FAK inhibitors in cancer, a patent review - an update on progress.

INTRODUCTION: Focal adhesion kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase over-expressed in various malignancies which is related to various cellular functions such as adhesion, metastasis and proliferation. AREAS COVERED: There is growing evidence that FAK is a promising therapeutic target for designing inhibitors by regulating the downstream pathways of FAK. Some potential FAK inhibitors have entered clinical phase research. EXPERT OPINION: FAK could be an effective target in medicinal chemistry research and there were a variety of FAKIs have been patented recently. Here, we updated an overview of design, synthesis and structure-activity relationship of chemotherapeutic FAK inhibitors (FAKIs) from 2017 until now based on our previous work. We hope our efforts can broaden the understanding of FAKIs and provide new ideas and insights for future cancer treatment from medicinal chemistry point of view.

MiR-3074-5p suppresses non-small cell lung cancer progression by targeting the YWHAZ/Hsp27 axis.

Non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases, and the 5-year survival rate of patients remains unsatisfactory. MicroRNAs (miRNAs) are small endogenous noncoding RNAs that are considered essential posttranscriptional regulators of tumorigenesis, including NSCLC. In this study, we aimed to investigate the biological role of miR-3074-5p in NSCLC cells and the underlying molecular mechanisms. We showed that miR-3074-5p expression was decreased in human NSCLC specimens and cell lines. Moreover, miR-3074-5p overexpression inhibited cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. In addition, miR-3074-5p overexpression not only suppressed tumor growth but also enhanced the antitumor effect of paclitaxel (PTX) on NSCLC cells in vitro and in vivo. A transcriptome sequencing assay revealed genes that were differentially expressed after miR-3074-5p overexpression, and among the genes whose expression levels were most significantly decreased, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) was a target of miR-3074-5p. The regulatory effect of miR-3074-5p on YWHAZ expression was verified by Western blotting and dual-luciferase reporter assays. The inhibition of A549 cell growth, migration and invasion was reversed by YWHAZ overexpression. Furthermore, we showed that PTX stimulated the expression of the YWHAZ and Hsp27 proteins and promoted the phosphorylation of Hsp27 (at S15 and S78). YWHAZ was confirmed to interact with Hsp27 in A549 cells, and downregulating YWHAZ expression promoted the degradation of the Hsp27 protein. Taken together, these results suggest that the miR-3074-5p/YWHAZ/Hsp27 axis may be a novel therapeutic target for NSCLC treatment.

BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study.

BACKGROUND: Antibody-drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR-HER3 bispecific antibody-drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours. METHODS: This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18-75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing. FINDINGS: Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5-8·9) and 60 (34%; 95% CI 27-42) patients had an objective response. INTERPRETATION: Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients. FUNDING: Sichuan Baili Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

γ-Glutamyltranspeptidase fluorescence lifetime response probe for precision tumor detection unveiling A549 cancer cell specificity.

γ-Glutamyltranspeptidase (γ-GGT), as a key enzyme, exhibits markedly higher expression levels in tumor cells compared to normal cells. Under normal conditions, γ-GGT activity on the cell membrane is relatively low, but it undergoes a significant upregulation in cancer cells, making it a potential cancer biomarker. Particularly in A549 cells, a prominent cancer cell line, the pronounced upregulation of γ-GGT expression emphasizes its potential as a unique recognition target and a robust marker for A549 cells. This study successfully synthesized a highly selective γ-GGT fluorescent probe, the exhibits commendable sensitivity (LOD = 0.0021U/mL) and selectivity, achieving efficient detection at the cellular level and providing accurate insights into differential expression between normal and cancer cells. The alterations in fluorescence lifetime observed before and after the probe's reaction with γ-GGT serve as a crucial foundation for fluorescence lifetime imaging on living cells. The probe has become a powerful tool for precise localization of tumor cells, particularly demonstrating its capability for specific recognition in A549 cells. Overall, this research highlights the potential of γ-GGT as a target for fluorescent probes, emphasizing its prospects in specific recognition, particularly in A549 cells, with profound implications for advancing early cancer diagnosis and treatment methods.

