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Two LD-targeting photosensitizers (CCOH and CCN) were designed and synthesized by introducing coumarin into the curcumin structure, which could generate reactive oxygen species in type I and II synergy upon light irradiation.

Two hydrophilic macrocycles can strongly bind hypocrellin B. The resulting supramolecular photosensitizers show excellent photodynamic efficiency with different cellular delivery.

Interaction between carcinoma-associated fibroblasts (CAFs) and tumor cells leads to the invasion and metastasis of breast cancer. Herein, we prepared a redox-responsive chondroitin sulfate (CS)-based nanomedicine, in which hydrophobic cabazitaxel (CTX) was conjugated to the backbone of CS via glutathione (GSH)-sensitive dithiomaleimide (DTM) to form an amphipathic CS-DTM-CTX (CDC) conjugate, and dasatinib (DAS) co-assembled with the CDC conjugate to obtain DAS@CDC. After CD44 receptor-mediated internalization by CAFs, the nanomedicine could reverse CAFs to normal fibroblasts, blocking their crosstalk with tumor cells and reducing synthesis of major tumor extracellular matrix proteins, including collagen and fibronectin. Meanwhile, the nanomedicine internalized by tumor cells could effectively inhibit tumor proliferation and metastasis, leading to shrinkage of the tumor volume and inhibition of lung metastasis in a subcutaneous 4T1 tumor model with low side effects. Collectively, the nanomedicine showed a remarkably synergistic therapy effect against breast cancer by modulating tumor-stromal crosstalk.

Purpose The detection rate of colorectal neuroendocrine tumours (CR-NETs) is increasing, but their treatment is still controversial. Lymph node metastasis is an important reference index for the selection of treatment. The aim of our study was to investigate the factors associated with lymph node metastasis and prognosis of CR-NETs. Methods The case characteristics of patients with colorectal neuroendocrine tumours from January 2011 to December 2020 were retrospectively analysed, including age, gender, tumour size, tumour location, lymph node metastasis, pathological grade and follow-up. Results A total of 195 cases of CR-NETs were included in this study. When 15 mm was used as the cut-off value, the sensitivity, specificity and area under the curve (AUC) of lymph node metastases were 95.9%, 95.2% and 0.986, respectively. Multivariate analysis suggested that tumour size ≥ 15 mm (OR: 30.517, 95% CI: 1.250 ~ 744.996, p = 0.036) and lymphovascular invasion (OR: 42.796, 95% CI: 2.882 ~ 635.571, p = 0.006) were independent risk factors for lymph node metastasis. Age ≥ 56 (HR: 7.434, 95% CI: 1.334 ~ 41.443, p = 0.022) and distant metastasis (HR: 24.487, 95% CI: 5.357 ~ 111.940, p Conclusions When the size of a CR-NET is ≥ 15 mm, the risk of lymph node metastasis is higher, and it is recommended to choose the surgical method carefully. Tumour size and lymphovascular invasion were independent risk factors for lymph node metastasis. Age ≥ 56 and distant metastasis were independent prognostic factors.

The non-invasive treatment of glioblastoma (GBM) is of great significance and can greatly reduce the complications of craniotomy. Sonodynamic therapy (SDT) is an emerging tumor therapeutic strategy that overcomes some fatal flaws of photodynamic therapy (PDT). Different from PDT, SDT has deep tissue penetration and can be applied in the non-invasive treatment of deep-seated tumors. However, effective sonosensitizers that can be used for SDT of GBM are still very rare. Herein, we have prepared a suitable assembly based on a hypocrellin derivative (CTHB) with good biocompatibility. Excitedly, the hypocrellin-based assembly (CTHB NPs) can effectively produce reactive oxygen species under ultrasound stimulation. The inherent fluorescence and photoacoustic imaging characteristics of the CTHB NPs are conducive to the precise positioning of the tumors. It has been proved both in subcutaneous and in intracranial tumor models that CTHB NPs can be used as an effective sonosensitizer to inhibit tumor growth under ultrasound irradiation. This hypocrellin-based assembly has a good clinical prospect in the non-invasive treatment of GBM.

