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Background The Wnt/β-catenin signaling pathway is a major target of p53. β-Catenin/p53 coexpression predicts poorer survival in carcinoma patients. Conversely, CD99 inhibits tumor metastasis through the Wnt/β-catenin pathway. We therefore assessed p53, β-catenin, and CD99 by immunohistochemistry. Patients and Methods We studied 45 patients with systemic anaplastic large-cell lymphoma (ALCL), including 20 anaplastic lymphoma kinase (ALK)-positive and 25 ALK-negative ALCL. β-Catenin expression was analyzed using phospho-β-catenin-S552 antibody because its nuclear localization indicates Wnt signaling. Results In this cohort, p53 expression was associated with ALK-negative ALCL. Furthermore, p53 or β-catenin expression alone or β-catenin/p53 double expression showed poorer overall survival and disease-free survival in patients with ALCL overall and in patients with ALK-negative ALCL. CD99 expression was more frequent in ALK-positive ALCL but had no prognostic significance. Conclusion This is the first study to evaluate phospho-β-catenin-S552 expression in ALCL. The results of this study, although limited by small patient size, suggest that β-catenin and p53 may play a role in pathogenesis and may be helpful in risk stratification of ALCL patients.

The course of multiple myeloma (MM) is influenced by a variety of factors, including the specificity of the tumour microenvironment (TME). The aim of this review is to provide insight into the interplay of treatment modalities used in the current clinical practice and TME. Bortezomib-based triplets are the standard for MM first-line treatment. Bortezomib is a proteasome inhibitor (PI) which inhibits the nuclear factor kappa B (NF-kappa B) pathway. However, bortezomib is decreasing the expression of chemokine receptor CXCR4 as well, possibly leading to the escape of extramedullary disease. Immunomodulatory drugs (IMiDs), lenalidomide, and pomalidomide downregulate regulatory T cells (Tregs). Daratumumab, anti-cluster of differentiation 38 (anti-CD38) monoclonal antibody (MoAb), downregulates Tregs CD38+. Bisphosphonates inhibit osteoclasts and angiogenesis. Sustained suppression of bone resorption characterises the activity of MoAb denosumab. The plerixafor, used in the process of stem cell mobilisation and harvesting, block the interaction of chemokine receptors CXCR4-CXCL12, leading to disruption of MM cells' interaction with the TME, and mobilisation into the circulation. The introduction of several T-cell-based immunotherapeutic modalities, such as chimeric-antigen-receptor-transduced T cells (CAR T cells) and bispecific antibodies, represents a new perspective in MM treatment affecting TME immune evasion. The optimal treatment approach to MM patients should be adjusted to all aspects of the individual profile including the TME niche.

Here, we report the outcome of 226 myeloma patients presenting with extramedullary plasmacytoma or paraosseous involvement in a retrospective study conducted in 19 centers from 11 countries. Extramedullary disease was detected at diagnosis or relapse between January 2010 and November 2017. Extramedullary plasmacytoma and paraosseous involvement were observed in 130 patients at diagnosis (92 of 38) and in 96 at relapse (84 of 12). The median time from multiple myeloma diagnosis to the development of extramedullary disease was 25.1 months (range 3.1-106.3 months) in the relapse group (median follow up: 15 months). Imaging approach for extramedullary disease was computed tomography (n=133), positron emission tomography combined with computed tomography (n=50), or magnetic resonance imaging (n=35). The entire group received a median two lines of treatment and autologous stem cell transplantation (44%) following the diagnosis of extramedullary disease. Complete response was higher for paraosseous involvement versus extramedullary plasmacytoma at diagnosis (34.2% vs. 19.3%; P=NS.) and relapse (54.5% vs. 9%; P=0.001). Also paraosseous involvement patients had a better progression-free survival (PFS) when recognized at initial diagnosis of myeloma than at relapse (51.7 vs. 38.9 months). In addition, overall survival was better for paraosseous involvement compared to extramedullary plasmacytoma at diagnosis (not reached vs. 46.5 months). Extramedullary plasmacytoma at relapse had the worst prognosis with a PFS of 13.6 months and overall survival of 11.4 months. In the multivariate analysis, paraosseous involvement, extramedullary disease at diagnosis, International Staging System (ISS-I), and undergoing autologous stem cell transplantation improved overall survival independently. This cohort demonstrated that extramedullary disease benefits from front-line autologous stem cell transplantation and extramedullary plasmacytoma differs from paraosseous involvement in terms of rate and duration of response, with even worse outcomes when detected at relapse, constituting an unmet clinical need.

