Academy of Medical Sciences

Postoperative recurrence, distant metastasis, and chemotherapy resistance in breast cancer present significant challenges in clinical treatment. Improving perioperative intervention strategies is crucial for enhancing patient prognosis. Lidocaine, a commonly used local anesthetic, has recently been shown to possess potential anti-breast cancer effects, offering a novel therapeutic direction through its drug repurposing potential. This review explores the multifaceted mechanisms by which lidocaine exerts anti-cancer effects, including nuclear regulation, membrane receptor channel inhibition, tumor microenvironment reprogramming, autophagy activation, and synergistic effects when combined with chemotherapy agents. Furthermore, the review discusses the limitations of current research, incorporating clinical evidence. This article provides a theoretical foundation for the perioperative application of lidocaine in breast cancer and the development of combination therapies, while also outlining future research directions to promote the clinical translation of “old drugs, new uses.”

BackgroundHuman cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are globally prevalent herpesviruses. While typically self-limiting in immunocompetent individuals, infections can cause severe consequences even in this population. In immunocompromised groups, such as transplant recipients and HIV-infected individuals, viral reactivation or coinfection frequently triggers graft rejection, multi-organ invasion, and malignancies, often exhibiting synergistic pathogenicity. Current serological assays are limited by “window periods” and delayed immune responses, while traditional quantitative PCR (qPCR) relies on standard curves for quantification. Consequently, there is an urgent need for precise, interference-resistant methods. This study aimed to develop and validate a duplex droplet digital PCR (ddPCR) assay for the simultaneous, absolute quantification of CMV and EBV in plasma.MethodsBased on the TD-1 platform, a single-tube duplex detection system targeting conserved viral regions was optimized to minimize the “rain effect” and maximize signal-to-noise ratios. Leveraging the absolute quantification capability of ddPCR without standard curves, we compared its performance, including dynamic range and limit of detection (LOD), against a homologous qPCR assay. Clinical validation was conducted using 117 plasma samples from suspected cases, utilizing a commercial qPCR kit as the reference standard. Additionally, tolerance to endogenous interfering substances was assessed.ResultsThe optimized duplex ddPCR demonstrated high analytical sensitivity, with LODs for CMV and EBV at 7.9 and 6.5 copies/reaction, respectively, which were approximately 6- to 7-fold lower than homologous qPCR (53.4 and 45.6 copies/reaction).No competitive inhibition was observed at low concentrations. In clinical validation, the assay achieved 100% sensitivity and specificity compared to the reference kit, with high quantitative correlation (R2 = 0.80–0.87). Notably, ddPCR detected four weak positive samples (1 CMV, 3 EBV) missed by homologous qPCR. Furthermore, the method maintained accurate quantification in plasma containing hyperlipidemia or hyperbilirubinemia.ConclusionThis study successfully established a duplex ddPCR assay characterized by high sensitivity, specificity, and robust interference resistance. By enabling precise absolute quantification, it serves as a powerful complement to existing technologies for the early diagnosis and monitoring of CMV and EBV active infections.

Chronic spontaneous urticaria (CSU) poses a significant burden on both patient and caregiver. Currently treatments for CSU are inadequate for some patients. TLL-018, an oral TYK2/JAK1 inhibitor, is under investigation for CSU treatment. To evaluate the efficacy and safety of TLL-018 for treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines. In this multicenter, double-blind, randomized, placebo-controlled, parallel-group pilot study (NCT05373355), patients with CSU who showed an inadequate response to antihistamines received either 10 mg or 30 mg of TLL-018, or placebo orally twice daily. After 4 weeks, patients on placebo were switched to 20 mg of TLL-018, and continuing treatment for an additional 8 weeks. The primary endpoint was safety, while secondary endpoints included efficacy measures, such as weekly Urticaria Activity Score (UAS7) ≤ 6, UAS7 = 0, and a Dermatology Life Quality Index of 0 or 1 at weeks 4 and 12. The study involved of 41 patients. At week 4, the ANCOVA versus change from placebo of UAS7/weekly Itch Severity Score/weekly Hive Severity Score were -11.5/-8.0/-3.8 in the 10-mg groups and -16.0/-9.0/-7.0 in the 30-mg groups. At week 12, the percentages achieving UAS7 ≤ 6 and UAS7 = 0 were 53.8%/38.5%, 71.4%/64.3%, and 61.5%/53.8% in the placebo-to-20 mg, the 10-mg, and the 30-mg TLL-018 groups, respectively. Common treatment-emergent adverse events included elevated serum creatine kinase and blood lipid levels, hyperglycemia, and urinary occult blood. TLL-018 was well-tolerated and effective in treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines.

