4-n-butylresorcinol (4-nBR) has a significant effect on skin pigmentation, but its poor solubility, low stability and strong irritation to the skin limit its application. In this study, 4-nBR was prepared into 4-n-butylresorcinol nanoemulsion (4-nBR-NE) for the first time, which improved the solubility and stability of 4-nBR and greatly reduced the irritation of 4-nBR on skin. On this basis, the relationship between the viscosity of nanoemulsion and the formulation process, and the relationship between the ratio of surfactant and the formability of 4-nBR-NE were further studied. A nanoemulsion with adjustable viscosity (AV-NE) and nanoemulsion with low surfactant content has been successfully developed. The particle size of 4-nBR-NE was 13.34 ± 0.1646 nm, and PDI (0.08532 ± 0.0191) was small, and the particle size distribution was uniform. The encapsulation rate of 4-nBR-NE was 80.05 ± 0.75% by UV-VIS spectrophotometry. In addition, 4-nBR-NE had excellent stability for several months that the particle size was almost unchanged. We also confirmed through cells and transdermal evaluations that the original irritation of 4-nBR on cells and skin could be effectively reduced after preparation of 4-nBR-NE. Then 4-nBR-NE was prepared into essence. TEM showed that the shape of the 4-nBR-NE could still be observed after the essence was prepared, indicating that the shape of the 4-nBR-NE could still be maintained when the 4-nBR-NE was added to other products as an intermediate. In summary, 4-nBR-NE could not only improve the stability, solubility and transdermal delivery efficiency of 4-nBR, but also effectively reduce the original irritation of 4-nBR, which can be used to help treat pigmentation, melasma, freckles and other skin diseases. 4-nBR has increased its applicability in the pharmaceutical and cosmetic industries.

In the study, lycopene and resveratrol nanoemulsion hydrogel beads were prepared by using agarose‑sodium alginate as a carrier and the semi-interpenetrating polymer network technique, characteristics and morphologies were evaluated by scanning electron microscopy, fluorescence microscopy, rheological measurement. The synergistic antioxidant effect of lycopene and resveratrol was confirmed, the best synergistic antioxidant performance is achieved when the ratio of 1:1. To increase the solubility and improve the stability, the lycopene was prepared as solid dispersion added to the nanoemulsion. The encapsulation rate of lycopene and resveratrol reached 93.60 ± 2.94 % and 89.30 ± 1.75 %, respectively, and the cumulative release showed that the addition of agarose slowed down the release rate of the compound, which improves the applicability of lycopene and resveratrol and development of carriers for the delivery of different bioactive ingredients.

BACKGROUND Tumor budding (TB) has emerged as a promising independent prognostic biomarker in colorectal cancer (CRC). The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC. However, existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies. Consequently, this study investigated the correlation among TB categories, clinicopathological features, and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification. AIM To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC. METHODS The clinical data of 547 CRC patients were collected for this retrospective study. Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines. RESULTS Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy (P = 0.004), clinical stage IV (P < 0.001), ≥ 4 regional lymph node metastases (P = 0.004), left-sided colonic cancer (P = 0.040), and Bd 2-3 (P = 0.002) were independent prognostic factors in patients with stage III-IV CRC. Moreover, the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3, both in the tumor stroma and its invasive margin. CONCLUSION TB has an independent predictive prognostic value in patients with stage III-IV CRC. It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.

4-n-butylresorcinol (4-nBR) is a valuable ingredient to lighten skin and reduce pigmentation, contributing to an even skin tone and a more youthful appearance. However, its poor solubility, low stability, and strong irritation to the skin limit its application. In this study, 4-nBR was prepared into 4-n-butylresorcinol nanoemulsion (4-nBR-NE) for the first time, enhancing the solubility and stability of 4-nBR while greatly reducing its skin irritation. The relationship between the viscosity of nanoemulsion and the formulation process, as well as the impact of surfactant ratio on the formability of 4-nBR-NE were further studied. This led to the successful development of a nanoemulsion with adjustable viscosity (AV-NE) and with a low surfactant content. The particle size of 4-nBR-NE was 13.34 ± 0.16 nm with a PDI of 0.0853 ± 0.0191, indicating a uniform particle size distribution. The encapsulation rate of 4-nBR-NE was determined to be 80.05 ± 0.75 % via UV-Vis spectrophotometry. In addition, 4-nBR-NE demonstrated excellent stability over several months, with negligible changes in particle size. Cellular and transdermal evaluations confirmed that the preparation of 4-nBR-NE effectively reduced the original irritation cause by 4-nBR on cells and skin. Then, 4-nBR-NE was incorporated into an essence. This advancement enhances the applicability of 4-nBR in treating pigmentation disorders such as melasma and freckles, thereby increasing its applicability in pharmaceutical and cosmetic industries.

