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Supplementary Data from Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma

Monoclonal antibody (mAb) therapy for multiple myeloma, a malignancy of plasma cells, has not been clinically efficacious in part due to a lack of appropriate targets. We recently reported that the cell surface glycoprotein CS1 (CD2 subset 1, CRACC, SLAMF7, CD319) was highly and universally expressed on myeloma cells while having restricted expression in normal tissues. Elotuzumab (formerly known as HuLuc63), a humanized mAb targeting CS1, is currently in a phase I clinical trial in relapsed/refractory myeloma. In this report we investigated whether the activity of elotuzumab could be enhanced by bortezomib, a reversible proteasome inhibitor with significant activity in myeloma. We first showed that elotuzumab could induce patient-derived myeloma cell killing within the bone marrow microenvironment using a SCID-hu mouse model. We next showed that CS1 gene and cell surface protein expression persisted on myeloma patient-derived plasma cells collected after bortezomib administration. In vitro bortezomib pretreatment of myeloma targets significantly enhanced elotuzumab-mediated antibody-dependent cell-mediated cytotoxicity, both for OPM2 myeloma cells using natural killer or peripheral blood mononuclear cells from healthy donors and for primary myeloma cells using autologous natural killer effector cells. In an OPM2 myeloma xenograft model, elotuzumab in combination with bortezomib exhibited significantly enhanced in vivo antitumor activity. These findings provide the rationale for a clinical trial combining elotuzumab and bortezomib, which will test the hypothesis that combining both drugs would result in enhanced immune lysis of myeloma by elotuzumab and direct targeting of myeloma by bortezomib. [Mol Cancer Ther 2009;8(9):2616–24]

The coronavirus disease 2019 (COVID-19) pandemic continues to spread globally, highlighting the urgent need for safe and effective vaccines that could be rapidly mobilized to immunize large populations. We report the preclinical development of a self-amplifying mRNA (SAM) vaccine encoding a prefusion stabilized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein and demonstrate strong cellular and humoral immune responses at low doses in mice and rhesus macaques. The homologous prime-boost vaccination regimen of SAM at 3, 10 and 30 μg induced potent neutralizing antibody (nAb) titers in rhesus macaques following two SAM vaccinations at all dose levels, with the 10 μg dose generating geometric mean titers (GMT) 48-fold greater than the GMT of a panel of SARS-CoV-2 convalescent human sera. Spike-specific T cell responses were observed with all tested vaccine regimens. SAM vaccination provided protective efficacy against SARS-CoV-2 challenge as both a homologous prime-boost and as a single boost following ChAd prime, demonstrating reduction of viral replication in both the upper and lower airways. The SAM vaccine is currently being evaluated in clinical trials as both a homologous prime-boost regimen at low doses and as a boost following heterologous prime.

Proton therapy is a fast growing treatment modality for cancer and is in selected cases preferred over conventional radiotherapy with photons because of the highly conformal dose distribution that can be achieved with protons due to their steep dose gradients. However, these steep gradients also make proton therapy sensitive to range uncertainties. Proton ranges are calculated from proton stopping powers relative to that in water (Relative Stopping Power, RSP). The RSPs needed for a treatment plan can be estimated from CT (Computed Tomography) data of a patient. High accuracy reference values of RSPs are required to assess the accuracy of these CT based estimates. In this paper we present a water phantom that enables accurate measurement of depth dose profiles in water. Experimental RSPs with a relative standard uncertainty smaller than 0.4% (1 σ ) for samples with a water equivalent thickness of about 2 cm can be derived from the measured depth dose distributions. Most CT based RSP estimates use an approximate RSP model based on the Bethe-Bloch formula without the shell, density, Barkas and Bloch correction. In the Geant4 Monte Carlo code these corrections are included and RSP calculations with this code are expected to be more accurate. In this work, a set of 32 well defined (composition and density), mostly clinically relevant materials is used to assess the correspondence between RSPs that were measured, that were estimated from the approximate RSP model and that were calculated from Monte Carlo simulations. With the measured RSPs we provide a ground-truth bench mark to test the validity of RSPs derived from CT imaging and Monte Carlo simulations.

The mitogen-activated protein kinase (MAPK) signaling pathway is frequently activated in human cancers due to genetic alterations that can occur at multiple nodes, the most prevalent of which are mutations in RAS or BRAF. While BRAFV600 mutant tumors are responsive to RAF inhibitors such as dabrafenib and vemurafenib, these drugs are ineffective in RAS mutant cancers and tumors expressing other RAF mutations. CRAF kinase functions as a critical effector in mutant RAS and Class II/III BRAF mutant tumors and plays a role in feedback-mediated pathway reactivation following MEK inhibition. Thus, selective inhibitors that potently inhibit the activity of CRAF could be both effective in blocking mutant RAS and BRAF signaling and in inhibiting feedback-mediated activation in combination with a MEK inhibitor. LXH254 is a type II ATP-competitive inhibitor that inhibits both B- and CRAF kinase activities at picomolar concentrations with a high degree of selectivity against a panel of 456 human kinases and in cell-based assays. LXH254 not only inhibits MAPK signaling activity in tumor models harboring BRAFV600 mutation, but also inhibits mutant N- and KRAS-driven signaling due to its ability to inhibit both RAF monomers and dimers with similar potencies. LXH254 is orally bioavailable, demonstrates a direct PK/PD relationship and causes tumor regression in multiple cell line and primary human tumor derived xenograft models at well-tolerated doses. LXH254 represents a next generation RAF inhibitor that is differentiated from other RAF inhibitors in this class due to the high degree of selectivity. In preclinical efficacy and toxicology studies, LXH254 demonstrated a relatively wide therapeutic index which should enable effective interrogation of RAF inhibition in patients with decreased risk for off-target toxicity. LXH254 is currently in a Phase I trial in patients with solid tumors expressing MAPK pathway mutations. Citation Format: Darrin D. Stuart, Wenlin Shao, Yuji Mishina, Yun Feng, Giordano Caponigro, Vesselina G. Cooke, Stacey Rivera, Fang Shen, Joshua Korn, Lesley A. Mathews Griner, Giselle Nishiguchi, Benjamin Taft, Lifeng Wan, Sharadha Subramanian, Yan Lou, Lina Setti, Matthew Burger, Victor Tamez, Alice Rico, Robert Aversa, John Tellew, Jacob R. Haling, Valery Polyakov, Amy Lambert, Richard Zang, Ann Van Abbema, Mohamad Hekmat-Nejad, Payman Amiri, Mallika Singh, Nicholas Keen, Michael P. Dillon, Emma Lees, William R. Sellers, Savithri Ramurthy. Pharmacological profile and anti-tumor properties of LXH254, a highly selective RAF kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr DDT01-04.

Purpose: Patients with breast cancer may develop dental problems due to treatment. We examined the prevalence of their dental care use and needs, compared the prevalence of use with that of the general population, and examined which factors predict patients' dental care use.Methods: Patients with primary breast cancer completed a questionnaire at 6 and 15 months post diagnosis. Medical data were retrieved from medical records. The prevalence of dental care use and needs was examined with descriptive analyses. Associations between predictors and dental care use were examined with multivariate analyses.Results: Twenty-one percent of 746 participants visited their dentist at least once in the past three months at 6 months, and 23% at 15 months post-diagnosis. The estimated percentage of women with at least one contact with their dentist in 12 months was low compared to the general female population (31.9% versus 79.5%). One to two percent of the respondents wanted more contact. Having dental care insurance (odds ratio 1.80; 95% CI, 1.08-3.00), chemotherapy (odds ratio 1.93; 95% CI, 1.21-3.06), and clinical distress 6 months post-diagnosis (odds ratio 2.53; 95% CI, 1.70-3.79) predicted use of dental care 9 months later.Conclusions: Up to 15 months post-diagnosis, breast cancer patients' dental care use is lower than warranted. Oncologists and cancer nurses are recommended to inform patients about dental risks, and to encourage them - particularly those without insurance to visit their dentist. Occurrence of dental problems should be monitored, especially in patients who receive chemotherapy or who are clinically distressed. (C) 2016 Elsevier Ltd. All rights reserved.

Objectives We studied the frequency and evolution of social and emotional loneliness in older cancer patients in comparison with younger cancer patients and older people without cancer. We evaluated if changes in common cancer-related and ageing-related problems such as fatigue, cognitive functioning and functional status contributed to the occurrence of loneliness. Methods This study was part of the KLIMOP study (Dutch acronym for project on older cancer patients in Belgium and the Netherlands) and included older (≥70 years) and younger cancer patients (50-69 years) and older people without cancer. Data were collected at baseline and 1-year follow-up. Loneliness was measured with the loneliness scale of De Jong-Gierveld. The relationship between loneliness after 1 year and changes in fatigue, cognitive functioning and functional status was tested in multivariate logistic regression analyses. Results Data were available for 475 participants. At baseline, older cancer patients were less lonely compared with older people without cancer. After 1 year, the frequency of emotional loneliness had significantly increased for older cancer patients (26-42%, p < 0.001) and had reached levels of older people without cancer. Emotional loneliness also increased for younger cancer patients (25-34%, p = 0.02), but not for older people without cancer (40-38%, p = 0.69). Frequency of social loneliness did not change significantly. People who were persistently fatigued and people who became or were persistently impaired on cognitive functioning were at increased risk of becoming lonely. Conclusion Loneliness, in particular emotional loneliness, is a common problem in cancer patients, and its frequency changes considerably over time.

Purpose: Spectral information of the output of x-ray tubes in (dual source) computer tomography (CT) scanners can be used to improve the conversion of CT numbers to proton stopping power and can be used to advantage in CT scanner quality assurance. The purpose of this study is to design, validate, and apply a compact portable Compton spectrometer that was constructed to accurately measure x-ray spectra of CT scanners. Methods: In the design of the Compton spectrometer, the shielding materials were carefully chosen and positioned to reduce background by x-ray fluorescence from the materials used. The spectrum of Compton scattered x-rays alters from the original source spectrum due to various physical processes. Reconstruction of the original x-ray spectrum from the Compton scattered spectrum is based on Monte Carlo simulations of the processes involved. This reconstruction is validated by comparing directly and indirectly measured spectra of a mobile x-ray tube. The Compton spectrometer is assessed in a clinical setting by measuring x-ray spectra at various tube voltages of three different medical CT scanner x-ray tubes. Results: The directly and indirectly measured spectra are in good agreement (their ratio being 0.99) thereby validating the reconstruction method. The measured spectra of the medical CT scanners are consistent with theoretical spectra and spectra obtained from the x-ray tube manufacturer. Conclusions: A Compton spectrometer has been successfully designed, constructed, validated, and applied in the measurement of x-ray spectra of CT scanners. These measurements show that our compact Compton spectrometer can be rapidly set-up using the alignment lasers of the CT scanner, thereby enabling its use in commissioning, troubleshooting, and, e.g., annual performance check-ups of CT scanners.

OBJECTIVE: The aim of this systematic review was to investigate patient-related factors (e.g. depressive symptoms, cognition, mobility, activities of daily living (ADL)) as well as tumor-related factors (e.g. tumor type, chemotherapy regimen) influencing chemotherapy intolerance in cancer patients aged 65 years or older. METHODS: We included observational studies that reported data on possible predictors of chemotherapy intolerance in older patients with cancer. We studied chemotherapy intolerance using the following outcomes: chemotherapy toxicity grade 3 to 5, unplanned hospitalization, chemotherapy discontinuation, chemotherapy dose reduction, functional decline, and chemotherapy mortality. We searched PubMed, Embase, and PsycInfo for articles between January 1995 and July 2016. The quality of the included studies was assessed using the Quality in Prognosis Studies (QUIPS) tool. RESULTS: The search yielded 1774 articles, and 30 articles from 27 studies were included. The patient-related factors associated with chemotherapy intolerance, in terms of the size of the association and the consistency of the results, were more than one fall in the last six months, mobility problems, poor performance status and the presence of severe comorbid conditions. The tumor-related factors that were associated with chemotherapy intolerance in older patients with cancer were certain regimens of chemotherapy and polychemotherapy, as compared to monochemotherapy. The number of studies on unplanned hospitalization and functional decline was small. CONCLUSION: The included studies were heterogeneous with respect to endpoints and included parameters. Nevertheless, the size of the association and the consistency of results suggest that all these factors are relevant for everyday oncological practice. ispartof: JOURNAL OF GERIATRIC ONCOLOGY vol:10 issue:1 pages:31-41 ispartof: location:Netherlands status: published

Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.

RAS oncogenes have been implicated in30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.

A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine 1 as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity.

Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.

The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.

The paper presents the changes in perceived comfort while hiking in a sailing boat (in this case the Laser, a single-handed Olympic dinghy) due to a new design of hiking pads. The project used a ‘research by design method’. The aim was to improve sailing comfort which leads to lower fatigue and therefor improved performance. While hiking, a large force is exerted on the thigh of the sailor by the boat rim while existing hiking pads only partly distribute this force over the upper leg. In order to find directions for improvements we analyzed the interaction between upper leg and boat rim and forces involved, studied the anatomy of the upper leg and quantified the pressure distribution over the upper leg using an experimental set-up. A new hiking pad was designed and tests showed an improved pressure distribution over the upper leg. First field test showed positive results. The hiking pads will be made available to the Dutch Olympic Sailing Team in order to improve their competitiveness at the 2012 Olympics in Weymouth.

INTRODUCTION: Functional capacity tests are standardized instruments to evaluate patients' capacities to execute work-related activities. Functional capacity test results are associated with biopsychosocial factors, making it unclear what is being measured in capacity testing. An overview of these factors was missing. The objective of this review was to investigate the level of evidence for factors that are associated with functional capacity test results in patients with non-specific chronic low back pain. METHODS: A systematic literature review was performed identifying relevant studies from an electronic journal databases search. Candidate studies employed a cross-sectional or RCT design and were published between 1980 and October 2010. The quality of these studies was determined and level of evidence was reported for factors that were associated with capacity results in at least 3 studies. RESULTS: Twenty-two studies were included. The level of evidence was reported for lifting low, lifting high, carrying, and static lifting capacity. Lifting low test results were associated with self-reported disability and specific self-efficacy but not with pain duration. There was conflicting evidence for associations of lifting low with pain intensity, fear of movement/(re)injury, depression, gender and age. Lifting high was associated with gender and specific self-efficacy, but not with pain intensity or age. There is conflicting evidence for the association of lifting high with the factors self-reported disability, pain duration and depression. Carrying was associated with self-reported disability and not with pain intensity and there is conflicting evidence for associations with specific self-efficacy, gender and age. Static lifting was associated with fear of movement/(re)injury. CONCLUSIONS: Much heterogeneity was observed in investigated capacity tests and candidate associated factors. There was some evidence for biological and psychological factors that are or are not associated with capacity results but there is also much conflicting evidence. High level evidence for social factors was absent.

Tumor-specific neoantigens (TSNAs) are present in a majority of tumor types and are key targets for T cells released by immune checkpoint blockade therapy. Given that TSNAs are non-self antigens, they are particularly attractive cancer vaccine targets. We have developed a potent heterologous prime/boost immunization approach to deliver predicted TSNAs to patients, which is comprised of a replication incompetent chimpanzee adenoviral vector (ChAdV) for the prime vaccination and a self-replicating, synthetic viral vector (srRNA) for repeated boost vaccinations. The ChAdV vector is similar in design to other adenoviral vectors that have demonstrated induction of high titer, polyfunctional and durable CD4 and CD8 T-cell responses against non-self antigens that protected humans against infections. The srRNA vector is based on Venezuelan equine encephalitis virus (VEE), where sequences encoding the structural proteins of VEE were deleted and replaced by a TSNA expression cassette. For delivery in vivo, the srRNA is formulated with a lipid nanoparticle (LNP), which facilitates efficient cellular uptake of the RNA and enhances antigen expression as well as the resulting immune response. We demonstrate that the srRNA vector effectively replicates in vitro and in vivo resulting in durable and high levels of antigen expression. To characterize the vectors in pre-clinical animal models, a prototypical expression cassette that encodes multiple mouse MHC class I tumor antigens as well as Mamu-A01 restricted class I antigens for monitoring immune responses in mice and non-human primates (NHPs) was introduced into both vector systems. We demonstrate that immunization of mice with either vector results in strong antigen-specific CD8 T-cell responses against the encoded murine epitopes. The heterologous prime/boost approach provided a statistically significant survival advantage to tumor bearing mice when compared to untreated mice. The potency of the immunization platform was also assessed in Indian rhesus macaques and the platform demonstrated a quick onset of T-cell responses 1 week post ChAdV prime vaccination with peak T-cell responses against all delivered Mamu-A01 restricted class I antigens at 2-3 weeks. Such ChAdV primed T-cell responses were effectively boosted by the LNP formulated srRNA vector. Co-administration of anti-CTLA4 with the vaccine demonstrated enhanced vaccine induced immune response. These data demonstrate that the heterologous prime/boost platform effectively programs robust T-cell immunity toward encoded non-self antigens in NHPs, which is a highly predictive model of vaccine responses in humans. This vaccine platform is targeted for entry into clinical trials in mid 2018. Citation Format: Wade Blair, Gijsbert Grotenbreg, Ciaran Scallan, Amy Rappaport, Renee Greer, Leonid Gitlin, Kieu Lam, James Heyes, Anne Van Abbema, Hadley Hanson, Petra Schreiner, karin Jooss. A novel heterologous prime boost vaccine system drives tumor specific and potent CD8 T cell responses for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 724.

Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination.

Purpose: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models.Experimental Design: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice.Results: CS1 mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1 antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like T cells, and CD8+ T cells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice.Conclusions: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma.

Mother-child dyads who experienced a devastating tornado talked about the storm and about two affectively more positive or neutral events at each of two time points: 4 months and 10 months after the storm. The conversations were analyzed to determine whether mothers and/or children's contributions differed as a function of event type and whether there were concurrent and/or cross-lagged relations between mothers and children's contributions to the conversations. For both members of the dyads, contributions were similar (and correlated) across event types. Maternal narrative style related to children's levels of participation and to the amount of unique information the children contributed to the conversations, both concurrently and over time; cross-lagged relations were more robust for the tornado relative to the nontornado related events. The implications of the patterns for socialization models of autobiographical memory development are discussed.

Spectral information of the output of x-ray tubes in (dual source) computer tomography (CT) scanners can be used to improve the conversion of CT numbers to proton stopping power and can be used to advantage in CT scanner quality assurance. The purpose of this study is to design, validate, and apply a compact portable Compton spectrometer that was constructed to accurately measure x-ray spectra of CT scanners.In the design of the Compton spectrometer, the shielding materials were carefully chosen and positioned to reduce background by x-ray fluorescence from the materials used. The spectrum of Compton scattered x-rays alters from the original source spectrum due to various physical processes. Reconstruction of the original x-ray spectrum from the Compton scattered spectrum is based on Monte Carlo simulations of the processes involved. This reconstruction is validated by comparing directly and indirectly measured spectra of a mobile x-ray tube. The Compton spectrometer is assessed in a clinical setting by measuring x-ray spectra at various tube voltages of three different medical CT scanner x-ray tubes.The directly and indirectly measured spectra are in good agreement (their ratio being 0.99) thereby validating the reconstruction method. The measured spectra of the medical CT scanners are consistent with theoretical spectra and spectra obtained from the x-ray tube manufacturer.A Compton spectrometer has been successfully designed, constructed, validated, and applied in the measurement of x-ray spectra of CT scanners. These measurements show that our compact Compton spectrometer can be rapidly set-up using the alignment lasers of the CT scanner, thereby enabling its use in commissioning, troubleshooting, and, e.g., annual performance check-ups of CT scanners.

Mother-child conversations about a devastating tornado and about 2 nontraumatic events were examined to determine whether there were (a) differences in use of internal states language when talking about traumatic and nontraumatic events and (b) similarities in mothers' and children's use of internal states language. At Session 1, which took place 4 months after the tornado, with conversational length controlled, there was no evidence of differential use of internal states language as a function of event for mothers or children. At Session 2, which took place 6 months later (10 months after the tornado), older children's narratives about the tornado were more saturated with internal states language, relative to their narratives about nontornado events. For both the traumatic and the nontraumatic events, there were cross-lagged correlations between maternal use of emotion language at Session 1 and children's use of emotion language at Session 2. The pattern of findings is consistent with the suggestion that...

When they are tested nonverbally, even young children demonstrate long-term recall. There have been few studies of whether early memories later are verbally accessible; the results of those that exist are mixed. Inconsistencies may be due to differences in the contextual cues provided at the time of recall. In two experiments, children 13–20 months were exposed to multi-step sequences and tested for nonverbal recall after 3–6 months. At age 3 years, they were tested verbally, under varying conditions of contextual support: in the original laboratory with event-related props versus at home with photographs of the props (Experiment 1), and at home with props (Experiment 2). Children younger than 20 months at initial experience of the events did not demonstrate verbal recall. Children who were 20 months at the initial exposure recalled verbally, as long as they had physical props as cues, regardless of whether testing took place at home or in the laboratory. This research informs the conditions under which memories from very early childhood later can be recalled verbally. Copyright © 2004 John Wiley & Sons, Ltd.

Wat is de huidige stand van zaken binnen de fysiotherapie voor ouderen van 70 jaar en ouder. Met welke klachten komen ze binnen in de eerste lijn? Hoe ziet de behandeling en huidige groepsinterventies er uit? Hoe kunnen we werken vanuit Evidence Based practice met deze patienten populatie. Waarom is fysieke activiteit van belang voor ouderen? Wat is er bekend uit interventieonderzoek? Korte omschrijving van de inhoud van de beweegstandaard voor kwetsbare ouderen van het KNGF.

We studied the frequency and evolution of social and emotional loneliness in older cancer patients in comparison with younger cancer patients and older people without cancer. We evaluated if changes in common cancer-related and ageing-related problems such as fatigue, cognitive functioning and functional status contributed to the occurrence of loneliness.This study was part of the KLIMOP study (Dutch acronym for project on older cancer patients in Belgium and the Netherlands) and included older (≥70 years) and younger cancer patients (50-69 years) and older people without cancer. Data were collected at baseline and 1-year follow-up. Loneliness was measured with the loneliness scale of De Jong-Gierveld. The relationship between loneliness after 1 year and changes in fatigue, cognitive functioning and functional status was tested in multivariate logistic regression analyses.Data were available for 475 participants. At baseline, older cancer patients were less lonely compared with older people without cancer. After 1 year, the frequency of emotional loneliness had significantly increased for older cancer patients (26-42%, p 0.001) and had reached levels of older people without cancer. Emotional loneliness also increased for younger cancer patients (25-34%, p = 0.02), but not for older people without cancer (40-38%, p = 0.69). Frequency of social loneliness did not change significantly. People who were persistently fatigued and people who became or were persistently impaired on cognitive functioning were at increased risk of becoming lonely.Loneliness, in particular emotional loneliness, is a common problem in cancer patients, and its frequency changes considerably over time.

Depression is an important health issue in cancer patients. People use different coping strategies and health locus of control to manage stressful situations, which relate to different risks of depression. Coping strategies and health locus of control can be changed by cognitive behavioral interventions.In a cohort study, we investigated differences in coping strategy and health locus of control in older (≥70 years) and middle-aged (50-69 years) cancer patients, and older patients without cancer (≥70 years), and their association with presence of depression. We also investigated how these factors interact. We used the short version of the Utrecht Coping List, the Multidimensional Health Locus of Control scale, and the 15-item Geriatric Depression Scale.Data were available from 1317 participants. Overall prevalence of depression was 12%. Older cancer patients tended to use an avoiding coping strategy more frequently than middle-aged cancer patients. This was associated with higher risk of depression. Older cancer patients less often used an active coping strategy, in comparison with middle-aged cancer patients, which was associated with a lower risk of depression. Especially in women using a seeking social support strategy, there was a lower risk of depression. Overall, the internal health locus of control was associated with higher and the external 'powerful others' locus with lower risk of depression.Older cancer patients strongly differ from middle-aged cancer patients, in particular with respect to coping. Interventions to prevent or alleviate depression should incorporate these differences.

This study describes the integrated application of parallel synthesis and computational chemistry to the design of potent nonpeptide antagonists for the neuropeptide Y-1 (NPY1) receptor. A lead molecule was modeled in the active site of the NPY1 receptor, and a potentially fruitful region for analog construction was identified. Synthesis of suitable scaffolds followed by solution phase generation of a small library of analogs produced a compound with 5-fold improvement in binding over the already potent lead. This new compound was shown to be an unanticipated side product of the parallel synthesis reaction.

Using elicited imitation of multi-step sequences we compared immediate and short-term delayed recall in 20-month-old children. In Experiment 1, levels of recall after a delay of 10 minutes did not differ from those immediately after exposure. In Experiment 2, levels of immediate and 12 minute delayed recall did not differ and were greater than those after 48 hours. In Experiment 3, levels of immediate and 12-minute delayed recall did not differ. Neither did performance differ as a function of whether the 12 minute delay was filled with potentially distracting or interfering material or whether it was essentially unfilled. Patterns of correlation between tasks are consistent with the suggestion that recall after delays of 10–12 minutes and 48 hours are mediated by long-term memory representations, whereas immediate recall is mediated by short-term memory representations. The findings inform both the parameters and the processes of remembering and forgetting in children approaching two years of age.

