Clinical significance of serum estradiol monitoring in women receiving adjuvant aromatase inhibitor for hormone receptor-positive early breast cancer.

PURPOSE: The limited understanding of long-term estradiol (E2) suppression poses challenges to the effectiveness of adjuvant therapy with aromatase inhibitors (AI), necessitating comprehensive serum E2 monitoring to address this issue. Therefore, our objective was to investigate serum E2 levels in women undergoing adjuvant AI treatment and evaluate the significance of such monitoring. PATIENTS AND METHODS: In this prospective cohort study, we recruited women who had received adjuvant AI treatment, including those who underwent ovarian function suppression (OFS). Serum E2 levels were measured using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The primary endpoint was the proportion of women with E2 levels exceeding 2.72 pg/mL, indicating inadequate suppression achieved with AI therapy. RESULTS: A total of 706 patients were enrolled, including 482 women with OFS in combination with AI. Among them, 116 women (16.4 %) exhibited E2 levels exceeding 2.72 pg/mL. The majority of serum E2 elevations (77.6 %) occurred within the first two years of initiating endocrine therapy. Younger age, no prior chemotherapy, shorter duration of the current treatment regimen, and lower follicle stimulating hormone (FSH) levels were associated with inadequate E2 suppression. Serum E2 concentrations demonstrated dynamic variations and occasional rebound following adjuvant AI therapy. CONCLUSIONS: Despite receiving adjuvant AI treatment for nearly two years, a certain proportion of patients failed to achieve the adequate threshold of E2 suppression. Our findings emphasize the significance of monitoring serum E2 levels during adjuvant AI therapy, particularly within the first two years. Further research is imperative to facilitate a more comprehensive comprehension of E2 monitoring.

Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells.

Inflammatory signals lead to recruitment of circulating monocytes and induce their differentiation into pro-inflammatory macrophages. Therefore, whether blocking inflammatory monocytes can mitigate disease progression is being actively evaluated. Here, we employ multiple lineage-tracing models and show that monocyte-derived macrophages (mo-mac) are the major population of immunosuppressive, liver metastasis-associated macrophages (LMAM), while the proportion of Kupffer cells (KC) as liver-resident macrophages is diminished in metastatic nodules. Paradoxically, genetic ablation of mo-macs results in only a marginal decrease in LMAMs. Using a proliferation-recording system and a KC-tracing model in a monocyte-deficient background, we find that LMAMs can be replenished either via increased local macrophage proliferation or by promoting KC infiltration. In the latter regard, KCs undergo transient proliferation and exhibit substantial phenotypic and functional alterations through epigenetic reprogramming following the vacating of macrophage niches by monocyte depletion. Our data thus suggest that a simultaneous blockade of monocyte recruitment and macrophage proliferation may effectively target immunosuppressive myelopoiesis and reprogram the microenvironment towards an immunostimulatory state.

Improving efficacy of TNBC immunotherapy: based on analysis and subtyping of immune microenvironment.

Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer that encompasses several distinct subtypes. Recent advances in immunotherapy offer a promising future for the treatment of these highly heterogeneous and readily metastatic tumors. Despite advancements, the efficacy of immunotherapy remains limited as shown by unimproved efficacy of PD-L1 biomarker and limited patient benefit. To enhance the effectiveness of TNBC immunotherapy, we conducted investigation on the microenvironment, and corresponding therapeutic interventions of TNBC and recommended further investigation into the identification of additional biomarkers that can facilitate the subtyping of TNBC for more targeted therapeutic approaches. TNBC is a highly aggressive subtype with dismal long-term survival due to the lack of opportunities for traditional endocrine and targeted therapies. Recent advances in immunotherapy have shown promise, but response rates can be limited due to the heterogeneous tumor microenvironments and developed therapy resistance, especially in metastatic cases. In this review, we will investigate the tumor microenvironment of TNBC and corresponding therapeutic interventions. We will summarize current subtyping strategies and available biomarkers for TNBC immunotherapy, with a particular emphasis on the need for further research to identify additional prognostic markers and refine tailored therapies for specific TNBC subtypes. These efforts aim to improve treatment sensitivity and ultimately enhance survival outcomes for advanced-stage TNBC patients.

