Complete remission of gallbladder neuroendocrine carcinoma with liver metastasis by tislelizumab plus chemotherapy: a case report.

Background: Gallbladder neuroendocrine carcinoma (GB-NEC) is an extremely rare cancer with a poor prognosis in the clinic. Although surgical resection remains the primary and preferred therapeutics, many patients are in a late stage and lose the opportunity for surgery. However, due to the extremely low morbidity, the specific treatment guidelines for GB-NEC have not been established. Case presentation: A 52-year-old woman was admitted to our hospital with the chief complaint of "almost 1 month after palliative surgery for metastatic gallbladder carcinoma." According to the results of pathological findings and imaging manifestations, the patient was diagnosed with GB-NEC with a clinical stage of pT3N1M1 (IVB). The patient then received tislelizumab plus EP chemotherapy (etoposide 100 mg + cisplatin 30 mg, d1-3) every 3 weeks for 8 cycles from 12 November, 2021, followed by maintenance therapy (tislelizumab alone) every 3 weeks until now. The tumor response was evaluated as complete remission since 13 February, 2023. As of the last follow-up, the patient remains alive, with no complaints of discomfort. Conclusions: Gallbladder NEC has no specific symptoms, and the diagnosis is based on pathological and immunohistochemical results. The therapeutic course and efficacy of the case in this study indicates that the application of PD-1 inhibitor might be a feasible therapeutic option for GB-NEC. However, this potential strategy needs validation by further clinical studies in the future.

Targeted delivery of Dbait by an artificial extracellular vesicle for improved radiotherapy sensitivity of esophageal cancer.

Intensification of radiotherapy has been shown to be an effective way for improving the therapeutic efficacy of radiation sensitive malignancies such as esophageal cancer (EC). The application of DNA Bait (Dbait), a type of DNA repair inhibitor, is an emerging strategy for radiosensitization. In this study, a Eca-109 cancerous cytomembrane-cloaked biomimetic drug delivery system (DDS), CMEC-Dbait, was designed and successfully fabricated, for targeted delivery of Dbait. Our systematic evaluation demonstrated that the ingenious artificial gastrointestinal extracellular vesicle owns neat spherical structure, proper particle size (154.6±5.5 nm) and surface charge (2.6±0.3 mV), favourable biocompatibility and immunocompatibility, being conducive to in vivo drug delivery. Besides, Eca-109 cytomembrane coating endowed CMEC-Dbait with effective targeting ability to homologous EC cells. Owing to these advantages, the biomimetic DDS was proved to be a potent radiosensitizer in vitro, indicated by remarkably reduced cell viability and enhanced cellular apoptosis by the combination therapy of radiation and CMEC-Dbait. The result was validated in vivo using mouse xenograft models of EC, the results illustrated that radiotherapy plus CMEC-Dbait significantly suppressed tumor growth and prolonged survival of tumor bearing mice. Western blotting results showed that CMEC-Dbait can significantly inhibit DNA damage repair signaling pathways by simulating DNA double-strand breaks both in and ex vivo. In conclusion, the versatile biomimetic CMEC-Dbait was characterized of low toxicity, excellent biocompatibility and satisfactory drug delivery efficiency, which is confirmed to be an ideal radiosensitizer for homologous cancer and merits further investigation in both pre-clinical and clinical studies.

Targeted delivery of a PROTAC induced PDEδ degrader by a biomimetic drug delivery system for enhanced cytotoxicity against pancreatic cancer cells.

