JS-K Combined with a Melanin-Based Theranostic Agent: A Novel Sequential Delivery Strategy to Enhance the Near-Infrared Fluorescence Imaging of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5 year survival rate less than 12%. This malignancy is closely related to the unique tumor microenvironment (TME), which is characterized by a hypovascular and hyperdense extracellular matrix, making it difficult for drugs to permeate the tumor center. Near-infrared fluorescence (NIRF) imaging, which has high sensitivity and resolution, may improve the survival rate of PDAC patients. In this study, we first used JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazine-1-yl] diazene-1-ium-1,2-diolate) to specifically dilate blood vessels within the TME of PDAC patients and subsequently injected IR820-PEG-MNPs (IPM NPs) to diagnose and treat orthotopic PDAC. We found that JS-K promoted the accumulation of IPM NPs in orthotopic Pan02 tumor-bearing mice and was able to increase the tumor signal-to-background ratio (SBR) in the orthotopic PDAC area by 41.5%. In addition, surgical navigation in orthotopic Pan02 tumor-bearing mice and complete tumor resection based on fluorescence imaging were achieved with a detection sensitivity of 81.0%. Moreover, we verified the feasibility of the combination of laparoscopy and photothermal ablation (PTA) for the treatment of PDAC. Finally, we demonstrated that IPM NPs had greater affinity for human PDAC tissues than for normal pancreatic tissues ex vivo, preliminarily highlighting the potential for clinical translation of these NPs. In conclusion, we developed and validated a novel sequential delivery strategy that promotes the accumulation of nanoagents in the tumor area and can be used for the diagnosis and treatment of PDAC.

A rationally designed nuclei-targeting FAPI 04-based molecular probe with enhanced tumor uptake for PET/CT and fluorescence imaging.

PURPOSE: Fibroblast activation protein inhibitor (FAPI) -based probes have been widely studied in the diagnosis of various malignant tumors with positron emission tomography/computed tomography (PET/CT). However, current imaging studies of FAPI-based probes face challenges in rapid clearance rate and potential false-negative results. Furthermore, FAPI has been rarely explored in optical imaging. Considering this, further modifications are imperative to improve the properties of FAPI-based probes to address existing limitations and broaden their application scenarios. In this study, we rationally introduced methylene blue (MB) to FAPIs, thereby imparting nuclei-targeting and fluorescence imaging capabilities to the probes. Furthermore, we evaluated the added value of FAPI-based fluorescence imaging to traditional PET/CT, exploring the potential application of FAPI-based probes in intraoperative fluorescence imaging. METHODS: A new FAPI-based probe, namely NOTA-FAPI-MB, was designed for both PET/CT and fluorescence imaging by conjugation of MB. The targeting efficacy of the probe was evaluated on fibroblast activation protein (FAP)-transfected cell line and human primary cancer-associated fibroblasts (CAFs). Subsequently, PET/CT and fluorescence imaging were conducted on tumor-bearing mice. The tumor detection and boundary delineation were assessed by fluorescence imaging of tissues from hepatocellular carcinoma (HCC) patients. RESULTS: NOTA-FAPI-MB demonstrated exceptional targeting ability towards FAP-transfected cells and CAFs in comparison to NOTA-FAPI. This benefit arises from the cationic methylene blue (MB) affinity for anionic nucleic acids. PET/CT imaging of tumor-bearing mice revealed significantly higher tumor uptake of [18F]F-NOTA-FAPI-MB (standard uptake value of 2.20 ± 0.31) compared to [18F]F-FDG (standard uptake value of 1.66 ± 0.14). In vivo fluorescence imaging indicated prolonged retention at the tumor site, with retention lasting up to 24 h. In addition, the fluorescent probes enabled more precise lesion detection and tumor margin delineation than clinically used indocyanine green (ICG), achieving a 100.0% (6/6) tumor-positive rate for NOTA-FAPI-MB while 33.3% (2/6) for ICG. These findings highlighted the potential of NOTA-FAPI-MB in guiding intraoperative surgical procedures. CONCLUSIONS: The NOTA-FAPI-MB was successfully synthesized, in which FAPI and MB simultaneously contributed to the targeting effect. Notably, the nuclear delivery mechanism of the probes improved intracellular retention time and targeting efficacy, broadening the imaging time window for fluorescence imaging. In vivo PET/CT demonstrated favorable performance of NOTA-FAPI-MB compared to [18F]F-FDG. This study highlights the significance of fluorescence imaging as an adjunct technique to PET/CT. Furthermore, the encouraging results obtained from the imaging of human HCC tissues hold promise for the potential application of NOTA-FAPI-MB in intraoperative fluorescent surgery guidance within clinical settings.

