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The direction of integrin signalling is found to be determined by the coordinated and opposing binding waves of talin and Gα 13 to the same region of the integrin β 3 cytoplasmic domain at mutually exclusive but distinct sites, and a potent new anti-thrombotic drug that does not cause bleeding is designed on the basis of these findings. A novel inhibitor of thrombosis Integrins are cell adhesion molecules that transmit signals in a bidirectional manner to mediate both inside-out and outside-in signalling. The cytoplasmic domain interacts with intracellular molecules such as the cytoskeletal proteins talin and Gα 13 . In this study, Xiaoping Du and colleagues demonstrate that the direction of signalling can be switched and transmitted by the coordinated and opposing binding waves of talin and Gα 13 to the same region of the integrin cytoplasmic domain with distinct recognition motifs. The authors also designed an inhibitor that selectively targets outside-in signalling, and this molecule inhibits thrombosis in vivo without causing bleeding as a side effect. Integrins have a critical role in thrombosis and haemostasis 1 . Antagonists of the platelet integrin α IIb β 3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding 2 , 3 . It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally 4 , 5 . Inside-out signalling activates integrins through a talin-dependent mechanism 6 , 7 . Integrin ligation mediates thrombus formation and outside-in signalling 8 , 9 , which requires Gα 13 and greatly expands thrombi. Here we show that Gα 13 and talin bind to mutually exclusive but distinct sites within the integrin β 3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Gα 13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Gα 13 –integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding.

Neuromorphic networks of artificial neurons and synapses can solve computationally hard problems with energy efficiencies unattainable for von Neumann architectures. For image processing, silicon neuromorphic processors outperform graphic processing units in energy efficiency by a large margin, but deliver much lower chip-scale throughput. The performance-efficiency dilemma for silicon processors may not be overcome by Moore’s law scaling of silicon transistors. Scalable and biomimetic active memristor neurons and passive memristor synapses form a self-sufficient basis for a transistorless neural network. However, previous demonstrations of memristor neurons only showed simple integrate-and-fire behaviors and did not reveal the rich dynamics and computational complexity of biological neurons. Here we report that neurons built with nanoscale vanadium dioxide active memristors possess all three classes of excitability and most of the known biological neuronal dynamics, and are intrinsically stochastic. With the favorable size and power scaling, there is a path toward an all-memristor neuromorphic cortical computer. The neuromorphic computing based on complementary metal-oxide-semiconductor transistors holds promise for artificial intelligence, but it suffers from the trade-off between scalability and biological fidelity. Yi et al. emulate 23 types of biological neuronal behaviors using scalable VO 2 active memristors.

Acute myeloid leukaemia (AML) carrying internal tandem duplication (ITD) of Fms-Like Tyrosine kinase 3 (FLT3) gene is associated with high risk of relapse and poor clinical outcome upon treatment with conventional chemotherapy. FLT3 inhibitors have been approved for the treatment of this AML subtype but leukaemia relapse remains to be a major cause of treatment failure. Mechanisms of drug resistance have been proposed, including evolution of resistant leukaemic clones; adaptive cellular mechanisms and a protective leukaemic microenvironment. These models have provided important leads that may inform design of clinical trials. Clinically, FLT3 inhibitors in combination with conventional chemotherapy as induction treatment for fit patients; with low-intensity treatment as salvage treatment or induction for unfit patients as well as maintenance treatment with FLT3 inhibitors post HSCT hold promise to improve survival in this AML subtype.

Smoking is the number one risk factor for cancer mortality but only 15–20% of heavy smokers develop lung cancer. It would, therefore, be of great benefit to identify those at high risk early on so that preventative measures can be initiated. To investigate this, we evaluated the effects of smoking on inflammatory markers, innate and adaptive immune responses to bacterial and viral challenges and blood cell composition. We found that plasma samples from 30 heavy smokers (16 men and 14 women) had significantly higher CRP, fibrinogen, IL-6 and CEA levels than 36 non-smoking controls. Whole blood samples from smokers, incubated for 7 h at 37 °C in the absence of any exogenous stimuli, secreted significantly higher levels of IL-8 and a number of other cytokines/chemokines than non-smokers. When challenged for 7 h with E. coli, whole blood samples from smokers secreted significantly lower levels of many inflammatory cytokines/chemokines. However, when stimulated with HSV-1, significantly higher levels of both PGE 2 and many cytokines/chemokines were secreted from smokers’ blood samples than from controls. In terms of blood cell composition, red blood cells, hematocrits, hemoglobin levels, MCV, MCH, MCHC, Pct and RDW levels were all elevated in smokers, in keeping with their compromised lung capacity. As well, total leukocytes were significantly higher, driven by increases in granulocytes and monocytes. In addition, smokers had lower NK cells and higher Tregs than controls, suggesting that smoking may reduce the ability to kill nascent tumor cells. Importantly, there was substantial person-to person variation amongst smokers with some showing markedly different values from controls and others showing normal levels of many parameters measured, indicating the former may be at significantly higher risk of developing lung cancer.