Pancreatic carcinoma (PC) has one of the highest mortality-to-incidence ratios of any solid tumor worldwide. Although KRAS mutation is commonly found in 95% of PCs, directly targeting KRAS remains to be a highly challenging task because of its lacking catalytic pockets where molecule inhibitors can bind with. Proteolysis-targeting chimeric (PROTAC) represents an effective approach for specific degradation of disease-causing proteins by hijacking the endogenous ubiquitin-proteasome system (UPS). Previously, we designed a first-in-class PROTAC induced PDEδ degrader (PIPD), which demonstrated improved anti-tumor efficacy against KRAS mutant malignancies. However, translating cellular degradative effects from bench to beside remains a highly challenging task because of PROTAC's poor penetration efficiency across target cytomembranes and non-targeting delivery induced undesired "off target" side-effects. Herein, a smart nano-drug delivery system (CM8988-PIPD) was successfully constructed by biomimetic strategy for targeted delivery of PIPD. The biomimetic nanoparticle showed well-defined regular spherical structure with an average particle size of approximately 124.8 nm. Cancer cytomembrane camouflage endows CM8988-PIPD with excellent in vivo serum stability, controlled drug release profile, favorable biocompatibility & immunocompatibility, and prominent targeting ability to homologous PC cells. Owing to these advantages, the smart DDS significantly enhanced PDEδ degrading efficacy, resulting in induced cellular apoptosis (more than 50% for both PC cells) and suppressed cell proliferation via the inhibition of RAS signaling. In vitro studies illustrated that CM8988-PIPD hold great potential for the treatment of PC, which merits further investigation in both pre-clinical and clinical investigations in the future.

Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms.

The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors - CX3CR1 and L-selectin - were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.

Potential of the cell-free blood-based biomarker uroplakin 2 RNA to detect recurrence after surgical resection of lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, and ~30% of patients with LUAD develop cancer recurrence after surgery. The present study aimed to identify and validate biomarkers that may be used to monitor recurrence following LUAD surgery. Data from patients with LUAD were downloaded from The Cancer Genome Atlas database and postoperative recurrence samples were selected. Subsequently, weighted gene co-expression network analysis (WGCNA) was subsequently performed to identify key co-expression gene modules. Additionally, enrichment analysis of the key gene modules was performed using the Database for Annotation, Visualization and Integrated Discovery. Furthermore, survival analysis was performed on the most notable biomarker, uroplakin 2 (UPK2), which was downloaded from the Oncomine database, and its effect on prognosis was assessed. WGCNA identified 39 gene modules, of which one was most associated with recurrence. Among them, UPK2, kelch domain containing 3, galanin receptor 2 and tyrosinase-related protein 1 served a central role in the co-expression network and were significantly associated with the survival of patients. A total of 132 blood samples were collected from patients with LUAD with free UPK2 in the plasma. The expression levels of UPK2 relative to GADPH were 0.1623 and 0.2763 in non-relapsed and relapsed patients, respectively. Receiver operating characteristic curve analysis was used to detect free UPK2 mRNA in the blood in order to monitor postoperative recurrence, resulting in an area under the curve of 0.767 and a 95% CI of 0.675-0.858. Patients with high free UPK2 mRNA expression had unfavorable survival outcomes compared with those with low UPK2 expression. Therefore, free UPK2 mRNA expression in the plasma may have the potential to act as an indicator of postoperative recurrence in patients with early stage LUAD.

Ursodeoxycholic acid protects against lung injury induced by fat embolism syndrome.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening disease with a high mortality rate, which was a common complication of fat embolism syndrome (FES). Ursodeoxycholic acid (UDCA) has been reported to exert potent anti-inflammatory effects under various conditions. In vivo, perinephric fat was injected via tail vein to establish a rat FES model, the anti-inflammatory effects of UDCA on FES-induced lung injury were investigated through histological examination, ELISA, qRT-PCR, Western blot and immunofluorescence. In vitro, human lung microvascular endothelial cells (HPMECs) were employed to understand the protective effects of UDCA. The extent of ALI/ARDS was evaluated and validated by reduced PaO2 /FiO2 ratios, increased lung wet/dry (W/D) ratios and impaired alveolar-capillary barrier, up-regulation of ALI-related proteins in lung tissues (including myeloperoxidase [MPO], vascular cell adhesion molecule 1 [VCAM-1], intercellular cell adhesion molecule-1 [ICAM-1]), elevated protein concentration and increased proinflammatory cytokines levels (TNF-α and IL-1ß) in bronchoalveolar lavage fluid (BALF). Pre-treatment with UDCA remarkably alleviated these pathologic and biochemical changes of FES-induced ALI/ARDS; our data demonstrated that pre-treatment with UDCA attenuated the pathologic and biochemical changes of FES-induced ARDS, which provided a possible preventive therapy for lung injury caused by FES.

Growth of U-Shaped Graphene Domains on Copper Foil by Chemical Vapor Deposition.

