TMV-CP based rational design and discovery of α-Amide phosphate derivatives as anti plant viral agents.

The tobacco mosaic virus coat protein (TMV-CP) is indispensable for the virus's replication, movement and transmission, as well as for the host plant's immune system to recognize it. It constitutes the outermost layer of the virus particle, and serves as an essential component of the virus structure. TMV-CP is essential for initiating and extending viral assembly, playing a crucial role in the self-assembly process of Tobacco Mosaic Virus (TMV). This research employed TMV-CP as a primary target for virtual screening, from which a library of 43,417 compounds was sourced and SH-05 was chosen as the lead compound. Consequently, a series of α-amide phosphate derivatives were designed and synthesized, exhibiting remarkable anti-TMV efficacy. The synthesized compounds were found to be beneficial in treating TMV, with compound 3g displaying a slightly better curative effect than Ningnanmycin (NNM) (EC50 = 304.54 µg/mL) at an EC50 of 291.9 µg/mL. Additionally, 3g exhibited comparable inactivation activity (EC50 = 63.2 µg/mL) to NNM (EC50 = 67.5 µg/mL) and similar protective activity (EC50 = 228.9 µg/mL) to NNM (EC50 = 219.7 µg/mL). Microscale thermal analysis revealed that the binding of 3g (Kd = 4.5 ± 1.9 µM) to TMV-CP showed the same level with NNM (Kd = 5.5 ± 2.6 µM). Results from transmission electron microscopy indicated that 3g could disrupt the structure of TMV virus particles. The toxicity prediction indicated that 3g was low toxicity. Molecular docking showed that 3g interacted with TMV-CP through hydrogen bond, attractive charge interaction and π-Cation interaction. This research provided a novel α-amide phosphate structure target TMV-CP, which may help the discovery of new anti-TMV agents in the future.

Blood Lead Level as Marker of Increased Risk of Ovarian Cancer in BRCA1 Carriers.

BRCA1 mutations substantially elevate the risks of breast and ovarian cancer. Various modifiers, including environmental factors, can influence cancer risk. Lead, a known carcinogen, has been associated with various cancers, but its impact on BRCA1 carriers remains unexplored. A cohort of 989 BRCA1 mutation carriers underwent genetic testing at the Pomeranian Medical University, Poland. Blood lead levels were measured using inductively coupled plasma mass spectrometry. Each subject was assigned to a category based on their tertile of blood lead. Cox regression analysis was used to assess cancer risk associations. Elevated blood lead levels (>13.6 µg/L) were associated with an increased risk of ovarian cancer (univariable: HR = 3.33; 95% CI: 1.23-9.00; p = 0.02; multivariable: HR = 2.10; 95% CI: 0.73-6.01; p = 0.17). No significant correlation was found with breast cancer risk. High blood lead levels are associated with increased risk of ovarian cancer in BRCA1 carriers, suggesting priority for preventive salpingo-oophorectomy. Potential risk reduction strategies include detoxification. Validation in diverse populations and exploration of detoxification methods for lowering lead levels are required.

The risk of skin cancer in women who carry BRCA1 or BRCA2 mutations.

BACKGROUND: It has not been clearly established if skin cancer or melanoma are manifestations of BRCA1 or BRCA2 mutation carrier status. Estimating the risk of skin cancer is an important step towards developing screening recommendations. METHODS: We report the findings of a prospective cohort study of 6,207 women from North America who carry BRCA1 or BRCA2 mutations. Women were followed from the date of baseline questionnaire to the diagnosis of skin cancer, to age 80 years, death from any cause, or the date of last follow-up. RESULTS: During the mean follow-up period of eight years, 3.7% of women with a BRCA1 mutation (133 of 3,623) and 3.8% of women with a BRCA2 mutation (99 of 2,584) reported a diagnosis of skin cancer (including both keratinocyte carcinomas and melanoma). The cumulative risk of all types of skin cancer from age 20 to 80 years was 14.1% for BRCA1 carriers and 10.7% for BRCA2 carriers. The cumulative risk of melanoma was 2.5% for BRCA1 carriers and 2.3% for BRCA2 carriers, compared to 1.5% for women in the general population in the United States. The strongest risk factor for skin cancer was a prior diagnosis of skin cancer. CONCLUSION: The risk of non-melanoma skin cancer in women who carry a mutation in BRCA1 or BRCA2 is similar to that of non-carrier women. The risk of melanoma appears to be slightly elevated. We suggest that a referral to a dermatologist or primary care provider for BRCA mutation carriers for annual skin examination and counselling regarding limiting UV exposure, the use of sunscreen and recognizing the early signs of melanoma might be warranted, but further studies are necessary.

