courses and a literature review, we discuss the role of CRRM in breast cancer patients with PALB2 gene mutations. Results: Out of the 5 patients, 3 patients underwent CRRM and 2 patients chose unilateral surgery for their breast cancer and active surveillance for the contralateral breast. Of the 3 patients who underwent CRRM, 1 patient experienced a surgical complication from reconstruction on the prophylactic side. None of the patients developed any recurrences with an average length of follow up of 15.4 months. Conclusions: Based on our experience and the currently available literature, CRRM in patients with a PALB2 mutation should be performed on a case-by-case basis through a shared decision-making process taking into consideration overall risk, family history, patient preference and quality of life.

VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux.

Cell adhesion plays a critical role in the development of chemoresistance, which is a major issue in anti-cancer therapies. In this study, we have examined the role of the VLA-4 integrin, a major adhesion molecule of the immune system, in the chemoresistance of T-ALL cells. We found that attachment of Jurkat and HSB-2 T-ALL cells to VCAM-1, a VLA-4 ligand, inhibits doxorubicin-induced apoptosis. However, their adhesion to fibronectin, which is mainly mediated via VLA-5, had no effect. Even the presence of the chemoattractant SDF1α (Stromal cell-derived factor-1α), which enhances the adhesion of T-ALL cells to fibronectin, did not modify the sensitivity of the cells attached on fibronectin towards doxorubicin-induced apoptosis. Mechanistically, we found that VLA-4 promoted T-ALL chemoresistance by inducing doxorubicin efflux. Our results showed that cell adhesion to both fibronectin and VCAM-1-induced Focal adhesion kinase (FAK) phosphorylation in T-ALL cells. However, only cell adhesion to VCAM-1 led to PYK2 phosphorylation. Inhibition studies indicated that FAK is not involved in doxorubicin efflux and chemoresistance, whereas PYK2 inhibition abrogated both VLA-4-induced doxorubicin efflux and chemoresistance. Together, these results indicate that the VLA-4/PYK2 pathway could participate in T-ALL chemoresistance and its targeting could be beneficial to limit/avoid chemoresistance and patient relapse.

Beta1 integrin blockade overcomes doxorubicin resistance in human T-cell acute lymphoblastic leukemia.

Growing evidence indicates that cell adhesion to extracellular matrix (ECM) plays an important role in cancer chemoresistance. Leukemic T cells express several adhesion receptors of the ß1 integrin subfamily with which they interact with ECM. However, the role of ß1 integrins in chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL) is still ill defined. In this study, we demonstrate that interactions of human T-ALL cell lines and primary blasts with three-dimensional matrices including Matrigel and collagen type I gel promote their resistance to doxorubicin via ß1 integrin. The blockade of ß1 integrin with a specific neutralizing antibody sensitized xenografted CEM leukemic cells to doxorubicin, diminished the leukemic burden in the bone marrow and resulted in the extension of animal survival. Mechanistically, Matrigel/ß1 integrin interaction enhanced T-ALL chemoresistance by promoting doxorubicin efflux through the activation of the ABCC1 drug transporter. Finally, our findings showed that Matrigel/ß1 interaction enhanced doxorubicin efflux and chemoresistance by activating the FAK-related proline-rich tyrosine kinase 2 (PYK2) as both PYK2 inhibitor and siRNA diminished the effect of Matrigel. Collectively, these results support the role of ß1 integrin in T-ALL chemoresistance and suggest that the ß1 integrin pathway can constitute a therapeutic target to avoid chemoresistance and relapsed-disease in human T-ALL.

PLAC1 as a serum biomarker for breast cancer.