Coating seeds with biocontrol bacteria-loaded sodium alginate/pectin hydrogel enhances the survival of bacteria and control efficacy against soil-borne vegetable diseases.

Microbial seed coatings serve as effective, labor-saving, and ecofriendly means of controlling soil-borne plant diseases. However, the survival of microbial agents on seed surfaces and in the rhizosphere remains a crucial challenge. In this work, we embedded a biocontrol bacteria (Bacillus subtilis ZF71) in sodium alginate (SA)/pectin (PC) hydrogel as a seed coating agent to control Fusarium root rot in cucumber. The formula of SA/PC hydrogel was optimized with the highest coating uniformity of 90 % in cucumber seeds. SA/PC hydrogel was characterized using rheological, gel content, and water content tests, thermal gravimetric analysis, and Fourier transform infrared spectroscopy. Bacillus subtilis ZF71 within the SA/PC hydrogel network formed a biofilm-like structure with a high viable cell content (8.30 log CFU/seed). After 37 days of storage, there was still a high number of Bacillus subtilis ZF71 cells (7.23 log CFU/seed) surviving on the surface of cucumber seeds. Pot experiments revealed a higher control efficiency against Fusarium root rot in ZF71-SA/PC cucumber seeds (53.26 %) compared with roots irrigated with a ZF71 suspension. Overall, this study introduced a promising microbial seed coating strategy based on biofilm formation that improved performance against soil-borne plant diseases.

Clinical outcome and prognostic factors for immunotherapy-based treatments in patients with platinum-refractory germ cell tumor.

BACKGROUND: Germ cell tumors (GCTs) are a heterogeneous group of cancers associated with a favorable prognosis when treated with platinum-based chemotherapy. However, patients with platinum-refractory GCTs face limited options and poorer outcomes, necessitating innovative treatment approaches. This study aims to evaluate the clinical outcomes and identify prognostic factors associated with immunotherapy-based treatments in this challenging patient population. METHODS: This retrospective analysis included individuals with platinum-refractory GCTs treated with immunotherapy between 2017 and 2023. Clinical outcomes, safety, and biomarkers were analyzed. RESULTS: The study included 37 male patients with a median age of 26 years (range: 18-65). The overall response rate was 24.32 %, with a median progression-free survival (PFS) and overall survival (OS) of 4.67 months and 22.67 months, respectively. Patients with both serum levels of alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) below 100 (AFP & hCG < 100) demonstrated significantly better PFS and OS. Multivariate analysis indicated that lower serum tumor marker levels (AFP & hCG < 100) and treatment initiation at earlier lines were significantly associated with improved PFS. Notably, genomic analysis revealed that one patient with an MDM4 mutation experienced hyperprogression after the initiation of immunotherapy. Immune-related adverse events occurred in two patients: one developed grade 1 hyperthyroidism, and the other experienced grade 2 immune-related pneumonitis. CONCLUSIONS: Immunotherapy offers a promising treatment option for selected patients with platinum-refractory GCTs, demonstrating moderate response rates and potential survival benefits in a real-world scenario. Identifying specific prognostic factors may help tailor treatment strategies and enhance outcomes in this challenging patient cohort.

Eribulin plus carboplatin combination for HER2-negative metastatic breast cancer: a multicenter, real-world cohort study.

BACKGROUND: Pre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC. PATIENTS AND METHODS: This multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. RESULTS: From March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 - mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 - subtype. The median treatment was 6 cycles (range, 2 - 8 cycles). In the full cohort, TNBC, and HR + HER2 - subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed. CONCLUSION: ErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment.

Transcriptome analysis provides new insight into the mechanism of Bombyx mori under zinc exposure.