Incidence, risk factors and outcome of postoperative acute kidney injury in China.

BACKGROUND: Postoperative acute kidney injury (AKI) is a common condition after surgery, however, the available data about nationwide epidemiology of postoperative AKI in China from large and high-quality studies are limited. This study aimed to determine the incidence, risk factors and outcomes of postoperative AKI among patients undergoing surgery in China. METHODS: This was a large, multicentre, retrospective study performed in 16 tertiary medical centres in China. Adult patients (≥18 years of age) who underwent surgical procedures from 1 January 2013 to 31 December 2019 were included. Postoperative AKI was defined by the Kidney Disease: Improving Global Outcomes creatinine criteria. The associations of AKI and in-hospital outcomes were investigated using logistic regression models adjusted for potential confounders. RESULTS: Among 520 707 patients included in our study, 25 830 (5.0%) patients developed postoperative AKI. The incidence of postoperative AKI varied by surgery type, which was highest in cardiac (34.6%), urologic (8.7%) and general (4.2%) surgeries. A total of 89.2% of postoperative AKI cases were detected in the first 2 postoperative days. However, only 584 (2.3%) patients with postoperative AKI were diagnosed with AKI on discharge. Risk factors for postoperative AKI included older age, male sex, lower baseline kidney function, pre-surgery hospital stay ≤3 days or >7 days, hypertension, diabetes mellitus and use of proton pump inhibitors or diuretics. The risk of in-hospital death increased with the stage of AKI. In addition, patients with postoperative AKI had longer lengths of hospital stay (12 versus 19 days) and were more likely to require intensive care unit care (13.1% versus 45.0%) and renal replacement therapy (0.4% versus 7.7%). CONCLUSIONS: Postoperative AKI was common across surgery type in China, particularly for patients undergoing cardiac surgery. Implementation and evaluation of an alarm system is important for the battle against postoperative AKI.

Mild photothermal/radiation therapy potentiates ferroptosis effect for ablation of breast cancer via MRI/PA imaging guided all-in-one strategy.

BACKGROUND: Nanotheranostics advances anticancer management by providing therapeutic and diagnostic functions, that combine programmed cell death (PCD) initiation and imaging-guided treatment, thus increasing the efficacy of tumor ablation and efficiently fighting against cancer. However, mild photothermal/radiation therapy with imaging-guided precise mediating PCD in solid tumors, involving processes related to apoptosis and ferroptosis, enhanced the effect of breast cancer inhibition is not fully understood. RESULTS: Herein, targeted peptide conjugated gold nano cages, iRGD-PEG/AuNCs@FePt NPs ternary metallic nanoparticles (Au@FePt NPs) were designed to achieve photoacoustic imaging (PAI)/Magnetic resonance imaging (MRI) guided synergistic therapy. Tumor-targeting Au@FePt forms reactive oxygen species (ROS), initiated by X-ray-induced dynamic therapy (XDT) in collaboration with photothermal therapy (PTT), inducing ferroptosis-augmented apoptosis to realize effective antitumor therapeutics. The relatively high photothermal conversion ability of Au@FePt increases the temperature in the tumor region and hastens Fenton-like processes to achieve enhanced synergistic therapy. Especially, RNA sequencing found Au@FePt inducting the apoptosis pathway in the transcriptome profile. CONCLUSION: Au@FePt combined XDT/PTT therapy activate apoptosis and ferroptosis related proteins in tumors to achieve breast cancer ablation in vitro and in vivo. PAI/MRI images demonstrated Au@FePt has real-time guidance for monitoring synergistic anti-cancer therapy effect. Therefore, we have provided a multifunctional nanotheranostics modality for tumor inhibition and cancer management with high efficacy and limited side effects.

A microenvironment-responsive FePt probes for imaging-guided Fenton-enhanced radiotherapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) continues to be one of the most fatal malignancies with increasing morbidity, and potent therapeutics are urgently required given its insensitivity to traditional treatments. Here, we have developed a microenvironment-responsive FePt probes for the highly efficient Fenton-enhanced radiotherapy (FERT) of HCC. The selective release of Fe2+ in the acidic tumor microenvironment, but not in normal tissue, together with enhanced levels of hydrogen peroxide produced through the Pt radiosensitization effect, facilitates the generation of an enormous amount of hydroxyl radicals through the Fenton reaction, thereby extending the radiotherapeutic cascade and realizing a powerful therapeutic efficacy for HCC. Moreover, the "burst" release of Fe2+ contributes to the T2-to-T1 magnetic resonance imaging (MRI) switching effect, which informs the release of Fe2+, making imaging-guided cancer therapy feasible. This work not only breaks the bottleneck of traditional radiotherapy for HCC while minimally affecting normal tissues, but also provides a new strategy for FERT imaging guidance.

