Nitrogen-containing heterocyclic drug products approved by the FDA in 2023: Synthesis and biological activity.

This article profiles 13 newly approved nitrogen-containing heterocyclic drugs by the U.S. Food and Drug Administration (FDA) in 2023. These drugs target a variety of therapeutic areas including proteinuria in patients with IgA nephropathy, migraine in adults, Rett syndrome, PI3Kδ syndrome, vasomotor symptoms, alopecia areata, acute myeloid leukemia, postpartum depression, myelofibrosis, and various cancer and tumor types. The molecular structures of these approved drugs feature common aromatic heterocyclic compounds such as pyrrole, imidazole, pyrazole, isoxazole, pyridine, and pyrimidine, as well as aliphatic heterocyclic compounds like caprolactam, piperazine, and piperidine. Some compounds also contain multiple heteroatoms like 1,2,4-thiadiazole and 1,2,4-triazole. The article provides a comprehensive overview of the bioactivity spectrum, medicinal chemistry discovery, and synthetic methods for each compound.

PCMT1 confirmed as a pan-cancer immune biomarker and a contributor to breast cancer metastasis.

Protein L-isoaspartyl (D-aspartyl) methyltransferase (PIMT, gene name PCMT1) is an enzyme that repairs proteins with altered aspartate residues by methylation, restoring their normal structure and function. This study conducted a comprehensive analysis of PCMT1 in pan-cancer. The Cancer Genome Atlas, Human Protein Atlas website, and the Genotype-Tissue Expression were utilized in analysis of PCMT1 expression. We examined the association between PCMT1 expression and various factors, including gene modifications, DNA methylation, immune cell infiltration, immunological checkpoints, drug susceptibility, tumor mutation burden (TMB), and microsatellite instability (MSI). Enrichment analyses determined the potential biological roles and pathways involving PCMT1. Our focus then shifted to the role of PCMT1 in breast invasive carcinoma (BRCA). We found that PCMT1 expression was aberrant in many tumors and significantly influenced the prognosis across several cancer types. Gene alterations in PCMT1 predominantly involved deep deletions and amplifications. A negative correlation was observed between DNA methylation and PCMT1 expression across all studied cancer types except thyroid carcinoma PCMT1 exhibited positive correlations with common lymphoid progenitor and CD4(+) T helper 2 cells, whereas it was inversely correlated with central and effector memory T cells, memory CD8(+) T cells, and CD4(+) T helper 1 cells. In many cancer types, PCMT1 expression closely correlated with immunological checkpoint inhibitors, TMB, and MSI. It was also significantly linked to pathways involved in epithelial-mesenchymal transition (EMT), highlighting its role in cancer metastasis. PCMT1 emerged as a significant predictor of breast cancer progression. In vitro experiments demonstrated that reducing PCMT1 expression decreased BRCA cell migration and invasiveness. Additionally, animal studies confirmed that inhibition of PCMT1 slowed tumor growth.

GLT-1 downregulation in hippocampal astrocytes induced by type 2 diabetes contributes to postoperative cognitive dysfunction in adult mice.

