For more than 50 years, investigators have considered a malignant stem cell as the potential origin of and a key therapeutic target for acute myeloid leukemia (AML) and other forms of cancer.1-4 The ...nature and existence of tumor-initiating cells for leukemia and other malignancies have long been the subject of intense and rigorous study; indeed, the promise of the potential to eradicate such cells is clear. However, until recently, deficiencies in our understanding of the nature of these cell populations, coupled with a limited ability to therapeutically exploit their weaknesses, have been limiting factors in realizing the goal of targeting leukemic stem cells (LSCs). Exciting new insights into the fundamental underpinnings of LSCs are now being made in an era in which drug development pipelines offer the potential to specifically target pathways of significance. Therefore, the focus in this new era, characterized by the confluence of understanding LSCs and the ability to target them, is shifting from “if it can be done” to “how it will be done.” Moving from a theoretical stage to this hopeful era of possibilities, new challenges expectedly arise, and our focus now must shift to determining the best strategy by which to target LSCs, with their well-documented heterogeneity and readily evident intra- and interpatient variability. The purpose of this review is therefore both to summarize the key scientific findings pertinent to AML LSC targeting and to consider methods of clinical evaluation that will be most effective for identifying successful LSC-directed therapies.
Distributed fiber-optic sensing technology coupled to existing subsea cables (dark fiber) allows observation of ocean and solid earth phenomena. We used an optical fiber from the cable supporting the ...Monterey Accelerated Research System during a 4-day maintenance period with a distributed acoustic sensing (DAS) instrument operating onshore, creating a ~10,000-component, 20-kilometer-long seismic array. Recordings of a minor earthquake wavefield identified multiple submarine fault zones. Ambient noise was dominated by shoaling ocean surface waves but also contained observations of in situ secondary microseism generation, post-low-tide bores, storm-induced sediment transport, infragravity waves, and breaking internal waves. DAS amplitudes in the microseism band tracked sea-state dynamics during a storm cycle in the northern Pacific. These observations highlight this method's potential for marine geophysics.
Summary
The number of novel therapies for the treatment of myeloma is rapidly increasing, as are the clinical trials evaluating them in combination with other novel and established therapies. ...Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are the most well known and studied classes of novel agents targeting myeloma, with histone deacetylase inhibitors, nuclear export inhibitors and several other approaches also being actively investigated. However, in parallel with the development and clinical use of these novel myeloma therapies is the emergence of novel mechanisms of resistance, many of which remain elusive, particularly for more recently developed agents. Whilst resistance mechanisms have been best studied for proteasome inhibitors, particularly bortezomib, class effects do not universally apply to all class members, and within‐class differences in efficacy, toxicity and resistance mechanisms have been observed. Although immunomodulatory agents share the common cellular target cereblon and thus resistance patterns relate to cereblon expression, the unique cell surface antigens to which monoclonal antibodies are directed means these agents frequently exhibit unique within‐class differences in clinical efficacy and resistance patterns. This review describes the major classes of novel therapies for myeloma, highlights the major clinical trials within each class and discusses known resistance mechanisms.
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•A comprehensive review of sea-level rise impacts on coastal aquifers is presented.•The main remaining challenges for future research opportunities are presented.•The need for an ...integrated assessment of controlling factors is identified.•Both analytical and numerical models are employed to investigate influential factors in an integrated framework.•Sensitivity assessment based on dimensionless parameters is implemented to scrutinize influential factors.
Sea-level rise (SLR) influences groundwater hydraulics and in particular seawater intrusion (SWI) in many coastal aquifers. The quantification of the combined and relative impacts of influential factors on SWI has not previously been considered in coastal aquifers. In the present study, a systematic review of the available literature on this topic is first provided. Then, the potential remaining challenges are scrutinized. Open questions on the effects of more realistic complexities such as gradual SLR, parameter uncertainties, and the associated influences in decision-making models are issues requiring further investigation.
