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Abstract Background HER2-targeted antibody–drug conjugates (ADCs) have revolutionized the treatment landscape of metastatic breast cancer. However, the efficacy of these therapies may be compromised by genomic alterations. Hence, this study aims to identify factors predicting sensitivity to HER2 ADC in metastatic breast cancer. Methods This comprehensive real-world retrospective study collected clinical data from patients diagnosed with metastatic breast cancer and performed genomic profiling using targeted next-generation sequencing. The study analyzed the associations between genomic alterations and clinical outcomes of HER2 ADC treatment. Results Sixty-three patients were included in this study, 33 with HER2-low breast cancer and 30 with HER2-positive breast cancer, respectively. The most frequently altered genes were TP53 (69%), PIK3CA (45%), MYC (35%), and ERBB2 (35%). Patients with amplifications in cell cycle-related genes showed inferior median progression-free survival (PFS) than those without amplifications (2.07 months vs. 8.40 months; HR = 5.24; 95% CI 2.11–13.01; p

Abstract 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.

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.

Abstract Background Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide, characterized by persistent respiratory symptoms and airflow limitation. The involvement of C–C motif chemokine ligand 2 (CCL2) in COPD pathogenesis, particularly in macrophage regulation and activation, is poorly understood despite its recognized role in chronic inflammation. Our study aims to elucidate the regulatory role and molecular mechanisms of CCL2 in the pathogenesis of COPD, providing new insights for therapeutic strategies. Methods This study focused on the CCL2-CCR2 signaling pathway, exploring its role in COPD pathogenesis using both Ccl2 knockout (KO) mice and pharmacological inhibitors. To dissect the underlying mechanisms, we employed various in vitro and in vivo methods to analyze the secretion patterns and pathogenic effects of CCL2 and its downstream molecular signaling through the CCL2-CCR2 axis. Results Elevated Ccl2 expression was confirmed in the lungs of COPD mice and was associated with enhanced recruitment and activation of macrophages. Deletion of Ccl2 in knockout mice, as well as treatment with a Ccr2 inhibitor, resulted in protection against CS- and LPS-induced alveolar injury and airway remodeling. Mechanistically, CCL2 was predominantly secreted by bronchial epithelial cells in a process dependent on STAT1 phosphorylation and acted through the CCR2 receptor on macrophages. This interaction activated the PI3K-AKT signaling pathway, which was pivotal for macrophage activation and the secretion of inflammatory cytokines, further influencing the progression of COPD. Conclusions The study highlighted the crucial role of CCL2 in mediating inflammatory responses and remodeling in COPD. It enhanced our understanding of COPD's molecular mechanisms, particularly how CCL2's interaction with the CCR2 activates critical signaling pathways. Targeting the CCL2-CCR2 axis emerged as a promising strategy to alleviate COPD pathology. Graphical Abstract

Abstract Background Ferroptosis is associated with the pathological progression of hemorrhagic injury and ischemia–reperfusion injury. According to our previous study, exosomes formed through bone marrow mesenchymal stem cells modified with miR-340-3p (MB-exos) can restore damaged endometrium. However, the involvement of ferroptosis in endometrial injury and the effect of MB-exos on ferroptosis remain elusive. Methods The endometrial injury rat model was developed. Exosomes were obtained from the supernatants of bone marrow mesenchymal stromal cells (BMSCs) and miR-340/BMSCs through differential centrifugation. We conducted RNA-seq analysis on endometrial tissues obtained from the PBS and MB-exos groups. Ferroptosis was induced in endometrial stromal cells (ESCs) by treating them with erastin or RSL3, followed by treatment with B-exos or MB-exos. We assessed the endometrial total m6A modification level after injury and subsequent treatment with B-exos or MB-exos by methylation quantification assay. We performed meRIP-qPCR to analyze m6A modification-regulated endogenous mRNAs. Results We reveal that MB-exos facilitate the injured endometrium to recover by suppressing ferroptosis in endometrial stromal cells. The injured endometrium showed significantly upregulated N 6-methyladenosine (m6A) modification levels; these levels were attenuated by MB-exos through downregulation of the methylase METTL3. Intriguingly, METTL3 downregulation appears to repress ferroptosis by stabilizing HMOX1 mRNA, thereby potentially elucidating the mechanism through which MB-exos inhibit ferroptosis in ESCs. We identified YTHDF2 as a critical m6A reader protein that contributes to HMOX1 mRNA degradation. YTHDF2 facilitates HMOX1 mRNA degradation by identifying the m6A binding site in the 3′-untranslated regions of HMOX1. In a rat model, treatment with MB-exos ameliorated endometrial injury-induced fibrosis by inhibiting ferroptosis in ESCs. Moreover, METTL3 short hairpin RNA-mediated inhibition of m6A modification enhanced the inhibitory effect of MB-exos on ferroptosis in endometrial injury. Conclusions Thus, these observations provide new insights regarding the molecular mechanisms responsible for endometrial recovery promotion by MB-exos and highlight m6A modification-dependent ferroptosis inhibition as a prospective therapeutic target to attenuate endometrial injury.

