One-two Punch Research Articles

The one-two punch of plastic exposure: Macro- and micro-plastics induce multi-organ damage in seabirds.

Plastic pollution in the world's oceans is ubiquitous and increasing. The environment is inundated with microplastics (<1mm), and the health effects of these less conspicuous pollutants is poorly known. In addition, there is now evidence that macroplastics can release microplastics in the form of shedding or digestive fragmentation, meaning there is potential for macroplastic exposure to induce direct and indirect pathology through microplastics. Therefore, there is an urgent need for data from wild populations on the relationship between macro- and microplastic exposure and the potential compounding pathological effects of these forms of plastics. We investigated the presence and impact of microplastics in multiple tissues from Flesh-footed Shearwaters Ardenna carneipes, a species that ingests considerable quantities of plastics, and used histopathological techniques to measure physiological responses and inflammation from the plastics. All organs examined (kidney, spleen, proventriculus) had embedded microplastic particles and this correlated with macroplastic exposure. Considerable tissue damage was recorded, including a significant reduction in tubular glands and rugae in the proventriculus, and evidence of inflammation, fibrosis, and loss of organ structures in the kidney and spleen. This indicates macroplastics can induce damage directly at the site of exposure, while microplastics can be mobilised throughout the body causing widespread pathology. Collectively, these results indicate the scope and severity of the health impacts of plastic pollution may be grossly underestimated.

CFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis.

Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies; however, this remains challenging due to a lack of broadly acting senolytic drugs. Using CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify loss of the death receptor inhibitor cFLIP as a common vulnerability of senescent cancer cells. Senescent cells are primed for apoptotic death by NF-κB-mediated upregulation of death receptor 5 (DR5) and its ligand TRAIL, but are protected from death by increased cFLIP expression. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of a variety of senescent cancer cells. Moreover, senescent cells sensitize adjacent non-senescent cells to killing by DR5 agonist through a bystander effect mediated by secretion of cytokines. We validate this 'one-two punch' cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.

Targeting senescence as an anticancer therapy.

Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age-related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis. In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anticancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. "One-two punch" therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment. Future challenges of "one-two punch" approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy.

MYC inhibition reprograms tumor immune microenvironment by recruiting T lymphocytes and activating the CD40/CD40L system in osteosarcoma

The efficacy of immune checkpoint blockade (ICB) therapy depends on sufficient infiltration and activation of primed tumor-specific cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. However, many tumor types, including osteosarcoma, mainly display immune-desert or immune-excluded phenotypes, which are characterized by a lack of tumor-infiltrating lymphocytes and a poor response to ICB monotherapy. Thus, novel therapeutic strategies are urgently needed to surmount these obstacles. In this study, we found that the expression of the c-Myc oncogene is negatively correlated with the T cell infiltration rate in osteosarcoma. Pharmacological inhibition of c-Myc with JQ-1 significantly reduced tumor burden and improved overall survival in an immunocompetent syngeneic murine model of osteosarcoma (K7M2). A mechanistic study revealed that JQ-1 administration dramatically reprogrammed the tumor immune microenvironment (TIME) within K7M2 tumors. On the one hand, JQ-1 can promote T cell trafficking into tumors by increasing the expression and secretion of T cell-recruiting chemokines. On the other hand, JQ-1 is capable of facilitating crosstalk between antigen-presenting dendritic cells and T cells through the CD40/CD40L costimulatory pathway, leading to activation of tumor-specific CTLs. Combined treatment with anti-PD-1 antibody and JQ-1 resulted in more pronounced tumor regression than either monotherapy, showing an obvious synergistic effect. These findings uncover for the first time that c-Myc inhibition can promote T cell infiltration and activation in osteosarcoma in multiple ways, delivering a one-two punch for modulating TIME. The present work also provides the basis for establishing c-Myc inhibitor and ICB coadministration as a novel therapeutic regimen for patients with osteosarcoma.

Exploiting senescence for the treatment of cancer.

Senescence is a cellular response to a variety of stress signals that is characterized by a stable withdrawal from the cell cycle and major changes in cell morphology and physiology. While most research on senescence has been performed on non-cancer cells, it is evident that cancer cells can also mount a senescence response. In this Review, we discuss how senescence can be induced in cancer cells. We describe the distinctive features of senescent cancer cells and how these changes in cellular physiology might be exploited for the selective eradication of these cells (senolysis). We discuss activation of the host immune system as a particularly attractive way to clear senescent cancer cells. Finally, we consider the challenges and opportunities provided by a 'one-two punch' sequential treatment of cancer with pro-senescence therapy followed by senolytic therapy.