We assess and quantify the seawater toe location under the impacts of SLR in combination with recharge rate variations, land-surface inundation (LSI) due to SLR, aquifer bed slope variation, and changing landward boundary conditions (LWBCs). This is the first study to include all of these factors in a single analysis framework. Both analytical and numerical models are used for these sensitivity assessments. It is demonstrated that (1) LSI caused by SLR has a significant incremental impact on the seawater toe location, especially in the flatter coasts and the flux-controlled (FC) LWBCs, however this impact is less than the reported orders of magnitude differences which were estimated using only analytical solutions; (2) LWBCs significantly influence the SLR impacts under almost all conditions considered in this study; (3) The main controlling factors of seawater toe location are the magnitudes of fresh groundwater discharge to sea and recharge rate. Regional freshwater flux entering from the landward boundary and the groundwater hydraulic gradient are the major contributors of fresh groundwater discharge to sea for both FC and head-controlled (HC) systems, respectively; (4) A larger response of the aquifer and larger seawater toe location changes are demonstrable for a larger ratio of the aquifer thickness to the aquifer length particularly in the HC systems; (5) The lowest sensitivity of seawater toe location is found for the density difference ratio of the seawater and freshwater, and also for the aquifer bed slope; (6) The early-time observations show seawater fingers below the inundated lands due to SLR which are diminished and ultimately extinguished; and (7) A less than 2% reversal effect on the seawater toe location after overshoot mechanism is observed in the transient simulations which suggests that this mechanism is an insignificant and impractical factor compared to other more significant factors.
Malignant stem cells have long been considered a key therapeutic target in leukemia. Therapeutic strategies designed to target the fundamental biology of leukemia stem cells while sparing normal ...hematopoietic cells may provide better outcomes for leukemia patients. One process in leukemia stem cell biology that has intriguing therapeutic potential is energy metabolism. In this article we discuss the metabolic properties of leukemia stem cells and how targeting energy metabolism may provide more effective therapeutic regimens for leukemia patients. In addition, we highlight the similarities and differences in energy metabolism between leukemia stem cells and malignant stem cells from solid tumors.
Cancer stem cells have unique metabolic biology that can in some instances be exploited for therapeutic intervention. This review summarizes the progress and challenges inherent to this field, including metabolic flexibility, inter and intra-patient heterogeneity, and commonalities and differences in energy metabolism between leukemia and solid tumors.
Over the last two decades, there has been a rapid increase of studies testing the efficacy and acceptability of virtual reality in the assessment and treatment of mental health problems. This ...systematic review was carried out to investigate the use of virtual reality in the assessment and the treatment of psychosis. Web of Science, PsychInfo, EMBASE, Scopus, ProQuest and PubMed databases were searched, resulting in the identification of 638 articles potentially eligible for inclusion; of these, 50 studies were included in the review. The main fields of research in virtual reality and psychosis are: safety and acceptability of the technology; neurocognitive evaluation; functional capacity and performance evaluation; assessment of paranoid ideation and auditory hallucinations; and interventions. The studies reviewed indicate that virtual reality offers a valuable method of assessing the presence of symptoms in ecologically valid environments, with the potential to facilitate learning new emotional and behavioural responses. Virtual reality is a promising method to be used in the assessment of neurocognitive deficits and the study of relevant clinical symptoms. Furthermore, preliminary findings suggest that it can be applied to the delivery of cognitive rehabilitation, social skills training interventions and virtual reality-assisted therapies for psychosis. The potential benefits for enhancing treatment are highlighted. Recommendations for future research include demonstrating generalisability to real-life settings, examining potential negative effects, larger sample sizes and long-term follow-up studies. The present review has been registered in the PROSPERO register: CDR 4201507776.
The investigation and study of cancer stem cells (CSCs) have received enormous attention over the past 5 to 10 years but remain topics of considerable controversy. Opinions about the validity of the ...CSC hypothesis, the biological properties of CSCs, and the relevance of CSCs to cancer therapy differ widely. In the following commentary, we discuss the nature of the debate, the parameters by which CSCs can or cannot be defined, and the identification of new potential therapeutic targets elucidated by considering cancer as a problem in stem cell biology.