Abstract 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.

Over 60% of breast cancer cases are diagnosed with estrogen-receptor (ER) positive. Tamoxifen (TAM), a commonly employed medication for ER-positive breast cancer, often yields suboptimal therapeutic outcomes due to the emergence of TAM resistance, leading to the recurrence and a poor prognosis. The copper transporter, solute carrier family 31 member 1 (SLC31A1), has been associated with tumor aggressiveness and unfavorable outcomes in various types of tumors. In our current study, we found high expression of SLC31A1 that predicted poor survival in patients with breast cancer. Significantly, ER-positive breast cancer tissues in patients with recurrence post-TAM treatment exhibited considerably stronger SLC31A1 expression levels. In vitro experiments verified that TAM-resistant ER-positive breast cancer cell lines expressed notably higher SLC31A1 levels compared to the parental cell lines. Of great significance, SLC31A1 depletion notably rescued TAM sensitivity in chemoresistant ER-positive breast cancer cells, as demonstrated by the attenuated cell proliferative and invasive capabilities. Conversely, promoting SLC31A1 significantly facilitated the proliferation and invasion of wild-type breast cancer cells. Subsequently, we detected reduced copper levels in TAM-resistant breast cancer cells with SLC31A1 depletion. Mechanistically, we observed that in chemoresistant breast cancer cell lines, SLC31A1 knockdown resulted in a substantial decrease in the expression of carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of fatty acid oxidation (FAO). RNA-Seq analysis indicated that FAO might be implicated in SLC31A1-mediated breast cancer progression. CPT1A was also overexpressed in TAM-resistant breast cancer cells, accompanied by enhanced FAO rates and ATP levels. Suppressing CPT1A significantly enhanced the chemosensitivity of TAM-resistant breast cancer cells in response to TAM treatments. Intriguingly, copper exposure dose-dependently increased CPT1A expression in chemoresistant breast cancer cells, but this could be abolished upon SLC31A1 knockdown, along with enhanced apoptosis, which elucidated that copper uptake contributed to CPT1A expression. Furthermore, SLC31A1 overexpression significantly augmented CPT1A expression in parental breast cancer cells, accompanied by facilitated copper levels, FAO rates, and ATP levels, while being notably diminished upon CPT1A suppression. Finally, our in vivo studies confirmed that SLC31A1 deficiency re-sensitized TAM-resistant breast cancer cells to TAM treatment and abolished tumor growth. Collectively, all our studies demonstrated that SLC31A1/copper suppression could enhance TAM responses for chemoresistant ER-positive breast cancer cells through constraining the CPT1A-mediated FAO process.

ABSTRACT: Goose astrovirus (GAstV) has been widespread in China since 2016, causing significant growth inhibition and gout symptoms in goslings and leading to substantial economic losses in the goose industry. To better understand the epidemiological characteristics of GAstV in Guangdong Province, 682 samples were collected from geese with suspected GAstV infection across different regions of Guangdong Province from January 2022 to January 2024. Virus isolation, identification, and genetic evolution analysis were performed. The results showed that all samples were GAstV positive, with 52.64% co-infected with GAstV-1 and GAstV-2, and 42.38% positive for GAstV-2 alone, indicating that GAstV-2 remains the most prevalent subtype. Additionally, three GAstV isolates were identified using molecular detection, immunofluorescence, and transmission electron microscopy on LMH cells or goose embryos. Compared with GDYJ2304 and other reported GAstV-2 strains, the ORF2 region of the GDYJ2210 isolates lacked 3 bases, and the replication ability of GDYJ2210 was significantly higher than that of GDYJ2304. Whole genome sequence alignment and genetic evolution analysis revealed that the GDFS2209 isolate was located in the GAstV-1 branch, with a sequence similarity of 89.70 to 99.00% to GAstV-1 reference strains. The GDYJ2210 and GDYJ2304 isolates were located in the GAstV-2 branch, showing a sequence similarity of 96.80 to 98.90% to GAstV-2 reference strains. These results demonstrated that the GAstV isolates were highly similar to each other despite being prevalent in 5 different regions of Guangdong Province. These findings enhance the understanding of the genetic diversity and evolution of GAstV and may facilitate the development of effective preventive strategies.

