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O'Rourke's book offers a onestop shop for understanding foreignimposed regime change. Covert Regime Change is an impressive book and required reading for anyone interested in understanding hidden power in world politics. ― Political Science Quarterly States seldom resort to war to overthrow their adversaries. They are more likely to attempt to covertly change the opposing regime, by assassinating a foreign leader, sponsoring a coup d'état, meddling in a democratic election, or secretly aiding foreign dissident groups. In Covert Regime Change , Lindsey A. O'Rourke shows us how states really act when trying to overthrow another state. She argues that conventional focus on overt cases misses the basic causes of regime change. O'Rourke provides substantive evidence of types of security interests that drive states to intervene. Offensive operations aim to overthrow a current military rival or break up a rival alliance. Preventive operations seek to stop a state from taking certain actions, such as joining a rival alliance, that may make them a future security threat. Hegemonic operations try to maintain a hierarchical relationship between the intervening state and the target government. Despite the prevalence of covert attempts at regime change, most operations fail to remain covert and spark blowback in unanticipated ways. Covert Regime Change assembles an original dataset of all American regime change operations during the Cold War. This fund of information shows the United States was ten times more likely to try covert rather than overt regime change during the Cold War. Her dataset allows O'Rourke to address three foundational questions: What motivates states to attempt foreign regime change? Why do states prefer to conduct these operations covertly rather than overtly? How successful are such missions in achieving their foreign policy goals?

Cost-benefit is an important consideration for ( eradication in Japan, where 1.5 million patients were reported to receive first-line eradication annually. This study aimed to identify the optimal cost-saving triple therapy regimen for eradication in Japan. This retrospective observational study used data from a large-scale, nationwide health insurance claims database (2015‒2018). Using success rates of first-line eradication, mean total costs of first-line and second-line eradications per patient were compared between regimens including a potassium-competitive acid blocker (P-CAB) or a proton pump inhibitor (PPI), and between two clarithromycin (CAM) doses (400 and 800 mg/day). Subgroup analyses by smoking habit or body mass index (BMI) were performed. Among propensity score (age, gender, CAM dose, disease name)-matched patients (P-CAB regimen, n=22,002; PPI regimen, n=22,002), total costs were lower with the P-CAB than the PPI regimen (Japanese yen [JPY] 12,952 vs 13,146) owing to significantly higher first-line eradication rates with the P-CAB regimen (93.6% vs 79.7%; <0.001). For both regimens, even among current smokers or patients with BMI ≥25 kg/m , eradication rates did not differ by CAM dose, and total costs were approximately JPY1000 lower with CAM 400 mg/day than with CAM 800 mg/day. High success rate of first-line eradication contributes to saving in total eradication costs by reducing costs of subsequent therapy, irrespective of patients' smoking status or BMI class. The combination of more potent acid-inhibitory medicine and low-dose CAM may be the optimal regimen in terms of efficacy and cost-benefit in Japan.

Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase β-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.

Tuberculosis remains the world's leading cause of death from an infectious disease, responsible for an estimated 1 674 000 deaths annually. WHO estimated 600 000 cases of rifampicin-resistant tuberculosis in 2016—of which 490 000 were multidrug resistant (MDR), with less than 50% survival after receiving recommended treatment regimens. Concerted efforts of stakeholders, advocates, and researchers are advancing further development of shorter course, more effective, safer, and better tolerated treatment regimens. We review the developmental pipeline and landscape of new and repurposed tuberculosis drugs, treatment regimens, and host-directed therapies (HDTs) for drug-sensitive and drug-resistant tuberculosis. 14 candidate drugs for drug-susceptible, drug-resistant, and latent tuberculosis are in clinical stages of drug development; nine are novel in phase 1 and 2 trials, and three new drugs are in advanced stages of development for MDR tuberculosis. Specific updates are provided on clinical trials of bedaquiline, delamanid, pretomanid, and other licensed or repurposed drugs that are undergoing investigation, including trials aimed at shortening duration of tuberculosis treatment, improving treatment outcomes and patient adherence, and reducing toxic effects. Ongoing clinical trials for shortening tuberculosis treatment duration, improving treatment outcomes in MDR tuberculosis, and preventing disease in people with latent tuberculosis infection are reviewed. A range of HDTs and immune-based treatments are under investigation as adjunctive therapy for shortening duration of therapy, preventing permanent lung injury, and improving treatment outcomes of MDR tuberculosis. We discuss the HDT development pipeline, ongoing clinical trials, and translational research efforts for adjunct tuberculosis treatment.

