Search

For a simple, finite, and connected graph G, the spherical maximal operator is defined as ... where ... is the sphere with center at t and having radius r. In this paper, we consider the spherical maximal operator ... on ... spaces and calculate the ... for ... and estimate the ... for ..., when G is Km. Furthermore, We establish the maximum and minimum bounds for the spherical maximum operator on finite graphs and indicate the graphs that achieve these bounds. [ABSTRACT FROM AUTHOR]

This paper presents an innovative approach to enhance the querying capability of ChatGPT, a conversational artificial intelligence model, by incorporating voice-based interaction and a convolutional neural network (CNN)-based impaired vision detection model. The proposed system aims to improve user experience and accessibility by allowing users to interact with ChatGPT using voice commands. Additionally, a CNN-based model is employed to detect impairments in user vision, enabling the system to adapt its responses and provide appropriate assistance. This research tackles head-on the challenges of user experience and inclusivity in artificial intelligence (AI). It underscores our commitment to overcoming these obstacles, making ChatGPT more accessible and valuable for a broader audience. The integration of voice-based interaction and impaired vision detection represents a novel approach to conversational AI. Notably, this innovation transcends novelty; it carries the potential to profoundly impact the lives of users, particularly those with visual impairments. The modular approach to system design ensures adaptability and scalability, critical for the practical implementation of these advancements. Crucially, the solution places the user at its core. Customizing responses for those with visual impairments demonstrates AI's potential to not only understand but also accommodate individual needs and preferences. [ABSTRACT FROM AUTHOR]

Advances in electro‐ionic soft actuators hold significant potential as next‐generation bioelectronic interfaces due to mechanical compliance and operation in agreement with soft biological tissues and low voltages. However, current devices call for encapsulation strategies to accommodate high mechanical demands and long‐term stability in environmental changes. In this study, a durability of polyvinylidene‐fluoride‐co‐hexafluoropropylene (PVDF‐co‐HFP) honeycomb skeleton electrolyte encapsulated with a biocompatible polyisobutylene (PIB) thin film is being investigated. A low water vapor transmission rate (0.61 g m−2 day−1) and elastic modulus (10 kPa) are measured from a 7.5 µm‐thick thin‐modified PIB‐encapsulation layer. The PIB‐encapsulated soft actuator maintains 68% of its mechanical durability after 40 000 cycles of zero‐to‐tension fatigue loading at room temperature. A cantilever actuation test of the PIB‐encapsulated 3mm‐wide 30mm‐long actuator film shows a large tip displacement (15.90 mm) at a low voltage (±1.5 V) under 0.1 Hz, 37 °C, 50% relative humidity (RH). Most importantly, while the unencapsulated actuator immediately degrades in a few cycles at 37 °C, 50%RH, and 0.1% applied strain, PIB‐encapsulated soft actuator performs up to 6500 dynamic actuation cycles without any functionality degradation. Exceptional durability against mechanical fatigue and stability at elevated temperature and humidity meet the prerequisite for future soft biomedical robots that enable long‐lasting safe operations. [ABSTRACT FROM AUTHOR]

This paper examines the propagation of M-shape solitons and their interactions with kink waves to the (2 + 1)-dimensional integrable Schwarz-Korteweg-de Vries (ISKdV) problem by applying the symbolic computation with ansatz functions technique and logarithmic transformation. The governing model usually appears in the nonlinear shallow water waves and fluid mechanics. We discuss various nonlinear waves like multiwave solutions (MSs), homoclinic breather (HB), M-shape solitons, single exponential form (one-kink), and double exponential form (two-kink). These waves have lot of applications in fluid dynamics, nonlinear optics, chemical reaction networks, biological systems, climate science, and material science. We also study interaction among M-shape solitons with kink wave. At the end, we discuss the stability characteristics of all solutions. [ABSTRACT FROM AUTHOR]