BackgroundMyocardial fibrosis, characterized by excessive collagen deposition and fibroblast activation, is a pivotal pathological process driving heart failure after myocardial infarction (MI). Our prior research revealed that Brahma-related gene 1 (BRG1) expression is elevated after MI and exacerbated cardiac electrophysiological remodeling; however, its precise role and molecular mechanism in post-MI fibrosis remain undefined.MethodsBRG1 expression was assessed in a mouse MI model and in TGF-β1-stimulated cardiac fibroblasts (CFs). Gain- and loss-of-function studies were performed using adenoviral vectors, siRNA, and plasmids in vitro and in vivo. Cardiac function and fibrosis were evaluated by echocardiography and histology. The molecular mechanism was dissected through co-immunoprecipitation (Co-IP), dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP), and functional rescue experiments targeting the PP2A/Smad3 axis.ResultsBRG1 was upregulated in fibrotic mouse hearts post-MI and in activated CFs. In vivo, BRG1 knockdown via AAV9-shRNA improved cardiac function, reduced infarct size, and attenuated fibrosis. In vitro, BRG1 promoted CFs proliferation, migration, and collagen production. Mechanistically, TGF-β1 enhanced the interaction between BRG1 and the transcription factor ZEB1. This complex transcriptionally repressed Ppp2r1a, the gene encoding the PP2A structural subunit Aα, leading to diminished PP2A activity. Consequently, Smad3 phosphorylation and nuclear translocation were enhanced, amplifying the pro-fibrotic TGF-β/Smad3 cascade. Crucially, ZEB1 knockdown or PP2A inhibition (okadaic acid) could respectively block or rescue the fibrotic effects of BRG1. Finally, BRG1 knockdown similarly suppressed fibrotic activation in human CFs.ConclusionOur study defines a novel BRG1/ZEB1/PP2A transcriptional axis as a key driver of myocardial fibrosis and suggests BRG1 as a potential therapeutic target for mitigating fibrotic remodeling after MI.

BackgroundChina’s healthcare system is confronting a rising burden of antimicrobial resistance, chronic complex diseases, and an aging population requiring long-term, post-acute care. As a value-based care model in the USA for over 50 years, home infusion therapy (HIT), combined with home health services (HHS), presents a sustainable alternative to prolonged hospitalization for intravenous medication administration. In this two-part narrative review, Part 1 provides a needs assessment describing the demographic, clinical, and public health factors driving the demand for HIT and HHS in China.MethodsWe conducted a literature search up to January 2026 using MEDLINE, EMBASE, PubMed, Web of Science, and China National Knowledge Infrastructure.ResultsIn Part 1, we present the impact of the aging population and chronic conditions requiring prolonged infusion therapy (including cancer, malnutrition and infections like osteomyelitis, endocarditis, and bacteremia) on the rising antimicrobial resistance, hospital burden and healthcare expenditures. Through the patient-centric solution of HIT and HHS, patients can receive intravenous medications and nutrition in the comfort of their homes, enabling the continuity of care beyond the hospital. Services include outpatient parenteral antibiotic therapy, hospice and palliative care in patients with cancer, and management of nutritional needs through total parenteral nutrition. Under this care model, reimbursement is tied to success in improved patient outcomes and reduced hospital readmissions. A detailed reimbursement and cost-effectiveness considerations are addressed in Part 2 of this review.ConclusionWith proper infrastructure development and reimbursement mechanisms that align payment with value, HIT and HHS could mitigate antimicrobial resistance, and transform and sustain affordable care delivery in China, especially for older adults and those with chronic conditions.Part 2 is available at https://doi.org/10.3389/fpubh.2026.1761870.