Clinical features and risk factors of bilateral granulomatous lobular mastitis.

Granulomatous lobular mastitis (GLM) is an idiopathic inflammatory breast disease that tends to recur on the same side. With the accumulation of clinical cases, it has been observed that GLM can also occur contralaterally. Currently, most studies on GLM focus on treatment methods and risk factors for ipsilateral recurrence, and there are few reports on bilateral GLM. The study aimed to summarize the clinical characteristics of patients with bilateral GLM by reviewing their clinical data, and to discuss the risk factors affecting the occurrence of bilateral GLM. A retrospective study of the medical records database of patients with GLM admitted between May 2019 and August 2022 was performed. Patients were divided into bilateral GLM group (bilateral GLM group) and unilateral GLM patients (unilateral GLM group). Demographic and clinical characteristics, treatment, and follow-up were collected and analyzed. In this study, by reviewing the clinical data of 59 cases of bilateral GLM, we found that the median time between the onset of bilateral GLM on both sides was 6.63 (0-18) months. Additionally, because of the simultaneous or interval onset on both sides, the duration of the disease was longer compared to unilateral cases. Regarding the history of external hospital treatment, it was found that about 57.63% of patients with bilateral GLM received 2 or more treatment modalities, with a higher involvement of herbal medicine. Meanwhile, by counting the clinical data of the 2 groups of patients with bilateral GLM and unilateral GLM, it was shown by univariate analysis that fertility, nipple development, absolute CD4 value, and CD4/CD8 ratio were associated with contralateral onset of GLM in both groups, with inverted nipple being an independent risk factor.

Phase II study of novel orally PI3Kα/δ inhibitor TQ-B3525 in relapsed and/or refractory follicular lymphoma.

This registration study assessed clinical outcomes of TQ-B3525, the dual phosphatidylinositol-3-kinase (PI3K) α/δ inhibitor, in relapsed and/or refractory follicular lymphoma (R/R FL). This phase II study (ClinicalTrials.gov NCT04324879. Registered March 27, 2020) comprised run-in stage and stage 2. R/R FL patients after ≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until intolerable toxicity or disease progression. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Based on results (ORR, 88.0%; duration of response [DOR], 11.8 months; progression-free survival [PFS], 12.0 months) in 25 patients at run-in stage, second stage study was initiated and included 82 patients for efficacy/safety analysis. Patients received prior-line (median, 3) therapies, with 56.1% refractory to previous last therapies; 73.2% experienced POD24 at baseline. At stage 2, ORR was 86.6% (71/82; 95% CI, 77.3-93.1%), with 28 (34.2%) complete responses. Disease control rate was 95.1% due to 7 (8.5%) stable diseases. Median time to response was 1.8 months. Among 71 responders, median DOR was not reached; 18-month DOR rate was 51.6%. with median follow-up of 13.3 months, median PFS was 18.5 (95% CI, 10.2-not estimable) months. Median overall survival (OS) was not reached by cutoff date; 24-month OS rate was estimated as 86.1%. Response rates and survival data were consistent across all subgroups. Grade 3 or higher treatment-related adverse events were observed in 63 (76.8%) cases, with neutropenia (22.0%), hyperglycemia (19.5%), and diarrhea (13.4%) being common. TQ-B3525 showed favorable efficacy and safety for R/R FL patients after ≥2 lines prior therapies.