The course of multiple myeloma (MM) is influenced by a variety of factors, including the specificity of the tumour microenvironment (TME). The aim of this review is to provide insight into the interplay of treatment modalities used in the current clinical practice and TME. Bortezomib-based triplets are the standard for MM first-line treatment. Bortezomib is a proteasome inhibitor (PI) which inhibits the nuclear factor kappa B (NF-κB) pathway. However, bortezomib is decreasing the expression of chemokine receptor CXCR4 as well, possibly leading to the escape of extramedullary disease. Immunomodulatory drugs (IMiDs), lenalidomide, and pomalidomide downregulate regulatory T cells (Tregs). Daratumumab, anti-cluster of differentiation 38 (anti-CD38) monoclonal antibody (MoAb), downregulates Tregs CD38+. Bisphosphonates inhibit osteoclasts and angiogenesis. Sustained suppression of bone resorption characterises the activity of MoAb denosumab. The plerixafor, used in the process of stem cell mobilisation and harvesting, block the interaction of chemokine receptors CXCR4-CXCL12, leading to disruption of MM cells’ interaction with the TME, and mobilisation into the circulation. The introduction of several T-cell-based immunotherapeutic modalities, such as chimeric-antigen-receptor-transduced T cells (CAR T cells) and bispecific antibodies, represents a new perspective in MM treatment affecting TME immune evasion. The optimal treatment approach to MM patients should be adjusted to all aspects of the individual profile including the TME niche.

Hypercalcemia in patients with cancer is a common laboratory finding affecting up to 44% of that patient population. 1,25-Dihydroxyvitamin D3mediated hypercalcemia is one of the rare mechanisms of this endocrine emergency in cancer patients. It is even rarer for solid organ neoplasms to present with hypercalcemia mediated through the production of 1,25-dihydroxyvitamin D3. We report a case of a 77-year-old female who presented to the hospital with hypercalcemia and later was found to have metastatic gastrointestinal stromal tumor. There have been only 5 cases of gastrointestinal stromal tumor described in literature resulting in hypercalcemia. In our case, the mechanism of hypercalcemia was thought to be related to overproduction of 1,25-dihydroxyvitamin by tumor cells. The patient had a favorable response to imatinib with normalization of serum calcium level. Unfortunately, she developed fluid retention due to imatinib which was discontinued resulting in relapse of hypercalcemia that was resistant to all other treatment options.

