Single-agent mosunetuzumab shows durable complete responses in patients with relapsed or refractory B-cell lymphomas: Phase I dose-escalation study

PURPOSE: Mosunetuzumab is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells and is being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs). METHODS: This first-in-human trial (ClinicalTrials.gov identifier: NCT02500407) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. Data from dose escalation are presented. Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 (group A) or with ascending (step-up) doses during cycle 1 on days 1, 8, and 15 (group B), for eight or 17 cycles on the basis of tumor response. RESULTS: Two hundred thirty patients were enrolled. Doses up to 2.8 mg and 60 mg were assessed in groups A and B, respectively; maximum tolerated dose was not exceeded. In group B (n = 197), common adverse events (≥ 20% of patients) were neutropenia (28.4%), cytokine release syndrome (27.4%), hypophosphatemia (23.4%), fatigue (22.8%), and diarrhea (21.8%). Cytokine release syndrome was mostly low-grade (grade ≥ 3: 1.0%) and mainly confined to cycle 1. Across the doses investigated (group B), best overall response rates were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively, and complete response rates were 19.4% and 48.5%. Among patients with a complete response, the median duration of response was 22.8 months (95% CI, 7.6 to not estimable) and 20.4 (95% CI, 16 to not estimable) in patients with aggressive and indolent B-NHL, respectively. CONCLUSION: Mosunetuzumab, administered with step-up dosing, has a manageable safety profile and induces durable complete responses in R/R B-NHL. The expansion stage of the study is ongoing at the dose level of 1/2/60/60/30 mg selected for further study

The Role of IS Capabilities in the Development of Multi-Sided Platforms: The Digital Ecosystem Strategy of Alibaba.com

Multi-sided platforms (MSP) are revolutionizing the global competitive landscape in the new networked economy. Yet, although these MSPs are underpinned by information systems (IS), there is currently little research on how the IS capabilities of the platform sponsor can influence, and co-evolve with, the development of the platform over time. The lack of knowledge in this area may account for the difficulties faced by a significant number of platform sponsors in developing their MSPs effectively. Using a case study of Alibaba.com, one of the world’s largest and most commercially successful online MSP, we inductively derive a process theory of MSP development from an IS capability perspective to address this knowledge gap. The process model reveals that the role of IS capabilities in MSP development is evolutionary in nature, and the antecedent IS capabilities, nature, and outcomes of MSP development can be dramatically different in the various stages of development

Insulinase-like protease 1 contributes to macrogamont formation in Cryptosporidium parvum

The apicomplexan parasit

An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration

As one of the key nutrient sensors, insulin signaling plays an important role in integrating environmental energy cues with organism growth. In adult organisms, relative insufficiency of insulin signaling induces compensatory expansion of insulin-secreting pancreatic beta (β) cells. However, little is known about how insulin signaling feedback might influence neogenesis of β cells during embryonic development. Using genetic approaches and a unique cell transplantation system in developing zebrafish, we have uncovered a novel role for insulin signaling in the negative regulation of pancreatic progenitor cell differentiation. Blocking insulin signaling in the pancreatic progenitors hastened the expression of the essential β cell genes insulin and pdx1, and promoted β cell fate at the expense of alpha cell fate. In addition, loss of insulin signaling promoted β cell regeneration and destabilization of alpha cell character. These data indicate that insulin signaling constitutes a tunable mechanism for β cell compensatory plasticity during early development. Moreover, using a novel blastomere-to-larva transplantation strategy, we found that loss of insulin signaling in endoderm-committed blastomeres drove their differentiation into β cells. Furthermore, the extent of this differentiation was dependent on the function of the β cell mass in the host. Altogether, our results indicate that modulation of insulin signaling will be crucial for the development of β cell restoration therapies for diabetics; further clarification of the mechanisms of insulin signaling in β cell progenitors will reveal therapeutic targets for both in vivo and in vitro β cell generation

Entanglement Perturbation Theory for Infinite Quasi-1D Quantum Systems

We develop Entanglement Perturbation Theory (EPT) for infinite Quasi-1D quantum systems. The spin 1/2 Heisenberg chain with ferromagnetic nearest neighbor (NN) and antiferromagnetic next nearest neighbor (NNN) interactions with an easy-plane anisotropy is studied as a prototypical system. The obtained accurate phase diagram is compared with a recent prediction [Phys.Rev.B,81,094430(2010)] that dimer and Neel orders appear alternately as the XXZ anisotropy Delta approaches the isotropic limit Delta=1. The first and second transitions (across dimer, Neel, and dimer phases) are detected with improved accuracy at Delta\approx 0.722 and 0.930. The third transition (from dimer to Neel phases), previously predicted to be at Delta\approx 0.98, is not detected at this Delta in our method, raising the possibility that the second Neel phase is absent.Comment: 5 pages, 5 figure

Brushing Element Fields

Aggregate elements following certain directions have a variety of applications in graphics, design, and visualization. However, authoring oriented elements in various output domains, especially in 3D, remains challenging. We propose a novel brushing system to facilitate interactive authoring of aggregate elements with diverse properties over given output domains via an element synthesis approach. To increase output quality and reduce input workload, we further propose element fields that can automatically orient the entire elements in better alignments over the output domains according to partially user-specified strokes. The proposed system can effectively synthesize distinct types of elements within various output domains in higher quality and efficiency and offer more user friendliness than existing practices. Our method can be applied to practical applications such as graphic design, artistic collage, and aggregate modelin

Rediscovery and stratigraphic calibration of the classic Nihewan Fauna, Hebei Province, China

The classic Nihewan Fauna, as the representative of early Pleistocene Asian Land Mammal Age Nihewanian, has long been cited for bio- and chronostratigraphic correlation. However, its precise provenance and stratigraphic horizon have remained unsolved till now. The authors successfully extracted the vital information by rediscovering 30 of the original excavation localities. The fossils were catalogued with their provenance through an extensive field survey and comprehensive inspection of the Tianjin Natural History Museum collection. A review of the original description of these fossil localities, using satellite images, and subsequent lithological examination of the Xiashagou strata in the field verified the new findings. The survey produced the first stratigraphic profile calibrated with fossil horizons of the Nihewan formation in the Xiashagou section. Correlated with the published magnetostratigraphical profile of the section, an age of similar to 2.4-1.8 Ma is estimated for the classic Nihewan Fauna.Peer reviewe