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Background Previous clinical trials have demonstrated that entinostat in combination with exemestane had good tolerability and significant clinical efficacy in patients with advanced hormone receptor positive (HR+) and HER2 negative (HER2−) metastatic breast cancer (MBC) in the USA. However, no clinical trials have been conducted in Chinese populations. Objective To investigate the safety, pharmacokinetics, and pilot efficacy of entinostat with or without exemestane in Chinese postmenopausal patients with locally advanced or metastatic HR+ /HER2− MBC. Patients and methods Nineteen patients received entinostat for 4 weeks (dose-limiting toxicity (DLT) observation stage) at 3, 5, or 7 mg/week, with a “3+3” dose-escalation design and in combination with exemestane thereafter (extended treatment stage: entinostat, 3 or 5 mg/week; exemestane, 25 mg/day). An additional 21 patients were enrolled to assess the entinostat (5 mg) plus exemestane (25 mg) pharmacokinetic profile and potential efficacy. Results The peak entinostat serum concentration and area under the curve increased dose proportionally, without significant interaction between entinostat and exemestane. Entinostat was well tolerated at all doses. The most common grade 3/4 adverse effects (AEs) included neutropenia (31.6%) and thrombocytopenia (15.8%). In the DLT observation stage, grade 3/4 AEs accounted for 16.7% in the 5 mg group with one suspicious DLT (G3 ventricular tachycardia) and 33.3% in the 7 mg group. In the extended treatment stage, 2/16 patients achieved partial response and three patients experienced stable disease (> 12 weeks). The median progression-free survival was 9.41 months for the additional 21 patients, who experienced grade 3/4 AEs of neutropenia (38%), thrombocytopenia (9.5%), anemia (9.5%), and fatigue (9.5%). Conclusion Entinostat with exemestane showed reasonable safety, tolerability, and encouraging efficacy in Chinese patients with HR+/HER2− MBC. These results support further evaluation in a randomized, double-blind Phase III study with a weekly 5 mg entinostat dose in a Chinese population. Trial Registration NCT02833155.

Acinetobacter baumannii is an important pathogen in hospital acquired infections. Although tigecycline currently remains a potent antibiotic for treating infections caused by multidrug resistant A. baumannii (MDRAB) strains, reports of tigecycline resistant isolates have substantially increased. The resistance mechanisms to tigecycline in A. baumannii are far more complicated and diverse than what has been described in the literature so far. Here, we characterize in vitro-selected MDRAB strains obtained by increasing concentrations of tigecycline. We have identified mutations in adeS, rrf and rpoB that result in reduced susceptibility to tigecycline. Using in situ complementation experiments, we confirm that mutations in rrf, rpoB, and two types of mutations in adeS correlate with tigecycline resistance. By Western blot and polysome profile analysis, we demonstrate that the rrf mutation results in decreased expression of RRF, which affects the process of ribosome recycling ultimately leading to increased tigecycline tolerance. A transcriptional analysis shows that the mutated rpoB gene plays a role in regulating the expression of the SAM-dependent methyltransferase (trm) and transcriptional regulators, to confer moderate tigecycline resistance. This study provides direct in vitro evidence that mutations in the adeS, rpoB and rrf are associated with tigecycline resistance in A. baumannii.

Acinetobacter baumannii is an important nosocomial pathogen. Upon colonizing a host, A. baumannii are subjected to selective pressure by immune defenses as they adapt to the host environment. However, the mechanism of this pathoadaptation is unknown. Here, we established an in vitro system to evolve A. baumannii driven by the continuous selective pressure exerted by epithelial cells, and we used a combination of experimental evolution, phenotypic characterization and multi-omics analysis to address the underlying mechanism. When continuously exposed to selective pressure by pulmonary epithelial cells, A. baumannii showed ptk mutation-mediated mucoid conversion (reduced adhesion and increased anti-phagocytic ability) by enhancement of capsular exopolysaccharide chain length; rsmG mutation-mediated deficiency of 7-methylguanosine modification in the 524th nucleotide of 16S rRNA, which increased ribosome translation efficiency; and rnaseI mutation-mediated changes in outer membrane permeability and efflux pump expression. Together, these mutations altered susceptibility to a variety of antimicrobial agents, including the novel antibiotic cefiderocol, by regulating siderophore and siderophore-receptor biosynthesis. In conclusion, pulmonary epithelial cells modulate A. baumannii pathoadaptation, implicating the host–microbe interaction in the survival and persistence of A. baumannii.