Abstract Lung cancer is the leading cause of cancer mortality worldwide, and at only 18%, it has one of the lowest 5-year survival rates of all malignancies. With its highly complex mutational landscape, treatment strategies against lung cancer have proved largely ineffective. However with the recent success of immunotherapy trials in lung cancer, there is renewed enthusiasm in targeting the immune component of tumors. Macrophages make up the majority of the immune infiltrate in tumors and are a key cell type linking inflammation and cancer. Although the mechanisms through which inflammation promotes cancer are not fully understood, two connected hypotheses have emerged: an intrinsic pathway, driven by genetic alterations that lead to neoplasia and inflammation, and an extrinsic pathway, driven by inflammatory conditions that increase cancer risk. Here, we discuss the contribution of macrophages to these pathways and subsequently their roles in established tumors. We highlight studies investigating the association of macrophages with lung cancer prognosis and discuss emerging therapeutic strategies for targeting macrophages in the tumor microenvironment.

The Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement on the treatment strategy for patients with intermediate-stage hepatocellular carcinoma (HCC) was established on August 31, 2019, in Sapporo, Hokkaido during the 10th Annual APPLE Meeting. This manuscript summarizes the international consensus statements developed at APPLE 2019. Transarterial chemoembolization (TACE) is the only guideline-recommended global standard of care for intermediate-stage HCC. However, not all patients benefit from TACE because intermediate-stage HCC is a heterogeneous disease in terms of tumor burden and liver function. Ten important clinical questions regarding this stage of HCC were raised, and consensus statements were generated based on high-quality evidence. In intermediate-stage HCC, preservation of liver function is as important as achieving a high objective response (OR) because the treatment goal is to prolong overall survival. Superselective conventional TACE (cTACE) is recommended as the first choice of treatment in patients eligible for effective (curative) TACE, whereas in patients who are not eligible, systemic therapy is recommended as the first choice of treatment. TACE is not indicated as the first-line therapy in TACE-unsuitable patients. Another important statement is that TACE should not be continued in patients who develop TACE failure/refractoriness in order to preserve liver function. Targeted therapy is the recommended first-line treatment for TACE-unsuitable patients. Especially, the drug, which can have higher OR rate, is preferred. Immunotherapy, transarterial radioembolization, TACE + targeted therapy or other modalities may be considered alternative options in TACE-unsuitable patients who are not candidates for targeted therapy. Better liver function, such as albumin-bilirubin grade 1, is an important factor for maximizing the therapeutic effect of systemic therapy.

Background: The pandemic of coronavirus disease 2019 (COVID-19) has diverted resources from healthcare services for patients with chronic medical illness such as cancer. COVID-19 also causes organ dysfunction, complicating cancer treatment. In most countries with an outbreak of COVID-19, modifications of cancer management have been adopted to accommodate the crisis and minimize the exposure of cancer patients to the infection. In countries where COVID-19 numbers are subsiding, medical teams should also be prepared to resume normal practices gradually. Here, we aim to review the literature on the impact of COVID-19 on patients with hepatocellular carcinoma (HCC) as well as discuss modifications to the management of HCC during and after recovery from the pandemic. Summary: Based on current data, 10–40% of patients with COVID-19 have hepatic injury characterized by an elevation of transaminases and/or hyperbilirubinemia. Multiple mechanisms contribute to the hepatic injury, including direct viral entry to hepatocytes/cholangiocytes, immune-mediated hepatitis, hypoxia, and drug-related hepatotoxicity. In patients with HCC, COVID-19 may exacerbate existing chronic liver disease and complicate the management of cancer. Cancer patients generally have a higher risk of infection and worse outcome, especially those who have recently undergone cancer treatment. Although HCC is under-represented in COVID-19 series, mitigation measures should be implemented to minimize the exposure of patients to the virus. A decision on the treatment of HCC should be balanced with consideration of the availability of medical resources, the level of infection risk of COVID-19, and the risk-benefit ratio of the individual patient. In areas where the COVID-19 outbreak is subsiding, clinicians should be prepared to manage a surge of HCC patients with higher disease burdens and complications. Key Messages: Mitigation measures to protect at-risk patients, such as those with cancers, from SARS-CoV-2 infection should be exercised and the impact of COVID-19 on this group of patients should be thoroughly studied.