AIMS: Type 2 diabetes mellitus (T2DM) is related to an increased risk of postoperative cognitive dysfunction (POCD), which may be caused by neuronal hyperexcitability. Astrocyte glutamate transporter 1 (GLT-1) plays a crucial role in regulating neuron excitability. We investigated if T2DM would magnify the increased neuronal excitability induced by anesthesia/surgery (A/S) and lead to POCD in young adult mice, and if so, determined whether these effects were associated with GLT-1 expression. METHODS: T2DM model was induced by high fat diet (HFD) and injecting STZ. Then, we evaluated the spatial learning and memory of T2DM mice after A/S with the novel object recognition test (NORT) and object location test (OLT). Western blotting and immunofluorescence were used to analyze the expression levels of GLT-1 and neuronal excitability. Oxidative stress reaction and neuronal apoptosis were detected with SOD2 expression, MMP level, and Tunel staining. Hippocampal functional synaptic plasticity was assessed with long-term potentiation (LTP). In the intervention study, we overexpressed hippocampal astrocyte GLT-1 in GFAP-Cre mice. Besides, AAV-Camkllα-hM4Di-mCherry was injected to inhibit neuronal hyperexcitability in CA1 region. RESULTS: Our study found T2DM but not A/S reduced GLT-1 expression in hippocampal astrocytes. Interestingly, GLT-1 deficiency alone couldn't lead to cognitive decline, but the downregulation of GLT-1 in T2DM mice obviously enhanced increased hippocampal glutamatergic neuron excitability induced by A/S. The hyperexcitability caused neuronal apoptosis and cognitive impairment. Overexpression of GLT-1 rescued postoperative cognitive dysfunction, glutamatergic neuron hyperexcitability, oxidative stress reaction, and apoptosis in hippocampus. Moreover, chemogenetic inhibition of hippocampal glutamatergic neurons reduced oxidative stress and apoptosis and alleviated postoperative cognitive dysfunction. CONCLUSIONS: These findings suggest that the adult mice with type 2 diabetes are at an increased risk of developing POCD, perhaps due to the downregulation of GLT-1 in hippocampal astrocytes, which enhances increased glutamatergic neuron excitability induced by A/S and leads to oxidative stress reaction, and neuronal apoptosis.

Dose-response relationship between serum N-glycan markers and liver fibrosis in chronic hepatitis B.

BACKGROUND: Evaluation of liver fibrosis played a monumental role in the diagnosis and monitoring of chronic hepatitis B (CHB). We aimed to explore the value of serum N-glycan markers in liver fibrosis. METHODS: This multi-center (33 hospitals) study recruited 760 treatment-naïve CHB patients who underwent liver biopsy. Serum N-glycan markers were analyzed by DNA sequencer-assisted fluorophore-assisted with capillary electrophoresis (DSA-FACE) technology. First, we explore the relationship between 12 serum N-glycan markers and the fibrosis stage. Then, we developed a Px score for diagnosing significant fibrosis using the LASSO regression. Next, we compared the diagnostic performances between Px, LSM, APRI, and FIB-4. Finally, we explored the relationships between glycosyltransferase gene and liver fibrosis with RNA-transcriptome sequencing. RESULTS: We included 622 CHB participants: male-dominated (69.6%); median age 42.0 (IQR 34.0-50.0); 287 with normal ALT; 73.0% with significant fibrosis. P5(NA2), P8(NA3), and P10(NA4) were opposite to the degree of fibrosis, while other profiles (except for P0[NGA2]) increased with the degree of fibrosis. Seven profiles (P1[NGA2F], P2[NGA2FB], P3[NG1A2F], P4[NG1A2F], P7[NA2FB], P8[NA3], and P9[NA3Fb]) were selected into Px score. Px score was associated with an increased risk of significant fibrosis (for per Px score increase, the risk of significant fibrosis was increased by 3.54 times (OR = 4.54 [2.63-7.82]) in the fully-adjusted generalized linear model. p for trend was <0.001. The diagnostic performance of the Px score was superior to others. Glycosyltransferase genes were overexpressed in liver fibrosis, and glycosylation and glycosyltransferase-related pathways were significantly enriched. CONCLUSIONS: Serum N-glycan markers were positively correlated with liver fibrosis. Px score had good performance in distinguishing significant fibrosis.

Impaired synaptic plasticity and decreased glutamatergic neuron excitability induced by SIRT1/BDNF downregulation in the hippocampal CA1 region are involved in postoperative cognitive dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice. METHODS: Open field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated. RESULTS: The research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction. CONCLUSIONS: The decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery.

EH domain-containing protein 2 (EHD2): Overview, biological function, and therapeutic potential.