Abstract Long non‐coding RNA RP11‐64B16.4 (myocardial infarction protection‐related lncRNA [MIPRL]) is among the most abundant and the most upregulated lncRNAs in ischemic human hearts. However, its role in ischemic heart disease is unknown. We found MIPRL was conserved between human and mouse and its expression was increased in mouse hearts after acute myocardial infarction (AMI) and in cultured human and mouse cardiomyocytes after hypoxia. The infarcted size, cardiac cell apoptosis, cardiac dysfunction, and cardiac fibrosis were aggravated in MIPRL knockout mice after AMI. The above adverse results could be reversed by re‐expression of MIPRL via adenovirus expressing MIPRL. Both in vitro and in vivo, we identified that heat shock protein beta‐8 (HSPB8) was a target gene of MIPRL, which was involved in MIPRL‐mediated anti‐apoptotic effects on cardiomyocytes. We further discovered that MIPRL could combine with the messenger RNA (mRNA) of HSPB8 and increase its expression in cardiomyocytes by enhancing the stability of HSPB8 mRNA. In summary, we have found for the first time that the ischemia‐enhanced lncRNA MIPRL protects against AMI via its target gene HSPB8. MIPRL might be a novel promising therapeutic target for ischemic heart diseases such as AMI.

Abstract Background The unique expression pattern endows oncofetal genes with great value in cancer diagnosis and treatment. However, only a few oncofetal genes are available for clinical use and the underlying mechanisms that drives the fetal-like reprogramming of cancer cells remain largely unknown. Methods Microarray assays and bioinformatic analyses were employed to screen for potential oncofetal long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC). The expression levels of MIR4435-2HG, NOP58 ribonucleoprotein (NOP58), insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) and stem markers were detected by quantitative polymerase chain reaction. The 2′-O-methylation (2′-O-Me) status of rRNA were detected through reverse transcription at low dNTP concentrations followed by PCR. The regulation of MIR4435-2HG by IGF2BP1 was explored by RNA immunoprecipitation (RIP), methylated RIP (MeRIP) and dual-luciferase assays. The interaction between MIR4435-2HG and NOP58 was investigated by RNA Pulldown, RIP and protein stability assays. In vitro and in vivo function assays were performed to detect the roles of MIR4435-2HG/NOP58 in HCC. Results MIR4435-2HG was an oncofetal lncRNA associated with poor prognosis in HCC. Functional experiments showed that overexpression of MIR4435-2HG remarkably enhanced the stem-cell properties of HCC cells, promoting tumorigenesis in vitro and in vivo. Mechanically, MIR4435-2HG directly bound NOP58 and IGF2BP1. IGF2BP1 upregulated MIR4435-2HG expression in HCC through N6-methyladenosine (m6A) modification. Moreover, MIR4435-2HG protected NOP58 from degradation, which raised rRNA 2’-O-Me levels and promoted internal ribosome entry site (IRES)-dependent translation of oncogenes. Conclusions This study identified an oncofetal lncRNA MIR4435-2HG, characterized the role of MIR4435-2HG/NOP58 in stemness maintenance and proliferation of HCC cells, and confirmed m6A as a ‘driver’ that reactivated MR4435-2HG expression in HCC.

Abstract Background Genitourinary small cell carcinoma is rare, and has a poor prognosis. However, effective treatment options for this disease are limited. We present a study to assess the efficacy of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma (GSCC). Methods We performed a retrospective analysis of patients with locally advanced or metastatic GSCC from Jan 2013 to September 2022 at Sun Yat-sen University Cancer Center. The survival and safety profiles were analyzed. Results Forty-two GSCC patients were enrolled, which included 20 with chemotherapy plus immunotherapy and 22 with chemotherapy alone. The median follow-up time was 15.13 months (95% CI, 8.84–21.42). The addition of immunotherapy to chemotherapy demonstrated no significant difference in median progression-free survival (p = 0.37). However, the median overall survival (OS) was 22.97 and 14.03 months with immunotherapy plus chemotherapy and chemotherapy alone, respectively (HR = 0.69, 95%CI 0.08–0.55, p = 0.017). Two patients with immunotherapy plus chemotherapy achieved clinical complete remission. The overall response rate for patients receiving chemotherapy combined with immunotherapy was 65%, which was higher in comparison to those treated with chemotherapy alone (50%). Univariate and multivariate analyses demonstrated that chemotherapy combined with immunotherapy independently achieved favorable OS. Four patients experienced immunotherapy-related adverse events, with one developing grade 3 hypothyroidism. Conclusions Among patients with locally advanced or metastatic GSCC, immunotherapy combined with chemotherapy might be thought of as a potentially effective treatment option for patients with GSCC.