Near-Infrared II Fluorescence Imaging Highlights Tumor Angiogenesis in Hepatocellular Carcinoma with a VEGFR-Targeted Probe.

Hepatocellular carcinoma (HCC) is typically characterized by rich vascularity, with angiogenesis playing a crucial role in its growth and invasion. Molecular imaging of specific receptors in blood vessels is crucial in HCC diagnosis. In particular, in vivo imaging utilizing the second near-infrared (NIR-II) window offers improved tissue penetration, reduced light scattering, and lower autofluorescence. Despite the great potential of the NIR-II window, developing safe and effective probes to provide better imaging performance for HCC is urgently needed. In this study, NIR-II imaging integrated with a vascular endothelial growth factor receptor (VEGFR)-targeted probe generated by combining a VEGFR-targeted peptide with indocyanine green (ICG) is used to characterize HCC-related angiogenesis at a resolution of 56.0 µm. For the first time, liver metabolic curves and parameters of liver function reserve (LFR) are obtained by fitting NIR-II fluorescence signals with high spatiotemporal resolution, showing significant differences between HCC mice and controls. Moreover, unlike ICG, the targeting probe has a targeted effect on blood vessels in vivo. The tumor-to-normal (T/N) ratio in NIR-II imaging reaches up to 3.30 after post-injection of the targeting probe. The results indicate that the VEGFR-targeted probe is a powerful tool for NIR-II fluorescence imaging to enhance early diagnosis of HCC.

The relationship between dietary inflammatory index and metabolic syndrome and its components: a case study in Kashi urban, Xinjiang.

Introduction: This paper examines the association between the dietary inflammatory index (DII) and the risk of metabolic syndrome (MS) and its components among Uygur adults in Kashi, Xinjiang. Methods: The study used the multi-stage random cluster sampling method to investigate the adult residents of Uighu aged over 18 years old in one county and one township/street of three cities in Kashi between May and June 2021. All dietary data collected were analyzed for energy and nutrient intake with a nutritional analysis software, followed by a calculation of DII. Logistic regression was used to estimate the association between DII and the risks of MS and its components. Results: The maximum DII value across our 1,193 respondents was 4.570 to 4.058, with an average value of 0.256. When we analyzed the DII as a continuous variable, we determined the anti-inflammatory diet has been identified as a mitigating factor for metabolic syndrome (OR = 0.586, 95% CI = 0.395-0.870), obesity (OR = 0.594, 95% CI = 0.395-0.870), elevated fasting glucose levels (OR = 0.422, 95% CI = 0.267-0.668), and hypertension (OR = 0.698, 95% CI = 0.488-0.996). When the model was adjusted by sex, age, and occupation, we found a significant correlation between high- and low-density lipoproteinemia and DII (OR = 1.55, 95% CI = 1.040-2.323). The present study identified four distinct dietary patterns among the population under investigation. There was a linear trend in the incidence of MS and hypertension across low, middle, and high levels of fruits and milk dietary pattern model (p = 0.027; p = 0.033), within this dietary pattern may serve as protective factors against MS and hypertension, suggesting that fruits and milk within this dietary pattern may serve as protective factors against MS and hypertension. And the linear trend in the incidence of elevated fasting glucose and obesity across the low, medium, and high scores of meet and eggs dietary pattern (p = 0.006; p < 0.001), suggest that a diet rich in meat may potentially contribute to an increased risk of developing elevated fasting glucose levels and obesity. An observed linear trend in the incidence rate of high fasting blood glucose across low, moderate, and high scores of dried fruits and nuts dietary pattern (p = 0.014), indicating that increased consumption of nuts acted as a protective factor against elevated fasting blood glucose levels and contributed to their reduction. Discussion: The dietary inflammation index was integrated with the findings from the study on the dietary patterns of the sampled population, revealing that an anti-inflammatory diet demonstrated a protective effect against metabolic syndrome, obesity, high fasting blood glucose, and hypertension in this specific population. laying the foundation for further research.

Review and Application of Integrin Alpha v Beta 6 in the Diagnosis and Treatment of Cholangiocarcinoma and Pancreatic Ductal Adenocarcinoma.

