Normal Blood Vessels Research Articles

IMbrave150: Exploratory analysis to examine the association between bevacizumab (bev) ever being skipped and bev never being skipped in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab (atezo) + bev in a global phase 3 study.

538 Background: Treatment with atezo + bev has been approved globally for patients with unresectable HCC who have not received prior systemic therapy, based on results from the Phase 3 IMbrave150 study (NCT03434379, Finn NEJM 2020 and Cheng J Hepatol 2022). According to Phase 1b study data (Lee Lancet Oncol 2020), when combined with atezo, bev has a clinically relevant contribution in terms of immune enhancement and normalization of tumor blood vessels. However, it is unknown if bev being skipped due to bev adverse events of special interest (AESIs) has an impact on the efficacy of atezo + bev. Here, we conducted an exploratory efficacy analysis examining patients who had skipped bev vs those who never skipped bev using IMbrave150 study data. Methods: In Arm A of IMbrave150, patients were assigned to receive atezo + bev. Group A-1 included patients whose bev was ever skipped due to bev AESIs. Group A-2 included the patients who were not included in group A-1. Landmark analyses of overall survival (OS) and progression-free survival (PFS) were performed in patients who received atezo + bev for ≥6 months to minimize immortal time bias. Results: Of 210 patients who received ≥6 months of atezo + bev, 69 were assigned to group A-1 and 141 were assigned to group A-2. No obvious differences between groups were observed in the distribution of baseline characteristics. Of the group A-1 patients, 75.4% were BCLC stage C and 76.8% were Child-Pugh A5, while group A-2 patients were 80.1% BCLC stage C and 77.0% were Child-Pugh A5. At the data cutoff (Aug 20, 2020), median OS was 25.8 vs 26.2 months (HR, 1.04; 95% CI: 0.64, 1.69) and median PFS per independent review facility-assessed RECIST 1.1 was 15.5 vs 10.0 months (HR, 1.07; 95% CI: 0.74, 1.55) for groups A-1 and A-2, respectively. Conclusions: The patients who had ever skipped bev did not show different efficacy compared with those who had never skipped bev in this post hoc analysis. Although limitations due to the non-randomized and exploratory nature of this comparison should be acknowledged, the results suggest that skipping bev did not have considerable impact on the efficacy of atezo + bev. Clinical trial information: NCT03434379 .

A COMPARATIVE STUDY ON THE FATIGUE STRENGTH AND SERVICE LIFE OF LOWER LIMB ARTERIAL STENT AT DIFFERENT STENOSIS RATES

In order to study the influence of different stenosis rates of blood vessels on the fatigue strength and service life of lower limb arterial stent, numerical simulation was conducted for the mechanical behavior of four types of nickel-titanium alloy lower limb arterial stents (Absolute Pro, Complete SE, E-luminexx-B and Pulsar-35) under the action of radial compression, release and pulsating loads, so as to predict the fatigue life and safety of stents at different stenosis rates (0%, 30%, 50% and 70%). The study found that with increased vascular stenosis rate, both the elastic stress and strain of stent tend to increase, while the fatigue strength, service life and safety tend to decrease. When a stent is implanted in a normal blood vessel, its fatigue strength satisfies the requirement of a 10-year service life requirement, with maximum elastic stress and strain occurring on both sides of the connecting ribs at the end of stent. When the vascular stenosis rate is greater than 30%, the fatigue strength of the stent does not meet requirement of a 10-year service life, and fatigue fracture is likely to occur at the most stenotic part of the blood vessel. With increased vascular stenosis rate, the E-luminexx-B stent with the largest width of support had a significant decrease in its service life. The stent whose supporting unit is of symmetric wave peak structure has a longer service life compared with that whose supporting unit is of offset wave peak structure. The revealing of the influence of vascular stenosis rate on the mechanical properties and fatigue life of stents provides theoretical reference for the fracture failure mechanism of stents.

