Combination of MHI148 Targeted Photodynamic Therapy and STING Activation Inhibits Tumor Metastasis and Recurrence.

Metastasis and recurrence are notable contributors to mortality associated with breast cancer. Although immunotherapy has shown promise in mitigating these risks after conventional treatments, its effectiveness remains constrained by significant challenges, such as impaired antigen presentation by dendritic cells (DCs) and inadequate T cell infiltration into tumor tissues. To address these limitations, we developed a multifunctional nanoparticle platform, termed GM@P, which consisted of a hydrophobic shell encapsulating the photosensitizer MHI148 and a hydrophilic core containing the STING agonist 2'3'-cGAMP. This design elicited robust type I interferon responses to activate antitumor immunity. The GM@P nanoparticles loaded with MHI148 specifically targeted breast cancer cells. Upon exposure to 808 nm laser irradiation, the MHI148-loaded nanoparticles produced toxic reactive oxygen species (ROS) to eradicate tumor cells through photodynamic therapy (PDT). Notably, PDT stimulated immunogenic cell death (ICD) to foster the potency of antitumor immune responses. Furthermore, the superior photoacoustic imaging (PAI) capabilities of MHI148 enabled the simultaneous visualization of diagnostic and therapeutic procedures. Collectively, our findings uncovered that the combination of PDT and STING activation facilitated a more conducive immune microenvironment, characterized by enhanced DC maturation, infiltration of CD8+ T cells, and proinflammatory cytokine release. This strategy stimulated local immune responses to augment systemic antitumor effects, offering a promising approach to suppress tumor growth, inhibit metastasis, and prevent recurrence.

Gut microbiota and serum metabolite signatures along the colorectal adenoma-carcinoma sequence: Implications for early detection and intervention.

AIM: Our study focuses on the microbial and metabolomic profile changes during the adenoma stage, as adenomas can be considered potential precursors to colorectal cancer through the adenoma-carcinoma sequence. Identifying possible intervention targets at this stage may aid in preventing the progression of colorectal adenoma (CRA) to malignant lesions. Furthermore, we evaluate the efficacy of combined microbial and metabolite biomarkers in detecting CRA. METHODS: Fecal metagenomic and serum metabolomic analyses were performed for the discovery of alterations of gut microbiome and metabolites in CRA patients (n = 26), Colorectal cancer (CRC) patients (n = 19), Familial Adenomatous Polyposis (FAP) patients (n = 10), and healthy controls (n = 20). Finally, analyzing the associations between gut microbes and metabolites was performed by a Receiver Operating Characteristic (ROC) curve. RESULTS: Our analysis present that CRA patients differ significantly in gut microflora and serum metabolites compared with healthy controls, especially for Lachnospiraceae and Parasutterella. Its main metabolite, butyric acid, concentrations were raised in CRA patients compared with the healthy controls, indicating its role as a promoter of colorectal tumorigenesis. α-Linolenic acid and lysophosphatidylcholine represented the other healthy metabolite for CRA. Combining five microbial and five metabolite biomarkers, we differentiated CRA from CRC with an Area Under the Curve (AUC) of 0.85 out of this performance vastly superior to the specificity recorded by traditional markers CEA and CA199 in such differentiation of these conditions. CONCLUSIONS: The study underlines significant microbial and metabolic alterations in CRA with a novel insight into screening and early intervention of its tumorigenesis.

Vacuum bell therapy for pectus excavatum: a retrospective study.

