Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key ...KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, a MEK inhibitor approved by the US Food and Drug Administration, which acts downstream of KRAS to suppress signalling through the mitogen-activated protein kinase (MAPK) cascade. Informed by a short-hairpin RNA screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signalling rebound and adaptive drug resistance. As a consequence, genetic or pharmacological inhibition of FGFR1 in combination with trametinib enhances tumour cell death in vitro and in vivo. This compensatory response shows distinct specificities: it is dominated by FGFR1 in KRAS-mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells. Importantly, KRAS-mutant lung cancer cells and patients’ tumours treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer.
Context:
In cross-sectional studies, serum TSH concentrations increase with age. This has not been examined longitudinally, and it is uncertain whether the TSH increase reflects healthy aging or ...occult thyroid failure.
Methods:
We measured serum TSH, free T4, thyroid peroxidase, and thyroglobulin antibodies in 1100 participants in the 1981 and 1994 Busselton Health Surveys and derived a reference group of 908 individuals without thyroid disease or thyroid antibodies. We examined changes in thyroid function longitudinally and, in 781 participants, explored associations with the CAPZB polymorphism rs10917469.
Results:
At 13 yr follow-up, mean serum TSH increased from 1.49 to 1.81 mU/liter, a change in mean TSH (ΔTSH) of 0.32 mU/liter 95% confidence interval (CI) 0.27, 0.38, P < 0.001, whereas mean free T4 concentration was unchanged (16.6 vs. 16.6 pmol/liter, P = 0.7). The TSH increase was most marked in the elderly, such that gender-adjusted ΔTSH increased by 0.08 mU/liter (95% CI 0.04, 0.11) for each decade of baseline age. People with higher baseline TSH values had proportionally smaller increases in TSH, with each additional 1.0 mU/liter of baseline TSH associated with a 0.13 mU/liter decrease (age and gender adjusted) in ΔTSH (95% CI 0.09, 0.16). The ΔTSH did not differ significantly by CAPZB genotype.
Conclusions:
Aging is associated with increased serum TSH concentrations, with no change in free T4 concentrations. The largest TSH increase is in people with the lowest TSH at baseline. This suggests that the TSH increase arises from age-related alteration in the TSH set point or reduced TSH bioactivity rather than occult thyroid disease.
Missense mutations in the p53 tumor suppressor inactivate its antiproliferative properties but can also promote metastasis through a gain-of-function activity. We show that sustained expression of ...mutant p53 is required to maintain the prometastatic phenotype of a murine model of pancreatic cancer, a highly metastatic disease that frequently displays p53 mutations. Transcriptional profiling and functional screening identified the platelet-derived growth factor receptor b (PDGFRb) as both necessary and sufficient to mediate these effects. Mutant p53 induced PDGFRb through a cell-autonomous mechanism involving inhibition of a p73/NF-Y complex that represses PDGFRb expression in p53-deficient, noninvasive cells. Blocking PDGFRb signaling by RNA interference or by small molecule inhibitors prevented pancreatic cancer cell invasion in vitro and metastasis formation in vivo. Finally, high PDGFRb expression correlates with poor disease-free survival in pancreatic, colon, and ovarian cancer patients, implicating PDGFRb as a prognostic marker and possible target for attenuating metastasis in p53 mutant tumors.
Hepatic steatosis, the excess storage of intrahepatic lipids, is a rampant clinical problem associated with the obesity epidemic. Hepatic steatosis is linked to increased risk for insulin resistance, ...type 2 diabetes, and cardiovascular and advanced liver disease. Accumulating evidence shows that physical activity, exercise, and aerobic capacity have profound effects on regulating intrahepatic lipids and mediating susceptibility for hepatic steatosis. Moreover, exercise can effectively reduce hepatic steatosis independent of changes in body mass. In this perspective, we highlight
) the relationship between obesity and metabolic pathways putatively driving hepatic steatosis compared with changes induced by exercise;
) the impact of physical activity, exercise, and aerobic capacity compared with caloric restriction on regulating intrahepatic lipids and steatosis risk;
) the effects of exercise training (modalities, volume, intensity) for treatment of hepatic steatosis, and
) evidence for a sustained protection against steatosis induced by exercise. Overall, evidence clearly indicates that exercise powerfully regulates intrahepatic storage of fat and risk for steatosis.
In the organizational sciences, scholars are increasingly using experience sampling methods (ESM) to answer questions tied to intraindividual, dynamic phenomenon. However, employing this method to ...answer organizational research questions comes with a number of complex—and often difficult—decisions surrounding: (1) how the implementation of ESM can advance or elucidate prior between-person theorizing at the within-person level of analysis, (2) how scholars should effectively and efficiently assess within-person constructs, and (3) analytic concerns regarding the proper modeling of interdependent assessments and trends while controlling for potentially confounding factors. The current paper addresses these challenges via a panel of seven researchers who are familiar not only with implementing this methodology but also related theoretical and analytic challenges in this domain. The current paper provides timely, actionable insights aimed toward addressing several complex issues that scholars often face when implementing ESM in their research.
