Neoadjuvant targeted immunotherapy followed by surgical resection versus upfront surgery for hepatocellular carcinoma with macrovascular invasion: A multicenter study.

Background: This study aimed to investigate the safety and efficacy of preoperative targeted immunotherapy followed by surgical resection for hepatocellular carcinoma (HCC) patients with macrovascular invasion. Method: Clinical information of HCC patients with macrovascular invasion was collected from four medical centers. These patients were divided into two cohorts: the upfront surgery group (n=40) and the neoadjuvant group (n=22). Comparisons between the two groups were made with appropriate statistical methods. Results: HCC Patients with macrovascular invasion in the neoadjuvant group were associated with increased incidence of postoperative ascites (72.73% vs. 37.5%, P=0.008), but shorter postoperative hospital stay (10 days vs. 14 days, P=0.032). Furthermore, targeted immunotherapy followed by surgical resection significantly reduced the postoperative recurrence rate at both 3 months and 1 year (9% versus 28.9%, 32.1% versus 67.9%, respectively; P=0.018), but increased the postoperative nononcologic mortality rate within 1 year (20.1% vs. 2.8%; P= 0.036). Conclusion: For HCC patients with macrovascular invasion, preoperative targeted immunotherapy significantly decreased the postoperative tumor recurrence rate while maintaining relative safety, but such a treatment may also result in chronic liver damage and increased risk of nononcologic mortality.

Efficacy and safety of robotic versus laparoscopic liver resection for hepatocellular carcinoma: a propensity score-matched retrospective cohort study.

BACKGROUND: Evidence concerning long-term outcome of robotic liver resection (RLR) and laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) patients is scarce. METHODS: This study enrolled all patients who underwent RLR and LLR for resectable HCC between July 2016 and July 2021. Propensity score matching (PSM) was employed to create a 1:3 match between the RLR and LLR groups. A comprehensive collection and analysis of patient data regarding efficacy and safety have been conducted, along with the evaluation of the learning curve for RLR. RESULTS: Following PSM, a total of 341 patients were included, with 97 in the RLR group and 244 in the LLR group. RLR group demonstrated a significantly longer operative time (median [IQR], 210 [152.0-298.0] min vs. 183.5 [132.3-263.5] min; p = 0.04), with no significant differences in other perioperative and short-term postoperative outcomes. Overall survival (OS) was similar between the two groups (p = 0.43), but RLR group exhibited improved recurrence-free survival (RFS) (median of 65 months vs. 56 months, p = 0.006). The estimated 5-year OS for RLR and LLR were 74.8% (95% CI: 65.4-85.6%) and 80.7% (95% CI: 74.0-88.1%), respectively. The estimated 5-year RFS for RLR and LLR were 58.6% (95% CI: 48.6-70.6%) and 38.3% (95% CI: 26.4-55.9%), respectively. In the multivariate Cox regression analysis, RLR (HR: 0.586, 95% CI (0.393-0.874), p = 0.008) emerged as an independent predictor of reducing recurrence rates and enhanced RFS. The operative learning curve indicates that approximately after the 11th case, the learning curve of RLR stabilized and entered a proficient phase. CONCLUSIONS: OS was comparable between RLR and LLR, and while RFS was improved in the RLR group. RLR demonstrates oncological effectiveness and safety for resectable HCC.

Case Report: Long-term survival of a patient with advanced rectal cancer and multiple pelvic recurrences after seven surgeries.