Human Tail in a New Born: A Case Report

Background Human tails are rare congenital anomalies protruding from midline of the lumbosacral region covered by skin. Human tails are classified as true tail and pseudo tail. True tails, also known as vestigial tails are caudal, midline protrusion capable of spontaneous or reflex motion, consisting of skin covering with a combination of striated muscle, adipose and connective tissue, normal blood vessels and nerves. Case Presentation A 47-days-old-female infant born from 28-years old prime parous women present with cutaneous appendage arising from the sacrococcygeal region, in the midline, above the intergluteal cleft. The tail-like structure was 9 cm in length, with a diameter between 3 cm and 2 cm in all its length, cylindrical, and pointy towards the end. The structure was soft, covered in skin, it shows spontaneous movement. The magnetic resonance imaging (MRI) report shows S1-S2 level spinal bifida. Conclusion This is a rare case of vestigial human tail with spinal bifida on 47-days old female infant born from prime parous mother through spontaneous vaginal delivery diagnosed by histopathologic examination

Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop.

The lack of Tcell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 Tcell progenitors that differentiate into GrzB+PD1+ CD8T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

NIMG-13. DEEP LEARNING-BASED AUTOMATIC DETECTION AND SEGMENTATION OF BRAIN METASTASES FOR STEREOTACTIC ABLATIVE RADIOTHERAPY USING BLACK-BLOOD MAGNETIC RESONANCE IMAGING

Abstract PURPOSE/OBJECTIVES Stereotactic ablative radiotherapy (SABR) is becoming popular in the treatment of Brain metastases (BM). However, detection and manual delineation of BM are labor-intense processes, and normal blood vessels are occasionally mistaken for metastatic lesions. In this study, we investigated the efficacy and accuracy of a deep learning (DL) model for the detection and segmentation of BM using black-blood (BB) magnetic resonance imaging (MRI). MATERIALS/METHODS The BB MRI data of 48 patients with 806 BMs were collected to train and validate the DL model. Since MRI data have an inconsistent intensity scale across the patients, we applied piecewise linear histogram matching algorithm, also called the Nyul normalization. To deal with bias corruption in the patient, N4 bias field correction was applied. The modified U-Net was implemented to automatically detect and segment BMs. The detection performance was measured with sensitivity and average false positives and the segmentation performance was measured with the dice score (DSC). RESULTS Twelve patients with 132 BMs were randomly selected as the test-set for evaluating our trained model. In the test-set, 19.2% BMs had a volume of < 0.02 cc, max volume of 16.642 cc, min volume of 0.009 cc, median volume of 0.071 cc, and mean volume of 1.158 cc. The sensitivity was 96.87% and average false positives were 0.2. We consider < 0.02 cc volume as the small volume. 100% sensitivity for BMs with volumes ≥ 0.02 cc, and 84.6% sensitivity for BMs with volumes < 0.02 cc volume. The DSC was 86.27 (range, 77-91.2). CONCLUSIONS Our model can detect and segment BMs on BB MRI data with good detection and segmentation performance. Further study is on a way to generate a synthetic BB image from the T1-Gd image by applying this model.

HSPB1 Regulates Autophagy and Apoptosis in Vascular Smooth Muscle Cells in Arteriosclerosis Obliterans.

Small heat shock protein-1 (HSPB1) is a small heat shock protein that participates in many cellular processes and alleviates stress-induced cell injury. Autophagy protects cells from many types of stress and plays a key role in preventing stress in arteriosclerosis obliterans (ASO). However, the roles of HSPB1 in autophagy and apoptosis in the context of ASO pathogenesis remain unclear. In vivo and in vitro studies were used to determine whether HSPB1 is associated with ASO progression. The expression of HSPB1 was measured in normal and sclerotic blood vessels. The role of HSPB1 and its potential downstream signaling pathway were determined in VSMCs by overexpressing and silencing HSPB1. A total of 91 ASO patients admitted to and treated at our hospital from Sep. 2020 to Sep. 2021 were selected, and plasma HSPB1 expression was assessed. We divided the patients with ASO into the grade I (n = 39), II (n = 29), III (n = 10), and IV (n = 13) groups according to Fontaine's classification. Plasma HSPB1 levels were markedly decreased in patients with grade III (n = 10) and IV (n = 13) ASO compared with patients with grade I ASO. Furthermore, HSPB1 expression was significantly decreased, and p62 and cleaved caspase-3 were increased in the sclerotic vasculature compared to the normal vasculature (p < 0.05). Overexpression of HSPB1 promoted apoptosis of VSMCs following ox-LDL treatment. Knockdown of HSPB1 led to a marked increase in the expression of LC3II and Beclin-1 in ox-LDL-stimulated VSMCs, whereas knockdown of HSPB1 attenuated these changes (p < 0.05). Importantly, overexpression of HSPB1 promoted the dephosphorylation of JNK in ox-LDL-stimulated VSMCs. Conversely, downregulation of HSPB1 induced the opposite change. Loss of HSPB1 promotes VSMC autophagy and inhibits VSMC apoptosis, which are associated with ASO. HSPB1 and its downstream signaling pathways could be potential therapeutic targets for ASO treatment.