EH domain-containing protein 2 (EHD2) is a member of the EHD protein family and is mainly located in the plasma membrane, but can also be found in the cytoplasm and endosomes. EHD2 is also a nuclear-cytoplasmic shuttle protein. After entering the cell nuclear, EHD2 acts as a corepressor of transcription to inhibit gene transcription. EHD2 regulates a series of biological processes. As a key regulator of endocytic transport, EHD2 is involved in the formation and maintenance of endosomal tubules and vesicles, which are critical for the intracellular transport of proteins and other substances. The N-terminal of EHD2 is attached to the cell membrane, while its C-terminal binds to the actin-binding protein. After binding, EHD2 connects with the actin cytoskeleton, forming the curvature of the membrane and promoting cell endocytosis. EHD2 is also associated with membrane protein trafficking and receptor signaling, as well as in glucose metabolism and lipid metabolism. In this review, we highlight the recent advances in the function of EHD2 in various cellular processes and its potential implications in human diseases such as cancer and metabolic disease. We also discussed the prospects for the future of EHD2. EHD2 has a broad prospect as a therapeutic target for a variety of diseases. Further research is needed to explore its mechanism, which could pave the way for the development of targeted treatments.

Integrated genomic and proteomic analyses identify PYGL as a novel experimental therapeutic target for clear cell renal cell carcinoma.

Sunitinib, the first-line targeted therapy for metastatic clear cell renal cell carcinoma (ccRCC), faces a significant challenge as most patients develop acquired resistance. Integrated genomic and proteomic analyses identified PYGL as a novel therapeutic target for ccRCC. PYGL knockdown inhibited cell proliferation, cloning capacity, migration, invasion, and tumorigenesis in ccRCC cell lines. PYGL expression was increased in sunitinib-resistant ccRCC cell lines, and CP-91149 targeting the PYGL could restore drug sensitivity in these cell lines. Moreover, chromatin immune-precipitation assays revealed that PYGL upregulation is induced by the transcription factor, hypoxia-inducible factor 1α. Overall, PYGL was identified as a novel diagnostic biomarker by combining genomic and proteomic approaches in ccRCC, and sunitinib resistance to ccRCC may be overcome by targeting PYGL.

Green synthesis of iron nanoparticles using mulberry leaf extract: characterization, identification of active biomolecules, and catalytic activity.

The synthesis of iron-based nanoparticles (Fe NPs) using traditional preparation methods suffered from the disadvantages of high cost, environmental harm, and easy agglomeration. In this study, a novel eco-friendly method was proposed for the synthesis of iron nanomaterials (ML-Fe NPs): using antioxidant components extracted from mulberry leaf to reduce divalent iron (II). The preparation conditions of ML-Fe NPs were optimized by orthogonal tests. The prepared ML-Fe NPs exhibited an amorphous core-shell structure, displaying excellent dispersion and stability. During the synthesis process of ML-Fe NPs, the polyphenol molecules in mulberry leaf extract played a dominant role. A possible synthetic mechanism involving complexation, reduction, and encapsulation was proposed. Furthermore, the ML-Fe NPs were utilized to construct an ML-Fe NPs/peroxymonosulfate catalytic system for the degradation of Rhodamine B dye wastewater. The ML-Fe NPs demonstrated remarkable catalytic potential, achieving a 99% degradation efficiency for Rhodamine B within a span of 40 min.

Global, regional, and national burdens of cirrhosis in children and adolescents aged under 19 years from 1990 to 2019.

