Efficient Ablation Research Articles

Abstract 12906: Atypical Atrial Flutter Ablation Utilizing Ultra-High-Density Activation Mapping

Background: The incidence of atypical atrial flutters has increased in recent years, especially in the presence of atrial scar following valvular surgery involving atriotomy, surgical Maze procedures, or prior extensive radiofrequency ablation for persistent atrial fibrillation. Most are poorly tolerated and ablation is indicated. Ablation of these arrhythmias has historically presented a challenge with lower success rates and high recurrence rates. The concurrent advancement of mapping technology and the development of high-density mapping has allowed for more precise representation of the substrate of these complex arrhythmias. Objective: In this series, we report our experience utilizing CARTO3 Coherent mapping and the Confidense module (Biosense Webster, Inc.) in ablating complex left atrial flutters. Methods: Twelve patients with atypical atrial flutters and past history of valve surgery, Maze procedure, or persistent atrial fibrillation ablation were identified. We created ultra-high-density 3D maps using 3,000-6,000 points collected with a multipolar PENTARAY catheter and CARTO3 Coherent mapping. Radiofrequency ablation was performed at the narrowest isthmus using a Thermocool Smarttouch SF ablation catheter. Ambulatory ECG monitoring or CIED interrogation following the 3-month blanking period was utilized to evaluate the effectiveness of therapy. Results: In all cases, we had success in identifying and ablating small conduction gaps resulting in immediate termination of the arrhythmia. These gaps were not perceptible with voltage mapping and would have led to more extensive ablation and longer procedure time utilizing previous processing systems. Rhythm monitoring at least 3-months post-procedure demonstrated 8 of the 12 patients have not had recurrence of the arrhythmia. Conclusion: In our experience, the creation of ultra-high-density 3D mapping utilizing CARTO3 Coherent mapping has allowed for more precise mapping and simplifies the interpretation of arrhythmia mechanisms. Small gaps often responsible for these flutters are now more easily identifiable in comparison to previous mapping systems, facilitating efficient ablation, reducing procedure time, and reducing recurrence rates.

Effects of frequency on bubble-cloud behavior and ablation efficiency in intrinsic threshold histotripsy

Objective. Histotripsy is a non-thermal focused ultrasound ablation method that destroys tissue through the generation of a cavitation bubble cloud. Previous work studying intrinsic threshold histotripsy has shown that dense bubble clouds can be formed by a single-cycle pulse when the negative pressure exceeds an intrinsic threshold of ∼25–30 MPa, with the ablation efficiency dependent upon the size and density of bubbles within the cloud. This work investigates the effects of frequency on bubble-cloud behavior and ablation efficiency in intrinsic threshold histotripsy. Approach. A modular transducer was used to expose agarose tissue phantoms to 500 kHz, 1 MHz, or 3 MHz, histotripsy pulses. Optical imaging was used to measure the bubble-cloud dimensions, bubble density, and bubble size. The effects of frequency on ablation efficiency were also investigated by applying histotripsy to red blood cell (RBC) phantoms. Main results. Results revealed that the bubble-cloud size closely matched theoretical predictions for all frequencies. The bubble density, which is a measure of the number of bubbles per unit area, was shown to increase with increasing frequency while the size of individual bubbles within the cloud decreased at higher frequencies. Finally, RBC phantom experiments showed decreasing ablation efficiency with increasing frequency. Significance. Overall, results demonstrate the effects of frequency on histotripsy bubble-cloud behavior and show that lower frequency generates more efficient tissue ablation, primarily due to enhanced bubble expansion.

