Subdiffusion and weak ergodicity breaking in the presence of a reactive boundary

We derive the boundary condition for a subdiffusive particle interacting with a reactive boundary with finite reaction rate. Molecular crowding conditions, that are found to cause subdiffusion of larger molecules in biological cells, are shown to effect long-tailed distributions with identical exponent for both the unbinding times from the boundary to the bulk and the rebinding times from the bulk. This causes a weak ergodicity breaking: typically, an individual particle either stays bound or remains in the bulk for very long times. We discuss why this may be beneficial for in vivo gene regulation by DNA-binding proteins, whose typical concentrations are nanomolarComment: 4 pages, 1 figure, REVTeX4, accepted to Phys Rev Lett, some typos correcte

Bulk Mediated Surface Diffusion: Non Markovian Desorption with Finite First Moment

Here we address a fundamental issue in surface physics: the dynamics of adsorbed molecules. We study this problem when the particle's desorption is characterized by a non Markovian process, while the particle's adsorption and its motion in the bulk are governed by a Markovian dynamics. We study the diffusion of particles in a semi-infinite cubic lattice, and focus on the effective diffusion process at the interface $z = 1$. We calculate analytically the conditional probability to find the particle on the $z=1$ plane as well as the surface dispersion as functions of time. The comparison of these results with Monte Carlo simulations show an excellent agreement.Comment: 16 pages, 7 figs. European Physical Journal B (in press

The Role of Checkpoint Kinase 1 in Sensitivity to Topoisomerase I Poisons

Agents that target topoisomerase I are widely utilized to treat human cancer. Previous studies have indicated that both the ataxia telangiectasia mutated (ATM)/ checkpoint kinase (Chk) 2 and ATM- and Rad 3-related (ATR)/Chk1 checkpoint pathways are activated after treatment with these agents. The relative contributions of these two pathways to survival of cells after treatment with topoisomerase I poisons are currently unknown. To address this issue, we assessed the roles of ATR, Chk1, ATM, and Chk2 in cells treated with the topoisomerase I poisons camptothecin and 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Colony forming assays demonstrated that down-regulation of ATR or Chk1 sensitized cells to SN-38 and camptothecin. In contrast, ATM and Chk2 had minimal effect of sensitivity to SN-38 or camptothecin. Additional experiments demonstrated that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin, which down-regulates Chk1, also sensitized a variety of human carcinoma cell lines to SN-38. Collectively, these results show that the ATR/Chk1 pathway plays a predominant role in the response to topoisomerase I inhibitors in carcinoma cells and identify a potential approach for enhancing the efficacy of these drugs

CCR6+ Th cell populations distinguish ACPA positive from ACPA negative rheumatoid arthritis

Introduction: Patients with rheumatoid arthritis (RA) can be separated into two major subpopulations based on the absence or presence of serum anti-citrullinated protein antibodies (ACPAs). The more severe disease course in ACPA+ RA and differences in treatment outcome between these subpopulations suggest that ACPA+ and ACPA- RA are different disease subsets. The identification of T-helper (Th) cells specifically recognizing citrullinated peptides, combined with the strong association between HLA-DRB1 and ACPA positivity, point toward a pathogenic role of Th cells in ACPA+ RA. In this context we recently identified a potential pathogenic role for CCR6+ Th cells in RA. Therefore, we examined whether Th cell population distributions differ by ACPA status. Methods: We performed a nested matched case-control study including 27 ACPA+ and 27 ACPA- treatment-naive early RA patients matched for disease activity score in 44 joints, presence of rheumatoid factor, sex, age, duration of complaints and presence of erosions. CD4+CD45RO+ (memory) Th cell distribution profiles from these patients were generated based on differential chemokine receptor expression and related with disease duration. Results: ACPA status was not related to differences in total CD4+ T cell or memory Th cell proportions. However, ACPA+ patients had significantly higher proportions of Th cells expressing the chemokine receptors CCR6 and CXCR3. Similar proportions of CCR4+ and CCR10+ Th cells were found. Within the CCR6+ cell population, four Th subpopulations were distinguished based on differential chemokine receptor expression: Th17 (CCR4+CCR10-), Th17.1 (CXCR3+), Th22 (CCR4+CCR10+) and CCR4/CXCR3 double-positive (DP) cells. In particular, higher proportions of Th22 (p = 0.02), Th17.1 (p = 0.03) and CCR4/CXCR3 DP (p = 0.01) cells were present in ACPA+ patients. In contrast, ACPA status was not associated with differences in Th1 (CCR6-CXCR3+; p = 0.90), Th2 (CCR6-CCR4+; p = 0.27) and T-regulatory (CD25hiFOXP3+; p = 0.06) cell proportions. Interestingly, CCR6+ Th cells were inversely correlated with disease duration in ACPA- patients (R2 = -0.35; p < 0.01) but not in ACPA+ (R2 < 0.01; p = 0.94) patients. Conclusions: These findings demonstrate that increased peripheral blood CCR6+ Th cells proportions distinguish ACPA+ RA from ACPA- RA. This suggests that CCR6+ Th cells are involved in the differences in disease severity and tr