Background: Rectal cancer has a high risk of recurrence and metastasis, with median survival ranging from 24 months to 36 months. K-RAS mutation is a predictor of poor prognosis in rectal cancer. Advanced rectal cancer can be stopped in its tracks by pelvic exenteration. Case summary: A 51-year-old woman was diagnosed with advanced rectal cancer (pT4bN2aM1b, stage IV) with the KRAS G12D mutation due to a change in bowel habits. The patient had experienced repeated recurrences of rectal cancer after initial radical resection, and the tumor had invaded the ovaries, sacrum, bladder, vagina and anus. Since the onset of the disease, the patient had undergone a total of seven surgeries and long-term FOLFIRI- or XELOX-based chemotherapy regimens, with the targeted agents bevacizumab and regorafenib. Fortunately, the patient was able to achieve intraoperative R0 resection in almost all surgical procedures and achieve tumor-free survival after pelvic exenteration. The patient has been alive for 86 months since her diagnosis. Conclusions: Patients with advanced rectal cancer can achieve long-term survival through active multidisciplinary management and R0 surgery.

Multifunctional theragnostic ultrasmall gold nanodot-encapsuled perfluorocarbon nanodroplets for laser-focused ultrasound sequence irradiation (LFSI)-based enhanced tumor ablation.

Despite the substantial potential of focused ultrasound therapy, its efficacy in cancer therapy has been limited due to the high cavitation threshold and safety concerns regarding the use of high-intensity energy pulses. Here, ultrasmall Au nanodot-loaded PEG-modified perfluorocarbon nanodroplets (Au-PFCnDs) were prepared and used as a therapeutic enhancer. A LFSI method was designed to achieve enhanced tumor ablation at a mild focused ultrasound (FUS) energy pulse with the assistance of the instinct photothermal effect of intratumor-permeable ultrasmall Au nanodots under 808 nm NIR laser irradiation. In addition to their therapeutic function, Au-PFCnDs can also generate multimodal images to provide information for tumor surveillance and treatment guidance. The experimental results also showed that the cRGD-targeted Au-PFCnDs could be more efficiently delivered into the tumor and selectively destroy tumors with no observable side effects on normal tissue under LFSI treatment.

A Preliminary Study of miR-144 Inhibiting the Stemness of Colon Cancer Stem Cells by Targeting Krüppel-Like Factor 4.

Colon cancer is a prevalent clinical malignant tumor of the digestive system. The current study aims to explore the miR-144 expression in colorectal cancer (CRC) cell lines and CRC stem cells (CSCs) and to explore its effect on the stemness of CSCs and the targeted regulation of Krüppel-like factor 4 (KLF4). Use qRT-PCR to detect the expression level of miR-144 in CRC cells SW480, HCT116, and H129 and the healthy colon cell NCM460. The CSCs that were used were cultured in HCT116 cells. Use western blot to explore the expressions of Nanog, SOX2, and OCT4 stemness marker protein. After it was transfected with miR-144 mimics or KLF4 plasmid, use MTT to explore the cell viability of CSCs, use flow cytometry to evaluate apoptosis, and use transwell assay to evaluate the ability of invasive of CSCs. The targeting effect of miR-144 on the KLF4 gene was verified using TargetScan prediction and the double-luciferase reporter gene test. Use qRT-PCR to evaluate the role of miR-144 mimics on KLF4 mRNA expression in CSCs. The qRT-PCR results exhibited that the miR-144 expression in CRC cells was higher than that in the healthy colon cell line. The expressions of OCT4, Nanog, and SOX2 stem cell markers were up-regulated in CSCs, and the expression of miR144 increased in CSCs. The cell viability, apoptosis, and invasion of CSCs increased after miR-144 was transfected. The TargetScan prediction and double-luciferase reporter gene assay confirmed that miR-144 was targeted by KLF4, and the expression of KLF4 mRNA in the miR-144 mimics group reduced. Moreover, the overexpression of KLF4 could partially reverse the role of miR-144 mimics on CSCs. In summary, miR-144 was highly expressed in CRC cell lines and CSCs, and the overexpression of miR-144 in CSCs significantly promoted the proliferation of CSCs, inhibited its apoptosis, and promoted its invasion ability. In addition, its preliminary mechanism, possibly through negative regulation KLF4, promotes the stemness of CSCs, and miR-144 is likely to be a potential target for eliminating CSC from CRC treatment.

Yb3+ doped gain guided index anti-guided fiber based on the nanoporous silica glass rod.