Disruption of HIV-1 co-receptors CCR5 and CXCR4 in primary human T cells and hematopoietic stem and progenitor cells using base editing

Disruption of CCR5 or CXCR4, the main human immunodeficiency virus type 1 (HIV-1) co-receptors, has been shown to protect primary human CD4+ Tcells from HIV-1 infection. Base editing can install targeted point mutations in cellular genomes, and can thus efficiently inactivate genes by introducing stop codons or eliminating start codons without double-stranded DNA break formation. Here, we applied base editors for individual and simultaneous disruption of both co-receptors in primary human CD4+ Tcells. Using cytosine base editors we observed premature stop codon introduction in up to 89% of sequenced CCR5 or CXCR4 alleles. Using adenine base editors we eliminated the start codon in CCR5 in up to 95% of primary human CD4+ Tcell and up to 88% of CD34+ hematopoietic stem and progenitor cell targetalleles. Genome-wide specificity analysis revealed low numbers of off-target mutations that were introduced by base editing, located predominantly in intergenic or intronic regions. We show that our editing strategies prevent transduction with CCR5-tropic and CXCR4-tropic viral vectors in up to 79% and 88% of human CD4+ Tcells, respectively. The engineered Tcells maintained functionality and overall our results demonstrate the effectiveness of base-editing strategies for efficient and specific ablation of HIV co-receptors in clinically relevant cell types.

Epicardial course of the musculature related to the great cardiac vein: Anatomical considerations and clinical implications for mitral isthmus block after vein of Marshall ethanol infusion.

Mitral isthmus gaps have been ascribed to an epicardial musculature anatomically related to the great cardiac vein (GCV) and the vein of Marshall (VOM). Their lumen offers an access for radiofrequency application or ethanol infusion, respectively. The purpose of this study was to evaluate the frequency of mitral isthmus gaps accessible via the GCV lumen, to assess their location around the GCV circumference, and to propose an efficient ablation strategy when present. One hundred consecutive patients underwent VOM ethanol infusion (step 1) and endocardial linear ablation from the mitral annulus to the left inferior pulmonary vein (step 2). In cases of mitral isthmus gap, endovascular ablation of the GCV anchored wall facing the left atrium was systematically performed (step 3), while the opposite GCV free wall was targeted in case of block failure only (step 4). After VOM ethanol infusion and endocardial ablation, mitral isthmus block occurred in 51 patients (51%). Pacing maneuvers and activation sequences demonstrated an epicardial gap via the VOM in 2 patients (2%) and via the GCV in 47 patients (47%). In the latter case, block was achieved at the GCV anchored wall in 42 patients (89%) and the GCV free wall in 5 patients (11%). Global success rate of mitral isthmus block was 98%. No tamponade occurred. With the advent of VOM ethanol infusion, residual mitral isthmus gaps are mostly eliminated within the first centimeter of the GCV. Thorough mapping of the entire circumference of the GCV wall can help identify these epicardial gaps.

A benzophenoxazine-dyad as cancer indicator using for fluorescence-guided phototherapy

Clinically, phototherapy is adapted to tumors in semi-enclosed location, such as cervical, head & neck and gastric cancer, using optical fibers to introduce light. Different with general photodynamic therapy, it has special demands of tumor recognition and lower light dose. However, a merge of primary photosensitizer (ALA et.al) and magnetic resonance (or ultrasound) imaging is commonly used in the therapeutic mode, having low efficacy and complicated operation. To realize a fluorescence-guided phototherapy, here we designed a benzophenoxazine-dyad photosensitizer, namely NBS-NBSe, firstly realize a dyad-caused quenching (DCQ) method to regulate the fluorescence of benzophenoxazine as cancer indicator. The DCQ of NBS-NBSe drastically decrease the fluorescence of benzophenothiazine (NBS), while glutathione in cancer can efficiently release the fluorescence (9.3-fold) to guide the optical source in phototherapy. Meanwhile, the high singlet oxygen generation of benzophenoselenzinium (NBSe) provide an efficient photo ablation ability, and the NBS of anti-hypoxia can assist the therapy of hypoxia deep-seated tumors to reduce tumor recurrence. Under the low light dose of 2.4 J/cm2, NBS-NBSe showed excellent therapeutic efficacy toward tumor cells (24-fold than chlorins e6). The fluorescence recognition ability between tumor/normal cells and the powerful phototoxicity ensure the fluorescence-guided therapeutic mode using for these tumors.

Strong Penetration-Induced Effective Photothermal Therapy by Exosome-Mediated Black Phosphorus Quantum Dots.