The clinical application of cisplatin (CisPt) is limited by its dose-dependent toxicity. To overcome this, we developed reduction-responsive nanoparticles (NP(3S)s) for the targeted delivery of a platinum(IV) (Pt(IV)) prodrug to improve efficacy and reduce the toxicity. NP(3S)s could release Pt(II) and hydrogen sulfide (H2S) upon encountering intracellular glutathione, leading to potent anticancer effects. Notably, NP(3S)s induced DNA damage and activated the STING pathway, which is a known promoter for T cell activation. Comparative RNA profiling revealed that NP(3S)s outperformed CisPt in enhancing T cell immunity, antitumor immunity, and oxidative stress pathways. In vivo experiments showed that NP(3S)s accumulated in tumors, promoting CD8(+) T cell infiltration and boosting antitumor immunity. Furthermore, NP(3S)s exhibited robust in vivo anticancer efficacy while minimizing the CisPt-induced liver toxicity. Overall, the results indicate NP(3S)s hold great promise for clinical translation due to their low toxicity profile and potent anticancer activity.

Radiofrequency ablation (RFA) is an effective alternative to surgery for managing some malignant solid tumors. However, for medium-to-large tumors (>3 cm), tumors adjacent to large blood vessels, and certain irregular tumors, sublethal radiofrequency hyperthermia (RFH) often produces a margin of ablated tumor owing to the "heat-sink" effect. This effect typically leaves behind viable residual tumors at the margin. Several studies have reported that a sublethal RFH can significantly enhance the efficacy of chemotherapy, radiotherapy, immunotherapy, and gene therapy for malignant solid tumors. The possible mechanisms by which RFH enhances these therapies include heat-induced tissue fracturing, increased permeability of the cytoplasmic membrane, exaggerated cellular metabolism, blockade of the repair pathways of radiation-damaged tumor cells, and activation of the heat shock protein pathways. Therefore, RFA in combination with chemotherapy, radiotherapy, immunotherapy, or gene therapy may help reduce the rates of residual and recurrent tumors after RFA of malignant solid tumors.

Objective To compare survival outcomes between primary radical surgery and primary radiation in early cervical cancer. Methods Patient information was extracted from the Surveillance, Epidemiology, and Results database. Patients diagnosed with early cervical cancer of stage T1a, T1b, and T2a (American Joint Committee on Cancer, 7th edition) from 1998 to 2015 were included in this study after propensity score matching. Overall survival (OS) was analyzed using the Kaplan-Meier method. Results Among the 4964 patients included in the study, 1080 patients were identified as having positive lymph nodes (N1), and 3884 patients were identified as having negative lymph nodes (N0). Patients with primary surgery had significantly longer 5-year OS than those with primary radiotherapy in both the N1 group ( P <0.001) and N0 group ( P <0.001). In the subgroup analysis, similar results were found in patients with positive lymph nodes of stage T1a (100.0% vs. 61.1%), T1b (84.1% vs. 64.3%), and T2a (74.4% vs. 63.8%). In patients with T1b1 and T2a1, primary surgery resulted in longer OS than primary radiation, but not in patients with T1b2 and T2a2. In multivariate analysis, the primary treatment was identified as an independent prognostic factor in both N1 and N0 patients (HR N1 =2.522, 95% CI=1.919–3.054, P N1 <0.001; HR N0 =1.895, 95% CI=1.689–2.126, P N0 <0.001). Conclusion In early cervical cancer stage T1a, T1b1, and T2a1, primary surgery may result in longer OS than primary radiation for patients with and without lymph node metastasis.

