Integrated Genomic and Gene Expression Profiling Identifies Two Major Genomic Circuits in Urothelial Carcinoma

Similar to other malignancies, urothelial carcinoma (UC) is characterized by specific recurrent chromosomal aberrations and gene mutations. However, the interconnection between specific genomic alterations, and how patterns of chromosomal alterations adhere to different molecular subgroups of UC, is less clear. We applied tiling resolution array CGH to 146 cases of UC and identified a number of regions harboring recurrent focal genomic amplifications and deletions. Several potential oncogenes were included in the amplified regions, including known oncogenes like E2F3, CCND1, and CCNE1, as well as new candidate genes, such as SETDB1 (1q21), and BCL2L1 (20q11). We next combined genome profiling with global gene expression, gene mutation, and protein expression data and identified two major genomic circuits operating in urothelial carcinoma. The first circuit was characterized by FGFR3 alterations, overexpression of CCND1, and 9q and CDKN2A deletions. The second circuit was defined by E3F3 amplifications and RB1 deletions, as well as gains of 5p, deletions at PTEN and 2q36, 16q, 20q, and elevated CDKN2A levels. TP53/MDM2 alterations were common for advanced tumors within the two circuits. Our data also suggest a possible RAS/RAF circuit. The tumors with worst prognosis showed a gene expression profile that indicated a keratinized phenotype. Taken together, our integrative approach revealed at least two separate networks of genomic alterations linked to the molecular diversity seen in UC, and that these circuits may reflect distinct pathways of tumor development

A qualitative study of culturally embedded factors in complementary and alternative medicine use

Abstract Background Within the intercultural milieu of medical pluralism, a nexus of worldviews espousing distinct explanatory models of illness, our research aims at exploring factors leading to complementary and alternative medicine (CAM) use with special attention to their cultural context. Methods The results are based on medical anthropological fieldwork (participant observation and in-depth interviews) spanning a period from January 2015 to May 2017 at four clinics of Traditional Chinese Medicine in Budapest, Hungary. Participant observation involved 105 patients (males N = 42); in-depth interviews were conducted with patients (N = 9) and practitioners (N = 9). The interviews were coded with Interpretative Phenomenological Analysis; all information was aggregated employing Atlas.ti software. Results In order to avoid the dichotomization of “push and pull factors,” results obtained from the fieldwork and interviews were structured along milestones of the patient journey. These points of reference include orientation among sources of information, biomedical diagnosis, patient expectations and the physician-patient relationship, the biomedical treatment trajectory and reasons for non-adherence, philosophical congruence, and alternate routes of entry into the world of CAM. All discussed points which are a departure from the strictly western therapy, entail an underlying socio-cultural disposition and must be scrutinized in this context. Conclusions The influence of one’s culturally determined explanatory model is ubiquitous from the onset of the patient journey and exhibits a reciprocal relationship with subjective experience. Firsthand experience (or that of the Other) signifies the most reliable source of information in matters of illness and choice of therapy. Furthermore, the theme of (building and losing) trust is present throughout the patient journey, a determining factor in patient decision-making and dispositions toward both CAM and biomedicine

A phase I/IIa trial using CD19-targeted third-generation CAR T cells for lymphoma and leukemia

Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19þ B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy. Patients and Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array. Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14þCD33þHLADR) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2. Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers