Introduction: Multiple myeloma (MM) is associated with profound and widespread disarray of both the adaptive and innate arms of the immune system including loss of effector T cell function, humoral ...immune deficiency, and natural killer (NK) cell immunity. This immunosuppressive milieu is crucial to promoting disease progression. Standard treatment options (immunomodulators (IMIDs) and proteosome inhibitors, radiation, and high-dose corticosteroids) offer modest benefit, but also contribute to further immune suppression. Little is known regarding the mechanisms by which immune dysfunction and immunoevasion occur. Our group has characterized an important role for the programmed death receptor-1 (PD-1) / PD-L1 signaling axis in these processes. MDV9300 (formerly CT-011 / Pidilizumab) is a novel IgG1 humanized monoclonal antibody (mAb) that modulates the immune response through interaction with PD-1. Lenalidomide (Len) an IMID exerts efficacy in MM in part through enhancement of NK cell versus MM effect - an effect likely mediated through T cell production of interleukin (IL)-2. In our in-vitro study, pretreatment of NK cells with MDV9300 with or without Len enhanced immune complex formation between NK cells and MM tumor targets and also augmented NK cell activation and cytotoxicity against MM. We sought to determine the safety, tolerability and any early signs of efficacy in relapsed or refractory MM patients using MDV9300 in combination with Len.
Methods: In the phase I portion, the primary endpoint is to determine the maximum tolerated dose (MTD) of the combination. Key eligibility criteria are relapsed or refractory disease but not progressed on Len 25 mg; ≥2 prior lines of therapy, absolute neutrophil count ≥ 1000/µL; Platelets ≥60,000/µL; and creatinine clearance of ≥ 40ml/min. Patients are treated with escalating doses of MDV9300 and Len utilizing a 3x3 escalation design (Table 1). If stable disease is the best response after 4 cycles, patients have the option of adding dexamethasone (20-40mg weekly). Len dose may be modified independently of MDV9300. Patients can receive a maximum of 12 cycles of therapy.
Results: Twelve patients are evaluable to date. The median age was 68.5 (range 49-82) and the median time from diagnosis 4.98 years (range 1.54-12.62). At study entry, 67% had high risk cytogenetics (del 17p, complex karyotype, gain 1q) and the median number of prior treatment lines was 2 (range 2-11). 100% of patients had received prior Len, bortezomib and Dex, 50% alkylating agents (cyclophosphamide, oral melphalan, bendamustine), 75% autologous stem cell transplant, 25% pomalidomide and 33% carfilzomib. MDV9300 infusion has been well tolerated with only one grade 2 infusion related toxicity with sore throat. The patient received hydrocortisone with no further reaction observed. Grade 3/4 Anemia, neutropenia, and thrombocytopenia attributable to therapy have been seen in 25%, 23%, and 34% of patients, respectively. Other common grade 2-3 therapy related adverse events are fatigue (50%), anorexia (17%), and hypophosphatemia (17%). There has been no grade 3 or higher infection and no worsening of neuropathy from baseline. Len dose was reduced in 3 patients (25%) and increased in one. There has been no dose reduction in MDV9300. Dex 20 mg or less was added in 2 patients for muscle cramps and < PR after 3 cycles. To date 7 patients are off therapy; 1 due to grade 3 fatigue and 6 due to disease progression. Five patients continue on therapy at respective 12, 11, 9, 5 and 3 months. Responses to date have been 3 Very good partial response,1 partial response, 2 minimal response and 2 stable disease.
Conclusion: The combination of steroid sparing MDV9300 and Len regimen has demonstrated an acceptable toxicity profile to date with evidence of anti-myeloma activity. This is the first reported combination anti-PD-1 based immune therapy for MM. Updated results will be presented at the meeting including the MTD dose for phase II.
Table 1MDV9300- mg/kg Intravenously given on day 3 every 28 daysLenalidomide- mg orally days 1-21 every 28 daysDLT EvaluableDLTsCohort 11.5156Grade 3 fatigue. Cohort extended to 6Cohort 23153noneCohort 33253noneCohort 46250
Acknowledgments: Drug has been provided by Medivation; The study is sponsored by the American Cancer Society
No relevant conflicts of interest to declare.
Population size estimation is performed for several reasons including disease surveillance and control, for example to design adequate control strategies such as vaccination programs or to estimate a ...vaccination campaign coverage. In this study, we aimed at investigating the possibility of using Unmanned Aerial Vehicles (UAV) to estimate the size of free-roaming domestic dog (FRDD) populations and compare the results with two regularly used methods for population estimations: foot-patrol transect survey and the human: dog ratio estimation. Three studies sites of one square kilometer were selected in Petén department, Guatemala. A door-to-door survey was conducted in which all available dogs were marked with a collar and owner were interviewed. The day after, UAV flight were performed twice during two consecutive days per study site. The UAV's camera was set to regularly take pictures and cover the entire surface of the selected areas. Simultaneously to the UAV's flight, a foot-patrol transect survey was performed and the number of collared and non-collared dogs were recorded. Data collected during the interviews and the number of dogs counted during the foot-patrol transects informed a capture-recapture (CR) model fit into a Bayesian inferential framework to estimate the dog population size, which was found to be 78, 259, and 413 in the three study sites. The difference of the CR model estimates compared to previously available dog census count (110 and 289) can be explained by the fact that the study population addressed by the different methods differs. The human: dog ratio covered the same study population as the dog census and tended to underestimate the FRDD population size (97 and 161). Under the conditions within this study, the total number of dogs identified on the UAV pictures was 11, 96, and 71 for the three regions (compared to the total number of dogs counted during the foot-patrol transects of 112, 354 and 211). In addition, the quality of the UAV pictures was not sufficient to assess the presence of a mark on the spotted dogs. Therefore, no CR model could be implemented to estimate the size of the FRDD using UAV. We discussed ways for improving the use of UAV for this purpose, such as flying at a lower altitude in study area wisely chosen. We also suggest to investigate the possibility of using infrared camera and automatic detection of the dogs to increase visibility of the dogs in the pictures and limit workload of finding them. Finally, we discuss the need of using models, such as spatial capture-recapture models to obtain reliable estimates of the FRDD population. This publication may provide helpful directions to design dog population size estimation methods using UAV.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes ...remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
Novel treatment options for metastatic colorectal cancer (CRC) are urgently needed to improve patient outcome. Here, we screen a library of non-characterized small molecules against a heterogeneous ...collection of patient-derived CRC spheroids. By prioritizing compounds with inhibitory activity in a subset of—but not all—spheroid cultures, NCT02 is identified as a candidate with minimal risk of non-specific toxicity. Mechanistically, we show that NCT02 acts as molecular glue that induces ubiquitination of cyclin K (CCNK) and proteasomal degradation of CCNK and its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of CRC cells in vitro and tumor growth in vivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 in vitro and in patient-derived xenografts. We thus demonstrate the efficacy of targeted CCNK/CDK12 degradation for a CRC subset, highlighting the potential of drug-induced proteolysis for difficult-to-treat types of cancer.
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•A screen for inhibitory compounds of colorectal cancer spheroids identifies NCT02•NCT02 acts as a molecular glue and induces degradation of CCNK and CDK12•Knockout of CCNK or CDK12 and targeted CCNK degradation decrease tumor growth•TP53 deficiency and consensus molecular subtype 4 predict sensitivity to NCT02
Dieter et al. identify the compound NCT02 as inhibitor of patient-derived colorectal cancer cell viability. They show that NCT02 acts as a molecular glue that induces CCNK ubiquitination and degradation. Targeted CCNK degradation is identified as a particular vulnerability of a subgroup of colorectal cancers that can be exploited therapeutically.
Chromothripsis is a form of genomic instability characterized by the occurrence of tens to hundreds of clustered DNA double‐strand breaks in a one‐off catastrophic event. Rearrangements associated ...with chromothripsis are detectable in numerous tumor entities and linked with poor prognosis in some of these, such as Sonic Hedgehog medulloblastoma, neuroblastoma and osteosarcoma. Hence, there is a need for therapeutic strategies eliminating tumor cells with chromothripsis. Defects in DNA double‐strand break repair, and in particular homologous recombination repair, have been linked with chromothripsis. Targeting DNA repair deficiencies by synthetic lethality approaches, we performed a synergy screen using drug libraries (n = 375 compounds, 15 models) combined with either a PARP inhibitor or cisplatin. This revealed a synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibition. Functional assays, transcriptome analyses and in vivo validation in patient‐derived xenograft mouse models confirmed the efficacy of the combinatorial treatment.
What's new?
Chromothripsis is a type of genomic instability in which hundreds of chromosomal rearrangements occur at once. In certain tumor types, including medulloblastoma, neuroblastoma and osteosarcoma, chromothripsis is associated with poor prognosis. Here, the authors screened for drug pairs that target and kill tumor cells with chromothripsis while sparing cells that have functional DNA repair. Their screen uncovered a strong synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibitors. Combination therapy worked well to stop tumor growth and induce apoptosis in patient‐derived xenografts.
Population size estimation is performed for several reasons including disease surveillance and control, for example to design adequate control strategies such as vaccination programs or to estimate a ...vaccination campaign coverage. In this study, we aimed at investigating the possibility of using Unmanned Aerial Vehicles (UAV) to estimate the size of free-roaming domestic dog (FRDD) populations and compare the results with two regularly used methods for population estimations: foot-patrol transect survey and the human: dog ratio estimation. Three studies sites of one square kilometer were selected in Petén department, Guatemala. A door-to-door survey was conducted in which all available dogs were marked with a collar and owner were interviewed. The day after, UAV flight were performed twice during two consecutive days per study site. The UAV's camera was set to regularly take pictures and cover the entire surface of the selected areas. Simultaneously to the UAV's flight, a foot-patrol transect survey was performed and the number of collared and non-collared dogs were recorded. Data collected during the interviews and the number of dogs counted during the foot-patrol transects informed a capture-recapture (CR) model fit into a Bayesian inferential framework to estimate the dog population size, which was found to be 78, 259, and 413 in the three study sites. The difference of the CR model estimates compared to previously available dog census count (110 and 289) can be explained by the fact that the study population addressed by the different methods differs. The human: dog ratio covered the same study population as the dog census and tended to underestimate the FRDD population size (97 and 161). Under the conditions within this study, the total number of dogs identified on the UAV pictures was 11, 96, and 71 for the three regions (compared to the total number of dogs counted during the foot-patrol transects of 112, 354 and 211). In addition, the quality of the UAV pictures was not sufficient to assess the presence of a mark on the spotted dogs. Therefore, no CR model could be implemented to estimate the size of the FRDD using UAV. We discussed ways for improving the use of UAV for this purpose, such as flying at a lower altitude in study area wisely chosen. We also suggest to investigate the possibility of using infrared camera and automatic detection of the dogs to increase visibility of the dogs in the pictures and limit workload of finding them. Finally, we discuss the need of using models, such as spatial capture-recapture models to obtain reliable estimates of the FRDD population. This publication may provide helpful directions to design dog population size estimation methods using UAV.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
What can planners do to restore equity to their craft? Drawing upon the perspectives of a diverse group of planning experts, Advancing Equity Planning Now places the concepts of fairness and equal ...access squarely in the center of planning research and practice. Editors Norman Krumholz and Kathryn Wertheim Hexter provide essential resources for city leaders and planners, as well as for students and others, interested in shaping the built environment for a more just world. Advancing Equity Planning Now remind us that equity has always been an integral consideration in the planning profession. The historic roots of that ethical commitment go back more than a century. Yet a trend of growing inequality in America, as well as other recent socio-economic changes that divide the wealthiest from the middle and working classes, challenge the notion that a rising economic tide lifts all boats. When planning becomes mere place-making for elites, urban and regional planners need to return to the fundamentals of their profession. Although they have not always done so, planners are well-positioned to advocate for greater equity in public policies that address the multiple objectives of urban planning including housing, transportation, economic development, and the removal of noxious land uses in neighborhoods. Thanks to generous funding from Cleveland State University, the ebook editions of this book are available as Open Access volumes from Cornell Open (cornellpress.cornell.edu/cornell-open) and other repositories.
Genetic instability and cellular proliferation have been associated with aurora kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of aurora-A, -B, ...and -C was determined by Affymetrix DNA microarrays in 784 samples including 2 independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive interphase fluorescence in situ hybridization and proliferation of primary myeloma cells by propidium iodine staining. We found aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient cohorts, but aurora-C in testis cell samples only. Myeloma cell samples with detectable versus absent aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations (aneuploidy), nor of subclonal aberrations (chromosomal instability). The clinical aurora kinase inhibitor VX680 induced apoptosis in 20 of 20 myeloma cell lines and 5 of 5 primary myeloma cell samples. Presence of aurora-A expression delineates significantly inferior event-free and overall survival in 2 independent cohorts of patients undergoing high-dose chemotherapy, independent from conventional prognostic factors. Using gene expression profiling, aurora kinase inhibitors as a promising therapeutic option in myeloma can be tailoredly given to patients expressing aurora-A, who in turn have an adverse prognosis.
As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes ...remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
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