Protein kinase C, an enzyme that is activated by the receptor-mediated hydrolysis of inositol phospholipids, relays information in the form of a variety of extracellular signals across the membrane to regulate many Ca2+-dependent processes. At an early phase of cellular responses, the enzyme appears to have a dual effect, providing positive forward as well as negative feedback controls over various steps of its own and other signaling pathways, such as the receptors that are coupled to inositol phospholipid hydrolysis and those of some growth factors. In biological systems, a positive signal is frequently followed by immediate negative feedback regulation. Such a novel role of this protein kinase system seems to give a logical basis for clarifying the biochemical mechanism of signal transduction, and to add a new dimension essential to our understanding of cell-to-cell communication.

https://science.sciencemag.org/content/sci/233/4761/305.full.pdf

Studies and perspectives of protein kinase C

▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

/pdf/short-term-synaptic-plasticity-5d4dx79319.pdf

Short-Term Synaptic Plasticity

Endocytic mechanisms control the lipid and protein composition of the plasma membrane, thereby regulating how cells interact with their environments. Here, we review what is known about mammalian endocytic mechanisms, with focus on the cellular proteins that control these events. We discuss the well-studied clathrin-mediated endocytic mechanisms and dissect endocytic pathways that proceed independently of clathrin. These clathrin-independent pathways include the CLIC/GEEC endocytic pathway, arf6-dependent endocytosis, flotillin-dependent endocytosis, macropinocytosis, circular doral ruffles, phagocytosis, and trans-endocytosis. We also critically review the role of caveolae and caveolin1 in endocytosis. We highlight the roles of lipids, membrane curvature-modulating proteins, small G proteins, actin, and dynamin in endocytic pathways. We discuss the functional relevance of distinct endocytic pathways and emphasize the importance of studying these pathways to understand human disease processes.

Mechanisms of Endocytosis

The heparan sulfate on the surface of all adherent cells modulates the actions of a large number of extracellular ligands. Members of both cell surface heparan sulfate proteoglycan families, the transmembrane syndecans and the glycosylphosphoinositide-linked glypicans, bind these ligands and enhance formation of their receptor-signaling complexes. These heparan sulfate proteoglycans also immobilize and regulate the turnover of ligands that act at the cell surface. The extracellular domains of these proteoglycans can be shed from the cell surface, generating soluble heparan sulfate proteoglycans that can inhibit interactions at the cell surface. Recent analyses of genetic defects in Drosophila melanogaster, mice, and humans confirm most of these activities in vivo and identify additional processes that involve cell surface heparan sulfate proteoglycans. This chapter focuses on the mechanisms underlying these activities and on the cellular functions that they regulate.

Functions of Cell Surface Heparan Sulfate Proteoglycans

Inositol phospholipids have long been known to have an important regulatory role in cell physiology. The repertoire of cellular processes known to be directly or indirectly controlled by this class of lipids has now dramatically expanded. Through interactions mediated by their headgroups, which can be reversibly phosphorylated to generate seven species, phosphoinositides play a fundamental part in controlling membrane-cytosol interfaces. These lipids mediate acute responses, but also act as constitutive signals that help define organelle identity. Their functions, besides classical signal transduction at the cell surface, include regulation of membrane traffic, the cytoskeleton, nuclear events and the permeability and transport functions of membranes.

Phosphoinositides in cell regulation and membrane dynamics

OAB-051: Salvage therapies and clinical outcomes after relapse following BCMA CAR-T in patients with relapsed/refractory multiple myeloma