Nanocancer medicine, such as photothermal therapy (PTT), as a promising way to solve cancer without side effects, faces a huge biological barrier during the circulation of nanoparticles in the body, including nanobiological interactions in the blood, isolation of nanoparticles in the macrophage system, tumor spillover effect, and especially uneven intratumoral distribution of nanoparticles, which cast a shadow over the hope. To address the problem of intratumoral distribution, an effective photothermal agent is introduced by packaging the black phosphorus quantum dots (BPQDs) into exosome vector (EXO) through electroporation method. With the improving and proper stability for better therapy, the resulting BPQDs@EXO nanospheres (BEs) exhibit good biocompatibility, long circulation time, and excellent tumor targeting ability, hence impressive PTT efficiency evidenced by highly efficient tumor ablation in vivo. Importantly, great permeability on organoids contributed by EXO appears with BEs, which strongly promotes the efficient killing ability. These BP-based nanospheres must promise high clinical potential due to the high PTT efficiency and minimal side effects.

Synergistic chemo-photothermal cancer therapy of pH-responsive polymeric nanoparticles loaded IR825 and DTX with charge-reversal property

IR825 is a kind of near-infrared (NIR) small molecule cyanine dye and has distinct near-infrared absorbance and excellent thermal conversion performance. Due to poor stability and insufficient therapy efficacy, various nano-systems have been developed as delivery vehicles for NIR dyes to improve their application in tumor treatment. Herein, we developed an intelligent polymer drug vehicle (Mal-PAH-PEG-DMMA/ poly (ethylene imine) – poly(ε-caprolactone) block polymers, MPPD/PEI-PCL) based on pH-responsive charge-reversal to deliver docetaxel (DTX) and photosensitizer (IR825) for chemo-photothermal combination therapy (MPPD@IR825/DTX NPs). MPPD@IR825/DTX NPs could undergo charge conversion in a slightly acidic microenvironment (pH 6.8), resulted in strong electrostatic repulsion to withdraw the shell of the polymer nanoparticles (MPPD), enhanced cellular uptake and increased drug release. MPPD@IR825/DTX NPs demonstrated nanoscale in size with good mono-dispersity and stability, triggered DTX release in response to acid environment and NIR stimulation, in the same time providing excellent photothermal conversion efficiency. In vitro and In vivo experiments confirmed that charge-reversal polymeric nanoparticles improved antitumor efficiency in 4T1 tumor cell modal than non-charge-reversal polymeric nanoparticles. Furthermore, in comparison with chemotherapy or photothermal therapy in a single treatment mode, chemo-photothermal combination therapy of MPPD@IR825/DTX NPs with laser irradiation showed highly efficient tumor ablation. In addition, the polymeric nanoparticles exhibited good biocompatibility and safety. Therefore, the design of charge-reversal polymeric nanoparticles (MPPD@IR825/DTX NPs) provides a new strategy and promising application for targeting and synergistic chemo-photothermal combination therapy.

Transferrin receptors/magnetic resonance dual-targeted nanoplatform for precise chemo-photodynamic synergistic cancer therapy

Various drug delivery strategies to improve cancer therapeutic efficacy have been actively investigated. One major challenge is to improve the targeting ability. Here elaborately designed nanocarriers (NCs) named as Tf-5-ALA-PTX-NCs are demonstrated to address this problem. In this nanostructure, paclitaxel (PTX) and 5-aminolevulinic acid (5-ALA) were co-encapsulated within magnetic nanocarriers to achieve synergistic chemotherapy and photodynamic therapy, while transferrin (Tf) was conjugated with modified copolymer Pluronic P123 and embedded in the surface of the nanocarriers, which endows nanocarriers with Tf targeting and magnetic targeting to enhance the anti-tumor outcome. Results demonstrated that Tf-5-ALA-PTX-NCs significantly enhanced the targeting drug delivery to MCF-7 cells and synergistically induced apoptosis and death of MCF-7 cells in vitro and highly efficient tumor ablation in vivo. Intriguingly, Tf-5-ALA-PTX-NCs have a controllable “on/off” switch to enhance the drug release. The dual-targeted nanocarriers would be a promising versatile anti-tumor drug delivery and imaging-guided cancer chemo-photodynamic synchronization therapy strategy.