Targeting CD300ld to normalize the tumor microenvironment: an emerging insight in cancer immunotherapy.

In a recent Nature elegant study, Wang et al. identified CD300ld, a novel functionally highly conserved tumor immunosuppressive receptor, highly expressed specifically on polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), as well as a key receptor in the regulation of recruitment and immunosuppressive function of PMN-MDSCs. Targeting CD300ld could remodel the tumor immune microenvironment, resulting in a broad-spectrum anti-tumor effect.

Multifunctional fluorescence/photoacoustic bimodal imaging of γ-glutamyltranspeptidase in liver disorders under different triggering conditions.

Hepatocellular carcinoma (HCC) seriously threatens the human health. Previous investigations revealed that γ-glutamyltranspeptidase (GGT) was tightly associated with the chronic injury, hepatic fibrosis, and the development of HCC, therefore might act as a potential indicator for monitoring the HCC-related processes. Herein, with the contribution of a structurally optimized probe ETYZE-GGT, the bimodal imaging in both far red fluorescence (FL) and photoacoustic (PA) modes has been achieved in multiple HCC-related models. To our knowledge, this work covered the most comprehensive models including the fibrosis and developed HCC processes as well as the premonitory induction stages (autoimmune hepatitis, drug-induced liver injury, non-alcoholic fatty liver disease). ETYZE-GGT exhibited steady and practical monitoring performances on reporting the HCC stages via visualizing the GGT dynamics. The two modes exhibited working consistency and complementarity with high spatial resolution, precise apparatus and desirable biocompatibility. In cooperation with the existing techniques including testing serum indexes and conducting pathological staining, ETYZE-GGT basically realized the universal application for the accurate pre-clinical diagnosis of as many HCC stages as possible. By deeply exploring the mechanically correlation between GGT and the HCC process, especially during the premonitory induction stages, we may further raise the efficacy for the early diagnosis and treatment of HCC.

An antagonist-based two-photon fluorogenic probe for imaging metabotropic glutamate receptor 5 in neuronal cells.

The expression of metabotropic glutamate receptor 5 (mGluR5) is subject to developmental regulation and undergoes significant changes in neuropsychiatric disorders and diseases. Visualizing mGluR5 by fluorescence imaging is a highly desired innovative technology for biomedical applications. Nevertheless, there are substantial problems with the chemical probes that are presently accessible. In this study, we have successfully developed a two-photon fluorogenic probe, mGlu-5-TP, based on the structure of mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP). Due to this antagonist-based probe selectively recognizes mGluR5, high expression of mGluR5 on living SH-SY5Y human neuroblastoma cells has been detected during intracellular inflammation triggered by lipopolysaccharides (LPS). Of particular significance, the probe can be employed along with two-photon fluorescence microscopy to enable real-time visualization of the mGluR5 in Aß fiber-treated neuronal cells, thereby establishing a connection to the progression of Alzheimer's disease (AD). These results revealed that the probe can be a valuable imaging tool for studying mGluR5-related diseases in the nervous system.

Attention pyramid pooling network for artificial diagnosis on pulmonary nodules.

The development of automated tools using advanced technologies like deep learning holds great promise for improving the accuracy of lung nodule classification in computed tomography (CT) imaging, ultimately reducing lung cancer mortality rates. However, lung nodules can be difficult to detect and classify, from CT images since different imaging modalities may provide varying levels of detail and clarity. Besides, the existing convolutional neural network may struggle to detect nodules that are small or located in difficult-to-detect regions of the lung. Therefore, the attention pyramid pooling network (APPN) is proposed to identify and classify lung nodules. First, a strong feature extractor, named vgg16, is used to obtain features from CT images. Then, the attention primary pyramid module is proposed by combining the attention mechanism and pyramid pooling module, which allows for the fusion of features at different scales and focuses on the most important features for nodule classification. Finally, we use the gated spatial memory technique to decode the general features, which is able to extract more accurate features for classifying lung nodules. The experimental results on the LIDC-IDRI dataset show that the APPN can achieve highly accurate and effective for classifying lung nodules, with sensitivity of 87.59%, specificity of 90.46%, accuracy of 88.47%, positive predictive value of 95.41%, negative predictive value of 76.29% and area under receiver operating characteristic curve of 0.914.

