Constrained Sustainability and Resilience of Agricultural Practices from Multiple Lock-In Factors and Possible Pathways to Tackle Them

Autophagy, a lysosome-dependent catabolic process involved in the turnover of cellular components, mediates normal homeostasis during development and protects multicellular eukaryotes from neurodegeneration, cancer and other diseases. However, the mechanisms regulating autophagy under normal nutritional conditions most frequently encountered by cells in organisms under physiological conditions remain unknown. Our recent studies highlight an important role of class III PI 3-kinase in regulating autophagy. First, we show that phosphorylation of Vps34 by Cdk1 and Cdk5 negatively regulate type III PI 3-kinase and production of PI3P in mitotic cells and in neurodegeneration. Second, we show that multiple growth factors negatively regulate the activity of type III PI 3-kinase. In an image-based genome-wide human siRNA screen, we show that upregulation of autophagy by only 14 (6.4%) of the identified hit genes was accompanied by downregulation of activity of mTORC1, an essential regulator of starvation-induced autophagy. On the other hand, we found that 110 (50.2%) of the hit genes, including a group of growth factors and cytokines, regulate autophagy by targeting the type III PI 3-kinase. These cytokines inhibit the type III PI 3-kinase through multiple pathways. Third, we show that ROS may have a general signaling function in autophagy. We uncovered a large group of genes (117, or 54% of all genes tested) whose knockdown led to vesicular translocation of LC3-GFP in the absence but not the presence of antioxidant, suggesting that ROS are required for the induction of autophagy. Finally, using a small-molecule inhibitor that promotes the degradation of class III PI 3-kinase, we show that successful targeting this pathway can lead to selective cancer cell death. Our study suggests that the type III PI 3-kinase integrates diverse signals to regulate cellular levels of autophagy. Thus, autophagy and cell proliferation may represent two alternative cell fates that are regulated in a mutually exclusive manner, implicating autophagy as a common tumor suppression mechanism downstream of multiple signaling pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY09-01. doi:10.1158/1538-7445.AM2011-SY09-01

Hepatocellular carcinoma (HCC) represents a highly heterogeneous malignancy whose pathogenesis involves multiple etiological factors, including hepatitis viruses, metabolic disorders, and environmental carcinogens. Nevertheless, clinical management continues to face significant challenges due to high rates of postoperative recurrence, metastasis, and drug resistance. Emerging evidence indicates that Annexin A2 (ANXA2), a calcium-dependent phospholipid-binding protein, plays a pivotal role throughout HCC progression by integrating multiple oncogenic pathways. This review systematically elucidates ANXA2’s multifaceted regulatory mechanisms in HCC pathogenesis. Functioning as a critical molecular nexus, ANXA2 is dynamically modulated in its expression and activity by hepatic insults, particularly HBV/HCV infection, Alcoholic Liver Disease (ALD), Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD), and tobacco exposure, thereby bridging chronic liver injury and malignant transformation. Mechanistically, ANXA2 promotes tumor progression through multiple pathways, including ubiquitination regulation, stem cell characteristic regulation, cytoskeletal remodeling, Epithelial–Mesenchymal Transition (EMT) induction, and autophagy modulation. Furthermore, it confers chemotherapy resistance specifically through regulating apoptosis evasion, ferroptosis suppression, and autophagy homeostasis, while its effects on radiotherapy and immunotherapy responses involve distinct mechanisms. Promisingly, emerging ANXA2-targeted strategies demonstrate therapeutic potential, including exosome and microenvironment modulation, molecular targeted therapy, regulation of the ANXA2-NF-κB axis, Nanotechnology, and radionuclide theranostics. Collectively, this review establishes an integrated “etiology-mechanism-intervention” framework while providing novel molecular targets and a theoretical foundation for precision medicine approaches in HCC.

