HER3 is a member of the HER （EGFR/ErbB） receptor family consisting of four closely related type 1 transmembrane receptors （EGFR, HER2, HER3, and HER4）. HER receptors are part of a complex sig- naling ...network intertwined with the Ras/Raf/MAPK, PI3K/AKT, JAK/STAT, and PKC signaling path- ways. Aberrant activation of the HER receptors and downstream signaling molecules tips the balance on cellular events, leading to various types of cancers. Monoclonal antibodies （mAbs） and small molecule inhibitors targeting EGFR and HER2 tyrosine kinase activities exhibit clinical ben- efits in the treatment of several types of cancers, but their clinical efficacy is limited by the occurrence of drug resistance. HER3 is the preferred dimerization partner of HER2 and it is well established that HER3 plays an important role in drug resistance to EGFR- and HER2-targeting therapies. Since HER3 has limited kinase activity, mAbs are being explored to target HER3 for cancer therapy. Currently, approximately a dozen of anti-HER3 mAbs are at different stages of clinical development. However, the lack of established biomarkers has made it more challenging to stratify cancer patients to whom HER3-targeting therapies can be more effective. In this review, we focus on the validation of HER3 as a cancer drug target, the recent development in biomarker discovery for anti-HER3 therapies, and the progress made in the clinical development of HER3-targeting mAbs.
Spinocerebellar ataxia type 3 (SCA3) is an inherited, autosomal, and rare neurodegenerative disease. Serum/plasma biomarkers or functional magnetic resonance imaging used to assess progression, ...except for neurological examinations, is either inconvenient or expensive. Handgrip strength (HGS) may be considered as a biomarker to predict the progress of SCA3 and align with the alteration of plasma neurofilament light chain (NfL) and Scale for the Assessment and Rating of Ataxia (SARA). This study recruited 31 patients and 36 controls. HGS in the SCA3 group revealed a profound decrease (P < 0.001) compared with normal subjects. HGS also had a negative correlation with SARA (r = - 0.548, P = 0.001), NfL (r = - 0.359, P = 0.048), and a positive correlation with BMI (r = 0.680, P < 0.001). Moreover, HGS/BMI ratio correlated with SARA (r = - 0.441, P = 0.013). Controlling for gender and age, HGS still correlated with the above clinical items. The initial hypothesis was also proved in SCA3 84Q transgenic mice, showing grip strength weakness compared to normal mice. HGS can be an alternative tool to assess the clinical severity of SCA3. Further research is needed to investigate the underlying mechanisms.
The full-length 16S rRNA sequencing can better improve the taxonomic and phylogenetic resolution compared to the partial 16S rRNA gene sequencing. The 16S-FAS-NGS (16S rRNA full-length amplicon ...sequencing based on a next-generation sequencing platform) technology can generate high-quality, full-length 16S rRNA gene sequences using short-read sequencers, together with assembly procedures. However there is a lack of a data analysis suite that can help process and analyze the synthetic long read data.
Herein, we developed software named 16S-FASAS (16S full-length amplicon sequencing data analysis software) for 16S-FAS-NGS data analysis, which provided high-fidelity species-level microbiome data. 16S-FASAS consists of data quality control,
assembly, annotation, and visualization modules. We verified the performance of 16S-FASAS on both mock and fecal samples. In mock communities, we proved that taxonomy assignment by MegaBLAST had fewer misclassifications and tended to find more low abundance species than the USEARCH-UNOISE3-based classifier, resulting in species-level classification of 85.71% (6/7), 85.71% (6/7), 72.72% (8/11), and 70% (7/10) of the target bacteria. When applied to fecal samples, we found that the 16S-FAS-NGS datasets generated contigs grouped into 60 and 56 species, from which 71.62% (43/60) and 76.79% (43/56) were shared with the Pacbio datasets.
16S-FASAS is a valuable tool that helps researchers process and interpret the results of full-length 16S rRNA gene sequencing. Depending on the full-length amplicon sequencing technology, the 16S-FASAS pipeline enables a more accurate report on the bacterial complexity of microbiome samples. 16S-FASAS is freely available for use at https://github.com/capitalbio-bioinfo/FASAS.