Submicrometer surface structuring with a Bessel beam generated by a reflective axicon

In ultrashort pulse (USP) laser ablation, focus diameters in the range of >20 μm are common for microstructuring, but the demand for much smaller structure sizes is rising, especially in the fields of filter technology, surface functionalization, and electronics. However, strong focusing of a Gaussian beam near the diffraction limit is accompanied by a very limited depth of focus, which leads to an extreme increase in process sensitivity. It is often too challenging to meet the necessary precision requirements for the system technology. A potential solution to overcome the problem of the short focus depth is the usage of a nondiffracting Bessel beam that is well known for providing a depth of field in the mm range while allowing the diameter of the central processing spot to be below 1 μm. There are several ways to generate a Bessel beam, but only an axicon is suitable for efficient high-power USP ablation. However, even high-precision manufactured axicons have a round tip resulting in a highly oscillating intensity along the propagation axis. This characteristic is a major obstacle for reproducible and reliable laser nanostructuring of metals. For this reason, reflective axicons were newly introduced to the market. They generate a Bessel beam much closer to the ideal axial intensity distribution. In this paper, we compare the Bessel beam generated by a reflective axicon with that of a conventional axicon in an application-oriented setting. Furthermore, we demonstrate the enormous potential of Bessel beams for surface structuring.

Molecular Design of Monochromophore-Based Bifunctional Photosensitizers for Simultaneous Ratiometric Oxygen Reporting and Photodynamic Cancer Therapy

Monitoring the tumor oxygen level when implementing photodynamic therapy (PDT) on malignant cancer has vital significance but remains challenging yet. Herein, by structurally manipulating a 2,4-dimethylpyrrole-engineered asymmetric BODIPY scaffold with different kinds, numbers, and positions of halogen atoms, we rationally designed several monochromophore-based bifunctional photosensitizers, named BDPs (BDP-I, BDP-II, and BDP-III), with self-sensitized photooxidation characteristics for accurate oxygen reporting and photodynamic tumor ablation. We show that different ways of halogen regulation allow available tuning of BDPs' oxygen-dependent ratiometric fluorescence turn-ons upon light irradiation as well as type-II PDT efficiencies before and after self-sensitized photooxidation. Encouragingly, measuring the specific ratiometric signals of the most promising BDP-II enabled the direct observation of initial oxygen concentration in both living 4T1 cells and a tumor-bearing mice model, affording an alternative way for evaluating oxygen supplementation strategies. Meanwhile, the "always on" PDT effect of BDP-II ensured efficient tumor ablation via apoptosis. Our research was thus believed to be of instructive significance for future application of oxygen-related auxiliary strategies and the design of unimolecular multifunctional PDT agents for cancer precision therapy.

PEGylated Indium Nanoparticles: A Metallic Contrast Agent for Multiwavelength Photoacoustic Imaging and Second Near-Infrared Photothermal Therapy.

Indium, a low melting point metal, is well-known for constructing eutectic gallium-indium liquid metal. However, unlike liquid metal nanoparticles, the biomedical applications of metallic indium nanoparticles (In NPs) remain in their infancy. Herein, an ultrasound-assisted liquid-reduction synthesis strategy was developed to prepare PEGylated In NPs, which were then used as a high-performance contrast agent for enhancing multiwavelength photoacoustic imaging and second near-infrared (NIR-II) photothermal therapy of the 4T1 breast tumor. The obtained In NPs depicted remarkable optical absorption from the first near-infrared (NIR-I) to NIR-II region and a high photothermal conversion efficiency of 41.3% at 1064 nm, higher than the majority of conventional NIR-II photothermal agents. Upon injection into the tumor, the photoacoustic intensities of the tumor section post-injection were obviously increased by 2.59-, 2.62-, and 4.27-fold of those of pre-injection by using excitation wavelengths of 750, 808, and 970 nm, respectively, depicting an excellent multiwavelength contrast capability of photoacoustic imaging. In addition, efficient ablation of the 4T1 tumor was achieved through the photothermal performance of PEGylated In NPs under NIR-II laser irradiation. Importantly, as the widely used element in the clinic, In NPs were highly biocompatible in vitro and in vivo. Therefore, this work pioneered the biomedical applications of PEGylated In NPs for cancer diagnosis and treatment.