Low oxygen tension, or hypoxia is the driving force behind tumor aggressiveness, leading to therapy resistance, metastasis, and stemness in solid cancers including breast cancer, which now stands as the leading cause of cancer-related mortality in women. With the great advancements in exploring the regulatory roles of the non-coding genome in recent years, the wide spectrum of hypoxia-responsive genome is not limited to just protein-coding genes but also includes multiple types of non-coding RNAs, such as micro RNAs, long non-coding RNAs, and circular RNAs. Over the years, these hypoxia-responsive non-coding molecules have been greatly implicated in breast cancer. Hypoxia drives the expression of these non-coding RNAs as upstream modulators and downstream effectors of hypoxia inducible factor signaling in the favor of breast cancer through a myriad of molecular mechanisms. These non-coding RNAs then contribute in orchestrating aggressive hypoxic tumor environment and regulate cancer associated cellular processes such as proliferation, evasion of apoptotic death, extracellular matrix remodeling, angiogenesis, migration, invasion, epithelial-tomesenchymal transition, metastasis, therapy resistance, stemness, and evasion of the immune system in breast cancer. In addition, the interplay between hypoxia-driven non-coding RNAs as well as feedback and feedforward loops between these ncRNAs and HIFs further contribute to breast cancer progression. Although the current clinical implications of hypoxia-driven non-coding RNAs are limited to prognostics and diagnostics in breast cancer, extensive explorations have established some of these hypoxia-driven non-coding RNAs as promising targets to treat aggressive breast cancers, and future scientific endeavors hold great promise in targeting hypoxia-driven ncRNAs at clinics to treat breast cancer and limit global cancer burden. [ABSTRACT FROM AUTHOR]

Consumer knowledge of the goods produced or processed by the numerous suppliers and processors is still relatively low due to the growing complexity of the structure of pharmaceutical supply chains. Information asymmetry in the pharmaceutical sector has an effect on welfare, sustainability, and health. (1) Background: In this respect, we wanted to develop a productive structure for a pharmaceutical supply chain that satisfies the consumer information needs and fosters consumer confidence in the pharmacy goods they buy. By using blockchain technology, the main goals were to develop and implement a pharmaceutical supply chain. (2) Objectives: The main objectives of this work were to leverage an Ethereum platform for the development of a tractability system in a pharmaceutical supply chain environment and to analyze the efficiency of MSMAChain with respect to the cost and execution of transactions based on our designed smart contracts. (3) Results: This research looked into a variety of issues related to the value, viability, and effects of blockchain technology for use in supply chain applications. The methods and creations in this environment were monitored and researched. It is vital to identify a number of crucial subjects including future research areas, in order to achieve the widespread acceptance of the supply chain traceability provided by blockchain technology. (4) Conclusions: MSMAChain, an Ethereum blockchain-based approach, leverages smart contracts and decentralized off-chain storage for efficient product traceability in terms of the cost and execution of transaction for a health care supply chain. [ABSTRACT FROM AUTHOR]

In this paper, we will define a new metric space called n-gonal graphical b-metric space. We will also prove some fixed point theorems in said metric space and give suitable examples to illustrate our results. These results will help to solve many nonlinear convex models in machine learning and optimization by formulating them in fixed point schemes of optimization. Our paper opens the door for researchers to work in the intersecting area of machine learning and functional analysis in the frame work of n -gonal graphical b -metric space. [ABSTRACT FROM AUTHOR]

Content naming and lookup are decisive functions of the future architecture named data network (NDN). The core concept of NDN is the content distribution between consumers and content providers. The NDN supports advance vehicular networks that is famous with vehicular-named data network (VNDN) with different naming schemes such as hybrid, flat, attribute-based, and hierarchical names. These schemes are used in a static way for vehicular network, in summary, the hybrid, flat, and attribute-based makes a complex structure, and on the other hand, hierarchical names long in length and name lookup performance are a bottleneck in NDN, which can directly affect the network performance. Therefore, we introduce a dynamic naming scheme and lookup method (DNSL) for VNDN to mitigate these issues. We argue that the dynamic naming scheme is a better approach to VNDN, while the static name is a cost-effective, hefty, integrated fashion, and improper for the vehicular network. This study focuses on (1) a dynamic naming scheme using dynamic-tag and (2) a lookup method based on node partition of trie; the trie approach is very famed in data structure and extensively used for the lookup content, insertion, and deletion processes. Our experimental evaluation shows that the DNSL scheme is highly efficient, scalable, and provably correct for VNDN. [ABSTRACT FROM AUTHOR]

