Amorphous solid dispersion to facilitate the delivery of poorly water-soluble drugs: recent advances on novel preparation processes and technology coupling.

INTRODUCTION: Amorphous solid dispersion (ASD) technique has recently been used as an effective formulation strategy to significantly improve the bioavailability of insoluble drugs. The main industrialized preparation methods for ASDs are mainly hot melt extrusion and spray drying techniques; however, they face the limitations of being unsuitable for heat-sensitive materials and organic reagent residues, respectively, and therefore novel preparation processes and technology coupling for developing ASDs have received increasing attention. AREAS COVERED: This paper reviews recent advances in ASD and provides an overview of novel preparation methods, mechanisms for improving drug bioavailability, and especially technology coupling. EXPERT COVERED: As a mature pharmaceutical technology, ASD has broad application prospects and values. During the period from 2012 to 2024, the FDA has approved 49 formulation products containing ASDs. However, with the diversification of drug types and clinical needs, the traditional formulation technology of ASDs is gradually no longer sufficient to meet the needs of clinical medication. Therefore, this review summarizes the studies on both novel preparation processes and technology combinations; and provides a comprehensive overview of the mechanisms of ASD to improve drug bioavailability, in order to better select appropriate preparation methods for the development of ASD formulations.

A Multicenter Open-Label Randomized Phase II Study of Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor-Naïve EGFR-Mutant Metastatic Non-Small Cell Lung Cancer (RAMOSE trial).

PURPOSE: Preclinical studies demonstrated that dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways delay the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs), and in trials with first-generation EGFR TKIs, the combination of EGFR VEGF pathway inhibitors prolonged progression-free survival (PFS). METHODS: The RAMOSE trial (ClinicalTrials.gov identifier: NCT03909334, HCRN LUN-18-335) is a randomized, open-label multicenter phase II study comparing osimertinib with ramucirumab (arm A) to osimertinib (arm B) for initial treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC) with 2:1 random assignment. The primary end point is PFS for evaluable patients; secondary end points include objective response rates (ORRs), disease control rate (DCR), overall survival, and safety. The stratification criteria were EGFR mutation type and the presence of CNS metastasis. RESULTS: At data cutoff on August 29, 2023, 160 patients consented, 147 patients received treatment, and 139 patients were evaluable with at least one scan. In this preplanned interim analysis, the median follow-up was 16.6 months. Among the evaluable patients, 57 PFS events occurred. The median PFS was 24.8 (A) versus 15.6 (B) months (hazard ratio, 0.55 [95% CI, 0.32 to 0.93]; log-rank P = .023), 12-month PFS rate was 76.7% (A) versus 61.9% (B; P = .026). No significant difference was observed in the ORRs and DCRs between arms. Any-grade (G) adverse events (AEs) occurred in 100% (A) and 98% (B) of patients, with no G5 treatment-related AE (TRAE), one G4 TRAE (hyponatremia, A), and 53% (A) versus 41% (B) G3 TRAEs. AE-related discontinuation occurred in 13 patients (9.7% in A and 8.7% in B). The safety profile was in line with known safety of each drug. CONCLUSION: Ramucirumab plus osimertinib significantly prolonged PFS compared with osimertinib alone in patients with TKI-naïve EGFR-mutant NSCLC. The combination is safe and well tolerated.

Three-Year Overall Survival Outcomes and Correlative Analyses in Patients With NSCLC and High (50%-89%) Versus Very High (≥90%) Programmed Death-Ligand 1 Expression Treated With First-Line Pembrolizumab or Cemiplimab.

