Abstract It is well‐known that goal‐directed hand movements can be adjusted to small changes in target location with a latency of about 100 ms. We tested whether people make similar fast adjustments when a target location for foot placement changes slightly as they walk over a flat surface. Participants walked at 3 km/h on a treadmill on which stepping stones were projected. The stones were 50 cm apart in the walking direction. Every 5–8 steps, a stepping stone was unexpectedly displaced by 2.5 cm...
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YAP activation mediates resistance to EGFR and MEK inhibition in EGFR-mutant cancer cells.
Tue Mar 03, 2020 10:05
Two glioma driver mutations in PIK3CA promote neuronal hyperactivity via distinct mechanisms.
Tue Mar 03, 2020 10:05
A VEGFC-expressing mRNA construct improved immunotherapy response in mouse models of glioblastoma.
Tue Mar 03, 2020 10:05
Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of glioma stem cells (GSC). Pan-cancer analyses have revealed that stemness of cancer cells correlates positively with immunosuppressive pathways in many solid tumors, including GBM, prompting us to conduct a gain-of-function screen of epigenetic regulators that may influence GSC self-renewal and tumor immunity. The circadian regulator CLOCK emerged as a top hit in enhancing stem-cell self-renewal, which was amplified in about...
Tue Mar 03, 2020 10:05
Algorithms matching the performance of expert pathologists in prostate cancer diagnosis were designed.
Tue Mar 03, 2020 10:05
Thomas J. Lynch Jr., MD; Kenneth C. Anderson, MD; and Riccardo Dalla-Favera, MD, are featured.
Tue Mar 03, 2020 10:05
A Menin–MLL interaction inhibitor eradicated preleukemic cells in acute myeloid leukemia models.
Tue Mar 03, 2020 10:05
In low-grade gliomas, mutant forms of IDH1/2 trigger expression of tau, a protein typically associated with neurodegenerative disease that also inhibits EGFR signaling to impede tumor progression. The new findings provide a scientific rationale for pharmacologically mimicking the function of tau with microtubule-stabilizing drugs for the treatment of brain tumors.
Tue Mar 03, 2020 10:05
Summary:The Von Hippel-Lindau gene product is a tumor suppressor whose ubiquitin ligase function is key to oxygen-sensing in cells, whereas Tank-binding kinase (TBK1) is a kinase mostly implicated in innate immune response. The study by Hu and colleagues in this issue reveals that VHL suppresses TBK1 activity under normoxic conditions, and that loss of VHL in kidney cancer cells renders them sensitive to TBK1 inhibition, providing a new potential target for the treatment of clear cell renal cell...
Tue Mar 03, 2020 10:05
In a study from the American Cancer Society, researchers report that the cancer mortality rate dropped by 29% between 1991 and 2017, a trend possibly explained by improved treatments and public-health initiatives to reduce smoking—but access to quality care and the lack of effective screening methods for some cancers remain hurdles.
Tue Mar 03, 2020 10:05
Acalabrutinib is a selective irreversible Bruton tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase Ib/II study (NCT02296918) of patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naïve and 26 relapsed/refractory patients...
Tue Mar 03, 2020 10:05
The FDA has approved tazemetostat for treating epithelioid sarcoma. The drug produced responses in 15% of patients with the disease in a phase II trial, and 67% of the responses lasted at least 6 months. The drug is the first targeted treatment for epithelioid sarcoma.
Tue Mar 03, 2020 10:05
TANK binding kinase 1 (TBK1) is an important kinase involved in the innate immune response. Here we discover that TBK1 is hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia in cancer cells. Tumors from patients with kidney cancer with VHL loss display elevated TBK1 phosphorylation. Loss of TBK1 via genetic ablation, pharmacologic inhibition, or a new cereblon-based proteolysis targeting chimera specifically inhibits VHL-deficient kidney cancer cell growth, while leaving VHL wild-type cells...
Tue Mar 03, 2020 10:05
The FDA approved avapritinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors with mutations in exon 18 of PDGFRA—genetic alterations that render tumors insensitive to all previously approved therapies for this rare sarcoma of the digestive tract.
Tue Mar 03, 2020 10:05
The structure of the chromatin-remodeling BAF complex provides molecular-scale mechanistic insight.
Tue Mar 03, 2020 10:05
Pembrolizumab with the oncolytic virus talimogene laherparepvec was effective in treating sarcomas.
Tue Mar 03, 2020 10:05
Olufunmilayo Olopade, MD, discusses her research on genomic sequencing and breast cancer, which has led to insights into how the disease progresses—and how it can be prevented. What's key, she says, is that one-size-fits-all screening shouldn't be recommended.
Tue Mar 03, 2020 10:05
KRASG12C-mutant cells treated with KRASG12C inhibitors quickly became either quiescent or resistant.
Tue Mar 03, 2020 10:05
Amgen recently made a $2.7 billion deal with the Chinese biotechnology company BeiGene in an effort expedite oncology drug development and expand its market into China. The deal also reflects a broader shift in drug development: There is increasing collaboration between U.S. and Chinese firms as China's biotech scene has rapidly expanded due to policy and regulatory changes.
Tue Mar 03, 2020 10:05
Summary:Although CD4+ FOXP3+ T regulatory (Treg) cells are well-known mediators of immunologic tolerance, their influences in the tumor microenviroment are incompletely understood. Writing in this issue of Cancer Discovery, Zhang and colleagues demonstrate that in pancreatic cancer, Treg cells promote the differentiation of tumor-restraining myofibroblastic cancer-associated fibroblasts, challenging the existing notion that Treg cells enable tumor progression. See related article by Zhang et al.,...
Tue Mar 03, 2020 10:05
A noninvasive test for methylated cell-free DNA markers identified colorectal cancer.
Tue Mar 03, 2020 10:05
Drugs targeting the cell cycle–regulatory cyclin-dependent kinase (CDK) 4 and 6 have been approved for the treatment of hormone receptor–positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Another class of CDKs, the transcription-associated CDKs, including CDK7, CDK8, CDK9, CDK12 and CDK13, are critical regulators of gene expression. Recent evidence suggests several novel functions of these CDKs, including regulation of epigenetic modifications,...
Tue Mar 03, 2020 10:05
Crizotinib showed efficacy in non-small cell lung cancer (NSCLC) with alterations in MET exon 14.
Tue Mar 03, 2020 10:05
Type I interferons (IFN), which activate many IFN-stimulated genes (ISG), are known to regulate tumorigenesis. However, little is known regarding how various ISGs coordinate with one another in developing antitumor effects. Here, we report that the ISG UBA7 is a tumor suppressor in breast cancer. UBA7 encodes an enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of another ISG (ISG15) to cellular proteins in a process known as "ISGylation." ISGylation of other ISGs,...
Tue Mar 03, 2020 10:05
Anti-CD19 CAR-T cells with human binding domains were safer in B-cell lymphoma in a phase I trial.
Tue Mar 03, 2020 10:05
Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype...
Tue Mar 03, 2020 10:05
Granule neuron precursors transdifferentiate into astrocytes in the tumor microenvironment.
Tue Mar 03, 2020 10:05
CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6–HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse CREBBP-mutant...
Tue Mar 03, 2020 10:05
ARID1A is required for response of ER+ breast cancer cells to tamoxifen and fulvestrant but not JQ1.
Tue Mar 03, 2020 10:05
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