Noninvasive Skin Cancer Screening Using Vibrational Optical Coherence Tomography: Differentiation Between Cancerous and Other Lesions Based on Mechanovibrational Testing

Background and objectivesIn this study we use vibrational optical coherence tomography (VOCT) to study the mechanovibrational peak heights exhibited by benign and cancerous skin lesions. When a tissue is vibrated using audible sound it resonates at frequencies that represent the major components. The resonant frequency is related to the elastic modulus through a calibration equation developed in vitro using isolated tissue components. New cancerous skin lesions were identified based on the presence of a new cellular peak (80 Hz) with increased stiffness, a new blood vessel peak (130 Hz) that appears to be less stiff than normal blood vessels (150 Hz), and a fibrous tissue peak (260 Hz) present in carcinomas. The objective of this study was to differentiate different skin cancers using VOCT.

Endostatin induces normalization of blood vessels in colorectal cancer and promotes infiltration of CD8+ T cells to improve anti-PD-L1 immunotherapy

The purpose of this study was to evaluate recombinant human endostatin (rHE)-induced normalization of the tumor vasculature in colorectal cancer (CRC) and to evaluate the therapeutic effects of combined treatment with rHE and a programmed death ligand-1 (PD-L1) inhibitor. A mouse subcutaneous tumorigenesis model was established to evaluate the antitumor effects of endostatin combined with a PD-L1 inhibitor on CRC. Intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DW MRI) was used to evaluate changes in the intratumor microcirculation in response to combined treatment with endostatin and a PD-L1 inhibitor. The infiltration density and function of CD8+ T cells in tumors were evaluated using flow cytometry. Finally, clinical specimens were used to evaluate the expression area of tumor vascular pericytes and CD8+ T cells in tumor tissues. The antitumor effects of endostatin combined with a PD-L1 inhibitor were significantly greater than those of endostatin or a PD-L1 inhibitor alone. On the ninth day of intervention, the endostatin group showed significantly higher pseudo diffusion parameter (D*) and microvascular volume fraction (F) values in tumors than those in the control group or PD-L1 group. After 27 days of intervention, the endostatin groups showed significantly lower levels of vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β than those in the control group. Treatment of CD8+ T cells with endostatin for 24h did not alter the expression levels of markers of reduced T-cell activity. However, endostatin reversed the VEGF-mediated inhibition of the secretion of interferon (IFN)-γ from T cells. The results in CRC clinical samples showed that treatment with endostatin induced significantly higher infiltration of CD8+ T cells compared with treatment that did not include endostatin. Furthermore, the expression area of pericytes was significantly positively related to the infiltration density of CD8+ T cells and overall survival time. Endostatin improved the antitumor effects of PD-L1 inhibitors on CRC, significantly increased the activity of CD8+ T cells, and synergistically improved the tumor treatment effect of the two inhibitors.

Deep Learning-Based Automatic Detection and Segmentation of Brain Metastases for Stereotactic Ablative Radiotherapy Using Black-Blood Magnetic Resonance Imaging