Senolysis-Based Elimination of Chemotherapy-Induced Senescent Breast Cancer Cells by Quercetin Derivative with Blocked Hydroxy Groups.

Simple SummaryCellular senescence may contribute to aging and age-related diseases, and the elimination of senescent cells is considered a promising anti-aging strategy. Drug-induced senescence in cancer cells during chemotherapy may also promote a number of adverse effects. Thus, in the present study, the usefulness of three quercetin derivatives as senolytic agents was studied upon stimulation of senescence program in breast cancer cells. We have shown that quercetin derivative with blocked hydroxy groups (QD3) sensitized etoposide-induced senescent breast cancer cells to apoptotic cell death that was accompanied by a decrease in proinflammatory and HSP70-based responses. We suggest that these prosenescent and senolytic activities can be combined to design a novel anti-cancer strategy, at least, against breast cancer cells.Drug-induced senescence program may be activated both in normal and cancer cells as a consequence of chemotherapeutic treatment, leading to some adverse side effects such as senescence-associated secretory phenotype (SASP), secondary senescence, and cancer promotion. Targeted elimination of senescent cells can be achieved by drugs with senolytic activity (senolytics), for example, the plant-derived natural compound quercetin, especially when co-treated with kinase inhibitor dasatinib. In the present study, three quercetin derivatives were synthesized and tested for improved senolytic action against etoposide-induced senescent human normal mammary epithelial cells and triple-negative breast cancer cells in vitro. Transformation of catechol moiety into diphenylmethylene ketal and addition of three acetyl groups to the quercetin molecule (QD3 derivative) promoted the clearance of senescent cancer cells as judged by increased apoptosis compared to etoposide-treated cells. A QD3-mediated senolytic effect was accompanied by decreased SA-beta galactosidase activity and the levels of p27, IL-1β, IL-8, and HSP70 in cancer cells. Similar effects were not observed in senescent normal cells. In conclusion, a novel senolytic agent QD3 was described as acting against etoposide-induced senescent breast cancer cells in vitro. Thus, a new one-two punch anti-cancer strategy based on combined action of a pro-senescence anti-cancer drug and a senolytic agent is proposed.

I, theorist: Accrediting the “wild imagination” of Northanger Abbey

Abstract Tracking the major narratological trends that give treatment to Jane Austen’s narrators in Northanger Abbey and Persuasion, this paper at once seeks to consolidate a narratorial voice as distinct from an authorial voice in each work while simultaneously collapsing each of these narratorial voices into storyworld characters via metalepsis. This one-two punch of consolidation and collapse allows me to argue for the emergence of a “tangled indeterminacy” in Northanger Abbey, a discovery that leads to two original possibilities: either a second narratorial voice emerges toward the end of the novel, or the initial narratorial voice bifurcates, such that a part of her is left behind in the diegesis while another part of her retreats to the narratorial plane. In either case, any attempt to attribute “the wild imagination” of Northanger Abbey to a specific narratorial persona must account for one or both of these readings.

Lessons of the Cold War

Lessons of the Cold War

The One-Two Punch: Utilising Community Prosecution and Victim-Centred Strategies to Successfully Prosecute Trafficking in Persons in Uganda

Since the passage of the Palermo Protocol in 2000, most states have increased their efforts to investigate and prosecute trafficking in persons. According to the annual Department of State Trafficking in Persons Report, Uganda currently ranks as a Tier 2 country, partly due to ongoing difficulties in investigating and prosecuting of trafficking in persons. This article suggests community prosecution in Uganda could improve trafficking in persons prosecutions. Community prosecution is a non-traditional method of prosecution that focuses on preventing crime before it happens. By combining community prosecution methods with other prosecutorial best practices, such as prosecutor-led investigations, multi-disciplinary teams, and a continuum of care, prosecutors in Uganda could better prevent trafficking in persons and serve victims through a trauma-informed approach. This article outlines relevant community prosecution practices, including the advantages and challenges, and then proposes several recommendations for how Ugandan prosecutors could implement community prosecution methods specifically to address trafficking in persons cases.

The one-two punch of giant congenital melanocytic nevus in a child

The one-two punch of giant congenital melanocytic nevus in a child

Vaccine Exemptions and the Risk of Continued Disease Outbreaks.

Vaccine Exemptions and the Risk of Continued Disease Outbreaks.