Teclistamab (JNJ-64007957) is a bispecific antibody that binds to both B-cell maturation antigen (BCMA) and CD3 receptors to induce T cell-mediated cytotoxicity of BCMA-expressing myeloma cells. Results from phase 1 of the MajesTEC-1 study, an ongoing phase 1/2 study in heavily-pretreated relapsed/refractory multiple myeloma (RRMM; NCT03145181), showed a tolerable safety profile at the recommended phase 2 dose (RP2D) and encouraging efficacy. Here we report initial data from the phase 2 portion of MajesTEC-1 (NCT04557098) as well as updated results from phase 1. Patients (pts; ≥18 y) had MM per International Myeloma Working Group (IMWG) criteria, measurable disease, and were exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. In phase 1, pts were relapsed, refractory, or intolerant to established therapies. In phase 2, pts received ≥3 prior lines of therapy (LOT). The primary objectives were to identify the RP2D and to characterize safety and tolerability of teclistamab at the RP2D in phase 1, and to evaluate the efficacy at the RP2D (primary endpoint: ORR) in phase 2. The RP2D was weekly subcutaneous teclistamab 1500 μg/kg following step-up doses of 60 and 300 μg/kg. Responses were assessed by the investigator per IMWG criteria. Adverse events (AEs) were graded per CTCAE v4.03. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. As of June 14, 2021, 159 pts (median age 64.0 y [range 33–84]; 15% ≥75 y; 59% male) were treated at the RP2D (phase 1: 40 pts; phase 2: 119 pts). Pts received a median of 5 prior LOT (range 2–15); 100% were triple-class exposed, 69% were penta-drug exposed, 77% were triple-class refractory, and 29% were penta-drug refractory. In 159 pts, the most common nonhematologic AEs at the RP2D were CRS (any grade: 67%; grade 3 occurred in 1 pt, no grade 4 or 5), injection site erythema (23%; all grade 1/2), and fatigue (22%; grade 3/4: 2%). Of the hematologic AEs, most common were neutropenia (53%; grade 3/4: 45%), anemia (41%; grade 3/4: 27%), and thrombocytopenia (33%; grade 3/4: 18%). Four pts (2.5%) developed ICANS (all grade 1/2; all resolved). No new safety signals were identified in phase 2. Phase 2 pharmacokinetic and pharmacodynamic data supported those reported in phase 1. At the RP2D, teclistamab exposure was sustained across the dosing interval and exceeded target exposure levels. Across both phases, induction of proinflammatory cytokines and T cell activation were observed at the RP2D. Phase 2 efficacy data are immature. At 8.2-mo median follow-up (range 1.2–15.2), responses in the phase 1 pts at the RP2D (n=40) were consistent with previous reports (ORR: 65% [95% CI 48–79]; ≥VGPR: 60% [95% CI 43–75]; ≥complete response: 40% [95% CI 25–57]). Responses deepened over time, and with longer follow-up of responders compared with previously presented data (median follow-up of 9.5 mo vs 7.1 mo), remained durable (Figure). 85% (22/26) of responders are continuing on treatment, including 1 pt with 15.2 mo of follow-up. Median duration of response (DOR) was not reached, with 6-month DOR rate of 90% [95% CI 63–97]. The safety of teclistamab is supported by data from 159 pts treated at the RP2D. Teclistamab continues to show deep and durable responses with a manageable safety profile in heavily-pretreated pts with RRMM. 

P06: updated results from the phase 1/2 majestec-1 study of teclistamab, a b-cell maturation antigen x cd3 bispecific antibody, in patients with relapsed/refractory multiple myeloma

In this paper, we are presenting a model for multimodal content analysis. We are distinguishing between media and modality, which helps us to define and to characterize 3 inter-modal relations. Then we are applying this model for recorded course analysis for e-learning. Different useful relations between modalities are explained and detailed for this application. We are also describing on two other applications: telemonitoring and minute meetings. Then we compare the use of multimodality in these applications with existing inter-modal relations.

Thomas Martin

Papers

OAB-051: Salvage therapies and clinical outcomes after relapse following BCMA CAR-T in patients with relapsed/refractory multiple myeloma

P06: updated results from the phase 1/2 majestec-1 study of teclistamab, a b-cell maturation antigen x cd3 bispecific antibody, in patients with relapsed/refractory multiple myeloma

Multimodal Interactions for Multimedia Content Analysis

Single cell Dissection of Resistance to anti-BCMA CAR-T cell Therapy

22 Intra-operative brachytherapy in the treatment of locally advanced colorectal cancer