Crystal healing – it's science!

The words "crystal" and "healing" in the same sentence do not, by and large, connote solid scientific ground for the approach being advocated. But there is an exception to every rule, and researchers at Ghent University have described Charcot-Leyden crystals (CLCs) as a targetable feature of some allergic diseases. CLCs are made up of the protein galectin-10. They are rare overall, but are a frequent feature in diseases driven by eosinophils, most notably asthma. The team showed that in a mouse model of asthma, crystallized galectin-10 in the airways stimulated both innate and adaptive immune responses, while the soluble form of the protein was inert. "Antibodies directed against key epitopes of the CLC crystallization interface dissolved preexisting CLCs in patient-derived mucus within hours and reversed crystal-driven inflammation, goblet-cell metaplasia, immunoglobulin E (IgE) synthesis, and bronchial hyperreactivity (BHR) in a humanized mouse model of asthma," the authors wrote. "Thus, protein crystals may promote hallmark features of asthma and are targetable by crystal-dissolving antibodies." They reported their results in the May 24, 2019, issue of Science.

Fruit fly avatars identify drug sensitivity

Scientists at the Mount Sinai School of Medicine have published proof of principle that drosophila fruit flies could be used to identify drug sensitivities in a KRAS-mutated colorectal tumor. "Avatars" modeling patient tumors, including mice and organoids, are being tested for their ability to predict useful drug combinations for specific tumors, so far with mixed success. The team hypothesized that fruit flies, where it is possible to "alter a large number of genes in a single tissue and screen a large number of drugs and drug combinations in a whole-animal setting with a simple readout for efficacy and toxicity," could be useful avatars. They created a drosophila avatar for a metastatic colorectal cancer patient that predicted sensitivity to a combination of zoledronate and trametinib. Treatment with the combination led to a progression-free interval of three months followed by a partial response for eight months in the patient. The authors wrote that their success, though temporary, "emphasizes the potential for moderately high-throughput screens that can be accomplished in a time frame that is useful for treating a patient. This approach may prove especially useful in tumors with challenging profiles, for example, KRAS-mutant tumor types." They reported their findings in the May 22, 2019, issue of Science Advances.

Flu virus makes bacteria stick around

Scientists at St. Jude Children's Research Hospital have shown that influenza virus particles directly interacted with multiple different bacterial species, increasing their adherence to lung epithelial cells and thus boosting their ability to cause infection. Viral infection increases the risk of developing bacterial pneumonia, and it is, in fact, bacterial pneumonia that is the ultimate cause of death in many flu patients. Multiple mechanisms contribute to that bacterial-viral synergy. In their study, the team demonstrated that influenza virus directly bound to both gram-positive and gram-negative bacteria. That binding increased bacterial adherence to epithelial cells in culture, and led to higher bacterial burden in animal models of co-infection. The authors concluded that "these observations support an additional mechanism of bacteria–influenza virus synergy at the earliest steps of pathogenesis." Their work appeared in the May 20, 2019, issue of Nature Microbiology.

Targeting cancer stem cell metabolism

Researchers at the Italian University of Switzerland's Institute of Oncology Research have demonstrated that the epigenetic chromatin reader BRD4 controlled mitochondrial fission in prostate cancer stem cells (CSCs). Stem cells, including CSCs, need to maintain a balance between self-renewal and differentiation, and targeting that balance could be a novel strategy for specifically targeting CSCs, which are unaffected by many traditional therapies. In their work, the team showed that BRD4 controlled the expression of mitochondrial fission factor (Mff), and that either inhibiting BRD4 or knocking down Mff induced exhaustion in prostate CSCs. The authors noted, "Interference with prostate CSC expansion and maintenance occurred in both [androgen receptor] AR-positive and -negative models and did not depend on the inhibition of AR signaling but on the disruption of mitochondrial homeostasis. Accordingly, our data partially challenge the current view of the mechanism of action" of inhibiting BRD4 and other proteins in the same class, and suggest that such inhibition "might be effective at multiple stages and in different clinical contexts" of prostate cancer, and possibly other cancers. They reported their findings in the May 23, 2019, issue of Cell Metabolism.