Introduction: Responses to first-line programmed cell death protein 1 inhibition vary among patients with metastatic NSCLC and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. We previously reported improved clinical outcomes to first-line programmed cell death protein 1 inhibition in patients with metastatic NSCLC with a PD-L1 TPS of greater than or equal to 90% versus 50% to 89% in a pilot study. Here, we report the three-year survival with first-line pembrolizumab and cemiplimab in two large independent cohorts of patients with PD-L1 TPS greater than or equal to 90% versus 50% to 89% and characterize genomic and immunophenotypic differences between these PD-L1 expression groups, which were largely unknown. Methods: We analyzed three-year outcomes of the following two independent cohorts: (1) a multicenter cohort of patients from four academic centers in the United States treated with pembrolizumab and (2) EMPOWER-Lung 1, randomized, phase III trial comparing first-line cemiplimab with chemotherapy. Tumor genomic profiling and multiplexed immunofluorescence were performed to evaluate genomic and immunophenotypic correlates of very high PD-L1 expression. Results: At three years of follow-up, progression-free survival (hazard ratio [HR], 0.69; p < 0.001) and overall survival (HR, 0.70; p < 0.01) to first-line commercial pembrolizumab were significantly improved in patients with a PD-L1 TPS greater than or equal to 90% versus 50% to 89%. In the EMPOWER-Lung 1, patients assigned to the cemiplimab arm with a PD-L1 TPS greater than or equal to 90% also had significant improvements in progression-free survival (HR, 0.53; p < 0.0001) and overall survival (HR, 0.63; p = 0.007) compared with those with a PD-L1 of 50% to 89%. Tumor genomic profiling of 553 NSCLC samples revealed that mutations in STK11 and SMARCA4 were significantly more frequent in tumors with a PD-L1 TPS of 50% to 89% compared with those with a PD-L1 TPS greater than or equal to 90% (Q < 0.15), whereas BRCA2 was enriched in NSCLC samples with a PD-L1 TPS greater than or equal to 90% (Q < 0.15). Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8+PD1+ T cells (p = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%. Conclusion: Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%.

Utidelone-based therapy in advanced or metastatic solid tumors after failure of standard therapies: a prospective, multicenter, single-arm trial.

Treatment options are limited for tumors after failure of standard therapies. Utidelone (UTD1), a novel microtubule stabilizer, given via 5 days intermittent infusion, has demonstrated high activity in heavily pretreated metastatic breast cancer, while its efficacy in other cancers was unclear. Peripheral neuropathy is a common and severe adverse event (AE) of UTD1. We performed a prospective, multicenter, single-arm trial (ChiCTR2300074299) to evaluate the efficacy and safety of UTD1 with a changed administration mode in patients with advanced or metastatic solid tumors after failure of standard therapies. UTD1 (150 mg/m2, alone or in combination with other anticancer agents) was administrated via 120 h continuous intravenous infusion every 21 days until disease progression or intolerable toxicity. A total of 50 patients were enrolled and analyzed, including 20 breast cancer patients, 11 gynecological cancer patients, 8 gastrointestinal cancer patients, 6 lung cancer patients, and 5 patients with other solid tumors. The overall median progression-free survival (PFS) was 4 months, the overall objective response rate and disease control rate were 20% and 66%, respectively, and the median overall survival was not reached. Most of the AEs were grade 1 or 2 and were manageable and reversible, the rate of grade ≥3 AEs including peripheral neuropathy was 4%. This study demonstrated a promising anti-tumor activity of UTD1 in patients with advanced or metastatic solid tumors after failure of the standard therapies. Moreover, 120 h continuous intravenous infusion was a more tolerable administration mode than 5 days intermittent infusion, and worthy of further study.

Differentiation of puerarin chelate from salt by phase solubility test.

Different from salt, metal chelate is a novel state of drug constructed by more separate coordinate bonds to form a chelating circle. Due to their composition similarity, it is hard to distinguish them except identifying ionic bond (i.e., salt) or coordinate bond (i.e., chelate) in the single crystal structure. In this study, sodium chelate (CDCC No: 1865670) and lithium salt (CDCC No: 2161617) of puerarin (PUE) was prepared. In addition to difference in single crystal structure, it was found that they showed totally different phase solubility behaviors: lithium salt demonstrated a typical inverse proportion curve as other common salts, while sodium chelate exhibited disordered scatters. However, when incorporating the unit PUE-Na complex in solution state and complexation constant K11 in chemical equation, the scatters in phase solubility diagram of chelate could be well fitted and the value of K11 was dramatically higher with orders of magnitude than the dissociation constant Kc; while processing phase solubility curve of lithium salt by incorporating complex item, it could not well match the curve at all. PUE sodium chelate is more likely to be a weak electrolyte with partial dissociation, while PUE lithium salt acted as a strong electrolyte with complete dissociation. The phase solubility test would be served as a surrogate tool for differentiation of chelates from salts when single crystal was not available.

Molecular landscape of ERBB2 alterations in 3000 advanced NSCLC patients.