Goose astrovirus (GAstV) is a small, non-encapsulated virus, whose genome consists of a single-stranded, positive-stranded RNA molecule with a genome length of 7.1-7.3 kb. GAstV is a new member of the genus avian astrovirus in the family Astroviridae, which can be classified into two genetic subgroups (GAstV-1, GAstV-2) based on genetic homology and genetic distance, which are not yet involved in official classification. GAstV infection can lead to diarrhea, growth inhibition, and clinical signs dominated by joint urate deposition and visceral urate deposition in geese, and it is considered to be the main etiological agent causing gout in geese. There is a lack of commercialized vaccines or therapeutic drugs against GAstV, relying mainly on biosecurity measures for prevention and control. China's researchers first detected and isolated the GAstV strain in gouty geese flocks in Shandong Province in 2017. GAstV spreads quickly and radiates widely, with related cases reported in Guangdong, Fujian, and Anhui in the same year, resulting in up to 1.2 billion yuan to 1.5 billion yuan in economic losses. The incidence of GAstV can be up to 80%, and the mortality rate can be up to 50%. GAstV can lead to immunosuppression in geese, and they are susceptible to infection with other pathogens in the course of feeding, resulting in more severe clinical symptoms and increasing the difficulty of pathogen prevention and control. GAstV not only infects its natural host, geese, but also has the ability to cross the species barrier, causing diarrhea, growth inhibition, and triggering urate deposition in internal organs or joints in chickens and ducks. This suggests that GAstV may have the potential for human-animal transmission, and subsequent studies should strengthen the epidemiological monitoring of GAstV and pay close attention to the changes in its transmission characteristics. At present, scholars have made certain research progress in the pathogen detection of GAstV, and have established various technical methods that can efficiently and accurately detect GAstV. However, the research on the pathogenic mechanism of GAstV has not yet been in-depth, the research on vaccine preparation is relatively weak, and there is no uniform and effective in vitro culture method for GAstV, which has seriously hindered the pace of basic research on the pathogen. In order to better understand the impact of GAstV on goose farming industry in China, this paper reviews four aspects of GAstV, namely, pathogenesis, epidemiology, host immune response, and the association between GAstV and gout, which will provide a reference for the follow-up research and scientific control of GAstV.

Abstract Premature ovarian failure (POF) is defined by amenorrhea, ovarian atrophy, hypoestrogenism, elevated gonadotropin level, and infertility under the age of 40. POF is frequently induced by chemotherapeutic agents. However, the underlying mechanisms regarding chemotherapy-mediated damage to ovarian function are unclear. In this study, enhanced apoptosis of granulosa cells (GCs) and aberrant activation of primordial follicles were observed in a POF mouse model induced by cisplatin. We subsequently observed significant downregulation of miR-144-3p and upregulation of mitogen-activated protein kinase kinase kinase 9 (MAP3K9) in primary ovarian GCs from POF mice, as revealed by microarrays. Furthermore, MAP3K9 expression was higher in human ovarian granulosa cells (COV434) treated with cisplatin and was identified as a novel target of miR-144-3p. Functional analysis revealed that miR-144-3p attenuated cisplatin induced apoptosis of GCs via silencing MAP3K9 expression, which suppressed the activity of the downstream p38 mitogen activated protein kinase (MAPK) pathway. Meanwhile, miR-144-3p prevented premature primordial follicle depletion in cisplatin-induced POF mice through targeting Map3k9, which led to a decline in the phosphorylation and activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase b (AKT) pathway. Taken together, this study revealed the protective effects of miR-144-3p on ovarian function and shed light on the epigenetic regulatory mechanism in the development of POF, which might provide new biomarkers for the ovarian reserve.

Abstract Background Genetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large‐scale Chinese BC patients. Methods BC patients who had undergone genetic testing at the Sun Yat‐sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort. Results A total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only for BRCA1/2 genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high‐risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high‐risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non‐BRCA P/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non‐BRCA P/LPVs were PALB2 (11, 1.3%), TP53 (10, 1.2%), PTEN (3, 0.4%), CHEK2 (3, 0.4%), ATM (3, 0.4%), BARD1 (3, 0.4%), and RAD51C (2, 0.2%). Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes. Conclusions Desai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non‐BRCA P/LPVs than BRCA1/2 testing alone. Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies.

Sodium butyrate (NaB) has garnered attention in recent years for its ability to impede the malignant progression of tumors. In order to explore the potential inhibitory effects of NaB on the replication of Marek’s disease virus (MDV) and subsequent lymphoma formation, newly hatched chickens were infected with the vvMDV Md5 strain and administered NaB prior to (prevention group) or following (treatment group) Md5 inoculation. The results revealed that NaB played a pivotal role in diminishing both the incidence and fatality rates in chickens afflicted with Md5 infection. Notably, NaB exhibited a remarkable capacity to inhibit the expression of MDV immediate early genes, i.e., ICP4 and ICP27, thus attenuating tumorigenesis in the chicken spleen. To further elucidate the mechanism of NaB on lymphoma cells, MDV bearing lymphoma cells, i.e., MSB-1 were exposed to NaB for 24 h prior to various experimental tests. The results revealed that NaB effectively hindered the proliferation, migration, and colony formation of MSB-1 cells. Furthermore, NaB demonstrated the ability to modulate the key molecules in mitochondrial apoptosis pathway. Taken together, these findings reveal that NaB can impede the lymphoma caused by MDV via regulating the mitochondrial apoptosis pathway, both in vitro and in vivo. These results suggest that the utilization of NaB warrants serious consideration as a promising approach for the prevention of MDV.

