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The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals.

Neurons are complex cells that require a lot of time and resources to model completely. In spiking neural networks (SNN) though, not all that complexity is required. Therefore simple, abstract models are often used. These models save time, use less computer resources, and are easier to understand. This tutorial presents two such models: Izhikevich's model, which is biologically realistic in the resulting spike trains but not in the parameters, and the Leaky Integrate and Fire (LIF) model which is not biologically realistic but does quickly and easily integrate input to produce spikes. Izhikevich's model is based on Hodgkin-Huxley's model but simplified such that it uses only two differentiation equations and four parameters to produce various realistic spike patterns. LIF is based on a standard electrical circuit and contains one equation. Either of these two models, or any of the many other models in literature can be used in a SNN. Choosing a neural model is an important task that depends on the goal of the research and the resources available. Once a model is chosen, network decisions such as connectivity, delay, and sparseness, need to be made. Understanding neural models and how they are incorporated into the network is the first step in creating a SNN.

Artificial neural networks, or ANNs, have grown a lot since their inception back in the 1940s. But no matter the changes, one of the most important components of neural networks is still the node, which represents the neuron. Within spiking neural networks, the node is especially important because it contains the functions and properties of neurons that are necessary for their network. One important aspect of neurons is the ionic flow which produces action potentials, or spikes. Forces of diffusion and electrostatic pressure work together with the physical properties of the cell to move ions around changing the cell membrane potential which ultimately produces the action potential. This tutorial reviews the Hodkgin-Huxley model and shows how it simulates the ionic flow of the giant squid axon via four differential equations. The model is implemented in Matlab using Euler's Method to approximate the differential equations. By using Euler's method, an extra parameter is created, the time step. This new parameter needs to be carefully considered or the results of the node may be impaired.

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.

Adagrasib (MRTX849) is a KRASG12C inhibitor with favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system (CNS) penetration. As of September 1, 2022, a total of 853 patients with KRASG12C-mutated solid tumors, including patients with CNS metastases, had received adagrasib (monotherapy or in combination). Adagrasib-related treatment-related adverse events (TRAEs) are generally mild to moderate in severity, start early in treatment, resolve quickly with appropriate intervention, and result in a low rate of treatment discontinuation. Common TRAEs seen in clinical trials included gastrointestinal-related toxicities (diarrhea, nausea, and vomiting); hepatic toxicities (increased alanine aminotransferase/aspartate aminotransferase) and fatigue, which can be managed through dose modifications, dietary modifications, concomitant medications (such as anti-diarrheals and anti-emetics/anti-nauseants) and the monitoring of liver enzymes and electrolytes. To manage common TRAEs effectively, it is imperative that clinicians are informed, and patients are fully counseled on management recommendations at treatment initiation. In this review, we provide practical guidance on the management of adagrasib TRAEs and discuss some best practices for patient and caregiver counseling to facilitate optimal outcomes for patients. Safety and tolerability data from the phase II cohort of the KRYSTAL-1 study will be reviewed and presented with practical management recommendations based on our experience as clinical investigators.

Background: Right hemisphere communication disorders are neither consistently labelled nor adequately defined. Labels associated with right hemisphere brain damage (RHD) are broad and fail to capture the essence of communication challenges needed for stroke-related service provisions. Determination of rehabilitation needs and best-practice guidelines for the education, management and functional improvement of communication disorders after RHD are all predicated on an apt diagnostic label and disorder characteristics. Aims: In this paper "apragmatism" is proposed as a potential communication-specific diagnostic label for the impairments in communication that occur after RHD. In particular, the researchers aimed: (1) to establish an operational definition of apragmatism; and (2) to describe the linguistic, paralinguistic and extralinguistic communication deficits under the umbrella term "apragmatism." Methods & Procedures: An international collaborative of researchers with expertise in RHD followed a multilevel approach to consider the utility of apragmatism as a diagnostic label. Adopting the relational approach to concept mapping, the researchers engaged in a series of group meetings to complete four levels of mapping: (1) identify and review, (2) define, (3) expert discussion and (4) label determination. Main Contribution: Apragmatism was established as a suitable diagnostic label for the impairments in communication associated with RHD. The paper offers an operational definition and description of the linguistic, paralinguistic and extralinguistic features of apragmatism through evidence summaries and examples from people with RHD retrieved from the RHDBank. Conclusions & Implications: The adoption of the term apragmatism offers an opportunity to capture the hallmark of RHD communication deficits. The use of the term is recommended when referencing the pragmatic language impairments in this population. Apragmatism, which may co-occur with or be exacerbated by cognitive impairments, can interfere with the ability to interpret and convey intended meaning and impact the lives of right hemisphere stroke survivors and their families.

PurposeAdagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non-small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRASG12C mutation.Materials and methodsPatients with advanced KRASG12C-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated.ResultsTwenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRASG12C-mutant non-small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRASG12C-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%).ConclusionAdagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRASG12C mutation.