The Dominant Role of Recrystallization and Grain Growth Behaviors in the Simulated Welding Heat-Affected Zone of High-Mn Steel.

Single-pass-welding thermal cycles with different peak temperatures (Tp) were reproduced by a Gleeble 3800 to simulate the heat-affected zone (HAZ) of a Fe-24Mn-4Cr-0.4C-0.3Cu (wt.%) high manganese austenitic steel. Then, the effect of Tp on the microstructure and mechanical properties of the HAZ were investigated. The results indicate that recrystallization and grain growth play dominant roles. Based on this, the HAZ is proposed to categorize into three zones: the recrystallization heat-affected zone (RHAZ) with a Tp of 700~900 °C, the transition heat-affected zone (THAZ) with a Tp of 900~1000 °C, and the coarse grain heat-affected zone (CGHAZ) with a Tp of 1000~1300 °C. The recrystallization fraction was 29~44% in the RHAZ, rapidly increased to 87% in the THAZ, and exceeded 95% in the CGHAZ. The average grain size was 17~19 µm in the RHAZ, slightly increased to 22 µm in the THAZ, and ultimately increased to 37 µm in the CGHAZ. The yield strength in the RHAZ and THAZ was consistent with the change in recrystallization fraction, while in the CGHAZ, it satisfied the Hall-Petch relationship with grain size. In addition, compared with the base material, the Charpy impact absorbed energy at -196 °C decreased by 22% in the RHAZ, but slightly increased in the CGHAZ. This indicates that the theory of fine grain strengthening and toughening is not entirely applicable to the HAZ of the investigated high-Mn steel.

Hepatic artery restriction operation combined with ALPPS (HARO-ALPPS), a novel ALPPS procedure for the treatment of hepatocellular carcinoma with severe fibrosis: Retrospective clinical cohort study.

BACKGROUND: Associating liver partition with portal vein ligation for staged liver resection (ALPPS) has been used in the treatment of patients with advanced or massive liver cancer without sufficient future liver remnant, but concerns remain regarding tumor outcomes and surgical safety. This study aims to evaluate the efficacy and safety of a new procedure, Hepatic artery restriction operation combined with ALPPS (HARO-ALPPS), in the treatment of HCC patients especially with severe fibrosis. METHODS: This retrospective study analyzed 8 patients who underwent HARO-ALPPS for HCC and compared their outcomes with 64 patients who underwent conventional ALPPS. The primary outcomes assessed were liver regeneration ability (measured by relative and absolute kinetic growth rates), postoperative complications, and mortality. The secondary outcomes included overall survival and disease-free survival. RESULTS: HARO-ALPPS significantly restricted the blood supply of the hepatic artery. One week after surgery, the blood flow of the right hepatic artery dropped to 62.1%. At the same time, HARO-ALPPS shows superior liver regeneration ability, which is particularly prominent in the background of liver fibrosis. No serious complications occurred after HARO-ALPPS. The overall survival rate of HARO-ALPPS was 75%, which was higher than that of ALPPS (64%, P=0.816). CONCLUSION: Compared to conventional ALPPS, HARO-ALPPS exhibits a better liver regeneration ability, and favorable long-term outcomes. Further prospective studies are needed to validate these findings and evaluate the long-term oncologic outcomes of this novel procedure.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

[Comparative study of minimally invasive titanium elastic nail and steel plate on the treatment of fracture of tibiofibular fracture in adults].

