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HER2, human epidermal receptor 2(c-erbB-2 gene), is a hot targeted point in various cancers targeted therapy. Breast cancer including HER2 positive or negative. HER2 is an oncogenic receptor tyrosine kinase. HER2 gene amplification occurs in some of breast cancers (BCS), resulting in overexpression of the HER2 protein. Compared to the trastuzumab or pertuzumab, the performance of trastuzumab deruxtecan is excellent. Drug resistance is known to be the main cause of failure of tumor chemotherapy. Tumor drug resistance involves various mechanisms, such as those involving decreased intracellular drug concentration, changes of drug target molecules, metabolic detoxification, and imbalance of DNA damage repair function. HER2-positive breast cancer becomes resistant to trastuzumab, thereby blocking effective binding and developing resistance. The significance of this review is to understand the mechanism of drug resistance from molecular and chemotherapy perspectives by studying the structure and overexpression of HER2 protein as predictors, so as to grasp the progress of current targeted drug therapy. Our review starting from HER2 and its targeted therapy gets to the deep insight into the antibody drug conjugates and explores the possible proteins which may become the potential targeted points in future research.

Cloud gaming (CG) has gradually gained popularity. By leveling shared computing resources on the cloud, CG technology allows those without expensive hardware to enjoy AAA games using a low-end device. However, the bandwidth requirement for streaming game video is high, which can cause backbone network congestion for large-scale deployment and expensive bandwidth bills. To address this challenge, the authors proposed an innovative edge-assisted computing architecture that collaboratively uses AI-powered foveated rendering (FR) and super-resolution (SR). Using FR, the cloud server can stream gaming video in lower resolution, significantly reducing the transmitted data volume. The edge server will then upscale the video using a game-specific SR model, recovering the quality of the video, especially for the areas players pay the most attention. The authors built a prototype system called FRSR and did thorough, objective comparative experiments to demonstrate that this architecture can reduce bandwidth usage by 39.47% compared with classic CG implementation for similar perceived quality.

This paper investigates a pathway for transforming small and medium enterprise-based industrial districts to eco-industrial development in newly industrialised countries. Our framework conceptualises the eco-transformation of industrial districts as a reassembling process of local-regional industrial networks toward sustainability from an ‘arenas of development’ perspective, highlighting how an emerging eco-transformation arena may challenge existing unsustainable industrial networks. We employ a case-study method to illuminate how such an eco-transformation arena has emerged in Shunde District in Southern China and evolved in the dimensions of continuity, scale and depth of transformation. The results show the pathway is driven by national policy intervention and local government responses. The subsequent development is likely to shift into a fluid, non-linear process unfolded through the continuing interaction of agenda setting, actors and their relationships, strategies and actions performed, translation projects and spaces of negotiation (i.e. the arena’s five components) while being influenced by context and place-specificity.

Alternative polyadenylation (APA) enables a gene to generate multiple transcripts with different 3′ ends, which is dynamic across different cell types or conditions. Many computational methods have been developed to characterize sample-specific APA using the corresponding RNA-seq data, but suffered from high error rate on both polyadenylation site (PAS) identification and quantification of PAS usage (PAU), and bias toward 3′ untranslated regions. Here we developed a tool for APA identification and quantification (APAIQ) from RNA-seq data, which can accurately identify PAS and quantify PAU in a transcriptome-wide manner. Using 3′ end-seq data as the benchmark, we showed that APAIQ outperforms current methods on PAS identification and PAU quantification, including DaPars2, Aptardi, mountainClimber, SANPolyA, and QAPA. Finally, applying APAIQ on 421 RNA-seq samples from liver cancer patients, we identified >540 tumor-associated APA events and experimentally validated two intronic polyadenylation candidates, demonstrating its capacity to unveil cancer-related APA with a large-scale RNA-seq data set.

With the rapid development of integrated circuits, asynchronous First Input First Output (FIFO) is often used to solve the problem of data transmission across the clock domain. This paper mainly studies the key problem of asynchronous FIFO design - the generation of empty - full signal. To solve this problem, it is necessary to realize the synchronization of signal across the clock domain and convert binary code into gray code to reduce the probability of metastable state. The null and full signals generated by the asynchronous FIFO designed in this paper are false null and false full, but this does not affect the function of the asynchronous FIFO, and will only lose part of the performance. Through Modelsim simulation verification, the designed asynchronous FIFO can realize first-in, first-out of data and correctly generate empty and full signal, which meets the design requirements. The research of this paper is helpful for further application of asynchronous FIFO in data transmission across clock domains.

