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This paper provides a conceptual elaboration of the role of Problem-based Learning (PBL) in the integration of social sciences and humanities (SSH) with science, technology, engineering and mathematics (STEM), and an analysis of the challenges this brings about. SSH-STEM integration is an endeavor that is timely, relevant and urgent given the insufficient answers that higher education provides to the challenges social science and (especially) humanity faces. PBL can be argued as a pedagogical model to naturally cater to this demand. Based on two caseses of integrated study programs from Aalborg University, Denmark, we analyze and discuss challenges and potential pitfalls in integrating SSH and STEM. As a result, we pinpoint learnings that can serve as timely guides in future iterations of problem-based, inter- and transdisciplinary endeavors in higher education. This paper provides a conceptual elaboration of the role of Problem-based Learning (PBL) in the integration of social sciences and humanities (SSH) with science, technology, engineering, and mathematics (STEM), and an analysis of the challenges this brings about. SSH-STEM integration is an endeavor that is timely, relevant, and urgent given the insufficient answers that higher education provides to the challenges social science and (especially) humanity faces. PBL can be argued as a pedagogical model to naturally cater to this demand. Based on two cases of integrated study programs from Aalborg University, Denmark, we analyze and discuss challenges and potential pitfalls in integrating SSH and STEM. As a result, we pinpoint learnings that can serve as timely guides in future iterations of problem-based, inter- and transdisciplinary endeavors in higher education.

Highlights Addressing the complex political, economic, and societal challenges inherent in sustainable agriculture and food production requires interdisciplinary thinking and approaches. Relevant pedagogical models and extracurricular experiences can be provided by the Grand Challenges Scholars Program, now spread to nearly 100 universities globally. The complexities of agriculture and food production today can be addressed by future engineering leaders based on this program. Abstract. The education of engineers and other professionals to address the global grand challenge of sustainable food production will require much more than excellent technical skills. New mindsets, human-centered design principles, and collaborative leadership skills will be required to develop leaders who will be successful in addressing the complex political, economic, and societal challenges inherent in sustainable agriculture and food production today. This will require supplementing—not replacing—the technical core of engineering education with new pedagogical models and extracurricular experiences. One such model that has proven effective in this area and has spread to nearly 100 universities globally is the Grand Challenges Scholars Program. This article explains how the complexities of agriculture and food production today can be addressed by future engineering leaders based on this program. Keywords: Food chain, Sustainable agriculture.

There is increasing interest in measuring metals concentrations in human placentas to better understand physiology, disease, and toxic and diagnostic exposures. For these purposes, formalin-fixed paraffin embedded (FFPE) tissues obtained at clinical pathology examination represent a valuable potential store of well-characterized tissues for analysis. However, the limited data that exist comparing metal concentrations in FFPE tissue to recently collected frozen tissues paints a confusing picture, and there is no published data directly comparing frozen and FFPE placental villus tissues.Paired samples of fresh frozen and FFPE tissue from 22 rapidly processed human singleton placentae were weighed and digested using standard clean laboratory procedures and subsequently analyzed for a suite of 13 metals using a PerkinElmer DRC II ICP-MS. The analytical results were compared using either a paired t-test or a sign test depending on data normality.Concentrations of metals (aluminum (Al), arsenic (As), barium (Ba), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), gadolinium (Gd), mercury (Hg), manganese (Mn), lead (Pb), strontium (Sr), and zinc (Zn)) measured in both types of tissue preparations (frozen and FFPE) displayed a consistent range with other studies and did not display significantly different values from each of the paired specimens for any of the 13 specific metals analyzed.Within placentae, metals concentrations of measured trace, toxic and diagnostic elements (Al, As, Ba, Cd, Cr, Cu, Fe, Gd, Hg, Mn, Pb, Sr, and Zn) are consistent between FFPE and fresh placental villus tissue, without indications of systematic element loss or bias. FFPE from archived pathology specimens may offer an important and convenient alternative for measuring trace metals in human frozen placental tissues.