Managing the integrity of products and processes in a multi-stakeholder supply chain environment is a significant challenge. Many current solutions suffer from data fragmentation, lack of reliable provenance, and diverse protocol regulations across multiple distributions and processes. Amongst other solutions, Blockchain has emerged as a leading technology, since it provides secure traceability and control, immutability, and trust creation among stakeholders in a low cost IT solution. Although Blockchain is making a significant impact in many areas, there are many impediments to its widespread adoption in supply chains. This article is the first survey of its kind, with detailed analysis of the challenges and future directions in Blockchain-enabled supply chains. We review the existing digitalization of the supply chain including the role of GS1 standards and technologies. Current use cases and startups in the field of Blockchain-enabled supply chains are reviewed and presented in tabulated form. Technical and non-technical challenges in the adoption of Blockchain for supply chain applications are critically analyzed, along with the suitability of various consensus algorithms for applications in the supply chain. The tools and technologies in the Blockchain ecosystem are depicted and analyzed. Some key areas as future research directions are also identified which must be addressed to realize mass adoption of Blockchain-based in supply chain traceability. Finally, we propose MOHBSChain, a novel framework for Blockchain-enabled supply chains. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC), the most common cause of cancer death in women, overtook lung cancer as the leading cause of cancer worldwide in 2020. Although many studies have proposed KIN17 as a biomarker of tumorigenesis in different cancer types, its role in tumor metastasis, particularly in BC metastasis, has been underexplored. This study aimed to explore the role of KIN17 in BC metastasis. Methods: Survival analyses was performed to identify the association between KIN17 expression and BC patient survival in silico. Using lentivirus constructs, we developed bidirectional KIN17 expression (KD, knockdown; OE, overexpression) cellular models of luminal‐A (Lum‐A) breast cancer MCF‐7 cells. We performed in vitro wound healing, transwell with and without Matrigel assays, and in vivo tail‐vein metastasis assay to evaluate the migration and invasion abilities of MCF‐7 with stable KIN17 knockdown or overexpression. Western blotting was performed to compare the changes in protein expression. Results: We found that KIN17 expression was associated with poor overall survival (OS), relapse‐free survival (RFS), distant metastasis‐free survival (DMFS) and post‐progression survival (PPS), particularly in Lum‐A breast cancer patients. Later, we found that KIN17 knockdown inhibited migration and invasion of MCF‐7 cells via regulating EMT‐associated signaling pathways in vitro and decreases metastatic spread of the disease in vivo. In contrast, KIN17 overexpression promoted migration and invasion of MCF‐7 cells in vitro and increased the metastatic spread of the disease in vivo. Conclusions: Overall, our findings provide preliminary data which suggests KIN17 of importance to target in metastatic Lum‐A patients. [ABSTRACT FROM AUTHOR]

In order to promote the electrochemical reduction of CO2 into valuable products and chemical feedstock, the refinement of inexpensive, functioning, highly discerning catalysts is of utmost importance to alleviate inordinate carbon dioxide emissions in the atmosphere. This study presents an innovative electrocatalyst composed of MnO and CuO nanoparticles anchored onto Mn: Cu(1:2)@MOF. These nanocomposites offer multiple active sites for electrochemical carbon dioxide reduction, resulting in a striking current density of almost − 58 mAcm−2 at − 2 V vs. Ag/AgCl (reference electrode) in 0.1 M aqueous KHCO3 electrolyte with faradic efficiency of nearly 52% for CO and 54% for methane at − 1.5 V and − 1.4 V vs. Ag/AgCl, respectively. This performance is in stark contrast to the Mn: Cu(1:1)@MOF and Mn: Cu(2:1)@MOF, which exhibit current densities of − 56 mAcm−2 and − 51 mAcm−2 respectively under similar cathodic voltages. The excellent catalytic accomplishment can be credited to the interaction between nanoparticles and MOFs, which allows enhanced absorption and activation for CO2 molecules due to approachable metallic components and matchless 2-D formation of Mn: Cu(1:2)@MOF. These finding presents a straightforward approach to promote CO2 to valuable products through the analytical formulation of MOF alloy. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a disease with complex pathobiology, significant morbidity and mortality, and remains without a cure. It is characterized by vascular remodelling associated with uncontrolled proliferation of pulmonary artery smooth muscle cells, endothelial cell proliferation and dysfunction, and endothelial-to-mesenchymal transition, leading to narrowing of the vascular lumen, increased vascular resistance and pulmonary arterial pressure, which inevitably results in right heart failure and death. There are multiple molecules and signalling pathways that are involved in the vascular remodelling, including non-coding RNAs, i.e. microRNAs and long non-coding RNAs (lncRNAs). It is only in recent years that the role of lncRNAs in the pathobiology of pulmonary vascular remodelling and right ventricular dysfunction is being vigorously investigated. In this review, we have summarized the current state of knowledge about the role of lncRNAs as key drivers and gatekeepers in regulating major cellular and molecular trafficking involved in the pathogenesis of PAH. In addition, we have discussed the limitations and challenges in translating lncRNA research in vivo and in therapeutic applications of lncRNAs in PAH. [ABSTRACT FROM AUTHOR]

