Doxorubicin conjugated with a trastuzumab epitope and an MMP-2 sensitive peptide linker for the treatment of HER2-positive breast cancer

<p>HER2-positive breast cancer correlates with more aggressive tumor growth, a poorer prognosis and reduced overall survival. Currently, trastuzumab (Herceptin), which is an anti-HER2 antibody, is one of the key drugs. There is evidence indicating that conjugation of trastuzumab with chemotherapy drugs, such as doxorubicin (DOX), for multiple targets could be more effective. However, incomplete penetration into tumors has been noted for those conjugates. Compared to an antibody, peptides may represent an attractive alternative. For HER2, a similar potency has been observed for a 12-amino-acid anti-HER2 peptide mimetic Y<u>C</u>DGFYA<u>C</u>YMDV-NH₂ (AHNP, disulfide-bridged) and full-length trastuzumab. Thus, a peptide, GPLGLAGDDY<u>C</u>DGFYA<u>C</u>YMDV-NH₂, which consists of AHNP and an MMP-2 cleavable linker GPLGLAGDD, was first designed, followed by conjugation with DOX <i>via</i> a glycine residue at the N-terminus to form a novel DOX-peptide conjugate MAHNP-DOX. Using HER2-positive human breast cancer cells BT474 and SKBR3 as <i>in vitro</i> model systems and nude mice with BT474 xenografts as an <i>in vivo</i> model, this conjugate was comprehensively characterized, and its efficacy was evaluated and compared with that of free DOX. As a result, MAHNP-DOX demonstrated a much lower <i>in vitro</i> IC₅₀, and its <i>in vivo</i> extent of inhibition in mice was more evident. During this process, enzymatic cleavage of MAHNP-DOX is critical for its activation and cellular uptake. In addition, a synergistic response was observed after the combination of DOX and AHNP. This effect was probably due to the involvement of AHNP in the PI3K–AKT signaling pathway, which can be largely activated by DOX and leads to anti-apoptotic signals.</p

Image1_Petrogenesis of late triassic high-silica granites in the North Qiangtang terrane, central Tibetan Plateau.pdf

Although high-silica granites can provide unique insights into the maturity of the continental crust and rare metal enrichment, the origin of high-silica granitic magmatism remains uncertain. In this paper, we present an integrated study of zircon U-Pb geochronology and trace elements, whole-rock geochemistry, and Sr-Nd isotopes for two typical high-silica granites (namely, the Longbao granitic porphyry and the Yushu granite) found in the North Qiangtang terrane, central Tibetan Plateau. Zircon geochronological data indicate that these high-silica granites crystallized at 217–214 Ma. All the samples from the Longbao granitic porphyry and the Yushu granite exhibited high SiO2, low MgO, depletion of Ba, Nb, Sr, P, and Ti, and enrichment of Th and U. They exhibited relatively high (87Sr/86Sr)i ratios of 0.7120–0.7136 and low εNd(t) values of −8.58 ∼ −7.58; together with their old ages according to the two-stage Nd model (1.6–1.7 Ga), these features indicate the involvement of crustal materials. Geochemical and isotopic variation indicated that the high-silica granites studied were mainly produced by the dehydration melting of a muscovite (Ms)-bearing source, and that the Triassic turbidites might be a good candidate for the magma source. Combining this evidence with new regional studies, it can be concluded that partial melting of Triassic turbidites induced by slab roll-back might be the key factor controlling the origin of Late Triassic magmatism in the North Qiangtang terrane.</p

Table_1_Predicting non-small cell lung cancer-related genes by a new network-based machine learning method.xlsx

Lung cancer is the leading cause of cancer death globally, killing 1.8 million people yearly. Over 85% of lung cancer cases are non-small cell lung cancer (NSCLC). Lung cancer running in families has shown that some genes are linked to lung cancer. Genes associated with NSCLC have been found by next-generation sequencing (NGS) and genome-wide association studies (GWAS). Many papers, however, neglected the complex information about interactions between gene pairs. Along with its high cost, GWAS analysis has an obvious drawback of false-positive results. Based on the above problem, computational techniques are used to offer researchers alternative and complementary low-cost disease–gene association findings. To help find NSCLC-related genes, we proposed a new network-based machine learning method, named deepRW, to predict genes linked to NSCLC. We first constructed a gene interaction network consisting of genes that are related and irrelevant to NSCLC disease and used deep walk and graph convolutional network (GCN) method to learn gene–disease interactions. Finally, deep neural network (DNN) was utilized as the prediction module to decide which genes are related to NSCLC. To evaluate the performance of deepRW, we ran tests with 10-fold cross-validation. The experimental results showed that our method greatly exceeded the existing methods. In addition, the effectiveness of each module in deepRW was demonstrated in comparative experiments.</p

Additional file 2 of Optimizing yeast for high-level production of kaempferol and quercetin

Additional file 2: Feeding profile for glucose limited fed-batch fermentation of kaempferol and quercetin

Additional file 1 of Optimizing yeast for high-level production of kaempferol and quercetin

Additional file 1: Table S1. Plasmids used in this study. Table S2. S.cerevisiae strains used in this study. Table S3. Codon optimized genes used in this study. Table S4. Oligonucleotides used in this study. Table S5. Constructed DNA modules in this study. Table S6. Homology sequences for integration sites at S. cerevisiae chromosome