<h3>Purpose/Objective(s)</h3> Brain metastases (BM) are the most common intracranial tumors in adults. Benefiting from efficient local control, stereotactic ablative radiotherapy (SABR) is becoming popular in the treatment of BM. Detection and manual delineation of BM are labor-intense processes, and normal blood vessels, which demonstrate high signal intensity on contrast enhanced magnetic resonance imaging (CE-MRI), are occasionally mistaken for metastatic lesions. Recently, several efforts have been made to develop automatic detection and segmentation for BM using advanced deep learning (DL) algorithms. In this study, we investigated the efficacy and accuracy of a DL model for the detection and segmentation of BM using black-blood (BB) MRI. <h3>Materials/Methods</h3> The BB MRI data of 48 patients with 806 BMs were collected to train and validate the DL model. BMs was contoured by a radiation oncologist. Since MRI data have an inconsistent intensity scale across the patients, we applied piecewise linear histogram matching algorithm, also called the Nyul normalization. To deal with bias corruption in the patient, N4 bias field correction was applied. The modified U-Net was implemented to automatically detect and segment BMs. One of the main strengths of modified U-Net is preserving the edge that occurs during the down-sampling process. The evaluation was conducted in both detection and segmentation. The detection performance was measured with detection sensitivity and average false positives and the segmentation performance was measured with the dice score (DSC). <h3>Results</h3> Twelve patients with 132 BMs were randomly selected as the test-set for evaluating our trained model. In the test-set, 19.2% BMs had a volume of <0.02 cc, max volume of 16.642 cc, min volume of 0.009 cc, median volume of 0.071 cc, and mean volume of 1.158 cc. The detection sensitivity was 96.87% by finding 128 among 132 BMs and average false positives were 0.2. When the results were analyzed, we consider <0.02 cc volume as the small volume. As the results, 100% sensitivity for BMs with volumes ≥0.02 cc, and 84.6% sensitivity for BMs with volumes <0.02 cc volume. The DSC of modified U-Net was 86.27 (range, 77-91.2), which is a significant improvement over DSC of U-Net of 81 (range, 64.71-89.2). Due to the edge preservation characteristics of the modified U-Net, the contour is well segmented along the boundary in the image even for a BM of a very small volume. <h3>Conclusion</h3> In this study, our model can detect and segment BMs on BB MRI data with good detection and segmentation performance, suggesting its considerable benefit for SABR.

"Fingerprinting" Benign and Cancerous Skin Lesions Using Vibrational Optical Coherence Tomography: Differentiation among Cancerous Lesion Types Based on the Presence of New Cells, Blood Vessels, and Fibrosis.

In this study, we use vibrational optical coherence tomography (VOCT) to examine the morphology and stiffness of benign and cancerous lesions. Lesion images and 3D plots of weighted displacement versus frequency and depth were used to compare the cellular, dermal collagen, new blood vessels, and fibrotic composition of normal skin, actinic keratoses (AK), nodular and superficial basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs), and melanomas. The results of this study suggest that benign and cancerous lesions differ based on the addition of new cells with increased resonant frequency and stiffness (80 Hz, 1.8 MPa), new blood vessel peaks (130 Hz, 4.10 MPa) that appear to be less stiff than normal blood vessels, and new fibrous tissue peaks (260 Hz, 15–17 MPa) that are present in carcinomas but not in normal skin and only partially present (80 Hz and 130 Hz only) in AKs. Results obtained by creating images based on the location of the 80 Hz, 130 Hz, and 260 Hz peaks of cancerous skin lesions suggest that the fibrous tissue appears to surround the new cells and new lesion blood vessels. The results of this study suggest that the morphology and location of the fibrous tissues in relation to the new cancer-associated cells and lesion blood vessels may provide information on the invasiveness and metastatic potential of skin cancers. The invasiveness and metastatic potential of melanomas may be a result of the cancer-associated cells laying down fibrous tissue that is used as a pathway for migration. The new cancer-associated blood vessels in the vicinity of the new cancer-associated cells may promote this migration and eventual metastasis. The ratios of peak heights 50/130 Hz and 80/130 Hz of normal cells, new lesion cells, new lesion blood vessels, and fibrotic tissue may be used as a “fingerprint” for detecting melanoma and to differentiate it from other skin cancers non-invasively using VOCT.

Transforming growth factor-β-induced secretion of extracellular vesicles from oral cancer cells evokes endothelial barrier instability via endothelial-mesenchymal transition