Zinc is a significant source of heavy metal pollution that poses risks to both human health and biodiversity. Excessive concentrations of zinc can hinder the growth and development of insects and trigger cell death through oxidative damage. The midgut is the main organ affected by exposure to heavy metals. The silkworm, a prominent insect species belonging to the Lepidoptera class and widely used in China, serves as a model for studying the genetic response to heavy metal stress. In this study, high-throughput sequencing technology was employed to investigate detoxification-related genes in the midgut that are induced by zinc exposure. A total of 11,320 unigenes and 14,723 transcripts were identified, with 553 differentially expressed genes (DEGs) detected, among which 394 were up-regulated and 159 were down-regulated. The Gene Ontology (GO) analysis revealed that 452 DEGs were involved in 18 biological process subclasses, 14 cellular component subclasses and 8 molecular functional subclasses. Furthermore, the KEGG analysis demonstrated enrichment in pathways such as Protein digestion, absorption and Lysosome. Validation of the expression levels of 9 detoxification-related DEGs through qRT-PCR confirmed the accuracy of the RNA-seq results. This study not only contributes new insights into the detoxification mechanisms mechanism of silkworms against zinc contamination, but also serves as a foundation basis for understanding the molecular detoxification processes in lepidopteran insects.

First Report of Xanthomonas campestris pv. raphani Causing Leaf Spot Disease on Broccoli in China.

Broccoli (Brassica oleracea L. var. italica) is one of the important cruciferous vegetables in China, known for its considerable economic and nutritional value (Li et al. 2021). In September 2023, leaf spot disease was observed on broccoli seedlings in the commercial fields in Weifang City, Shandong Province, China (119°15'E, 36°70'N). Further investigation revealed that the disease incidence was approximately 60% in 4.5 square hectometers (hm2) broccoli field, resulting in substantial economic losses. This disease primarily affects the leaves, manifesting distinct symptoms such as circular, dark necrotic spots that gradually lighten and are encircled by a chlorotic halo. Some lesions further develop a black or purplish border, exhibit concentric zonation, and eventually fall off, leaving behind holes, as shown in Figure S1B and C. In severe cases, decay originates from the central perforation and spreads outwards, as shown in Figure S1A. To identify the causal agent of this disease, infected leaf tissues were collected and surface disinfected by immersing in 75% ethanol for 30 seconds, followed by three rinses with sterile water. The samples were grinded in sterile deionized water, and the extract was plated on NA. After incubation at 28°C for 48 h, individual colonies were transferred to fresh NA plates. A total of 12 strains with the similar morphological characteristics were isolated from diseased samples collected from the three plots. After 48 hours of growth on NA medium at 28℃, each colony attained a diameter ranging from 3 to 5 mm. These colonies appeared yellow, slightly elevated, nearly circular in shape, with a smooth and moist edge. Three representative strains were selected for further investigation. All strains were Gram-negative, aerobic, and rod-shaped. The analysis of BIOLOG GENIII microplate system revealed the capability of three isolates using cellobiose, trehalose, glucose, mannose, galactose, and sucrose. Furthermore, the isolates were unable to hydrolyze arginine and utilize rhamnose and inositol. The 16S rRNA gene was amplified and sequenced to confirm that three isolated bacteria belong to the genus Xanthomonas (OR772321-OR772323), followed by PCR amplification for 4 housekeeping genes atpD, dnaK, gyrB, and rpoD (Young et al. 2008; Saux et al. 2015). The obtained sequences were submitted to the GenBank under accessions OR789628-OR789630, OR785471-OR785473, OR789631-OR789633, and OR785468-OR785470. Gene sequences were aligned, concatenated, and used to generate a phylogenetic tree using the neighbor-joining method in MEGA11 (Tamura et al. 2021). The phylogenetic analysis revealed that all the three isolates were clustered with Xanthomonas campestris pv. raphani strains 5055 and 576, respectively (Figure S2). (Dubrow et al. 2022). These results were consistent with those of the reported X. campestris pv. raphanin (Cruz et al. 2015). To verify the pathogenicity of these strains, we used a spray inoculation method. In detail, bacterial suspensions (30 mL per treatment) containing approximately 108 CFU/ml were sprayed onto healthy, four-week-old broccoli plants and incubated in a phytotron at 28°C and above 90% RH. Negative controls were performed using sterile distilled water. Each isolate underwent three trials and each treatment included 12 broccoli seedlings. Leaf spot symptoms were observed on 5 days post inoculation, as shown in Figure S1E, F and G. Negative control plants showed no symptoms (Figure S1D). We further re-isolated the bacterium from the symptomatic plants and verifying the bacteria as X. campestris pv. raphanin with the aforementioned sequence analysis, thereby fulfilling Koch's postulates. To our knowledge, this is the first report of X. campestris pv. raphani causing leaf spot disease on broccoli in China. This study enhances our understanding of the pathogenic bacterium on broccoli and lays the groundwork for developing targeted management strategies.