The Therapeutic Effect of Second Near-Infrared Absorbing Gold Nanorods on Metastatic Lymph Nodes via Lymphatic Delivery System.

Photothermal therapy has been established recently as a non-invasive treatment protocol for cancer metastatic lymph nodes. Although this treatment approach shows efficient tumour ablation towards lymph node metastasis, the monitoring and reporting of treatment progress using the lymphatic delivery channel still need to be explored. Herein, we investigated the anti-tumour effect of pegylated gold nanorods with a high aspect ratio (PAuNRs) delivered via the lymphatic route in a mouse model. In this study, breast carcinoma (FM3A-Luc) cells were inoculated in the subiliac lymph node (SiLN) to induce metastasis in the proper axillary lymph node (PALN). The treatment was initiated by injecting the PAuNRs into the accessory axillary lymph node (AALN) after tumour metastasis was confirmed in the PALN followed by external NIR laser irradiation under a temperature-controlled cooling system. The anti-tumour impact of the treatment was evaluated using an in vivo bioluminescence imaging system (IVIS). The results showed a time-dependent reduction in tumour activity with significant treatment response. Tumour growth was inhibited in all mice treated with PAuNRs under laser irradiation; results were statistically significant (** p < 0.01) even after treatment was concluded on day 3. We believe that this non-invasive technique would provide more information on the dynamics of tumour therapy using the lymphatically administered route in preclinical studies.

Vestibular and Auditory Hair Cell Regeneration Following Targeted Ablation of Hair Cells With Diphtheria Toxin in Zebrafish.

Millions of Americans experience hearing or balance disorders due to loss of hair cells in the inner ear. The hair cells are mechanosensory receptors used in the auditory and vestibular organs of all vertebrates as well as the lateral line systems of aquatic vertebrates. In zebrafish and other non-mammalian vertebrates, hair cells turnover during homeostasis and regenerate completely after being destroyed or damaged by acoustic or chemical exposure. However, in mammals, destroying or damaging hair cells results in permanent impairments to hearing or balance. We sought an improved method for studying hair cell damage and regeneration in adult aquatic vertebrates by generating a transgenic zebrafish with the capacity for targeted and inducible hair cell ablation in vivo. This model expresses the human diphtheria toxin receptor (hDTR) gene under the control of the myo6b promoter, resulting in hDTR expressed only in hair cells. Cell ablation is achieved by an intraperitoneal injection of diphtheria toxin (DT) in adult zebrafish or DT dissolved in the water for larvae. In the lateral line of 5 days post fertilization (dpf) zebrafish, ablation of hair cells by DT treatment occurred within 2 days in a dose-dependent manner. Similarly, in adult utricles and saccules, a single intraperitoneal injection of 0.05 ng DT caused complete loss of hair cells in the utricle and saccule by 5 days post-injection. Full hair cell regeneration was observed for the lateral line and the inner ear tissues. This study introduces a new method for efficient conditional hair cell ablation in adult zebrafish inner ear sensory epithelia (utricles and saccules) and demonstrates that zebrafish hair cells will regenerate in vivo after this treatment.

Efficient milling and cutting of borosilicate glasses through a thin flowing water film with a picosecond laser