Abstract Background Stomach hemorrhage and perforation are very severe and common complications in patients with primary gastric diffuse large B‐cell lymphoma (PG‐DLBCL) during treatment with immunochemotherapy. However, no relevant clinical studies have been performed on the prevention of these serious complications. Methods Patients diagnosed with PG‐DLBCL were enrolled in this retrospective study. The prevention group received standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) treatment without prednisone combined with antacids and anti‐Helicobacter pylori (Hp) therapy. These patients received R‐CHOP‐based treatment until the complete recovery of gastric ulcers, as proven by gastroscopy. The control group received a standard R‐CHOP regimen. Toxicity and survival were the main endpoints. Results A total of 52 patients received preventative treatment, while 146 patients did not. Among patients with stage I, II‐1, and II‐2 disease, the prevention group had a lower rate of hemorrhage and perforation (0/40) than the control group (10/78, p = 0.044). At a median follow‐up time of 25 months, the 5‐year event‐free survival (EFS) rates were 97.1% in the prevention group and 66.1% in the control group (p = 0.025), and the 5‐year overall survival (OS) rates were 100% and 72.0%, respectively (p = 0.021). However, the differences in the 5‐year EFS and OS of patients with disseminated disease were not statistically significant. Conclusions Preventative treatment can decrease the risk of hemorrhage and perforation in patients with localized PG‐DLBCL during immunochemotherapy, leading to better EFS and OS in these patients. However, preventative treatment failed to reduce the risk of gastric hemorrhage and perforation and did not improve survival (EFS and OS) in advanced‐stage patients.

Abstract Background The high heterogeneity of de novo metastatic nasopharyngeal carcinoma (dmNPC) makes its prognosis and treatment challenging. We aimed to accurately stage dmNPC and assess the patterns of treatment strategies for different risk groups. Methods The study enrolled a total of 562 patients, 264 from 2007 to 2013 in the training cohort and 298 from 2014 to 2017 in the validation cohort. Univariate and multivariate Cox regression analyses were conducted to determine the independent variables for overall survival (OS). Recursive partitioning analysis (RPA) was applied to establish a novel risk-stratifying model based on these variables. Results After pairwise comparisons of OS, three risk groups were generated: low-risk (involved lesions ≤ 4 without liver involvement), intermediate-risk (involved lesions ≤ 4 with liver involvement or involved lesions > 4 with Epstein–Barr virus (EBV)-DNA 4 with EBV-DNA > 62,000 copies/ml). The 3-year OS rate differed significantly between groups (80.4%, 42.0%, and 20.4%, respectively, all P

Abstract The prognosis of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) remained unsatisfactory currently, more anti-HER2 agents are needed. Here we report a phase I study that evaluated the safety, activity, and biomarkers of LZM005, a HER2 antibody, used as a monotherapy or in combination with trastuzumab plus docetaxel in patients with HER2-positive MBC. From October 2017 to December 2019, 34 patients received LZM005 (14 monotherapy, 20 combination therapy). No DLT was observed. The common adverse events (AEs) in phase Ia included diarrhea (21.4%), infusion reaction (21.4%), and hypertriglyceridemia (21.4%), while those in phase Ib were leukopenia (85.0%), neutropenia (75.0%), anemia (60.0%), diarrhea (60.0%), and rash/pruritus (50.0%). All AEs were manageable. In phase Ia, partial response (PR) was achieved in one case (1/14, overall response rate [ORR]: 7.1%); the disease control rate was 42.90% (6/14). In phase Ib, 11 patients (55.0%) achieved PR, and eight (40.0%) had stable disease. The ORR was 100% (6/6) in trastuzumab-naive and 35.7% (5/14) in trastuzumab-pretreated patients. Biomarker analysis showed that chromatin remodeling genes KMT2B and BRWD1 were associated with better progression-free survival. LZM005 is well tolerated and shows potent activity in patients with HER2-positive MBC.