OBJECTIVE: To compare the clinical outcomes of using elastic intramedullary nail and plate to fix fibular fracture. METHODS: The 60 patients with tibiofibular fractures admitted from January 2015 to December 2022 were divided into two groups:intramedullary nail group and plate group, 30 cases each, intramedullary nail group was treated with elastic intramedullary nail fixation group, plate group was treated with steel plate and screw fixation group. Intramedullary nail group, there were 18 males and 12 females, aged from 22 to 75 years old with an average of (39.4±9.8) years old, including 24 cases of traffic accidents injury, 6 cases of falling injury, 23 cases of closed fractures, 7 cases of open fractures. Steel plate group, there were 15 males and 15 females, aged from 24 to 78 years old with an average of (38.6±10.2) years old. The 22 cases were injured by traffic accident, 8 cases were injured by falling. The 24 cases were closed fractures and 6 cases were open fractures. The operation time, intraoperative bleeding, American Orthopedic Foot and Ankle Society (AOFAS) ankle and hind foot scores, clinical healing time of fibula and the incidence of wound complications were compared between the two groups. RESULTS: The patients in both groups were followed up for 6 to 21 months, with an average of (14.0±2.8) months. Compared with plate group, intramedullary nail group had shorter operative time, less bleeding, shorter clinical healing time of fibula, and lower infection rate of incision, and the difference was statistically significant (P<0.05). There were 2 cases of delayed healing in intramedullary nail group, 1 case of nonunion in plate group, and 2 cases of delayed healing in plate group, and there was no statistically significant difference between the two groups (P>0.05). In the last follow-up, according to the AOFAS scoring standard, the ankle function in intramedullary nail group was excellent in 17 cases, good in 12 cases, fair in 1 case, with an average of (88.33±4.57) points, while in plate group, excellent in 16 cases, good in 10 cases, fair in 4 cases, with an average of (87.00±4.14) points;There was no statistical difference between the two groups (P>0.05). CONCLUSION: Elastic intramedullary nail has the advantages of short operation time, less intraoperative bleeding, short fracture healing time and less incision complications in the treatment of fibular fracture, which is worthy of clinical application.

Responsive regularity of neurons in the hindlimb region of primary somatosensory cortex to different temperature thermal needle stimulation of "Zusanli"(ST36) in mice. / å°é¼ åˆçº§ä½“æ„Ÿçš®å±‚åŽè‚¢åŒºç¥žç»å ƒå¯¹"足三里"不同温度热刺激的响应规律.

OBJECTIVES: To study the regularity of central response to thermal needle stimulation of "Zusanli" (ST36) at different temperature, and to analyze the temperature difference of central responses. METHODS: Six male C57BL/6j adult mice were used in the present study. For observing activities of neurons in the hindlimb region of left primary somatosensory cortex (S1HL, A/P=0.46 mm, M/L=1.32 mm, D/V=-0.14 mm) by using a fast high-resolution miniature two-photon microscopy (FHIRM-TPM), the mice were anesthetized with 3% isoflurane (inhalation), with its head fixed in a stereotaxic apparatus, then, adeno-associated virus (AAV-hSyn-GCaMP6f-WPRE-hGHpA, for showing intracellular calcium transients in neurons transfected) was injected into the left S1HL region using a micro-syringe after scalp surgical operation. The mice's right ST36 were stimulated using internal thermal needles with the temperature being 43 ℃, or 45 ℃, or 47 ℃, separately. Image J software and MATLAB 2020b software were used to process the image data of neuronal calcium activity (Ca2+ signaling) in the left S1HL region, including the instant maximum calcium peak value (ΔF/F) in 2 s, instant calcium spike frequency in 2 s, short-term calcium peak value (ΔF/F) in 3.5 min, short-term calcium spike frequency in 3.5 min, calcium peak duration in 3.5 min, maximum calcium peak value (ΔF/F) at the 1st , 2nd and 3rd min, and calcium spike frequency at the 1st, 2nd and 3rd min after thermal needle stimulation. RESULTS: In comparison with the normal temperature needle stimulation, the instant intracellular maximum calcium peak value, instant calcium spike frequency, short-term maximum calcium peak value, short-term calcium spike frequency, and calcium peak duration of S1HL neurons in response to 43 ℃, 45 ℃ and 47 ℃ internal thermal needle stimulation of ST36 were significantly increased (P<0.001, P<0.01). Comparison among the 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation showed that the 45 ℃ thermal needle stimulation was obviously superior to 43 ℃ and 47 ℃ thermal needle stimulation in increasing instant calcium spike frequency, short-term calcium spike frequency and calcium peak duration of S1HL neurons (P<0.001, P<0.01). The 47 ℃ thermal needle stimulation was stronger than 43 ℃ and 45 ℃ thermal needle stimulation in increasing the instant maximum calcium peak value (P<0.001). The maximum calcium peak value was apparently higher (P<0.001) at the 2nd min than that at the 1st and 3rd min after 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation. No significant differences were found in the short-term maximum calcium peak value among the 3 thermal needle stimulation and in the calcium spike frequency among the 3 time points after 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation. CONCLUSIONS: S1HL neurons respond to all 43 ℃, 45 ℃ and 47 ℃ thermal needle stimulation of ST36 in mice, while more actively to 45 ℃ thermal needle stimulation.