BACKGROUND: Pectus excavatum, the most common chest wall deformity, is frequently treated with Nuss procedure. Here we will describe non-invasive procedure and analyze the variables associated vacuum bell therapy for patients with pectus excavatum. METHODS: Retrospective case-control study in a single center between July 2018 and February 2022, including patients with pectus excavatum treated with vacuum bell. Follow-up was continued to September 2022. The Haller index and Correction index was calculated before and after treatment to analysis the effectiveness of vacuum bell therapy. RESULTS: There were 98 patients enrolled in the treatment group, with 72 available for analysis, and the follow-up period ranged from 1.1 to 4.4 years (mean 3.3 years). When analyzing with the Haller Index, 18 patients (25.0%) showed excellent correction, 13 patients (18.1%) achieved good correction, and 4 patients (5.6%) had fair correction. The remaining patients had a poor outcome. Characteristics predicting a non-poor prognosis included initial age ≤ 11 years (OR = 3.94, p = 0.013) and patients with use over 24 consecutive months (OR = 3.95, p = 0.013). A total of 9 patients (12.5%) achieved a CI reduction below 10. Patients who started vacuum bell therapy at age > 11 had significantly less change compared to those who started at age ≤ 11 (P < 0.05). Complications included chest pain (5.6%), swollen skin (6.9%), chest tightness (1.4%) and erythema (15.3%). CONCLUSIONS: A certain percentage of patients with pectus excavatum can achieve excellent correction when treated with pectus excavatum therapy. Variables predicting better outcome including initial age ≤ 11 years both in HI and CI and vacuum bell use over 24 consecutive months in HI. In summary, pectus excavatum is an emerging non-invasive therapy for pectus excavatum and will be widely performed in a certain group of patients.

Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy.

BACKGROUND: Breast cancer ranks first among malignant tumors, of which triple-negative breast cancer (TNBC) is characterized by its highly invasive behavior and the worst prognosis. Timely diagnosis and precise treatment of TNBC are substantially challenging. Abnormal tumor vessels play a crucial role in TNBC progression and treatment. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis, while effective NO delivery can normalize the tumor vasculature. Accordingly, we have proposed here a tumor vascular microenvironment remodeling strategy based on NO-induced vessel normalization and extracellular matrix collagen degradation with multimodality imaging-guided nanoparticles against TNBC called DNMF/PLGA. RESULTS: Nanoparticles were synthesized using a chemotherapeutic agent doxorubicin (DOX), a NO donor L-arginine (L-Arg), ultrasmall spinel ferrites (MnFe2O4), and a poly (lactic-co-glycolic acid) (PLGA) shell. Nanoparticle distribution in the tumor was accurately monitored in real-time through highly enhanced magnetic resonance imaging and photoacoustic imaging. Near-infrared irradiation of tumor cells revealed that MnFe2O4 catalyzes the production of a large amount of reactive oxygen species (ROS) from H2O2, resulting in a cascade catalysis of L-Arg to trigger NO production in the presence of ROS. In addition, DOX activates niacinamide adenine dinucleotide phosphate oxidase to generate and supply H2O2. The generated NO improves the vascular endothelial cell integrity and pericellular contractility to promote vessel normalization and induces the activation of endogenous matrix metalloproteinases (mainly MMP-1 and MMP-2) so as to promote extravascular collagen degradation, thereby providing an auxiliary mechanism for efficient nanoparticle delivery and DOX penetration. Moreover, the chemotherapeutic effect of DOX and the photothermal effect of MnFe2O4 served as a chemo-hyperthermia synergistic therapy against TNBC. CONCLUSION: The two therapeutic mechanisms, along with an auxiliary mechanism, were perfectly combined to enhance the therapeutic effects. Briefly, multimodality image-guided nanoparticles provide a reliable strategy for the potential application in the fight against TNBC.

Self-Reinforced Bimetallic Mito-Jammer for Ca2+ Overload-Mediated Cascade Mitochondrial Damage for Cancer Cuproptosis Sensitization.

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO2) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO2 and Cu2+ in the tumor microenvironment. The exposed CaO2 further yields hydrogen peroxide (H2O2) and Ca2+ in a weakly acidic environment to strengthen the Cu2+-based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

The Roles and Targeting of Tumor-Associated Macrophages.

Tumor-associated macrophages (TAMs) are the most abundant infiltrating immune cells in the tumor microenvironment (TME) and play an important role in tumor progression. Clinically, the increase of TAMs infiltration is linked to poor prognosis of patients with various cancer types. Multiple studies have demonstrated that reducing or reprogramming TAMs can inhibit the occurrence or development of tumors. Therefore, TAMs have been identified as novel targets for the treatment of cancer therapy. In this review, the origin, polarization, roles, and targeting of TAMs in malignancies, are discussed.

