PTPN2 elicits cell autonomous and non-cell autonomous effects on antitumor immunity in triple-negative breast cancer.

The tumor-suppressor PTPN2 is diminished in a subset of triple-negative breast cancers (TNBCs). Paradoxically, PTPN2-deficiency in tumors or T cells in mice can facilitate T cell recruitment and/or activation to promote antitumor immunity. Here, we explored the therapeutic potential of targeting PTPN2 in tumor cells and T cells. PTPN2-deficiency in TNBC associated with T cell infiltrates and PD-L1 expression, whereas low PTPN2 associated with improved survival. PTPN2 deletion in murine mammary epithelial cells TNBC models, did not promote tumorigenicity but increased STAT-1-dependent T cell recruitment and PD-L1 expression to repress tumor growth and enhance the efficacy of anti-PD-1. Furthermore, the combined deletion of PTPN2 in tumors and T cells facilitated T cell recruitment and activation and further repressed tumor growth or ablated tumors already predominated by exhausted T cells. Thus, PTPN2-targeting in tumors and/or T cells facilitates T cell recruitment and/or alleviates inhibitory constraints on T cells to combat TNBC.

Tumor inherent interferon regulators as biomarkers of long-term chemotherapeutic response in TNBC.

Patients diagnosed with triple negative breast cancer (TNBC) have an increased risk of rapid metastasis compared to other subtypes. Predicting long-term survival post-chemotherapy in patients with TNBC is difficult, yet enhanced infiltration of tumor infiltrating lymphocytes (TILs) has been associated with therapeutic response and reduced risk of metastatic relapse. Immune biomarkers that predict the immune state of a tumor and risk of metastatic relapse pre- or mid-neoadjuvant chemotherapy are urgently needed to allow earlier implementation of alternate therapies that may reduce TNBC patient mortality. Utilizing a neoadjuvant chemotherapy trial where TNBC patients had sequential biopsies taken, we demonstrate that measurement of T-cell subsets and effector function, specifically CD45RO expression, throughout chemotherapy predicts risk of metastatic relapse. Furthermore, we identified the tumor inherent interferon regulatory factor IRF9 as a marker of active intratumoral type I and II interferon (IFN) signaling and reduced risk of distant relapse. Functional implications of tumor intrinsic IFN signaling were demonstrated using an immunocompetent mouse model of TNBC, where enhanced type I IFN signaling increased anti-tumor immunity and metastasis-free survival post-chemotherapy. Using two independent adjuvant cohorts we were able to validate loss of IRF9 as a poor prognostic biomarker pre-chemotherapy. Thus, IRF9 expression may offer early insight into TNBC patient prognosis and tumor heat, allowing for identification of patients that are unlikely to respond to chemotherapy alone and could benefit from further immune-based therapeutic intervention.

Do Web-based and clinic samples of gay men living with HIV differ on self-reported physical and psychological symptoms? A comparative analysis.

BACKGROUND: Although the Internet is commonly used to recruit samples in studies of human immunodeficiency virus (HIV)-related risk behaviors, it has not been used to measure patient-reported well-being. As the burden of long-term chronic HIV infection rises, the Internet may offer enormous potential for recruitment to research and interventions. OBJECTIVE: This study aimed to compare two samples of gay men living with HIV, one recruited via the Web and the other recruited in outpatient settings, in terms of self-reported physical and psychological symptom burden. METHODS: The Internet sample was recruited from a UK-wide Web-based survey of gay men with diagnosed HIV. Of these, 154 respondents identified themselves as resident in London and were included in this analysis. The HIV clinic sample was recruited from five HIV outpatient clinics. Of these participants, 400 gay men recruited in London clinics were included in this analysis. RESULTS: The Web-based sample was younger than the clinic sample (37.3 years, SD 7.0 vs 40.9 years, SD 8.3), more likely to be in paid employment (72.8%, 99/136 vs 60.1%, 227/378), less likely to be on antiretroviral therapy (ART) (58.4%, 90/154 vs 68.0%, 266/391), and had worse mean psychological symptom burden compared to the clinic sample (mean scores: 1.61, SD 1.09 vs 1.36, SD 0.96) but similar physical symptom burden (mean scores: 0.78, SD 0.65 vs 0.70, SD 0.74). In multivariable logistic regression, for the physical symptom burden model, adjusted for age, ethnicity, employment status, and ART use, the recruitment setting (ie, Web-based vs clinic) was not significantly associated with high physical symptom score. The only variable that remained significantly associated with high physical symptom score was employment status, with those in employment being less likely to report being in the upper (worst) physical symptom tertile versus the other two tertiles (adjusted OR 0.41, 95% CI 0.28-0.62, P<.001). For the psychological symptom burden model, those recruited via the Web were significantly more likely to report being in the upper (worst) tertile (adjusted OR 2.20, 95% CI 1.41-3.44, P=.001). In addition, those in employment were less likely to report being in the upper (worst) psychological symptom tertile compared to those not in employment (adjusted OR 0.32, 95% CI 0.21-0.49, P<.001). CONCLUSIONS: Our data have revealed a number of differences. Compared to the clinic sample, the Web-based sample had worse psychological symptom burden, younger average age, higher prevalence of employment, and a lower proportion on ART. For future research, we recommend that Web-based data collection should include the demographic variables that we note differed between samples. In addition, we recognize that each recruitment method may bring inherent sampling bias, with clinic populations differing by geographical location and reflecting those accessing regular medical care, and Web-based sampling recruiting those with greater Internet access and identifying survey materials through specific searches and contact with specific websites.