Visually evaluating drug efficacy in living cells using COF-based fluorescent nanoprobe via CHA amplified detection of miRNA and simultaneous apoptosis imaging.

BACKGROUNDS: Cancer is a highly fatal disease which is close relative of miRNA aberrant expression and apoptosis disorders. Elucidation of the therapeutic efficacy through investigating the changes in miRNA and apoptosis holds immense importance in advancing the development of miRNA-based precision therapy. However, it remains a challenge as how to visually evaluate the efficacy during protocol optimization of miRNA-based anticancer drugs at the cellular level. Therefore, exploring effective and noninvasive methods for real-time monitoring of therapeutic efficacy in living cells is of great significance. RESULTS: Herein, we reported a novel fluorescent nanoprobe COF-H1/H2-Peptide for visually evaluating drug efficacy in living cells through amplified imaging of low-abundant miRNA-221 with catalytic hairpin assembly (CHA) circle amplification, as well as simultaneous caspase-3 imaging. With strong stability and good biocompatibility, this newly fabricated amplified nanoprobe showed high sensitivity and specificity for the detection of miRNA-221 and caspase-3, and the limit of detection (LOD) of miRNA-221 was as low as 2.79 pM. The fluorescent imaging results showed that this amplified nanoprobe could not only detect caspase-3 in living cells, but also effectively detect low levels of miRNA-221 with increasing anticancer drug concentration and treatment time. The smart nanoprobe had effective performance for optimizing miRNA-based drug treatment schedules by dual-color fluorescence imaging. SIGNIFICANCE: This nanoprobe combined CHA amplified detection of intracellular miRNA-221 and synchronous apoptosis imaging, with excellent sensitivity for the detection of cellular low-level miRNA, enabling the realization of real-time assessment of the efficacy of miRNA-based therapy in living cells. This work presents a promising approach for revealing the regulatory mechanisms between miRNAs and apoptosis in cancer occurrence, development, and treatment.

Incidence of thromboembolic events in non-small cell lung cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

ABSTRACT: The incidence of thromboembolic events (TEs) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) has rarely been reported. The MEDLINE, EMBASE, and the Cochrane Library databases were searched. The primary outcome was the incidence of TEs, and the secondary outcome was the relationship between TEs and overall survival (OS) following ICI therapy. A subgroup analysis of TE incidents was performed according to the TE type and combination regimens. The I2 statistic was used to determine the heterogeneity, and funnel plots and Egger's test were used to assess publication bias. A total of 16,602 patients with NSCLC in 63 experimental arms were included in the analysis. The rate of TEs ranged from 0.1% to 13.8%, and the pooled overall incidence of all-grade TEs was 3% (95% confidence interval [CI], 2%-4%). The pooled rate of high-grade TEs was 1% (95% CI, 1%-2%). The venous and arterial TE rates were 3% (95% CI, 2%-4%) and 1% (95% CI, 1%-2%), respectively. Patients who received immunotherapy + chemoradiotherapy had the highest incidence of TEs (7%). The TE pooled rate was higher in patients treated with combined ICIs than in those treated with mono ICIs (4% vs. 2%). The OS was lower in patients with TEs than in those without TEs (hazard ratio, 1.4; 95% CI, 1.02%-1.92%). The incidence of TEs in NSCLC patients treated with ICIs was reasonable. Nonetheless, clinicians must be aware of potential thrombotic complications and treat them promptly.

DOT1L promotes expression of CD44 through the Wnt/ß-catenin signaling pathway in early gastric carcinoma.