Tissue damage increases the risk of cancer through poorly understood mechanisms
. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating ...mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma
. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an 'acinar-to-neoplasia' chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.
KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show ...that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8+ T cells into otherwise immunologically “cold” tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.
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•Therapy-induced senescence in PDAC triggers SASP-dependent vascular remodeling•SASP-mediated vascularization facilitates chemotherapy uptake and efficacy•SASP-mediated endothelial activation drives T cell infiltration into PDAC lesions•Senescence-inducing treatment potentiates PD-1 blockade in PDAC models
In mouse models of KRAS mutant pancreatic ductal adenocarcinoma, tumor cell senescence following MEK and CDK4/6 inhibition promotes vascular remodeling through induction of a pro-angiogenic senescence-associated secretory phenotype, leading to enhanced drug delivery and T cell infiltration that sensitizes these tumors to chemotherapy and immune checkpoint blockade.
Active reinforcement learning enables dynamic prediction and control, where one should not only maximize rewards but also minimize costs such as of inference, decisions, actions, and time. For an ...embodied agent such as a human, decisions are also shaped by physical aspects of actions. Beyond the effects of reward outcomes on learning processes, to what extent can modeling of behavior in a reinforcement-learning task be complicated by other sources of variance in sequential action choices? What of the effects of action bias (for actions per se) and action hysteresis determined by the history of actions chosen previously? The present study addressed these questions with incremental assembly of models for the sequential choice data from a task with hierarchical structure for additional complexity in learning. With systematic comparison and falsification of computational models, human choices were tested for signatures of parallel modules representing not only an enhanced form of generalized reinforcement learning but also action bias and hysteresis. We found evidence for substantial differences in bias and hysteresis across participants-even comparable in magnitude to the individual differences in learning. Individuals who did not learn well revealed the greatest biases, but those who did learn accurately were also significantly biased. The direction of hysteresis varied among individuals as repetition or, more commonly, alternation biases persisting from multiple previous actions. Considering that these actions were button presses with trivial motor demands, the idiosyncratic forces biasing sequences of action choices were robust enough to suggest ubiquity across individuals and across tasks requiring various actions. In light of how bias and hysteresis function as a heuristic for efficient control that adapts to uncertainty or low motivation by minimizing the cost of effort, these phenomena broaden the consilient theory of a mixture of experts to encompass a mixture of expert and nonexpert controllers of behavior.
Cancer cells rely on altered metabolism to support abnormal proliferation. We performed a CRISPR/Cas9 functional genomic screen targeting metabolic enzymes and identified PDXK—an enzyme that produces ...pyridoxal phosphate (PLP) from vitamin B6—as an acute myeloid leukemia (AML)-selective dependency. PDXK kinase activity is required for PLP production and AML cell proliferation, and pharmacological blockade of the vitamin B6 pathway at both PDXK and PLP levels recapitulated PDXK disruption effects. PDXK disruption reduced intracellular concentrations of key metabolites needed for cell division. Furthermore, disruption of PLP-dependent enzymes ODC1 or GOT2 selectively inhibited AML cell proliferation and their downstream products partially rescued PDXK disruption induced proliferation blockage. Our work identifies the vitamin B6 pathway as a pharmacologically actionable dependency in AML.
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•CRISPR/Cas9 screen identifies PDXK as an AML selective metabolic dependency•PDXK kinase activity and PLP are selectively required for leukemic cell proliferation•PLP-dependent enzymes ODC1 and GOT2 selectively support leukemic cell proliferation•The vitamin B6 pathway is a therapeutically actionable dependency in leukemia
In a CRISPR/Cas9 functional screen targeting metabolic enzymes, Chen et al. identify PDXK, which produces pyridoxal phosphate (PLP) from vitamin B6, as an AML dependency. PLP-dependent enzymes ODC1 and GOT2 support AML proliferation. Blockade of the vitamin B6 metabolic pathway exhibits anti-leukemic activity.
Wartime experiences have long been known to cause ethical conflict, guilt, self-condemnation, difficulty forgiving, loss of trust, lack of meaning and purpose, and spiritual struggles. "Moral injury" ...(MI) (also sometimes called "inner conflict") is the term used to capture this emotional, cognitive, and behavioral state. In this article, we provide rationale for developing and testing Spiritually Oriented Cognitive Processing Therapy, a version of standard cognitive processing therapy for the treatment of MI in active duty and veteran service members (SMs) with posttraumatic stress disorder symptoms who are spiritual or religious (S/R). Many SMs have S/R beliefs that could increase vulnerability to MI. Because the injury is to deeply held moral standards and ethical values and often adversely affects spiritual beliefs and worldview, we believe that those who are S/R will respond more favorably to a therapy that directly targets this injury from a spiritually oriented perspective. An evidence-based treatment for MI in posttraumatic stress disorder that not only respects but also utilizes SMs' spiritual beliefs/behaviors may open the door to treatment for many S/R military personnel.
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