Placental-specific protein 1 (PLAC1) is an X-linked trophoblast gene that is re-expressed in several malignancies, including breast cancer, and is therefore a potential biomarker to follow disease onset and progression. Sera from 117 preoperative/pretreatment breast cancer patients and 51 control subjects, including those with fibrocystic disease, were analyzed for the presence of PLAC1 protein as well as its expression by IHC in tumor biopsies in a subset of subjects. Serum PLAC1 levels exceeded the mean plus one standard deviation (mean+SD) of the level in control subjects in 67% of subjects with ductal carcinoma in situ (DCIS), 67% with HER2+ tumors, 73% with triple-negative cancer and 73% with ER+/PR+ tumors. Greater sensitivity was achieved using the mean+2 SD of control PLAC1 serum values, where the false positive rate was 3% and was exceeded by 38%, 40%, 60% and 43% of subjects with DCIS, HER2+, TNBC and ER+/PR+/HER2- tumors. PLAC1 was detected in 97% of tumor biopsies, but did not correlate quantitatively with serum levels. There was no significant correlation of serum PLAC1 levels with race, age at diagnosis, body mass index (BMI) or the presence of metastatic disease. It remains to be determined whether PLAC1 serum levels can serve as a diagnostic biomarker for the presence or recurrence of disease post-surgery and/or therapy.

Human Th17 Migration in Three-Dimensional Collagen Involves p38 MAPK.

T cell migration across extracellular matrix (ECM) is an important step of the adaptive immune response but is also involved in the development of inflammatory autoimmune diseases. Currently, the molecular mechanisms regulating the motility of effector T cells in ECM are not fully understood. Activation of p38 MAPK has been implicated in T cell activation and is critical to the development of immune and inflammatory responses. In this study, we examined the implication of p38 MAPK in regulating the migration of human Th17 cells through collagen. Using specific inhibitor and siRNA, we found that p38 is necessary for human Th17 migration in three-dimensional (3D) collagen and that 3D collagen increases p38 phosphorylation. We also provide evidence that the collagen receptor, discoidin domain receptor 1 (DDR1), which promotes Th17 migration in 3D collagen, is involved in p38 activation. Together, our findings suggest that targeting DDR1/p38 MAPK pathway could be beneficial for the treatment of Th17-mediated inflammatory diseases. J. Cell. Biochem. 118: 2819-2827, 2017. © 2017 Wiley Periodicals, Inc.

Genomic profiling of breast cancer in African-American women using MammaPrint.

Breast cancer in African-American females (AAF) has a less favorable outcome than that in Caucasians. More information is needed regarding its biology. We evaluated gene expression in tumors from AAF presenting with early stage or locally advanced breast cancer using MammaPrint(®), BluePrint (®) (molecular subtype) and TargetPrint (®) [estrogen receptor (ER), progesterone receptor, and Human Epidermal Growth Factor Receptor 2 (HER2) mRNA levels]. Genomic information was correlated with clinical and pathologic characteristics and Oncotype DX(®) Recurrence Score(®) (RS). One hundred Patients were enrolled, 1 not evaluable by BluePrint. The median age was 60 years (range 22-98), and eighty-four (84 %) patients had stage I or II disease. High Risk MammaPrint was present in 66 % of patients and in 52 % of patients with stage I disease. High Risk MammaPrint was associated with young age (p = 0.02), high grade (p < 0.0001), HER2 expression (p = 0.016), and triple-negative phenotype (p < 0.001). Sixty-four tumors (65 %) were Luminal type (47 % of these were classified as High Risk), 26 (26 %) were Basal type, and 9 (9 %) HER2 type. Twenty-two cancers were triple negative (TN) by IHC and 19 (90 %) Basal type. Among the 15 tumors HER2 positive by IHC/FISH, 8 (53 %) were HER2 type by BluePrint. Eleven tumors with ER expression of 1-9 % were ER negative by TargetPrint and none of these was Luminal type. None of the seven tumors HER2 positive by IHC/FISH but negative by TargetPrint was HER type. RS results were available in 29 patients: two had High Risk both by RS and MammaPrint; eight had intermediate RS, with four High Risk by MammaPrint; 19 had a low RS, with eight High Risk by MammaPrint. AAF with stage I to III breast cancer often present with High Risk disease. Molecular heterogeneity is present within TN, HER2-positive, and ER-positive breast cancer. RS and MammaPrint offer different prognostic information.