Discriminating lymphomas and reactive lymphadenopathy in lymph node biopsies by gene expression profiling.

BACKGROUND: Diagnostic accuracy of lymphoma, a heterogeneous cancer, is essential for patient management. Several ancillary tests including immunophenotyping, and sometimes cytogenetics and PCR are required to aid histological diagnosis. In this proof of principle study, gene expression microarray was evaluated as a single platform test in the differential diagnosis of common lymphoma subtypes and reactive lymphadenopathy (RL) in lymph node biopsies. METHODS: 116 lymph node biopsies diagnosed as RL, classical Hodgkin lymphoma (cHL), diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL) were assayed by mRNA microarray. Three supervised classification strategies (global multi-class, local binary-class and global binary-class classifications) using diagonal linear discriminant analysis was performed on training sets of array data and the classification error rates calculated by leave one out cross-validation. The independent error rate was then evaluated by testing the identified gene classifiers on an independent (test) set of array data. RESULTS: The binary classifications provided prediction accuracies, between a subtype of interest and the remaining samples, of 88.5%, 82.8%, 82.8% and 80.0% for FL, cHL, DLBCL, and RL respectively. Identified gene classifiers include LIM domain only-2 (LMO2), Chemokine (C-C motif) ligand 22 (CCL22) and Cyclin-dependent kinase inhibitor-3 (CDK3) specifically for FL, cHL and DLBCL subtypes respectively. CONCLUSIONS: This study highlights the ability of gene expression profiling to distinguish lymphoma from reactive conditions and classify the major subtypes of lymphoma in a diagnostic setting. A cost-effective single platform "mini-chip" assay could, in principle, be developed to aid the quick diagnosis of lymph node biopsies with the potential to incorporate other pathological entities into such an assay.

The effect of running exercise on intervertebral disc extracellular matrix production in a rat model.

STUDY DESIGN: Using a running rat model, the effects of physical exercise on cellular function and intervertebral disc (IVD) extracellular matrix were studied. OBJECTIVE: To investigate whether 3-weeks treadmill running exercise can stimulate matrix production and cellular proliferation of the IVD. SUMMARY OF BACKGROUND DATA: Appropriate physical exercise plays an important role in the treatment of patients with low back pain-associated IVD disorder. However, it is unknown how regular exercise affects the disc at the cellular level. METHODS: Twelve Sprague-Dawley rats underwent a daily treadmill exercise regime for a total of 3 weeks. Twelve nonexercised rats served as controls. The spinal lumbar IVD were collected and paraffin embedded for histologic analysis. Cell counts were determined on hematoxylin-eosin- and Masson-Trichrome-stained paraffin sections. Protein expression of collagen-I, collagen-II, aggrecan, Sox-9, and Sox-6 was evaluated with immunohistochemical staining. mRNA expression of Sox-9 and collagen-2 were studied by in situ hybridization. Proteoglycans were visualized with Alcian blue. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. RESULTS: The cell numbers in the anulus fibrosus (AF) increased by 25% (P < 0.05) after 3 weeks of exercise. Collagen-2 and Sox-9 mRNA were strongly expressed in the nucleus pulposus (NP) samples of the running group, but weakly expressed in the controls. An increase in collagen-II, aggrecan, and Sox-9 protein expression in NP and AF regions of the disc was detected in the exercised rats compared with controls. Quantification of Alcian blue staining demonstrated increased proteoglycan in both NP (8-fold) and AF (7-fold) in the exercised group compared with controls (P < 0.05). In addition, no significant differences were observed between the experimental groups in cellular apoptosis, collagen-I, or Sox-6 expression. CONCLUSION: In this study, increased extracellular matrix production and cell proliferation with no induction of disc cell apoptosis was observed in the lumbar IVD after a 3-week running regimen in rats, suggesting that regular exercise may have an augmentative effect on cells and matrix production.