The objective of this article is to establish some Hermite–Hadamard-type inequalities via harmonic s , m -convex functions in the framework of conformal fractional integral. [ABSTRACT FROM AUTHOR]

The events after 9/11 have changed the conditions, especially for Muslims living in the US. They have been victimized and stereotyped as negative individuals to the extent of being liars and bigots. These semantic and religious sentiments and prejudice have been pervasive at all levels, ranging from public to private, political, and media platforms. These strong sentiments have penetrated the political campaigns in the US, thus creating Islamophobia. Traditionally, the presidential election Campaigns focus on the diversity and address every group and member of the society. The same practice was anticipated in 2016 Electoral Campaigns, but Donald Trump chose a different path. He focused more on anti-minority rhetoric with a particular focus on Muslims. Since the Muslim expats are the second-largest expat community after Jews, in the US, Trump's speeches were considered a direct insult. As a result, the Muslim community reacted vehemently towards such antics. The current study focuses on Muslim sentiments towards Trump's hate speeches. The medium explored is Twitter, where Muslims vent out their sentiments. In addition to the private accounts, the twitter accounts of Muslim representative organizations have been used. The research on the tweets has done through quantitative content analysis. The results reflect the substantial use of words against Trump's speech and his intended policies. The dominant emotions reflected in the tweets were anger, fear, and sadness. Some measures are also suggested after the research for conflict resolution of the effects of such speeches. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is ranked the third deadliest cancer worldwide whose molecular pathogenesis is not fully understood. Although deregulated metabolic pathways have been implicated in HCC onset and progression, the mechanisms triggering this metabolic imbalance are yet to be explored. Here, we identified a gene signature coding catabolic enzymes (Cat-GS) involved in key metabolic pathways like amino acid, lipid, carbohydrate, drug, and retinol metabolism as suppressed in HCC. A higher expression of deregulated Cat-GS is associated with good survival and less aggressive disease state in HCC patients. On the other hand, we identified mTOR signaling as a key determinant in HCC onset and progression, whose hyperactivation is found associated with poor survival and aggressive disease state in HCC patients. Next, out of Cat-GS, we established two key regulators of alcohol metabolism, alcohol dehydrogenase 1A (ADH1A) and aldehyde dehydrogenase 2 (ALDH2), as being transcriptionally suppressed by histone deacetylase 1 (HDAC1) at the downstream of mTORC1 signaling. Suppressed ADH1A and ALDH2 expression aligns well with HCC-specific molecular profile and can efficiently predict disease onset and progression, whereas higher ADH1A and ALDH2 expression is associated with good survival and less aggressive disease state in HCC patients. Overall, our in silico findings suggest that transcriptional suppression of alcohol metabolism regulators, ADH1A and ALDH2, at the downstream of mTOR signaling is, in part, responsible for triggering oncogenic transformation of hepatocytes resulting in disease onset and progression in HCC. [ABSTRACT FROM AUTHOR]