BACKGROUND & AIMS: Cirrhosis was the leading cause of morbidity and mortality in adults, but data on the burden and trends were sparse in children and adolescents. We aimed to assess the trends in 204 countries and territories over the past 30 years in children and adolescents aged 0-19 years. METHODS: Data on cirrhosis was collected by the Global Burden of Disease (GBD) 2019 database from 1990 to 2019. We reported on the number, rates, and average annual percentage changes (AAPCs) of incidence and disability-adjusted life-years (DALYs) of cirrhosis at global, regional, and national level. RESULTS: Globally, the incident numbers of cirrhosis in children and adolescents increased from 204,767 in 1990 to 241,364 in 2019, an increase of 17.9%, with an AAPC 0.13(0.10 to 0.16). Prevalence (AAPC = - 2.27[- 2.39 to - 2.15]), mortality (AAPC = - 1.68 [- 1.86 to - 1.5]), and DALYs rate (AAPC = - 1.72[- 1.88 to - 1.56]) of cirrhosis have decreased significantly. Cirrhosis incident rates varied between different ages. Cirrhosis caused by alcohol use (AAPC = 1[0.8 to 1.1]; incidence cases increased 48%), hepatitis C (AAPC = 0.4 [0.4 to 0.5]), NAFLD (AAPC = 0.5 [0.3 to 0.6]) have been increasing, while only hepatitis B (- 0.3[- 0.4 to - 0.2]) decreasing. Incidence cases of cirrhosis were increased in low (101.6%) and low-middle sociodemographic index (SDI 21.1%) areas, while decreasing in middle and above SDI areas. At the regional level, the largest increases count was observed in Sub-Saharan Africa. CONCLUSIONS: Global incidence rate of cirrhosis has been increasing, while the DALYs rate has been decreasing in children and adolescents. Morbidity of cirrhosis caused by hepatitis B declined, while hepatitis C, NAFLD, and alcohol use increased.

Clinical significance of serum S100 calcium-binding protein A12 concentrations in patients with community-acquired pneumonia.

OBJECTIVE: This study aimed to investigate the clinical significance of serum S100 calcium-binding protein A12 (S100A12) concentrations in patients with community-acquired pneumonia (CAP). METHODS: This was a case-control study. We selected 120 patients with CAP treated in Xichang People's Hospital from January to June 2022 as the case group. Sixty healthy adults without a history of basic diseases were selected as the control group. The patients in the case group were divided into the low S100A12 and high S100A12 subgroups. Serum S100A12, C-reactive protein (CRP), and procalcitonin (PCT) concentrations, the leukocyte count, and other study parameters were compared. RESULTS: Serum S100A12, CRP, and PCT concentrations and the leukocyte count were higher in the case group than in the control group. The baseline confusion, urea, respiratory rate, blood pressure, and age ≥ 65 score, baseline pneumonia severity index score, and 30-day mortality rate were higher in the high S100A12 subgroup than in the low S100A12 subgroup. Serum CRP and PCT concentrations and the leukocyte count were higher in the high S100A12 subgroup than in the low S100A12 subgroup. CONCLUSION: Patients with high serum S100A12 concentrations have more severe CAP, a more serious inflammatory reaction, and higher 30-day mortality.

CPNE1 mediates glycolysis and metastasis of breast cancer through activation of PI3K/AKT/HIF-1α signaling.

CPNE1 regulates multiple signaling pathways and can stimulate cell proliferation and differentiation by activating the AKT-mTOR signaling pathway. In addition, CPNE1 is associated with various cancers; however, its role in breast cancer, particularly in TNBC, has not been fully elucidated. Our study aimed to reveal the impact of the CPNE1/PI3K/AKT/HIF-1α axis on TNBC. We first measured the expression of CPNE1 in the tumor tissues of TNBC patients and examined its prognostic value. Subsequently, we used sh-CPNE1 and overexpression vectors to transfect TNBC cell lines and analyzed cell viability, migration, and invasive abilities using colony formation and CCK-8 assays. Metabolites were analyzed through metabolomics. We found that higher expression of CPNE1 predicted poor prognosis in TNBC patients. Knockdown of CPNE1 reduced the viability, migration, invasion, and proliferation capabilities of TNBC cells. Furthermore, metabolomics analysis showed that glucose metabolism was the most dominant pathway, and knockdown of CPNE1 significantly limited the glycolytic activity of TNBC cells. We verified these conclusions in mouse models. Additionally, we overexpressed CPNE1 and treated TNBC cell lines with a PI3K inhibitor (LY294002). The results indicated that CPNE1 promoted aerobic glycolysis in TNBC cells through the PI3K/AKT/HIF-1α signaling pathway. This suggests that CPNE1 regulates cell glycolysis and participates in the development of TNBC. Our study may provide a new therapeutic target for TNBC treatment.

