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"Walz, Richard"
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A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor
Elizabeth Perlman and colleagues use genome-wide sequencing, RNA expression, DNA copy number and methylation analyses to characterize the genomic landscape of Wilms tumors. Their integrated analyses implicate two major classes of genetic changes in Wilms tumors that preserve the progenitor state and/or interrupt normal kidney development.
We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (
WT1
,
CTNNB1
,
AMER1
,
DROSHA
,
DGCR8
,
XPO5
,
DICER1
,
SIX1
,
SIX2
,
MLLT1
,
MYCN
, and
TP53
), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being
BCOR
,
BCORL1
,
NONO
,
MAX
,
COL6A3
,
ASXL1
,
MAP3K4
, and
ARID1A.
DNA copy number changes resulted in recurrent 1q gain,
MYCN
amplification,
LIN28B
gain, and
MIRLET7A
loss. Unexpected germline variants involved
PALB2
and
CHEK2.
Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.
Journal Article
The fly on the ceiling : a math reader
A story about how the very messy French philosopher, Renâe Descartes, invented an ingenious way to keep track of his possessions.
Book
Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.
The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.
G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005).
Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.
Journal Article
George Washington and the general's dog
Recounts events in the life of George Washington which focus on his fondness for animals.
BOOK
A mechanism of viral immune evasion revealed by cryo-EM analysis of the TAP transporter
The cryo-electron microscopy structure of human TAP transporter, a peptide transporter central to MHC class I antigen presentation and cellular immunity, in complex with the herpes simplex virus protein ICP47.
A viral immune evasion mechanism
Jue Chen and colleagues provide the first cryo-electron microscopy structure of the TAP transporter, a peptide transporter central to MHC class I antigen presentation and cellular immunity. The authors solve the structure of TAP in complex with the herpes virus protein ICP47, and reveal how the herpes virus protein plugs a long helical hairpin into the peptide translocation pathway of TAP, thereby blocking viral antigens from entering the endoplasmic reticulum and facilitating immune evasion.
Cellular immunity against viral infection and tumour cells depends on antigen presentation by major histocompatibility complex class I (MHC I) molecules. Intracellular antigenic peptides are transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP) and then loaded onto the nascent MHC I molecules, which are exported to the cell surface and present peptides to the immune system
1
. Cytotoxic T lymphocytes recognize non-self peptides and program the infected or malignant cells for apoptosis. Defects in TAP account for immunodeficiency and tumour development. To escape immune surveillance, some viruses have evolved strategies either to downregulate TAP expression or directly inhibit TAP activity. So far, neither the architecture of TAP nor the mechanism of viral inhibition has been elucidated at the structural level. Here we describe the cryo-electron microscopy structure of human TAP in complex with its inhibitor ICP47, a small protein produced by the herpes simplex virus I. Here we show that the 12 transmembrane helices and 2 cytosolic nucleotide-binding domains of the transporter adopt an inward-facing conformation with the two nucleotide-binding domains separated. The viral inhibitor ICP47 forms a long helical hairpin, which plugs the translocation pathway of TAP from the cytoplasmic side. Association of ICP47 precludes substrate binding and prevents nucleotide-binding domain closure necessary for ATP hydrolysis. This work illustrates a striking example of immune evasion by persistent viruses. By blocking viral antigens from entering the endoplasmic reticulum, herpes simplex virus is hidden from cytotoxic T lymphocytes, which may contribute to establishing a lifelong infection in the host.
Journal Article
Thomas Jefferson's feast
Tells of Thomas Jefferson's trip to France in 1784, and all the exotic foods he learned about and then introduced to America, including ice cream, macaroni and cheese, and tomatoes.