Most eukaryotes reproduce sexually. Although the benefits of sex in diploids mainly stem from recombination and segregation, the relative effects of recombination and segregation are relatively less ...known. In this study, we adopt an infinite loci model to illustrate how dominance coefficient of mutations affects the above-mentioned genetic events. However, we assume mutational effects to be independent and also ignore the effects of epistasis within loci. Our simulations show that with different levels of dominance, segregation and recombination may play different roles. In particular, recombination more commonly has a major impact on the evolution of sex when deleterious mutations are partially recessive. In contrast, when deleterious mutations are dominant, segregation becomes more important than recombination, a finding that is consistent with previous studies stating that segregation, rather than recombination, is more likely to drive the evolution of sex. Moreover, beneficial mutations alone remarkably increases the effects of recombination. We also note that populations favor sexual reproduction when deleterious mutations become more dominant or beneficial mutations become more recessive. Overall, these results illustrate that the existence of dominance is an important mechanism that affects the evolution of sex.
To solve the problem of the high bearing capacity of structures in deep and weak soil layers, we invented a new type of pile group foundation in which the soil was continuously solidified between ...piles (hereinafter referred to as the SCS pile group foundation). Considering the two key factors of pile spacing and CSM depth, the antipulling load characteristics of SCS pile group foundations in dry sand were studied via indoor half-model tests and numerical simulations. The results showed that the ultimate uplift capacity of the SCS pile group foundation with a 2D–6D CSM depth was about 2–3 times that of the traditional pile group. When the stiffness of the CSM is so large that its effect can be ignored, the greater the pile spacing is, the greater the ultimate uplift capacity is. For the same pile spacing, the greater the depth of the CSM is, the greater the ultimate uplift bearing capacity is. When the CSM depth is greater than 10D, the uplift effect of the CSM can be effectively exerted, and the antipulling advantage of the SCS pile group foundation can be fully utilized. This study provided a reference for the antipulling design of SCS pile foundations.
Medicinal plants show important therapeutic value in chronic disease treatment. However, due to their diverse ingredients and complex biological effects, the molecular mechanisms of medicinal plants ...are yet to be explored. By means of several high-throughput platforms, here we show hawk tea extract (HTE) inhibits Niemann-Pick C1-like 1 (NPC1L1)-mediated free cholesterol uptake, thereby inducing the transcription of low-density lipoprotein receptor (
) downstream of the sterol response element binding protein 2 (SREBP2) pathway. Meanwhile, HTE suppresses hepatocyte nuclear factor 4α (HNF4α)-mediated transcription of microsomal triglyceride transfer protein (
) and apolipoprotein B (
), thereby decreasing the production of very-low-density lipoprotein. The catechin EGCG ((-)-epigallocatechin gallate) and the flavonoids kaempferol and quercetin are identified as the bioactive components responsible for the effects on the NPC1L1-SREBP2-LDLR axis and HNF4α-MTP/APOB axis, respectively. Overall, hawk tea works as a previously unrecognized cholesterol-lowering agent in a multi-target and multi-component manner.
Emerging evidence has suggested the association of the gut microbiome with some human diseases, including type 2 diabetes (T2D). In this study, we analyzed the gut microbiota from a cohort of healthy ...and diabetic Chinese individuals from Northern China. Pyrosequencing of the V4V5 region of 16S rRNA genes revealed a significant decrease in the gut microbiota diversity of diabetic patients as compared to healthy individuals. Butyrate-producing bacteria such as Bifidobacterium and Akkermansia were significantly decreased in diabetic patients. Furthermore, the abundance of Dorea was significantly increased in T2D individuals and negatively correlated with the abundance of butyrate-producing bacteria. The increase of Dorea could play a role in the development of T2D and has been previously overlooked. Importantly, functional analysis of the gut microbiome revealed for the first time that increased levels of butyrate production via transferases and the degradation of several amino acids due to gut microbial metabolism have strong correlations with T2D in Northern China. Moreover, the potential of gut microbiota-based classifiers to identify individuals with a high risk for T2D has been demonstrated in this study. Taken together, our findings have revealed a previously unappreciated association of the gut microbiome with T2D and have also suggested that changes in gut microbiota may be used to identify individuals at high risk for T2D.
