Research focused on the analysis and classification of breast tumors, primarily using DNA microarrays and patterns of gene expression, has resulted in distinct tumor subtypes. Although no knowledge ...of patient survival or outcomes was used to derive these gene descriptions, these different classes based upon patterns of gene expression have important prognostic implications. Predictive markers in estrogen receptor–negative and triple‐negative disease will be particularly important because in the absence of therapy, these tumor subtypes tend to have a poor prognosis. In addition, the claudin‐low subgroup has been found to be common within the triple‐negative cancers and may have further prognostic and therapeutic implications. Patients with triple‐negative breast cancer do benefit from chemotherapy, but better treatment options are needed that are less toxic, reduce the risk of disease progression, and are more targeted to this patient population. Potential treatments include poly (ADP‐ribose) polymerase inhibitors, and therapies that target cancer stem cells could also have an important impact in these patients. This article will focus on the molecular stratification of triple‐negative breast cancers and the therapeutic implications of these classifications.
This article focuses on the molecular stratification of triple‐negative breast cancers and the therapeutic implications of these classifications.
Contemporary medicinal chemistry faces diverse challenges from several directions, including the need for both potency and specificity of any therapeutic agent; the increasingly demanding ...requirements of low toxicity shown across all patients treated; and the need for novelty in intellectual property, given the extensive use of benzenoid and heteroaromatic ring systems in numerous patents. Increasingly, such challenges are being met by a shift to new and/or unusual ring systems (scaffolds) that lie outside the field of (hetero)aromatic systems. This critical review surveys a necessarily limited selection of currently atypical scaffolds, chiefly drawn from the literature of the last three years, that have found application in medicinal chemistry, some being present in agents with therapeutic potential while others are found in agents already in clinical use (163 references).
Reactions in which several components are combined in sequence, and without isolation of intermediates, are greatly sought because of the inherent molecular diversity, efficiency, and atom-economy. ...However, organocatalytic reactions, employing an organic catalyst to assemble products of high enantiomeric excess (a single optical isomer), are also cutting-edge methodology. This
tutorial review
covers the overlap of these two areas, outling the structural diversity and stereocontrol arising from one-pot combinations of at least three components, powerful approaches with great potential that minimise formation of by-products and operating costs.
Highly enantioselective reactions involving at least three components and which require an organocatalyst are described.
The classic view of sensorineural hearing loss (SNHL) is that the “primary” targets are hair cells, and that cochlear-nerve loss is “secondary” to hair cell degeneration. Our recent work in mouse and ...guinea pig has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of cochlear-nerve/hair-cell synapses. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained hidden for three reasons: 1) the spiral ganglion cells, the cochlear neural elements commonly assessed in studies of SNHL, survive for years despite loss of synaptic connection with hair cells, 2) the synaptic terminals of cochlear nerve fibers are unmyelinated and difficult to see in the light microscope, and 3) the degeneration is selective for cochlear-nerve fibers with high thresholds. Although not required for threshold detection in quiet (e.g. threshold audiometry or auditory brainstem response threshold), these high-threshold fibers are critical for hearing in noisy environments. Our research suggests that 1) primary neural degeneration is an important contributor to the perceptual handicap in SNHL, and 2) in cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from spiral ganglion neurons and re-establishment of their peripheral synapses.
This article is part of a Special Issue entitled <Auditory Synaptology>.
•Noise causing reversible threshold shifts causes permanent cochlear synaptopathy.•In age-related hearing loss, synaptopathy also precedes hair cell loss.•Synaptopathy is selective for high-threshold fibers.•Therefore synaptopathy likely causes problems hearing in noise.•Neurotrophin therapies may re-establish these peripheral synapses.
A series of recent discoveries harnessing the adaptive immune system of prokaryotes to perform targeted genome editing is having a transformative influence across the biological sciences. The ...discovery of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) proteins has expanded the applications of genetic research in thousands of laboratories across the globe and is redefining our approach to gene therapy. Traditional gene therapy has raised some concerns, as its reliance on viral vector delivery of therapeutic transgenes can cause both insertional oncogenesis and immunogenic toxicity. While viral vectors remain a key delivery vehicle, CRISPR technology provides a relatively simple and efficient alternative for site-specific gene editing, obliviating some concerns raised by traditional gene therapy. Although it has apparent advantages, CRISPR/Cas9 brings its own set of limitations which must be addressed for safe and efficient clinical translation. This review focuses on the evolution of gene therapy and the role of CRISPR in shifting the gene therapy paradigm. We review the emerging data of recent gene therapy trials and consider the best strategy to move forward with this powerful but still relatively new technology.
Interferon-stimulated gene (ISG) products take on a number of diverse roles. Collectively, they are highly effective at resisting and controlling pathogens. In this review, we begin by introducing ...interferon (IFN) and the JAK-STAT signaling pathway to highlight features that impact ISG production. Next, we describe ways in which ISGs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the JAK-STAT pathway. Several ISGs that directly inhibit virus infection are described with an emphasis on those that impact early and late stages of the virus life cycle. Finally, we describe ongoing efforts to identify and characterize antiviral ISGs, and we provide a forward-looking perspective on the ISG landscape.