Correlative analysis of transcriptome and 16S rDNA in Procambarus clarkii reveals key signaling pathways are involved in Chlorantraniliprole stress response by phosphoinositide 3-kinase (PI3K).

Chlorantraniliprole (CAP), a diamide insecticide, is extensively used in agricultural production. With the increasing adoption of the rice-crayfish integrated farming model, pesticide application has become more frequent. However, the potential risk of CAP to crayfish (Procambarus clarkii) remains unclear. In this study, crayfish were exposed to 30, 60, 90 mg/L CAP for 96 h. As CAP exposure time and concentration increased, crayfish survival rates and total hemocyte counts (THC) decreased. Biochemical indicators revealed that CAP exposure induced oxidative stress and immunosuppression in crayfish, leading to metabolic disorders and reduced ATP content. Additionally, pathological analysis and 16S rDNA sequencing demonstrated that CAP exposure compromised the intestinal barrier of crayfish, altered the intestinal microbial community structure, and caused apoptosis. Differential gene expression analysis showed that CAP exposure significantly suppressed the expression of genes related to immune and energy metabolism pathways, resulting in immune dysfunction and insufficient energy supply, while activating the PI3K/AKT/mTOR signaling pathway. PI3K knockdown reduced antioxidant and digestive activities, increased the expression of proinflammatory and apoptosis genes, and exacerbated CAP-induced intestinal toxicity. This study is the first to explore the characterization and function of PI3K in crustaceans, providing new insights for further research on crustacean antioxidants and defense mechanisms.

A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta (POLE/POLD1) mutation.

Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors. Yet, prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking. A phase II clinical trial was initiated to evaluate the efficacy of toripalimab, a humanized IgG4K monoclonal antibody to human PD-1, in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high. A total of 15 patients were enrolled, 14 of whom were assessed for treatment efficacy. There was a 21.4% overall response rate, with a disease control rate of 57.1%. The median overall survival and median progression-free survival were 17.9 (95% CI 13.5-not reach) months and 2.5 (95% CI 1.4-not reach) months, respectively. For patients with exonuclease domain mutations, the objective response rate was 66.7% (2/3), with a disease control rate of 66.7% (2/3). For those with non-exonuclease domain mutations, the rates were 9.1% (1/11) and 54.5% (6/11), respectively. Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.

Seed coating with biocontrol bacteria encapsulated in sporopollenin exine capsules for the control of soil-borne plant diseases.

Coating seeds with biocontrol agents represents an effective approach for managing soil-borne plant diseases. However, improving the viability of biocontrol microorganisms on the seed surface or in the rhizosphere remains a big challenge due to biotic and abiotic stresses. In this work, we developed a microbial seed coating strategy that uses sporopollenin exine capsules (SECs) as carriers for the encapsulation of the biofilm-like biocontrol bacteria. SECs was extracted from camellia bee pollen, and then characterized by Fourier Transform infrared spectroscopy (FTIR), elemental analysis and thermal gravity analysis (TG). The Paenibacillus polymyxa ZF129, a biocontrol bacterium, was introduced into SECs using the vacuum-incubation method and characterized by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Notably, the ZF129 cell formed a biofilm-like structure inside the SECs, which enhanced their tolerance to acidic stress. As a proof of concept, we applied ZF129-loaded SECs to coat pak choi seeds using a straightforward plate-shaking technique. The coated seeds demonstrated a high control efficacy of up to 60.46 % against clubroot disease. Overall, this study sheds light on the application of SECs as promising carrier for the encapsulation of biofilm-like biocontrol bacteria, further augmenting the biocontrol functionality of microbial seed coating.