The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infected over 3300 healthcare workers in early 2020 in China. Little information is known about nosocomial ...infections of healthcare workers in the initial period. We analysed data from healthcare workers with nosocomial infections in Wuhan Union Hospital (Wuhan, China) and their family members.
We collected and analysed data on exposure history, illness timelines and epidemiological characteristics from 25 healthcare workers with laboratory-confirmed coronavirus disease 2019 (COVID-19) and two healthcare workers in whom COVID-19 was highly suspected, as well as 10 of their family members with COVID-19, between 5 January and 12 February 2020. The demographics and clinical features of the 35 laboratory-confirmed cases were investigated and viral RNA of 12 cases was sequenced and analysed.
Nine clusters were found among the patients. All patients showed mild to moderate clinical manifestation and recovered without deterioration. The mean period of incubation was 4.5 days, the mean±sd clinical onset serial interval (COSI) was 5.2±3.2 days, and the median virus shedding time was 18.5 days. Complete genomic sequences of 12 different coronavirus strains demonstrated that the viral structure, with small irrelevant mutations, was stable in the transmission chains and showed remarkable traits of infectious traceability.
SARS-CoV-2 can be rapidly transmitted from person to person, regardless of whether they have symptoms, in both hospital settings and social activities, based on the short period of incubation and COSI. The public health service should take practical measures to curb the spread, including isolation of cases, tracing close contacts, and containment of severe epidemic areas. Besides this, healthcare workers should be alert during the epidemic and self-quarantine if self-suspected of infection.
is an important infectious pathogen of lower respiratory tract infection in children and adolescents. Macrolide resistant
(MRMP) has become increasingly prevalent, and identifying pathogen resistance ...genes is crucial for treatment.
We report a patient with severe refractory
pneumonia (MPP). The failure of initial clinical treatment prompted the re-analysis of metagenomic next-generation sequencing (mNGS) data for macrolide-resistant gene. Macrolide-resistance 23S ribosomal RNA gene was confirmed with read depth of 64 X for the A2063G mutation, which can decrease the affinity of macrolide with
ribosome resulting in macrolide resistance. Furthermore, antimicrobial susceptibility testing demonstrated that
was resistant to macrolide. PCR confirmatory test about
resistance A2063G mutation, clinical treatment course and prognosis with altered treatment strategy, and
antimicrobial susceptibility confirmed that the severe refractory MPP was due to macrolide resistant
.
As a new molecular level detection, mNGS is an effective method for detecting
resistance genes. Early recognition of macrolide resistance and suitable antibiotics strategy is of vital importance for the prognosis of severe refractory MPP.
We have previously reported that the carboxy-terminal proteolytic cleavage product of the COL6α3 chain that we refer to as "endotrophin" has potent effects on transformed mammary ductal epithelial ...cells in rodents. Endotrophin (ETP) is abundantly expressed in adipose tissue. It is a chemoattractant for macrophages, exerts effects on endothelial cells and through epithelial-mesenchymal transition (EMT) enhances progression of tumor cells. In a recombinant form, human endotrophin exerts similar effects on human macrophages and endothelial cells as its rodent counterpart. It enhances EMT in human breast cancer cells and upon overexpression in tumor cells, the cells become chemoresistant. Here, we report the identification of endotrophin from human plasma. It is circulating at higher levels in breast cancer patients. We have developed neutralizing monoclonal antibodies against human endotrophin and provide evidence for the effectiveness of these antibodies to curb tumor growth and enhance chemosensitivity in a nude mouse model carrying human tumor cell lesions. Combined, the data validate endotrophin as a viable target for anti-tumor therapy for human breast cancer and opens the possibility for further use of these new reagents for anti-fibrotic approaches in liver, kidney, bone marrow and adipose tissue.
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