Deletion of pregnancy-associated plasma protein-A (PAPP-A), a protease that cleaves some but not all IGF1 binding proteins, postpones late-life diseases and extends lifespan in mice, but the mechanism of this effect is unknown. Here we show that PAPP-A knockout (PKO) mice display a set of changes, in multiple tissues, that are characteristic of other varieties of slow-aging mice with alterations in GH production or GH responsiveness, including Ames dwarf, Snell dwarf, and GHRKO mice. PKO mice have elevated UCP1 in brown and white adipose tissues (WAT), and a change in fat-associated macrophage subsets that leads to diminished production of inflammatory cytokines. PKO mice also show increased levels of muscle FNDC5 and its cleavage product, the myokine irisin, thought to cause changes in fat cell differentiation. PKO mice have elevated production of hepatic GPLD1 and plasma GPLD1, consistent with their elevation of hippocampal BDNF and DCX, used as indices of neurogenesis. In contrast, disruption of PAPP-A limited to muscle (“muPKO” mice) produces an unexpectedly complex set of changes, in most cases opposite in direction from those seen in PKO mice. These include declines in WAT UCP1, increases in inflammatory macrophages and cytokines in WAT, and a decline in muscle FNDC5 and plasma irisin. muPKO mice do, however, resemble global PKO mice in their elevation of hippocampal BDNF and DCX. The data for the PKO mice support the idea that these changes in fat, macrophages, liver, muscle, plasma, and brain are consistent and biologically significant features of the slow-aging phenotype in mice. The results on the muPKO mice provide a foundation for further investigation of the complex, local, and global circuits by which PAPP-A modulates signals ordinarily controlled by GH and/or IGF1. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00692-3.

In this article, the environmental sustainability of a circular economy concept applied to the management of biowaste was studied. To achieve this goal, the composting performance, compost-amended soil health, and phytotoxicity were assessed in the case of management of solid waste from a small swine slaughterhouse. Microorganisms present in a similar composting process were used as inoculums to improve the efficiency of composting. Addition of the inoculum promoted a faster and more efficient composting process than composting without the inoculum. The physical, chemical, and microbiological characteristics of soil were considered to be improved after compost application. Phytotoxicity tests in soils with and without compost amendment showed that a soil-compost mixture (90:10 and 70:30 mass ratios) was not phytotoxic to the plant species

Pharmacological treatments can extend the life span of mice. For optimal translation in humans, treatments should improve health during aging, and demonstrate efficacy when started later in life. Acarbose (ACA) and rapamycin (RAP) extend life span in mice when treatment is started early or later in life. Both drugs can also improve some indices of healthy aging, although there has been little systematic study of whether health benefits accrue differently depending on the age at which treatment is started. Here we compare the effects of early (4 months) versus late (16 months) onset ACA or RAP treatment on physical function and cardiac structure in genetically heterogeneous aged mice. ACA or RAP treatment improve rotarod acceleration and endurance capacity compared to controls, with effects that are largely similar in mice starting treatment from early or late in life. Compared to controls, cardiac hypertrophy is reduced by ACA or RAP in both sexes regardless of age at treatment onset. ACA has a greater effect on the cardiac lipidome than RAP, and the effects of early-life treatment are recapitulated by late-life treatment. These results indicate that late-life treatment with these drugs provide at least some of the benefits of life long treatment, although some of the benefits occur only in males, which could lead to sex differences in health outcomes later in life.

We sought to characterize if prehospital transfer origin from the scene of injury (SCENE) or from a referral emergency department (REF) alters the survival benefit attributable to prehospital plasma resuscitation in patients at risk of hemorrhagic shock.We performed a secondary analysis of data from a recently completed prehospital plasma clinical trial. All of the enrolled patients from either the SCENE or REF groups were included. The demographics, injury characteristics, shock severity and resuscitation needs were compared. The primary outcome was a 30-day mortality. Kaplan-Meier analysis and Cox-hazard regression were used to characterize the independent survival benefits of prehospital plasma for transport origin groups.Of the 501 enrolled patients, the REF group patients (n = 111) accounted for 22% with the remaining (n = 390) originating from the scene. The SCENE group patients had higher injury severity and were more likely intubated prehospital. The REF group patients had longer prehospital times and received greater prehospital crystalloid and blood products. Kaplan-Meier analysis revealed a significant 30-day survival benefit associated with prehospital plasma in the SCENE group (P.01) with no difference found in the REF group patients (P = .36). The Cox-regression verified after controlling for relevant confounders that prehospital plasma was independently associated with a 30-day survival in the SCENE group patients (hazard ratio 0.59; 95% confidence interval 0.39-0.89; P = .01) with no significant relationship found in the REF group patients (hazard ratio 1.03, 95% confidence interval 0.4-3.0).Important differences across the SCENE and REF cohorts exist that are essential to understand when planning prehospital studies. Prehospital plasma is associated with a survival benefit primarily in SCENE group patients. The results are exploratory but suggest transfer origin may be an important determinant of prehospital plasma benefit.