Alectinib was approved by the US, Europe and China in 2024 as the first adjuvant targeted therapy for ALK+ NSCLC, lowering risk of disease recurrence or death by 76%. Alectinib addresses a critical gap in postoperative adjuvant therapy for ALK+ NSCLC. From Chinese healthcare-system perspective, this study evaluates the impact of introducing alectinib in adjuvant therapy for stage IB (tumor ≥ 4 cm) to IIIA (UICC/AJCC 7th edition) ALK+ NSCLC on prevention of recurrence and the associated direct medical costs, compared to platinum-based chemotherapy. A Markov model was developed to estimate the number of locoregional and metastatic recurrences over a 10-year period by defining four health states: disease-free survival, locoregional recurrence, metastatic recurrence, and death. In the control group, all patients received platinum-based chemotherapy, while in the intervention group, 75% received alectinib and 25% received platinum-based chemotherapy. Clinical data were collected from open-label, randomized phase 3 trials ALINA and ALEX. Cost parameters were derived from local charges, expert consultation, and published literature. Compared to control group, the intervention group would reduce recurrences by 11,300 cases over 10 years, including 3,684 locoregional and 7,616 metastatic cases. This corresponds to a 45.82% lower recurrence rate. Estimated recurrence-related cost savings amounted to 6.910 billion RMB, with 1.445 billion RMB saved from locoregional recurrences and 5.465 billion RMB from metastatic recurrences. This represents a 41.49% reduction in costs compared to control group. These findings were robust across various scenario analyses. Using alectinib in postoperative adjuvant therapy significantly reduces both the recurrence rate and recurrence-related treatment costs for stage IB (tumor ≥ 4 cm) to IIIA ALK+ NSCLC patients, compared to platinum-based chemotherapy. From perspective of Chinese healthcare system, this approach shows substantial potential for preventing recurrence and achieving cost savings.

Abstract Objective Patients with advanced esophageal squamous cell carcinoma (ESCC) who have received first-line immunotherapy and radiotherapy remain uncertain as to which individuals may benefit from immunotherapy maintenance. This study aims to establish a deep learning model based on interactive automated 3D segmentation to predict immunotherapy + radiotherapy efficacy and identify patients likely to benefit from immunotherapy maintenance. Methods This study collected CT images and clinical information from three centers for patients with advanced ESCC. This study employs the validated high-precision, strong-generalization-capability VISTA3D to process CT images. By combining automatic segmentation with point-prompt segmentation guidance, it achieves automated tumor identification in ESCC patients and establishes a DL model based on ResNet18. The model's performance is evaluated using metrics such as AUC. Based on this model, patients who may benefit from immunotherapy maintenance are identified. Results The study included a total of 362 patients. When performing automatic segmentation based on the VISTA3D segmentation model, the model achieved a Dice coefficient of 0.87 on the external validation cohort, with a C-index reaching 0.86 (95% CI: 0.73–0.94). In analyses of PFS and OS, patients classified as low risk by the model demonstrated significantly better outcomes than those classified as high risk (HR: 0.61, 95% CI: 0.46–0.79, P < 0.001; HR: 0.55, 95% CI: 0.39–0.77, P < 0.001). Among high-risk patients, those receiving immunotherapy maintenance demonstrated significantly improved PFS and OS (HR: 0.39, 95% CI: 0.26–0.75, P < 0.001; HR: 0.57, 95% CI: 0.31–0.89, P = 0.023). Conclusion The DL model developed in this study, based on automated segmentation combined with point-prompt segmentation, can replace prediction models relying on manual segmentation. This model effectively assists clinicians in predicting the prognosis of advanced ESCC patients undergoing immunotherapy and radiotherapy, validating the feasibility of a two-stage automated prediction framework integrating “image segmentation-prognosis prediction”. Additionally, patients identified as high-risk by the model can significantly benefit from immunotherapy maintenance. This approach supports clinical decision-making for advanced ESCC patients, helps avoid overtreatment, and advances the progress toward personalized and precision cancer care.

Abstract Background HIV-1 genetic diversity and the spread of pretreatment drug resistance (PDR) complicate epidemic control. Southwestern China has a heterogeneous HIV epidemic, but molecular transmission dynamics in many prefecture-level settings remain poorly described. Methods We analyzed HIV-1 pol sequences from 208 newly diagnosed individuals in Zunyi, Guizhou Province. Genotypes were assigned by reference-based phylogenetic analysis; PDR was interpreted using the Stanford HIV Drug Resistance Database. Molecular transmission networks were inferred from pairwise genetic distances calculated with the TN93 model, and factors associated with PDR and clustering were evaluated using logistic regression. Results CRF07_BC (56.3%) and CRF01_AE (29.3%) were the predominant genotypes. PDR was detected in 21.2% of participants and varied significantly across genotypes, with higher prevalence observed in CRF08_BC and other recombinant forms. Molecular network analysis identified 31 transmission clusters involving 36.1% of sequences, with cluster sizes ranging from 2 to 6 nodes. Most clusters were small, and both densely connected subgraphs and simple linear chains were observed, indicating heterogeneous transmission patterns. Clustered cases were largely heterosexual and included a high proportion of individuals aged ≥ 50 years. CRF07_BC formed more tightly connected clusters, whereas CRF01_AE exhibited greater structural diversity. Multivariate analysis showed that divorced or widowed individuals were less likely to be included in transmission clusters. Conclusions The HIV epidemic in Zunyi is characterized by high genetic diversity, fragmented molecular transmission networks, and genotype-specific clustering patterns. Integrating molecular network analysis with routine drug resistance surveillance can improve understanding of local transmission dynamics and support precision HIV prevention strategies in southwestern China.