We report a heavily Yb3+/Al3+/B3+/F- co-doped high silica rod with a negative refractive index relative to pure silica. The high silica rod was fabricated from nanoporous silica rod using glass phase-separation technology. To lower the refractive index, B3+ and F- were simultaneously introduced into the silica rod and the optical properties of the silica rod were investigated. The fiber preform was prepared with the rod-in-tube method by which the Yb3+ doped high silica rod was only used as an active core. The fiber has a core diameter of 80 µm and a cladding diameter of 400 µm. The measurements show that the Yb3+ in the high silica fiber core is 15856 ppm by weight, while the refractive index is 0.0024 lower than that of the inner cladding. The amplification performance of the fiber was investigated. The results indicate that nanoporous silica glass based on the glass phase-separation technology has great potential for gain-guided index anti-guided high silica fiber.

High coupling efficiency technology of large core hollow-core fiber with single mode fiber.

With the research of hollow-core fiber with large core diameter, the coupling efficiency from hollow-core fiber with large core diameter to single-mode fiber is difficult to increase through the traditional technology, we proposed a novel coupling method to improve the coupling efficiency by attaching a pure silica small ball at the front end of single-mode fiber, the coupling efficiency of 50% from hollow-core fiber with a large core diameter of 110 µm to single-mode fiber can be achieved.

Temperature-Insensitive Refractive Index Sensor with Etched Microstructure Fiber.

A Mach-Zehnder interferometer (MZI) based on an etched all-solid microstructure fiber (MOF) has been demonstrated. The MZI works on the basis of interference between the vibrant core and cladding modes in the MOF. The all-solid MOF has a heterostructure cladding composed of Ge-doped rod arrays and pure silica, and thus can support and propagate a vibrant cladding mode with a large mode area. When the outermost cladding of MOF is etched, the cladding mode becomes sensitive to the ambient refractive index (RI). The etched MOF can work as a sensing head for RI sensing. By comparing the interference spectra, the extinction ratio has remained stable at around 20 dB after the MOF was etched. The RI sensing characteristics of the MZI with an etched MOF have also been investigated. The results show that the RI sensitivity can reach up to 2183.6 nm/RIU with a low-temperature coefficient (<10 pm/°C).

Double negative curvature anti-resonance hollow core fiber.

We report on a double negative curvature anti-resonance hollow core fiber, in which, the cladding is constituted of 6 large tubes and 6 small tubes arranged in a staggered pattern. The simulation shows that the loss of the fiber can reach or even exceed the loss of double-clad negative curvature anti-resonance hollow core fibers in short wavelength band, due to the staggered arrangement of two kind of tubes and the double negative curvature on the core boundary. The best single mode performance with a loss ratio as high as 100,000 between LP11 mode and LP01 mode is obtained due to simultaneously inhibited LP11 modes and LP21 modes in the fiber structure. The reason for loss oscillations in long wavelength band and the fabrication feasibility of proposed fiber are also discussed.

Towards more accurate bioimaging of drug nanocarriers: turning aggregation-caused quenching into a useful tool.

One of the current challenges in the monitoring of drug nanocarriers lies in the difficulties in discriminating the carrier-bound signals from the bulk signals of probes. Environment-responsive probes that enable signal switching are making steps towards a solution to this problem. Aggregation-caused quenching (ACQ), a phenomenon generally regarded as unfavorable in bioimaging, has turned out to be a promising characteristic for achieving environment-responsiveness and eliminating free-probe interference. So-called ACQ probes emit fluorescence when dispersed molecularly within the carrier matrix but quench immediately and absolutely once they are released into the ambient aqueous environment upon the degradation of the nanocarriers. Therefore, the fluorescence observed represents integral nanocarriers. Based on this rationale, the in vivo fates of various nanocarriers have been explored using live imaging equipment, with very interesting findings revealing the role of the particles. The current applications are however restricted to nanocarriers with highly hydrophobic matrices (lipid or polyester nanoparticles) or with a hydrophobic core-hydrophilic shell structure (micelles). The ACQ-based bioimaging strategy is emerging as a promising tool to achieve more accurate bioimaging of drug nanocarriers. This review article provides an overview of the ACQ phenomenon and the rationale for and examples of applications, as well as the limitations of the ACQ-based strategy, with a focus on improving the accuracy of bioimaging of nanoparticles.