Bu doktora tezi, Bosna- Hersek gibi çatışma sonrası bir topluma gönüllü geri göç olgusunu inceler. Bu çalışma örneğinde, geri göç eden kişi, yurtdışında sürdürülebilir bir geçinme alternatifine sahiptir ve oradaki topluma da iyi entegre olmuştur, fakat kendi özgür iradesi ile geri dönmeyi seçer. Benim ilk iddiam, bu tür bir geri göçte temel motivasyonun duygusal olduğu yönündedir. Literatürde önemli bir yeri olan `vatan sevgisi` duygusu (Brown, 2014) şüphesiz geri göç edenlerin duygusal çerçevesinde önemli bir yer teşkil ederken, diğer duyguların da bir o kadar, hatta bazı durumlarda daha da önemli bir yeri vardır. İkinci olarak, duygusal nedenlerle geri dönenler, ki pek çoğu aynı zamanda çift vatandaştır, bu tez ile ilgili teorik kavramlar üzerinde eşsiz bir önem arz eden bir perkpektif sunmaktadır. Bu çalışmanın bütünleştirici kavramsal çerçevesi, `siyasi olanı yansıtan prizma`(Nyers, 2007, s.3) olarak da tanımlanan, akademisyenlerin yuva ve aidiyet aracılığı ile kavramsallaştırdığı vatandaşlıkkavramı, ve özellikle de vatandaşlığın duygusal boyutudur. Bu bakış açısıyla vatandaşlık, David Hume'dan esinlenen George Marcus tarafından belirlenen temeller üzerine kurulmuştur. Vatandaşlık ve duygular arasında bağ olduğunu öne süren tezi ile David Hume, siyaset teorisindeki geleneksel görüşün aksine, insanları demokratik eyleme teşvik ettiği için, rasyonelliği ve iyi vatandaşlığı duyguların mümkün kıldığını öne sürmüştür. Vatandaşlığın duygusal boyutu Elaine Lynn-Ee Ho ve Lucy Jackson gibi coğrafya akademisyenleri tarafından da kuramlaştırılmıştır. Her ikisi de yuva ve aidiyet kavramlarını kullanarak bunların vatandaşlık kavramını anlamamızda önem arz ettiğini savunurlar. Her ne kadar bu kavramlar feminist akademisyenler, coğrafyacılar, sosyal psikologlar ve antropologların katkılarıyla geliştirilmişse de, vatandaşlık ve duygular arasındaki kuramsal bağların esaslı bir incelemesi henüz başlangıç düzeyindedir. Ayrıca, literatürde, yuva, aidiyet ve vatandaşlığın duygusal boyutunu kapsayan asli, özgül ve farklı duyguların incelenmesi hususunda ciddi bir eksiklik vardır. Memleketlerine kendi iradeleri ile geri dönüp yerleşen Bosna-Hersek diaspora/göçmenlerinden 35 kişiyi içeren derinlemesine mülakatlara dayanan nitel çalışmama dayanarak, ben, çatışma sonrası bir toplumda, öncelikle devletin vatandaşlarına sağladığı güvenlik/korumanın eksikliğinden ve sürüdürülebilir bir yurttaşlık aidiyeti geliştirilmesine içkin zorluklar sebebiyle, vatandaşlığın duygusal boyutunun, yuva ve aidiyet olarak kavramsallaştırılmadığını savunuyorum.. This Ph.D. thesis examines the case of voluntary return migration to a post-conflict society, such as Bosnia and Herzegovina, where the returnee, given a viable alternative of livelihood and a well-integrated social presence abroad, freely chooses to go back. My first claim that the motivation for this type of return is primarily emotional and, although the much researched (Brown, 2014) emotion of `patriotic love` is certainly part of the returnees' emotional landscape, other emotions play an equal, and in some cases more important, role. Secondly, due to the emotionally motivated return, the returnees, many of whom are also dual citizens, possess a uniquely significant perspective on the theoretical concepts relevant to this thesis. The unifying conceptual framework of the study is citizenship, also seen as a `prism through which to address the political` (Nyers, 2007, p. 3), and more specifically its emotional dimension, which scholars have so far conceptualized through home and belonging. This perspective on citizenship builds on the foundations set by George Marcus, inspired by David Hume, who presents a treatise of the connection between citizenship and emotions, radically asserting that, contrary to the conventional view in political theory, emotions enable rationality and good citizenship, mainly because they foster democratic action. The emotional dimension of citizenship has been further theorized by geography scholars, such as Elaine Lynn-Ee Ho and Lucy Jackson, both of whom employ the concepts of home and belonging as instrumental to our understanding of citizenship. Although these concepts have been developed with contributions from feminist scholars, geographers, social psychologists and anthropologists, a thorough analysis of the theoretical connections between citizenship and emotions is still in its initial stages. Also, an analysis of the actual, specific and distinct emotions comprising home, belonging and the emotional dimension of citizenship, is gravely missing. Based on a qualitative study of 35 in-depth interviews conducted with members of the Bosnia and Herzegovinian diaspora/transmigrants, who have voluntarily decided to return and settle in BiH, I argue that, in the case of a post-conflict society, the emotional dimension of citizenship is not conceptualized as home and belonging, primarily due to the lack of security/safety provided by the state to its citizens and the inherent challenges of developing sustainable civic belonging. 400

