The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors

While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development

Escherichia coli O157:H7 in Feral Swine near Spinach Fields and Cattle, Central California Coast1

We investigated involvement of feral swine in contamination of agricultural fields and surface waterways with Escherichia coli O157:H7 after a nationwide outbreak traced to bagged spinach from California. Isolates from feral swine, cattle, surface water, sediment, and soil at 1 ranch were matched to the outbreak strain

Molecular Population Structure for Feral Swine in the United States

Feral swine (Sus scrofa) have invaded most of the United States and continue to expand throughout North America. Given the ecological and economic threats posed by increasing feral swine abundance, it is imperative to develop an understanding of their patterns of natural range expansion and human-mediated introductions. Towards this goal, we used molecular markers to elucidate the genetic structure of feral swine populations throughout the United States and evaluated the association between historical introductions and contemporary patterns of genetic organization. We used STRUCTURE and discriminant analysis of principal components (DAPC) to delineate genetic clusters for 959 individuals genotyped at 88 single nucleotide polymorphism loci. We identified 10 and 12 genetic clusters for the 2 clustering approaches, respectively. We observed strong agreement in clusters across approaches, with both describing clusters having strong geographic association at regional levels reflecting past introduction and range expansion patterns. In addition, we evaluated patterns of isolation by distance to test for and estimate spatial scaling of population structure within western, central, and eastern regions of North America. We found contrasting spatial patterns of genetic relatedness among regions, suggesting differences in the invasion process, likely as a result of regional variation in landscape heterogeneity and the influence of human mediated introductions. Our results indicate that molecular analyses of population genetic structure can provide reliable insights into the invasion processes of feral swine, thus providing a useful basis for management focused on minimizing continued range expansion by this problematic species

Fecal Methylmercury Correlates With Gut Microbiota Taxa in Pacific Walruses (Odobenus rosmarus divergens)

ObjectivesMethylmercury metabolism was investigated in Pacific walruses (Odobenus rosmarus divergens) from St. Lawrence Island, Alaska, United States.MethodsTotal mercury and methylmercury concentrations were measured in fecal samples and paired colon samples (n = 16 walruses). Gut microbiota composition and diversity were determined using 16S rRNA gene sequencing. Associations between fecal and colon mercury and the 24 most prevalent gut microbiota taxa were investigated using linear models.ResultsIn fecal samples, the median values for total mercury, methylmercury, and %methylmercury (of total mercury) were 200 ng/g, 4.7 ng/g, and 2.5%, respectively, while in colon samples, the median values for the same parameters were 28 ng/g, 7.8 ng/g, and 26%, respectively. In fecal samples, methylmercury was negatively correlated with one Bacteroides genus, while members of the Oscillospirales order were positively correlated with both methylmercury and %methylmercury (of total mercury). In colon samples, %methylmercury (of total mercury) was negatively correlated with members of two genera, Romboutsia and Paeniclostridium.ConclusionsMedian %methylmercury (of total mercury) was 10 times higher in the colon compared to the fecal samples, suggesting that methylmercury was able to pass through the colon into systemic circulation. Fecal total mercury and/or methylmercury concentrations in walruses were comparable to some human studies despite differences in seafood consumption rates, suggesting that walruses excreted less mercury. There are no members (at this time) of the Oscillospirales order which are known to contain the genes to methylate mercury, suggesting the source of methylmercury in the gut was from diet and not in vivo methylation

Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu[superscript 230], located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.Glenn Foundation for Medical ResearchEllison Medical FoundationJuvenile Diabetes Research Foundation InternationalUnited Mitochondrial Disease FoundationNational Institutes of Health (U.S.)National Institute of Allergy and Infectious Diseases (U.S.