Glutathione responsive cubic gel particles cyclodextrin metal-organic frameworks for intracellular drug delivery.

Novel cubic gel particles (ssCGP) with Glutathione (GSH) triggered drug release features were prepared by crosslinking the cyclodextrin based metal-organic frameworks (CD-MOFs) templets with a newly synthesized biodegradable disulfide bond-bearing linker and removing of the potassium ion in sequence. The morphology and size of ssCGP were investigated by field emission scanning electron microscope (FESEM) and dynamic light scattering. Energy dispersive x-ray spectroscopy (EDX), fourier transform infrared spectroscopy (FT-IR), powder x-ray diffraction (PXRD) and Brunauer-Emmett-Teller (BET) were employed to characterize the structure of ssCGP. ssCGP have regular hexahedron shape with edge length about 200-400 nm. Excellent ability of drug adsorption was achieved by using doxorubicin (DOX) as a model drug. The GSH triggered drug release of ssCGP was observed both in GSH contained solutions and intracellular environments. ssCGP have been demonstrated as a biocompatible porous nanocarrier, particular for intracellular drug delivery.

ATP Aptamer-Modified Quantum Dots with Reduced Glutathione/Adenosine Triphosphate Dual Response Features as a Potential Probe for Intracellular Drug Delivery Monitoring of Vesicular Nanocarriers.

Nanoparticles have great promise in drug delivery, but their functional mechanisms are very complicated. Monitoring the payloads or carriers by conventional labeling strategies may result in an inaccurate perception of the effectiveness of nano drug delivery systems (NDDSs). A GSH/ATP dual-responsive fluorescence enhancement probe was developed by manipulating the electron transfer pathways of surface-modified quantum dots (QDs). Because the intracellular concentrations of GSH and ATP are one hundred times greater than those in the extracellular environment, the intracellular drug release process could be observed by the fluorescence signal of this probe after it is loaded into NDDSs as drug simulants. As a proof-of-concept investigation, the intracellular drug release behaviors of classical liposomes were studied by loading this probe, and the observed results strongly support the known drug delivery mechanism of these systems. Although more studies are needed to investigate the in vivo performance of the probe, this study may encourage further investigations of other intracellular environment-responsive smart probes for deciphering the in vivo fate of NDDSs.

A Privacy-Preserving Multi-Task Learning Framework for Face Detection, Landmark Localization, Pose Estimation, and Gender Recognition.

Recently, multi-task learning (MTL) has been extensively studied for various face processing tasks, including face detection, landmark localization, pose estimation, and gender recognition. This approach endeavors to train a better model by exploiting the synergy among the related tasks. However, the raw face dataset used for training often contains sensitive and private information, which can be maliciously recovered by carefully analyzing the model and outputs. To address this problem, we propose a novel privacy-preserving multi-task learning approach that utilizes the differential private stochastic gradient descent algorithm to optimize the end-to-end multi-task model and weighs the loss functions of multiple tasks to improve learning efficiency and prediction accuracy. Specifically, calibrated noise is added to the gradient of loss functions to preserve the privacy of the training data during model training. Furthermore, we exploit the homoscedastic uncertainty to balance different learning tasks. The experiments demonstrate that the proposed approach yields differential privacy guarantees without decreasing the accuracy of HyperFace under a desirable privacy budget.

Long-Acting Release Microspheres Containing Novel GLP-1 Analog as an Antidiabetic System.