BackgroundAlzheimer’s disease (AD) pathology is associated with complex interactions among multiple factors, involving an intertwined network of various signaling pathways. The polypharmacological approach is an emerging therapeutic strategy that has been proposed to overcome the multifactorial nature of AD by targeting multiple pathophysiological factors including amyloid-β (Aβ) and phosphorylated tau. We evaluated a blood-brain barrier penetrating phosphodiesterase 5 (PDE5) inhibitor, mirodenafil (5-ethyl-2-7-n-propyl-3,5-dihydrro-4H-pyrrolo[3,2-d]pyrimidin-4-one), for its therapeutic effects on AD with polypharmacological properties.MethodsTo evaluate the potential of mirodenafil as a disease-modifying AD agent, mirodenafil was administered to test its effects on the cognitive behaviors of the APP-C105 AD mouse model using the Morris water maze and passive avoidance tests. To investigate the mechanisms of action that underlie the beneficial disease-modifying effects of mirodenafil, human neuroblastoma SH-SY5Y cells and mouse hippocampal HT-22 cells were used to show mirodenafil-induced alterations associated with the cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG)/cAMP-responsive element-binding protein (CREB) pathway, apoptotic cell death, tau phosphorylation, amyloidogenesis, the autophagy-lysosome pathway, glucocorticoid receptor (GR) transcriptional activity, and the Wnt/β-catenin signaling.ResultsHere, mirodenafil is demonstrated to improve cognitive behavior in the APP-C105 mouse model. Mirodenafil not only reduced the Aβ and phosphorylated tau burdens in vivo, but also ameliorated AD pathology induced by Aβ through the modulation of the cGMP/PKG/CREB signaling pathway, glycogen synthase kinase 3β (GSK-3β) activity, GR transcriptional activity, and the Wnt/β-catenin signaling in neuronal cells. Interestingly, homodimerization and nuclear localization of GR were inhibited by mirodenafil, but not by other PDE5 inhibitors. In addition, only mirodenafil reduced the expression levels of the Wnt antagonist Dickkopf-1 (Dkk-1), thus activating the Wnt/β-catenin signaling.ConclusionsThese findings strongly suggest that the PDE5 inhibitor mirodenafil shows promise as a potential polypharmacological drug candidate for AD treatment, acting on multiple key signaling pathways involved in amyloid deposition, phosphorylated tau burden, the cGMP/PKG/CREB pathway, GSK-3β kinase activity, GR signaling, and the Wnt/β-catenin signaling. Mirodenafil administration to the APP-C105 AD mouse model also improved cognitive behavior, demonstrating the potential of mirodenafil as a polypharmacological AD therapeutic agent.

An important feature of animal behavior is the ability to switch rapidly between activity states, however, how the brain regulates these spontaneous transitions based on the animal’s perceived environment is not well understood. Here we show a C. elegans sleep-like state on a scalable platform that enables simultaneous control of multiple environmental factors including temperature, mechanical stress, and food availability. This brief quiescent state, which we refer to as microfluidic-induced sleep, occurs spontaneously in microfluidic chambers, which allows us to track animal movement and perform whole-brain imaging. With these capabilities, we establish that microfluidic-induced sleep meets the behavioral requirements of C. elegans sleep and depends on multiple factors, such as satiety and temperature. Additionally, we show that C. elegans sleep can be induced through mechanosensory pathways. Together, these results establish a model system for studying how animals process multiple sensory pathways to regulate behavioral states.

Bim is a pro-apoptotic member of the Bcl-2 family that is induced and contributes to neuron death in response to nerve growth factor (NGF) deprivation. Past work has revealed that Bim is downstream of multiple independent transcriptional pathways in neurons, including those culminating in activation of the c-Jun, FoxO, and Myb transcription factors. This study addresses the issue of whether the three signaling pathways are redundant with respect to Bim induction or whether they act cooperatively. Examination of the proximal Bim promoter reveals binding sites for FoxO, Mybs, and, as shown here, c-Jun. We find that mutation of any one of these types of sites abolishes induction of a Bim promoter-driven reporter in response to NGF deprivation. Moreover, down-regulation of either c-Jun, FoxOs, or Mybs by short hairpin RNAs blocks induction of Bim promoter-reporter activity triggered by withdrawal of NGF. This was the case for reporters driven by either the proximal promoter or a promoter that also includes additional regulatory elements in the first intron of the Bim gene. Such short hairpin RNAs also suppressed the induction of endogenous Bim protein. These findings thus indicate that the Bim promoter acts as a coincidence detector that optimally responds to the simultaneous activation of three different pro-apoptotic transcriptional pathways. Such a mechanism provides a "fail-safe" that prevents neurons from dying by accidental activation of any single pathway. It also permits neurons to utilize individual pathways such as JNK signaling for other purposes without risk of demise.