BackgroundDuring metastasis, cancer cells undergo epithelial-mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β), which is abundant in the tumor microenvironment, and acquire invasive and metastatic potentials. Metastasis to distant organs requires intravascular invasion and extravasation of cancer cells, which is accompanied by the disruption of the adhesion between vascular endothelial cells. Cancer cell-derived extracellular vesicles (EVs) have been suggested to induce the destabilization of normal blood vessels at the metastatic sites. However, the roles of EVs secreted from cancer cells that have undergone EMT in the destabilization of blood vessels remain to be elucidated. In the present study, we characterized EVs secreted by oral cancer cells undergoing TGF-β-induced EMT and elucidated their effects on the characteristics of vascular endothelial cells.MethodsInduction of EMT by TGF-β in human oral cancer cells was assessed using quantitative RT-PCR (qRT-PCR) and immunocytochemistry. Oral cancer cell-derived EVs were isolated from the conditioned media of oral cancer cells that were treated with or without TGF-β using ultracentrifugation, and characterized using nanoparticle tracking analysis and immunoblotting. The effects of EVs on human umbilical artery endothelial cells were examined by qRT-PCR, cellular staining, and permeability assay. The significant differences between means were determined using a t-test or one-way analysis of variance with Tukey’s multiple comparisons test.ResultsOral cancer cells underwent EMT in response to TGF-β as revealed by changes in the expression of epithelial and mesenchymal cell markers at both the RNA and protein levels. Oral cancer cells treated with TGF-β showed increased EV production and altered EV composition when compared with untreated cells. The EVs that originated from cells that underwent EMT by TGF-β induced endothelial-mesenchymal transition, which was characterized by the decreased and increased expression of endothelial and mesenchymal cell markers, respectively. EVs derived from oral cancer cells also induced intercellular gap formation which led to the loss of endothelial cell barrier stability.ConclusionsEVs released from oral cancer cells that underwent TGF-β-induced EMT target endothelial cells to induce vascular destabilization. Detailed characterization of oral cancer-derived EVs and factors responsible for EV-mediated vascular instability will lead to the development of agents targeting metastasis.

Immunomodulatory effects of regorafenib: Enhancing the efficacy of anti-PD-1/PD-L1 therapy.

Anti-PD-1/PD-L1 therapy has shown significant benefits in the treatment of a variety of malignancies. However, not all cancer patients can benefit from this strategy due to drug resistance. Therefore, there is an urgent need for methods that can effectively improve the efficacy of anti-PD-1/PD-L1 therapy. Combining anti-PD-1/PD-L1 therapy with regorafenib has been demonstrated as an effective method to enhance its therapeutic effect in several clinical studies. In this review, we describe common mechanisms of resistance to anti-PD-1/PD-L1 therapy, including lack of tumor immunogenicity, T cell dysfunction, and abnormal expression of PD-L1. Then, we illustrate the role of regorafenib in modifying the tumor microenvironment (TME) from multiple aspects, which is different from other tyrosine kinase inhibitors. Regorafenib not only has immunomodulatory effects on various immune cells, but can also regulate PD-L1 and MHC-I on tumor cells and promote normalization of abnormal blood vessels. Therefore, studies on the synergetic mechanism of the combination therapy may usher in a new era for cancer treatment and help us identify the most appropriate individuals for more precise treatment.

Specular Reflection Suppression through the Adjustment of Linear Polarization for Tumor Diagnosis Using Fluorescein Sodium.

In tumor surgery, the edges of the tumor can be visually observed using a fluorescent contrast agent and a fluorescent imaging device. By distinguishing it from normal tissues and blood vessels, it is possible to objectively judge the extent of resection while visually observing it during surgery, and it guarantees safe tumor resection based on more information. However, the main problem of such an imaging device is the specular reflection phenomenon. If specular reflection overlaps with important lesion locations, they are a major factor leading to diagnostic errors. Here, we propose a method to reduce specular reflection that occurs during tumor diagnosis using a linear polarization filter and fluorescent contrast agent. To confirm the effect of removing specular reflection, a self-made fluorescein sodium vial phantom was used, and the reliability of the results was increased using a large animal (pig) test. As a result of the experiment, it was possible to obtain an image in which specular reflection was removed by controlling the rotation angle of the filter by 90° and 270°, and the same results were confirmed in the phantom experiment and the animal experiment.