A pooled analysis of clinical outcome in driver-gene negative non-small cell lung cancer patients with MET overexpression treated with gumarontinib.

Background: MET overexpression represents the most MET aberration in advanced non-small-cell lung cancer (NSCLC). However, except MET exon 14 (METex14) skipping mutation was recognized as a clinical biomarker, the role of MET overexpression as a predictive factor to MET inhibitor is not clear. Objectives: The purpose of the pooled analysis is to explore the safety and efficiency of gumarontinib, a highly selective oral MET inhibitor, in drive-gene negative NSCLC patients with MET overexpression. Design and methods: NSCLC patients with MET overexpression [immunohistochemistry (IHC) ⩾3+ as determined by central laboratory] not carrying epidermal growth factor receptor mutation, METex14 skipping mutation or other known drive gene alternations who received Gumarontinib 300 mg QD from two single arm studies were selected and pooled for the analysis. The efficacy [objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS)] and safety [treatment emergent adverse event (TEAE), treatment related AE (TRAE) and serious AE (SAE) were assessed. Results: A total of 32 patients with MET overexpression were included in the analysis, including 12 treatment naïve patients who refused or were unsuitable for chemotherapy, and 20 pre-treated patients who received ⩾1 lines of prior systemic anti-tumour therapies. Overall, the ORR was 37.5% [95% confidence interval (CI): 21.1-56.3%], the DCR was 81.3% (95% CI: 63.6-92.8%), median PFS (mPFS) and median OS (mOS) were 6.9 month (95% CI: 3.6-9.7) and 17.0 month (95% CI: 10.3-not evaluable), respectively. The most common AEs were oedema (59.4%), hypoalbuminaemia (40.6%), alanine aminotransferase increased (31.3%). Conclusion: Gumarontinib showed promising antitumour activity in driver-gene negative locally advanced or metastatic NSCLC patients with MET overexpression, which warranted a further clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT03457532; NCT04270591.

First Report of Gibellulopsis nigrescens Causing Yellow Wilt on Chinese Cabbage in China.

Chinese cabbage (Brassica rapa L. ssp. pekinensis), in the family Brassicaceae, is a widely planted crop in China valued for its nutritional benefits. In May 2023, wilt symptoms on Chinese cabbage (cv. 'Dongtian118') were observed in several commercial fields located in Sheqi County, (32.47ºN, 112.46ºE), Nanyang, Henan Province, China. A disease survey noted that disease incidence on plants was approximately 20% to 50% within observed fields. Symptoms included yellowing and wilting leaves, and vascular discoloration of the stem bases. To isolate the pathogen, ten symptomatic leaves collected from different diseased cabbage in two field were cut into small pieces (5 × 5 mm), surface disinfected with 75% ethanol for 30 s, then washed three times in sterile water. After drying, tissues were transferred onto potato dextrose agar (PDA). Plates were incubated at 28℃ for 7 days in the dark. Twelve morphologically similar fungal isolates were obtained by single-spore subculture. The mycelia on PDA were originally white, later becoming dark gray due to the formation of masses of melanized chlamydospores after 15 days of culture. Conidiophores were hyaline and most had secondary branches. In addition, verticillate branches had three to four phialides in each whorl. The conidia were hyaline, elliptical or nearly circular, measuring from 3.2 to 9.5 × 2.6 to 3.8 µm (n=40). These morphological characteristics were similar to those described for Gibellulopsis nigrescens (Zare et al. 2007). The isolates were further identified based on PCR amplification. The ITS, GAPDH, and TEF1 genes were amplified using primers ITS1/ITS4, VGPDf2/VGPDr (Inderbitzin et al. 2011) and EF-2/EF1-728F (O'Donnell et al. 1998). BLAST analysis revealed 12 isolates were highly similar to G. nigrescens, with 99.82% similarity for ITS (OR818474, KJ534578), 93.17% similarity for GAPDH (JN188192.1, JN188166.1) and 91.07% similarity for TEF1 (EF543798.1, EF543804.1). Sequences of the representative isolate BC230515 were deposited into NCBI GenBank with accession nos. OR889646 for ITS and PP135039 for GAPDH. Pathogenicity of all 12 isolates was tested on potted Chinese cabbage plants (cv. 'Dongtian118'). Twenty-four healthy Chinese cabbage plants were inoculated by applying a 10 mL conidial suspension (1×107 conidial/mL) at the artificially wounded root region of each plant. Twenty-four control plants wounded similarly were treated with sterile distilled water. All plants were kept in a growth chamber at 22~25°C (day)/18~20°C (night) , 85% relative humidity and a photoperiod of 12 h per day. After 15 days, inoculated plants exhibited wilting symptoms similar to those observed in the field, whereas control plants remained healthy. The pathogenicity test was repeated three times. The associated fungus on the artificially inoculated plants was reisolated from the symptomatic leaves, and its identity was confirmed by PCR with the primers described above. Reisolated G. nigrescens had identical morphological and molecular characteristics to the original isolates, confirming Koch's postulates. To our knowledge, this is the first report of G. nigrescens causing yellowing and wilt of Chinese cabbage in China. G. nigrescens is a destructive pathogen with multiple hosts such as beet (Zhou et al. 2017), alfalfa (Hu et al. 2011), prevention and control measures should be taken in advance.

Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody-drug conjugates-induced interstitial lung disease/pneumonitis: An expert consensus in China.

Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.

Pyrotinib and trastuzumab plus palbociclib and fulvestrant in HR+/HER2+ breast cancer patients with brain metastasis.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients are at a high risk of developing metastases in the brain. However, research focusing on treatment strategies for hormonal receptor positive (HR+), HER2+ BC patients with brain metastases (BM) remains limited. Thus, a multi-center, prospective trial was conducted in China. Women over the age of 18 who were naive to whole brain radiotherapy and had estrogen receptor (ER)/progesterone-receptor (PgR) positive, HER2+ BM were treated with palbociclib, fulvestrant, trastuzumab and pyrotinib, until disease progression or the development of intolerable side effects. The primary endpoint was objective response rate (ORR) in the central nervous system (CNS). This ongoing study is still recruiting participants and is registered with ClinicalTrials.gov (NCT04334330). This report presents the findings from an interim analysis. From December 4, 2020, to November 2, 2022, 15 patients were enrolled. Among the 14 patients who were evaluable for clinical response, the ORR was 35.7% (95% CI: 12.8-64.9%), with a CNS-ORR of 28.6% (95% CI: 8.4-58.1%). The median follow-up period was 6.3 months (range, 2.1-14.3 months), during which the median progression-free survival (PFS) was 10.6 months (95% CI: 4.3-16.9 months), and the median time to CNS progression was 8.5 months (95% CI: 5.9-11.1 months). The most common adverse event was diarrhea (93%), with 33% having grade 3 and 6.7% having grade 4. The study suggests that the combination of palbociclib, trastuzumab, pyrotinib and fulvestrant offers a promising chemo-free treatment strategy for HR+, HER2+ BC patients with BM.

Transcriptome Analysis Reveals Antioxidant Defense Mechanisms in the Silkworm Bombyx mori after Exposure to Lead.