Abstract Background Lymphoepithelioma-like carcinoma (LELC) is a rare and unique subtype of cancer that histologically resembles undifferentiated nasopharyngeal carcinoma (NPC). The population-based analysis of LELC and the optimal treatment remains unclear. Materials and methods This real-world, retrospective study investigated 770 patients with LELC for primary site, treatment, and survival outcomes from 2005 to 2019 from five cancer centres in China. The overall survival (OS) of different subgroups was appraised by log-rank tests and Kaplan–Meier analysis. Results Primary sites LELC included the lung (597 cases, 77.5%), salivary gland (115 cases, 14.9%), and others. The median progression-free survival (PFS) of LELC patients was 47.4 months. The median overall survival (OS) was not reached. The 5-year survival rate for LELC patients was 77.8%. Most patients in stages I and II received surgery. The majority of patients in stage III received surgery and radiotherapy. More than half of the patients in stage IV received chemotherapy. Among relapsed or metastatic cases receiving chemotherapy, patients who received immunotherapy at any time presented with a superior OS than those without immunotherapy (P

Monocyte-to-M0/M1 macrophage differentiation with unclear molecular mechanisms is a pivotal cellular event in many cardiovascular diseases including atherosclerosis. Long non-coding RNAs (lncRNAs) are a group of protein expression regulators; however, the roles of monocyte-lncRNAs in macrophage differentiation and its related vascular diseases are still unclear. The study aims to investigate whether the novel leukocyte-specific lncRNA Morrbid could regulate macrophage differentiation and atherogenesis. We identified that Morrbid was increased in monocytes and arterial walls from atherosclerotic mouse and from patients with atherosclerosis. In cultured monocytes, Morrbid expression was markedly increased during monocyte to M0 macrophage differentiation with an additional increase during M0 macrophage-to-M1 macrophage differentiation. The differentiation stimuli-induced monocyte–macrophage differentiation and the macrophage activity were inhibited by Morrbid knockdown. Moreover, overexpression of Morrbid alone was sufficient to elicit the monocyte–macrophage differentiation. The role of Morrbid in monocyte–macrophage differentiation was also identified in vivo in atherosclerotic mice and was verified in Morrbid knockout mice. We identified that PI3-kinase/Akt was involved in the up-regulation of Morrbid expression, whereas s100a10 was involved in Morrbid-mediated effect on macrophage differentiation. To provide a proof of concept of Morrbid in pathogenesis of monocyte/macrophage-related vascular disease, we applied an acute atherosclerosis model in mice. The results revealed that overexpression of Morrbid enhanced but monocyte/macrophage-specific Morrbid knockout inhibited the monocytes/macrophages recruitment and atherosclerotic lesion formation in mice. The results suggest that Morrbid is a novel biomarker and a modulator of monocyte–macrophage phenotypes, which is involved in atherogenesis.

Abstract Hypoxia is important in ischemic heart disease. Excessive Insulin-like growth factor binding protein-1 (IGFBP-1) amounts are considered to harm cardiomyocytes in acute myocardial infarction. However, the mechanisms by which IGFBP-1 affects cardiomyocytes remain undefined. The present study demonstrated that hypoxia up-regulates IGFBP-1 and HIF-1α protein expression in cardiomyocytes. Subsequent assays showed that IGFBP-1 suppression decreased HIF-1α expression and inhibited hypoxia-induced apoptosis in cardiomyocytes, which was reversed by HIF-1α overexpression, indicating that HIF-1α is essential to IGFBP-1 function in cellular apoptosis. In addition, we showed that IGFBP-1 regulated HIF-1α stabilization through interacting with VHL. The present findings suggest that IGFBP-1–HIF-1α could be targeted for treating ischemic heart disease.

Objective: To characterize modified R-CODOX-M/IVAC-based chemotherapy to lower the severe adverse events in Chinese adult patients with sporadic Burkitt lymphoma. Methods: We enrolled a retrospective cohort including 123 adult patients with untreated sporadic Burkitt lymphoma from August 2008 to September 2019 at Sun Yat-sen University Cancer Center. We studied a dose-modified and long-course R-CODOX-M/IVAC regimen utilizing a low dose of 1.0 g/m2/cycle cyclophosphamide, 2 g/m2/cycle methotrexate, 4,500 mg/m2/cycle ifosfamide, and 4.0 g/m2/cycle cytarabine. Forty-nine patients with low risk disease underwent 4–6 cycles of dose-modified R-CODOX-M-based chemotherapy. Seventy-four patients with high risk disease underwent 6–8 cycles of dose-modified alternating R-CODOX-M/IVAC regimens. Results: The objective remission was 87.0%. The event-free survival rate and overall survival at 3 years were 81.2% and 92.1%, respectively. Major grade 3–4 adverse events included leukopenia (91.9%), anemia (58.5%), thrombocytopenia (73.2%), and febrile neutropenia (48.8%). A total of 26.0% and 37.4% of patients received red blood cell and platelet transfusions, respectively. We observed 4 cases (3.3%) of septic shock after chemotherapy. Two treatment-related deaths occurred from severe infection. Conclusions: The modified R-CODOX-M/IVAC chemotherapy regimen was effective for sporadic Burkitt lymphoma in the Chinese population, with a lower toxicity than standard regimens.