ERBB2 (HER2) represents a newly recognized actionable oncogenic driver in non-small cell lung cancer (NSCLC), with approved targeted therapy available. Understanding the landscape of ERBB2 alterations and co-occurring mutations is essential for guiding treatment decisions. We conducted an analysis involving 3000 NSCLC patients with all types of ERBB2 alterations, drawn from two extensive retrospective cohorts: 1281 from Geneplus (Chinese) and 1719 from Guardant360 (the United States, US). The incidence of all types of ERBB2 alterations was found to be 5.6% in the Chinese group and 5.2% in the US group. In both cohorts, among oncogenic alterations of ERBB2, exon 20 insertion Y772_A775dupYVMA was the most frequent alteration (58% vs 41.6% in the Chinese vs the US), followed by G776delinsVC/LC/VV/IC (10.7% vs 9.7%), and S310X (10.5% vs 15.4%). EGFR ex20 insertions were identified in the A767-V774 region, whereas ERBB2 ex20 insertions were observed in the Y772-P780 region. Notably, EGFR ex20 insertions exhibited greater insertion diversity. Clinical characteristics of EGFR and ERBB2 ex20 NSCLC were similar, characterized by low tumor mutation burden (TMB), a predominant never-smoker population, and a majority of lung adenocarcinoma cases.

Thioredoxin reductase inhibition and glutathione depletion mediated by glaucocalyxin A promote intracellular disulfide stress in gastric cancer cells.

Thioredoxin reductase 1 (TXNRD1) has been identified as one of the promising chemotherapeutic targets in cancer cells. Therefore, a novel TXNRD1 inhibitor could accelerate chemotherapy in clinical anticancer research. In this study, glaucocalyxin A (GlauA), a natural diterpene extracted from Rabdosia japonica var. glaucocalyx, was identified as a novel inhibitor of TXNRD1. We found that GlauA effectively inhibited recombinant TXNRD1 and reduced its activity in gastric cancer cells without affecting the enzyme's expression level. Mechanistically, the selenocysteine residue (U498) of TXNRD1 was irreversibly modified by GlauA through a Michael addition. Additionally, GlauA formed a covalent adduct with glutathione (GSH) and disrupted cellular redox balance by depleting cellular GSH. The inhibition of TXNRD1 and depletion of GSH by GlauA conferred its cytotoxic effects in spheroid culture and Transwell assays in AGS cells. The disulfide stress induced cytotoxicity of GlauA could be mitigated by adding reducing agents, such as DTT and ß-ME. Furthermore, the FDA-approval drug auranofin, a TXNRD1 inhibitor, triggered oligomerization of the cytoskeletal protein Talin-1 in AGS cells, indicating that inhibiting TXNRD1 triggered disulfide stress. In conclusion, this study uncovered GlauA as an efficient inhibitor of TXNRD1 and demonstrated the potential of TXNRD1 inhibition as an effective anticancer strategy by disrupting redox homeostasis and inducing disulfide stress.

Multiregional transcriptomic profiling provides improved prognostic insight in localized non-small cell lung cancer.

Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with survival) across different regions within a tumor were more prognostic than the average expression. Following that, we examined whether multiregional expression profiling can improve the performance of prognostic signatures. We investigated 11 gene signatures collected from previous publications and one signature developed in this study. For all of them, the prognostic prediction accuracy can be significantly improved by converting the regional expression of signature genes into sample-specific expression with a simple function-taking the maximal expression of hazardous genes and the minimal expression of protective genes. In the tumor microenvironment, we found a similar rule also seems applicable to immune ITH. We calculated the infiltration levels of major immune cell types in each region of a sample based on expression deconvolution. Prognostic analysis indicated that the region with the lowest infiltration level of protective or highest infiltration level of hazardous immune cells determined the prognosis of NSCLC patients. Our study highlighted the impact of RNA-ITH on the prognostication of NSCLC, which should be taken into consideration to optimize the design and application of expression-based prognostic biomarkers and models. Multiregional assays have the great potential to significantly improve their applications to prognostic stratification.

Factors associated with early sexual onset and delaying sex in rural middle school youth.

