Natural killer cells, multiple myeloma, and daratumumab : a love-hate relationship

Multiple myeloma is a treatable, but not yet curable, malignant plasma cell disease. Over the last decades, the overall survival time of multiple myeloma patients has constantly increased thanks to improvements in conventional treatment methods like chemotherapy as well as autologous stem cell transplantation both in combination with novel drugs such as proteasome inhibitors or immunomodulatory drugs. However, no cure has been found yet. The only treatment that has the potential to cure multiple myeloma is allogeneic stem cell transplantation. However, it is seldomly used due to lack of donor availability, high risk for treatment related mortality and occurrence of graft versus host disease. The development of monoclonal antibody treatments for several cancer indications has shown great success. Lately, the emergence of Daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells, has given a new hope for patients. Daratumumab has a minor direct effect on the MM cells but the majority of its effectiveness lies in utilizing the patient’s own immune cells to find and clear the body from MM cells. Several immune cells are known to be involved in this process such as natural killer cells, T cells and macrophages. Natural killer cells are experts in detecting virus infected or malignant transformed cells without the need for prior activation, and they are at the forefront of immune response against malignant cells and thus a promising option for cancer immunotherapy. In study I we could show that two heavily pretreated, triple refractory multiple myeloma patients, who received Daratumumab treatment and progressed, could be re-challenged with the same drug. We observed that the recurring multiple myeloma cells showed normal CD38 expression after a short treatment interruption. This made those patients eligible for a second line of Daratumumab treatment which has proven to be save. In both patients a partial response could be observed. Additionally, we reported that natural killer cells were depleted immediately after Daratumumab administration. The lack of natural killer cells in Daratumumab treated patients leaves them at risk for viral reactivation or bacterial infection. In study II we observed that an unusually high percentage of Daratumumab treated patients suffered from infectious complications, of which viruses of the herpes family were the most prominent. We monitored the immune status of those patients and their clinical parameters and one of our observations was that natural killer cells were reduced in general, but in particular the more mature natural killer cell population was depleted. These findings led us to the conclusion that combining monoclonal antibody treatment with adoptive cell transfer may have a synergistic effect and allow for better disease control. Producing natural killer cells in large quantities for clinical trials is challenging. One pivotal factor for robust cell expansion is serum, which is an undefined component with big batch to batch variation that will have a big impact on expansion rates und functionality of the cells. In order to circumvent this problem, we adapted the clinically used natural killer cell line NK-92 to serum-free conditions with inherited phenotype and growth rate. Additionally, we reported that serum-free NK-92 cells showed elevated functionality towards K562 cells after reintroduction of serum. We also performed RNA sequencing to compare serum-free cultured NK-92 cells with cells cultured under standard conditions to investigate the biological mechanisms involved in serum reduction. Altogether we propose that growing serum-free NK-92 cells is feasible and the reported protocol is robust, cheap and can be adapted for clinical grade production. Whether the combination of these cells with other advanced treatments will show additive or synergistic treatment outcomes for multiple myeloma patients, needs to be evaluated in future studies

Google-truthing to assess hot spots of food retail change: A repeat cross-sectional Street View of food environments in the Bronx, New York

Google Street View (GSV) images can be used to “ground-truth” current and historical food retail data from approximately 2007 - when GSV was launched in a few US cities - to the present, facilitating analyses of food environments over time. A review of GSV images of all food retailers listed in a government database of licensed establishments in the Bronx, New York enabled records to be verified, businesses classified, and retail change quantified. The data revealed several trends likely to affect food access and health: increasing overall numbers of food retailers; the growth of dollar stores; and numerous openings, closings, and ownership changes across all food retail segments. Hot spot analysis identified statistically significant clusters of new dollar stores and bodegas, purveyors of less healthy processed foods, in lower-income neighborhoods in the South Bronx that face elevated rates of diet-related diseases. This article demonstrates the benefits and limitations of using GSV to conduct “virtual” food environment research

Prediction of Treatment Outcome in Patients with Obsessive-Compulsive Disorder with Low-Resolution Brain Electromagnetic Tomography: A Prospective EEG Study

The issue of predicting treatment response and identifying, in advance, which patient will profit from treating obsessive-compulsive disorder (OCD) seems to be an elusive goal. This prospective study investigated brain electric activity [using Low-Resolution Brain Electromagnetic Tomography (LORETA)] for the purpose of predicting response to treatment. Forty-one unmedicated patients with a DSM-IV diagnosis of OCD were included. A resting 32-channel EEG was obtained from each participant before and after 10 weeks of standardized treatment with sertraline and behavioral therapy. LORETA was used to localize the sources of brain electrical activity. At week 10, patients were divided into responders and non-responders (according to a reduction of symptom severity > 50% on the Y-BOCS). LORETA analysis revealed that at baseline responders showed compared to non-responders a significantly lower brain electric activity within the beta 1 (t = 2.86, p < 0.05), 2 (t = 2.81, p < 0.05), and 3 (t = 2.76, p < 0.05) frequency bands and ROI analysis confirmed a reduced activity in alpha 2 (t = 2.06, p < 0.05) in the anterior cingulate cortex (ACC). When baseline LORETA data were compared to follow-up data, the analysis showed in the responder group a significantly lower brain electrical resting activity in the beta 1 (t = 3.17. p < 0.05) and beta 3 (t = 3.11. p < 0.05) frequency bands and equally for the ROI analysis of the orbitofrontal cortex (OFC) in the alpha 2 (t = 2.15. p < 0.05) frequency band. In the group of non responders the opposite results were found. In addition, a positive correlation between frequency alpha 2 (rho = 0.40, p = 0.010), beta 3 (rho = 0.42, p = 0.006), delta (rho = 0.33, p = 0.038), theta (rho = 0.34, p = 0.031), alpha 1 (rho = 0.38, p = 0.015), and betal (rho = 0.34, p = 0.028) of the OFC and the bands delta (rho = 0.33, p = 0.035), alpha 1 (rho = 0.36, p = 0.019), alpha 2 (rho = 0.34, p = 0.031), and beta 3 (rho = 0.38, p = 0.015) of the ACC with a reduction of the Y-BOGS scores was identified. Our results suggest that measuring brain activity with LORETA could be an efficient and applicable technique to prospectively identify treatment responders in OCD

Just “Like Coffee” or Neuroenhancement by Stimulants?