To assess telomere silencing 1-like (DOTIL) gene expression within gastric cancer (GC) tissues as well as its function of promoting cancer stem cell (CSC)-mediated epithelial-mesenchymal switching, tissue samples from 8 patients each in 3 stages (normal, low-grade intraepithelial neoplasia (LGIN), as well as early gastric carcinoma (EGC)) were collected for whole-exome sequencing, which revealed differentially expressed genes (DEGs). The DEGs and their prognostic value were verified through TCGA and GTEx analyses. We also verified the role of DOT1L in EGC development. We collected samples from three patients each with LGIN and EGC for single-cell sequencing. We conducted single-cell transcriptomic analysis, DEG analysis, cell‒cell interaction analysis, and pseudotime analysis using R language. Sites and levels of DOT1L, CD44 and DOT1L expression were verified by IF. We found 703 deleterious mutation sites in the LGIN group and 389 deleterious mutation sites in the EGC group. The LGIN as well as EGC categories exhibited increased levels of DOT1L expression compared to the standard category (P<0.05) in TCGA and GTEx. DOT1L also correlated significantly with TMB (P=8.45E-06), MSI (P=0.001), and tumor proliferation index (P=7.17E-09) in the TCGA and GTEx datasets. In single cells, we found that DOT1L promotes CD44 expression via the Wnt/ß-catenin signaling pathway and the development for stemness properties within GC. In addition, we found that DOT1L, CD44 and CTNNB1 colocalize and correlate positively. In conclusion, one important CSC regulator in GC, DOT1L may be crucial in coordinating the expression of genes specific to a certain lineage during MSC development.

[Screening value and correlation of body measurement indices for metabolic syndrome in the population undergoing physical examinations in Chengdu during 2018-2020].

OBJECTIVE: To investigate the screening value and correlation of body measurement indicators for metabolic syndrome(MS) and to provide evidence for MS screening. METHODS: Through a cross-sectional research approach, data from individuals aged 18 and above who participated in health examinations at the North Health Management Center of Sichuan Provincial People's Hospital from 2018 to 2020 were reviewed. Data including height, weight, waist circumference, hip circumference, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, smoking history, and alcohol consumption history were collected. Subsequently, a body shape index(ABSI), body roundness index(BRI), body adiposity index(BAI), abdominal volume index(AVI), relative fat mass index(RFM), and body mass index(BMI) were computed. The individuals were then divided into MS and non-MS groups. The value of body measurement indices in screening for MS in the population aged 18 and above was assessed using ROC curves. Regression analysis was employed to explore the correlation between body measurement indices and MS. RESULTS: A total of 73 411 valid health examination data were obtained, including 44 426 males and 28 985 females. The MS group comprised 9181 males(21%) and 1668 females(6%). In the comparison between the MS and non-MS groups, there were statistically significant differences in ABSI((0.08±0.00) vs. (0.08±0.00)), BRI((4.95±0.67) vs. (4.17±0.68)), BAI((28.08±3.52) vs. (26.39±3.39)), AVI((17.51±2.77) vs. (12.85±2.91)), BMI((27.15±2.99) vs. (23.00±3.04)) and RFM((29.77±5.35) vs. (27.13±6.39))(P<0.05). Univariate Logistic regression analysis showed that ABSI(OR=2.303, 95%CI 1.190-4.457), BRI(OR=4.596, 95%CI 4.446-4.752), BAI(OR=1.144, 95%CI 1.137-1.151), AVI(OR=1.668, 95%CI 1.652-1.684), RFM(OR=1.067, 95%CI 1.064-1.071) and BMI(OR=1.516, 95%CI 1.503-1.528) were associated with MS(P<0.05). Multifactorial Logistic regression analysis corrected for sex, age, smoking and alcohol consumption showed that ABSI(OR=1.767, 95% CI 4.237-7.371), BRI(OR=5.441, 95% CI 5.228-5.663), BAI(OR=1.269, 95% CI 1.260-1.279), AVI(OR=1.648, 95% CI 1.631-1.665), RFM(OR=1.504, 95% CI 1.491-1.517) and BMI(OR=1.508, 95% CI 1.495-1.522) were associated with MS(P<0.05). The ROC curve analysis showed that in adults, the AVI had the highest screening value for MS in males(AUC=0.855, optimal cutoff value=16.18), followed by RFM(AUC=0.844, optimal cutoff value=25.71), BMI(AUC=0.811, optimal cutoff value=25.21), BRI(AUC=0.793, optimal cutoff value=4.39), BAI(AUC=0.709, optimal cutoff value=25.88), and ABSI(AUC=0.671, optimal cutoff value=0.08). In adult females, the RFM had the highest screening value for MS(AUC=0.918, optimal cutoff value=37.01), followed by AVI(AUC=0.911, optimal cutoff value=13.43), BRI(AUC=0.901, optimal cutoff value=4.71), BMI(AUC=0.860, optimal cutoff value=23.94), ABSI(AUC=0.804, optimal cutoff value=0.08), and BAI(AUC=0.797, optimal cutoff value=29.92). CONCLUSION: ABSI, BRI, BAI, AVI, BMI and RFM are all capable of screening for MS. Among males, AVI has the highest screening value for MS, followed by RFM, BMI, BRI, BAI and ABSI. Among females, RFM has the highest screening value for MS, followed by AVI, BRI, BMI, ABSI and BAI. ABSI, BRI, BAI, AVI, RFM and BMI are positively correlated with MS.