Real-time monitoring of abnormal mitochondrial viscosity in glioblastoma with a novel mitochondria-targeting fluorescent probe.

Glioblastoma is the most fatal and insidious malignancy, due to the existence of the blood-brain barrier (BBB) and the high invasiveness of tumor cells. Abnormal mitochondrial viscosity has been identified as a key feature of malignancies. Therefore, this study reports on a novel fluorescent probe for mitochondrial viscosity, called ZVGQ, which is based on the twisted intramolecular charge transfer (TICT) effect. The probe uses 3-dicyanomethyl-1,5,5-trimethylcyclohexene as an electron donor moiety and molecular rotor, and triphenylphosphine (TPP) cation as an electron acceptor and mitochondrial targeting group. ZVGQ is highly selective, pH and time stable, and exhibits rapid viscosity responsiveness. In vitro experiments showed that ZVGQ could rapidly recognize to detect the changes in mitochondrial viscosity induced by nystatin and rotenone in U87MG cells and enable long-term imaging for up to 12 h in live U87MG cells. Additionally, in vitro 3D tumor spheres and in vivo orthotopic tumor-bearing models demonstrated that the probe ZVGQ exhibited exceptional tissue penetration depth and the ability to penetrate the BBB. The probe ZVGQ not only successfully visualizes abnormal mitochondrial viscosity changes, but also provides a practical and feasible tool for real-time imaging and clinical diagnosis of glioblastoma.

A novel near-infrared fluorescent probe for real-time monitoring of leucine aminopeptidase activity and metastatic tumor progression.

This article discusses the importance of early tumor detection, particularly in liver cancer, and the role of leucine aminopeptidase (LAP) as a potential marker for liver cancer diagnosis and prognosis assessment. The article highlights the limitations of current tumor markers and the need for new markers and multi-marker approaches to improve accuracy. The authors introduce a novel near-infrared fluorescent probe, NTAP, designed for LAP detection. They describe the synthesis of the probe and evaluate its spectral properties, including the LOD was 0.0038 U/mL, and QY was 0.32 %. The kinetic properties of NTAP, such as the relationship between LAP concentration (0-0.08 U/mL), reaction time (3 min), and fluorescence excitation spectra (475 nm) and emission spectra (715 nm) are investigated. The article also discusses the stability and selectivity of the probe and its ability to detect LAP in complex samples. Cellular imaging experiments demonstrate the NATP specificity and selectivity in detecting LAP activity and its inhibition. Animal models of liver and lung metastasis are used to evaluate the probe's imaging capabilities, showing its ability to accurately locate and detect metastatic lesions. The article concludes by emphasizing the potential applications of the NTAP probe in early tumor diagnosis, treatment monitoring, and the study of tumor metastasis mechanisms.