Schober, D. A., A. M. Van Abbema, D. L. Smiley, R. F. Bruns and D. R. Gehlert. The neuropeptide Y Y1 antagonist, 1229U91, a potent agonist for the human pancreatic polypeptide-preferring (NPY Y4) receptor. Peptides 19(3) 537–542, 1998.—Recently, a novel high-affinity peptide antagonist, 1229U91, was published as a selective neuropeptide Y Y1 antagonist. The selectivity of 1229U91 was evaluated in the human NPY Y1 receptor containing cell line, SK-N-MC, and cells containing the cloned human NPY Y2, the pancreatic polypeptide-preferring (NPY Y4), and the NPY Y5 receptors. 1229U91 potently displaced [125I]-peptide YY (PYY) binding to human NPY Y1 receptors (IC50 = 0.245 ± 0.004 nM, n = 4), but displayed little affinity for the human NPY Y2 and Y5 receptors (IC50 > 1000 nM). Interestingly, 1229U91 displaced [125I]-PYY with even greater affinity at the human NPY Y4 receptor (IC50 = 0.081 ± 0.009 nM, n = 4). Using a cyclic AMP accumulation assay, 1229U91 blocked NPY inhibition of forskolin-induced adenylate cyclase activity in NPY Y1 receptor containing SK-N-MC cells. In the human NPY Y4 receptor expressing cell line, 1229U91 did not block pancreatic polypeptide (PP) inhibition of forskolin stimulated adenylate cyclase. However, in the absence of PP, 1229U91 was able to inhibit forskolin stimulated cyclic AMP accumulation (IC50 = 7.16 ± 2.8 nM, n = 4). We conclude that 1229U91 binds non-selectively with high affinity to both human NPY Y1 and Y4 receptors. Furthermore, 1229U91 displays antagonist activity at the NPY Y1 receptor, while having agonist activity at the NPY Y4 receptor.

A highly ligand efficient, novel 8-oxo-pyridopyrimidine containing inhibitor of Jak1 and Jak2 isoforms with a pyridone moiety as the hinge-binding motif was discovered. Structure-based design strategies were applied to significantly improve enzyme potency and the polarity of the molecule was adjusted to gain cellular activity. The crystal structures of two representative inhibitors bound to Jak1 were obtained to enable SAR exploration.

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).

Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.

Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.

Background Detection and quantification of monoclonal proteins is hampered when the monoclonal peak coincides with one of the regular bands in serum proteinelectrophoresis. The objective of this study was to evaluate four procedures for serum proteinelectrophoresis with respect to detection and quantification of monoclonal proteins. Methods For 466 patient samples with a monoclonal protein, three variants of agarose gel electrophoresis (5-band, split-β and high resolution) and one variant of capillary electrophoresis were compared with the results of the routinely used agarose gel electrophoresis followed by immunofixation analysis using specific or pentavalent antisera. Results In total, 310 patient samples were analyzed by the four methods, consisting of 295 samples with a monoclonal protein, seven with oligoclonal bands and eight without any bands. Suspicion of a monoclonal protein was raised in 295/256/256/232/265 of the samples using the reference/5-band/split-β/high resolution/capillary procedure. In 152/147/135/142/126 of the samples the concentration of monoclonal protein was >1.0 g/L and in 51/33/53/33/67 of the cases, the monoclonal protein was not separated from one of the normal protein zones. Conclusions In high resolution agarose gel electrophoresis, monoclonal bands of low concentration often remain undetected. In split-β agarose gel electrophoresis as well as capillary electrophoresis monoclonal bands more often were not separated from the regular protein bands.

Despite the widespread use of rituximab, a chimeric monoclonal antibody with demonstrated efficacy in the treatment of non-Hodgkin's lymphomas, there is a recognized need to develop new agents with improved efficacy. Towards this end, using XenoMouse technology, a fully human IgG1 anti-CD20 monoclonal antibody was generated. This antibody, denoted mAb 1.5.3, evoked enhanced pro-apoptotic activity in vitro, as compared to rituximab, in the Ramos lymphoma cell line. Also, mAb 1.5.3 mediated both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) similar to rituximab in human B-lymphoma lines. Interestingly, mAb 1.5.3 demonstrated superior ADCC compared to rituiximab when FcgammaRIIIa F/F allotype donors were profiled and superior cytolytic activity across multiple human B-lymphoma and chronic B-cell leukemia lines in an in vitro whole blood assay. Furthermore, mAb 1.5.3 exhibited enhanced anti-tumor activity in Ramos, Daudi, and Namalwa tumour xenograft models. Lastly, mAb 1.5.3 produced a superior B-cell depletion profile in lymph node organs and bone marrow as compared to rituximab in a primate pharmacodynamic (PD) model. These findings underscore the potential of mAb 1.5.3 to exhibit improved clinical activity in the treatment of B-cell malignancies compared to rituximab.

Cognities vormen de basis voor veel menselijk gedrag. In samenspel met emoties hebben cognities een grote rol in de uiting van (ziekte)-gedrag. Het verkrijgen van inzicht in cognities heeft meerwaarde voor de fysiotherapeut. Fysiotherapeuten hebben te maken met een groeiende groep patiinten met chronische klachten. Het ziektegedrag van patienten met chronische klachten blijkt niet altijd effectief te zijn, met als gevolg meer klachten ofuitval bij therapie. Het veranderen van dit gedrag speelt in de fysiotherapie een steeds grotere rol. Het is voor de fysiotherapeut van belang, meer te weten te komen over de cognities en emoties die aan het gedrag van een patient voorafgaan. De cognities betreffende een aandoening of klachten noemen we ziektepercepties. Deze ziektepercepties kunnen de mogelijke oorzaken van de aandoening betreffen maar ook de consequenties en de mate van controle die men denkt te hebben over de aandoening. Het zelfregulatiemodel van Leventhal biedt een mogelijkheid om de cognities en emoties van patiinten in kaart te brengen. In het model wordt een relatie gelegd tussen de klacht, de gedachten, de emoties en het gedrag van de patient. Op basis van dit model is de Illness Perception Questionnaire ontwikkeld. Deze vragenlijst vormt een praktisch hulpmiddel om inzicht in de ziekteperceptie van patiinten te krijgen. Vervolgens kunnen inefficiente en onjuiste ziektepercepties met behulp van bijvoorbeeld educatie aangepast worden. Het veranderen van ziektepercepties kan een eerste voorwaarde zijn om tot een effectieve gedragsverandering te komen.