Until recently, acute myeloid leukemia (AML) patients used to have limited treatment options, depending solely on cytarabine + anthracycline (7 + 3) intensive chemotherapy and hypomethylating agents. Allogeneic stem cell transplantation (Allo-SCT) played an important role to improve the survival of eligible AML patients in the past several decades. The exploration of the genomic and molecular landscape of AML, identification of mutations associated with the pathogenesis of AML, and the understanding of the mechanisms of resistance to treatment from excellent translational research helped to expand the treatment options of AML quickly in the past few years, resulting in noteworthy breakthroughs and FDA approvals of new therapeutic treatments in AML patients. Targeted therapies and combinations of different classes of therapeutic agents to overcome treatment resistance further expanded the treatment options and improved survival. Immunotherapy, including antibody-based treatment, inhibition of immune negative regulators, and possible CAR T cells might further expand the therapeutic armamentarium for AML. This review is intended to summarize the recent developments in the treatment of AML.

Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the host’s immune system becomes debilitated. The current front-line treatment regimen for drug-sensitive (DS) M. tb strains is a 6-month protocol involving four different drugs that requires stringent adherence to avoid relapse and resistance. Poverty, difficulty to access proper treatment, and lack of patient compliance contributed to the emergence of more sinister drug-resistant (DR) strains, which demand a longer duration of treatment with more toxic and more expensive drugs compared to the first-line regimen. Only three new drugs, bedaquiline (BDQ) and the two nitroimidazole derivatives delamanid (DLM) and pretomanid (PMD) were approved in the last decade for treatment of TB—the first anti-TB drugs with novel mode of actions to be introduced to the market in more than 50 years—reflecting the attrition rates in the development and approval of new anti-TB drugs. Herein, we will discuss the M. tb pathogenesis, current treatment protocols and challenges to the TB control efforts. This review also aims to highlight several small molecules that have recently been identified as promising preclinical and clinical anti-TB drug candidates that inhibit new protein targets in M. tb.

Cancer microenvironment is critical for tumorigenesis and cancer progression. The extracellular matrix (ECM) interacts with tumor and stromal cells to promote cancer cells proliferation, migration, invasion, angiogenesis and immune evasion. Both ECM itself and ECM stiffening-induced mechanical stimuli may activate cell membrane receptors and mechanosensors such as integrin, Piezo1 and TRPV4, thereby modulating the malignant phenotype of tumor and stromal cells. A better understanding of how ECM stiffness regulates tumor progression will contribute to the development of new therapeutics. The rapidly expanding evidence in this research area suggests that the regulators and effectors of ECM stiffness represent potential therapeutic targets for cancer. This review summarizes recent work on the regulation of ECM stiffness in cancer, the effects of ECM stiffness on tumor progression, cancer immunity and drug resistance. We also discuss the potential targets that may be druggable to intervene ECM stiffness and tumor progression. Based on these advances, future efforts can be made to develop more effective and safe drugs to interrupt ECM stiffness-induced oncogenic signaling, cancer progression and drug resistance.

Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives.

Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERβ), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.

Inhibiting cell survival and inducing cell death are the main approaches of tumor therapy. Autophagy plays an important role on intracellular metabolic homeostasis by eliminating dysfunctional or unnecessary proteins and damaged or aged cellular organelles to recycle their constituent metabolites that enable the maintenance of cell survival and genetic stability and even promotes the drug resistance, which severely limits the efficacy of chemotherapeutic drugs. Currently, targeting autophagy has a seemingly contradictory effect to suppress and promote tumor survival, which makes the effect of targeting autophagy on drug resistance more confusing and fuzzier. In the review, we summarize the regulation of autophagy by emerging ways, the action of targeting autophagy on drug resistance and some of the new therapeutic approaches to treat tumor drug resistance by interfering with autophagy-related pathways. The full-scale understanding of the tumor-associated signaling pathways and physiological functions of autophagy will hopefully open new possibilities for the treatment of tumor drug resistance and the improvement in clinical outcomes.