The design and synthesis of single-molecule amphiphilic and multifunctional phototherapeutic agents are important to cancer diagnosis and therapy. In this work, we developed three amphiphilic diketopyrrolopyrrole derivatives (TPADPP, DTPADPP, and TPADDPP) with different donor–acceptor structures and poly(ethylene glycol) side chains. The corresponding nanoparticles (NPs) were obtained via a self-assembly from three amphiphilic DPP derivatives and used as smart phototherapeutic agents for tumor diagnosis and treatment. The three amphiphilic DPP NPs exhibited near-infrared (NIR) emissions and good biocompatibility. Thus, they could be used as fluorescence (FL) imaging agents for guided therapy. DTPADPP NPs and TPADDPP NPs also displayed excellent photothermal performance and high accumulation in the tumor. Owing to these beneficial features, the DTPADPP NPs and TPADDPP NPs synthesized herein are suitable for NIR FL imaging and effective photothermal therapy against the tumor in vivo.

The reliability and validity of three digital occlusion analysis methods was evaluated in vivo.The three method evalueated were:scanning of articulating paper marks (SA), dental prescale occlusal analysis system (DP) and a virtual occlusion constructed method (VO). A conventional silicone transmission method (ST) was used as the standard for comparison. Each of the 20 enroled human subjects was tested with the four methods. Retest of each method was performed at 2-week intervals. Occlusal contact area (OCA) and occlusal contact numbers (OCN) were calculated for analyses. For reliability evaluation, intraclass correlation coefficients (ICC) of the OCA and OCN values obtained from each method were compared. For validity evaluation, Pearson correlations coefficients, paired t-tests, regression analysis and Bland-Altman analysis were examined.The ICC values of OCA and OCN were in the order: STSADPVO. The highest OCA and OCN values were found ST while the lowest values were obtained from DP. Paired t-test identified a significant difference when OCA values obtained from the three digital methods were compared with ST, and between the OCN values of DP and ST. Pearson correlation showed high coefficients between ST and three digital methods (0.583-0.885 for OCA; 0.779-0.836 for OCN). A significant linear correlation was found between the results from ST and those from SA or VO. Bland-Altman analysis showed good agreement between OCN values of SA and ST, and between those of VO and ST.The three digital occlusal analysis methods showed good reliability and validity for in vivo clinical application.The three digital occlusion analysis systems examined demonstrate good potential in in vivo quantitative analysis, with good reliability and validity. The use of these analytical methods should facilitate digital workflow in clinical practice.

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer. Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment. A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate, conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a (Ppa) with a branched glycopolymer. The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B, and PTX was simultaneously released to exert its therapeutic effect. The theranostic nanomedicine, branched glycopolymer-PTX-DOTA-Gd, had an extended circulation time, enhanced accumulation in tumors, and excellent biocompatibility with significantly reduced gadolinium ion (Gd3+) retention after 96 h post-injection. Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90% were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity. This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer., Highlights • A cathepsin B-responsive theranostic nanomedicine (glycopolymer-PTX-DOTA-Gd) based on a branched glycopolymer was prepared. • Glycopolymer-PTX-DOTA-Gd can be specifically degradated and release drug at tumor enviornment. • Glycopolymer-PTX-DOTA-Gd enhance the contrast of magnetic resonance imaging (MRI) at tumor sites. • The nanomedicine have good biocompatibility, excellent tumor targeting and anti-tumor efficacy., Graphical abstract Cathepsin B-responsive biodegradable branched glycopolymer-based prodrug was designed and prepared as theranostic nanomedicine for cancer treatments, resulting in significantly enhanced therapeutic indexes and strengthened contrast of magnetic resonance imaging (MRI) at tumor sites.Image 1

Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity. Here we report a dendronized polymer-doxorubicin (DOX) hybrid (DPDH) with an improved in vivo drug delivery efficiency for cancer therapy compared with a linear polymer-DOX conjugate (LPDC). The in vitro drug release profile of DOX indicates that DPDH displays pH-responsive drug release due to cleavage of hydrazone bonds since a greater amount of DOX is released at pH 5.2 at a faster rate than at pH 7.4. DPDH efficiently enters 4T1 cells and releases DOX to induce cytotoxicity and apoptosis. Owing to the dendronzied structure, DPDH has a significantly longer blood circulation time than LPDC. DPDH substantially enhances the therapeutic efficacy to suppress tumor growth in a 4T1 mammary cancer model than LPDC as well as free drug, evidenced from tumor growth inhibition, TUNEL assessment and histological analysis. Biosafety of DPDH is also confirmed from hemolysis, body weight shifts during treatment and pathological analysis. This study demonstrates the use of dendronized polymer-DOX hybrids for specific drug molecules is a promising approach for drug delivery.