U-shaped graphene domains have been prepared on a copper substrate by chemical vapor deposition (CVD), which can be precisely tuned for the shape of graphene domains by optimizing the growth parameters. The U-shaped graphene is characterized by using scanning electron microscopy (SEM), atomic force microscopy (AFM), transmission electron microscopy (TEM), and Raman. These show that the U-shaped graphene has a smooth edge, which is beneficial to the seamless stitching of adjacent graphene domains. We also studied the morphology evolution of graphene by varying the flow rate of hydrogen. These findings are more conducive to the study of morphology evolution, nucleation, and growth of graphene domains on the copper substrate.

A N-doped graphene-cobalt nickel sulfide aerogel as a sulfur host for lithium-sulfur batteries.

Herein, three-dimensional (3D) N-doped reduced graphene oxide (N-rGO) nanosheets were decorated with a uniform distribution of Co-Ni-S (CNS) nanoparticles to form the CNS/N-rGO composite as a sulfur host material for lithium-sulfur batteries. The CNS nanoparticles and N in CNS/N-rGO strongly interact with polysulfides, whereas graphene, as a conductive network, can improve its electrical conductivity. A CNS/N-rGO/sulfur composite cathode was prepared via the sulfur melting diffusion method. The electrochemical study showed that the CNS/N-rGO/sulfur cathode delivered an initial discharge capacity of 1430 mA h g-1 at a current density of 0.1C. Moreover, it retained a specific capacity of 685 mA h g-1 after 300 cycles at 0.5C with a coulombic efficiency of 98%, which was better than that of commercial rGO. This composite was used as a sulfur cathode for a lithium-sulfur battery, exhibiting excellent rate capability and remarkable performance in terms of long cycling stability.

One-Step Chemical Vapor Deposition Synthesis of 3D N-doped Carbon Nanotube/N-doped Graphene Hybrid Material on Nickel Foam.

3D hybrid nanostructures connecting 1D carbon nanotubes (CNTs) with 2D graphene have attracted more and more attentions due to their excellent chemical, physical and electrical properties. In this study, we firstly report a novel and facile one-step process using template-directed chemical vapor deposition (CVD) to fabricate highly nitrogen doped three-dimensional (3D) N-doped carbon nanotubes/N-doped graphene architecture (N-CNTs/N-graphene). We used nickel foam as substrate, melamine as a single source for both carbon and nitrogen, respectively. The morphology and microstructure were characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, isothermal analyses, X-ray photoelectron microscopy and Raman spectra. The obtained 3D N-CNTs/N-graphene exhibits high graphitization, a regular 3D structure and excellent nitrogen doping and good mesoporosity.

Cancer nanomedicine: mechanisms, obstacles and strategies.

Targeting nanoparticles to cancers for improved therapeutic efficacy and decreased side effects remains a popular concept in the past decades. Although the enhanced permeability and retention effect serves as a key rationale for all the currently commercialized nanoformulations, it does not enable uniform delivery of nanoparticles to all tumorous regions in all patients with sufficient quantities. Also, the increase in overall survival is often modest. Many factors may influence the delivering process of nanoparticles, which must be taken into consideration for the promise of nanomedicine in patients to be realized. Herein, we review the mechanisms and influencing factors during the delivery of cancer therapeutics and summarize current strategies that have been developed for the fabrication of smart drug delivery systems.

Enhanced Performance of E-Bike Motive Power Lead-Acid Batteries with Graphene as an Additive to the Active Mass.

The effects of both graphene nanoplatelets and reduced graphene oxide as additives to the negative active material in valve-regulated lead-acid batteries for electric bikes were investigated. Low-temperature performance, charge acceptance, cycle performance, and water loss were investigated. The test results show that the low-temperature performance, charge acceptance, and large-current discharge performance of the batteries with graphene additives were significantly improved compared to the control battery, and the cycle life under 100% depth of discharge condition was extended by more than 52% from 250 to 380 cycles. Meanwhile, the amount of water loss from the batteries with graphene changed only slightly compared with the control cells. The excellent performance of the batteries can be ascribed to the graphene promoting the negative-plate charge and discharge processes and suppressing the growth of lead sulfate crystals.

Melamine as a single source for fabrication of mesoscopic 3D composites of N-doped carbon nanotubes on graphene.