PURPOSE: Early sexual onset contributes to poor health outcomes through the life course. We use the social behavioral model to examine the behaviors and attitudes associated with early sexual onset and the intention to delay sex in middle school youth. METHODS: Youth in rural communities with high rates of hepatitis C and HIV filled out a survey prior to implementation of an evidence-based sex education program. Participants were asked if they had ever had sex and whether they planned to abstain from sex until the end of high school. We collected demographics, attitudes about abstinence, agency for sexual refusal, parent communication, sexual health knowledge, and history of system involvement. Logistic regression was utilized to examine factors associated with each outcome. FINDINGS: Our sample included 6,799 students, 12.7 years old ± 0.9 and 50.3% female. 5.1% had ever had sex and 73.9% planned to abstain until the end of high school. Early sexual onset was associated with older age, negative attitudes toward abstinence, lower agency for sexual refusal, more frequent parent communication about sex, history of child welfare, and history of juvenile involvement. Planning to abstain until the end of high school was associated with being younger, female, positive attitudes toward abstinence, higher agency for sexual refusal, less communication with parents about sex, more communication with parents about relationships, not having a history of foster involvement, and not having a history of juvenile involvement. CONCLUSIONS: Age, agency, and parent communication were all associated with both outcomes. Our findings highlight the importance of early comprehensive, trauma-informed sex education.

Building Asymmetric Zn-N3 Bridge between 2D Photocatalyst and Co-catalyst for Directed Charge Transfer toward Efficient H2O2 Synthesis.

Two-dimensional (2D) polymeric semiconductors are a class of promising photocatalysts; however, it remains challenging to facilitate their interlayer charge transfer for suppressed in-plane charge recombination and thus improved quantum efficiency. Although some strategies, such as π-π stacking and van der Waals interaction, have been developed so far, directed interlayer charge transfer still cannot be achieved. Herein, we report a strategy of forming asymmetric Zn-N3 units that can bridge nitrogen (N)-doped carbon layers with polymeric carbon nitride nanosheets (C3N4-Zn-N(C)) to address this challenge. The symmetry-breaking Zn-N3 moiety, which has an asymmetric local charge distribution, enables directed interfacial charge transfer between the C3N4 photocatalyst and the N-doped carbon co-catalyst. As evidenced by femtosecond transient absorption spectroscopy, charge separation can be significantly enhanced by the interfacial asymmetric Zn-N3 bonding bridges. As a result, the designed C3N4-Zn-N(C) catalyst exhibits dramatically enhanced H2O2 photosynthesis activity, outperforming most of the reported C3N4-based catalysts. This work highlights the importance of tailoring interfacial chemical bonding channels in polymeric photocatalysts at the molecular level to achieve effective spatial charge separation.

Overcoming EGFR-TKI resistance by targeting the tumor microenvironment.

Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer (NSCLC). Currently, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) stand as the recommended first-line therapy for advanced NSCLC harboring sensitive EGFR mutations. Nevertheless, most patients inevitably confront the challenge of drug resistance. This phenomenon arises not solely from intrinsic alterations within cancer cells but also from the intricate dynamics of the tumor microenvironment and the complex interactions that occur between cancer cells and their immediate surroundings. This review consolidates the current knowledge regarding EGFR-TKI resistance mechanisms, with a specific emphasis on unraveling the role played by the tumor microenvironment. In addition, the review delineates strategic approaches to surmount TKI resistance, thereby enriching the understanding of the interplay between therapeutic agents and the intricate milieu surrounding cancer cells.

Emerging roles of small extracellular vesicles in metabolic reprogramming and drug resistance in cancers.

Studies of carcinogenic metabolism have shown that cancer cells have significant metabolic adaptability and that their metabolic dynamics undergo extensive reprogramming, which is a fundamental feature of cancer. The Warburg effect describes the preference of cancer cells for glycolysis over oxidative phosphorylation (OXPHOS), even under aerobic conditions. However, metabolic reprogramming in cancer cells involves not only glycolysis but also changes in lipid and amino acid metabolism. The mechanisms of these metabolic shifts are critical for the discovery of novel cancer therapeutic targets. Despite advances in the field of oncology, chemotherapy resistance, including multidrug resistance, remains a challenge. Research has revealed a correlation between metabolic reprogramming and anticancer drug resistance, but the underlying complex mechanisms are not fully understood. In addition, small extracellular vesicles (sEVs) may play a role in expanding metabolic reprogramming and promoting the development of drug resistance by mediating intercellular communication. The aim of this review is to assess the metabolic reprogramming processes that intersect with resistance to anticancer therapy, with particular attention given to the changes in glycolysis, lipid metabolism, and amino acid metabolism that accompany this phenomenon. In addition, the role of sEVs in disseminating metabolic reprogramming and promoting the development of drug-resistant phenotypes will be critically evaluated.

The potential of supramolecular synthon to develop coamorphous systems with tailored physical stability: Mechanistic insights integrating kinetics and thermodynamics.