Discoidin domain receptor 1 promotes Th17 cell migration by activating the RhoA/ROCK/MAPK/ERK signaling pathway.

Effector T cell migration through the tissue extracellular matrix (ECM) is an important step of the adaptive immune response and in the development of inflammatory diseases. However, the mechanisms involved in this process are still poorly understood. In this study, we addressed the role of a collagen receptor, the discoidin domain receptor 1 (DDR1), in the migration of Th17 cells. We showed that the vast majority of human Th17 cells express DDR1 and that silencing DDR1 or using the blocking recombinant receptor DDR1:Fc significantly reduced their motility and invasion in three-dimensional (3D) collagen. DDR1 promoted Th17 migration by activating RhoA/ROCK and MAPK/ERK signaling pathways. Interestingly, the RhoA/ROCK signaling module was required for MAPK/ERK activation. Finally, we showed that DDR1 is important for the recruitment of Th17 cells into the mouse dorsal air pouch containing the chemoattractant CCL20. Collectively, our results indicate that DDR1, via the activation of RhoA/ROCK/MAPK/ERK signaling axis, is a key pathway of effector T cell migration through collagen of perivascular tissues. As such, DDR1 can contribute to the development of Th17-dependent inflammatory diseases.

TARGIT-R (Retrospective): North American Experience with Intraoperative Radiation Using Low-Kilovoltage X-Rays for Breast Cancer.

BACKGROUND: Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America. METHODS: A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed. RESULTS: From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p < 0.001). The median patient age was 66.8 years. Most patients had disease that was <2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated. CONCLUSIONS: IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.

Impact of genomic testing and patient-reported outcomes on receipt of adjuvant chemotherapy.

Practice guidelines incorporate genomic tumor profiling, using results such as the Oncotype DX Recurrence Score (RS), to refine recurrence risk estimates for the large proportion of breast cancer patients with early-stage, estrogen receptor-positive disease. We sought to understand the impact of receiving genomic recurrence risk estimates on breast cancer patients' well-being and the impact of these patient-reported outcomes on receipt of adjuvant chemotherapy. Participants were 193 women (mean age 57) newly diagnosed with early-stage breast cancer. Women were interviewed before and 2-3 weeks after receiving the RS result between 2011 and 2015. We assessed subsequent receipt of chemotherapy from chart review. After receiving their RS, perceived pros (t = 4.27, P < .001) and cons (t = 8.54, P < .001) of chemotherapy increased from pre-test to post-test, while perceived risk of breast cancer recurrence decreased (t = 2.90, P = .004). Women with high RS tumors were more likely to receive chemotherapy than women with low RS tumors (88 vs. 5 %, OR 0.01, 0.00-0.02, P < .001). Higher distress (OR 2.19, 95 % CI 1.05-4.57, P < .05) and lower perceived cons of chemotherapy (OR 0.50, 95 % CI 0.26-0.97, P < .05) also predicted receipt of chemotherapy. Distressed patients who saw few downsides of chemotherapy received this treatment. Clinicians should consider these factors when discussing chemotherapy with breast cancer patients.

Cooperation between IL-7 Receptor and Integrin α2ß1 (CD49b) Drives Th17-Mediated Bone Loss.

Th17 cells are critical effectors in inflammation and tissue damage such as bone erosion, but the mechanisms regulating their activation in this process are not fully understood. In this study, we considered the cooperation between cytokine receptors and integrin pathways in Th17-osteoclast function. We found that human Th17 cells coexpress IL-7R and the collagen-binding integrin α2ß1 (CD49b), and IL-7 increases their adhesion to collagen via α2ß1 integrin. In addition, coengagement of the two receptors in human Th17 cells cooperatively enhanced their IL-17 production and their osteoclastogenic function. The functional cooperation between IL-7R and α2ß1 integrin involves activation of the JAK/PI3K/AKT (protein kinase B) and MAPK/ERK pathways. We also showed that IL-7-induced bone loss in vivo is associated with Th17 cell expansion. Moreover, blockade of α2ß1 integrin with a neutralizing mAb inhibited IL-7-induced bone loss and osteoclast numbers by reducing Th17 cell numbers in the bone marrow and reducing the production of IL-17 and the receptor activator of NF-κB ligand. Thus, the cooperation between IL-7R and α2ß1 integrin can represent an important pathogenic pathway in Th17-osteoclast function associated with inflammatory diseases.