Nanoparticles (NPs) play expanding roles in biomedical applications including imaging and therapy, however, their long-term fate and clearance profiles have yet to be fully characterized in vivo. NP delivery via the airway is particularly challenging, as the clearance may be inefficient and lung immune responses complex. Thus, specific material design is required for cargo delivery and quantitative, noninvasive methods are needed to characterize NP pharmacokinetics. Here, biocompatible poly(acrylamidoethylamine)-b-poly(DL-lactide) block copolymer-based degradable, cationic, shell-cross-linked knedel-like NPs (Dg-cSCKs) were employed to transfect plasmid DNA. Radioactive and optical beacons were attached to monitor biodistribution and imaging. The preferential release of cargo in acidic conditions provided enhanced transfection efficiency compared to non-degradable counterparts. In vivo gene transfer to the lung was correlated with NP pharmacokinetics by radiolabeling Dg-cSCKs and performing quantitative biodistribution with parallel positron emission tomography and Čerenkov imaging. Quantitation of imaging over 14 days corresponded with the pharmacokinetics of NP movement from the lung to gastrointestinal and renal routes, consistent with predicted degradation and excretion. This ability to noninvasively and accurately track NP fate highlights the advantage of incorporating multifunctionality into particle design.

p53 expression and MYC extra copies (MYC-EC) have been reported to serve as independent adverse prognostic markers in patients with diffuse large B-cell lymphoma (DLBCL). However, the impact of p53 expression in MYC-EC lymphomas has not been delineated. Conversely, CD99 expression has been shown to have a positive impact on survival in patients with germinal center-type DLBCL, yet nothing is reported about the impact of CD99 expression and MYC status. This is the first study to evaluate p53 expression in MYC-EC lymphomas and CD99 expression in relation to MYC status. We identified 122 patients diagnosed as having large B-cell lymphoma (44, MYC-negative; 29, MYC-EC; 23, MYC rearrangement; 22, MYC and BCL2 rearrangements; 4, MYC, BCL2, and BCL6 rearrangements). p53 expression significantly correlated with DLBCL with abnormal MYC status (MYC-EC, MYC rearrangement, and MYC overexpression), but adverse p53 prognostic effect was only seen with MYC-rearranged lymphoma. CD99 expression was significantly associated with MYC-negative DLBCL and had better prognostic impact on lymphoma-specific survival (LSS), but not on relapse-free survival and overall survival. Overall, patients with MYC-EC lymphoma had significantly worse relapse-free survival and LSS than did patients with MYC-negative lymphoma, yet better overall survival and LSS than did the patients with MYC-rearranged lymphoma. Thus, patients with MYC-EC lymphomas had prognostic features that were intermediate between MYC-negative and MYC-rearranged lymphomas. Lastly, high-intensity chemotherapy (either dose-adjusted rituximab and etoposide-prednisone-vincristine-cyclophosphamide-doxorubicin or rituximab and hyperfractionated cyclophosphamide-vincristine-doxorubicin-dexamethasone treatment) did not improve survival in patients with MYC-EC and MYC-rearranged lymphoma when compared with rituximab-cyclophosphamide-hydroxydaunomycin-vincristine-prednisone therapy.

[Figure][1] A 7-year-old previously healthy girl presented with fever, fatigue, and weight loss for 1 month. Laboratory test revealed normocytic anemia (hemoglobin, 7.1 g/dL), neutropenia (0.17 × 109/L), and 30% small- to medium-sized blasts with frequent (20%) cuplike nuclei (panels A-C

Neutrophils are critical mediators of innate immune responses and contribute to tissue injury. However, immune pathways that regulate neutrophil recruitment to injured tissues during noninfectious inflammation remain poorly understood. DAP12 is a cell membrane–associated protein that is expressed in myeloid cells and can either augment or dampen innate inflammatory responses during infections. To elucidate the role of DAP12 in pulmonary ischemia/reperfusion injury (IRI), we took advantage of a clinically relevant mouse model of transplant-mediated lung IRI. This technique allowed us to dissect the importance of DAP12 in tissue-resident cells and those that infiltrate injured tissue from the periphery during noninfectious inflammation. Macrophages in both mouse and human lungs that have been subjected to cold ischemic storage express DAP12. We found that donor, but not recipient, deficiency in DAP12 protected against pulmonary IRI. Analysis of the immune response showed that DAP12 promotes the survival of tissue-resident alveolar macrophages and contributes to local production of neutrophil chemoattractants. Intravital imaging demonstrated a transendothelial migration defect into DAP12-deficient lungs, which can be rescued by local administration of the neutrophil chemokine CXCL2. We have uncovered a previously unrecognized role for DAP12 expression in tissue-resident alveolar macrophages in mediating acute noninfectious tissue injury through regulation of neutrophil trafficking.

