While fluorescence recovery after photobleaching studies demonstrated that ROP dynamics do not depend on the cytoskeleton, acute depolymerization of the cytoskeleton removed ROP from the membrane only in recently divided cells, pointing to a feedback mechanism between the cell cycle, cytoskeleton, and ROP.Over 80,000 angiosperm species produce flowers with petals fused into a corolla tube. The corolla tube contributes to the tremendous diversity of flower morphology and plays a critical role in plant reproduction, yet it remains one of the least understood plant structures from a developmental genetics perspective. Through mutant analyses and transgenic experiments, we show that the tasiRNA-ARF pathway is required for corolla tube formation in the monkeyflower species Mimulus lewisii Loss-of-function mutations in the M. lewisii orthologs of ARGONAUTE7 and SUPPRESSOR OF GENE SILENCING3 cause a dramatic decrease in abundance of TAS3-derived small RNAs and a moderate upregulation of AUXIN RESPONSE FACTOR3 (ARF3) and ARF4, which lead to inhibition of lateral expansion of the bases of petal primordia and complete arrest of the upward growth of the interprimordial regions, resulting in unfused corollas. Using the DR5 auxin-responsive promoter, we discovered that auxin signaling is continuous along the petal primordium base and the interprimordial region during the critical stage of corolla tube formation in the wild type, similar to the spatial pattern of MlARF4 expression. Auxin response is much weaker and more restricted in the mutant. Furthermore, exogenous application of a polar auxin transport inhibitor to wild-type floral apices disrupted petal fusion. Together, these results suggest a new conceptual model highlighting the central role of auxin-directed synchronized growth of the petal primordium base and the interprimordial region in corolla tube formation.Efficient T cell activation and effector responses require an antigenic peptide presented on the MHC complex to the TCR (signal 1), costimulatory molecule interactions between T cells and APCs (signal 2), and the synthesis of innate immune-derived proinflammatory cytokines and reactive oxygen species (signal 3). We previously demonstrated that the third signal dissipation impairs autoreactive T cell activation. In this study, we tested the hypothesis that encapsulation of Ag with an antioxidant-containing biomaterial would induce Ag-specific hyporesponsiveness. We cocultured bone marrow-derived dendritic cells with microcapsules composed of multilayer-assembled poly(N-vinylpyrrolidone) (PVPON) and the antioxidant tannic acid (TA). LPS-activated dendritic cells cocultured with (PVPON/TA) microcapsules displayed a decrease in TNF-α, IL-12p70, and CXCL10 synthesis. To study Ag-specific T cell responses, we incorporated chicken OVA into the (PVPON/TA) multilayers and stimulated OT-II splenocytes in a primary recall assay. Flow cytometric analysis demonstrated a significant inhibition of CD4 T cell activation markers, upregulation of CTLA-4 and PD-1, and blunted secretion of IL-2, IFN-γ, TNF-α, and CXCL10 by ELISA. To test microcapsule efficacy in vivo, we immunized OT-II mice with (PVPON/TA)-OVA microcapsules and performed an OVA recall assay. Immunization of OT-II mice with (PVPON/TA)-OVA microcapsules elicited a decrease in CD4 T cell differentiation and effector responses including IFN-γ, TNF-α, CCL3, and CCL5 by ELISA compared with OVA immunization alone. These data show that microcapsules composed of antioxidant and encapsulated Ags can effectively blunt innate immune-derived proinflammatory third signal synthesis necessary for Ag-specific effector T cell responses and present a prospective strategy for T cell-mediated autoimmunity.

New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody-drug conjugate (ADC).

Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines

, orthotopic xenografts

, and patient samples

. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state.

The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity

and

. In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples.

We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.

We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.The BNF is jointly published by the Royal Pharmaceutical Society and BMJ. BNF is published in print twice a year and interim updates are issued and published monthly in the digital versions. BAY 1000394 CDK inhibitor The following summary provides a brief description of some recent key changes that have been made to BNF content.

To evaluate whether the use of dipeptidyl peptidase-4 (DPP-4) inhibitors and their cardiac tissue distribution profile and anticalcification abilities are associated with risk of aortic stenosis (AS) progression.

Out of the five different classes of DPP-4 inhibitors, two had relatively favourable heart to plasma concentration ratios and anticalcification ability in murine and in vitro experiments and were thus categorised as ‘favourable’. We reviewed the medical records of 212 patients (72±8 years, 111 men) with diabetes and mild-to-moderate AS who underwent echocardiographic follow-up and classified them into those who received favourable DPP-4 inhibitors (n=28, 13%), unfavourable DPP-4 inhibitors (n=69, 33%) and those who did not receive DPP-4 inhibitors (n=115, 54%).

Maximal transaortic velocity (Vmax) increased from 2.9±0.3 to 3.5±0.7 m/s during follow-up (median, 3.7 years), and the changes were not different between DPP-4 users as a whole and non-users (p=0.143). However, the favourable group showed significantly lower Vmax increase than the unfavourable or non-user group (p=0.