Proteogenomic Characterization of Endometrial Carcinoma.

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/ß-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.

Oncogenic Signaling Pathways in The Cancer Genome Atlas.

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFß signaling, p53 and ß-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.

Comprehensive Characterization of Cancer Driver Genes and Mutations.

Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.

Unified rhombic lip origins of group 3 and group 4 medulloblastoma.

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial1. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins2. However, the anatomical and cellular complexity of developing human tissues3-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.

Outcomes in patients with ETV6::RUNX1 or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies.

Children with ETV6::RUNX1 or high-hyperdiploid B-acute lymphoblastic leukemia (B-ALL) have favorable outcomes. The St. Jude (SJ) classification considers these patients low-risk, regardless of their National Cancer Institute (NCI) risk, except when there is slow minimal residual disease (MRD) response or central nervous system/testicular involvement. We analyzed outcomes in children (aged 1-18.99 years) with these genotypes in the SJ Total XV and XVI studies (2000-2017). Patients with ETV6::RUNX1 (n = 222) or high-hyperdiploid (n = 296) B-ALL had 5-year event-free survival (EFS) of 97.7% ± 1.1% and 94.7% ± 1.4%, respectively. For ETV6::RUNX1, EFS was comparable for NCI standard-risk and high-risk patients (97.8% ± 1.2% and 97.5% ± 2.6%, respectively; P = 0.917) and for SJ low-risk and standard-risk patients (97.4% ± 1.2% and 100.0%; P = 0.360). Thirty-seven of 40 NCI high-risk patients who received SJ low-risk therapy had excellent EFS (97.3% ± 2.8%). For high-hyperdiploid B-ALL, EFS was worse for NCI high-risk patients than for standard-risk patients (87.6% ± 4.5% and 96.4% ± 1.3%; P = 0.016). EFS was similar for NCI standard-risk and high-risk patients classified as SJ low-risk (96.0% ± 1.5% and 96.9% ± 3.2%; P = 0.719); however, EFS was worse for NCI high-risk patients than for NCI standard-risk patients receiving SJ standard/high-risk therapy (77.4% ± 8.2% and 98.0% ± 2.2%; P = 0.004). NCI high-risk patients with ETV6::RUNX1 or high-hyperdiploid B-ALL who received SJ low-risk therapy had lower incidences of thrombosis (P = 0.013) and pancreatitis (P = 0.011) than those who received SJ standard/high-risk therapy. Contemporary MRD-directed therapy yielded excellent outcomes, except for NCI high-risk high-hyperdiploid B-ALL patients with slow MRD response, who require new treatment approaches. Among NCI high-risk patients, 93% with ETV6::RUNX1 and 54% with high-hyperdiploid B-ALL experienced excellent outcomes with a low-intensity regimen. These trials were registered at www.clinicaltrials.gov as #NCT00137111 and #NCT00549848.

The orally bioavailable GSPT1/2 degrader SJ6986 exhibits in vivo efficacy in acute lymphoblastic leukemia.

Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells, sparing normal hematopoietic tissue. Molecular glues direct the ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel cereblon modulator, SJ6986, that exhibits potent and selective degradation of GSPT1 and GSPT2 and cytotoxic activity against childhood cancer cell lines. Here, we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome-wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed that components of the CRL4CRBN complex, associated adaptors, regulators, and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.

The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21-ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia.

Transcriptome sequencing has identified multiple subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL) of prognostic significance, but a minority of cases lack a known genetic driver. Here, we used integrated whole-genome (WGS) and -transcriptome sequencing (RNA-seq), enhancer mapping, and chromatin topology analysis to identify previously unrecognized genomic drivers in B-ALL. Newly diagnosed (n = 3221) and relapsed (n = 177) B-ALL cases with tumor RNA-seq were studied. WGS was performed to detect mutations, structural variants, and copy number alterations. Integrated analysis of histone 3 lysine 27 acetylation and chromatin looping was performed using HiChIP. We identified a subset of 17 newly diagnosed and 5 relapsed B-ALL cases with a distinct gene expression profile and 2 universal and unique genomic alterations resulting from aberrant recombination-activating gene activation: a focal deletion downstream of PAN3 at 13q12.2 resulting in CDX2 deregulation by the PAN3 enhancer and a focal deletion of exons 18-21 of UBTF at 17q21.31 resulting in a chimeric fusion, UBTF::ATXN7L3. A subset of cases also had rearrangement and increased expression of the PAX5 gene, which is otherwise uncommon in B-ALL. Patients were more commonly female and young adult with median age 35 (range,12-70 years). The immunophenotype was characterized by CD10 negativity and immunoglobulin M positivity. Among 16 patients with known clinical response, 9 (56.3%) had high-risk features including relapse (n = 4) or minimal residual disease >1% at the end of remission induction (n = 5). CDX2-deregulated, UBTF::ATXN7L3 rearranged (CDX2/UBTF) B-ALL is a high-risk subtype of leukemia in young adults for which novel therapeutic approaches are required.