Integration of two-dimensional graphene and one-dimensional carbon nanotubes (CNTs) to create potentially useful 3D mesoscopic carbon structures with enhanced properties relative to the original materials is very desirable. Here, we report a novel and simple route using chemical vapor deposition (CVD) methods to fabricate bead-like nitrogen-doped CNT/graphene composites (NCNT/G) via a simple pyrolysis of the N-rich melamine in the presence of graphene oxide (GO) as a substrate using a Mn-Ni-Co ternary catalyst. We have characterized these structures by field-emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Raman spectra, isothermal analyses, and X-ray photoelectron spectroscopy. The three dimensional NCNT/G hybrids have unique network structures, moderate graphitization, high specific surface area, good mesoporosity, and N doping, which makes them promising materials for applications in energy storage and conversion.

Combating rituximab resistance by inducing ceramide/lysosome-involved cell death through initiation of CD20-TNFR1 co-localization.

Despite the success of CD20 antibody rituximab in immunotherapy, acquired resistance is one of the prime obstacles for the successful treatment of B-cell malignancies. There is an urgent need to intensify efforts against resistance in cancer treatment. Growing evidence indicated that lysosomes may form an "Achilles heel" for cancer cells by sensitizing them to death pathways. Here, we uncover an important role of CD20 in initiation of ceramide/lysosomal membrane permeabilization (LMP)-mediated cell death, showing that colocalization of CD20-TNFR1 after type II CD20 antibody ligation can stimulate de novo ceramide synthesis by ceramide synthase and consequently induce remarkable lysosomal permeabilization (LMP) and lysosome-mediated cell death. Further studies show that the potent lysosome-mediated cell death induced by CD20 antibodies exhibits a profound killing effect against both rituximab-sensitive and -resistant (RR) lymphoma. Furthermore, engineering of rituximab by introducing a point mutation endows it with the ability to induce potent ceramide/LMP-mediated cell death in both RR lymphoma and primary B-cell malignancies from patients with rituximab-refractory, suggesting the potential clinical application to combat rituximab resistance.

DACH1 inhibits the proliferation and invasion of lung adenocarcinoma through the downregulation of peroxiredoxin 3.

In this study, we found the expression of Dachshund 1 (DACH1) is downregulated while peroxiredoxin 3 (PRX3) upregulated in both lung adenocarcinoma tissues and cells. Transfection of DACH1 can significantly downregulate PRX3 expression in targeting lung adenocarcinoma cells. Further experimental results demonstrated the evidence that overexpression of DACH1 resulted in significant retardation of in vitro proliferation and invasion of lung adenocarcinoma cells. Direct upregulation of PRX3 by co-transfection of PRX3 messenger RNA (mRNA) can prevent the above alteration caused by DACH1 transfection. Besides, lower DACH1 expression significantly correlated with tumor diameter and tumor invasion in all the 36 patients diagnosed with lung adenocarcinoma in our hospital during the past months. In conclusion, DACH1 can inhibit the proliferation and invasion of lung adenocarcinoma through the downregulation of PRX3. Decreased expression of DACH1 is involved in the initiation and development of lung cancer, which might be an adverse prognostic factor of lung adenocarcinoma.

Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity.

Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross-linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency.

Suppression of Rituximab-resistant B-cell lymphoma with a novel multi-component anti-CD20 mAb nanocluster.

Although the anti-CD20 antibody Rituximab has revolutionized the treatment of Non-Hodgkin Lymphoma (NHL), resistance to treatment still existed. Thus, strategies for suppressing Rituximab-resistant NHLs are urgently needed. Here, an anti-CD20 nanocluster (ACNC) is successfully constructed from its type I and type II mAb (Rituximab and 11B8). These distinct anti-CD20 mAbs are mass grafted to a short chain polymer (polyethylenimine). Compared with parental Rituximab and 11B8, the ACNC had a reduced "off-rate". Importantly, ACNC efficiently inhibited Rituximab-resistant lymphomas in both disseminated and localized human NHL xenograft models. Further results revealed that ACNC is significantly potent in inducing caspase-dependent apoptosis and lysosome-mediated programmed cell death (PCD). This may help explain why ACNC is effective in suppressing rituximab-resistant lymphoma while Rituximab and 11B8 are not. Additionally, ACNC experienced low clearance from peripheral blood and high intratumor accumulation. This improved pharmacokinetics is attributed to the antibody-antigen reaction (active targeting) and enhanced permeability and retention (ERP) effect (passive targeting). This study suggested that ACNC might be a promising therapeutic agent for treatment of rituximab-resistant lymphomas.