Throughout infancy and early childhood there are remarkable changes in the ability to remember everyday and emotional events. More frequent and effective use of memory strategies, increases in speed of processing, and developments in metamemory all contribute to the changes. Keywords: memory; metamemory; memory strategies; speed of processing; autobiographical memory

To address the question of whether memories from early childhood survive into later childhood, participants visited the laboratory at age 3 and again at 7, 8, or 9. At age 3, each talked with a parent about six events; at the later age each child talked with a researcher about four of these distant events as well as two more recent events. School-aged children recalled fewer than half of the distant events introduced. Further, the proportion of distant events recalled was negatively correlated with age. Those distant events that were recalled, however, were recounted in an accurate, detailed manner. Importantly, reports of distant events did not reflect the full extent of children's narrative ability. Reports of recent events were more coherent and included twice the detail. Implications for existing interpretations of autobiographical memory and childhood amnesia are discussed, and the need for further research employing innovative methods is emphasised.

Despite a growing literature on the collaborative reminiscing of mothers and children, little is known about the kinds of things mothers and children discuss as they recollect shared traumatic experiences. Do mother–child recollections of a traumatic event differ from their recollections of more benign events? To address this question, mother–child dyads (N=29) discussed a traumatic event, namely a devastating tornado, and two nontraumatic events (one that preceded and one that followed the tornado). Each dyad discussed all three events 4-months post-tornado and again 6 months later. Whereas conversations about both event types (traumatic and nontraumatic) varied with children’s age, dyads’ recollections of the tornado were significantly longer, more narratively coherent, and more complete than their recollections of nontraumatic events. These differences largely endured over the 6-month retention interval.

Introduction: HuLuc63 is a humanized monoclonal antibody that targets CS1 (CD2 subset 1, CRACC, SLAMF7, CD319), a cell surface glycoprotein that is highly and universally expressed on myeloma cells. In preclinical studies, we have shown that HuLuc63 treatment of mice with multiple myeloma (MM) xenograft tumors resulted in significant in vivo anti-tumor activity that is mediated at least in part by an antibody-dependent cellular cytotoxicity (ADCC) mechanism of action. The purpose of this study was to examine whether using HuLuc63 in combination with a panel of drugs having distinct modes of action (dexamethasone, thalidomide, bevacizumab (Avastin®), bortezomib (Velcade®)) could result in additional therapeutic benefit and provide a rationale for the design of future clinical trials. Methods: HuLuc63 in combination with other agents was tested in vivo for anti-tumor activity using the human L363 and OPM2 xenograft models. SCID mice were implanted subcutaneously with myeloma cells and randomized into different groups (10–15 mice per treatment group) when the average tumor volume reached ∼100 mm3. HuLuc63 was administered via intra-peritoneal injection twice per week at doses of 1–10 mg/kg. Dosing for dexamethasone was 10 mg/kg twice weekly, thalidomide 50 mg/kg daily, bevacizumab twice weekly at 0.5 mg/kg, and bortezomib 1 mg/kg for two dosing cycles, each cycle consisting of twice weekly dosing for 2 weeks followed by a week of rest. Results: The combination of dexamethasone with HuLuc63 showed a statistically significant increase in anti-tumor activity over either agent alone (p < 0.04). Combination with thalidomide only showed a slight enhancement of tumor inhibition when dosed in combination with HuLuc63 but its anti-tumor activity did not reach a statistically significant increase in over that of HuLuc63 alone. Co-treatment of the anti-VEGF anti-angiogenic monoclonal antibody bevacizumab with HuLuc63 resulted in a significant increase in tumor inhibition (p < 0.05) over that observed with either antibody when used as a single agent. The strongest anti-myeloma activity was observed when HuLuc63 was combined with bortezomib, which appeared to result in a synergistic inhibition of tumor cell growth. None of the agents tested changed the CS1 expression level on the myeloma cells or diminished the anti-myeloma activity of HuLuc63. Conclusions: These results suggest that HuLuc63 may be combined with different classes of drugs to enhance its anti-myeloma effects. In particular, agents that may induce apoptosis of myeloma cells (dexamethasone and bortezomib) and anti-angiogenics (bevacizumab) may be of particular interest for future clinical testing. Further preclinical studies using HuLuc63 in combination with other agents are in progress. HuLuc63 is currently being evaluated in a phase I clinical study as monotherapy for the treatment of relapsed/refractory multiple myeloma.