Coamorphous drug delivery systems have received increasing interest owing to their potential to improve the solubility, dissolution and bioavailability of poorly water-soluble drugs. However, the crystallization risk is one of major limitations in their application. It has been widely recognized that the coformer plays a vital role in physical stability of coamorphous formulation. Unfortunately, the screen of optimal coformer still adopts a trial-and-error method, which is time-consuming and expensive. Herein, a supramolecular synthon approach based on the interaction between functional groups, was exploited to design coamorphous systems (CMs) consisting of lurasidone hydrochloride (LH) and three coformers, saccharin (SAC), L-tryptophan (TRP), and L-cysteine hydrochloride (CYS). X-ray powder diffraction suggested the order of physical stability of the coamorphous systems was ranked as LH-CYS CM > LH-TRP CM > LH-SAC CM. The charge-assisted hydrogen bond between LH and coformer was confirmed by infrared spectroscopy and solid-state 13C NMR. Moreover, structural, electronic, and molecular interaction information, especially hydrogen bonding interactions, were quantified by theoretical calculations, including miscibility calculations, molecular dynamics simulations and quantum chemical calculations. It was revealed that LH-CYS CM exhibited the best miscibility, strongest binding energy and strongest H-bond with partially covalent character, demonstrating the significant role of supramolecular synthon in stabilizing coamorphous formulations. Interestingly, LH-TRP CM, not LH-CYS CM, exhibited the lowest molecular mobility among three coamorphous systems, which was inconsistent with their physical stability. But from thermodynamic perspective, the order of configurational entropy and physical stability of coamorphous systems was completely consistent. We shed light on the comprehensive effects of molecular mobility and configurational entropy on physical stability of coamorphous systems. Importantly, the relationship between supramolecular synthon and kinetic/thermodynamic mechanisms was also discussed, and the positive correlation between configurational entropy and intermolecular interactions was proposed in this paper. Our findings demonstrated the great potential of supramolecular synthon in designing coamorphous systems with tailored physical stability, and further provided a deeper insight into the mechanisms of physical stability of coamorphous systems.

Impact of select actionable genomic alterations on efficacy of neoadjuvant immunotherapy in resectable non-small cell lung cancer.

BACKGROUND: Neoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant ICIs remains unclear. We report the influence of AGAs on treatment failure (TF) in patients with resectable NSCLC treated with neoadjuvant ICIs. METHODS: Tumor molecular profiles were obtained from patients with stage I-IIIA resectable NSCLC (American Joint Committee on Cancer seventh edition) treated with either neoadjuvant nivolumab (N, n=23) or nivolumab+ipilimumab (NI, n=21) followed by surgery in a previously reported phase-2 randomized study (NCT03158129). TF was defined as any progression of primary lung cancer after neoadjuvant ICI therapy in patients without surgery, radiographic and/or biopsy-proven primary lung cancer recurrence after surgery, or death from possibly treatment-related complications or from primary lung cancer since randomization. Tumors with AGAs (n=12) were compared with tumors without AGAs and non-profiled squamous cell carcinomas (non-AGAs+NP SCC, n=20). RESULTS: With a median follow-up of 60.2 months, the overall TF rate was 34.1% (15/44). Tumor molecular profiling was retrospectively obtained in 47.7% (21/44) of patients and select AGAs were identified in 12 patients: 5 epidermal growth factor receptor (EGFR), 2 KRAS, 1 ERBB2, and 1 BRAF mutations, 2 anaplastic lymphoma kinase (ALK) and 1 RET fusions. The median time to TF in patients with AGAs was 24.7 months (95% CI: 12.6 to 40.4), compared with not reached (95% CI: not evaluable (NE)-NE) in the non-AGAs+NP SCC group. The TF risk was higher in AGAs (HR: 5.51, 95% CI: 1.68 to 18.1), and lower in former/current smokers (HR: 0.24, 95% CI: 0.08 to 0.75). The odds of major pathological response were 4.71 (95% CI: 0.49 to 45.2) times higher in the non-AGAs+NP SCC group, and the median percentage of residual viable tumor was 72.5% in AGAs compared with 33.0% in non-AGS+NP SCC tumors. CONCLUSIONS: Patients with NSCLC harboring select AGAs, including EGFR and ALK alterations, have a higher risk for TF, shorter median time to TF, and diminished pathological regression after neoadjuvant ICIs. The suboptimal efficacy of neoadjuvant chemotherapy-sparing, ICI-based regimens in this patient subset underscores the importance of tumor molecular testing prior to initiation of neoadjuvant ICI therapy in patients with resectable NSCLC.