Purpose This study was performed to evaluate the accuracy of endoscopic ultrasonography (EUS) for early gastric cancer (EGC) based on pathological results and to analyze the factors that may affect EUS misdiagnosis, especially underestimation. Methods We retrospectively analyzed 1075 cases of EGC which underwent EUS before ESD or surgery at the Fourth Hospital of Hebei Medical University from September 2015 to April 2021. We collected data on sex, age, tumor location, macroscopic type, tumor size, ulceration, histopathological type (differentiated or undifferentiated), depth of pathological diagnosis, and treatment for each case. Results The accuracy, sensitivity and specificity of EUS were 79.3%, 88.0% and 42.1%, respectively. The positive predictive value and negative predictive value were 86.6% and 45.5%, respectively. In the multivariate analysis, a tumor diameter ≥ 15 mm and the presence of ulceration were found to be independent risk factors for misdiagnosis. In the multivariate analysis of EGC with pT1b, the location of the tumor in the cardia, the lesion less than 15mm, and the absence of ulcers were independent risk factors that were underestimated. In the multivariate analysis of EGC with pT1a, lesion ≥ 15 mm and the presence of ulceration were independent risk factors that were overestimated. Conclusion This study confirmed that microprobe ultrasonic gastroscopy has high accuracy in judging the depth of EGC infiltration and is suitable for application. However, attention should be paid to factors affecting its specificity, especially in EGC located in the cardia, less than 15mm and without ulceration.

Gastroesophageal junction adenocarcinoma (GEJA) is a malignant tumor located at the junction of the esophagus and stomach, the incidence of which is increasing year by year, while screening for early biomarkers is limited. Tandem mass tagging (TMT) coupled with liquid chromatography-tandem mass spectrometry (LC/MS/MS) has been used to screen for differential proteins in various cancers.Differential proteins in GEJA and precancerous lesions were screened using TMT-LC/MS/MS, and then proteins that met expectations were selected for trend clustering analysis, combined with GO and KEGG analysis for functional annotation of differential proteins in GEJA. Then, parallel reaction monitoring and immunohistochemistry techniques were used to validate the accuracy of the proteomics data.Our group screened the differential proteins during GEJA progression using proteomics technology, analyzed the expression trends and functional regions involved in the differential proteins during carcinogenesis, and validated the accuracy of the experimental results.The screening of differential proteins in GEJA carcinogenesis based on TMT-LC/MS/MS technology provides detailed information for the elucidation of GEJA progression process, pathogenesis, early screening and screening of candidate markers.

Facile tailoring of photosensitizers (PSs) with advanced and synergetic properties is highly expected to broaden and deepen photodynamic therapy (PDT) applications. Herein, a catalyst-free thiol-yne click reaction was employed to develop the sulfur atom-based PSs by using the in situ formed sulfur "heavy atom effect" to enhance the intersystem crossing (ISC), while such an effect can be remarkably magnified by the polymerization. The introduction of a tetraphenylpyrazine-based aggregation-induced emission (AIE) unit was also advantageous in PS design by suppressing their non-radiative decay to facilitate the ISC in the aggregated state. Besides, the resulting sulfur atom electron donor, together with a double-bond π bridge and AIE electron acceptor, created a donor-π-acceptor (D-π-A) molecular system with good two-photon excitation properties. Combined with the high singlet oxygen generation efficiency, the fabricated polymer nanoparticles exhibited an excellent in vitro two-photon-excited PDT towards cancer cells, therefore possessing a huge potential for the deep-tissue disease therapy.

Hypocrellin B (HB) derived from naturally produced hypocrellins has attracted considerable attention in photodynamic therapy (PDT) because of its excellent photosensitive properties. However, the weak absorption within a "phototherapy window" (600-900 nm) and poor water solubility of HB have limited its clinical application. In this study, two HB derivatives (i. e., HE and HF) were designed and synthesized for the first time by introducing two different substituent groups into the HB structure. The obtained derivatives showed a broad absorption band covering the near-infrared (NIR) region, NIR emission (peaked at 805 nm), and singlet oxygen quantum yields of 0.27/0.31. HE-PEG-NPs were also prepared using 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2000) to achieve excellent dispersion in water and further explored their practical applications. HE-PEG-NPs not only retained their 1 O2 -generating ability, but also exhibited a photothermal conversion efficiency of 25.9%. In vitro and in vivo therapeutic results revealed that the synergetic effect of HE-PEG-NPs on PDT and photothermal therapy (PTT) could achieve a good performance. Therefore, HE-PEG-NPs could be regarded as a promising phototheranostic agent.