Glial dysfunction is part of chemo brain

Chemotherapy-related cognitive impairment (CRCI), colloquially known as "chemo brain," can be a long-term disability after cancer treatments. Research into CRCI has focused on neuronal dysfunction, but a Stanford University team has demonstrated that adaptive myelination also played a role in its development. In an animal model of CRCI, the chemotherapy methotrexate decreased the expression of brain-derived neurotrophic factor (BDNF) in the cerebral cortex, which impaired the ability of oligodendrocyte cells to form new myelin on neurons in response to neural activity. Reduced BDNF led to the loss of signaling protein TrkB in oligodendrocytes, and depleting microglia could restore BDNF expression, TrkB signaling and cognitive function in animals. "Modulation of microglial activation, and TrkB signaling each emerge as potential therapeutic strategies for those suffering long-term cognitive dysfunction following cancer chemotherapy," the authors wrote. Their work appeared in the May 20, 2019, issue of Neuron.

TLRs in DIO

Toll-like receptors (TLRs) are best known for their role as pathogen sensors and innate immune activators. Now, researchers at the University of Michigan have identified a role for TLR2 and TLR4 in beta cell proliferation in response to diet-induced obesity (DIO). Beta cells do not usually proliferate in adults, but they can do so in response to DIO and inducing such proliferation is a potential strategy for treating both type 1 and type 2 diabetes. The researchers showed that loss of both TLR2 and TLR4, but not of either one alone, increased the expression of the cell cycle regulators cyclin D2 and CDK4 and led to beta cell proliferation. "These data... suggest that selective targeting of the TLR2/TLR4 pathways may reverse beta cell failure in patients with diabetes," the authors wrote. They reported their results in the May 20, 2019, issue of Nature Immunology.

'R-AI-diologist' can outperform radiologists in lung cancer screening

Researchers from Google AI have developed an AI system that could perform at least as well as radiologists, and outperform them under some circumstances, in diagnosing lung cancer from low-dose computerized tomography (LDCT) screening images. LDCT screening reduces lung cancer rates by 20% to 40%, but the screening process has room to grow, with high rates of both false positives and false negatives. The Google team developed a deep learning algorithm to predict lung cancer based on 6,700 cases, and validated it with another 1,100 cases. The model was able to diagnose lung cancer risk with sensitivity and specificity that matched or exceeded that of each of six radiologists. The authors wrote their program "creates an opportunity to optimize the screening process via computer assistance and automation." They reported their results in the May 20, 2019, issue of Nature Medicine.

CD47 prevents gene therapy from being eaten

Scientists at the San Raffaele Telethon Institute for Gene Therapy have increased the efficacy of lentiviral gene therapy by protecting the vector from phagocytosis through increased expression of CD47. Optimizing the vectors used for delivery of the therapeutic payload is an ongoing concern for gene therapies with respect to both safety and efficacy. Adeno-associated viral (AAV) vectors have racked up a number of clinical successes, but the frequent pre-existing immunity to AAVs has been one of several challenges for that vector type. Lentiviral (LV) vectors have the potential to overcome that challenge but in preclinical experiments have been toxic at levels high enough for clinical efficacy in hemophilia. The scientists reasoned that protecting LV vectors from autophagy might increase their efficacy. LVs expressing the human phagocytosis inhibitor CD47 showed it protected LVs from "uptake by professional phagocytes and innate immune sensing, thus favoring biodistribution to hepatocytes after systemic administration," the authors reported. Nonhuman primates treated with CD47-expressing vectors showed "supraphysiological activity of human coagulation factor IX, the protein encoded by the transgene, without signs of toxicity or clonal expansion of transduced cells." The team reported its results in the May 22, 2019, issue of Science Translational Medicine.

In infection, T cells are cachexia drivers

Scientists at the Research Center for Molecular Medicine of the Austrian Academy of Sciences have reported that CD8 T cells induced cachexia during chronic viral infection. Cachexia, or wasting, can occur in chronic infections – AIDS was also known as "slim disease" in its early days because it induced cachexia – and is also a potentially fatal consequence of cancer. In their work, the team showed that infection-associated cachexia (IAC) occurred via at least partly separate mechanisms from cancer cachexia. Cancer cachexia is driven by cytokines, but those cytokines did not contribute to IAC. Instead, virus-specific CD8 T cells affected fat tissue and led to the depletion of lipid stores. "Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC)," the authors wrote. "Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8+ T cells in IAC." They reported their results in the May 20, 2019, issue of Nature Immunology.