Autologous stem cell transplantation (ASCT) is an established treatment for patients with hematologic malignancies. The minimum CD34+ cell dose needed to ensure hematopoietic recovery following ASCT is 2x106 cells/kg. The aim of this paper is to prove that absolute number of cells (ANC) CD34+>=20,01x106/L in the peripheral blood is confirmation of successful collection. The study was a retrospective-prospective. We analysed 44 patients Myeloma Multiplex 23(33.3%), Hodgkin lymphoma 29 (42.0%), non-Hodgkin Lymphoma 17 (24.6%) with 69 apheresis conducted in the process of autologous stem cell transplantation at Haematology clinic KCUS in the period from April 2013 to October 2016. Patients were divided into two groups: collection of CD34+ =2.0x106/kgin one day.Independent variables analyzed were: CD34+cell dose in peripheral blood in one collection, age, gender and diagnosis. The average age of patients was 45 ± 16.03 years. Youngest patient was 18 and the oldest was 67 years. There were 52.3% male patients and 47.7% female.Collection of CD34+ =2.0x106/kg had values in peripheral blood ANC CD34 + from 15.01 to 20.00x106 /l and only one collection ANC CD34+ between 10.01 and 15.00 x106 /l. Displayed difference is statistically significant p=0.0001. We used the c2 test, Kolmogorov Smirnov and Mann-Whitney U test. P = 20.01 x 106/L in the peripheral blood.

Early immune responses are important in shaping long-term outcomes of human lung transplants. To examine the role of early immune responses in lung rejection and acceptance we developed a method to retransplant mouse lungs. Retransplantation into T cell-deficient hosts showed that for lungs and hearts alloimmune responses occurring within 72 hours of transplantation are reversible. In contrast to hearts, a 72-hour period of immunosuppression with costimulation blockade in primary allogeneic recipients suffices to prevent rejection of lungs upon retransplantation into untreated allogeneic hosts. Long-term lung acceptance is associated with induction of bronchus-associated lymphoid tissue, where Foxp3+ cells accumulate and recipient T cells interact with CD11c+ dendritic cells. Acceptance of retransplanted lung allografts is abrogated by treatment of immunosuppressed primary recipients with anti-CD25 antibodies. Thus, events contributing to lung transplant acceptance are established early in the graft and induction of bronchus-associated lymphoid tissue can be associated with an immune quiescent state.

Activated T lymphocytes are abundant in the airway during lung allograft rejection. Based on respiratory viral studies, it is the current paradigm that T cells cannot divide in the airway, and that their accumulation in the lumen of the respiratory tract is the exclusive result of recruitment from other sites, such as mediastinal lymph nodes. Here, we show that CD8(+) T cell activation and proliferation can occur in the airway after orthotopic lung transplantation. We also demonstrate that airway epithelium expresses major histocompatibility class I predominantly on the apical surface, both in vitro and in vivo, and initiates CD8(+) T cell responses in a polarized fashion, favoring luminal activation. Our data identify a unique site for CD8(+) T cell activation after lung transplantation, and suggest that attenuating these responses may provide a clinically relevant target.

Activated T lymphocytes are abundant in the airway during lung allograft rejection. Based on respiratory viral studies, it is the current paradigm that T cells cannot divide in the airway, and that their accumulation in the lumen of the respiratory tract is the exclusive result of recruitment from other sites, such as mediastinal lymph nodes. Here, we show that CD8+ T cell activation and proliferation can occur in the airway after orthotopic lung transplantation. We also demonstrate that airway epithelium expresses major histocompatibility class I predominantly on the apical surface, both in vitro and in vivo, and initiates CD8+ T cell responses in a polarized fashion, favoring luminal activation. Our data identify a unique site for CD8+ T cell activation after lung transplantation, and suggest that attenuating these responses may provide a clinically relevant target.