Manifestation of pityriasis amiantacea following initiation of minoxidil

A minority of meningiomas are difficult to treat with surgery or radiotherapy, and chemotherapeutic alternatives are limited. This study aims to better understand pathways that are active in meningiomas, in order to direct future treatment strategies. We investigated the expression and activation of multiple growth factor receptors, their ligands and downstream signalling pathways in 30 meningiomas using immunohistochemistry. Expression was correlated with chromosome 22q loss. Membrane expression of VEGF receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR)β was seen in 83% of tumors, Axl in 70%, EGFR in 50% and insulin-like growth factor receptor in 47%. Expression was similar in low- and high-grade tumors, but membrane EGFR expression was not seen in tumors showing chromosome 22q loss (P < 0.05). Expression of ligands (IGF, NRG, VEGF, Gas 6), and signalling proteins (Mek, Erk, Jnk, Akt) and pS6RP, was widespread. Western blot confirmed widespread Axl expression and supported selective expression of EGFR in NF2-intact meningiomas. The majority of meningiomas express and show activation of multiple growth factor receptors and their signalling pathways, irrespective of tumor grade. In addition to previously reported receptors, Axl offers a new therapeutic target. The findings also suggest that anti-EGFR based therapies may be less effective in meningiomas with 22q loss.

Obesity is increasing worldwide and reaches to a large proportion of the population in developed countries. Thus, obesity-associated cancer has become a major health problem. Multiple cancer risk factors in obesity have been identified including insulin/insulin-like growth factor axis, adipokines and cytokines; and multiple intracellular signal pathways have been studied. However, the role of each signal pathway in obesity-associated cancer is controversial. In this review, the recent studies on signal pathways in obesity-associated cancer are summarized and a unified explanation is provided. Multiple risk factors could initially activate phosphoinositide 3-kinase (PI3K/Akt), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) pathways. With increased severity of obesity, mammalian target of rapamycin (mTOR), which is down-stream of both PI3K/Akt and MAPK, is highly activated. Activated mTOR in turn inhibits the PI3K/Akt pathway and further activates the STAT3 pathway. This may explain the activation of the PI3K/Akt pathway at the early stage of obesity and its inhibition at the later stage. mTOR inhibition may be used for cancer therapy, but it may be necessary to be combined with the PI3K/Akt inhibitor as decreased mTOR activity will release its feedback inhibition on the PI3K/Akt pathway, which is under the influence of multiple cancer risk factors in obesity. Thus, dual inhibitors of PI3K and mTOR may provide a novel approach.

Resistance to cancer therapy is a challenge because of innate tumor heterogeneity and constant tumor evolution. Since the pathway of resistance cannot be predicted, combination therapies may address this progression. We discovered that in addition to IGF1 and IGF2, IGFBP-3 binds bFGF, HGF, neuregulin, and PDGF AB with nanomolar affinity. Because growth factors drive resistance, simultaneous inhibition of multiple growth factor pathways may improve the efficacy of precision therapy. Growth factor sequestration by IGFBP-3-Fc enhances the activity of EGFR inhibitors by decreasing cell survival and inhibiting bFGF, HGF, and IGF1 growth factor rescue and also potentiates the activity of other cancer drugs. Inhibition of tumor growth in vivo with adjuvant IGFBP-3-Fc with erlotinib versus erlotinib after treatment cessation supports that the combination reduces cell survival. Inhibition of multiple growth factor pathways may postpone resistance and extend progression-free survival in many cancer indications.