Direct laser ablation allows high-quality processing, precision, and cutting of complex shapes. Unfortunately, this technology is usually not considered as the primary candidate for cutting and milling of glasses due to low processing speeds. Thus, laser-based rear side drilling and crack generation techniques are chosen instead. However, we report on the milling and cutting of borosilicate glass plates with high average power and high pulse repetition rate picosecond laser. We optimised laser processing parameters for the efficient direct material ablation and employed water-assisted ablation to improve the ablation efficiency and the cutting speed of borosilicate glasses. The laser process was realised through a thin flowing water film, which was formed by spraying water mist on the surface of the workpiece. Firstly, we characterised thin water film parameters, such as film thickness, flow velocity, and defined a working area with constant processing conditions. Next, we optimised laser processing parameters for both processing environments: ablation through the thin water film and in air. Under optimal parameters, ablation through the thin water film was much more effective, increasing the cutting speed of 420 μm thick glass plates nearly ten times – from 0.52 to 5 mm/s. Furthermore, the morphology of the cuts was improved as well: cut wall roughness and edge chipping were reduced, spatter deposition was avoided in the vicinity of the cut. We investigated the milling of 130 to 1700 μm wide and 50 to 500 μm deep grooves with a maximum depth-to-width ratio of 3.8. Findings revealed that the ablation efficiency increase provided by the water layer did not depend on the depth or the width of the groove and remained constant. Therefore, it became possible to predict the ablation efficiency through the thin water film by knowing the ablation efficiency in air and an absolute ablation efficiency difference between two processing environments. • Efficient borosilicate glass milling and cutting in the air and through the water film was conducted with a picosecond laser. • Optimal laser fluence for efficient glass ablation was 40% higher than in air. • An absolute change in ablation efficiency between two environments did not depend on the transverse dimensions of the groove. • Water film improved ablation efficiency significantly, resulting in nearly 10 times higher cutting speed than in air.

Brightly luminescent (NH4)xCs1-xPbBr3 quantum dots for in vitro imaging and efficient photothermal ablation therapy

Herein, we report for the first time a facile strategy for the highly efficient (NH4)xCs1-xPbBr3 quantum dots (QDs). By modulating the amount of ammonium, (NH4)xCs1-xPbBr3 QDs with different photoluminescence (PL) quantum yields (QY) were synthesized. The results of X-ray diffraction and X-ray photoelectron spectroscopy showed that the crystal structure of (NH4)xCs1-xPbBr3 was altered by incorporation of NH4+ cations into the CsPbBr3 lattice. The (NH4)xCs1-xPbBr3 QDs showed enhanced PL QY, higher photostability, and long-term storage stability compared to CsPbBr3 QDs. Furthermore, (NH4)xCs1-xPbBr3 QDs could be conjugated with a photothermal dye (IR780) via a one-pot reaction using poly(styrene-co-maleic anhydride) and IR780-MPTS. To the best of our knowledge, the present work is the first attempt integrating perovskite QDs and phototherapeutic molecules into one system (abbreviated as PQD-IR780), demonstrating good water dispersibility and high photothermal conversion efficiency of 57.85%. In vitro experiments performed to examine subcellular uptake showed high fluorescence brightness was observed in HeLa, B16F1, and HepG2 cancer cells cultured with PQD-IR780. The results indicate that the internalization mechanism for uptaking of PQD-IR780 inside HeLa cells is energy-dependent and caveolin-mediated endocytosis. The in vitro cell viability assays and photothermal therapy revealed that PQD-IR780 showed good biocompatibility and can induce hyperthermia upon laser irradiation.

Shuttle-Shape Carrier-Free Platinum-Coordinated Nanoreactors with O2 Self-Supply and ROS Augment for Enhanced Phototherapy of Hypoxic Tumor.

The synergistic nanotheranostics of reactive oxygen species (ROS) augment or phototherapy has been a promising method within synergistic oncotherapy. However, it is still hindered by sophisticated design and fabrication, lack of a multimodal synergistic effect, and hypoxia-associated poor photodynamic therapy (PDT) efficacy. Herein, a kind of porous shuttle-shape platinum (IV) methylene blue (Mb) coordination polymer nanotheranostics-loaded 10-hydroxycamptothecin (CPT) is fabricated to address the abovementioned limitations. Our nanoreactors possess spatiotemporally controlled O2 self-supply, self-sufficient singlet oxygen (1O2), and outstanding photothermal effect. Once they are taken up by tumor cells, nanoreactors as a cascade catalyst can efficiently catalyze degradation of the endogenous hydrogen peroxide (H2O2) into O2 to alleviate tumor hypoxia. The production of O2 can ensure enhanced PDT. Subsequently, under both stimuli of external red light irradiation and internal lysosomal acidity, nanoreactors can achieve the on-demand release of CPT to augment in situ mitochondrial ROS and highly efficient tumor ablation via phototherapy. Moreover, under the guidance of near-infrared (NIR) fluorescent imaging, our nanoreactors exhibit strongly synergistic potency for treatment of hypoxic tumors while reducing damages against normal tissues and organs. Collectively, shuttle-shape platinum-coordinated nanoreactors with augmented ROS capacity and enhanced phototherapy efficiency can be regarded as a novel tumor theranostic agent and further promote the research of synergistic oncotherapy.