Image_2_Immune-related adverse events with severe pain and ureteral expansion as the main manifestations: a case report of tislelizumab-induced ureteritis/cystitis and review of the literature.png

Immune checkpoint inhibitor (ICI) is an up-to-date therapy for cancer with a promising efficacy, but it may cause unique immune-related adverse events (irAEs). Although irAEs could affect any organ, irAEs-induced whole urinary tract expansion was rarely reported. Herein, we reported a 27-year-old male patient with thymic carcinoma who received the treatment of tislelizumab, paclitaxel albumin and carboplatin. He was hospitalized for severe bellyache and lumbago after 6 courses of treatment. Antibiotic and antispasmodic treatment did not relieve his symptoms. The imaging examinations reported whole urinary tract expansion and cystitis. Therefore, we proposed that the patient’s pain was caused by tislelizumab-induced ureteritis/cystitis. After the discontinuation of tislelizumab and the administration of methylprednisolone, his symptoms were markedly alleviated. Herein, we reported a rare case of ICI-induced ureteritis/cystitis in the treatment of thymic cancer and reviewed other cases of immunotherapy-related cystitis and tislelizumab-related adverse events, which will provide a reference for the diagnosis and treatment of ICI-related irAEs.</p

Image_1_Immune-related adverse events with severe pain and ureteral expansion as the main manifestations: a case report of tislelizumab-induced ureteritis/cystitis and review of the literature.jpeg

Immune checkpoint inhibitor (ICI) is an up-to-date therapy for cancer with a promising efficacy, but it may cause unique immune-related adverse events (irAEs). Although irAEs could affect any organ, irAEs-induced whole urinary tract expansion was rarely reported. Herein, we reported a 27-year-old male patient with thymic carcinoma who received the treatment of tislelizumab, paclitaxel albumin and carboplatin. He was hospitalized for severe bellyache and lumbago after 6 courses of treatment. Antibiotic and antispasmodic treatment did not relieve his symptoms. The imaging examinations reported whole urinary tract expansion and cystitis. Therefore, we proposed that the patient’s pain was caused by tislelizumab-induced ureteritis/cystitis. After the discontinuation of tislelizumab and the administration of methylprednisolone, his symptoms were markedly alleviated. Herein, we reported a rare case of ICI-induced ureteritis/cystitis in the treatment of thymic cancer and reviewed other cases of immunotherapy-related cystitis and tislelizumab-related adverse events, which will provide a reference for the diagnosis and treatment of ICI-related irAEs.</p

Table_1_Immune-related adverse events with severe pain and ureteral expansion as the main manifestations: a case report of tislelizumab-induced ureteritis/cystitis and review of the literature.docx

Immune checkpoint inhibitor (ICI) is an up-to-date therapy for cancer with a promising efficacy, but it may cause unique immune-related adverse events (irAEs). Although irAEs could affect any organ, irAEs-induced whole urinary tract expansion was rarely reported. Herein, we reported a 27-year-old male patient with thymic carcinoma who received the treatment of tislelizumab, paclitaxel albumin and carboplatin. He was hospitalized for severe bellyache and lumbago after 6 courses of treatment. Antibiotic and antispasmodic treatment did not relieve his symptoms. The imaging examinations reported whole urinary tract expansion and cystitis. Therefore, we proposed that the patient’s pain was caused by tislelizumab-induced ureteritis/cystitis. After the discontinuation of tislelizumab and the administration of methylprednisolone, his symptoms were markedly alleviated. Herein, we reported a rare case of ICI-induced ureteritis/cystitis in the treatment of thymic cancer and reviewed other cases of immunotherapy-related cystitis and tislelizumab-related adverse events, which will provide a reference for the diagnosis and treatment of ICI-related irAEs.</p

Steric Hindrance On–Off Mass-Tagged Probe Set Enables Detection of Protein Homodimer in Living Cells

The major challenge in the detection of protein homodimers is that the identical monomers in a homodimer are indistinguishable using most conventional methods and cannot be sequentially recognized. In this study, a steric hindrance on–off mass-tagged probe set strategy was developed for the quantification of HER2 homodimer in living cells. The probe set contained a hindrance probe and a detection probe. The hindrance probe had a DNA dendrimer as a hindrance group to achieve the steric hindrance on–off function and thus the assignment of monomer identity. The detection probe contained a mass tag released for mass spectrometric quantification. Using the steric hindrance on–off mass-tagged probe set, the level of HER2 homodimer in various breast cancer cell lines was quantified. This is the first report to determine the quantity of protein homodimers, and the steric hindrance on–off probe set developed herein can facilitate the illustration of protein function in cancer

Additional file 1 of Liquid–liquid phase separation of H3K27me3 reader BP1 regulates transcriptional repression

Additional file 1: Fig. S1. The statistics analysis of BP1 protein phase separation in vitro and in vivo. Fig. S2. 1,6-Hexanediol disturbs BP1 protein phase separation in vitro and in vivo. Fig. S3. His-BP1 protein phase separation assays. Fig. S4. The two IDRs of BP1 undergo phase separation in vitro. Fig. S5. Identification of truncated BP1ΔIDR1-C and BP1ΔIDR2-C strains. Fig. S6. H3K27me3 regulates transcriptional repression of DON biosynthesis genes