Lead (Pb) is a major source of heavy metal contamination, and poses a threat to biodiversity and human health. Elevated levels of Pb can hinder insect growth and development, leading to apoptosis via mechanisms like oxidative damage. The midgut of silkworms is the main organ exposed to heavy metals. As an economically important lepidopteran model insect in China, heavy metal-induced stress on silkworms causes considerable losses in sericulture, thereby causing substantial economic damage. This study aimed to investigate Pb-induced detoxification-related genes in the midgut of silkworms using high-throughput sequencing methods to achieve a deeper comprehension of the genes' reactions to lead exposure. This study identified 11,567 unigenes and 14,978 transcripts. A total of 1265 differentially expressed genes (DEGs) were screened, comprising 907 upregulated and 358 downregulated genes. Subsequently, Gene Ontology (GO) classification analysis revealed that the 1265 DEGs were distributed across biological processes, cellular components, and molecular functions. This suggests that the silkworm midgut may affect various organelle functions and biological processes, providing crucial clues for further exploration of DEG function. Additionally, the expression levels of 12 selected detoxification-related DEGs were validated using qRT-PCR, which confirmed the reliability of the RNA-seq results. This study not only provides new insights into the detoxification defense mechanisms of silkworms after Pb exposure, but also establishes a valuable foundation for further investigation into the molecular detoxification mechanisms in silkworms.

First report of Pectobacterium brasiliense causing soft rot on leaf mustard in China.

Leaf mustard (Brassica juncea [L.] Czern. et Coss.) belongs to Brassicaceae and is an important leaf vegetable widely cultivated in the Yangtze River basin and various southern provinces in China. In August 2023, the rhizome decay symptoms were observed at the stem base of leaf mustard plants (cv. Huarong) in the field of Changde City (29.05 °N; 111.59 °E), Hunan Province, China. The incidence of symptomatic leaf mustard was approximately 30% in several fields (2 ha in total). Brown and water-soaked symptoms appeared at the base of the outer leaves, and hollow rot at the base of the stem, accompanied by a fishy odor. To identify the causal agent, six infected stem samples were collected and surface sterilized by soaking in 75% ethanol for 60 seconds, rinsed three times with sterile distilled water, and finally cut into pieces (5 × 5 mm) in the sterile water. The extract was streaked on nutrient agar medium. After incubation at 28°C for 24 h, 17 strains were obtained and the colonies of all strains were creamy white, roughly circular, and convex elevation. Six single bacterial strains JC23121001-JC23121006, individually isolated from six different diseased stem samples, were selected as representative strains for further study. For preliminary identification, DNA from the six strains was extracted and identified by 16S rDNA sequencing using the universal primer pair 27F/1492R (Weisburg et al. 1991), and the sequences (accession nos. PP784484 to PP784489) showed 99% query coverage and 99.65% identity to Pectobacterium brasiliense type strain IBSBF1692T (Nabhan et al. 2012). In addition, five housekeeping genes acnA, mdh, mltD, pgi, and proA of the six strains were amplified with specially designed primers (Ma et al. 2007), and the resulting sequences from all six strains were 100% identical. The sequences of the representative strain JC23121001 were deposited into GenBank with accession numbers PP108247, PP066857, PP108248, PP066858, and PP066860, respectively. The maximum-likelihood phylogenetic tree clustered JC23121001 with P. brasiliense type strain IBSBF1692T (Nabhan et al. 2012). The pathogenicity test of six strains was carried out on the six-week-old leaf mustard (cv. Huarong) plants grown in the greenhouse by inoculating 10 µl of each bacterial suspension (108 CFU/ml) on needle-like wounds on the stem base of three healthy leaf mustard plants (Singh et al. 2013). Control plants were treated with sterile distilled water. After inoculation, the plants were incubated at 28°C and 90% relative humidity in a growth chamber. This trial was repeated three times. All inoculated mustard stems were slightly water-soaked after 24 hours and eventually developed into soft rot symptoms, consistent with the original symptoms observed. The control plants remained symptom-free. The strains were re-isolated from inoculated plants and re-identified as P. brasiliense by sequencing five housekeeping genes, thus fulfilling Koch's postulates. P. brasiliense has a broad host range and has been reported on other Brassica species, such as Bok choy (Brassica rapa var. chinensis) in China (Li et al. 2023). Soft rot of leaf mustard caused by Pectobacterium aroidearum has also been reported previously (Chu et al. 2023). To our knowledge, this is the first report of P. brasiliense causing soft rot on leaf mustard in China. The soft rot poses a significant threat to the local leaf mustard industry and requires further research into epidemiology and disease management options.