Canagliflozin (Cana), a clinically important anti-diabetes drug, leads to a 14% increase in median lifespan and a 9% increase in the 90th percentile age when given to genetically heterogeneous male mice from 7 months of age, but does not increase lifespan in female mice. A histopathological study was conducted on 22-month-old mice to see if Cana retarded diverse forms of age-dependent pathology. This agent was found to diminish incidence or severity, in male mice only, of cardiomyopathy, glomerulonephropathy, arteriosclerosis, hepatic microvesicular cytoplasmic vacuolation (lipidosis), and adrenal cortical neoplasms. Protection against atrophy of the exocrine pancreas was seen in both males and females. Thus, the extension of lifespan in Cana-treated male mice, which is likely to reflect host- or tumor-mediated delay in lethal neoplasms, is accompanied by parallel retardation of lesions, in multiple tissues, that seldom if ever lead to death in these mice. Canagliflozin thus can be considered a drug that acts to slow the aging process and should be evaluated for potential protective effects against many other late-life conditions.

The Systemic Clinical Outcome and Routine Evaluation version 15 (SCORE-15) is a measure used to assess family-level change in family therapy. The SCORE-15 has been demonstrated to be a reliable and valid measure, with high clinical utility; however, the SCORE-15 lacks the ability to determine whether the change in family functioning during the course of therapy is clinically significant. This study aimed to establish a reliable change index (RCI) and clinical cutoff score so that researchers and clinicians can determine clinically significant change in family therapy. US samples of 71 clinical participants and 244 community participants completed the SCORE-15. Results indicated a cutoff score of 40.37 and an RCI of 9.52. Consequently, family members who improve their SCORE-15 score during the course of therapy by at least 9 points and who cross the threshold of 40 during the course of therapy are considered to have experienced clinically significant change.

Scientific research that used animals as models for humans began in ancient Greece. Aristotle was the first researcher to use animals systematically for research purposes. Aristotle attributed feelings to animals but not reason, placing them below humans in importance. Aristotle’s approach became the dominant way of thinking about the use of animals in research. In the third century CE, Galen extended Aristotle’s experimental approach, writing numerous books about his studies. Galen described his extensive research program that included performing studies on many kinds of live animals including primates. Many of Galen’s experiments were extremely cruel. Interestingly, Galen never conducted studies on humans either alive or dead as this was considered unethical for much of antiquity. Galen’s thinking influenced many types of medicine: he used animal experimentation to devise models of the human cardiovascular system and many other important physiological systems. Galen became the most important influence in research for the next 1,300 years.

The chapter describes how and why universities abandoned their role as institutions that try to promote scientific truth and ethical behavior and how this has impacted the debate about the ethics of animal experimentation. The history of research funding and how it has accelerated since the Second World War is discussed. The chapter discusses the pressures on researchers to obtain funding and how this affects what they do. This has resulted in systemic problems in the quality of published data in the scientific literature. There has also been a lack of good mentors for training research students. The chapter discusses how the “scientists of the future” should be trained. There is a general lack of training in ethics for animal researchers, something that should be the responsibility of universities and pharmaceutical companies but is generally ignored. The chapter discusses how these situations can be improved in the future and welcoming the end of animal experimentation.

The author describes his thoughts while attending a lecture discussing experiments performed on a mouse into which investigators have inserted a large number of recording devices through which they can administer “aversive” stimuli and simultaneously monitor the animal’s brain activity and behavior. The experiments are scientifically interesting but objectively very cruel, although most members of the audience of professional scientists do not seem to see them that way. Why is this? The author starts to question the assumption that this kind of research really provides useful information that is relevant to humans. He also starts to think about whether there are better methods for answering questions about humans that don’t involve the abuse of animals, and concludes that such methods are now widely available and that animal experimentation is rapidly becoming obsolete as we enter a new era of biomedical research that is free of cruelty to animals.