Factors associated with persistent positive in HBV DNA level in patients with chronic Hepatitis B receiving entecavir treatment.

Introduction: The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir. Methods: A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development. Results: Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment. Discussion: In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578).

Non-coding RNAs in renal cell carcinoma: Implications for drug resistance.

Renal cell carcinoma (RCC) represents a malignant tumor of the urinary system. Individuals with early-stage RCC could be cured by surgical treatment, but a considerable number of cases of advanced RCC progress to drug resistance. Recently, numerous reports have demonstrated that a variety of non-coding RNAs (ncRNAs) contribute to tumor occurrence and development. ncRNAs can act as oncogenic or tumor suppressor genes to regulate proliferation, migration, drug resistance and other processes in RCC cells through a variety of signaling pathways. Considering the lack of treatment options for advanced RCC after drug resistance, ncRNAs may be a good choice as biomarkers of drug resistance in RCC and targets to overcome drug resistance. In this review, we discussed the effects of ncRNAs on drug resistance in RCC and the great potential of ncRNAs as a biomarker of or a new therapeutic method in RCC.

Effect of neutralization treatment on properties of chitosan/bamboo leaf flavonoids/nano-metal oxide composite films and application of films in antioxidation of rapeseed oil.

Neutralization treatment improved the slow-release antioxidant food packaging function of chitosan (CS)/bamboo leaf flavone (BLF)/nano-metal oxides composite films. The film cast from the CS composite solution neutralized by KOH solution had good thermal stability. The elongation at break of the neutralized CS/BLF film was increased by about 5 times, which provided the possibility for its packaging application. After 24 h of soaking in different pH solutions, the unneutralized films swelled severely and even dissolved, while the neutralized films maintained the basic structure with a small degree of swelling, and the release trend of BLF conformed to the logistic function (R2 ≥ 0.9186). The films had a good ability to resist free radicals, which was related to the release amount of BLF and the pH of the solution. The antimicrobial neutralized CS/BLF/nano-ZnO film, like the nano-CuO and Fe3O4 films, were effective in inhibiting the increase in peroxide value and 2-thiobarbituric acid induced by thermal oxygen oxidation of rapeseed oil and had no toxicity to normal human gastric epithelial cells. Therefore, the neutralized CS/BLF/nano-ZnO film is likely to become an active food packaging material for oil-packed food, which can prolong the shelf life of packaged food.

An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir.

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Fucosyltransferase 2 is involved in immune-related functions in Penaeus vannamei by modulating antimicrobial peptides' expression.

In mammals fucosyltransferase 2 (FUT2) plays an important regulatory role in inflammation, bacterial or viral infection, and tumor metastasis. However, the specific role of FUT2 in invertebrate immunity has not been reported. Here, the FUT2 homolog of Penaeus vannamei (designated as PvFUT2) was cloned and found to have a full-length cDNA of 1104 bp with an open reading frame (ORF) encoding 316 amino acids. PvFUT2 is constitutively expressed in all shrimp tissues tested with the highest found in intestines. Moreover, PvFUT2 was induced in the main immune organs (hemocytes and hepatopancreas) of shrimp by Gram-positive (Vibrio parahaemolyticus), Gram-negative (Streptococcus iniae) bacteria and virus (White Spot Syndrome Virus), indicating the involvement of PvFUT2 in shrimp antimicrobial response. Intriguingly, PvFUT2 knockdown with or without pathogen challenge reduced the expression of Pvß-catenin and antimicrobial peptides genes, particularly anti lipopolysaccharide factor and lysozyme. Further analysis revealed that the knockdown of PvFUT2 increased Vibrio abundance in hemolymph and resulted in an increase in shrimp cumulative mortality rate. Thus, during pathogen challenge, the expression of PvFUT2 is induced to regulate ß-catenin and subsequently antimicrobial peptides expression to augment shrimp antimicrobial immune response.