Combination Strategies to Optimize Efficacy of Dendritic Cell-Based Immunotherapy

Dendritic cells (DCs) are antigen-presenting cells (APCs) that are essential for the activation of immune responses. In various malignancies, these immunostimulatory properties are exploited by DC-therapy, aiming at the induction of effective anti-tumor immunity by vaccination with ex vivo antigen-loaded DCs. Depending on the type of DC-therapy used, long-term clinical efficacy upon DC-therapy remains restricted to a proportion of patients, likely due to lack of immunogenicity of tumor cells, presence of a stromal compartment, and the suppressive tumor microenvironment (TME), thereby leading to the development of resistance. In order to circumvent tumor-induced suppressive mechanisms and unleash the full potential of DC-therapy, considerable efforts have been made to combine DC-therapy with chemotherapy, radiotherapy or with checkpoint inhibitors. These combination strategies could enhance tumor immunogenicity, stimulate endogenous DCs following immunogenic cell death, improve infiltration of cytotoxic T lymphocytes (CTLs) or specifically deplete immunosuppressive cells in the TME, such as regulatory T-cells and myeloid-derived suppressor cells. In this review, different strategies of combining DC-therapy with immunomodulatory treatments will be discussed. These strategies and insights will improve and guide DC-based combination immunotherapies with the aim of further improving patient prognosis and care

Heterogeneity in immune cell content in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with limited therapy options and dismal prognosis. In recent years, the role of immune cells within the tumor microenvironment (TME) has become a major area of interest. In this review, we discuss the current knowledge of heterogeneity in immune cell content and checkpoint expression in MPM in relation to prognosis and prediction of treatment efficacy. Generally, immune-suppressive cells such as M2 macrophages, myeloid-derived suppressor cells and regulatory T cells are present within the TME, with extensive heterogeneity in cell numbers. Infiltration of effector cells such as cytotoxic T cells, natural killer cells and T helper cells is commonly found, also with substantial patient to patient heterogeneity. PD-L1 expression also varied greatly (16-65%). The infiltration of immune cells in tumor and associated stroma holds key prognostic and predictive implications. As such, there is a strong rationale for thoroughly mapping the TME to better target therapy in mesothelioma. Researchers should be aware of the extensive possibilities that exist for a tumor to evade the cytotoxic killing from the immune system. Therefore, no “one size fits all” treatment is likely to be found and focus should lie on the heterogeneity of the tumors and TME

Efficacy of nivolumab and ipilimumab in patients with malignant pleural mesothelioma is related to a subtype of effector memory cytotoxic T cells: Translational evidence from two clinical trials

Background: Combined immune checkpoint inhibitor (ICI) treatment targeting PD-1 and CTLA-4 was suggested to yield clinical benefit over chemotherapy in malignant pleural mesothelioma (MPM), whereas aPD1 monotherapy failed to provide benefit in phase-III trials. Success of ICI depends on the presence and activation of tumor-specific T cells. Therefore, we investigated whether T-cell characteristics are underlying clinical efficacy of ICI treatment in MPM. Methods: Comprehensive immune cell profiling was performed on screening and on treatment peripheral blood samples of mesothelioma patients treated with nivolumab (aPD-1) monotherapy (NCT02497508), or a combination of nivolumab and ipilimumab (aCTLA-4) (NCT03048474). Findings: aPD-1/aCTLA-4 combination treatment induced a profound increase in proliferation an

The influence of 'significant others' on persistent back pain and work participation: a qualitative exploration of illness perceptions

Background Individual illness perceptions have been highlighted as important influences on clinical outcomes for back pain. However, the illness perceptions of 'significant others' (spouse/partner/close family member) are rarely explored, particularly in relation to persistent back pain and work participation. The aim of this study was to initiate qualitative research in this area in order to further understand these wider influences on outcome. Methods Semi-structured interviews based on the chronic pain version of the Illness Perceptions Questionnaire-Revised were conducted with a convenience sample of UK disability benefit claimants, along with their significant others (n=5 dyads). Data were analysed using template analysis. Results Significant others shared, and perhaps further reinforced, claimants' unhelpful illness beliefs including fear of pain/re-injury associated with certain types of work and activity, and pessimism about the likelihood of return to work. In some cases, significant others appeared more resigned to the permanence and negative inevitable consequences of the claimant's back pain condition on work participation, and were more sceptical about the availability of suitable work and sympathy from employers. In their pursuit of authenticity, claimants were keen to stress their desire to work whilst emphasising how the severity and physical limitations of their condition prevented them from doing so. In this vein, and seemingly based on their perceptions of what makes a 'good' significant other, significant others acted as a 'witness to pain', supporting claimants' self-limiting behaviour and statements of incapacity, often responding with empathy and assistance. The beliefs and responses of significant others may also have been influenced by their own experience of chronic illness, thus participants lives were often intertwined and defined by illness. Conclusions The findings from this exploratory study reveal how others and wider social circumstances might contribute both to the propensity of persistent back pain and to its consequences. This is an area that has received little attention to date, and wider support of these findings may usefully inform the design of future intervention programmes aimed at restoring work participation