Socioeconomic status (SES) has been identified as a fundamental cause of disease (Link & Phelan, 1995, 1996; Phelan et al., 2004; Phelan, Link, & Tehranifar, 2010). People who are poor and powerles...

Should Slowing Be Considered a Distinct Geriatric Syndrome?

Epidermal Growth Factor Receptor Is a Critical Mediator of Ultraviolet B Irradiation-Induced Signal Transduction in Immortalized Human Keratinocyte HaCaT Cells

The ubiquitin ligase Nedd4 regulates craniofacial development by promoting cranial neural crest cell survival and stem-cell like properties

Specialized, Refined, Differentiated, and Innovative (SRDI) enterprises are crucial to China’s economic development. It is important to examine how various factors’ combinations impact the radical innovation performance of SRDI enterprises in order to promote high-quality regional economic development. Based on the Technology–Organization–Environment (TOE) framework, this study selected SRDI enterprises as research samples, used a hierarchical clustering algorithm to divide the enterprises into groups according to the characteristics of SRDI enterprises, and employed a classification and regression tree (CART) algorithm to reveal the complex nonlinear relationships between the combinations of multiple key influencing factors and radical innovation performance from multi-source big data. The findings indicate that (1) there are significant variations in the factors affecting the radical innovation performance of different types of SRDI enterprises; (2) the radical innovation performance of SRDI enterprises stems from the synergistic interaction among various factors; and (3) the impact of R&amp;D investment on radical innovation is not simply linear. This study effectively captures the complex nonlinear relationships between combinations of multiple influencing factors and radical innovation performance. It is of great practical significance for revealing SRDI enterprises’ radical innovation performance improvement pathways and enhancing their innovation capability.

ABSTRACTBackgroundChild development is affected by multiple factors throughout pregnancy and childhood. Multisectoral programs addressing these factors may improve children's development.ObjectiveWe evaluated the impact of a food-assisted multisectoral nutrition program (Tubaramure) on children's (4–41.9 mo) motor and language development. Tubaramure was targeted to Burundian women and children in the first 1000 d and provided micronutrient-fortified food rations; nutrition, health, and hygiene behavior change communication; and health system–strengthening activities.MethodsProgram impact was assessed using a cluster-randomized controlled trial with repeated cross-sections: 2010 (baseline, children 4–41.9 mo), 2012 (follow-up during implementation, children 4–23.9 mo), and 2014 (follow-up postimplementation, children 24–41.9 mo). Sixty villages were randomly assigned to 4 groups with varying timing and duration of food rations: pregnancy–24 mo; pregnancy–18 mo; 0–24 mo; and control, no direct Tubaramure benefits. Treatment groups were pooled and compared with control using difference-in-difference estimates. We examined impact pathways by assessing program impacts on intermediary variables and their associations with development outcomes.ResultsAt first follow-up, Tubaramure positively affected language (0.4 milestones, P < 0.05) but not motor development among children aged 4–23.9 mo. Among the 12–23.9 mo age subgroup, the program positively affected language (0.7 milestones, P < 0.01) and motor (0.6 milestones, P = 0.08) development. At second follow-up, among children aged 24–41.9 mo, Tubaramure marginally affected motor development (0.4 milestones, P = 0.09). In age subgroup analyses, program impacts were limited to children aged 24–29.9 mo [0.4 motor (P = 0.09) and 1.0 language (P < 0.01) milestones]. Pathway analyses revealed significant positive impacts on diet, health, and nutritional indicators of children aged 12–23.9 mo and health and nutritional indicators of children aged 24–29.9 mo, supporting the plausibility of program impacts on child development.ConclusionsTubaramure had small positive impacts on children's motor and language development through multiple pathways, demonstrating the role multisectoral nutrition programs can play in improving children's development. This trial was registered at clinicaltrials.gov as NCT01072279.