Modulating the Immunologic Microenvironment in AML By Blocking Both CXCR4 and PD-L1

BackgroundWe have shown the importance of microenvironments by displaying the restoration of dysfunctional natural killer (NK) cells' antitumor effects both in vitro and in vivo after a trial of CXCR4 inhibition combined with conventional chemotherapy in acute myeloid leukemia (AML). Recently, the inhibition of programmed death-1(PD-1) /PD-ligand1 (PD-L1) axis in solid cancer has been regarded as a key factor to treating cancer by activating the suppressed immune cells. However, the significance of PD-1/PD-L1 expression in AML has yet to be established, even though PD-1/PD-L1 has already been targeted in clinical trials. Thus, our aim was to revitalize suppressed immune cells by utilizing CXCR4 blockade and anti-PD-L1 in combination with chemotherapy in an AML mouse model.Methods and Results The leukemic mouse model was induced by injecting C1498 (murine AML cell line) cells into C57/Bl-6 mice at D0, and leukemic blasts of the organs of several subgroups treated with cytosine arabinoside (Ara-C) (2 mg/kg, I.P.), plerixafor (2.5 mg/kg, S.C.), and anti-PD-L1 (200 ug/kg, I.P.) in one-by-one additive manners were examined (Fig. 1). Flow cytometric analyses at D+3, D+14, D+19, D+26 and histologic examination after sacrifice were performed to read the therapy-responsive changes of immune cell subsets and blasts reduction. Our data indicated noticeable benefits of this triple combinational treatment with plerixafor, anti-PD-L1, and Ara-C (AMP subgroup in Fig. 2 & Fig. 3) in removal of blasts in vivo; especially, survival rates of leukemic mice in the triple-combined treatment subgroup were higher than those in other subgroups. Moreover, in immune cell subsets in the peripheral blood, the frequency of CD4+ and CD8+ T cells was significantly increased specifically early after completion of the treatment in the triple combinational subgroup with remarkable changes of monocytic myeloid-derived suppressor cells (M-MDSCs) as well as regulatory T cells (Tregs), compared to that of other subgroups. Interestingly, in the triple combinational subgroup, Tregs and M-MDSCs were both significantly decreased while G-MDSCs were significantly increased in the bone marrow (BM) of leukemic mice that were sacrificed alive at D+26. In addition, the phenotypic levels of PD-1 both in the BM and the spleen were relatively low compared to those of other subgroups. These findings implied that the modulation of immune status by applying plerixafor and anti-PD-L1 with Ara-C could lead to a more efficient leukemic blasts ablation through the activation of CD4+ and CD8+ T cells and possibly the suppression of Tregs and/or M-MDSCs in AML. Integrated responses of NK, NKT, and DC cells should be pursued in the future.Conclusion We demonstrated the impact of a strategic triple combinational therapy with anti-PD-L1 and plerixafor with Ara-C in AML. Our results suggest some clues and provide guidelines to developing therapeutic strategies for chemotherapy-resistant patients in clinic by the modulation of leukemic microenvironments. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Molecular Engineering of Efficient Singlet Oxygen Generators with Near‐Infrared AIE Features for Mitochondrial Targeted Photodynamic Therapy