Integrin Alpha v Beta 6 is expressed primarily in solid epithelial tumors, such as cholangiocarcinoma, pancreatic cancer, and colorectal cancer. It has been considered a potential and promising molecular marker for the early diagnosis and treatment of cancer. Cholangiocarcinoma and pancreatic ductal adenocarcinoma share genetic, histological, and pathophysiological similarities due to the shared embryonic origin of the bile duct and pancreas. These cancers share numerous clinicopathological characteristics, including growth pattern, poor response to conventional radiotherapy and chemotherapy, and poor prognosis. This review focuses on the role of integrin Alpha v Beta 6 in cancer progression. It addition, it reviews how the marker can be used in molecular imaging and therapeutic targets. We propose further research explorations and questions that need to be addressed. We conclude that integrin Alpha v Beta 6 may serve as a potential biomarker for cancer disease progression and prognosis.

In vivo liver function reserve assessments in alcoholic liver disease by scalable photoacoustic imaging.

We present a rapid and high-resolution photoacoustic imaging method for evaluating the liver function reserve (LFR). To validate its accuracy, we establish alcoholic liver disease (ALD) models and employ dual-wavelength spectral unmixing to assess oxygen metabolism. An empirical mathematical model fits the photoacoustic signals, obtaining liver metabolism curve and LFR parameters. Liver oxygen metabolism significantly drops in ALD with the emergence of abnormal hepatic lobular structure. ICG half-life remarkably extends from 241 to 568 s in ALD. A significant decline in LFR occurs in terminal region compared to central region, indicated by a 106.9 s delay in ICG half-life, likely due to hepatic artery and vein damage causing hypoxia and inadequate nutrition. Reduced glutathione repairs LFR with a 43% improvement by reducing alcohol-induced oxidative damage. Scalable photoacoustic imaging shows immense potential for assessing LFR in alcoholic-related diseases, providing assistance to early detection and management of liver disease.

Small-Molecule Absorber A1094 as a Stable and Fast-Clearing NIR-II Imaging Agent.

Photoacoustic imaging (PAI) in the second near-infrared window (NIR-II) is conducive to deep-tissue imaging due to small scattering coefficients, but often requires exogenous imaging agents. At present, nanoparticle-based NIR-II imaging agents are mainly used in non-clinical studies, some basic components of which are resistant to metabolism in vivo. The aim of this study was to examine the ∼600 Da croconaine absorber A1094, absorbing lights around 1094 nm, as a rare, small-molecule NIR-II imaging agent in vivo. The clinical translational potential of A1094 injection were systematically revealed, including sufficient solubility and freeness in blood, good anti-interference ability, and favourable pH/oxidation-reduction/metabolic stabilities. After intravenous administration of A1094 injection, PAI of murine ears exhibited comparable capillaries visibility to that of PAI with popular Au nanorods. The contrasts achieved with A1094 and Au nanorods were 1.78 and 1.29 times higher than before administration, in the healthy group, and 3.25 and 1.58 times higher in the inflammation group. Notably, A1094 demonstrated a desired faster liver clearance than Au nanorods. The PAI signal of A1094 was cleared by 74.2 % after 3 h, whereas Au nanorods were only cleared by 43.1 %. The main metabolic mechanisms of A1094 were identified as N-methylation and lipid hydrolysis by murine liver microsomes in vitro. Therefore, A1094 may have promising clinical potential as a stable and fast-clearing NIR-II imaging agent.

Minimally invasive photothermal ablation assisted by laparoscopy as an effective preoperative neoadjuvant treatment for orthotopic hepatocellular carcinoma.

Nanoparticle-based photothermal ablation (PTA) has been intensively investigated recently. However, the poor biocompatibility of most PTA agents and potential long-term toxicity obstruct their clinical translation. Meanwhile, previous PTA studies are limited to surface tumors because of insufficient light penetration depth of near-infrared (NIR) light for deep abdominal tumors. Therefore, minimally invasive PTA combined with biocompatible agents may pave a promising way to treat deep orthotopic hepatocellular carcinoma (HCC). Herein, a multifunctional agent based on superparamagnetic iron oxide (SPIO) and new indocyanine green (IR820) was constructed with good biocompatibility. Outstanding fluorescence, photoacoustic and magnetic resonance imaging capabilities were observed in vitro. Additionally, in vivo results indicated that early-stage HCC (diameter less than 2 mm) could be effectively detected by this agent. Furthermore, for the first time, we developed minimally invasive laparoscopic-assisted photothermal ablation (L-A PTA) method coupled with this agent to completely ablate orthotopic HCC in nude mice model, neither recurrences nor obvious side effects were observed during the experiments. Remarkable shrinkage of primary tumor and disappearance of intrahepatic metastasis were also observed. In summary, minimally invasive L-A PTA is an effective preoperative neoadjuvant treatment for HCC.