Disparities in breast cancer surgery delay: the lingering effect of race.

BACKGROUND: Delays to surgical breast cancer treatment of 90 days or more may be associated with greater stage migration. We investigated racial disparities in time to receiving first surgical treatment in breast cancer patients. METHODS: Insured black (56 %) and white (44 %) women with primary breast cancer completed telephone interviews regarding psychosocial (e.g., self-efficacy) and health care factors (e.g., communication). Clinical data were extracted from medical charts. Time to surgery was measured as the days between diagnosis and definitive surgical treatment. We also examined delays of more than 90 days. Unadjusted hazard ratios (HRs) examined univariate relationships between delay outcomes and covariates. Cox proportional hazard models were used for multivariate analyses. RESULTS: Mean time to surgery was higher in blacks (mean 47 days) than whites (mean 33 days; p = .001). Black women were less likely to receive therapy before 90 days compared to white women after adjustment for covariates (HR .58; 95 % confidence interval .44, .78). Health care process factors were nonsignificant in multivariate models. Women with shorter delay reported Internet use (vs. not) and underwent breast-conserving surgery (vs. mastectomy) (p < .01). CONCLUSIONS: Prolonged delays to definitive breast cancer surgery persist among black women. Because the 90-day interval has been associated with poorer outcomes, interventions to address delay are needed.

Co-culture of human bronchial fibroblasts and CD4+ T cells increases Th17 cytokine signature.

BACKGROUND: Airway inflammation is an important characteristic of asthma and has been associated with airway remodelling and bronchial hyperreactivity. The mucosal microenvironment composed of structural cells and highly specialised extracellular matrix is able to amplify and promote inflammation. This microenvironment leads to the development and maintenance of a specific adaptive response characterized by Th2 and Th17. Bronchial fibroblasts produce multiple mediators that may play a role in maintaining and amplifying this response in asthma. OBJECTIVE: To investigate the role of bronchial fibroblasts obtained from asthmatic subjects and healthy controls in regulating Th17 response by creating a local micro-environment that promotes this response in the airways. METHODS: Human bronchial fibroblasts and CD4(+)T cells were isolated from atopic asthmatics and non-atopic healthy controls. CD4(+)T were co-cultured with bronchial fibroblasts of asthmatic subjects and healthy controls. RORc gene expression was detected by qPCR. Phosphorylated STAT-3 and RORγt were evaluated by western blots. Th17 phenotype was measured by flow cytometry. IL-22, IL17, IL-6 TGF-ß and IL1-ß were assessed by qPCR and ELISA. RESULTS: Co-culture of CD4(+)T cells with bronchial fibroblasts significantly stimulated RORc expression and induced a significant increase in Th17 cells as characterized by the percentage of IL-17(+)/CCR6(+) staining in asthmatic conditions. IL-17 and IL-22 were increased in both normal and asthmatic conditions with a significantly higher amount in asthmatics compared to controls. IL-6, IL-1ß, TGF-ß and IL-23 were significantly elevated in fibroblasts from asthmatic subjects upon co-culture with CD4(+)T cells. IL-23 stimulates IL-6 and IL-1ß expression by bronchial fibroblasts. CONCLUSION: Interaction between bronchial fibroblasts and T cells seems to promote specifically Th17 cells profile in asthma. These results suggest that cellular interaction particularly between T cells and fibroblasts may play a pivotal role in the regulation of the inflammatory response in asthma.

α2ß1 integrin regulates Th17 cell activity and its neutralization decreases the severity of collagen-induced arthritis.