Abstract Heme oxygenase-1 (HO-1) has attracted accumulating attention for its antioxidant enzymatic activity. However, the exact regulatory role of its non-enzymatic activity in the cardiovascular system remains unaddressed. Here, we show that HO-1 was accumulated in the nuclei of stress-induced senescent endothelial cells, and conferred protection against endothelial senescence independent of its enzymatic activity. Overexpression of ΔHO-1, a truncated HO-1 without transmembrane segment (TMS), inhibited H2O2-induced endothelial senescence. Overexpression of ΔHO-1H25A, the catalytically inactive form of ΔHO-1, also exhibited anti-senescent effect. In addition, infection of recombinant adenovirus encoding ΔHO-1 with three nuclear localization sequences (NLS), alleviated endothelial senescence induced by knockdown of endogenous HO-1 by CRISPR/Cas9. Moreover, repression of HO-1 nuclear translocation by silencing of signal peptide peptidase (SPP), which is responsible for enzymatic cleavage of the TMS of HO-1, exacerbated endothelial senescence. Mechanistically, nuclear HO-1 interacted with NPM1 N-terminal portion, prevented NPM1 translocation from nucleolus to nucleoplasm, thus disrupted NPM1/p53/MDM2 interactions and inhibited p53 activation by NPM1, finally resisted endothelial senescence. This study provides a novel understanding of HO-1 as a promising therapeutic strategy for vascular senescence-related cardiovascular diseases.

Abstract Background Burkitt lymphoma (BL) is a highly aggressive, fast-growing B-cell non-Hodgkin's lymphoma, manifested in several subtypes, including sporadic, endemic, and immunodeficiency-related forms, the mechanism of which is still not clear. Abundant evidence reported that KIF15 was involved in the progression of human cancer. The emphasis of this study is to explore the functions of KIF15 in the development of BL. Methods Firstly, tumor and normal tissues were collected for detecting expression of KIF15 in BL. Lentivirus-mediated shRNA knockdown of KIF15 was used to construct BL cell model, which was verified by qRT-PCR and Western Blot. The cell proliferation was detected by CCK8 assay, cell apoptosis and cell cycle were measured through flow cytometry. Transwell assay was conducted to detect the migration. Results We first found that KIF15 is highly expressed in BL. Knockdown of KIF15 can inhibit proliferation and migration, promote apoptosis and arrest the cell cycle. Moreover, KIF15 is involved in BL cell activity through regulating expression of apoptosis-related proteins (Caspase3, Caspase8, HTRA, IGFBP-6, p53, SMAC, sTNF-R1, TNF-β and Bcl-2) and downstream pathways, such as p-Akt, CCND1, CDK6 and PIK3CA. Conclusions These findings justify the search for small molecule inhibitors targeting KIF15 as a novel therapeutic strategy in BL.

BackgroundMalignant urachal tumor is a rare subtype of genitourinary cancer. Our aim was to explore the optimal chemotherapy regimens for relapsed or metastatic urachal carcinoma.Materials and MethodsWe retrospectively enrolled 24 adult patients with relapsed or metastatic urachal carcinoma from January 2014 to September 2020 at Sun Yat-sen University Cancer Center. We summarized the chemotherapy regimens and classified them as fluorouracil based, platinum based, and paclitaxel based. Nine patients received XELOX (capecitabine and oxaliplatin) regimens, seven patients received TX (paclitaxel and capecitabine) regimens, and eight of them received chemotherapy including GP (gemcitabine and cisplatin), TP (paclitaxel and cisplatin), TN (paclitaxel and nedaplatin), and tislelizumab.ResultsThe disease control rate was 75%. Among all patients, one patient treated with XELOX achieved partial remission (PR), while 17 patients showed stable disease. The median progression-free survival (PFS) and overall survival (OS) in all treated patients was 7.43 and 29.7 months, respectively. The patients receiving first-line platinum-based chemotherapy presented better PFS than those without platinum (median PFS 8.23 vs. 3.80 months, p = 0.032), but not significant for OS between two groups. There is no significant difference in PFS and OS for fluorouracil-based and paclitaxel-based groups as first-line regimen. Next-generation gene sequencing revealed TP53 mutation and low tumor mutational burden in five out of seven cases.ConclusionThe platinum-based chemotherapy regimen is effective for relapsed or metastatic urachal carcinoma.