Preparation and Characterization of Fluorinated Acrylate and Epoxy Co-Modified Waterborne Polyurethane.

Conventional waterborne polyurethane (WPU) has poor water resistance and poor overall performance, which limits its application in outdoor coatings. A solution to this problem is urgently needed. The introduction of fluorine-containing groups can effectively improve the water resistance of WPU. In this study, a new fluorinated chain extender (HFBMA-HPA) synthesized by free radical copolymerization and epoxy resin (E-44) were used to co-modify WPU, and five waterborne fluorinated polyurethane (WFPU) emulsions with different fluorine contents were prepared by the self-emulsification method. The effects of HFBMA-HPA content on the emulsion particle properties, coating surface properties, mechanical properties, water resistance, thermal stability, and corrosion resistance were investigated. The results showed that the WFPU coating had excellent thermal stability, corrosion resistance, and mechanical properties. As the content of HFBMA-HPA increased from 0 wt% to 14 wt%, the water resistance of the WFPU coating gradually increased, the water contact angle (WCA) increased from 73° to 98°, the water absorption decreased from 7.847% to 3.062%, and the surface energy decreased from 32.8 mN/m to 22.6 mN/m. The coatings also showed impressive performances in the adhesion and flexibility tests in extreme conditions. This study provides a waterborne fluorinated polyurethane material with excellent comprehensive performance that has potential application value in the field of outdoor waterproof and anticorrosion coatings.

Single-cell and spatial proteo-transcriptomic profiling reveals immune infiltration heterogeneity associated with neuroendocrine features in small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.

Modulation of High-Frequency rTMS on Reward Circuitry in Individuals with Nicotine Dependence: A Preliminary fMRI Study.

Although previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) can ameliorate addictive behaviors and cravings, the underlying neural mechanisms remain unclear. This study aimed to investigate the effect of high-frequency rTMS with the left dorsolateral prefrontal cortex (L-DLPFC) as a target region on smoking addiction in nicotine-dependent individuals by detecting the change of spontaneous brain activity in the reward circuitry. We recruited 17 nicotine-dependence participants, who completed 10 sessions of 10 Hz rTMS over a 2-week period and underwent evaluation of several dependence-related scales, and resting-state fMRI scan before and after the treatment. Functional connectivity (FC) analysis was conducted with reward-related brain regions as seeds, including ventral tegmental area, bilateral nucleus accumbens (NAc), bilateral DLPFC, and bilateral amygdala. We found that, after the treatment, individuals showed reduced nicotine dependence, alleviated tobacco withdrawal symptoms, and diminished smoking cravings. The right NAc showed increased FC with right fusiform gyrus, inferior temporal gyrus (ITG), calcarine fissure and surrounding cortex, superior occipital gyrus (SOG), lingual gyrus, and bilateral cuneus. No significant FC changes were observed in other seed regions. Moreover, the changes in FC between the right NAc and the right ITG as well as SOG before and after rTMS were negatively correlated with changes in smoking scale scores. Our findings suggest that high-frequency L-DLPFC-rTMS reduces nicotine dependence and improves tobacco withdrawal symptoms, and the dysfunctional connectivity in reward circuitry may be the underlying neural mechanism for nicotine addiction and its therapeutic target.

A novel nomogram for predicting the recurrence of atrial fibrillation in patients treated with first-time radiofrequency catheter ablation for atrial fibrillation.