Steady Decline of HBV DNA Load under NAs in Lymphoma Patients and a Higher Level of qAnti-HBc Predict HBV Reactivation.

Background: Patients with lymphoma and chronic hepatitis B virus infection need to be treated with both chemotherapy and nucleotide analogue (NA) therapy. However, dynamic changes in HBV DNA loads with increasing chemotherapy cycles are lacking. It is unknown whether HBV replication markers, namely, the quantitative hepatitis B core antibody (qAnti-HBc), HBV RNA, and the hepatitis B virus core-related antigen (HBcrAg), are also markers for predicting HBV reactivation (HBVr). Methods: From 29 June 2010 to 6 December 2021, the data of patients with single-site diffuse large B-cell lymphoma and HBV infection (HBsAg+ and HBsAg-/anti-HBc+) were collected from a hospital medical record system, retrospectively. Serum HBV DNA loads (using real-time fluorescent quantitative PCR tests), qAnti-HBc levels (using a newly developed chemiluminescent particle immunoassay), HBV RNA levels (using the simultaneous amplification testing method based on real-time fluorescence detection), and HBcrAg levels (using a Lumipulse G HBcrAg assay) were tested, and factors related to HBVr were analyzed. Results: Under NAs, the HBV DNA loads of 69 HBsAg+ lymphoma patients declined from 3.15 (2.13-4.73) lg IU/mL to 1.00 (1.00-1.75) lg IU/mL, and further declined to 1.00 (1.00-1.04) lg IU/mL at the end of a 24-month follow-up. The qAnti-HBc levels decreased gradually during chemotherapy in HBsAg+ lymphoma patients (F = 7.090, p = 0.009). The HBV RNA and HBcrAg levels remained stable. A multivariate analysis revealed that higher qAnti-HBc levels (1.97 ± 1.20 vs. 1.12 ± 0.84 lg IU/mL, OR = 6.369, [95% CI: 1.523-26.641], p = 0.011) and higher HBV RNA levels (1.00 ± 1.13 vs. 0.37 ± 0.80 lg copies/mL, OR = 3.299, [95% CI: 1.229-8.854], p = 0.018) were related to HBVr in HBsAg-/anti-HBc+ lymphoma patients. Conclusions: HBV DNA loads declined under NAs during chemotherapy in lymphoma patients. In HBsAg-/anti-HBc+ lymphoma patients, a higher level of baseline serum qAnti-HBc and HBV RNA levels can predict the likelihood of HBVr during chemotherapy.

Effect of infection with hepatitis B virus on the survival outcome of diffuse large B-cell lymphoma in the prophylactic antiviral era.

Patients with lymphoma who are also infected with Hepatitis B virus (HBV) have a poor prognosis. This could be partly explained by the delay or premature termination of anti-tumor treatment because of HBV reactivation. However, there is limited data on the survival outcome of patients HBV-related lymphoma in the era of prophylactic antivirals. Data for 128 patients with HBV surface antigen-positive diffuse large B-cell lymphoma was collected. The median age was 54 years and the ratio of men to women was 1.2:1. All patients received immune-chemotherapy and prophylactic antiviral therapy. The median number of cycles of immune-chemotherapy was six. The overall response rate was 82%, with a complete remission rate of 75%. With a median follow-up of 58.4 months, the 5-year progression-free survival and overall survival rates were 75.7% and 74.7%, respectively. Nine patients experienced HBV reactivation but none experienced HBV-associated hepatitis. Patients with low and high HBV DNA loads had comparable survival outcomes. In conclusion, HBV infection had no negative effect on the prognosis of DLBCL in the era of prophylactic antiviral therapy.