Summary Background Lack of education and an economic dependence on men are often suggested as important risk factors for HIV infection in women. We assessed the efficacy of a cash transfer programme ...to reduce the risk of sexually transmitted infections in young women. Methods In this cluster randomised trial, never-married women aged 13–22 years were recruited from 176 enumeration areas in the Zomba district of Malawi and randomly assigned with computer-generated random numbers by enumeration area (1:1) to receive cash payments (intervention group) or nothing (control group). Intervention enumeration areas were further randomly assigned with computer-generated random numbers to conditional (school attendance required to receive payment) and unconditional (no requirements to receive payment) groups. Participants in both intervention groups were randomly assigned by a lottery to receive monthly payments ranging from US$1 to $5, while their parents were independently assigned with computer-generated random numbers to receive $4–10. Behavioural risk assessments were done at baseline and 12 months; serology was tested at 18 months. Participants were not masked to treatment status but counsellors doing the serologic testing were. The primary outcomes were prevalence of HIV and herpes simplex virus 2 (HSV-2) at 18 months and were assessed by intention-to-treat analyses. The trial is registered, number NCT01333826. Findings 88 enumeration areas were assigned to receive the intervention and 88 as controls. For the 1289 individuals enrolled in school at baseline with complete interview and biomarker data, weighted HIV prevalence at 18 month follow-up was 1·2% (seven of 490 participants) in the combined intervention group versus 3·0% (17 of 799 participants) in the control group (adjusted odds ratio OR 0·36, 95% CI 0·14–0·91); weighted HSV-2 prevalence was 0·7% (five of 488 participants) versus 3·0% (27 of 796 participants; adjusted OR 0·24, 0·09–0·65). In the intervention group, we noted no difference between conditional versus unconditional intervention groups for weighted HIV prevalence (3/235 1% vs 4/255 2%) or weighted HSV-2 prevalence (4/233 1% vs 1/255 <1%). For individuals who had already dropped out of school at baseline, we detected no significant difference between intervention and control groups for weighted HIV prevalence (23/210 10% vs 17/207 8%) or weighted HSV-2 prevalence (17/211 8% vs 17/208 8%). Interpretation Cash transfer programmes can reduce HIV and HSV-2 infections in adolescent schoolgirls in low-income settings. Structural interventions that do not directly target sexual behaviour change can be important components of HIV prevention strategies. Funding Global Development Network, Bill & Melinda Gates Foundation, National Bureau of Economic Research Africa Project, World Bank's Research Support Budget, and several World Bank trust funds (Gender Action Plan, Knowledge for Change Program, and Spanish Impact Evaluation fund).
Acute myelogenous leukemia is propagated by a subpopulation of leukemia stem cells (LSCs). In this article, we review both the intrinsic and extrinsic components that are known to influence the ...survival of human LSCs. The intrinsic factors encompass regulators of cell cycle and prosurvival pathways (such as nuclear factor kappa B NF-κB, AKT), pathways regulating oxidative stress, and specific molecular components promoting self-renewal. The extrinsic components are generated by the bone marrow microenvironment and include chemokine receptors (CXCR4), adhesion molecules (VLA-4 and CD44), and hypoxia-related proteins. New strategies that exploit potentially unique properties of the LSCs and their microenvironment are discussed.
Abstract Current approaches to RNA synthesis/manufacturing require substantial (and incomplete) purification post-synthesis. We have previously demonstrated the synthesis of RNA from a complex in ...which T7 RNA polymerase is tethered to promoter DNA. In the current work, we extend this approach to demonstrate an extremely stable system of functional co-tethered complex to a solid support. Using the system attached to magnetic beads, we carry out more than 20 rounds of synthesis using the initial polymerase-DNA construct. We further demonstrate the wide utility of this system in the synthesis of short RNA, a CRISPR guide RNA, and a protein-coding mRNA. In all cases, the generation of self-templated double stranded RNA (dsRNA) impurities are greatly reduced, by both the tethering itself and by the salt-tolerance that local co-tethering provides. Transfection of the mRNA into HEK293T cells shows a correlation between added salt in the transcription reaction (which inhibits RNA rebinding that generates RNA-templated extensions) and significantly increased expression and reduced innate immune stimulation by the mRNA reaction product. These results point in the direction of streamlined processes for synthesis/manufacturing of high-quality RNA of any length, and at greatly reduced costs.
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