Patients with COPD have increased peripheral airway resistance. In this study, increased peripheral airway resistance was strongly associated with a reduction in the number of terminal bronchioles rather than narrowing of airways. Direct measurement of the distribution of resistance in the lower respiratory tract has established that small airways (i.e., <2 mm in internal diameter) become the major sites of obstruction in patients with chronic obstructive pulmonary disease (COPD). 1 – 3 Resistance to flow through tubes is inversely related to the reduction in the radius raised to the fourth to fifth power. Since loss of half of such airways will only double the total peripheral resistance because of their parallel arrangement, 4 the increase in peripheral airway resistance by a factor of 4 to 40, as has been reported in patients with COPD, 1 is . . .

FLT3-ITD inhibitors are approved for acute myeloid leukemia (AML) treatment but relapse is common. In this study, the combined inhibition of FLT3 -ITD signal and protein translation by QUIZartinib and Omacetaxine Mepesuccinate (QUIZOM) synergistically suppressed the most critical FLT3 -ITD survival signals including mitochondrial respiration and proteostasis, which induced apoptosis and pro-inflammatory response. In a Phase 2 trial (NCT03135054) involving 40 chemo-refractory/unfit FLT3 -ITD AML patients, QUIZOM achieved a composite complete remission (CRc) of 83%, a median leukemia-free survival (LFS) of 10 months (Range: 0.7-68.2 months) and a median overall survival (OS) of 12.9 months (Range: 1.8-69.2 months). 13/33 (39%) received allogeneic HSCT after a median of 143 days (Range: 53-367 days). Higher CRc rates were observed in patients with NPM1 mutations, DNMT3A mutations, and wild-type WT1. Single-cell RNA-sequencing of QUIZOM cohort revealed positive correlation between pro-inflammatory response in blasts, CD8 + T activation and clinical responsiveness. Further, we identified a leukemic stem cell (LSC) subpopulation with activated JNK/JUN/HSPA1B axis via PLD1-driven phosphatidylcholine metabolism, which promoted proteostasis and drove QUIZOM resistance. PLD1-inhibitor remodeled phospholipid metabolism, induced ferroptosis and restored QUIZOM response in LSC. Our findings provided the therapeutic and resistant mechanisms of QUIZOM and paved the way for targeted interventions in this AML subtype. FLT3-ITD mutations drive relapse in acute myeloid leukemia (AML) despite targeted therapies. This group studies therapeutic potential and resistance mechanisms of FLT3-ITD inhibition with QUIZartinib and Omacetaxine Mepesuccinate (QUIZOM) in preclinical and clinical AML specimens.

Genome editing for therapeutic applications often requires cleavage within a narrow sequence window. Here, to enable such high-precision targeting with zinc-finger nucleases (ZFNs), we have developed an expanded set of architectures that collectively increase the configurational options available for design by a factor of 64. These new architectures feature the functional attachment of the FokI cleavage domain to the amino terminus of one or both zinc-finger proteins (ZFPs) in the ZFN dimer, as well as the option to skip bases between the target triplets of otherwise adjacent fingers in each zinc-finger array. Using our new architectures, we demonstrate targeting of an arbitrarily chosen 28 bp genomic locus at a density that approaches 1.0 (i.e., efficient ZFNs available for targeting almost every base step). We show that these new architectures may be used for targeting three loci of therapeutic significance with a high degree of precision, efficiency, and specificity. Genome editing often requires cleavage within a narrow sequence window. Here the authors develop an expanded set of zinc finger nuclease architectures that increase the available configurations by a factor of 64 and can target almost every base at loci of therapeutic significance.