Introduction: Pharmacological neuroenhancement (PN) is a topic of increasing importance and prevalence among students. However, there is a lack of differentiating PN substances, according to their psychoactive effects. In particular, there is a lack of data about PN by caffeinated drinks, even if coffee is a common and broadly used Neuroenhancer because of its cognitively enhancing effects regarding wakefulness, alertness and concentration. Materials and Methods: A web-survey was developed for German students and alumni about the non-medical use of caffeine for PN contained questions about coffee, caffeinated drinks and energy drinks, caffeine pills and methylxanthine tea regarding frequency and further contextual factors. Results: Six hundred and eighty-three participants completed the survey. Nearly all participants knew about PN (97.7%). 88.1% admitted using some over-the-counter substances. For PN purposes, coffee was used by 72.9% followed by energy drinks (68.2%) and cola drinks (62.4%). Methylxanthine containing tea was used for PN purposes, too (black tea 52.3%, green tea 51.7%). 1.8% admitted using illegal substances or prescription drugs, too. Discussion: Using legal methylxanthine containing drinks for PN seems to be extremely common with coffee and energy drinks being the preferred substances, while illegal and prescription drugs are only minimally used. Further studies should investigate the awareness of methylxanthine containing drinks as well as its character to be a flavoring drink or a neuroenhancer

Functional assessment for clinical use of serum-free adapted NK-92 cells

Natural killer (NK) cells stand out as promising candidates for cellular immunotherapy due to their capacity to kill malignant cells. However, the therapeutic use of NK cells is often dependent on cell expansion and activation with considerable amounts of serum and exogenous cytokines. We aimed to develop an expansion protocol for NK-92 cells in an effort to generate a cost-efficient, xeno-free, clinical grade manufactured master cell line for therapeutic applications. By making functional assays with NK-92 cells cultured under serum-free conditions (NK-92(SF)) and comparing to serum-supplemented NK-92 cells (NK-92(S)) we did not observe significant alterations in the viability, proliferation, receptor expression levels, or in perforin and granzyme levels. Interestingly, even though NK-92(SF) cells displayed decreased degranulation and cytotoxicity against tumor cells in vitro, the degranulation capacity was recovered after overnight incubation with 20% serum in the medium. Moreover, lentiviral vector-based genetic modification efficiency of NK-92(SF) cells was comparable with NK-92(S) cells. The application of similar strategies can be useful in reducing the costs of manufacturing cells for clinical use and can help us understand and implement strategies towards chemically defined expansion and genetic modification protocols

Disrupting the Food Desert/Oasis Binary: Ethnic Grocery Retailers and Perceptions of Food Access in Humbermede, Toronto

Contemporary studies of food accessibility often disregard ‘ethnic’ grocery retailers as sources of food or assume them to be attractive to all individuals. This body of research also frequently frames access as an issue of spatial proximity to grocery stores. Drawing on thirty interviews I conducted with residents of Humbermede, Toronto, I explore how food accessibility is perceived and experienced in a culturally-diverse neighbourhood where the only grocery retailers present are ethnic in nature. I argue that identity-related factors (food preferences, ethnic identification, language, and attitudes towards difference) and aspects of one’s life circumstances (purchasing power, mobility, and location or length of residence) – not merely distance – coalesce to influence understandings of one’s food retail environment and one’s store patronage decisions. These findings suggest that food shoppers are not homogenous, that all retailers are not equally attractive to all consumers, and that food accessibility has critical socio-cultural, economic, and spatiotemporal components

On-Line Simulation and . . .

We study an approach to forecast vehicular traffic using a micro-simulator. In order to provide network-wide information about the current traffic state a cellular automaton traffic flow model is combined with measured data. The framework is applied to the freeway network of North Rhine-Westphalia, where data from about 3,500 loop detectors are available and provided on-line minute by minute. Further, heuristics based on the statistical analysis of historical data are developed. Combining these methods and the results obtained we present an Internet application. This can provide the traffic information given by the on-line simulation such as travel times and the current traffic state for a broad public

A COTS Acquisition Process: Definition and Application Experience

software development has shown a substantial increase during the last few years. The benefits of COTS usage are clear: reduced development cost and shorter time-to-market. However, using COTS software in development activities also raises risks such as using software that does not sufficiently satisfy the requirements regarding, e.g., reliability, fault tolerance, functionality. Thus, a sound method that helps to decide which COTS software will be used in a specific development context has become mandatory. This paper introduces and describes a well-defined, systematic, and repeatable COTS acquisition process (CAP) and experience of using a tailored version of the process in a Siemens Business Unit. This includes the definition of the process, a brief description of the activities, and the description of the heuristics for effectiveness and efficiency integrated with the process. Moreover, we present data on cost, benefit, and quality aspects originating from an industrial case study in which the process was applied. From this data collected during the pilot project, conclusions are drawn on the process performance and whether it is worthwhile to apply the CAP