Current fluorescent reporters for assessing activity of CRISPR-Cas system, such as Stoplight or split-GFP based on frameshift activation, often suffer from limitations including large vector size, low viral packaging efficiency, and insensitivity to in-frame insertions or deletions. Although specialized reporters for base editing (e.g., BEAR) and prime editing (e.g., PEAR and fluoPEER) have been developed, there remains a significant demand for a compact, sensitive, and universal single-fluorescent reporter compatible with diverse editing types. We constructed a novel reporter system based on a single fluorescent protein employing a "dark-state quenching to bright-state activation" strategy, named CRISPR-Bright (CRB). Its core design involves fusing a green fluorescent protein with a 28-amino-acid quenching peptide derived from the influenza M2 protein. In unedited station, the fusion protein forms tetramers mediated by the quenching peptide, completely suppressing GFP fluorescence. When Cas9 or prime editor generates insertions or deletions (±1 or ±2 nt frameshift) or a designed premature stop codon at the target site, the coding sequence of the quenching peptide is disrupted or terminated. Upon impaired expression of the quenching peptide, GFP folds, matures, and emits strong green fluorescence. We engineered this design into a lentiviral vector with a total size of only 5.8 kb, significantly improving viral packaging and delivery efficiency. The result showed the CRB reporter efficiently reports Cas9 and prime editor mediated Indel events and enables sensitive, visual monitoring of prime editor activity. Its performance is notably superior to existing dual-fluorescent or large-vector-based reporter systems.

Abstract Background Obesity in people with HIV (PWH) has increased from 13.4% in 2014 to 21.5% in 2020. The usage of weight loss medications (WM) has expanded, and their potential in PWH remains underexplored. This study aimed to evaluate the factors affecting WM prescription in PWH at a non-academic Ryan White clinic in rural Pennsylvania. Methods A retrospective study including PWH on antiretroviral therapy with a BMI ≥ 25, and with at least 1 month of follow-up, was included. In this cohort, 88.4% received integrase-based triple therapy. Descriptive statistics and Fisher’s exact test were performed. Multivariate regression was conducted to identify factors. A p-value ≤ 0.05 was adopted. Results Of 69 patients included, 44.9% were on WM. In this, 14.5% were on semaglutide, 7.3% tirzepatide, and 23.2% bupropion. In this cohort, middle-aged patients (45-65 years) were higher than in younger patients (25-45 years), 60% vs 25%, p ≤ 0.01. Males were more than females (50% vs 37%, p > 0.1), and African Americans (AA) were less than American Whites (AW) to be on WM (25% vs 59.5%, p ≤ 0.01). Medicare patients were higher than those with Medicaid or commercial insurance (70.6% vs 26.7% vs 21.4%, p ≤ 0.05). Patients with hypertension, hyperlipidemia, or diabetes were more often on WM than those without (63.3% vs 30.8%, p < 0.01; 72.2% vs 35.3%, p = 0.01; 50% vs 43.6%, p > 0.1). The averages of BMI, weight (lbs), and HbA1c (SI) before treatment were 34.2 ± SE 1.3, 215.6 ± SE 11.1, and 6.6 ± SE 0.4, respectively. The mean BMI difference, mean weight change, and HbA1c change after WM were 0.2 ± SE 0.5, 0.7 ± SE 2.7, and -0.3 ± SE -0.4, respectively. Multivariate regression revealed that middle-aged patients had higher odds of being on WM than younger patients (OR 3.6, 95% CI 0.9-14.9, p < 0.1). AA had decreased odds of being on WM than AW (OR 0.2, p < 0.1). Patients with Medicaid (OR 0.1, 95% CI 0.0-0.6, p = 0.01) and commercial insurance (OR 0.04, 95% CI 0.0-0.4, p < 0.01) were less likely to receive WM than Medicare patients. Conclusion Our study revealed that race and insurance play a significant role in access to weight loss management in HIV patients. These disparities affect access to these medications in rural centers. Long-term studies are needed to evaluate the efficacy of weight loss medications in this population. Disclosures All Authors: No reported disclosures