Systemic aging influences various physiological processes and contributes to structural and functional decline in cardiac tissue. These alterations include an increased incidence of left ventricular hypertrophy, a decline in left ventricular diastolic function, left atrial dilation, atrial fibrillation, myocardial fibrosis and cardiac amyloidosis, elevating susceptibility to chronic heart failure (HF) in the elderly. Age-related cardiac dysfunction stems from prolonged exposure to genomic, epigenetic, oxidative, autophagic, inflammatory and regenerative stresses, along with the accumulation of senescent cells. Concurrently, age-related structural and functional changes in the vascular system, attributed to endothelial dysfunction, arterial stiffness, impaired angiogenesis, oxidative stress and inflammation, impose additional strain on the heart. Dysregulated mechanosignalling and impaired nitric oxide signalling play critical roles in the age-related vascular dysfunction associated with HF. Metabolic aging drives intricate shifts in glucose and lipid metabolism, leading to insulin resistance, mitochondrial dysfunction and lipid accumulation within cardiomyocytes. These alterations contribute to cardiac hypertrophy, fibrosis and impaired contractility, ultimately propelling HF. Systemic low-grade chronic inflammation, in conjunction with the senescence-associated secretory phenotype, aggravates cardiac dysfunction with age by promoting immune cell infiltration into the myocardium, fostering HF. This is further exacerbated by age-related comorbidities like coronary artery disease (CAD), atherosclerosis, hypertension, obesity, diabetes and chronic kidney disease (CKD). CAD and atherosclerosis induce myocardial ischaemia and adverse remodelling, while hypertension contributes to cardiac hypertrophy and fibrosis. Obesity-associated insulin resistance, inflammation and dyslipidaemia create a profibrotic cardiac environment, whereas diabetes-related metabolic disturbances further impair cardiac function. CKD-related fluid overload, electrolyte imbalances and uraemic toxins exacerbate HF through systemic inflammation and neurohormonal renin-angiotensin-aldosterone system (RAAS) activation. Recognizing aging as a modifiable process has opened avenues to target systemic aging in HF through both lifestyle interventions and therapeutics. Exercise, known for its antioxidant effects, can partly reverse pathological cardiac remodelling in the elderly by countering processes linked to age-related chronic HF, such as mitochondrial dysfunction, inflammation, senescence and declining cardiomyocyte regeneration. Dietary interventions such as plant-based and ketogenic diets, caloric restriction and macronutrient supplementation are instrumental in maintaining energy balance, reducing adiposity and addressing micronutrient and macronutrient imbalances associated with age-related HF. Therapeutic advancements targeting systemic aging in HF are underway. Key approaches include senomorphics and senolytics to limit senescence, antioxidants targeting mitochondrial stress, anti-inflammatory drugs like interleukin (IL)-1β inhibitors, metabolic rejuvenators such as nicotinamide riboside, resveratrol and sirtuin (SIRT) activators and autophagy enhancers like metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors, all of which offer potential for preserving cardiac function and alleviating the age-related HF burden., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Vestibular schwannomas are rare intracranial tumors originating from Schwann cells of the vestibular nerve. Despite their benign nature, these tumors can exert significant mass effects and debilitating symptoms, including gradual hearing loss, vertigo, facial nerve dysfunction, and headaches. Current clinical management options encompass wait-and-scan, surgery, radiation therapy, and off-label medication. However, each approach exhibits its own challenges and harbors limitations that underscore the urgent need for therapeutic treatments. Over the past 2 decades, extensive elucidation of the molecular underpinnings of vestibular schwannomas has unraveled genetic anomalies, dysregulated signaling pathways, downstream of receptor tyrosine kinases, disrupted extracellular matrix, inflammatory tumor microenvironment, and altered cerebrospinal fluid composition as integral factors in driving the development and progression of the disease. Armed with this knowledge, novel therapeutic interventions tailored to the unique molecular characteristics of those conditions are actively being pursued. This review underscores the urgency of addressing the dearth of Food and Drug Administration-approved drugs for vestibular schwannoma, highlighting the key molecular discoveries and their potential translation into therapeutics. It provides an in-depth exploration of the evolving landscape of therapeutic development, which is currently advancing from bench to bedside. These ongoing efforts hold the promise of significantly transforming the lives of vestibular schwannoma patients in the future., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Aging is a chronic yet natural physiological decline of the body. Throughout life, humans are continuously exposed to a variety of exogenous and endogenous stresses, which engender various counteractive responses at the cellular, tissue, organ, as well as organismal levels. The compromised cellular and tissue functions that occur because of genetic factors or prolonged stress (or even the stress response) may accelerate aging. Over the last two decades, the sirtuin (SIRT) family of lysine deacylases has emerged as a key regulator of longevity in a variety of organisms. SIRT7, the most recently identified member of the SIRTs, maintains physiological homeostasis and provides protection against aging by functioning as a watchdog of genomic integrity, a dynamic sensor and modulator of stresses. SIRT7 decline disrupts metabolic homeostasis, accelerates aging, and increases the risk of age-related pathologies including cardiovascular and neurodegenerative diseases, pulmonary and renal disorders, inflammatory diseases, and cancer, etc. Here, we present SIRT7 as the seventh key to unlock the mystery of aging, and its specific manipulation holds great potential to ensure healthiness and longevity.