What are the ethical and philosophical arguments for and against animal experimentation? Are there alternative approaches that might be considered today? In the nineteenth century Jeremy Bentham raised the issue that harm to animals should be considered as a reflection of whether they can suffer rather than whether they are rational. Utilitarian arguments have been widely used in modern critiques of animal experimentation. In this regard the absolute value of many scientific publications can be seen to be negligible and do not support utilitarian arguments. Other civilizations, such as those in India, have offered the concept of ahimsa or opposition to violence as an approach when considering animal experimentation. PETA and other groups have contributed to a widespread popular movement that opposes animal experimentation. The laws in different countries differ widely with respect to their views on animal protection. The “three Rs” are widely considered as a starting point to discussions of animal welfare.

If it would be scientifically more appropriate to use humans to investigate human disease, is there any way this could be done in an ethical manner? In the nineteenth century Ernst Haeckel coined the term “stem cell” to describe a type of cell from which all others are derived during embryonic development. This chapter discusses the history of stem cells and how they can be used to clone animals and animal tissues, including human tissues. There has been exceptionally rapid progress in producing cloned versions of human tissues that do not require producing intact humans. These preparations are known as organoids. Organoids can be made that represent any human tissue, and can be used as experimental models, the results of which are human specific. Together with other current techniques, including sequencing, imaging, and artificial intelligence, biomedical research is now moving toward a completely human-based set of paradigms, making animal models obsolete.

Are animals conscious beings? How do their conscious states compare to those of humans, and how does this impact their usefulness as experimental models? Recent research has demonstrated that animals such as mice use complex facial expressions and sounds to communicate. Animals also show complex behaviors involving empathy and planning. Animals are clearly conscious, but their experiences are unique to the species in question. Animals are not just incomplete versions of humans. The specific nature of animal consciousness, like that of another human being, is difficult for us to comprehend. Current research has demonstrated that conscious processes and physiological/pathological states constantly interact with one another. Hence, animal specific consciousness makes them poor models for many human diseases. This has resulted in very poor returns when using animals to model human diseases.

By the twentieth century science had become a widely practiced profession, and hundreds of millions of animals are now used every year for research purposes. Animals are used for conducting basic research and for testing purposes in the pharmaceutical industry. But how useful are these experiments? Do they generally provide results that help solve human-related problems? This chapter examines the types of animal models that are used in research today. In addition to very simple animals like worms and flies, mice are the most widely used animal for research purposes. How similar are mice to humans? Genetics tells us that they are 85% similar, but what does that mean in practice? Do experiments on mice accurately reflect human biology? In many instances scientists do not adequately consider this issue and mice and other animals fail to recapitulate humans, which makes their use problematic.

It is clear that humans have had close associations with animals, including pet keeping, which date back to antiquity. However, it wasn’t until the sixteenth century that the French philosopher Michel de Montaigne began to raise the issue as to the true nature of animal intelligence and the lack of human uniqueness. Subsequently, other writers such as Rousseau and Locke and artists such as Blake and Hogarth supported this idea. The first attempts to make cruelty to animals illegal took place in England at the start of the nineteenth century. Subsequently, the Royal Society for the Prevention of Cruelty to Animals and several antivivisection societies were formed. Opposition to scientific research in particular began with the Brown Dog affair, when activists infiltrated medical school classes and disclosed what they had seen. This was followed by a series of demonstrations and counterdemonstrations launching the animal welfare movement in its modern form.

Following Galen’s death and the fall of the Roman Empire, the works of great scientists such as Aristotle and Galen were preserved in the Arab empires for over a thousand years. In the seventeenth century Padua became the main center for modern research, attracting people like Andreas Vesalius and William Harvey, who began to conduct characteristically modern animal-based biomedical research programs. Harvey conducted a wide-ranging research program resulting in the discovery of mistakes in Galen’s work and a correct model for the circulation of the blood. Descartes theorized that animals were simply complex machines. Harvey’s experimental methods and Descartes’s thinking became the dominant influence on the development of science until the present day. Subsequently, many important researchers including Boyle, Galvani, and Bernard used vivisection extensively to carry out their important research programs. Many of these experiments were extremely cruel, but is such an approach still necessary today?