CRISPR-associated Cas9 endonuclease (CRISPR/Cas9) systems are widely used to introduce precise mutations, such as knocking in/out at targeted genomic sites. Herein, we successfully disrupted the transcription of multiple genes in Bacillus pumilus LG3145 using a series of unspecific guide RNAs (gRNAs) and UgRNA:Cas9 system-assisted cre-box editing. The bases used as gRNAs shared 30–70% similarity with a consensus sequence, a cis-acting element (cre-box) mediating carbon catabolite repression (CCR) of many genes in Bacillus. This triggers trans-crRNA:Cas9 complex wobble cleavage up/downstream of cre sites in the promoters of multiple genes (up to 7), as confirmed by Sanger sequencing and next-generation sequencing (NGS). LG3145 displayed an obvious CCR release phenotype, including numerous secondary metabolites released into the culture broth, ∼ 1.67 g/L white flocculent protein, pigment overflow causing orange-coloured broth (absorbance = 309 nm), polysaccharide capsules appearing outside cells, improved sugar tolerance, and a two-fold increase in cell density. We assessed the relationship between carbon catabolite pathways and phenotype changes caused by unspecific UgRNA-directed cre site wobble editing. We propose a novel strategy for editing consensus targets at operator sequences that mediates transcriptional regulation in bacteria.

PurposePeripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a clinically and biologically heterogeneous disease with poor prognosis. As the role of radiation therapy (RT) is still unclear, we carried out this study to evaluate the potential efficacy of RT in PTCL-NOS.MethodsPatients diagnosed with PTCL-NOS between 2000 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching was used to balance the characteristics between patients who received radiotherapy and those who did not receive radiotherapy. In addition, we validated the findings in an external validation cohort retrospectively recruited from two high-capacity cancer center in China between 2006 and 2016. Kaplan-Meier curves and Cox regression models were used for survival analysis.ResultsOf the 2,768 patients with chemotherapy records in the SEER cohort, 27.6% of 844 patients with early-stage disease and 6.8% of 1,924 patients with advanced-stage disease received RT. The application of RT was significantly associated with an improvement in overall survival (5-year OS rate 58.5 versus 35.1%, P

Printing and dyeing wastewater is characterized with complex water quality and poor biodegradability. In this study, a pilot-scale anaerobic baffled reactor (ABR) with packing was verified to effectively degrade the complex organic pollutants in the wastewater through the hydrolysis and acidification of anaerobic microorganisms. At a hydraulic retention time (HRT) of 12 h and an organic loading rate (OLR) of 2.0–2.5 kg COD/(m3·d), the ABR stabilized the fluctuation range of pH and achieved an average colority removal rate of 10.5%, which provided favorable conditions for subsequent aerobic treatment. During the early operation period, the reactor increased the alkalinity of the wastewater; after 97 days of operation, the volatile fatty acid (VFA) content in the wastewater decreased. To demonstrate the suitability of the support vector regression (SVR) technology in predicting the performance of the reactor, two SVR algorithms with three kernel functions were employed to relate the chemical oxygen demand (COD) removal rate to its influencing factors, and the predictions of both the training and validation groups agreed with the measurements. The results obtained from this study can contribute to the design and optimal operation of the anaerobic treatment project of the industrial wastewater treatment plant.

The soil-rock mixture (S-RM) is widely applied in the geotechnical engineering due to its better mechanical properties. The shear strength, an essential aspect of S-RM which governs the stability and the deformation, is rather necessary to be revealed properly. The extraordinary issue of S-RM compared to fine-grained soils is the grain size effect on the strength analysis. This paper proposes a systematic method to obtain the realistic shear strength of S-RM by detecting the rock size effect. Firstly, based on fractal theory, the rock size was determined as 5 mm by the multifractal property of granular size distribution. Then, based on 2 selected specimen sizes combining the engineering dimension, shear gaps (T) effect and specimen size effect on the shear strength of S-RM have been investigated. It is shown that the gap of the direct shear test decides the physical mechanism of particles forming the shear resistance of S-RM based on the variation of apparent cohesion and mobilized internal friction angle. Specimen size effect is weakened by the gap effect considering the boundary effect. Realistic and stable shear strength parameters of S-RM have been researched by a reasonable gap (0.2–0.4D, where D is the largest particle size).

Bacterial flagella are extracellular filaments that drive swimming in bacteria. During motor assembly, flagellins are transported unfolded through the central channel in the flagellum to the growing tip. Here, we applied in vivo fluorescent imaging to monitor in real time the Vibrio alginolyticus polar flagella growth. The flagellar growth rate is found to be highly length-dependent. Initially, the flagellum grows at a constant rate (50 nm/min) when shorter than 1500 nm. The growth rate decays sharply when the flagellum grows longer, which decreases to ~9 nm/min at 7500 nm. We modeled flagellin transport inside the channel as a one-dimensional diffusive process with an injection force at its base. When the flagellum is short, its growth rate is determined by the loading speed at the base. Only when the flagellum grows longer does diffusion of flagellin become the rate-limiting step, dramatically reducing the growth rate. Our results shed new light on the dynamic building process of this complex extracellular structure.