CBX7 regulates metastasis of basal-like breast cancer through Twist1/EphA2 pathway.

BACKGROUND: Basal-like breast cancer (BLBC) is an important subtype of breast cancer. Twist1 is a key transcription factor in BLBC metastasis, which serves a key role in tumorigenesis. The potential mechanism of Twist1 in BLBC remains to be elucidated. Here, we explored the role and molecular mechanism of Twist1 in BLBC. METHODS: The levels of CBX7, Twist1 and EphA2 in BLBC tissues and cells were determined by Western blot. ChIP and dual-luciferase reporter assays confirmed the interaction between CBX7, Twist1 and EphA2 promoter. The cellular functions were analyzed by CCK-8, colony formation, wound healing and Transwell assays. Expression of EMT related proteins was analyzed by Western blot. IHC measured the expression of CBX7, Twist1 and EphA2 in tumor tissues. RESULTS: CBX7 was down-regulated in BLBC tissues and cells, whereas Twist1 and EphA2 were up-regulated. Twist1 silencing inhibited the cell migration, invasion and cancer metastasis of BLBC through targeting EphA2 and regulating EphA2 expression. Additionally, CBX7 blocked the binding of Twist1 to EphA2 promoter and inhibited EphA2 expression and suppressed BLBC growth and metastasis via Twist1/EphA2 axis. CONCLUSION: CBX7 suppresses BLBC growth and metastasis through Twist1/EphA2 pathway. Our study may provide evidence and new therapeutic targets for the comprehensive treatment of BLBC.

Dose-response relationship between qAnti-HBc and liver inflammation in chronic hepatitis B with normal or mildly elevated alanine transaminase based on liver biopsy.

The proportion of chronic hepatitis B (CHB) patients with normal or mildly elevated alanine transaminase (NMALT) levels who have moderate to severe inflammation was not rare. However, we lacked appropriate biomarkers to evaluate liver inflammation in these populations. We aimed to explore the relationship between quantitative hepatitis B core antibody (qAnti-HBc) and hepatic histological inflammation. This multicenter cohort study enrolled participants from 34 Chinese hospitals including 1376 treatment-naive CHB patients with liver biopsy (934 with NMALT entered treatment-naive cohort; 423 with secondary liver biopsy entered treatment cohort). Using unadjusted and multivariate-adjusted generalized linear models, generalized additive models with smooth curve fitting, we evaluated the associations between qAnti-HBc and liver inflammation in these patients. In the treatment-naive patients, qAnti-HBc was positively associated with liver inflammation (histology activity index [HAI] evaluated by Ishak scoring system; fully adjusted model: ß = 0.48, 95% confidence interval [CI] [0.30-0.66], p < 0.001). For per-SD increase in qAnti-HBc, the risk of moderate to severe inflammation (HAI ≥ 5) increased by 56% (odds ratio [OR] = 1.56, 95% CI [1.28-1.91], p < 0.001). The curve fitting indicated a significant "threshold effect" (inflection point was 4.5 log10  IU/ml, p < 0.001). Subgroup analyses and interactions were not significant (all p > 0.05). In the treatment patients, there was no significant correlation between qAnti-HBc and liver inflammation, whether based on unadjusted, minimally adjusted, or fully adjusted models (all p > 0.100). Paired analyses showed a significant correlation between decreasing in qAnti-HBc and alleviation of liver inflammation. qAnti-HBc was positively correlated with liver inflammation in treatment-naive CHB patients with NMALT. The cutoff value of qAnti-HBc for the diagnosis of moderate to severe inflammation was 4.5 log10  IU/ml. Decreasing in qAnti-HBc was positively correlated with liver inflammation relieving.