Doublesex (DSX) proteins are members of the Doublesex/mab-3-related (DMRT) protein family and play crucial roles in sex determination and differentiation among the animal kingdom. In the present study, we identified two Doublesex (Dsx)-like mRNA isoforms in the brine shrimp Artemia franciscana (Kellogg 1906), which are generated by the combination of alternative promoters, alternative splicing and alternative polyadenylation. The two transcripts exhibited sex-biased enrichment, which we termed AfrDsxM and AfrDsxF. They share a common region which encodes an identical N-terminal DNA-binding (DM) domain. RT-qPCR analyses showed that AfrDsxM is dominantly expressed in male Artemia while AfrDsxF is specifically expressed in females. Expression levels of both isoforms increased along with the developmental stages of their respective sexes. RNA interference with dsRNA showed that the knockdown of AfrDsxM in male larvae led to the appearance of female traits including an ovary-like structure in the original male reproductive system and an elevated expression of vitellogenin. However, silencing of AfrDsxF induced no clear phenotypic change in female Artemia. These results indicated that the male AfrDSXM may act as inhibiting regulator upon the default female developmental mode in Artemia. Furthermore, electrophoretic mobility shift assay analyses revealed that the unique DM domain of AfrDSXs can specifically bind to promoter segments of potential downstream target genes like AfrVtg. These data show that AfrDSXs play crucial roles in regulating sexual development in Artemia, and further provide insight into the evolution of sex determination/differentiation in sexual organisms.

Background: Ending the global COVID-19 pandemic requires efficacious therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nevertheless, the emerging Omicron sublineages largely escaped the neutralization of current authorized monoclonal antibody therapies. Here we report a tetravalent bispecific antibody ISH0339, as a potential candidate for long-term and broad protection against COVID-19. Methods: We report here the making of ISH0339, a novel tetravalent bispecific antibody composed of a pair of non-competing neutralizing antibodies that binds specifically to two different neutralizing epitopes of SARS-CoV-2 receptor-binding domain (RBD) and contains an engineered Fc region for prolonged antibody half-life. We describe the preclinical characterization of ISH0339 and discuss its potential as a novel agent for both prophylactic and therapeutic purposes against SARS-CoV-2 infection. Results: ISH0339 bound to SARS-CoV-2 RBD specifically with high affinity and potently blocked the binding of RBD to the host receptor hACE2. ISH0339 demonstrated greater binding, blocking and neutralizing efficiency than its parental monoclonal antibodies, and retained neutralizing ability to all tested SARS-CoV-2 variants of concern. Single dosing of ISH0339 showed potent neutralizing activity for treatment via intravenous injection and for prophylaxis via nasal spray. Preclinical studies following single dosing of ISH0339 showed favorable pharmacokinetics and well-tolerated toxicology profile. Conclusion: ISH0339 has demonstrated a favorable safety profile and potent anti-SARS-CoV-2 activities against all current variants of concern. Furthermore, prophylactic and therapeutic application of ISH0339 significantly reduced the viral titer in lungs. Investigational New Drug studies to evaluate the safety, tolerability and preliminary efficacy of ISH0339 for both prophylactic and therapeutic purposes against SARS-CoV-2 infection have been filed.

Background: Diarrhea is the most common adverse event of pan-HER tyrosine kinase inhibitors. There is no consensus on therapeutic or prophylactic strategy of pyrotinib-related diarrhea. PHAEDRA is an ongoing multicenter, single-arm, phase II trial conducted to evaluate adjuvant pyrotinib plus nab-paclitaxel for patients with low-risk HER2-positive breast cancer. Here, we reported the results from the sub-study of PHAEDRA, which investigated the effect of different prophylactic strategies with loperamide for diarrhea. Methods: In PHAEDRA, patients with N0/N1mi, HER2-positive invasive breast cancer and primary tumor ≤3 cm received nab-paclitaxel 260 mg/m2 once every 3 weeks for 12 weeks and pyrotinib 400 mg once daily for one year within 90 days after surgery. In the sub-study, patients were randomly assigned to receive loperamide 4 mg three times a day on days 1-7 and twice a day on days 8-21 (cohort A) or days 8-42 (cohort B) since the initiation of adjuvant therapy. The primary endpoint of the sub-study was the incidence of grade ≥3 diarrhea. Results: Between January 2021 and May 2022, the enrollment of 120 patients in the sub-study was completed. Grade ≥3 diarrhea was reported in 18 (30%) of 60 patients in cohort A and 19 (32%) of 60 patients in cohort B. The median time to first grade ≥3 diarrhea was 4.5 days (IQR, 1.0-6.5) in cohort A and 4 days (IQR, 1.0-6.0) in cohort B. The median number of grade ≥3 diarrhea episodes was 1 (IQR, 1-1) in both cohorts. Three (5%) patients in each cohort had constipation events, respectively, which were all grade 1 or 2. One (2%) patient in cohort A and two (3%) in cohort B had dose reductions of loperamide due to constipation, and no patients discontinued loperamide. One (2%) patient in cohort A had dose reduction of pyrotinib and one (2%) in each cohort discontinued pyrotinib due to diarrhea. Conclusions: The effects of both loperamide regimens on antidiarrheal prophylaxis were consistent with that of loperamide prophylaxis in the CONTROL trial, but with extremely fewer constipation events. Long-course and short-course loperamide prophylaxis showed numerically similar incidence of grade ≥3 diarrhea. Proactive diarrhea management can promote the full-dose and full-course treatment with pyrotinib. It is still necessary to develop more effective antidiarrheal prophylaxis regimens for pan-HER tyrosine kinase inhibitors. Citation Format: Changjun Wang, Yan Lin, Yidong Zhou, Feng Mao, Jinghong Guan, Songjie Shen, Xuejing Wang, Xiaohui Zhang, Yanna Zhang, Bo Pan, Ying Zhong, Li Peng, Yan Li, Xin Huang, Ying Xu, Qiang Sun. Antidiarrheal prophylaxis with loperamide for patients with lymph node-negative (N0) or micrometastatic (N1mi), HER2-positive breast cancer who received adjuvant pyrotinib plus nab-paclitaxel: a randomized sub-study of PHAEDRA [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-03.