Low oxygen tension, or hypoxia is the driving force behind tumor aggressiveness, leading to therapy resistance, metastasis, and stemness in solid cancers including breast cancer, which now stands as the leading cause of cancer-related mortality in women. With the great advancements in exploring the regulatory roles of the non-coding genome in recent years, the wide spectrum of hypoxia-responsive genome is not limited to just protein-coding genes but also includes multiple types of non-coding RNAs, such as micro RNAs, long non-coding RNAs, and circular RNAs. Over the years, these hypoxia-responsive non-coding molecules have been greatly implicated in breast cancer. Hypoxia drives the expression of these non-coding RNAs as upstream modulators and downstream effectors of hypoxia inducible factor signaling in the favor of breast cancer through a myriad of molecular mechanisms. These non-coding RNAs then contribute in orchestrating aggressive hypoxic tumor environment and regulate cancer associated cellular processes such as proliferation, evasion of apoptotic death, extracellular matrix remodeling, angiogenesis, migration, invasion, epithelial-to-mesenchymal transition, metastasis, therapy resistance, stemness, and evasion of the immune system in breast cancer. In addition, the interplay between hypoxia-driven non-coding RNAs as well as feedback and feedforward loops between these ncRNAs and HIFs further contribute to breast cancer progression. Although the current clinical implications of hypoxia-driven non-coding RNAs are limited to prognostics and diagnostics in breast cancer, extensive explorations have established some of these hypoxia-driven non-coding RNAs as promising targets to treat aggressive breast cancers, and future scientific endeavors hold great promise in targeting hypoxia-driven ncRNAs at clinics to treat breast cancer and limit global cancer burden., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 H. Al-Zuaini, Rafiq Zahid, Xiao, Raza, Huang and Zeng.)

Neutrophils, the most copious leukocytes in human blood, play a critical role in tumorigenesis, cancer progression, and immune suppression. Recently, neutrophils have attracted the attention of researchers, immunologists, and oncologists because of their potential role in orchestrating immune evasion in human diseases including cancer, which has led to a hot debate redefining the contribution of neutrophils in tumor progression and immunity. To make this debate fruitful, this review seeks to provide a recent update about the contribution of neutrophils in immune suppression and tumor progression. Here, we first described the molecular pathways through which neutrophils aid in cancer progression and orchestrate immune suppression/evasion. Later, we summarized the underlying molecular mechanisms of neutrophil-mediated therapy resistance and highlighted various approaches through which neutrophil antagonism may heighten the efficacy of the immune checkpoint blockade therapy. Finally, we have highlighted several unsolved questions and hope that answering these questions will provide a new avenue toward immunotherapy revolution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zahid, Raza, Tumbath, Jiang, Xu and Huang.)

Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance. Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance. Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer ( n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis ( n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivo Conclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. Clin Cancer Res; 24(8); 1987-2001. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 ( AKR1B1 ) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro , mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFβ signature genes. Excess glucose was found to promote EMT through autocrine TGFβ stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target. Significance: A glucose-transforming pathway in TGFβ-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. Cancer Res; 78(7); 1604-18. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Tumor cells develop drug resistance which leads to recurrence and distant metastasis. MicroRNAs are key regulators of tumor pathogenesis; however, little is known whether they can sensitize cells and block metastasis simultaneously. Here, we report miR-644a as a novel inhibitor of both cell survival and EMT whereby acting as pleiotropic therapy-sensitizer in breast cancer. We showed that both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-Terminal Binding Protein 1 (CTBP1) whose knock-outs by the CRISPR-Cas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, downregulation of CTBP1 by miR-644a upregulates wild type- or mutant-p53 which acts as a 'molecular switch' between G1-arrest and apoptosis by inducing cyclin-dependent kinase inhibitor 1 (p21, CDKN1A, CIP1) or pro-apoptotic phorbol-12-myristate-13-acetate-induced protein 1 (Noxa, PMAIP1), respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR-644a or downregulation of CTBP1 was enough to shift this balance in favor of apoptosis through upregulation of Noxa. Notably, p53-mutant patients, but not p53-wild type ones, with high CTBP1 have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, re-activation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis., Competing Interests: The authors declare that they have no conflicts of interest.