Introduction: The purpose of this study was to investigate the predictive factors of atrial fibrillation (AF) recurrence in patients after first-time radiofrequency catheter ablation (RFCA) and to develop a nomogram predictive model that can provide valuable information for determining the ablation strategy. Methods: In total, 500 patients who had received first-time RFCA for AF were retrospectively enrolled in the study. The patients were divided into a training cohort (n = 300) and a validation cohort (n = 200) randomly at a 6:4 ratio. Lasso and multivariate logistic regression analyses were used to screen the predictors for AF recurrence during a 2-year follow-up. The C-index and a calibration plot were used to detect the discriminative ability and calibration of the nomogram. The performance of the nomogram was assessed compared with the APPLE score, CAAP-AF score, and MB-LATER score using the receiver operating characteristic (ROC) curve, decision curve analysis (DCA), integrated discrimination index (IDI), and net reclassification index (NRI). Results: A total of 78 patients experienced the recurrence of AF after first-time RFCA in the training cohort. The six strongest predictors for AF recurrence in the training cohort were persistent AF, duration of AF, left atrial diameter (LAD), estimated glomerular filtration rate (eGFR), N-terminal pro-brain natriuretic peptide (NT-proBNP), and autoantibody against M2-muscarinic receptor (anti-M2-R). Based on the above six variables, a nomogram prediction model was constructed with a C-index of 0.862 (95% CI, 0.815-0.909), while the C-index was 0.831 (95% CI, 0.771-0.890) in the validation cohort. DCA showed that this nomogram had greater net benefits compared with other models. Furthermore, the nomogram showed a noticeable improvement in predictive performance, sensitivity, and reclassification for AF recurrence compared with the APPLE score, CAAP-AF score, or MB-LATER score. Conclusion: We established a novel predictive tool for AF recurrence after the first-time RFCA during a 2-year follow-up period that could accurately predict individual AF recurrence.

The therapeutic effect of liver transplantation in 14 children with homozygous familial hypercholesterolemia: a prospective cohort: Liver transplant for familial hypercholesterolemia.

OBJECTIVES: Homozygous familial hypercholesterolemia (HoFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and early-onset cardiovascular disease. To assess the therapeutic effects of liver transplantation (LT) on HoFH patients, we observed and analyzed the outcomes of HoFH children after LT. STUDY DESIGN: This prospective cohort study included all LT candidates under 18 years old diagnosed with HoFH at Ren Ji Hospital between November 2017 and July 2021. The patients were followed until October 2023. They were treated according to the standard protocol at our center. We collected data on changes in lipid profiles, clinical manifestations, and cardiovascular complications at different time points, and recorded postoperative recipient and graft survival. RESULTS: Fourteen HoFH patients with a median age of 7 (2-12) years were included. Preoperatively, xanthomas and arcus corneas occurred in 14 and 3 patients, respectively, with 10 patients showing mild cardiovascular disease. All patients underwent LT. Recipient and graft survival rates were 100 % over a median follow-up duration of 35 (27-71) months. Median LDL-C levels dropped from 11.83 (7.99-26.14) mmol/L preoperatively to 2.3 (1.49-3.39) mmol/L postoperative at the last measurement. Thirteen patients discontinued lipid-lowering treatment after LT, while only one patient resumed statins 6 months post-operation. Xanthomas and arcus corneas significantly improved. Cardiovascular complications regressed in five patients, with no progression observed in the others. CONCLUSIONS: LT is a safe and effective treatment for severe HoFH patients beyond lipid-lowering control. Early LT improves prognosis and quality of life while minimizing the risk of cardiovascular complications.

Associations Between Intakes of Carotenoids and Tocopherols with Risk of Pancreatic Cancer in a Population-Based Case-Control Study.

OBJECTIVE: Experimental studies suggest that carotenoids and tocopherols modulate pancreatic carcinogenesis because they have antioxidant and other functions. We investigated the associations between intakes of these compounds and the risk of pancreatic cancer in a case-control study conducted in 1994-1998. METHODS: The present analysis included 150 cases of pancreatic cancer recruited from all hospitals in the metropolitan area of the Twin Cities and Mayo Clinic and 459 controls randomly selected from the general population and frequency matched to cases by age, sex, and race. The intakes of carotenoids and tocopherols were assessed with a validated food frequency questionnaire. Unconditional logistic regression analysis was performed to evaluate the associations of interest. RESULTS: The energy-adjusted intake of lutein/zeaxanthin was significantly lower in cases (2410 µg/day) than in controls (3020 µg/day). After adjustment for confounders, persons in the fourth quartile of lutein/zeaxanthin intake had a reduced risk of pancreatic cancer compared with those in the first quartile [odds ratio (OR) (95% CI): 0.40 (0.17-0.91)]. There were no significant associations with intakes of other carotenoids and tocopherols considered and with a composite score created from all individual carotenoids examined. We did not detect any significant interactions of intakes of carotenoids and tocopherols with age, sex, cigarette smoking, or alcohol intake in relation to pancreatic cancer risk. CONCLUSION: The present study suggests an inverse association between lutein/zeaxanthin intake and pancreatic cancer risk, but a potential beneficial effect was not observed for other carotenoids and tocopherols.