Abstract High-grade serous ovarian cancers (HGSOC) represent the most common of the ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell-engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 Fabs with the anti-CD3 SP34 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mpk. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles supportive of consideration for treatment of high-grade serous ovarian cancers.
Previously identified common variants explain only a small fraction of the trait heritability and at most loci the identities of the underlying causal genes and their functional variants still remain unknown. To identify the low-frequency and rare coding variants that influence lipid levels, we conducted a meta-analysis of exome-wide association studies in 14,473 Chinese subjects, followed by a joint analysis with 1000 genomes imputed data from 6,534 samples. We replicated 24 previously reported lipid loci with exome-wide significance (P < 3.3 × 10 - 7), including fourteen coding variants at ten confirmed lipid loci (P range from 1.44 × 10 - 7 to 1.64 × 10 - 45). Of these, six coding variants showed population-specific associations and were independent of previously identified associations in European populations, including four low-frequency (PCSK9 p.Arg93Cys, HMGCR p.Tyr311Ser, APOA5 p.Gly185Cys and CETP p.Asp399Gly) and two common (APOB p.Arg532Trp and APOA4 p.Ser147Asn) variants. Furthermore, we detected three new lead non-coding variants at LPA, LIPC and LDLR in Chinese. The independent variants at PCSK9, HMGCR, LPA, APOA5 and LDLR were also associated with increased risk of coronary artery disease in the expected direction. In gene-based tests, the burden of rare or low frequency variants in PCSK9, HMGCR and CEPT exhibited strong associations with blood lipid levels (P < 2.8 × 10 - 6). Our findings identify additional population-specific possible causal variants. Our data demonstrate that the inter-ethnic differences in allele frequencies of coding variants may lead to different association signals across ethnic groups, highlighting the importance of including diverse populations to uncover genetic variation associated with lipid levels.
Abstract Uterine serous carcinoma (USC) has a much worse chemotherapy response and prognosis than endometrioid endometrial carcinoma (EEC). A comprehensive understanding of the intra-tumoral heterogeneity and tumor-specific ecosystem of USC is essential for improving diagnosis, treatment, and prognosis. In this study, we performed 5′ single-cell RNA sequencing, along with T-cell receptor and B-cell receptor sequencing, on 16 USC samples and 5 normal endometrial samples. We then integrated data from 15 EEC samples obtained from public databases for comparative analysis. USC malignant cells exhibited novel subclonal genomic complexities and unique transcriptional states, with significantly activated MYC signaling and cell cycle-related pathways. Treatment with the CDK12 inhibitor (CDK12-IN-3) effectively inhibited cell viability and increased the chemotherapy sensitivity of USC cell lines. Additionally, we characterized the stromal niche and immune environment of USC and EEC, finding a higher degree of CD8+ T-cell exhaustion and SPP1+ macrophage infiltration in USC. USC-derived fibroblasts were found to promote malignant cell proliferation through CNTN1-NRCAM, THBS2-CD47, and THBS2-SDC4 interactions. In summary, our study provides a comprehensive single-cell transcriptome analysis of USC and its tumor microenvironment in comparison with EEC, explores intra-tumoral heterogeneity, and identifies CDK12 and CAF-CNTN1 as potential therapeutic targets for USC.
Human mitochondrial genome (mtDNA) variations, such as mtDNA heteroplasmies (the co-existence of mutated and wild-type mtDNA), have received increasing attention in recent years for their clinical relevance to numerous diseases. But large-scale population studies of mtDNA heteroplasmies have been lagging due to the lack of a labor- and cost-effective method. Here, we present a novel human mtDNA sequencing method called STAMP (sequencing by targeted amplification of multiplex probes) for measuring mtDNA heteroplasmies and content in a streamlined workflow. We show that STAMP has high-mapping rates to mtDNA, deep coverage of unique reads and high tolerance to sequencing and polymerase chain reaction errors when applied to human samples. STAMP also has high sensitivity and low false positive rates in identifying artificial mtDNA variants at fractions as low as 0.5% in genomic DNA samples. We further extend STAMP, by including nuclear DNA-targeting probes, to enable assessment of relative mtDNA content in the same assay. The high cost-effectiveness of STAMP, along with the flexibility of using it for measuring various aspects of mtDNA variations, will accelerate the research of mtDNA heteroplasmies and content in large population cohorts, and in the context of human diseases and aging.
We herein present a high-performance ultrawideband terahertz absorber with a silicon hemi-ellipsoid (SHE) on a monolayer graphene that is separated by a dielectric spacer from a bottom metal reflector. The constitution of the absorber, which includes dielectric-mode structures and unstructured monolayer graphene, can minimize undesired optical losses in metals and avoid graphene processing. The absorber achieved an ultrawide absorption bandwidth from 2 THz to more than 10 THz with an average absorption of 95.72%, and the relative bandwidth is 133%. The excellent absorption properties are owing to the presence of graphene and the shape morphing of the SHE, in which multiple discrete graphene plasmon resonances (GPRs) and continuous multimode Fabry–Perot resonances (FPRs) can be excited. By coupling the GPRs and FPRs, the absorption spectrum is extended and smoothed to realize an ultrawideband absorber. The incident angular insensitivity within 50° of the absorber is discussed. The results will shed light on the better performance of terahertz trapping, imaging, communication and detection.
The IASLC/ATS/ERS classification system was proposed in 2011 to improve the histological subtypes of lung adenocarcinoma, while the prognostic value of the combination of histological predominant subtypes is not consistent. IMP3 is an oncofetal protein which has been proved associated with aggressive tumor behavior in malignancies, but few reports were investigated in lung adenocarcinoma. The aim of this study is to explore the prognostic value of the IASLC/ATS/ERS classification and IMP3 expression in lung adenocarcinoma of Chinese cases. A total of 196 cases were classified according to the IASLC/ATS/ERS classification system and immunohistochemically analyzed by using a monoclonal antibody against IMP3. Univariate survival analysis indicated patients with solid-predominant subtype had shorter disease-free survival (P = 0.003) and overall survival (P = 0.014) compared to those with non-solid predominant subtype. Multivariate survival analysis revealed that solid-predominant subtype could be an independent prognostic factor for disease-free survival (HR: 1.22, 95% CI: 1.05-1.41; P = 0.008). Analysis of IMP3 expression showed that IMP3 was more frequently overexpressed in tumors with advanced pTNM stage (P < 0.001), larger tumor size (P = 0.036), poorer histological differentiation (P < 0.001), lymph node metastasis (P < 0.001), and solid-predominant subtype (P < 0.001). Survival analysis also confirmed that patients in IMP3 high-expression group had both worse disease-free survival (P = 0.039) and overall survival (P = 0.029) than those in IMP3 low-expression group. Our results illustrated that solid-predominant subtype according to the IASLC/ATS/ERS classification is an independent prognostic factor, and IMP3 overexpression is associated with aggressive tumor behavior and poor clinical outcome in lung adenocarcinoma.
<p>The effect of FOXM1-PVT1 loop on EZH2, c-Myc and NOP2 in GC AGS cells were transfected with the indicated plasmids or siRNA for 48 h. The western blot results showed the protein level of FOXM1, EZH2, c-Myc and NOP2 in each group.</p>
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