Background: 1. The 3-drug combination therapy, trastuzumab, pertuzumab, and taxane chemotherapy is one of the standard treatment options for the first-line treatment of HER2-positive recurrent/metastatic breast cancer. 2. KN026 is a novel bispecific HER2-targeted antibody : Fully humanized, IgG1-like antibody binds to two distinct HER2 epitopes, the same domains as trastuzumab (ECD4) and pertuzumab (ECD2). IgG1 Fc fragment of KN026 binding FcγRIIIa mediates potent ADCC 3. Preliminary safety and efficacy results from Phase 1 study data (data as of January 22, 2020) of KN026 monotherapy in HER2-positive advanced breast cancer were presented at ASCO 2020, showed promising efficacy and well tolerated safety. Herein, we present the results from the phase 2 trial. Methods:  Eligible subjects with HER2-positive and first-line systemic treatment-naïve (relapse ≥12 months after the end of neoadjuvant/adjuvant therapy) recurrent or metastatic breast cancer were enrolled in this study.  Subjects received KN026 30 mg/kg combined with docetaxel 75 mg/m2 Q3W until disease progression, unacceptable toxicity, withdrawal of informed consent from subjects, or other circumstances that require drug discontinuation.  The primary endpoints were ORR and duration of response (DoR). The secondary endpoints included safety, PFS and OS. Results:  At data cut-off date (Mar 26, 2022), the median follow-up was 13.8 months (Interquartile Range [IQR] 12.22, 14.00). 57 subjects were enrolled, the median age was 52 years, 100% were female, and 89.5 % (51/57) were stage IV.  Of the 55 subjects evaluable for efficacy, 21 had received prior taxane, 4 had received prior trastuzumab in combination with taxane, 30 without any prior trastuzumab and taxane. Nearly half of the subjects (25/55) had previously received trastuzumab and/or taxane chemotherapy.  The confirmed ORR within 55 evaluable subjects was 76.4% (95% CI: 62.98, 86.77) and DoR was 18.1 months (95% CI: 12.45, NE).  Median PFS was 19.3 months (95% CI: 13.86, NE) and median OS was not reached. Median PFS is not yet mature. The 12-, and 18-month OS rates were 93.5% (95% CI: 80.79, 97.89), and 88.3 % (95% CI: 68.93, 95.92), respectively.  The confirmed ORR was 80% in 30 trastuzumab-and taxane-naïve subjects. Among these subjects, OS rates at 12, and 18 months were 100% (95% CI: 100,100), and 90.0% (95% CI: 47.30, 98.53), and the median PFS was 19.3 months (95% CI:13.77, NE).  Treatment emergent adverse events with incidence rate ≥20% and TEAE≥Grade 3 were neutropenia (n=23, 40.4%) and leucopenia (n=16, 28.1%), respectively.  The incidence of serious adverse events was 15.8%(9/57), including 5.3% (3/57) for febrile neutropenia, 3.5% (2/57) for leucopenia, and less than 2% for other SAEs  There were no deaths due to KN026 drug-related AEs in this study. Conclusions: KN026 in combination with docetaxel is well tolerated and has shown promising clinical benefit as a 1L treatment for HER2-positive advanced breast cancer. At data cut-off date (Mar 26, 2022), median PFS was 19.3 months while 18-month OS rate was 88.3%, which is very encouraging. Efficacy and safety require large-scale phase III studies to verify. Citation Format: Qingyuan Zhang, Jingxuan Wang, Quchang Ouyang, Xiaojia Wang, Jingfen Wang, Lu Gan, Daren Lin, Zhong Ouyang, Ting Xu, Yilan Liu, Summer Xia. Efficacy and safety results of KN026, a HER2-targeted bispecific antibody combined with docetaxel in first-line treatment of HER2-positive recurrent/metastatic breast cancer [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 PD18-08.

Photosystem II (PSII) in the thylakoid membranes of plants, algae, and cyanobacteria catalyzes light-induced oxidation of water by which light energy is converted to chemical energy and molecular oxygen is produced. In higher plants and most eukaryotic algae, the PSII core is surrounded by variable numbers of light-harvesting antenna complex II (LHCII), forming a PSII–LHCII supercomplex. In order to harvest energy efficiently at low–light-intensity conditions under water, a complete PSII–LHCII supercomplex (C 2 S 2 M 2 N 2 ) of the green alga Chlamydomonas reinhardtii (Cr) contains more antenna subunits and pigments than the dominant PSII–LHCII supercomplex (C 2 S 2 M 2 ) of plants. The detailed structure and energy transfer pathway of the Cr-PSII–LHCII remain unknown. Here we report a cryoelectron microscopy structure of a complete, C 2 S 2 M 2 N 2 -type PSII–LHCII supercomplex from C. reinhardtii at 3.37-Å resolution. The results show that the Cr-C 2 S 2 M 2 N 2 supercomplex is organized as a dimer, with 3 LHCII trimers, 1 CP26, and 1 CP29 peripheral antenna subunits surrounding each PSII core. The N-LHCII trimer partially occupies the position of CP24, which is present in the higher-plant PSII–LHCII but absent in the green alga. The M trimer is rotated relative to the corresponding M trimer in plant PSII–LHCII. In addition, some unique features were found in the green algal PSII core. The arrangement of a huge number of pigments allowed us to deduce possible energy transfer pathways from the peripheral antennae to the PSII core.