Sonodynamic therapy (SDT), as a novel non-invasive strategy for eliminating tumor, has the advantages of deeper tissue penetration, fewer side effects, and better patient compliance, compared with photodynamic therapy (PDT). In SDT, ultrasound was used to activate sonosensitizer to produce cytotoxic reactive oxygen species (ROS), induce the collapse of vacuoles in solution, and bring about irreversible damage to cancer cells. In recent years, much effort has been devoted to developing highly efficient sonosensitizers which can efficiently generate ROS. However, the traditional organic sonosensitizers, such as porphyrins, hypericin, and curcumins, suffer from complex synthesis, poor water solubility, and low tumor targeting efficacy which limit the benefits of SDT. In contrast, inorganic sonosensitizers show good in vivo stability, controllable physicochemical properties, ease of achieving multifunctionality, and high tumor targeting, which greatly expanded their application in SDT. In this review, we systematically summarize the nanomaterials which act as the carrier of molecular sonosensitizers, and directly produce ROS under ultrasound. Moreover, the prospects of inorganic nanomaterials for SDT application are also discussed.

A GGT-activated two-photon fluorescent probe (4F-2CN-GSH) was developed based on a cascade reaction. 4F-2CN-GSH could selectivily detect GGT with low detection limit and distinguish ovarian cancer cells from normal cells using both one-photon and two-photon fluorescence imaging.

γ-Glutamyl transpeptidase (GGT) is one of the biomarker of cancer, hepatitis, and numerous other diseases. The accurate analysis of GGT is useful for the early diagnosis of these diseases. In this work, Probe 1, a ratiometric fluorescent probe based on 2,3,5,6-tetrafluoroterephthalonitrile, was designed for GGT detection. The results indicated that Probe 1 can sensitively and selectively detect GGT in phosphate buffered solution and complex biological systems (e.g., blood serum). Furthermore, Probe 1 has been successfully applied for ratiometric imaging of GGT in cancer cells and normal cells.

FTC dye with a D-π-A structure showed outstanding stability, high extinction coefficient, and good photothermal performance. Thus, nanoparticles based on FTC dye were first fabricated by a nanoprecipitation method for photothermal therapy (PTT) which was guided by photoacoustic imaging (PAI). The prepared FTC NPs showed a photothermal conversion efficiency of ∼52.71%, good photoacoustic performance, and excellent stability in in vitro experiments. Moreover, FTC NPs showed good performance in tumor ablation under a 635 nm laser irradiation and low cytotoxicity to the mice model without laser treatment. Histopathological analysis further confirmed that FTC NPs did not harm the major organs of mice. Given the abovementioned features, FTC NPs have great potential to be effective phototheranostic materials for PAI and PTT.

A huge challenge exists in the diagnosis and treatment of malignant glioblastoma (GBM) due to the presence of the blood-brain barrier (BBB). Herein, a multifunctional phototheranostic agent is designed on the basis of an octadecane-modified temozolomide (

Combination therapy is a promising approach for effective treatment of tumors through synergistically regulating pathways. However, the synergistic effect is limited, likely by uncontrolled co-delivery of different therapeutic payloads in a single nanoparticle. Herein, a combination nanotherapeutic is developed by using two amphiphilic conjugates, hyperbranched poly(ethylene glycol)-pyropheophorbide-a (Ppa) (HP-P) and hyperbranched poly(ethylene glycol)-doxorubicin (DOX) (HP-D) to construct co-assembly nanoparticles (HP-PD NPs) for controllably co-loading and co-delivering Ppa and DOX. In vitro and in vivo antitumor studies confirm the synergistic effect of photodynamic therapy and chemotherapy from HP-PD NPs. Metabolic variations reveal that tumor suppression is associated with disruption of metabolic homeostasis, leading to reduced protein translation. This study uncovers the manipulation of metabolic changes in tumor cells through disruption of cellular homeostasis using HP-PD NPs and provides a new insight into the rational design of synergistic nanotherapeutics for combination therapy.

The present in vitro study evaluated the reliability and validity of two computerised occlusion analysis systems.Three occlusion analysis methods were evaluated. The methods included one traditional method (scanning of articulating paper marks (SAP)) and two computerised systems: (dental prescale occlusion analysis system (DPO) and a modified virtual occlusion construction method (VOC)). For reliability evaluation, the occlusion of an articulator-mounted anatomical dentoform was analysed ten times with each of the three methods. Occlusal contact areas and contact number values were obtained and the coefficient of variation (CoV) of each method was compared. For validity evaluation, resin casts of the dentition of 10 human subjects were used for analysis. Paired t-tests, regression analysis and Bland-Altman analysis were used to evaluate the difference and agreement amongst the three methods.The CoV values of occlusal contact areas from the entire dentition were in the order: SAP (5.7%)DPO (12.7%)VOC (15.6%). Higher values was found in the anterior teeth (19.8-40.8%). Significant differences were identified in the occlusal contact areas of the entire dentition and posterior teeth obtained from SAP and DPO; a significant correlation was detected between the two methods (P0.01). Bland-Altman agreement analysis indicated good agreement between SAP and VOC.Both DPO and VOC have good reliability and validity. They are potential alternatives for analysis of occlusal contacts.The dental prescale occlusion analysis system and the modified virtual occlusion constructed method combine convenience with the objectivity of digital technology. These computerised occlusion analysis systems may be used for quantitative analysis of occlusal contacts in clinical practice, with good reliability and validity.