Cascading Detection of Hydrogen Sulfide and N-Acetyltransferase 2 in Hepatocellular Carcinoma Cells Using a Two-Photon Fluorescent Probe.

Hydrogen sulfide (H2S), a critical gas signaling molecule, and N-acetyltransferase 2 (NAT2), a key enzyme in drug metabolism, are both known active biomarkers for liver function. However, the interactions and effects of H2S and NAT2 in living cells or lesion sites remain unknown due to the lack of imaging tools to achieve simultaneous detection of these two substances, making it challenging to implement real-time imaging and precise tracking. Herein, we report an activity-based two-photon fluorescent probe, TPSP-1, for the cascade detection of H2S and NAT2 in living liver cells. Continuous conversion from TPSP-1 to TPSP-3 was achieved in liver cells and tissues. Significantly, leveraging the outstanding optical properties of this two-photon fluorescent probe, TPSP-1, has been effectively used to identify pathological tissue samples directly from clinical liver cancer patients. This work provides us with this novel sensing and two-photon imaging probe, which can be used as a powerful tool to study the physiological functions of H2S and NAT2 and will help facilitate rapid and accurate diagnosis and therapeutic evaluation of hepatocellular carcinoma.

Fully semantic segmentation for rectal cancer based on post-nCRT MRl modality and deep learning framework.

PURPOSE: Rectal tumor segmentation on post neoadjuvant chemoradiotherapy (nCRT) magnetic resonance imaging (MRI) has great significance for tumor measurement, radiomics analysis, treatment planning, and operative strategy. In this study, we developed and evaluated segmentation potential exclusively on post-chemoradiation T2-weighted MRI using convolutional neural networks, with the aim of reducing the detection workload for radiologists and clinicians. METHODS: A total of 372 consecutive patients with LARC were retrospectively enrolled from October 2015 to December 2017. The standard-of-care neoadjuvant process included 22-fraction intensity-modulated radiation therapy and oral capecitabine. Further, 243 patients (3061 slices) were grouped into training and validation datasets with a random 80:20 split, and 41 patients (408 slices) were used as the test dataset. A symmetric eight-layer deep network was developed using the nnU-Net Framework, which outputs the segmentation result with the same size. The trained deep learning (DL) network was examined using fivefold cross-validation and tumor lesions with different TRGs. RESULTS: At the stage of testing, the Dice similarity coefficient (DSC), 95% Hausdorff distance (HD95), and mean surface distance (MSD) were applied to quantitatively evaluate the performance of generalization. Considering the test dataset (41 patients, 408 slices), the average DSC, HD95, and MSD were 0.700 (95% CI: 0.680-0.720), 17.73 mm (95% CI: 16.08-19.39), and 3.11 mm (95% CI: 2.67-3.56), respectively. Eighty-two percent of the MSD values were less than 5 mm, and fifty-five percent were less than 2 mm (median 1.62 mm, minimum 0.07 mm). CONCLUSIONS: The experimental results indicated that the constructed pipeline could achieve relatively high accuracy. Future work will focus on assessing the performances with multicentre external validation.

A comparative study of mono-exponential and advanced diffusion-weighted imaging in differentiating stage IA endometrial carcinoma from benign endometrial lesions.

PURPOSE: The purpose of the current investigation is to compare the efficacy of different diffusion models and diffusion kurtosis imaging (DKI) in differentiating stage IA endometrial carcinoma (IAEC) from benign endometrial lesions (BELs). METHODS: Patients with IAEC, endometrial hyperplasia (EH), or a thickened endometrium confirmed between May 2016 and August 2022 were retrospectively enrolled. All of the patients underwent a preoperative pelvic magnetic resonance imaging (MRI) examination. The apparent diffusion coefficient (ADC) from the mono-exponential model, pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) from the bi-exponential model, distributed diffusion coefficient (DDC), water molecular diffusion heterogeneity index from the stretched-exponential model, diffusion coefficient (Dk) and diffusion kurtosis (K) from the DKI model were calculated. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic efficiency. RESULTS: A total of 90 patients with IAEC and 91 patients with BELs were enrolled. The values of ADC, D, DDC and Dk were significantly lower and D* and K were significantly higher in cases of IAEC (p < 0.05). Multivariate analysis showed that K was the only predictor. The area under the ROC curve of K was 0.864, significantly higher compared with the ADC (0.601), D (0.811), D* (0.638), DDC (0.743) and Dk (0.675). The sensitivity, specificity and accuracy of K were 78.89%, 85.71% and 80.66%, respectively. CONCLUSION: Advanced diffusion-weighted imaging models have good performance for differentiating IAEC from EH and endometrial thickening. Among all of the diffusion parameters, K showed the best performance and was the only independent predictor. Diffusion kurtosis imaging was defined as the most valuable model in the current context.