Chemokines such as stromal derived factor 1 and their G protein coupled receptors are well-known regulators of the development and functions of numerous tissues. C-X-C motif chemokine ligand 12 (CXCL12) has two receptors: C-X-C chemokine motif receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3). ACKR3 has been described as an atypical "biased" receptor because it does not appear to signal through G proteins and, instead, signals solely through the

Non-opioid targets are needed for addressing osteoarthritis pain, which is mechanical in nature and associated with daily activities such as walking and climbing stairs. Piezo2 has been implicated in the development of mechanical pain, but the mechanisms by which this occurs remain poorly understood, including the role of nociceptors. Here we show that nociceptor-specific Piezo2 conditional knock-out mice were protected from mechanical sensitization associated with inflammatory joint pain in female mice, joint pain associated with osteoarthritis in male mice, as well as both knee swelling and joint pain associated with repeated intra-articular injection of nerve growth factor in male mice. Single cell RNA sequencing of mouse lumbar dorsal root ganglia and in situ hybridization of mouse and human lumbar dorsal root ganglia revealed that a subset of nociceptors co-express Piezo2 and Ntrk1 (the gene that encodes the nerve growth factor receptor TrkA). These results suggest that nerve growth factor-mediated sensitization of joint nociceptors, which is critical for osteoarthritic pain, is also dependent on Piezo2, and targeting Piezo2 may represent a therapeutic option for osteoarthritis pain control.

Every year hundreds of millions of animals are used in the service of biomedical research, which costs taxpayers and the government billions of dollars. When these experiments are viewed objectively, there can be little doubt that the vast majority of them are extremely cruel to their animal subjects. What exactly are these experiments supposed to achieve from the scientific point of view, and in reality, how effective are they? Working scientists answer these questions by saying that their research is absolutely necessary if new therapies for human diseases are going to be developed. But is this really the case? Many people, including members of the general public and scholars in the humanities, have taken issue with the answers provided by science. Importantly, recent advances that employ new methodologies such as stem cell technology, genetic sequencing, and live human imaging have now rendered animal experimentation obsolete. This book describes how animal research began in antiquity as well as its subsequent historical and cultural development, what it is supposed to achieve, why it often fails, and what can expected in the future if we want to invent new therapies for human diseases. The book describes the rapidly developing field of stem cell research and the development of organoid systems that allow experiments to be performed on human tissues rather than animals, and how future scientists should be trained in the ethical appreciation of animal lives.

Adenosine signaling through A2A receptors (A2AR) expressed on immune cells suppresses antitumor immunity. CPI-444 is a potent, selective, oral A2AR antagonist. Blockade of A2AR with CPI-444 restored T-cell signaling, IL2, and IFNγ production that were suppressed by adenosine analogues in vitro. CPI-444 treatment led to dose-dependent inhibition of tumor growth in multiple syngeneic mouse tumor models. Concentrations of extracellular adenosine in the tumor microenvironment, measured using microdialysis, were approximately 100–150 nmol/L and were higher than corresponding subcutaneous tissue. Combining CPI-444 with anti–PD-L1 or anti–CTLA-4 treatment eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that incompletely responded to anti–PD-L1 or anti–CTLA-4 monotherapy. Tumor growth was fully inhibited when mice with cleared tumors were later rechallenged, indicating that CPI-444 induced systemic antitumor immune memory. CD8+ T-cell depletion abrogated the efficacy of CPI-444 with and without anti–PD-L1 treatment, demonstrating a role for CD8+ T cells in mediating primary and secondary immune responses. The antitumor efficacy of CPI-444 with and without anti–PD-L1 was associated with increased T-cell activation, a compensatory increase in CD73 expression, and induction of a Th1 gene expression signature consistent with immune activation. These results suggest a broad role for adenosine-mediated immunosuppression in tumors and justify the further evaluation of CPI-444 as a therapeutic agent in patients with solid tumors. Cancer Immunol Res; 6(10); 1136–49. ©2018 AACR.

Supplementary Data

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti–PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity.Significance:This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti–PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1