Purpose In the present study, we prepared collagen liposomes with the addition of polyol, which is expected to not only increase the solubility of collagen but also improve skin penetration. Methods Collagen liposomes were prepared by the film dispersion method, and their characteristics, integrity and biosafety were evaluated by Fourier transform infrared spectroscopy (FTIR), UV-VIS spectroscopy, polyacrylamide gel electrophoresis (SDS-PAGE), dynamic light scattering (DLS) and transmission electron microscope (TEM). The transdermal absorption of collagen and collagen liposomes were tested by an ex vivo horizontal Valia-Chien diffusion cell system. Results We first demonstrated that collagen extracted from bovine Achilles tendon was type I collagen. The results of DLS measurement and TEM observation showed that the collagen liposomes were spherical in shape with average diameter (75.34±0.93 nm) and maintained high stability at low temperature (4°C) for at least 42 days without toxicity. The encapsulation rate of collagen liposomes was 57.80 ± 0.51%, and SDS-PAGE analysis showed that collagen was intact in liposomes. Finally, permeability studies indicated that the collagen-loaded liposomes more easily penetrated the skin compared to collagen itself. Conclusion This study proposed a new method to improve the bioavailability and permeability of bovine type I collagen, which improves the applicability of collagen in biomedicine, cosmeceuticals and pharmaceutical industries.

Abstract Background The relationship between molecular characteristics and the prognosis of colorectal cancer (CRC) patients has not been fully understood. This study explored the impact of targeted therapy on the prognosis of CRC patients with different TP53 mutations, in the context of comprehensive treatment. Methods This study included patients with stage III/IV primary CRC from the electronic medical record system. TP53 mutations were detected via next‐generation sequencing (NGS) using formalin‐fixed paraffin‐embedded (FFPE) tissues. Applying two methods, we classified TP53 mutations as gain of function (GOF)/non‐GOF mutations or known/likely loss of function (LOF) mutations. Kaplan–Meier plot and parametric survival analysis were performed to evaluate the prognosis of CRC patients and identify potential predictors. Results There were 286 patients included, of which 166 (58.04%) patients received targeted therapy and 120 (41.96%) did not. There were 286 patients in the TP53 GOF classification set and 247 in the TP53 LOF classification set. Parametric survival analysis, adjusted for sex, onset, KRAS mutation, sidedness, stage, and surgery, showed that receiving targeted therapy predicted better overall survival (OS) among patients who harbored TP53 GOF mutations (HR 0.40, 95% confidence interval (CI) [0.21, 0.76], p = 0.005) or known LOF mutations (HR 0.21, 95% CI [0.07, 0.60], p = 0.002). However, there was no significant impact of receiving targeted therapy on OS among patients harboring TP53 non‐GOF mutations (HR 1.68, 95% CI [0.50, 5.63], p = 0.403) or likely LOF mutations (HR 0.90, 95% CI [0.34, 2.39], p = 0.837). Conclusions Receiving targeted therapy had a heterogeneous impact on the prognosis of CRC patients harboring different TP53 mutations. These results provide promising value for future personalized treatment and precision medicine.

In order to overcome the current LNP-mRNA delivery system's weakness of poor stability and rapid degradation by nuclease, a novel chol-CGYKK molecule and then the new phospholipid liposome were designed and prepared. A solid phase approach synthesized CGYKK and connected it to cholesterol via a disulfide linker to form the desired chol-CGYKK. Four formulated samples with different proportions of excipients were prepared by freeze-drying cationic liposomes and packaged S-mRNA. The stability test shows that after six months at 4 °C, the encapsulation rate of this novel phospholipid liposome was still approximately 90%, which would significantly improve the storage and transportation requirement. Transmission electron microscopy, atomic force microscopy, and scanning electron microscopy indicated that the liposomes were spherical and uniformly dispersed. On comparing the levels of mRNA protein expression of the four formulated samples, the S protein vaccine expression of formulated sample 1 was the highest. Uptake by vector cells for formulated sample 1 showed that compared to Lipo2000, and the transfection efficiency was 66.7%. Furthermore, the safety evaluation of the CGYKK and mRNA vaccine liposomes revealed no toxic effects. The in vivo study demonstrated that this novel mRNA vaccine had an immune response. However, it was still not as good as the LNP group right now, but its excellent physicochemical properties, stability, in vitro biological activity, and in vivo efficacy against SARS-CoV-2 provided new strategies for developing the next generation of mRNA delivery system.