Non-Covalent Interactions between Polyvinyl Chloride and Conjugated Polymers Enable Excellent Mechanical Properties and High Stability in Organic Solar Cells.

The incorporation of insulating polymers into conjugated polymers has been widely explored as a strategy to improve mechanical properties of flexible organic electronics. However, phase separation due to the immiscibility of these polymers has limited their effectiveness. In this study, we report the discovery of multiple non-covalent interactions that enhances the miscibility between insulating and conjugated polymers, resulting in improved mechanical properties. Specifically, we have added polyvinyl chloride (PVC) into the conjugated polymer PM6 and observed a significant increase in solution viscosity, indicative of favorable miscibility between these two polymers. This phenomenon has been rarely observed in other insulating/conjugated polymer composites. Thin films of PM6/PVC exhibit a much-improved crack-onset strain of 19.35 %, compared to 10.12 % for pristine PM6 films. Analysis reveal that a "cyclohexyl-like" structure formed through dipole-dipole interactions and hydrogen bonding between PVC and PM6 acted as a cross-linking site in the thin films, leading to improved mechanical properties. Moreover, PM6/PVC blend films have demonstrated excellent thermal and bending stability when applied as an electron donor in organic solar cells. These findings provide new insights into non-covalent interactions that can be utilized to enhance the properties of conjugated polymers and may have potential applications in flexible organic electronics.

Integrated serum pharmacochemistry, network pharmacology and pharmacokinetics to explore bioactive components of Gushudan in the treatment of osteoporosis.

Gushudan (GSD), a compound prescription on the basis of traditional Chinese medicine (TCM) theory and clinical practice, has been used in the treatment of osteoporosis (OP) for many years. Although studies have shown that GSD can treat OP, there is a lack of systematic screening method to explore the bioactive components, which are still unclear. Therefore, this study was aimed to establish an integrated method to screen and determine bioactive ingredients of GSD in the treatment of OP by serum pharmacochemistry, network pharmacology and pharmacokinetics. Firstly, 112 components of the GSD extract and 90 serum migrating constituents were identified by the ultra-high performance liquid chromatography-hybrid quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS), most of which were derived from flavonoids, tanshinones, coumarins and organic acids. Secondly, based on the network pharmacological analysis of the serum migrating constituents, 37 core targets and 20 main pathways related to both GSD and OP were obtained. More importantly, 7 bioactive ingredients were further screened as the PK markers by the network topology parameters including icariin, icariside II, isopimpinellin, bergapten, imperatorin, osthole and tanshinone IIA. Finally, a sensitive and accurate quantitative method based on ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was established and validated for simultaneous determination of the 7 bioactive ingredients in the rat plasma after oral administration of GSD extract, which was then applied to pharmacokinetic study. Besides, the overall pharmacokinetic characteristics were further calculated: Cmax was 180.52 ± 31.18 ng/mL, Tmax was 0.46 ± 0.20 h, t1/2 was 4.09 ± 0.39 h, AUC0-∞ was 567.24 ± 65.29 ng·h/mL, which displayed quick absorption and medium elimination in rats after oral administration of GSD extract. This study provided a new and holistic insight for exploring bioactive constituents and main targets to decode the therapeutic material basis of GSD against OP.

N-Annulated Perylene Bisimide-Based Double-Cable Polymers with Open-Circuit Voltage Approaching 1.20 V in Single-Component Organic Solar Cells.

In this work, we have introduced single/double-sided N-annulated perylene bisimide (PBI) with deep energy levels into double-cable polymers with poly[1-(5-(4,8-bis(4-chloro-5-(2-ethylhexyl)thiophen-2-yl)-6-methylbenzo[1,2-b:4,5-b']dithiophen-2-yl)thiophen-2-yl)-5,7-bis(2-ethylhexyl)-3-(5-methylthiophen-2-yl)-4H,8H-benzo[1,2-c:4,5-c']dithiophene-4,8-dione] (PBDB-T-Cl) as a donor backbone, marking as s-PPNR and as-PPNR, according to the molecular symmetry. Both double-cable polymers displayed a high open-circuit voltage approaching 1.20 V in light of high energy level discrepancy between electron-donating and electron-withdrawing parts, which is the highest open-circuit voltage among double-cable-based single-component organic solar cell (SCOSC) devices. Additionally, the asymmetric polymer displayed improved absorption spectra, thereby promoting crystallization and phase separation. Consequently, the as-PPNR-based SCOSCs achieved a power conversion efficiency of 5.05% along with a higher short-circuit current density and fill factor than their s-PPNR-based counterparts. In this work, we have successfully incorporated N-annulated PBI into double-cable polymers and revealed the important effects on structural symmetry and phase separation of double-cable polymers for higher SCOSC performance.