All-fiber hectowatt radially polarized laser system.

A high-power all-fiber radially polarized laser system is demonstrated, in which an integrated nanograting mode convertor (S-wave plate) is used for the generation of radially polarized beam. Experimentally, a 1-W radially polarized beam was used as the seed laser, whose mode purity and mode extinction ratio (MER) were 96.5% and 98.3%, respectively. A single-stage few-mode fiber amplifier was employed to boost the 1-W seed laser to an average power of 113.2 W, when the pump power was 160 W. The corresponding slope efficiency and beam quality factor (M2) were approximately 72% and 2.3%, respectively. Moreover, the mode purity and MER of the amplified radially polarized laser were measured to be 95.7% and 97%, respectively. To the best of our knowledge, this is the highest output power from an all-fiber radially polarized laser system without obvious degradations of the mode purity and MER.

Investigations of a 1018 nm gain-switched Yb-doped fiber oscillator.

In this paper, we investigate a 1018 nm gain-switched ytterbium-doped fiber oscillator at a low repetition rate in terms of theory and experiment. Theoretically, a numerical model applicable to a 1018 nm gain-switched ytterbium-doped fiber laser was established. The influence of the pump peak power and active fiber lengths on the 1018 nm gain-switched ytterbium-doped fiber laser was numerically simulated. Experimentally, a compact 1018 nm all-fiber-structured pulsed laser oscillator is constructed, in which a pulse width of 110 ns and a single-pulse energy of 0.1 mJ were obtained. Moreover, the experimental results are in agreement with the numerical simulation ones. To the best of our knowledge, this is the first time that gain-switching technology has been applied to 1018 nm fiber lasers to generate nanosecond pulsed lasers. The model and experimental results can provide a reference for the engineering design of the same type of low repetition rate fiber lasers below the kilohertz level.

80-W single-frequency Innoslab µs-amplifier at 1319†nm with high efficiency.

A single-frequency quasi-continuous-wave partially end-pumped slab (Innoslab) laser amplifier at 1319 nm was demonstrated. The 3-W single-frequency all-fiber seed laser was amplified to a maximum average power of 80.1 W and the power stability was 0.52% in 10 minutes. The corresponding optical-optical efficiency was 16.1% under absorbed pump power of 478 W. The output pulse width was 131 µs at the repetition of 500 Hz. The beam quality factors of M2 were 1.3 in both the vertical and horizontal directions. To the best of our knowledge, this is the first report on single-frequency Nd:YAG Innoslab amplifier at 1319 nm with such high output power and efficiency.

170-W Nd:YAG InnoSlab laser at 1319†nm.

In this paper, a continuous-wave Nd:YAG InnoSlab laser at 1319 nm with high output power and high beam quality is demonstrated. The maximum output power of 170 W at 1319-nm single wavelength is obtained with an optical-to-optical efficiency of 15.3% from absorbed pump power to laser output and the corresponding slope efficiency of 26.7%. The beam quality factors of M2 are 1.54 and 1.78 in the horizontal and vertical directions, respectively. To the best of our knowledge, this is the first report on Nd:YAG 1319-nm InnoSlab lasers with such high output power and good beam quality.

Nonlinear spectral compression in high-power narrow-linewidth polarization maintaining fiber amplifiers for SBS suppression.

In this paper, we propose a method for narrowing the spectrum in high-power narrow-linewidth polarization-maintaining (PM) fiber amplifiers and investigate its potential for suppressing the stimulated Brillouin scattering (SBS). In this method, in addition to common phase modulation to suppress SBS, precisely designed amplitude modulation is induced to generate self-phase modulation in a high-power PM fiber amplifier. In this co-modulation way, the spectrum can be gradually compressed along the fiber. Compared to phase modulation alone or fiber-Bragg-gratings (FBGs) based narrow-linewidth fiber oscillator schemes, in which the spectrum remains the same or broadens, this scheme can achieve a higher SBS threshold for the same output spectral linewidth. Experiments on a ∼ 3 kW peak power quasi-continuous wave (QCW) fiber amplifier show that the co-modulation scheme can compress the spectrum from 0.25 nm to 0.084 nm as output peak power increases from 13 W to 3.2 kW and enhances the SBS threshold by ∼1.7 times compared to traditional FBGs-based fiber oscillator schemes, and by ∼1.4 times compared to common phase modulation schemes. This co-modulation scheme has the potential for mitigating SBS in high-power fiber amplifiers.

Linearly polarized fiber amplifier with narrow linewidth of 5†kW exhibiting a record output power and near-diffraction-limited beam quality.