Supplemental Appendix

Purpose: Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium is a novel anticancer agent that targets redox-dependent pathways and enhances sensitivity of tumor cells to ionizing radiation.Experimental Design: We did preclinical studies examining motexafin gadolinium combined with rituximab and/or radiation in lymphoma cells. We subsequently completed a phase I clinical trial combining escalating doses of motexafin gadolinium concurrently with standard [90Y]ibritumomab tiuxetan for patients with relapsed/refractory non-Hodgkin's lymphoma.Results: In HF1 lymphoma cells, motexafin gadolinium and rituximab resulted in synergistic cytotoxicity (combination index, 0.757) through a mitochondrial-mediated caspase-dependent pathway, whereas cell death in Ramos and SUDHL4 cells was additive. Motexafin gadolinium/rituximab combined with radiation (1-3 Gy) resulted in additive apoptosis. Twenty-eight of 30 patients were evaluable on the phase I clinical trial. Median age was 65 years (47-87 years), and histologies were marginal-zone (n = 1), mantle-cell (n = 3), diffuse large cell (n = 6), and follicular lymphoma (n = 18). Of all patients, 86% were rituximab refractory. Therapy was well tolerated, and no dose-limiting toxicity was seen. Overall response rate was 57% [complete remission (CR), 43%], with median time–to–treatment failure of 10 months (1-48+ months) and median duration-of-response of 17 months. Of note, all responses were documented at 4 weeks. Furthermore, in rituximab-refractory follicular lymphoma (n = 14), overall response rate was 86% (CR, 64%), with a median time–to–treatment failure of 14 months (2-48+ months).Conclusions: This represents the first report of a novel agent to be combined safely concurrently with radioimmunotherapy. Furthermore, tumor responses with [90Y]ibritumomab tiuxetan/motexafin gadolinium were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma. (Clin Cancer Res 2009;15(20):6462–71)

Supplementary Data from The Novel Expanded Porphyrin, Motexafin Gadolinium, Combined with [90Y]Ibritumomab Tiuxetan for Relapsed/Refractory Non-Hodgkin's Lymphoma: Preclinical Findings and Results of a Phase I Trial

To gain a better understanding of the mechanism of action of the metal cation–containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling analyses were conducted on plateau phase human lung cancer (A549) cell cultures treated with MGd. Drug treatment elicited a highly specific response that manifested in elevated levels of metallothionein isoform and zinc transporter 1 (ZnT1) transcripts. A549 cultures incubated with MGd in the presence of exogenous zinc acetate displayed synergistic increases in the levels of intracellular free zinc, metallothionein transcripts, inhibition of thioredoxin reductase activity, and cell death. Similar effects were observed in PC3 prostate cancer and Ramos B-cell lymphoma cell lines. Intracellular free zinc levels increased in response to treatment with MGd in the absence of exogenous zinc, indicating that MGd can mobilize bound intracellular zinc. These findings lead us to suggest that an important component of the anticancer activity of MGd is related to its ability to disrupt zinc metabolism and alter cellular availability of zinc. This class of compounds may provide insight into the development of novel cancer drugs targeting control of intracellular free zinc and the roles that zinc and other metal cations play in biochemical pathways relevant to cancer.

Supplementary Methods from Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

PDF - 186K, Representative TUNEL assay images of RKO36 apoptotic cells.

Background Dual mobility components can be implanted during total hip arthroplasty (THA) for primary osteoarthritis via a direct anterior approach (DAA), anterolateral approach (ALA), direct lateral approach (DLA), or posterior/posterolateral approach (PLA). This review compares dual mobility hip dislocation rates using these approaches for elective primary THA. Methods PubMed, Embase, and Cochrane databases were systematically searched for articles published after January 1, 2006 that reported dislocation rates for adult patients after primary THA with dual mobility implants. Articles were excluded if they reported revision procedures, nonelective THA for femoral neck fractures, acetabular defects requiring supplemental implants, prior surgery, or ≤ 5 patients. The primary outcome was hip dislocation rate. Secondary outcomes included infection, Harris Hip Score (HHS), and Postel-Merle d’Aubigné (PMA) score. Results After screening 542 articles, 63 met inclusion criteria. Due to study heterogeneity, we did not perform a meta-analysis. Eight studies reported DAA, 5 reported ALA, 6 reported the DLA, and 56 reported PLA. Study size ranged from 41 to 2,601 patients. Mean follow-up time ranged from 6 months to 25 years. Rates of infection and dislocation were low; 80% of ALA, 87.5% of DAA, 100% of DLA, and 82.1% of PLA studies reported zero postoperative dislocations. Studies reporting postoperative HHS and PMA scores showed considerable improvement for all approaches. Conclusions Patients undergoing primary THA with dual mobility implants rarely experience postoperative dislocation, regardless of surgical approach. Additional studies directly comparing DAA, ALA, DLA, and PLA are needed to confirm these findings.