Background To clarify the relationship between p53 immunohistochemistry (IHC) staining and TP53 alterations (including mutations and deletions) in large B-cell lymphomas (LBCLs) and to explore the possibility of p53 IHC expression patterns as surrogate markers for TP53 alterations. Methods A total of 95 patients diagnosed with LBCLs were selected, and paraffin samples were taken for TP53 gene sequencing, fluorescence in situ hybridization and p53 IHC staining. The results were interpreted by experienced pathologists and molecular pathologists. Results Forty-three nonsynonymous TP53 mutations and p53 deletions were detected in 40 cases, whereas the remaining 55 cases had wild-type TP53 genes. The majority of TP53 mutations (34/43, 79.1%) occurred in exons 4-8, and R248Q was the most common mutation codon (4/43, 9.3%). The highest frequency single nucleotide variant was C > T (43.6%). p53 expression was interpreted as follows: Pattern A: p53 staining was positive in 0%-3% of tumor cells, Pattern B: p53 staining was positive in 4-65% of tumor cells, Pattern C: more than 65% of tumor cells were stained positive for p53. The p53 IHC expression patterns were associated with TP53 alterations. Gain of function variants and wild-type TP53 tended to exhibit type C and B p53 expression patterns, but loss of function variants were exclusively seen in type A cases. Additionally, interpretation of the staining by various observers produced significant reproducibility. Conclusions The p53 IHC expression patterns can be used to predict TP53 alterations and are reliable for diverse alteration types, making them possible surrogate biomarkers for TP53 alterations in LBCLs.

Platinum resistance represents a huge difficulty in ovarian cancer treatment, resulting in disease recurrence and deaths in patients. However, platinum-resistant, recurrent diseases still lack fundamentally effective treatment. Herein, four platinum(IV) (Pt(IV)) prodrugs were developed from the most widely used cisplatin (CisPt) and oxaliplatin (OxaPt), which were subsequently loaded with human serum albumin (HSA) to form nanoparticles (NP1-NP4). We found that NP1, also named Abplatin(iv), showed the best anticancer activity in six ovarian cancer cell lines of various pathological types. Hence, Abplatin(iv) was further evaluated in terms of translational potential. We established patient-derived cells (PDCs) and patient-derived organoids (PDOs) and observed enhanced antitumor effects of Abplatin(iv) in these ex vivo models. Furthermore, in mice bearing orthotopic ovarian cancer, intraperitoneal administration of Abplatin(iv) resulted in targeted drug accumulation in tumors and decreased tumor burden more effectively than CisPt, without causing any detectable side effects. In addition, by analyzing single-cell transcriptome sequencing results, we found a phenotypic shift toward stem-like cells in ovarian cancers undergoing chemotherapy. Therefore, cancer stem cells (SKOV3–3rd) mimicking such persistent tumor cells in postchemotherapeutic residual lesions were established. Abplatin(iv) exhibited a significantly improved antitumor effect on SKOV3–3rd cells both in vitro and in vivo. Finally, RNA sequencing revealed that Abplatin(iv) worked by boosting cell ferroptosis compared with CisPt. Taken together, Abplatin(iv) exhibits low systemic toxicity and high anticancer activity. In particular, it shows robust efficacy against platinum-resistant ovarian cancer derived from patients, indicating its great clinical translation potential.

In order to improve the targeting efficiency and reduce anti-breast cancer therapeutic side effects, paclitaxel (PTX), crizotinib (CRI), and Bcl-xL siRNA were co-loaded in cationic liposomes (CTL), which exhibited a substantial enhanced permeability and retention effect (EPR effect) in breast cancer. CTL containing crizotinib and paclitaxel (CRI-PTX-CTL) had particle sizes of (138.63 ± 1.53) nm and zeta potentials of (50.90 ± 0.30) mV, respectively. It was spherical and uniformly dispersed under TEM. The in vitro release of CRI-PTX-CTL showed that the cumulative release rates of CRI and PTX within 12 h were 64.37% and 54.71%, and released from liposomes at the same time. At the cellular level, CRI and PTX were discovered to have synergistic effects. Cell uptake experiments demonstrated that CRI, PTX, and siRNA contained in CTL can be effectively taken up by MCF-7 cells. It was further proved that CTL-siRNA could effectively inhibit the expression of Bcl-xL in cells. CRI, PTX and Bcl-xL siRNA delivered by CTL showed enhanced cytotoxicity during in vitro experiments. Therefore, this study proved that the CRI-PTX-CTL-siRNA was a very promising delivery system for the treatment of breast cancer.