Acinetobacter baumannii is an important pathogen in hospital acquired infections. Although tigecycline currently remains a potent antibiotic for treating infections caused by multidrug resistant A. baumannii (MDRAB) strains, reports of tigecycline resistant isolates have substantially increased. The resistance mechanisms to tigecycline in A. baumannii are far more complicated and diverse than what has been described in the literature so far. Here, we characterize in vitro-selected MDRAB strains obtained by increasing concentrations of tigecycline. We have identified mutations in adeS, rrf and rpoB that result in reduced susceptibility to tigecycline. Using in situ complementation experiments, we confirm that mutations in rrf, rpoB, and two types of mutations in adeS correlate with tigecycline resistance. By Western blot and polysome profile analysis, we demonstrate that the rrf mutation results in decreased expression of RRF, which affects the process of ribosome recycling ultimately leading to increased tigecycline tolerance. A transcriptional analysis shows that the mutated rpoB gene plays a role in regulating the expression of the SAM-dependent methyltransferase (trm) and transcriptional regulators, to confer moderate tigecycline resistance. This study provides direct in vitro evidence that mutations in the adeS, rpoB and rrf are associated with tigecycline resistance in A. baumannii.

Additional file 1 : Table S1. Population demographics and baseline characteristics in this study. Table S2. Safety profiles of patients enrolled in dose-escalation study. Table S3. Pharmacokinetics parameters calculated from phase 1b trial. Table S4. Pharmacokinetics analysis from dose-escalation phase 1b trial. Table S5. Safety profiles of patients included in randomized studies

Photosystem II (PSII) in the thylakoid membranes of plants, algae, and cyanobacteria catalyzes light-induced oxidation of water by which light energy is converted to chemical energy and molecular oxygen is produced. In higher plants and most eukaryotic algae, the PSII core is surrounded by variable numbers of light-harvesting antenna complex II (LHCII), forming a PSII–LHCII supercomplex. In order to harvest energy efficiently at low–light-intensity conditions under water, a complete PSII–LHCII supercomplex (C(2)S(2)M(2)N(2)) of the green alga Chlamydomonas reinhardtii (Cr) contains more antenna subunits and pigments than the dominant PSII–LHCII supercomplex (C(2)S(2)M(2)) of plants. The detailed structure and energy transfer pathway of the Cr-PSII–LHCII remain unknown. Here we report a cryoelectron microscopy structure of a complete, C(2)S(2)M(2)N(2)-type PSII–LHCII supercomplex from C. reinhardtii at 3.37-Å resolution. The results show that the Cr-C(2)S(2)M(2)N(2) supercomplex is organized as a dimer, with 3 LHCII trimers, 1 CP26, and 1 CP29 peripheral antenna subunits surrounding each PSII core. The N-LHCII trimer partially occupies the position of CP24, which is present in the higher-plant PSII–LHCII but absent in the green alga. The M trimer is rotated relative to the corresponding M trimer in plant PSII–LHCII. In addition, some unique features were found in the green algal PSII core. The arrangement of a huge number of pigments allowed us to deduce possible energy transfer pathways from the peripheral antennae to the PSII core.

Background Breast cancer is the most frequent carcinoma in females, which could be classified to 4 subtypes and the current treatment is still far from satisfactory. In this study, we explored the effects of autophagy inhibition on certain subtypes of breast cancer and the molecular mechanism underlying the different response for breast cancer subtypes initially. Methods Autophagy inhibitor hydroxychloroquine (HCQ) was used to identify the sensitivity of breast cancer subtypes to autophagy inhibition in the present study. Cell proliferation and cell invasion were assessed by Cell Counting Kit-8 assay (CCK-8) and transwell assay, respectively. Immunofluorescence staining and western blotting were applied to evaluate cell autophagy. In addition, levels of Ras/Raf/ERK signaling pathway were evaluated by western blotting. Results Our results showed that HCQ treatment suppressed breast cancer cell proliferation and migration in especially SUM-190 cells, which was most sensitive. Furthermore, HCQ inhibited cell autophagy in breast cancer cells by regulating levels of p62, LC3-I and LC3-II. Moreover, the expression of Ras was significant lower than other breast cancer cells. HCQ treatment markedly inhibited the activation of Ras/Raf/ERK signaling in SUM190 cells. Conclusion To conclude, basal-like breast cancer represented by SUM-190 cells may be most sensitive to HCQ induced autophagy inhibition and the mechanism might be relative to Ras/Raf/ERK signaling pathway.