BOOK
Cryo-electron microscopy structure of the Slo2.2 Na+-activated K+ channel
Na
+
-activated K
+
channels are members of the Slo family of large conductance K
+
channels that are widely expressed in the brain, where their opening regulates neuronal excitability. These channels fulfil a number of biological roles and have intriguing biophysical properties, including conductance levels that are ten times those of most other K
+
channels and gating sensitivity to intracellular Na
+
. Here we present the structure of a complete Na
+
-activated K
+
channel, chicken Slo2.2, in the Na
+
-free state, determined by cryo-electron microscopy at a nominal resolution of 4.5 ångströms. The channel is composed of a large cytoplasmic gating ring, in which resides the Na
+
-binding site and a transmembrane domain that closely resembles voltage-gated K
+
channels. In the structure, the cytoplasmic domain adopts a closed conformation and the ion conduction pore is also closed. The structure reveals features that can explain the unusually high conductance of Slo channels and how contraction of the cytoplasmic gating ring closes the pore.
The structure of the full-length Slo2.2 Na
+
-activated K
+
channel is determined by cryo-electron microscopy, revealing features that explain the high conductance and gating mechanism of the Slo K
+
channel family.
Slo2.2 Na
+
-activated K
+
channel structure
The structure of the full-length Slo2.2 Na
+
-activated K
+
channel has been determined by cryo-electron microscopy, revealing features that explain the high conductance and gating mechanism of the Slo K
+
channel family. Slo2.2 is present in many neurons, where it acts as a negative feedback regulator of excitation through its sensitivity to Na
+
and its high K
+
conductance. Mutations in the gene encoding the Slo2.2 protein are linked to a number of intellectual disabilities and some types of epilepsy.
Journal Article
Phase I study evaluating the Fc-optimized FLT3 antibody FLYSYN in AML patients with measurable residual disease
Background
About half of AML patients achieving complete remission (CR) display measurable residual disease (MRD) and eventually relapse. FLYSYN is an Fc-optimized antibody for eradication of MRD directed to FLT3/CD135, which is abundantly expressed on AML cells.
Methods
This first-in-human, open-label, single-arm, multicenter trial included AML patients in CR with persisting or increasing MRD and evaluated safety/tolerability, pharmacokinetics and preliminary efficacy of FLYSYN at different dose levels administered intravenously (cohort 1–5: single dose of 0.5 mg/m
2
, 1.5 mg/m
2
, 5 mg/m
2
, 15 mg/m
2
, 45 mg/m
2
; cohort 6: 15 mg/m
2
on day 1, 15 and 29). Three patients were treated per cohort except for cohorts 4 and 6, which were expanded to nine and ten patients, respectively. Primary objective was safety, and secondary efficacy objective was ≥ 1 log MRD reduction or negativity in bone marrow.
Results
Overall, 31 patients were treated, of whom seven patients (22.6%) experienced a transient decrease in neutrophil count (two grade 3, others ≤ grade 2). No infusion-related reaction or dose-limiting toxicity was observed. Adverse events (AEs) were mostly mild to moderate, with the most frequent AEs being hematologic events and laboratory abnormalities. Response per predefined criteria was documented in 35% of patients, and two patients maintained MRD negativity until end of study. Application of 45 mg/m
2
FLYSYN as single or cumulative dose achieved objective responses in 46% of patients, whereas 28% responded at lower doses.
Conclusions
FLYSYN monotherapy is safe and well-tolerated in AML patients with MRD. Early efficacy data are promising and warrant further evaluation in an up-coming phase II trial.
Trial registration
This clinical is registered on clinicaltrials.gov (NCT02789254).
Journal Article
Advanced ultrasound in the diagnosis of prostate cancer
The diagnosis of prostate cancer (PCa) can be challenging due to the limited performance of current diagnostic tests, including PSA, digital rectal examination and transrectal conventional US. Multiparametric MRI has improved PCa diagnosis and is recommended prior to biopsy; however, mp-MRI does miss a substantial number of PCa. Advanced US modalities include transrectal prostate elastography and contrast-enhanced US, as well as improved B-mode, micro-US and micro-Doppler techniques. These techniques can be combined to define a novel US approach, multiparametric US (mp-US). Mp-US improves PCa diagnosis but is not sufficiently accurate to obviate the utility of mp-MRI. Mp-US using advanced techniques and mp-MRI provide complementary information which will become even more important in the era of focal therapy, where precise identification of PCa location is needed.
Journal Article