Case Report: Pathological Complete Response to Neoadjuvant Alectinib in a Patient With Resectable ALK-Positive Non-Small Cell Lung Cancer.

Background: Alectinib, a highly selective inhibitor of ALK, is currently used in the first-line setting of untreated advanced ALK-positive NSCLC and in the second-line setting of crizotinib-resistant ALK-positive NSCLC. Despite promising efficacy and tolerability in the treatment of advanced ALK-positive NSCLC, the activity of alectinib as neoadjuvant therapy in resectable ALK-positive NSCLC remains to be investigated. Case presentation: Herein, we report a case of a 58-year-old female patient presented to our hospital with hemoptysis for 1 month. Contrast-enhanced computerized tomography (CT) of the chest showed an approximately 4.2 × 3.4 cm mass in the right hilum with localized obstructive pneumonia in the right lower lobe and multiple enlarged lymph nodes in the right hilum and mediastinum. Serum oncological markers results showed elevated levels of CA19-9, CEA, CA125, and CA242. Bronchoscopic biopsy of the mass showed poorly differentiated pulmonary adenocarcinoma and immunohistochemical testing results confirmed ALK positivity. Neoadjuvant alectinib was given at a dosage of 600 mg twice per day for two cycles (56 days), achieving a partial response of the disease with 90% shrinkage of the mass at the subsequent whole-body positron emission tomography. Repeat serum oncological markers results showed that only CA125 was elevated, but lower than before therapy. A bilobectomy of the right middle and lower lobes and systemic lymphadectomy under video-assisted thoracoscopic approach was successfully performed 7 days after the last dose of alectinib. Postoperative pathology showed pathological complete response (pCR). The patient experienced an uneventful postoperative course and continued to receive alectinib and did not report any specific discomfort at her 8-month follow-up. Thoracoabdominal CT at 8 months postoperatively showed no recurrence and repeated examination of serum oncological markers were negative. Conclusion: We report a case of resectable ALK-positive NSCLC treated with neoadjuvant aletinib achieving pCR. Our case highlights the feasibility of alectinib as neoadjuvant therapy for the treatment of resectable ALK-positive NSCLC. Undoubtedly, the safety and efficacy of this novel treatment modality needs to be explored in future large clinical trials.

Osimertinib as Neoadjuvant Therapy for Resectable Non-Small Cell Lung Cancer: A Case Series.

Background: Evidence of osimertinib as neoadjuvant therapy for resectable non-small cell lung cancer (NSCLC) are currently lacking. This case series study aimed to assess the safety and feasibility of neoadjuvant osimertinib therapy followed by surgery for resectable NSCLC. Materials and methods: Patients with resectable NSCLC with epidermal growth factor receptor (EGFR) mutation who received osimertinib as neoadjuvant therapy followed by surgery at our center were included. Demographic features, radiologic and pathological assessment of response, surgery-related details and complications, toxicity profiles, and prognostic outcomes were extracted. Results: A total of 13 patients were included in this study. The median age at the time of surgical resection was 57 years (interquartile range: 52-64 years), and eight (61.5%) patients were female. The objective response rate (ORR) was 69.2% (9/13), and the complete resection rate was 100%. The rates of pathologic downstaging and lymph node downstaging were 100% (13/13) and 66.7% (6/9), respectively. There were no perioperative deaths and only three (23.1%) patients had postoperative complications. Seven (53.8%) and 13 (100%) patients experienced grade 1 treatment-related adverse reactions and laboratory abnormalities, respectively. No patients experienced drug withdrawal or surgical delays due to the adverse events. No patients showed grade 2 or worse toxicity profiles. One patient was lost to follow-up. The other 12 patients were alive and free of disease recurrence with a median follow-up time of 9.5 months. Conclusion: Neoadjuvant osimertinib therapy seemed to be safe and feasible for resectable EGFR-mutated NSCLC. Future large prospective studies are warranted to confirm whether osimertinib as neoadjuvant therapy outperforms standard tyrosine kinase inhibitors (TKIs) or chemotherapy for resectable EGFR-mutated NSCLC.