TPS1106 Background: Paclitaxel is a microtubule-stabilizing drug used for various cancers including breast cancer (BC) and gastric cancer (GC). DHP107 is an oral paclitaxel solution formulated with non-toxic excipients using DH-LASED technology, which doesn’t require pre-treatment. DHP107 demonstrated comparable efficacy and safety to IV paclitaxel for patients with advanced GC (Ann Oncol 2018), and was market approved as the first oral paclitaxel in 2016 for GC in Korea. In previous OPTIMAL phase II study, the primary endpoint objective response rate (ORR) was 54.5% in HER2 negative metastatic BC (MBC) patients and 44.4% in triple negative BC (TNBC) patients. Disease control rate (DCR) was 90.9% by the investigators’ assessment. Toxicity was manageable (2019 ESMO). OPTIMAL phase III is being conducted in Korea, China and Eastern Europe based on this result and another phase II study (OPERA) is being performed in USA. Methods: OPTIMAL 3 study is a multinational, multi-center, randomized and open-label trial enrolling HER2 negative (HR+/HER2- or TNBC) recurrent or metastatic BC patients. Patients are randomized to either study (DHP107) or control group (IV paclitaxel) in a 1:1 ratio and stratified by disease free interval (DFI≤48 weeks vs >48 weeks), visceral metastasis status (visceral vs non-visceral) and country. Patients are administrated with DHP107 (200mg/m2 p.o. bid) or IV paclitaxel (80mg/m2 infused) on D1, 8, 15, q4wks. Tumor assessments are performed on every 8 weeks (±7 days) from C1D1 until disease progression (RECIST V1.1). Key inclusion & exclusion criteria are hormone receptor (ER/PR) positive or negative, HER2 negative, ECOG performance status ≤1 and no prior chemotherapy in recurrent or metastatic disease. The primary endpoint is progression free survival (PFS). Secondary endpoints include ORR, overall survival (OS), time to treatment failure (TTF), DCR, quality of life (QoL) and safety. Total target number of patients is 476 with an estimated 10% drop-out rate. The test is based on non-inferiority hypothesis (HR=1.33) with 80% power. The primary endpoint will be analyzed using a one-sided test at a 2.5% significance level, and other endpoints will be analyzed using a two-sided test at a 5% significance level, with 95% confidence interval. The first subject was enrolled in Jan 2019 and recruitment is ongoing and is expected to be completed in Dec 2020. Final results of this study will be announced by the end of 2022. Clinical trial information: NCT03315364 .

Objective: To explore the optimal dose of L-arginine to prevent acute high-dose (HD)-PDD nephrotoxicity. Methods: 128 cases using PDD with the dosage of 100 mg/m2 within two days (D1, 2) in combination with L-arginine were randomly divided into 3 groups of A, B and C. The dosages of Larginine in the 3 groups were 5 g/(m2·d), 10 g/(m2·d) and 15 g/(m2·d), respectively. Each patient received 2 cycles chemotherapy to form self control: 1 cycle combined with L-arginine, while 1 cycle chemotherapy alone. s2-MG in urine, BUN, Cr and uric acid in blood were detected just 24 h before and after using PDD. The changes of each index in the three groups were observed in the presence or absence, and the therapeutic effects were compared among the three groups. Results: There was no significant difference in BUN, Cr and uric acid in blood before and after chemotherapy in the presence or absence, showing these indexes could not be used as markers of early acute nephrotoxicity. Urine s2-MG values in the presence and absence were 0.9120±0.6618 vs 1.5167±0.7908 (P

Take-all, caused by soil-borne fungus Gaeumannomyces graminis var. tritici (Ggt), is a devastating root disease of wheat (Triticum aestivum) worldwide. Breeding resistant wheat cultivars is the most promising and reliable approach to protect wheat from take-all. Currently, no resistant wheat germplasm is available to breed cultivars using traditional methods. In this study, gene transformation was carried out using Snakin-1 (SN1) gene isolated from potato (Solanum tuberosum) because the peptide shows broad-spectrum antimicrobial activity in vitro. Purified SN1 peptide also inhibits in vitro the growth of Ggt mycelia. By bombardment-mediated method, the gene SN1 was transformed into Chinese wheat cultivar Yangmai 18 to generate SN1 transgenic wheat lines, which were used to assess the effectiveness of the SN1 peptide in protecting wheat from Ggt. Genomic PCR and Southern blot analyses indicated that the alien gene SN1 was integrated into the genomes of five transgenic wheat lines and heritable from T₀ to T₄ progeny. Reverse transcription-PCR and Western blot analyses showed that the introduced SN1 gene was transcribed and highly expressed in the five transgenic wheat lines. Following challenging with Ggt, disease test results showed that compared to segregants lacking the transgene and untransformed wheat plants, these five transgenic wheat lines expressing SN1 displayed significantly enhanced resistance to take-all. These results suggest that SN1 may be a potentially transgenic tool for improving the take-all resistance of wheat.