Linear-dendritic block copolymer (LDBCs) are highly attractive candidates for smart drug delivery vehicles. Herein, we report an amphiphilic poly[(ethylene glycol) methyl ether methacrylate] (POEGMA) linear-peptide dendritic prodrug of doxorubicin (DOX) prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. A hydrophobic dye-based photosensitizer chlorin e6 (Ce6) was employed for encapsulation in the prodrug nanoparticles (NPs) to obtain a LDBCs-based drug delivery system (LD-DOX/Ce6) which offered a combination cancer therapy. Due to the presence of Gly-Phe-Leu-Gly peptides and hydrazone bonds in the prodrug structure, LD-DOX/Ce6 were degraded into small fragments, thus specifically triggering the intracellular release of DOX and Ce6 in the tumor microenvironment. Bioinformatics analysis suggested that LD-DOX/Ce6 with laser irradiation treatment significantly induced apoptosis, DNA damage and cell cycle arrest. The combination treatment could not only suppress tumor growth, but also significantly reduced tumor metastasis compared with treatments with DOX or Ce6 through regulating EMT pathway, TGFβ pathway, angiogenesis and the hypoxia pathway. LD-DOX/Ce6 displayed a synergistic chemo-photodynamic anti-tumor efficacy, resulting in a high inhibition in tumor growth and metastasis, while maintaining an excellent biosafety. Therefore, this study has demonstrated potential of the biodegradable and tumor microenvironment-responsive LDBCs as an intelligent multifunctional drug delivery vehicle for high-efficiency cancer combination therapy. This article is protected by copyright. All rights reserved.

Background The placenta is a highly specialized temporary organ that is related to fetal development and pregnancy outcomes, and epidemiological data demonstrate an increased risk of placental abnormality after in vitro fertilization and embryo transfer (IVF-ET). Methods This study examines alterations in the transcriptome profile of first-trimester placentas from IVF-ET pregnancies and analyzes the potential mechanisms that play a role in the adverse perinatal outcomes associated with IVF-ET procedures. Four human placental villi from first-trimester samples were obtained through fetal bud aspiration from patients subjected to IVF-ET due to oviductal factors. An additional four control human placental villi were derived from a group of subjects who spontaneously conceived a twin pregnancy. We analyzed their transcriptomes by microarray. Then, RT-qPCR and immunohistochemistry were utilized to analyze several dysregulated genes to validate the microarray results. Biological functions and pathways were analyzed with bioinformatics tools. Results A total of 3405 differentially regulated genes were identified as significantly dysregulated (> 2-fold change; P

Carbon dots (CDs), a kind of phototheranostic agent with the capability of simultaneous bioimaging and phototherapy [i.e., photodynamic therapy (PDT) or photothermal therapy (PTT)], have received considerable attention because of their remarkable properties, including flexibility for surface modification, high biocompatibility, low toxicity and photo-induced activity for malignant tumor cells. Among numerous carbon sources, it has been found that natural biomass are good candidates for the preparation of CD phototheranostic agents. In this study, pheophytin, a type of Mg-free chlorophyll derivative and also a natural product with low toxicity, was used as a raw carbon source for the synthesis of CDs by using a microwave method. The obtained hydrophobic CDs exhibited a maximum near-infrared (NIR) emission peak at approximately 680 nm, and high singlet oxygen (1 O2 ) generation with a quantum yield of 0.62. The self-assembled CDs from the as-prepared CDs with DSPE-mPEG2000 retained efficient 1 O2 generation. The obtained carbon dot assembly was not only an efficient fluorescence (FL) imaging agent but also a smart PDT agent. Our studies indicated that the obtained hydrophilic CD assembly holds great potential as a new phototheranostic agent for cancer therapy. This work provides a new route for synthesis of CDs and proposes a readily available candidate for tumor treatment.