Glucagon-like peptide 1 (GLP-1) has recently received significant attention as an efficacious way to treat diabetes mellitus. However, the short half-life of the peptide limits its clinical application in diabetes. In our previous study, a novel GLP-1 analog (PGLP-1) with a longer half-life was synthesized and evaluated. Herein, we prepared the PGLP-1-loaded poly(d,l-lactide- co-glycolide) microspheres to achieve long-term effects on blood glucose control. The incorporation of zinc ion into the formulation can effectively decrease the initial burst release, and a uniform drug distribution was obtained, in contrast to native PGLP-1 encapsulated microspheres. We demonstrated that the solubility of the drug encapsulated in microspheres played an important role in in vitro release behavior and drug distribution inside the microspheres. The Zn-PGLP-1 microspheres had a prominent acute glucose reduction effect in the healthy mice. A hypoglycemic effect was observed in the streptozotocin (STZ) induced diabetic mice through a 6-week treatment of Zn-PGLP-1-loaded microspheres. Meanwhile, the administration of Zn-PGLP-1 microspheres led to the ß-cell protection and stimulation of insulin secretion. The novel GLP-1 analog-loaded sustained microspheres may greatly improve patient compliance along with a desirable safety feature.

Design and fabrication of a heterostructured cladding solid-core photonic bandgap fiber for construction of Mach-Zehnder interferometer and high sensitive curvature sensor.

A heterostructured cladding solid-core photonic bandgap fiber (HCSC-PBGF) is designed and fabricated which supports strong core mode and cladding mode transmission in a wide bandgap. An in-line Mach-Zehnder interferometer (MZI) curvature sensor is constructed by splicing single mode fibers at both ends of a HCSC-PBGF. Theoretical analysis of this heterostructured cladding design has been implemented, and the simulation results are consistent with experiment results. Benefiting from the heterostructured cladding design, an enhanced curvature sensing sensitivity of 24.3 nm/m-1 in the range of 0-1.75 m-1 and a high quality interference spectrum with 20 dB fringe visibility are achieved. In order to eliminate the interference of longitudinal strain and transverse torsion on the result of the curvature sensing experiment, we measure the longitudinal strain and transverse torsion sensing properties of HCSC-PBGF, and the results show that the impact is negligible. It is obvious that this high-sensitivity and cost-effective all fiber sensor with a compact structure will have a promising application in fiber sensing.

Yb3+ heavily doped photonic crystal fiber lasers prepared by the glass phase-separation technology.

We report a Yb3+ heavily doped photonic crystal fiber with 30 µm core diameter manufactured for the first time by an alternative technique. Silica core rods with a diameter of 3 mm and a length of 280 mm were prepared by the sodium-borosilicate glass phase-separation technology. The measurements show that the fiber has an Yb3+ concentration of 22810 ppm by weight, and a resultant absorption of approximately 8.5 dB/m at 976 nm. The Yb3+ ions are distributed throughout the fiber core with an excellent homogeneity. The laser performance demonstrates a high slope efficiency of 64.5% for laser emission at 1033.4 nm and a low power threshold of 3 W within a short fiber length of 1 m. This novel approach provides an alternative means of preparing large active silica rods with high doping levels and excellent material homogeneity for large mode area fibers with complex designs.

Positron emission tomography (PET) guided glioblastoma targeting by a fullerene-based nanoplatform with fast renal clearance.