Morusin suppresses the stemness characteristics of gastric cancer cells induced by hypoxic microenvironment through inhibition of HIF-1α accumulation.

Gastric cancer (GC) is a common, life-threatening malignancy that contributes to the global burden of cancer-related mortality, as conventional therapeutic modalities show limited effects on GC. Hence, it is critical to develop novel agents for GC therapy. Morusin, a typical prenylated flavonoid, possesses antitumor effects against various cancers. The present study aimed to demonstrate the inhibitory effect and mechanism of morusin on the stemness characteristics of human GC in vitro under hypoxia and to explore the potential molecular mechanisms. The effects of morusin on cell proliferation and cancer stem cell-like properties of the human GC cell lines SNU-1 and AGS were assessed by MTT assay, colony formation test, qRT-PCR, flow cytometry analysis, and sphere formation test under hypoxia or normoxia condition through in vitro assays. The potential molecular mechanisms underlying the effects of morusin on the stem-cell-like properties of human GC cells in vitro were investigated by qRT-PCR, western blotting assay, and immunofluorescence assay by evaluating the nuclear translocation and expression level of hypoxia-inducible factor-1α (HIF-1α). The results showed that morusin exerted growth inhibitory effects on SNU-1 and AGS cells under hypoxia in vitro. Moreover, the proportions of CD44+/CD24- cells and the sphere formation ability of SNU-1 and AGS reduced in a dose-dependent manner following morusin treatment. The expression levels of stem cell-related genes, namely Nanog, OCT4, SOX2, and HIF-1α, gradually decreased, and the nuclear translocation of the HIF-1α protein was apparently attenuated. HIF-1α overexpression partially reversed the abovementioned effects of morusin. Taken together, morusin could restrain stemness characteristics of GC cells by inhibiting HIF-1α accumulation and nuclear translocation and could serve as a promising compound for GC treatment.

Engineering of 4-hydroxyphenylacetate 3-hydroxylase derived from Pseudomonas aeruginosa for the ortho-hydroxylation of ferulic acid.

Polyphenolic compounds have natural antioxidant properties, and their antioxidant activity is usually related to the number and position of hydroxyls. Here, we successfully applied the engineered 4-hydroxyphenylacetate 3-hydroxylases (4HPA3Hs) derived from Pseudomonas aeruginosa to catalyze ferulic acid (FA) synthesis of ortho-hydroxyferulic acid (5-hydroxyferulic acid, 5-OHFA). Through optimization of co-expression, the oxygenase component (PaHpaB) and the reductase component (PaHpaC) in E. coli, and optimization of whole-cell catalytic conditions, the engineered strain BC catalyzed ortho-hydroxylation of 2 g/L of FA with a yield of 75 % from 39 %. Through tunnel engineering of PaHpaB, the obtained mutants F301A and Q376A almost completely transformed 2 g/L of FA. Further, a multiple mutant L214A/F301A/Q376A converted 4 g/L FA into 5-OHFA within 12 h, and the yield reached 99.9 %, which was approximately 2.39-fold of the wild type. The kcat/Km value of L214A/F301A/Q376A was about 307 times greater than that of the wide type. Analysis of three-dimensional structural models showed that L214, F301, and Q376 mutated into Ala, which greatly shortened the side chain and broadened the tunnel size, thereby significantly improving the catalytic efficiency of L214A/F301A/Q376A. This biosynthesis of 5-OHFA is simple, efficient, and green, suggesting that it is useful for efficient biosynthesis of polyphenolic compounds.

Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations.

Importance: Preventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined. Objective: To evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation. Design, Setting, and Participants: In this international, longitudinal cohort study of women with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023. Exposures: Self-reported bilateral oophorectomy (with or without salpingectomy). Main Outcomes and Measures: All-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality. Results: There were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P < .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P < .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estimated cumulative all-cause mortality to age 75 years for women who had an oophorectomy at age 35 years was 25%, compared to 62% for women who did not have an oophorectomy. For women with BRCA2 sequence variations, the estimated cumulative all-cause mortality to age 75 years was 14% for women who had an oophorectomy at age 35 years compared to 28% for women who did not have an oophorectomy. Conclusions and Relevance: In this cohort study among women with a BRCA1 or BRCA2 sequence variation, oophorectomy was associated with a significant reduction in all-cause mortality.

MRI Surveillance and Breast Cancer Mortality in Women With BRCA1 and BRCA2 Sequence Variations.

Importance: Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. Objective: To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. Design, Setting, and Participants: Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. Exposures: Entrance into an MRI surveillance program. Main Outcomes and Measures: Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. Results: A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P < .001) for women with BRCA1 sequence variations and 0.87 (95% CI, 0.10-17.25; P = .93) for women with BRCA2 sequence variations. Conclusion and Relevance: Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.

Recent advances of novel targeted drug delivery systems based on natural medicine monomers against hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the most prevalent type of liver cancer, is often diagnosed at an advanced stage. Surgical interventions are often ineffective, leading HCC patients to rely on systemic chemotherapy. Unfortunately, commonly used chemotherapeutic drugs have limited efficacy and can adversely affect vital organs, causing significant physical and psychological distress for patients. Natural medicine monomers (NMMs) have shown promising efficacy and safety profiles in HCC treatment, garnering attention from researchers. In recent years, the development of novel targeted drug delivery systems (TDDS) combining NMMs with nanocarriers has emerged. These TDDS aim to concentrate drugs effectively in HCC cells by manipulating the characteristics of nanomedicines, leveraging receptor and ligand interactions, and utilizing endogenous stimulatory responses to promote specific nanomedicines distribution. This comprehensive review presents recent research on TDDS for HCC treatment using NMMs from three perspectives: passive TDDS, active TDDS, and stimuli-responsive drug delivery systems (SDDS). It consolidates the current state of research on TDDS for HCC treatment with NMMs and highlights the potential of these innovative approaches in improving treatment outcomes. Moreover, the review also identifies research gaps in the related fields to provide references for future targeted therapy research in HCC.

Protective effect of low-intensity pulsed ultrasound on immune checkpoint inhibitor-related myocarditis via fine-tuning CD4+ T-cell differentiation.