7-Difluoromethyl-5,4’-dimethoxygenistein inhibited the angiogenesis induced by cervical cancer SiHa cells via inhibiting TLR4/VEGF-A axis (217)

<b>Objectives:</b> VEGF inhibitors, such as bevacizumab, inhibit angiogenesis and improve the prognosis of patients with recurrent or metastatic cervical cancer. Antiangiogenic drugs reduce the formation of immature and poorly functional blood vessels and induce the normalization of blood vessels. However, in many cases, features of the vascular normalization brought by VEGF inhibitors are quickly replaced by marked vascular regression, which in turn will exacerbate the degree of hypoxia in the tumor microenvironment. In addition, a variety of adverse effects of antiangiogenic drugs have also been found at present. Therefore, it is a very attractive work to extract natural molecules that are non-toxic or low in toxicity from plants as antiangiogenic drugs. 7-Difluoromethyl-5,4'-dimethoxygenistein (DFMG) is a new chemical entity synthesized from the genistein extracted from the natural plant fruit soybean by ourselves. Previously, DFMG has been found to maintain plaque stability in atherosclerosis through antiangiogenesis. This study explored the effect of DFMG on angiogenesis in cervical cancer and its possible mechanism. <b>Methods:</b> Cell proliferation was detected by the CCK-8 experiment. The expressions of TLR4 and VEGF-A were detected by Q-PCR and Western blot. Angiogenesis was detected by tubule formation test and chorioallantoic membrane (CAM) test. TLR4 was overexpressed and silenced on SiHa cells to detect its effect on VEGF-A secretion and angiogenesis. The effects of DFMG on VEGF-A secretion and angiogenesis were detected on TLR4-overexpressed or -silenced SiHa cells. <b>Results:</b> 1) 50 μM DFMG can inhibit the activity of Siha cells, but not HUVE-12 cells. 2) DFMG inhibits the formation of tubules induced by Siha cells, while bevacizumab can inhibit the ability of HUVE-12 cells to form tubules, but DFMG and genistein have no effect on it. 3) DFMG inhibits the expression and secretion of VEGF-A protein in Siha cells. 4) Overexpression of TLR4 in Siha cells can antagonize the angiogenesis-inhibiting effect caused by bevacizumab, and the silent expression of TLR4 can antagonize the angiogenesis-promoting effect caused by VEGF-A. 5) The numbers of tubules in the tubule formation experiment and new blood vessels in CAM in the DFMG-treated Siha cells with TLR4 overexpression was significantly higher than that in the DFMG-treated Siha cells with TLR4 silence. 6) The overexpression of TLR4 could antagonize the effect of DFMG on the secretion and expression of VEGF-A in SiHa cells, while the silent expression of TLR4 could cooperate with DFMG to inhibit the secretion and expression of VEGF-A.Fig. 1 <b>Conclusions:</b> DFMG inhibits the angiogenesis induced by cervical cancer Siha cells which could be regulated by TLR4/VEGF-A signaling pathway. DFMG reduces angiogenesis by inhibiting VEGF-A secretion of SiHa cells, which is not observed in normal cells.

A Small-Molecule Based Organic Nanoparticle for Photothermal Therapy and Near-Infrared-IIb Imaging.

Near-infrared window IIb (NIR-IIb, 1500-1700 nm) fluorescence imaging demonstrates attractive properties including low scattering, low absorption, and deep tissue penetration, and photothermal therapy (PTT) is also a promising modality for cancer treatment. However, until now, there is no report on theranostic systems based on small organic molecules combining fluorescence imaging in the NIR-IIb and PTT, highlighting the challenge and strong need for development of such agents. Herein, we report a novel small molecule NIR-IIb dye IT-TQF with a D-A-D structure, which exhibited high fluorescence intensity in the NIR-IIb window. To further translate IT-TQF into an effective theranostic agent, IT-TQF was encapsulated into DSPE-PEG2000 to construct IT-TQF NPs. The physical and photochemical properties of the nanoprobe were investigated in vitro, and the in vivo NIR-IIb imaging and PTT performance were evaluated in normal, subcutaneous, orthotopic, and metastatic tumor mice models. IT-TQF NP-based NIR-IIb imaging demonstrated high spatial resolution and high tissue penetration depth, and small normal blood vessels (55.3 μm) were successfully imaged in the NIR-IIb window. Subcutaneous, orthotopic, and metastatic tumors were all clearly delineated. A high tumor signal-to-background ratio (SBR) of 9.42 was achieved for orthotopic osteosarcoma models, and the erosions of bone tissue caused by tumor cells were precisely visualized. Moreover, NIR-II image-guided surgery was successfully performed to completely remove the orthotopic tumor. Importantly, IT-TQF NPs displayed high PTT efficacy (photothermal conversion efficiency: 47%) for effective treatment of tumor mice. In conclusion, IT-TQF NPs are a novel and promising phototheranostic agent in the NIR-IIb window, and the nanoprobe has high potential for a broad range of biomedical applications.