Silver is a centuries old antibiotic agent currently used to treat infected burns. The sensitivity of a wide range of drug-resistant microorganisms to silver killing suggests that it may be useful for treating refractory lung infections. Toward this goal, we previously developed a methylated caffeine silver acetate compound, SCC1, that exhibits broad-spectrum antimicrobial activity against clinical strains of bacteria in vitro and when nebulized to lungs in mouse infection models. Preclinical testing of high concentrations of SCC1 in primary culture mouse tracheal epithelial cells (mTEC) showed selective ciliated cell death. Ciliated cell death was induced by both silver- and copper-containing compounds, but not by the methylated caffeine portion of SCC1. We hypothesized that copper transporting P-type ATPases, ATP7A and ATP7B, play a role in silver detoxification in the airway. In mTEC, ATP7A was expressed in non-ciliated cells, whereas ATP7B was expressed only in ciliated cells. The exposure of mTEC to SCC1 induced the trafficking of ATP7B, but not ATP7A, suggesting the presence of a cell-specific silver uptake and detoxification mechanisms. Indeed, the expression of the copper uptake protein CTR1 was also restricted to ciliated cells. A role of ATP7B in silver detoxification was further substantiated when treatment of SCC1 significantly increased cell death in ATP7B shRNA treated HepG2 cells. Additionally, mTEC from ATP7B-/- mice showed enhanced loss of ciliated cells compared to wild type. These studies are the first to demonstrate a cell-type specific expression of the Ag+/Cu+ transporters ATP7A, ATP7B and CTR1 in airway epithelial cells, and a role for ATP7B in detoxification of these metals in the lung.

The expanding clinical challenge of respiratory tract infections due to resistant bacteria necessitates the development of new forms of therapy. The development of a compound composed of silver coupled to a methylated caffeine carrier (silver carbene complex 1 [SCC1]) that demonstrated in vitro efficacy against bacteria, including drug-resistant organisms, isolated from patients with respiratory tract infections was described previously. The findings of current in vitro studies now suggest that bactericidal concentrations of SCC1 are not toxic to airway epithelial cells in primary culture. Thus, it was hypothesized that SCC1 could be administered by the aerosolized route to concentrate delivery to the lung while minimizing systemic toxicity. In vivo, aerosolized SCC1 delivered to mice resulted in mild aversion behavior, but it was otherwise well tolerated and did not cause lung inflammation following administration over a 5-day period. The therapeutic efficacy of SCC1 compared to that of water was shown in a 3-day prophylaxis protocol, in which mice infected with a clinical strain of Pseudomonas aeruginosa had increased survival, decreased amounts of bacteria in the lung, and a lower prevalence of bacteremia. Similarly, by using an airway infection model in which bacteria were impacted in the airways by agarose beads, the administration of SCC1 was significantly superior to water in decreasing the lung bacterial burden and the levels of bacteremia and markers of airway inflammation. These observations indicate that aerosolized SCC1, a novel antimicrobial agent, warrants further study as a potential therapy for bacterial respiratory tract infections.

Recent human infections caused by the highly pathogenic avian influenza virus H5N1 strains emphasize an urgent need for assessment of factors that allow viral transmission, replication, and intra-airway spread. Important determinants for virus infection are epithelial cell receptors identified as glycans terminated by an α2,3-linked sialic acid (SA) that preferentially bind avian strains and glycans terminated by an α2,6-linked SA that bind human strains. The mouse is often used as a model for study of influenza viruses, including recent avian strains; however, the selectivity for infection of specific respiratory cell populations is not well described, and any relationship between receptors in the mouse and human lungs is incompletely understood. Here, using in vitro human and mouse airway epithelial cell models and in vivo mouse infection, we found that the α2,3-linked SA receptor was expressed in ciliated airway and type II alveolar epithelial cells and was targeted for cell-specific infection in both species. The α2,6-linked SA receptor was not expressed in the mouse, a factor that may contribute to the inability of some human strains to efficiently infect the mouse lung. In human airway epithelial cells, α2,6-linked SA was expressed and functional in both ciliated and goblet cells, providing expanded cellular tropism. Differences in receptor and cell-specific expression in these species suggest that differentiated human airway epithelial cell cultures may be superior for evaluation of some human strains, while the mouse can provide a model for studying avian strains that preferentially bind only the α2,3-linked SA receptor.