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KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRASG12C inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We found that cancer cells resistant to KRASG12C inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line-derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment.

Small water supplies face similar problems worldwide, regardless of ownership or management type. Non-compliance with water quality regulations is more frequent in small supplies than in large ones, as are waterborne disease outbreaks. The new European Union Drinking Water Directive requires risk-based approach (RBA) to secure water safety as is recommended in the World Health Organization's Guidelines for drinking water quality through ‘water safety plans’. This is already in regulation in the Nordic countries, although less used in small supplies. In this research, we explore the challenges, barriers and possible solutions to implementing RBA and improving compliance in small supplies. This was achieved by conducting and analysing interviews with 53 stakeholders from all eight Nordic countries to produce recommendations for action by the different implicated actors. Our findings suggest the centrality of governmental policy, including support for continuous training, provision of simple RBA guidelines and increasing cooperation in the water sector. The Nordic experience reflects global challenges with small water supplies and the trend towards systematic preventive management epitomized in the framework for drinking water safety advocated by the World Health Organization since 2004. HIGHLIGHTS Small systems drinking water safety are challenged by staffing, infrastructure and pollution management, single source dependence, and financing. Remote systems also face expertise and supply chain difficulties.; Cooperation between regulators/surveillance authorities and water suppliers enhances performance.; Governments should clarify roles and responsibilities of stakeholders in consultation with them.; Legislation should require training and increase availability of training.; RBA facilitates cooperation between small water supplies and would be facilitated by easy-to-use RBA form.;

UNLABELLED: The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor-resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin1 (XPO1), as a single agent. KRAS G12C inhibitors in combination with selinexor suppressed the proliferation of KRAS G12C mutant cancer cell lines in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C mutant cancer cells. Mechanistically, the combination of selinexor with KRAS G12C inhibitors suppressed cell growth signaling and downregulated the expression of cell cycle markers, KRAS and NF-kB as well as increased nuclear accumulation of tumor suppressor protein Rb. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models. SIGNIFICANCE: In this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment.

BackgroundStudies analyzing optimal voltage thresholds for scar detection with electroanatomic mapping frequently lack a gold standard for comparison.ObjectiveThe purpose of this study was to use a porcine infarct model with ex vivo magnetic resonance imaging (MRI) integration to characterize the relationship between interelectrode spacing and bipolar voltage thresholds and examine the influence of 3-dimensional scar on unipolar voltages.MethodsThirty-two combined endocardial-epicardial electroanatomic maps were created in 8 postinfarct porcine subjects (bipolar 2-mm, 5-mm, and 8-mm interelectrode spacing and unipolar) for comparison with ex vivo MRI. Two thresholds were compared: (1) 95% normal distribution and (2) best fit to MRI. Direct electrogram analysis was performed in regions across from MRI-defined scar and adjacent to scar border zone.ResultsA linear increase in optimal thresholds was observed with wider bipole spacing. The 95% thresholds for scar were lower than MRI-matched thresholds with moderate sensitivity for nontransmural scar (54% endo, 63% epi). Unipolar endocardial scar area exceeded MRI-defined scar, resulting in mismatched false scar in 5 of 8 (63%). Endocardial and epicardial unipolar voltages were lower than normal in regions adjacent and across from scar.ConclusionVariations in interelectrode spacing necessitate tailored bipolar voltage thresholds to optimize scar detection. Statistical 95% thresholds appear to be conservative and not fully sensitive for the detection of scar defined by high-resolution ex vivo MRI. In the presence of endocardial scar, unipolar mapping to quantitatively characterize epicardial scar may be overly sensitive due to 3-dimensional spatial averaging.

Hippocampal place cells convey spatial information through a combination of spatially selective firing and theta phase precession. The way in which this information influences regions like the subiculum that receive input from the hippocampus remains unclear. The subiculum receives direct inputs from area CA1 of the hippocampus and sends divergent output projections to many other parts of the brain, so we examined the firing patterns of rat subicular neurons. We found a substantial transformation in the subicular code for space from sparse to dense firing rate representations along a proximal-distal anatomical gradient: neurons in the proximal subiculum are more similar to canonical, sparsely firing hippocampal place cells, whereas neurons in the distal subiculum have higher firing rates and more distributed spatial firing patterns. Using information theory, we found that the more distributed spatial representation in the subiculum carries, on average, more information about spatial location and context than the sparse spatial representation in CA1. Remarkably, despite the disparate firing rate properties of subicular neurons, we found that neurons at all proximal-distal locations exhibit robust theta phase precession, with similar spiking oscillation frequencies as neurons in area CA1. Our findings suggest that the subiculum is specialized to compress sparse hippocampal spatial codes into highly informative distributed codes suitable for efficient communication to other brain regions. Moreover, despite this substantial compression, the subiculum maintains finer scale temporal properties that may allow it to participate in oscillatory phase coding and spike timing-dependent plasticity in coordination with other regions of the hippocampal circuit.