Background Clinically relevant postoperative pancreatic fistulas (CR-POPF) are serious inherent risks of pancreatic resection. Preoperative CR-POPF risk assessment is currently inadequate and rarely ...disqualifies patients who need resection. The best evaluation of risk occurs intraoperatively, and should guide fistula prevention and response measures thereafter. We sought to develop a risk prediction tool for CR-POPF that features intraoperative assessment and reveals associated clinical and economic significance. Study Design Based on International Study Group of Pancreatic Fistula classification, recognized risk factors for CR-POPF (small duct, soft pancreas, high-risk pathology, excessive blood loss) were evaluated during pancreaticoduodenectomy. An optimal risk score range model, selected from 3 different constructs, was first derived (n = 233) and then validated prospectively (n = 212). Clinical and economic outcomes were evaluated across 4 ranges of scores (negligible risk, 0 points; low risk, 1 to 2; intermediate risk, 3 to 6; high risk, 7 to 10). Results Clinically relevant postoperative pancreatic fistulas occurred in 13% of patients. The incidence was greatest with excessive blood loss. Duct size <5 mm was associated with increased fistula rates that rose with even smaller ducts. These factors, together with soft pancreatic parenchyma and certain disease pathologies, afforded a highly predictive 10-point Fistula Risk Score. Risk scores strongly correlated with fistula development (p < 0.001). Notably, patients with scores of 0 points never developed a CR-POPF, while fistulas occurred in all patients with scores of 9 or 10. Other clinical and economic outcomes segregated by risk profile across the 4 risk strata. Conclusions A simple 10-point Fistula Risk Score derived during pancreaticoduodenectomy accurately predicts subsequent CR-POPF. It can be readily learned and broadly deployed. This prediction tool can help surgeons anticipate, identify, and manage this ominous complication from the outset.
Summary Insomnia is a major public health problem considering its high prevalence, impact on daily life, co-morbidity with other disorders and societal costs. Cognitive behavioral treatment for ...insomnia (CBTI) is currently considered to be the preferred treatment. However, no meta-analysis exists of all studies using at least one component of CBTI for insomnia, which also uses modern techniques to pool data and to analyze subgroups of patients. We included 87 randomized controlled trials, comparing 118 treatments (3724 patients) to non-treated controls (2579 patients). Overall, the interventions had significant effects on: insomnia severity index (ISI; g =0.98), sleep efficiency (SE; g =0.71), Pittsburgh sleep quality index (PSQI; g =0.65), wake after sleep onset (WASO; g=0.63) and sleep onset latency (SOL; g =0.57), number of awakenings (NWAK; g = 0.29) and sleep quality (SQ; g = 0.40). The smallest effect was on total sleep time (TST; g =0.16). Face-to-face treatments of at least 4 sessions seem to be more effective than self-help interventions or face-to-face interventions with fewer sessions. Otherwise the results seem to be quite robust (similar for patients with or without comorbid disease, younger or older patients, using or not using sleep medication). We conclude that CBTI, either its components or the full package, is effective in the treatment of insomnia.
Background
The US EPA considers glyphosate as “not likely to be carcinogenic to humans.” The International Agency for Research on Cancer (IARC) has classified glyphosate as “probably carcinogenic to ...humans (Group 2A).” EPA asserts that there is no convincing evidence that “glyphosate induces mutations in vivo via the oral route.” IARC concludes there is “strong evidence” that exposure to glyphosate is genotoxic through at least two mechanisms known to be associated with human carcinogens (DNA damage, oxidative stress). Why and how did EPA and IARC reach such different conclusions?
Results
A total of 52 genotoxicity assays done by registrants were cited by the EPA in its 2016 evaluation of technical glyphosate, and another 52 assays appeared in the public literature. Of these, one regulatory assay (2%) and 35 published assays (67%) reported positive evidence of a genotoxic response. In the case of formulated, glyphosate-based herbicides (GBHs), 43 regulatory assays were cited by EPA, plus 65 assays published in peer-reviewed journals. Of these, none of the regulatory, and 49 published assays (75%) reported evidence of a genotoxic response following exposure to a GBH. IARC considered a total of 118 genotoxicity assays in six core tables on glyphosate technical, GBHs, and aminomethylphosphonic acid (AMPA), glyphosate’s primary metabolite. EPA’s analysis encompassed 51 of these 118 assays (43%). In addition, IARC analyzed another 81 assays exploring other possible genotoxic mechanisms (mostly related to sex hormones and oxidative stress), of which 62 (77%) reported positive results. IARC placed considerable weight on three positive GBH studies in exposed human populations, whereas EPA placed little or no weight on them.
Conclusions
EPA and IARC reached diametrically opposed conclusions on glyphosate genotoxicity for three primary reasons: (1) in the core tables compiled by EPA and IARC, the EPA relied mostly on registrant-commissioned, unpublished regulatory studies, 99% of which were negative, while IARC relied mostly on peer-reviewed studies of which 70% were positive (83 of 118); (2) EPA’s evaluation was largely based on data from studies on technical glyphosate, whereas IARC’s review placed heavy weight on the results of formulated GBH and AMPA assays; (3) EPA’s evaluation was focused on typical, general population dietary exposures assuming legal, food-crop uses, and did not take into account, nor address generally higher occupational exposures and risks. IARC’s assessment encompassed data from typical dietary, occupational, and elevated exposure scenarios. More research is needed on real-world exposures to the chemicals within formulated GBHs and the biological fate and consequences of such exposures.
The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has ...challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a "hidden hearing loss" for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.
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