Survivin suppression heightens BZML-induced mitotic catastrophe to overcome multidrug resistance by removing therapy-induced senescent A549/Taxol cells

Mitotic catastrophe (MC) is a newly identified type of anticancer mechanism for multidrug resistance (MDR) prevention. However, the long cellular death process resulting from MC is not beneficial for anticancer treatment. BZML is a novel colchicine-binding site inhibitor which can overcome MDR by inducing MC; however, BZML-induced MC cells underwent a long cellular death process. Thus, to improve anticancer therapies based on drug-induced MC, BZML-induced MC was served as a model to further study the underlying molecular mechanisms in the process of MC. Here, BZML could induce p53-dependent senescence in A549/Taxol cells, a MDR cell line. This senescence was a secondary effect of MC in overcoming MDR. During MC, BZML-induced destruction of protein-degradation system contributed not only to an increase of p53 protein but also to the accumulation of survivin in nucleus of A549/Taxol cells. Importantly, the nuclear accumulation of survivin was not the inducer but the result of BZML-induced MC, and it promoted the survival of senescent cells. Moreover, it provided additional vulnerability and critical opportunities for sequentially applied therapies. Further, targeting survivin with YM155 accelerated the death of MC cells by timely eliminating therapy-induced senescent cells and strengthening the efficiency of BZML in overcoming MDR in A549/Taxol cells. Collectively, nuclear accumulation of survivin delayed cellular death during MC by promoting the survival of BZML-induced senescent A549/Taxol cells. Moreover, “one-two punch” approach to cancer treatment based on combination therapy with YM155 for survivin suppression might be a new strategy for potentiating MC to overcome MDR.

Making pointer analysis more precise by unleashing the power of selective context sensitivity

Traditional context-sensitive pointer analysis is hard to scale for large and complex Java programs. To address this issue, a series of selective context-sensitivity approaches have been proposed and exhibit promising results. In this work, we move one step further towards producing highly-precise pointer analyses for hard-to-analyze Java programs by presenting the Unity-Relay framework, which takes selective context sensitivity to the next level. Briefly, Unity-Relay is a one-two punch: given a set of different selective context-sensitivity approaches, say S = S1, . . . , Sn, Unity-Relay first provides a mechanism (called Unity)to combine and maximize the precision of all components of S. When Unity fails to scale, Unity-Relay offers a scheme (called Relay) to pass and accumulate the precision from one approach Si in S to the next, Si+1, leading to an analysis that is more precise than all approaches in S. As a proof-of-concept, we instantiate Unity-Relay into a tool called Baton and extensively evaluate it on a set of hard-to-analyze Java programs, using general precision metrics and popular clients. Compared with the state of the art, Baton achieves the best precision for all metrics and clients for all evaluated programs. The difference in precision is often dramatic — up to 71% of alias pairs reported by previously-best algorithms are found to be spurious and eliminated.

Hurricane Ida shows the one-two punch of poverty and climate change

Hurricane Ida shows the one-two punch of poverty and climate change

The Clinical Pause: An Augmented Approach to Simulation Debriefing in Nursing Education.

Debriefing after simulation, a form of reflection-on-action, is widely practiced in nursing education. A lesser used alternative is a faculty-facilitated clinical pause. During natural breaks within an unfolding simulation scenario, faculty incorporated Caputi's thinking skills to facilitate clinical reasoning, reflection-in-action, and timely feedback. The clinical pause enabled well-timed validation of correct thinking, resolution of erroneous thinking, and deliberate practice opportunities to construct contextual meaning. Written student comments, obtained after the simulation, suggest the clinical pause teaching innovation enhanced learning and clinical reasoning. Combining the clinical pause with end-of-simulation debriefing can provide a powerful one-two punch that maximizes clinical judgment.

The One-Two Punch of High Wages and Empowerment on CNA Retention

The objective of this study was to examine the relationship between high wages and empowerment practices on certified nursing assistant (CNA) retention, necessary for providing high-quality care for nursing home (NH) residents. Measures of provider-level CNA empowerment and wages from the 2015 Ohio Biennial Survey were used to estimate two regression models on retention (n = 719), one without and one with an interaction term of high wages and high empowerment. Only in the context of the interacted model were NHs that provided both high wages and high empowerment associated with a 7.09 percentage-point improvement in the CNA retention rate (p = .0003). Individually, high wages and a high empowerment score were not statistically significant in either regression model. Retaining CNAs in NH communities requires a combination of empowerment practices (e.g., involving CNAs in decision-making about hiring other staff) and high hourly wages.