In this work, a narrow-linewidth polarization-maintaining (PM) all-fiber amplifier with near-diffraction-limited beam quality and record output power is presented. First, a 4.45-kW PM fiber amplifier with a 3-dB linewidth of 0.08 nm and root mean square (rms) linewidth of 0.22 nm is achieved based on optimized phase modulation. However, the sideband of the spectrum broadens significantly during the amplification process, which is mainly caused by the additional intensity variation of the injected signal. Meanwhile, an up to 5.04-kW linearly polarized fiber laser with a relatively stable spectral bandwidth is achieved by effectively suppressing spectral broadening. At the maximum output power, the rms linewidth is 0.2 nm, the beam quality factor M2 is less than 1.3, the polarization extinction ratio (PER) is 16.5 dB, and the signal-to-noise ratio (SNR) is approximately 53 dB. The further power scaling of the amplifier is mainly limited by the pump power. To the best of our knowledge, this is the maximum output power of a narrow linewidth linearly polarized fiber amplifier to date.

Coherent beam combining of cylindrical vector beams for power scaling.

Coherent beam combining (CBC) of cylindrical vector beams (CVBs) based on an active phase controller is proposed and demonstrated. Experimentally, two pieces of spatially variant wave plates (S-wave plate) were employed as vector mode convertors for two individual 1064-nm fiber amplifier channels. When the system was in a closed loop, a combined output power of 10 W and a CBC efficiency of higher than 94% were achieved, for both TM01 (radially polarized) mode and TE01 (azimuthally polarized) mode cases. Moreover, the laser system showed a high vector mode purity, which was measured to be ∼97.4% (TM01) and ∼97.3% (TE01). To the best of knowledge, this could possibly be the first demonstration of CBC of CVBs, which paves the way for power scaling of CVBs.

1.36 J nanosecond laser at 1 kHz repetition based on a slab amplifier chain.

A high beam quality diode-pumped Nd:YAG master oscillator power-amplifier (MOPA) laser with three end-pumped slab amplifiers is developed. The Q-swtiched side-pumped rod oscillator presented a pulse energy 3.1 mJ with beam quality factors of M x2=1.17 and M y2=1.15 at a repetition of 1 kHz. The MOPA system delivered a pulse energy of 1.36 J with a pulse width of 48.2 ns and an extraction efficiency of 44.8%. The beam quality factors of M x2=1.72 and M y2=3.85 are measured without any phase-conjugators or adaptive optics.

Understanding the cultivation mechanism for mental health education of college students in campus culture construction from the perspective of deep learning.

Nowadays, there is an increase in attention to the college student's mental health, and to enhance the awareness related to college students' mental health, colleges and universities have executed an immense range of mental health publicity activities. In order to better combine deep learning with classroom teaching, this paper puts forward a deep learning algorithm formulated on convolutional neural networks. The purpose of this research is to investigate the development and use of a cultivation mechanism for mental health education of college students in campus culture creation from the perspective of deep learning. The study's primary goal is to comprehend college students' mental health training in campus culture creation. The study's objective is to develop experimental outcomes of college students utilizing mental health education courses as an optional or mandatory course. Finally, investigations related to college students' mental health from the current situation in China, the investigation, statistics and analysis related to the college students in China are carried out in this situation. The experimental results of this study show that 62 of the 156 schools and universities assessed provide courses on mental health education for college students that are both obligatory and optional. According to the students questionnaire survey, 86.7% of respondents believe that it is critical to establish mental health related educational courses, 61.9% believe that compulsory courses should be established, and students want to add group guidance or activities to the teaching process to improve their experience and participation.

FAM46B is a prokaryotic-like cytoplasmic poly(A) polymerase essential in human embryonic stem cells.

Family with sequence similarity (FAM46) proteins are newly identified metazoan-specific poly(A) polymerases (PAPs). Although predicted as Gld-2-like eukaryotic non-canonical PAPs, the detailed architecture of FAM46 proteins is still unclear. Exact biological functions for most of FAM46 proteins also remain largely unknown. Here, we report the first crystal structure of a FAM46 protein, FAM46B. FAM46B is composed of a prominently larger N-terminal catalytic domain as compared to known eukaryotic PAPs, and a C-terminal helical domain. FAM46B resembles prokaryotic PAP/CCA-adding enzymes in overall folding as well as certain inter-domain connections, which distinguishes FAM46B from other eukaryotic non-canonical PAPs. Biochemical analysis reveals that FAM46B is an active PAP, and prefers adenosine-rich substrate RNAs. FAM46B is uniquely and highly expressed in human pre-implantation embryos and pluripotent stem cells, but sharply down-regulated following differentiation. FAM46B is localized to both cell nucleus and cytosol, and is indispensable for the viability of human embryonic stem cells. Knock-out of FAM46B is lethal. Knock-down of FAM46B induces apoptosis and restricts protein synthesis. The identification of the bacterial-like FAM46B, as a pluripotent stem cell-specific PAP involved in the maintenance of translational efficiency, provides important clues for further functional studies of this PAP in the early embryonic development of high eukaryotes.