Introduction: We have recently shown that CS1 (CD2 subset 1, CRACC, SLAMF7), a cell surface glycoprotein of the CD2 family, is uniformly expressed on myeloma cells from multiple myeloma (MM) patients. Based on its high expression in MM and limited expression in normal cells, we propose CS1 as a novel and specific antibody target for the treatment of MM. Methods: A panel of monoclonal anti-CS1 antibodies (mAbs) was generated to identify a potential therapeutic candidate. MAb clones MuLuc63 and MuLuc90 were selected for testing in CS1 positive MM xenograft models in vivo in severe combined immunodeficient mice. HuLuc63, a humanized IgG1 version of MuLuc63, was generated as the potential therapeutic candidate for the treatment of MM. HuLuc63 and Fc-modified versions of HuLuc63 were tested for anti-tumor activity in mouse models vivo. In vitro antibody-dependent cellular cytotoxicity (ADCC) assays were performed to define the potential mechanism of action for HuLuc63. Results: Both MuLuc63 and MuLuc90 exhibited significant in vivo anti-tumor activity compared to isotype control antibodies in the L363 MM xenograft model. MuLuc63 was significantly more potent, resulting in rapid tumor eradication in most of the animals for the length of the study (~4 months). Based on these results, MuLuc63 was humanized to generate HuLuc63, which exhibited similar affinity for CS1 when compared to the mouse parent antibody. In two different MM xenograft models, L363 and OPM2, HuLuc63 exhibited significant anti-tumor activity resulting in tumor eradication in a high proportion of animals. To investigate the mechanism of action, two modified versions of HuLuc63 were tested in xenograft models. One version, HuLuc63-Ala,Ala, exhibits a mutation in the Fc region that decreases the ability to interact with the Fc receptor on natural killer (NK) cells. The second version, HuLuc63-LF, exhibits low levels of fucosylation in the Fc region that would result in increased binding to the Fc receptor. Compared to HuLuc63, the LF version exhibited significantly better in vivo anti-tumor activity towards, while the Ala,Ala mutant exhibited no anti-tumor activity. These data indicate that the Fc region of HuLuc63 is critical for its anti-tumor activity, and suggest ADCC as a possible mechanism of action. In vitro, HuLuc63 exhibits substantial ADCC towards L363 and OPM2 cells. The activity was dose-dependent, with increasing cytotoxicity being observed with concentrations ranging from 0.01μg/mL to10 μg/mL. Conclusions: These pre-clinical data support HuLuc63 as a new therapeutic for the treatment of MM and suggest that ADCC is part of the mechanism of action. HuLuc63 will be entering a phase I clinical study for multiple myeloma.

Introduction: Current monoclonal antibody (mAb) therapies for multiple myeloma (MM) have had limited success due to narrow target expression across MM patient samples. A preferred strategy would be to develop cytotoxic human mAbs against novel antigens that are highly expressed in MM cells yet have limited expression in other cell types. CS1 (CD2 subset 1, CRACC, SLAMF7), a member of the CD2 family of cell surface glycoproteins, was found to be highly expressed in myeloma cells. In this study, we investigated the anti-myeloma activity of HuLuc63, a novel humanized anti-CS1 mAb. Methods: Microarray expression profiling was used to determine the CS1 mRNA levels in CD138-expressing myeloma cells from 101 MM patient samples. For detection of CS1 protein, flow cytometry was performed using the anti-CS1 mAb HuLuc63. Functional characterization of HuLuc63 was performed by assessing antibody-dependent cellular cytotoxicity (ADCC) and by assessing MM and bone marrow stromal cell (BMSC) interactions. Results: CS1 mRNA was expressed in CD138 cells from more than 96% (97/101) of MM patients. Flow cytometric analysis confirmed that protein expression mirrors the mRNA profile. Importantly, CS1 is also present in 12 MM cell lines that are either drug-sensitive or resistant. HuLuc63, but not an isotype control antibody, induced ADCC in a CS1-specific, dose-dependent manner against CD138-expressing MM lines and patient MM cells including dexamethasone (dex)-sensitive MM1S and dex-resistant MM1R cells. Significantly, HuLuc63 triggered autologous ADCC against CS1-expressing CD138-purified tumor cells from 11 MM patients resistant to conventional or novel therapies such as bortezomib (Velcade®) and an HSP90 inhibitor. Since CS1 may regulate cell adhesion, we next studied whether HuLuc63 alters MM cell adhesion to BMSCs. HuLuc63 inhibited MM cell adhesion to BMSCs in a dose-dependent manner, whereas human control IgG did not. However, the presence of BMSC appeared to reduce HuLuc63-induced cell lysis against MM1S and MM1R cells. Since the immunomodulatory drug lenalidomide (Revlimid®) enhances NK cell function, we further tested whether HuLuc63-induced ADCC against MM cells is augmented by lenalidomide. Pretreatment with lenalidomide markedly enhanced NK-cell-mediated lysis of autologous patient MM cells triggered by HuLuc63. Conclusions: We show that the new MM antigen, CS1, is expressed in myeloma cells from more than 96% of MM patients. The novel humanized anti-CS1 mAb, HuLuc63, induced significant cytotoxicity against MM cells including drug-resistant cells, and inhibited their interaction with BMSCs. These data suggest that HuLuc63 may have clinical utility in a spectrum of MM patients including those newly diagnosed with the disease as well as patients with late stage refractory disease.