One-two punch of techniques helps pin down the activated configuration of KcsA ion channel

Combining experiment and simulation to identify the activated state of a biologically important potassium channel.

Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy.

Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of “one-two punch” cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.

Asian Voices on the Future of US-Asia Relations: Trade and Economic Policy under the Biden Administration

President-elect Joseph Biden faces challenges both at home and abroad in the aftermath of the Trump administration. The COVID-19 pandemic has deeply affected the United States, with over 23.5 million reported cases by early 2021. Much like many nations under lockdown and reeling from supply disruptions and the chilling effect on demand, the US economy is forecasted to shrink in the near term. It is expected to contract by 4.3% in 2020, with a tentative rebound of 3.1% growth in 2021. The roll-out of vaccines in the US commenced in late 2020, and it is a welcome precursor of health and economic recovery, but the second stimulus package was delayed. Meanwhile, the Democrats managed to flip two Senate seats in Georgia, and thus maintain a slim control in both the Senate and the House of Representatives. Nevertheless, unprecedented political turmoil erupted in Washington, D.C. in early January, prior to the inauguration, signalling a difficult and noisy transition to the next administration. Abroad, the one-two punch of the pandemic and populist wave may continue to push many nations towards protectionism, even as multilateralism has been in retreat even before the pandemic. Part of the populist wave was driven by a push-back against globalization, owing to factors such as its un-equalizing impact as well as valid concerns over dominant lobbying by corporations and weak influence from the labor sector. In Asia, the Trump administration abandoned the Trans-Pacific Partnership Agreement while turning to protectionist rhetoric (and some tentative policies) against trading partners like China, Canada and Mexico. Most of these were short-lived as they amounted to more self-harm than any strategic benefits to the US or key segments of the population like its blue-collar workers. Meanwhile, the other TPP countries moved ahead and form the Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) even without the US.Meanwhile, China’s sphere of influence in Asia expanded, as the US withdrawal from its traditional leadership role in the multilateral and regional economic policy discussions was matched by a ratcheting of China’s ambitions to solidify its position as a political, economic and military power. The Regional Comprehensive Economic Partnership Agreement (RCEP) was finally signed in November 2020 producing the largest agglomeration of potential consumers (about 2.2 billion people) of any regional trade agreement conceived. And it is seen as the competing China-influenced framework vis-a-vis the TPP which intended as a centerpiece of the US pivot to Asia under President Obama. In addition, China’s ambitious infrastructure plan--the Belt and Road Initiative (BRI)--intended to fuel economic integration in the region while inter-connecting it with key markets in Europe and the Americas. Rather than channel all its resources into existing multilateral platforms, China has also advanced alternative financial institutions such as the Asian Infrastructure Investment Bank (AIIB) and the Silk Road Fund. China’s influence on “writing the rules” for regional economic integration has been increasing, yet it is not clear to what extent these new rules and institutions reflect existing norms in international cooperation.

One-Two Punch Therapy for the Treatment of T-Cell Malignancies Involving p53-Dependent Cellular Senescence.

T-cell malignancies are still difficult to treat due to a paucity of plans that target critical dependencies. Drug-induced cellular senescence provides a permanent cell cycle arrest during tumorigenesis and cancer development, particularly when combined with senolytics to promote apoptosis of senescent cells, which is an innovation for cancer therapy. Here, our research found that wogonin, a well-known natural flavonoid compound, not only had a potential to inhibit cell growth and proliferation but also induced cellular senescence in T-cell malignancies with nonlethal concentration. Transcription activity of senescence-suppression human telomerase reverse transcriptase (hTERT) and oncogenic C-MYC was suppressed in wogonin-induced senescent cells, resulting in the inhibition of telomerase activity. We also substantiated the occurrence of DNA damage during the wogonin-induced aging process. Results showed that wogonin increased the activity of senescence-associated β-galactosidase (SA-β-Gal) and activated the DNA damage response pathway mediated by p53. In addition, we found the upregulated expression of BCL-2 in senescent T-cell malignancies because of the antiapoptotic properties of senescent cells. Following up this result, we identified a BCL-2 inhibitor Navitoclax (ABT-263), which was highly effective in decreasing cell viability and inducing apoptotic cell death in wogonin-induced senescent cells. Thus, the “one-two punch” approach increased the sensibility of T-cell malignancies with low expression of BCL-2 to Navitoclax. In conclusion, our research revealed that wogonin possesses potential antitumor effects based on senescence induction, offering a better insight into the development of novel therapeutic methods for T-cell malignancies.