'Gain with no pain’: anabolic-androgenic steroids trafficking in the UK

Anabolic-androgenic steroids are performance and image enhancing drugs (PIED) that can improve endurance and athletic performance, reduce body fat and stimulate muscle growth. The use of steroids has been studied extensively in the medical and psychological literature, as well as in the sociology of sport, health and masculinity. From the late 2000s, the worldwide trade in steroids increased significantly. However, trafficking in steroids remains a largely under-researched criminological phenomenon with a few notable exceptions. Currently in the UK there are only small and fragmented pieces of information available relating to steroids trafficking in autobiographical accounts of professional criminals. Drawing on original empirical data, the purpose of this article is to provide an account of the social organization of the steroids trafficking business in the UK. The trade in steroids is decentralized, highly flexible with no hierarchies, and open to anyone willing to either order the merchandise online or travel to producing countries and obtain steroids in bulk from legitimate manufacturers. The patterns of trafficking of this specific type of substance are patently conditioned by its embeddedness in the gym/bodybuilding scene and this greatly affects relations between actors in the business. In the steroids market, one typically encounters a multitude of individuals likely to drift between legality and illegality, online and offline, use and supply

Glycine Inhibitory Dysfunction Turns Touch into Pain through PKCgamma Interneurons

Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. During tactile allodynia, activation of the sensory fibers which normally detect touch elicits pain. Here we provide a new behavioral investigation into the dynamic component of tactile allodynia that developed in rats after segmental removal of glycine inhibition. Using in vivo electrophysiological recordings, we show that in this condition innocuous mechanical stimuli could activate superficial dorsal horn nociceptive specific neurons. These neurons do not normally respond to touch. We anatomically show that the activation was mediated through a local circuit involving neurons expressing the gamma isoform of protein kinase C (PKCγ). Selective inhibition of PKCγ as well as selective blockade of glutamate NMDA receptors in the superficial dorsal horn prevented both activation of the circuit and allodynia. Thus, our data demonstrates that a normally inactive circuit in the dorsal horn can be recruited to convert touch into pain. It also provides evidence that glycine inhibitory dysfunction gates tactile input to nociceptive specific neurons through PKCγ-dependent activation of a local, excitatory, NMDA receptor-dependent, circuit. As a consequence of these findings, we suggest that pharmacological inhibition of PKCγ might provide a new tool for alleviating allodynia in the clinical setting

Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol

Severe acute respiratory syndrome coronavirus 2 (SARS- CoV- 2), the virus responsible for coronavirus disease 2019 (COVID- 19), is associated with high incidence of multiorgan dysfunction and death. Angiotensin- converting enzyme 2 (ACE2), which facilitates SARS- CoV- 2 host cell entry, may be impacted by angiotensin- converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two commonly used antihypertensive classes. In a multicenter, international randomized controlled trial that began enrollment on March 31, 2020, participants are randomized to continuation vs withdrawal of their long- term outpatient ACEI or ARB upon hospitalization with COVID- 19. The primary outcome is a hierarchical global rank score incorporating time to death, duration of mechanical ventilation, duration of renal replacement or vasopressor therapy, and multiorgan dysfunction severity. Approval for the study has been obtained from the Institutional Review Board of each participating institution, and all participants will provide informed consent. A data safety monitoring board has been assembled to provide independent oversight of the project.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163400/2/jch14011_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163400/1/jch14011.pd

Effects of Sacubitril-Valsartan, versus Valsartan, in Women Compared to Men with Heart Failure and Preserved Ejection Fraction: Insights from PARAGON-HF

Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction (HFpEF), the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women, compared with men. In a pre-specified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial which compared sacubitril-valsartan and valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older, had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI 0.59-0.90) in women and 1.03 (0.84-1.25) in men; P interaction=0.017. The benefit from sacubitril-valsartan was due to reduction in heart failure hospitalization. The improvement in NYHA class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in KCCQ-CSS was less in women than in men. The difference in adverse events, between sacubitril-valsartan and valsartan, was similar in women and men. As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. While the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. URL: https://clinicaltrials.gov Unique Identifier: NCT01920711