Various carbonaceous nanomaterials, including fullerene, carbon nanotube, graphene, and carbon dots, have attracted increasing attention during past decades for their potential applications in biological imaging and therapy. In this study, we have developed a fullerene-based tumor-targeted positron emission tomography (PET) imaging probe. Water-soluble functionalized C60 conjugates were radio-labeled with 64Cu and modified with cyclo (Arg-Gly-Asp) peptides (cRGD) for targeting of integrin αvß3 in glioblastoma. The specificity of fluorescein-labeled C60 conjugates against cellular integrin αvß3 was evaluated in U87MG (integrin αvß3 positive) and MCF-7 cells (integrin αvß3 negative) by confocal fluorescence microscopy and flow cytometry. Our results indicated that cRGD-conjugated C60 derivatives showed better cellular internalization compared with C60 derivatives without the cRGD attachment. Moreover, an interesting finding on intra-nuclei transportation of cRGD-conjugated C60 derivatives was observed in U87MG cells. In vivo serial PET studies showed preferential accumulation of cRGD-conjugated C60 derivatives at in U87MG tumors. In addition, the pharmacokinetic profiles of these fullerene-based nanoparticles conjugated with cRGD and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) fit well with the three compartment model. The renal clearance of C60-based nanoparticles is remarkably fast, which makes this material very promising for safer cancer theranostic applications. STATEMENT OF SIGNIFICANCE: Safety is one of the major concerns for nanomedicine and nanomaterials with fast clearance profile are highly desirable. Fullerene is a distinct type of zero-dimensional carbon nanomaterial with ultrasmall size, uniform dispersity, and versatile reactivity. Here we have developed a fullerene-based tumor-targeted positron emission tomography imaging probe using water-soluble functionalized C60 conjugates radio-labeled with 64Cu and modified with cyclo (Arg-Gly-Asp) peptides (cRGD) for glioblastoma targeting. The improved tumor targeting property along with fast renal clearance behavior of C60-based nanoparticles makes this material very promising for future safer cancer theranostic applications.

Bioimaging of nanoparticles: the crucial role of discriminating nanoparticles from free probes.

The biological fate of nanocarriers has yet to be fully explored, mainly because of the lack of functional tools like probes to identify integral nanocarriers in the body. Understanding their in vivo fate remains as the bottleneck to the development of nanomedicines. Bioimaging results based on conventional fluorescent or radioactive probes should be judged critically because images merely reflect bulk signals of an admixture of the nanoparticles and free probes. It is crucial to discriminate between nanocarrier-bound and free signals. This review analyzes the state-of-the-art of bioimaging of nanoparticles in vivo and highlights directions for future endeavours.

All fiber M-Z interferometer for high temperature sensing based on a hetero-structured cladding solid-core photonic bandgap fiber.

We proposed and experimentally demonstrated a high temperature fiber sensor using a hetero-structured cladding solid-core photonic bandgap fiber (HCSC-PBGF) for the first time to our knowledge. A hetero-structured cladding solid-core photonic bandgap fiber is designed and fabricated that supports vibrant core mode and cladding mode transmission. Then, an all fiber M-Z interference sensor is constructed by splicing single mode fiber at both ends of HCSC-PBGF without any other micromachining. The transmission characteristics of HCSC-PBGF are analyzed with a full-vector beam propagation method and a full-vector finite element method, and the simulation results are consistent with experiment results. The sensitivity of this fiber sensor is as high as 0.09 nm/°C when operating from room temperature to 1000 °C, and the fringe contrast keeps stable and clear. It is obvious that this all fiber sensor will have great application prospects in fiber sensing with the advantages of a compact structure, high sensitivity, and cost-effectiveness.

Lipids-based nanostructured lipid carriers (NLCs) for improved oral bioavailability of sirolimus.

The main purpose of this study was to improve the oral bioavailability of sirolimus (SRL), a poorly water-soluble immunosuppressant, by encapsulating into lipids-based nanostructured lipid carriers (NLCs). SRL-loaded NLCs (SRL-NLCs) were prepared by a high-pressure homogenization method with glycerol distearates (PRECIROL ATO-5) as the solid lipid, oleic acid as the liquid lipids, and Tween 80 as the emulsifier. The SRL-NLCs prepared under optimum conditions was spherical in shape with a mean particle size of about 108.3 nm and an entrapment efficiency of 99.81%. In vitro release of SRL-NLCs was very slow, about 2.15% at 12 h, while in vitro lipolysis test showed fast digestion of the NLCs within 1 h. Relative oral bioavailability of SRL-NLCs in Beagle dogs was 1.81-folds that of the commercial nanocrystalline sirolimus tablets Rapamune®. In conclusion, the NLCs show potential to improve the oral bioavailability of SRL.