Screening optimal candidates with operable, early-stage triple-negative breast cancer benefitting from capecitabine maintenance: A post-hoc analysis of the SYSUCC-001 study.

BACKGROUND: To explore whether specific clinicopathological covariates are predictive for a benefit from capecitabine maintenance in early-stage triple-negative breast cancer (TNBC) in the SYSUCC-001 phase III clinical trial. METHODS: Candidate covariates included age, menstrual status, type of surgery, postoperative chemotherapy regimen, Ki-67 percentage, histologic grade, primary tumor size, lymphovascular invasion, node status, and capecitabine medication. Their nonlinear effects were modeled by restricted cubic spline. The primary endpoint was disease-free survival (DFS). A survival prediction model was constructed using Cox proportional hazards regression analysis. RESULTS: All 434 participants (306 in development cohort and 128 in validation cohort) were analyzed. The estimated 5-year DFS in development and validation cohorts were 77.8 % (95 % CI, 72.9%-82.7 %) and 78.2 % (95 % CI, 70.9%-85.5 %), respectively. Age and node status had significant nonlinear effects on DFS. The prediction model constructed using four covariates (node status, lymphovascular invasion, capecitabine maintenance, and age) demonstrated satisfactory calibration and fair discrimination ability, with C-index of 0.722 (95 % CI, 0.662-0.781) and 0.764 (95 % CI, 0.668-0.859) in development and validation cohorts, respectively. Moreover, patient classification was conducted according to their risk scores calculated using our model, in which, notable survival benefits were reported in low-risk subpopulations. An easy-to-use online calculator for predicting benefit of capecitabine maintenance was also designed. CONCLUSIONS: The evidence-based prediction model can be readily assessed at baseline, which might help decision making in clinical practice and optimize patient stratification, especially for those with low-risk, capecitabine maintenance might be a potential strategy in the early-disease setting.

Optimal Sequential Strategies for Antibody-Drug Conjugate in Metastatic Breast Cancer: Evaluating Efficacy and Cross-Resistance.

BACKGROUND: The optimal sequential strategy for antibody-drug conjugates (ADCs) in breast cancer remains uncertain. This study aimed to evaluate the efficacy and potential resistance of second ADC (ADC2) following the first ADC (ADC1) in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low MBC. METHODS: This retrospective, multicenter, real-world study enrolled patients with MBC who received at least 2 different types of ADCs in 3 hospitals in China between July 1, 2017 and May 1, 2023. Outcomes included the objective response rate (ORR) for ADC1 and ADC2, progression free survival 2 (PFS2), defined as the time from initiation of ADC2 to progression, and overall survival (OS). RESULTS: Seventy-nine female patients were included, 64 of whom had HER2-positive disease. The ORR for ADC2 with similar payload of ADC1 was found to be 5.3%. When switching to a different payload, the ORR of ADC2 increased to 22.6%. The PFS2 for ADC2 remained similar regardless of whether the payload was similar or different. Switching to different payload showed a higher ORR in patients with rapid progression and a durable response longer than 6 months (41.2% vs 15.0%). Specifically, significantly longer PFS2 and OS were seen in patients treated with trastuzumab deruxtecan (T-Dxd) compared to those treated with disitamab vedotin (RC48) after progression from trastuzumab emtansine (T-DM1; median PFS2 5.37 months vs 3.30 months, HR = 0.40, 95% CI 0.17-0.93, P = .034; median OS 50.6 months vs 20.2 months, HR = 0.27, 95% CI 0.08-0.91, P = .034). For patients who progressed after T-Dxd, the median PFS2 was 6.05 months for those treated with RC48 versus 0.93 months for those treated with T-DM1 (HR = 0.03, 95% CI 0.002-0.353, P = .0093). Genomic analysis revealed that alternation of retinoblastoma1 was significantly associated with superior PFS. CONCLUSION: The alternation of payload achieves different responses in different settings. T-Dxd followed by RC48 may be a potentially beneficial strategy in HER2-positive disease. Further research is needed to elucidate the mechanism of cross-resistance.