Positive futures? The impact of HIV infection on achieving health, wealth and future planning.

Although HIV is now cast as a chronic condition with favourable clinical outcomes under new treatments, it is unclear how living with HIV affects expectations and planning for the future. This mixed-methods study aimed to investigate UK gay men's expectations of their own future when living with HIV, and to identify the heath and social interventions required to enhance roles, participation and personal fulfilment. A preliminary focus group identified relevant domains of enquiry for a subsequent online cross-sectional survey. A total of 347 gay men living in the UK with HIV participated in the survey, and 56.6% were currently on treatment. However, high 7-day prevalence of psychological and physical symptoms was identified (42.6% in pain, 80.2% worrying); 57.8% perceived reduced career options due to their infection and 71.8% reduced life expectancy. Being on treatment was not significantly associated with perceived life expectancy. Coded open-ended survey data identified eight principle themes related to goal planning and attainment. The integrated open and closed data items offer an understanding of barriers and challenges that focus on poor mental health due to clinical inattention, discrimination and stigma, poor career and job opportunities due to benefit and workplace inflexibility and lack of understanding, a lack of personal goals and associated skills deficit related to confidence and self esteem. Gay men living with HIV require an integrated holistic approach to wellbeing that incorporates clinical, social and individual intervention in order to lead productive lives with maximum benefit from treatment gains.

Recent advances in metastasis research.

Advances in the early prediction, detection, and treatment of metastatic disease has improved the outlook in cancer patients in recent decades, however, metastasis remains the major cause of death in affected individuals. Metastasis occurs in a series of discreet biological steps in which a single, frequently clinically occult micrometastatic cell travels from the primary tumor to a distant location, where it lodges, grows, and ultimately results in the patient's death. Recent work has provided many new insights in the mechanisms and biology behind metastatic spread. This short review surveys some of the most important recent developments that have helped increase our understanding of the three broad phases of metastasis - the genesis of the metastatic cell through the loss of local constraints in the primary tumor microenvironment, dissemination of the cell to a distant organ while avoiding immune surveillance, and finally lodging and growth of the overt metastasis. These studies are providing mounting evidence that the interactions between tumor and normal cells and tissues are critical for disease progression - a paradigm that will provide a fertile area for future research.

Is antiretroviral therapy associated with symptom prevalence and burden?

Although distressing pain and other symptoms have been reported at all stages of HIV disease, studies have not taken account of the relative contribution of treatment side-effects and underlying disease. This study aimed to assess the prevalence of symptoms, their burden and the association with use of highly active antiretroviral therapy (HAART). Three hundred and forty-seven gay men with HIV disease completed an online survey, reporting data on age, CD4, viral load, year of diagnosis, HAART use, and the Memorial Symptom Assessment Scale Short Form (MSAS-SF).Those men currently receiving HAART (n=210, 56.6%) reported a higher number of symptoms than those without (14 versus 10.3, P=0.001). Fourteen physical symptoms were significantly more frequent among HAART users. Symptoms of psychological distress were the most common in both groups, ranging from 69.2% to 79.5%. Mean distress indices were higher for those on treatment with respect to both global (P=0.011) and physical (P=0.001) distress. In multivariate analysis, use of HAART was independently associated with number of physical symptoms (b=2.81, P=0.006), and physical distress score (b=2.45, P=0.017); both increasing with HAART use when controlling for age, year of diagnosis, CD4 and viral load. The high symptom prevalence, particularly psychological symptoms, is comparable with end-stage malignant and non-malignant diseases. Greater attention needs to be paid to the assessment and management of burdensome symptoms.