AbstractAggregation‐caused fluorescence quenching with insufficient production of reactive oxygen species (ROS) has limited the application of photosensitizers (PSs) in fluorescence‐imaging‐guided photodynamic therapy (PDT). Aggregation‐induced emission PSs (AIE‐PSs) exhibit enhanced fluorescence intensity and a high efficiency of ROS generation in the aggregation state, which provides an opportunity to solve the above problems. Herein, a series of AIE‐PSs are successfully designed and synthesized by adjusting the D–A intensity through molecular engineering. The photophysical properties and theoretical calculations prove that the synergistic effect of 3,4‐ethylenedioxythiophene and quinolinium increases the intramolecular charge transfer effect (ICT) of the whole molecule and promotes the intersystem crossing (ISC) from the lowest excited singlet state (S1) to the lowest triplet state (T1). Among these AIE‐PSs, the optimal AIE‐PS (TPA‐DT‐Qy) exhibits the highest generation yield of 1O2 (5.3‐fold of Rose Bengal). Further PDT experiments show that the TPA‐DT‐Qy has a highly efficient photodynamic ablation of breast cancer cells (MCF‐7 and MDA‐MB‐231) under white light irradiation. Moreover, the photodynamic antibacterial study indicates that TPA‐DT‐Qy has the discrimination and excellent photodynamic inactivation of S. aureus. This work provides a feasible strategy for the molecular engineering of novel AIE‐PSs to improve the development of fluorescence‐imaging‐guided PDT.

Preparation of multifunctional polyvinyl alcohol microspheres by electrospinning and its properties and application

In this paper, MnO2-polydopamine (PDA)/polyvinyl alcohol (PVA) and MnO2-PVA-5-fluorouracil (5-Fu)/PVA composite microspheres were prepared by electrospinning. Specifically, dopamine (DA) and KMnO4 were added to the PVA solution, where a redox reaction happened between DA and KMnO4 to form PDA and MnO2. Thus, the MnO2-PDA/PVA microspheres were prepared by electrospinning the MnO2-PDA/PVA solution. MnO2-PDA-5-Fu/PVA microspheres were prepared by electrospinning the MnO2-PDA-5-Fu/PVA solution, which was prepared by directly dissolving 5-Fu in the MnO2-PDA/PVA solution. The water stability of the electrospun microspheres was given by a glutaraldehyde crosslinking method. The composite microspheres have excellent photothermal conversion, controlled drug release and good biosafety, which were used to prevent the recurrence of tumor after the operation. The photothermal conversion efficiency of MnO2-PDA-5-Fu/PVA microspheres reaches 24.5% under the irradiation of 808 nm NIR laser, which can achieve the efficient tumor thermal ablation; on the other hand, the released 5-Fu can kill the residual tumor cells after operation. This study confirms the application potential of the microspheres in the field of preventing tumor recurrence, and provides a new strategy for the design of multifunctional composite nanomaterials.

The role of Hashimoto thyroiditis in predicting radioiodine ablation efficacy and prognosis of low to intermediate risk differentiated thyroid cancer

ObjectiveThe baseline treatment of differentiated thyroid cancer (DTC) consists of thyroidectomy followed by postoperative risk-adapted radioiodine therapy (RAIT) when indicated. The choice of most appropriate RAI activities to administer with the aim to reach an efficient remnant ablation and reduce the risk of recurrence is yet an open issue and the detection of basal factors that may predict treatment response seems fundamental. The aim of this study was to investigate the potential role of Hashimoto thyroiditis (HT) in predicting 1-year and 5-year treatment response after RAIT and prognosis.MethodsWe retrospectively included 314 consecutive patients (174 low-risk and 140 intermediate-risk) who received thyroidectomy plus RAIT. One-year and 5-year disease status was evaluated according to 2015 ATA categories response based upon biochemical and structural findings.ResultsHT was reported histopathologically in 120 patients (38%). DTC patients with concomitant HT received a higher number of RAITs and cumulative RAI activities. Initial RAIT reached an excellent response in 63% after one year and 84% after 5 years. The rate of excellent response one year and 5-year after first RAIT was significantly lower in HT groups, compared to not HT (p < 0.001). Instead, HT did not have a prognostic role considering PFS and OS; while stimulate thyroglobulin (sTg) at ablation was significantly related to survival.ConclusionsHT may affect the efficacy of RAIT in low to intermediate risk DTC, particularly reducing the successful rate of excellent response after RAIT. Instead, HT did not have a prognostic impact such as stimulated sTg.