Acute progressive large-area cerebral infarction caused by wasp sting: a case report

ABSTRACT Acute renal failure, multiple organ failure, and allergic reactions caused by wasp sting have been reported in many clinical reports, however, there are few reports on cerebral infarction due to wasp sting. We report a patient who developed acute progressive cerebral infarction after wasp stings, suffered from left-sided hemiplegia, clumsy speech, and left facial droop, only left the MRC grade 2 power and left conjugate gaze palsy after treatment. The MRA showed normal blood vessels. And the wasp sting was detected in head and right shoulder. We explored the mechanism by which the bee venom induced vasospasm and stimulated the superior cervical sympathetic ganglion leading to cerebral infarction. The treatment strategy is presented to provide experience for other clinicians.

Recent Patents on Vascular Stent Material and Its Preparation

Background: A vascular stent is a kind of internal stent implanted in the lesion segment when the vessel is stenosis or pathologically expanded, but there will be stenosis complications in the long-term after stent implanta-tion. Therefore, the ideal vascular stent material should have good tissue and blood compatibility, which is the key to controlling the stent in the occurrence of stenosis. Besides, it has good biodegrada-bility, non-toxicity and good mechanical properties. It should be smooth and flexible enough, and the stent should have good compliance when implanted in human body. It should also have biological properties and physiological characteristics that are close to normal blood vessels to ensure that cells can be well attached and grown to avoid any adverse immune exclusion or post-metabolism. The re-sulting undesirable products should finally ensure that the materials are widely available and inexpen-sive, and can be produced on a large scale to meet different clinical needs. Objective: In order to solve the long-term complications of stenosis after vascular stent placement, the vascular stent material and its preparation have been continuously optimized and improved. Methods: A review of various representative patents and papers on vascular stent materials and their p-reparation at home and abroad are reviewed. Results: A review of various representative patents and papers on vascular stent materials and their p-reparation at home and abroad are reviewed. Results: By summarizing a large number of vascular stent materials and their preparation patents and papers, the preparation methods of vascular stents, the optimization of preparation methods, the performance of vascular stents, and the development trend of vascular stent materials and their preparation a-re discussed. Conclusion: The preparation method of the vascular stent material and the optimization of the structure are bene-ficial to improving the performance of the vascular stent material. More related patents and p-apers will appear in the future.

Research on injection flow velocity planning method for embolic agent injection system

Interventional embolization therapy is widely used for procedures such as targeted tumour therapy, anti-organ hyperactivity and haemostasis. During embolic agent injection, doctors need to work under X-ray irradiation environment. Moreover, embolic agent injection is largely dependent on doctors' experience and feelings, and over-injection of embolic agent can lead to reflux, causing ectopic embolism and serious complications. As an effective way to reduce radiation exposure and improve the success rate of interventional embolization therapy, embolic agent injection robot is highly anticipated, but how to decide the injection flow velocity of embolic agent is a problem that remains to be solved. On the basis of fluid dynamics simulation and experiment, we established an arterial pressure-injection flow velocity boundary curve model that can avoid reflux, which provides a design basis for the control of embolic agent injection system. An in vitro experimental platform for injection system was built and validation experiments were conducted. The results showed that the embolic agent injection flow speed curve designed under the guidance of the critical flow speed curve model of reflux could effectively avoid the embolic agent reflux and shorten the embolic agent injection time. Exceeding the flow speed limit of the model would lead to the risk of embolization of normal blood vessels. This paper confirms the validity of designing the embolic agent injection flow speed based on the critical flow speed curve model of reflux, which can achieve rapid injection of embolic agent while avoiding reflux, and provide a basis for the design of the embolic agent injection robot.