Surgical Outcomes After Neoadjuvant Chemoimmunotherapy for Resectable Non-Small Cell Lung Cancer.

BACKGROUND: Neoadjuvant chemoimmunotherapy for resectable non-small cell lung cancer (NSCLC) represents an important research topic. Despite the potential benefits of this approach, the inflammatory responses and adverse events associated with neoadjuvant chemoimmunotherapy can present technical challenges and compromise a planned resection. This study assessed the safety and feasibility of neoadjuvant chemoimmunotherapy followed by surgery for resectable NSCLC. METHODS: The study was conducted from May 2019 to March 2021. Patients who were age 18 years or older, were diagnosed with stage Ib-IIIb NSCLC, and received neoadjuvant chemoimmunotherapy followed by surgery were included. Demographic information, clinical and pathologic characteristics, data about neoadjuvant therapy, and surgical details were collected by retrospective chart review. Toxicity profiles were collected retrospectively or by telephone follow-up. RESULTS: Twenty patients were included in this study. The median age was 56 years (range, 48-72 years), and 18 patients (90%) were men. Squamous carcinoma (14/20, 70%) was the most common cancer type, followed by adenocarcinoma (4/20, 20%), adenosquamous carcinoma (1/20, 5%), and large cell neuroendocrine carcinoma (1/20, 5%). All patients received two to four cycles of neoadjuvant therapy, and the median interval between final therapy and surgery was 49 days (range, 23-133 days). Computed tomography evaluation after neoadjuvant therapy showed partial response in 15 patients (75%) and stable disease in 5 (25%). Final pathologic examinations showed major pathologic response in eight patients, including pathologic complete response in five (25%). Most patients (18/20, 90%) had reduced pathologic staging. Twelve patients (60%) underwent open thoracotomy; the other eight patients underwent minimally invasive surgery, which was uneventful and without intraoperative conversion to open thoracotomy. No perioperative deaths occurred, and only seven patients (35%) developed postoperative complications. Most patients experienced only grade 1-2 adverse effects and laboratory abnormalities during neoadjuvant therapy, and no grade 3 or worse adverse effects or laboratory abnormalities occurred. No patients experienced surgical delays as a result of immune-related adverse events. CONCLUSIONS: Preoperative administration of chemoimmunotherapy for patients with resectable NSCLC was safe and feasible.

Barrier Properties and Hydrophobicity of Biodegradable Poly(lactic acid) Composites Reinforced with Recycled Chinese Spirits Distiller's Grains.

Adding natural biomass to poly(lactic acid) (PLA) as a reinforcing filler is a way to change the properties of PLA. This paper is about preparing PLA/biomass composites by physically melting and blending Chinese Spirits distiller's grains (CSDG) biomass and PLA to optimize the composite performance. Composites of modified PLA (MPLA) with varying amounts of CSDG were also prepared by the melt-mixing method, and unmodified PLA/CSDG composites were used as a control group for comparative analysis. The functional groups of MPLA enhanced the compatibility between the polymer substrate and CSDG. The composite water vapor/oxygen barrier and mechanical properties were studied. It was found that the barrier and mechanical properties of MPLA/CSDG composites were significantly improved. SEM was adopted to examine the tensile section structure of the composites, and the compatibility between the filler and the matrix was analyzed. An appropriate amount of CSDG had a better dispersibility in the matrix, and it further improved the interfacial bonding force, which in turn improved the composite mechanical properties. X-ray diffraction, thermogravimetric analysis, and differential scanning calorimetry were conducted to determine the crystalline properties and to analyze the stability of the composites. It was found that the CSDG content had a significant effect on the crystallinity. Barrier and biodegradation mechanisms were also discussed.