Construction and characterization of an anti-CD20 mAb nanocomb with exceptionally excellent lymphoma-suppressing activity.

The CD20-directed monoclonal antibody rituximab (RTX) established a new era in the treatment of non-Hodgkin lymphoma (NHL); however, suboptimal response and/or resistance to RTX still limit its clinical merits. Although four effector mechanisms are validated to participate in CD20-based immunotherapy, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, caspase-dependent apoptosis, and lysosome-mediated programmed cell death (PCD), they could hardly be synchronously activated by any anti-CD20 mAb or mAb derivative until now. Herein, a novel mAb nanocomb (polyethylenimine polymer-RTX-tositumomab [PPRT nanocomb]) was firstly constructed through mass arming two different anti-CD20 mAbs (RTX and tositumomab) to one polymer by nanotechnology. Comparing with free mAbs, PPRT nanocomb possesses a comparable binding ability and reduced "off-rate" to surface CD20 of NHL cells. When treated by PPRT nanocomb, the caspase-dependent apoptosis was remarkably enhanced except for concurrently eliciting complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and lysosome-mediated PCD. Besides, "cross-cell link"-assisted homotypic adhesion by PPRT nanocomb further enhanced the susceptibility to PCD of lymphoma cells. Pharmacokinetic assays revealed that PPRT nanocomb experienced a relatively reduced clearance from peripheral blood compared with free antibodies. With the cooperation of all the abovementioned superiorities, PPRT nanocomb exhibits exceptionally excellent in vivo antitumor activities in both disseminated and localized human NHL xenotransplant models.

Controlled and Targeted Drug Delivery by a UV-responsive Liposome for Overcoming Chemo-resistance in Non-Hodgkin Lymphoma.

Although chemotherapy plays a vital role in treating non-Hodgkin lymphomas, the clinical applications are limited because of intolerable side-effects and multidrug resistance at the beginning or during the course of therapy. In this study, we successfully fabricated a CD20-targeting immuno-liposome based on 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC-8,9PC), which can form intermolecular cross-linking through the diacetylenic group by ultraviolet irradiation. This immuno-liposome showed appropriate size distribution, well-defined regular spherical structure, favorable biocompatibility, high serum stability, and prolonged circulation time in blood vessels. The in and ex vivo experiments demonstrate enhanced tumor suppression abilities against both wild-type and resistant non-Hodgkin lymphomas for liposomal doxorubicin when compared with free drugs. The outstanding antitumor activities are attributed to the accumulation and retention of liposomal drugs in malignant tissues and cells, which are realized by the co-operation of active targeting via antibody-antigen reaction and passive targeting via enhanced permeability and retention effect.

WITHDRAWN: Effective suppression of Rituximab-resistant B-cell lymphoma by a comb-like anti-CD20 mAb nanocluster.

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Cancer nanoimmunotherapy using advanced pharmaceutical nanotechnology.

Immunotherapy is a promising option for cancer treatment that might cure cancer with fewer side effects by primarily activating the host's immune system. However, the effect of traditional immunotherapy is modest, frequently due to tumor escape and resistance of multiple mechanisms. Pharmaceutical nanotechnology, which is also called cancer nanotechnology or nanomedicine, has provided a practical solution to solve the limitations of traditional immunotherapy. This article reviews the latest developments in immunotherapy and nanomedicine, and illustrates how nanocarriers (including micelles, liposomes, polymer-drug conjugates, solid lipid nanoparticles and biodegradable nanoparticles) could be used for the cellular transfer of immune effectors for active and passive nanoimmunotherapy. The fine engineering of nanocarriers based on the unique features of the tumor microenvironment and extra-/intra-cellular conditions of tumor cells can greatly tip the triangle immunobalance among host, tumor and nanoparticulates in favor of antitumor responses, which shows a promising prospect for nanoimmunotherapy.