Abstract 5970: Tumor vessel normalization by a novel anti-TIE2 antibody PMC-403 enhances the effectiveness of radiation therapy on cancer therapy

Abstract Purpose: The delivery of drugs and immune cells into the tumor microenvironment is limited due to abnormal tumor vessel which is characterized as low oxygen concentration, low perfusion rate and leakage. It leads to diminish the efficacy radiation therapy. Traditional anti-angiogenesis strategies attempt to reduce the tumor vascular supply, but their success is restricted by insufficient efficacy or development of resistance. To solve the problem, we try to using PMC-403, which can normalize the abnormal condition of tumor vessel. Experimental procedures: Target selectivity: It was measured by Surface Plasmon Resonance (SPR) assay. Human TIE2 Cho-K1 cells or mouse TIE2 Cho-K1 cells were tested for species cross-reactive assay based on flow cytometry (FACS).In vitro studies: Human umbilical vein endothelial cells (HUVEC) were used for TIE2 signal pathway analysis with western blot assay and efficacy analysis with VEGF-induced vessel permeability assay.In vivo study: Glioblastoma model mice were employed for the assessment of tumor vessel normalizing activity of 1 mg/mouse PMC-403. CT26 colon cancer model mice were used to evaluate the anti-tumor efficacy of PMC403 (10 mg/kg) in combination with radiation therapy. Hypoxyprobe was used to measure the improvement of hypoxic conditions in tumor tissue. Summary of data: PMC-403 has a nanomolar range of affinity for both human or mouse TIE2 expressing cells. This contributed to dose-dependent ANG1-like TIE2 and FOXO1 phosphorylation and inhibited VEGF-induced vascular leakage, thereby contributing to ANG1-like vascular normalization. Moreover, similar to ANG-1, p-VEGFR2 and p-VE-Cadherin levels were significantly reduced by PMC-403, suggesting that PMC-403 can normalize blood vessels. In addition, PMC-403 stabilized abnormal tumor blood vessels in the glioblastoma mouse model and significantly reduced tumor growth and tumor hypoxia in the combination treatment (PMC-403 + radiation therapy) compared to radiation therapy alone, although the antitumor effect of PMC-403 alone was not effective in the same condition model. Conclusions: PMC-403, an anti-TIE2 monoclonal antibody, is a novel tumor vessel stabilizer. PMC-403 improved tumor microenvironment hypoxic condition that synergized with radiotherapy when it combined together for the anticancer therapy. These data strongly support the notion that PMC-403 can effectively treat tumors even with low doses of radiation by stabilizing tumor blood vessels. Citation Format: Eun-Ah Lee, Beom Yong Park, Nuri Kang, Cheon Ho Park, Weon Sup Lee. Tumor vessel normalization by a novel anti-TIE2 antibody PMC-403 enhances the effectiveness of radiation therapy on cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5970.

Promoting Angiogenesis Effect and Molecular Mechanism of Isopropyl Caffeate (KYZ), a Novel Metabolism-Derived Candidate Drug, Based on Integrated Network Pharmacology and Transgenic Zebrafish Models.

Aim of the study: Ischemic diseases have a huge impact on people’s health, which can cause blood supply blockage or restriction in specific tissues. Researchers must develop novel drugs with great efficacy and low toxicity for the prevention and treatment of such diseases. Isopropyl caffeic acid (KYZ) was one of the metabolites of caffeic acid in vivo. This study is to explore the protective effect and mechanism of KYZ on ischemic disease from the perspective of angiogenesis in vivo and in vitro, providing support for the treatment of ischemic diseases and the discovery of a new candidate drug. Methods: The network pharmacology and molecular docking were used to predict the targets of KYZ. In addition, the effects of KYZ on damaged and normal blood vessels were evaluated using the Tg (fli1: EGFP) transgenic zebrafish. The HUVECs model was used to study the effects of KYZ on proliferation, migration, and tube formation. The same dosage of caffeic acid (CA) was also administered in vitro and in vivo at the same time to assess the pharmacodynamic difference between the two compounds. Western Blot and ELISA methods were used to detect the expression of related target proteins. Results: The result from the network pharmacology indicated that the targets of KYZ were related to angiogenesis. It was also found that KYZ could repair the vascular damage induced by the PTK787 and promote the growth of subintestinal vessels in normal zebrafish. The result also indicated that KYZ’s angiogenic ability is better than the precursor compound CA. In HUVECs, KYZ could promote cell proliferation, migration, and tube formation. Further mechanistic study suggested that the KYZ could induce the release of VEGF factor in HUVECs, up-regulate the expression of VEGFR2, and activate the PI3K/AKT and MEK/ERK signaling pathways. Conclusions: These data show that KYZ may promote angiogenesis through VEGF, PI3K/AKT, and MEK/ERK signaling pathways, suggesting that KYZ exhibited great potential in the treatment of ischemic cardio-cerebrovascular diseases.