Th17 cells play a critical role in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms by which these cells regulate the development of RA are not fully understood. We have recently shown that α2ß1 integrin, the receptor of type I collagen, is the major collagen-binding integrin expressed by human Th17 cells. In this study, we examined the role of α2ß1 integrin in Th17-mediated destructive arthritis in the murine model of collagen-induced arthritis (CIA). We found that α2ß1 integrin is expressed on synovial Th17 cells from CIA mice and its neutralization with a specific mAb significantly reduced inflammation and cartilage degradation, and protected the mice from bone erosion. Blockade of α2ß1 integrin led to a decrease in the number of Th17 cells in the joints and to a reduction of IL-17 levels in CIA mice. This was associated with an inhibition of receptor activator of NF-κB ligand levels and osteoclast numbers, and reduction of bone loss. We further show that α2ß1 integrin is expressed on synovial Th17 cells from RA patients, and that its ligation with collagen costimulated the production of IL-17 by polarized human Th17 cells by enhancing the expression of retinoic acid receptor-related orphan receptor C through ERK and PI3K/AKT. Our findings provide the first evidence, to our knowledge, that α2ß1 integrin is an important pathway in Th17 cell activation in the pathogenesis of CIA, suggesting that its blockade can be beneficial for the treatment of RA and other Th17-associated autoimmune diseases.

Narrowing racial gaps in breast cancer chemotherapy initiation: the role of the patient-provider relationship.

Chemotherapy improves breast cancer survival but is underused more often in black than in white women. We examined associations between patient-physician relationships and chemotherapy initiation and timeliness of initiation among black and white patients. Women with primary invasive, non-metastatic breast cancer were recruited via hospitals (in Washington, DC and Detroit) and community outreach between July 2006 and April 2011. Data were collected via telephone interviews and medical records. Logistic regression models evaluated associations between chemotherapy initiation and independent variables. Since there were race interactions, analyses were race-stratified. Factors associated with time from surgery to chemotherapy initiation and delay of ≥90 days were evaluated with linear and logistic regressions, respectively. Among eligible women, 82.8 % were interviewed and 359 (90.9 %) of those had complete data. The odds of initiating chemotherapy were 3.26 times (95 % CI: 1.51, 7.06) higher among black women reporting greater communication with physicians (vs. lesser), after considering covariates. In contrast, the odds of starting chemotherapy were lower for white women reporting greater communication (vs. lesser) (adjusted OR 0.22, 95 % CI: 0.07, 0.73). The opposing direction of associations was also seen among the sub-set of black and white women with definitive clinical indications for chemotherapy. Among those initiating treatment, black women had longer mean time to the start of chemotherapy than whites (71.8 vs. 55.0 days, p = 0.005), but race was not significant after considering trust in oncologists, where initiation time decreased as trust increased, controlling for covariates. Black women were also more likely to delay ≥90 days than whites (27 vs. 8.3 %; p = 0.024), but this was not significant after considering religiosity. The patient-physician dyad and sociocultural factors may represent leverage points to improve chemotherapy patterns in black women.

Out-of-plane Stokes imaging polarimeter for early skin cancer diagnosis.

Optimal treatment of skin cancer before it metastasizes critically depends on early diagnosis and treatment. Imaging spectroscopy and polarized remittance have been utilized in the past for diagnostic purposes, but valuable information can be also obtained from the analysis of skin roughness. For this purpose, we have developed an out-of-plane hemispherical Stokes imaging polarimeter designed to monitor potential skin neoplasia based on a roughness assessment of the epidermis. The system was utilized to study the rough surface scattering for wax samples and human skin. The scattering by rough skin-simulating phantoms showed behavior that is reasonably described by a facet scattering model. Clinical tests were conducted on patients grouped as follows: benign nevi, melanocytic nevus, melanoma, and normal skin. Images were captured and analyzed, and polarization properties are presented in terms of the principal angle of the polarization ellipse and the degree of polarization. In the former case, there is separation between different groups of patients for some incidence azimuth angles. In the latter, separation between different skin samples for various incidence azimuth angles is observed.