Excess iron accumulation is a risk factor for osteopenia and osteoporosis, and ferroptosis is becoming well understood as iron-dependent form of cell death resulting from lipid peroxide accumulation. However, any pathological impacts of ferroptosis on osteoporosis remain unknown. Here, we show that ferroptosis is involved in excess-iron-induced bone loss and demonstrate that osteoporotic mice and humans have elevated skeletal accumulation of the NADPH oxidase 4 (NOX4) enzyme. Mechanistically, we found that the NOX4 locus contains iron-response element-like (IRE-like) sequences that are normally bound (and repressed) by the iron regulatory protein 1 (IRP1) protein. Binding with iron induces dissociation of IRP1 from the IRE-like sequences and thereby activates NOX4 transcription. Elevated NOX4 increases lipid peroxide accumulation and causes obvious dysregulation of mitochondrial morphology and function in osteoblasts. Excitingly, the osteoporotic bone loss which we initially observed in an excessive-iron accumulating mouse line (Hepc1−/−) was blocked upon treatment with the ferroptosis-inhibitor ferrostatin-1 (Ferr-1) and with the iron chelator deferoxamine (DFO), suggesting a potential therapeutic strategy for preventing osteoporotic bone loss based on disruption of ferroptosis.

Aiming at the problems of low data conversion efficiency, low accuracy and low data utilization rate after conversion in traditional methods, this paper proposes a vector conversion method for building indoor space data based on attribute classification. Firstly, the transformation process of data vectors is analyzed. Secondly, block matching detection and fusion recognition were carried out on the building interior space images, and fuzzy feature extraction method was used to optimize the collection and feature recognition of the building interior space data. Then, the attribute classification method is used to obtain the condition attribute and decision attribute of the data, and realize the building interior space data mining. Then, the K-means algorithm is used to cluster the indoor spatial data samples, and the wavelet transform method is used to de-noise the noisy data in advance. Finally, the obtained data is processed by vector transformation. The experimental results show that the data conversion efficiency of this method is high, and the data conversion accuracy and data utilization rate have been improved.

Cuticular wax protects plants from various biotic and abiotic stresses. However, the genetic network of wax biosynthesis and the environmental factors influencing leaf wax production in rapeseed (Brassica napus) remains unclear. Here, we demonstrated the role of leaf wax in the resistance to Sclerotinia infection in rapeseed. We found that leaves grown under high light intensity had higher expression of genes involved in wax biosynthesis, and produced more wax on the leaf surface, compared with those grown under low light conditions. Genome-wide association study (GWAS) identified 89 single nucleotide polymorphisms significantly associated with leaf wax coverage. A cross-analysis between GWAS and differentially expressed genes (DEGs) in the leaf epidermis of the accessions with contrasting differences in wax content revealed 17 candidate genes that control this variation in rapeseed. Selective sweep analysis combined with DEG analysis unveiled 510 candidate genes with significant selective signatures. From the candidate genes, we selected BnaA02.LOX4, a putative lipoxygenase, and BnaCnn.CER1, BnaA02.CER3, BnaC02.CER3, and BnaA01.CER4 (ECERIFERUM1–4) that were putatively responsible for wax biosynthesis, to analyse the allelic forms and haplotypes corresponding to high or low leaf wax coverage. These data enrich our knowledge about wax formation, and provide a gene pool for breeding an ideal leaf wax content in rapeseed.

Construction of multi-component heterostructures as a flame retardant reinforcer within a polymer is a favorable option to realize the synergistic effects between different types of reinforcers. However, it is difficult to improve polymer flame retardance as the poor compatibility of retardants with polymer matrix can lead to low dispersion. Herein, 3-D flower-like templated layered double hydroxides (LDH) and graphene (rGO) were prepared on the surface of a caprolactam-modified casein micelle template for integration with casein latex based on a blending-casting method. Temp@LDH-rGO hardly affected the stability of the casein-based latex, as its casein-based composite latex was used as a leather surface coating. The limiting oxygen index of finished leather increased up to 27.4% when casein-based 4% Temp@LDH-rGO composite latex was applied for leather finishing. In contrast, its heat release rate and smoke production rate were lowered to 55.686 kW/m