Development of a hypoxia-activated red-emission fluorescent probe for in vivo tumor microenvironment imaging and anti-tumor therapy.

Hypoxia, a significant feature of the tumor microenvironment, is closely associated with tumor growth, metastasis, and drug resistance. In the field of tumor microenvironment analysis, accurately imaging and quantifying hypoxia - a critical factor associated with tumor progression, metastasis, and resistance to therapy - remains a significant challenge. Herein, a hypoxia-activated red-emission fluorescent probe, ODP, for in vivo imaging of hypoxia in the tumor microenvironment is presented. Among various imaging methods, optical imaging is particularly convenient due to its rapid response and high sensitivity. The ODP probe specifically targets nitroreductase (AzoR), an enzyme highly expressed in hypoxic cells, playing a vital role by catalyzing the cleavage of azo bonds. The optical properties of ODP exhibited excellent performance in terms of fluorescence enhancement, fluorescence lifetime (0.81 ns), and detection limit (0.86 µM) in response to SDT. Cell imaging experiments showed that ODP could effectively detect and image intracellular hypoxia and the imaging capability of ODP was studied under various conditions including cell migration, antioxidant treatment, and different incubation times. Through comprehensive in vitro and in vivo experiments, including cellular imaging and mouse tumor models, this work demonstrates the efficacy of ODP in accurately detecting and imaging hypoxia. Moreover, ODP's potential in inducing apoptosis in cancer cells offers a promising avenue for integrating diagnostic and therapeutic strategies in cancer treatment. This innovative approach not only contributes to the understanding and assessment of tumor hypoxia but also opens new possibilities for targeted cancer therapy.

Remedial Dosing Recommendations for Sirolimus Delayed or Missed Dosages Caused by Poor Medication Compliance in Pediatric Tuberous Sclerosis Complex Patients.

BACKGROUND: Delayed or missed dosages caused by poor medication compliance significantly affected the treatment of diseases in children. AIMS: The present study aimed to investigate the influence of delayed or missed dosages on sirolimus pharmacokinetics (PK) in pediatric tuberous sclerosis complex (TSC) patients and to recommend remedial dosages for nonadherent patients. METHODS: A published sirolimus population PK model in pediatric TSC patients was used to assess the influence of different nonadherence scenarios and recommend optimally remedial dosages based on Monte Carlo simulation. Thirteen nonadherent scenarios were simulated in this study, including delayed 2h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, 23.5 h, and missed one dosage. Remedial dosing strategies contained 10-200% of scheduled dosages. The optimal remedial dosage was that with the maximum probability of returning the individual therapeutic range. RESULTS: For delayed or missed sirolimus dosages in pediatric TSC patients, when the delayed time was 0-8 h, 8-10 h, 10-18 h, 18-22.7 h, 22.7-24 h, 70%, 60%, 40%, 30%, 20% scheduled dosages were recommended to take immediately. When one dosage was missed, 120% of scheduled dosages were recommended at the next dose. CONCLUSION: It was the first time to recommend remedial dosages for delayed or missed sirolimus therapy caused by poor medication compliance in pediatric TSC patients based on Monte Carlo simulation. Meanwhile, the present study provided a potential solution for delayed or missed dosages in clinical practice.