PURPOSE: Immune checkpoint inhibitors (ICIs) have transformed traditional cancer treatments. Specifically, ICI-related myocarditis is an immune-related adverse event (irAE) with high mortality. ICIs activate CD4+ T-lymphocyte reprogramming, causing an imbalance between Th17 and Treg cell differentiation, ultimately leading to myocardial inflammatory damage. Low-intensity pulsed ultrasound (LIPUS) can limit inflammatory responses, with positive therapeutic effects across various cardiovascular inflammatory diseases; however, its role in the pathogenesis of ICI-related myocarditis and CD4+ T-cell dysfunction remains unclear. Accordingly, this study investigated whether LIPUS can alleviate ICI-related myocarditis inflammatory damage and, if so, aimed to elucidate the beneficial effects of LIPUS and its underlying molecular mechanisms. METHODS: An in vivo model of ICI-related myocarditis was obtained by intraperitonially injecting male A/J mice with an InVivoPlus anti-mouse PD-1 inhibitor. LIPUS treatment was performed via an ultrasound-guided application to the heart via the chest wall. The echocardiographic parameters were observed and cardiac function was assessed using an in vivo imaging system. The expression of core components of the HIPPO pathway was analyzed via western blotting. RESULTS: LIPUS treatment reduced cardiac immune responses and inflammatory cardiac injury. Further, LIPUS treatment alleviated the inflammatory response in mice with ICI-related myocarditis. Mechanistically, in the HIPPO pathway, the activation of Mst1-TAZ axis improved autoimmune inflammation by altering the interaction between the transcription factors FOXP3 and RORγt and regulating the differentiation of Treg and Th17 cells. CONCLUSION: LIPUS therapy was shown to reduce ICI-related myocarditis inflammatory damage and improve cardiac function, representing an exciting finding for irAEs treatment.

A novel nanoprobe for visually investigating the controversial role of miRNA-34a as an oncogene or tumor suppressor in cancer cells.

MiRNA-targeted therapy has become a hot topic in current cancer research. The key to this treatment strategy is to clarify the specific role of miRNA in cancer. However, the roles of some miRNAs acting as oncogenic or tumor suppressors are still controversial, which are influenced by different tumor types, even in the same cancer type. Hence, we designed a novel fluorescent nanoprobe based on polydopamine nanoparticles (PDA NPs) for simultaneously detecting caspase-3 and miRNA-34a within living cells. The specific role of miRNA-34a in different cancer cells could be further identified by studying the expression alterations of caspase-3 and miRNA-34a. Confocal imaging indicated that miRNA-34a indeed acted as a tumor suppressor in anticancer drug-treated MCF-7 and HeLa cells, where the effect of miRNA-34a remains controversial. The designed nanoprobe can offer a promising approach to ascertain the oncogenic or tumor-suppressing role of miRNA in different cancer cells with a simple visualization method, which has valuable implications for exploring the practicability of precision therapy focused on miRNA and evaluating the efficacy of new miRNA-targeted anticancer medications.

Rational design and synthesis of triazene-amonafide derivatives as novel potential antitumor agents causing oxidative damage towards DNA through intercalation mode.

In this work, we rationally designed and synthesized two novel triazene-amonafide derivatives 2-(2-(diisopropylamino)ethyl)-5-(3,3-dimethyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-11) and 5-(3,3-diethyltriaz-1-en-1-yl)-2-(2-(diisopropylamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-12) as potential antitumor agents. The DNA damage induced by the intercalation mode of D-11 (D-12) towards DNA was electrochemically detected through the construction of efficient biosensors. The consecutive processes of reversible redox of naphthylimide ring and irreversible oxidation of triazene moiety were elucidated on the surface of glassy carbon electrode (GCE) by CV, SWV, and DPV methods. Electrochemical biosensors were obtained through the immobilization of ctDNA, G-quadruplexes, poly(dG), and poly(dA), respectively, on the clean surface of GCE. After the incubation of biosensors with D-11 or D-12, the peaks of dGuo and dAdo decreased prominently, and the peak of 8-oxoGua appeared at +0.50 V, suggesting that the interaction between D-11 (D-12) and DNA could result in the oxidative damage of guanine. Unexpected, the as-prepared DNA biosensor possessed satisfactory anti-interference property and good practicability in real samples. UV-vis and fluorescence spectra, and gel electrophoresis assays were employed to further confirm the intercalation mode of D-11 (D-12) towards DNA base pairs. Moreover, D-11 was proved to exhibit stronger anti-proliferation activity than mitionafide and amonafide against both A549 and HeLa cell lines.