Biocompatible melanin based theranostic agent for in vivo detection and ablation of orthotopic micro-hepatocellular carcinoma.

Early diagnosis and therapy of hepatocellular carcinoma (HCC) is critical to improve the five-year survival rates of patients. Theranostic agents synergized with photothermal ablation are expected to realize the early detection and treatment of orthotopic HCC. However, conventional metallic nanoagents are limited by their potential bio-toxicity to surrounding normal organs. Recently, endogenous biological melanin pigments have been utilized to develop nanoplatforms due to their excellent biocompatibility and degradability. Whereas, the insufficient capability of PEGylated melanin nanoparticles (PEG-MNPs) in photoacoustic (PA) imaging limits their further biomedical applications. Paradoxically, it is difficult to meet these two different requirements. Herein, a multifunctional nanoagent based on melanin (MNPs) conjugating the near-infrared (NIR) dye IR820 was successfully designed and fabricated. Encapsulation by polyethylene glycol (PEG) renders the solubility in water and allows the physical absorption of IR820 for enhanced photoacoustic (PA) performance and photothermal therapy. Besides, PEG coating on the surface of IR820-PEG-MNPs resulted in a reduction in swallowing in the reticuloendothelial system of the liver and spleen, prolonging the circulation time in the blood and increasing the accumulation in the tumor. The IR820-PEG-MNPs displayed satisfactory PA and T1-weighted magnetic resonance imaging (MRI) signals in aqueous solution as well as strong photothermal efficiency. Compared with prior injection, PA/MR signals of the tumor region were enhanced by 4.13- and 1.60-fold, respectively, which could effectively detect lesions smaller than ∼1.8 mm. Furthermore, the high photothermal conversion efficiency (40.2%) endowed the IR820-PEG-MNPs with the capability of selectively ablating tumors in orthotopic HCC mouse models under the guidance of PA/MR imaging. This work broadens the biomedical applications of melanin-based agent, which are promising for the precise diagnosis of orthotopic micro HCC and imaging guided photothermal ablation.

Contrast-Enhanced Multispectral Photoacoustic Imaging for Irregular Hepatectomy Navigation: A Pilot Study.

Irregular hepatectomy plays a prominent role in the treatment of small hepatocellular carcinoma (HCC) patients with severe cirrhosis and localized liver metastasis. In clinical practices, intraoperative tumor boundaries delineation facilitates to accomplish tumor resection with negative margin, remarkably decreasing the recurrence rates. Currently, ultrasound (US) and ICG fluorescence-guided surgery has been used for intraoperative navigation in irregular hepatectomy, but insufficient specificity results in a limited prevalence. Inspired by the high resolution of photoacoustic (PA) imaging and established clinical efficacy of 18F-Alfatide that is specific for integrin αvß3-overexpressed tumors, we herein developed a fluorescent analogue IR820-E[c(RGDfK)]2, and a proof-of-concept intraoperative multispectral PA imaging navigation for precise irregular hepatectomy using hand-held PA/US imaging system. An integrin αvß3-targeted fluorescent contrast agent IR820-E[c(RGDfK)]2 was designed, synthesized, and characterized. In vitro studies were performed to determine optical and PA properties, affinity and specificity and biocompatibility. Multispectral PA imaging, the optimal imaging time point and contrast, multispectral PA imaging-guided irregular hepatectomy, pharmacokinetics, and safety profile were evaluated in subcutaneous and orthotopic HCC tumor models. Ex vivo macroscopic three-dimensions (3D) PA imaging with IR820-E[c(RGDfK)]2 staining was also performed in surgical biospecimens from patients with HCC. IR820-E[c(RGDfK)]2 has a simple synthetic method at gram scale, high affinity, and specificity for integrin αvß3, excellent pharmacokinetic and safety profile can effectively differentiate tumor from normal liver tissues in animal models and surgical biospecimens from HCC patients. Preoperative tumor localization, intraoperative tumor boundaries delineation, and tumor excision, and postoperative negative margin assessment were successfully achieved during irregular hepatectomy. This initial attempt allows one to preoperatively detect tumor lesions, intraoperatively delineate tumor boundaries and guide tumor resection, and postoperatively evaluate tumor margin status during irregular hepatectomy. IR820-E[c(RGDfK)]2 has the potential to be an investigational new drug for clinical use in multispectral photoacoustic imaging-guided irregular hepatectomy.