Ho(III)-coordination Complex: Fluorescence Performances and Combined with Captopril-Hydrogels against Glioma.

In this study, a novel dinuclear lanthanide complex, denoted as [Ho2(L)2(acac)2(CH3OH)2]·CH3OH (1) (where H2L is 2-[((4-methyl)-2-(carboxyl)-imino)]methyl]-8-hydroxyquinoline, and Hacac is acetylacetonate), was successfully synthesized and characterized using single-crystal and elemental analysis, with the auxiliary ligand ß-diketonate and the 8-hydroxyquinoline Schiff base derivative serving as the foundation. Through ligand-to-metal charge transfer, Compound 1 demonstrated remarkable green fluorescence properties, showcasing potential applications in green fluorescence materials and fluorescence sensing. Additionally, Hyaluronic Acid (HA)/Carboxymethyl Chitosan (CMCS) hydrogels were synthesized through a chemical method. Utilizing captopril as a drug model, a novel metal gel granule of captopril was developed and assessed for its inhibitory activity against glioma cells. Molecular docking simulations revealed that only the methanol group in the Ho complex could contribute a polar atom for the formation of binding interactions.

Charge-conversional click polyprodrug nanomedicine for targeted and synergistic cancer therapy.

Polyprodrug nanomedicines hold great potential for combating tumors. However, the functionalization of polyprodrug nanomedicines to improve therapeutic efficacy is restricted by conventional polymerization methods. Herein, we fabricated a charge-conversional click polyprodrug nanomedicine system by metal-free azide-alkyne cycloaddition click polymerization (AACCP) for targeted and synergistic cancer therapy. Specifically, Pt(IV) prodrug-backboned diazide monomer, DMC prodrug-pendent diazide monomer, dialkyne-terminated PEG monomer and azide-modified folate were click polymerized to obtain the target polyprodrug (P1). P1 could self-assemble into nano-micelles (1-NM), where PEG was the hydrophilic shell with folate on the surface, Pt(IV) and DMC prodrugs as the hydrophobic core. Taking advantage of PEGylation and folate-mediated tumor cell targeting, 1-NM achieved prolonged blood circulation time and high tumor accumulation efficiency. Tumor acidic microenvironment-responsive cleavage and cascade activation of pendant DMC prodrug induced surface charge conversion of 1-NM from negative to positive, which promoted tumor penetration and cellular internalization of the remaining 1-NM. After internalization into tumor cells, the reduction-responsive activation of Pt(IV) prodrug to Pt(II) further showed synergetic effect with DMC for enhanced apoptosis. This first designed charge-conversional click polyprodrug nanomedicine exhibited targeted and synergistic efficacy to suppress tumor proliferation in living mice bearing human ovarian tumor model.

Vision transformer-based weakly supervised histopathological image analysis of primary brain tumors.

Diagnosis of primary brain tumors relies heavily on histopathology. Although various computational pathology methods have been developed for automated diagnosis of primary brain tumors, they usually require neuropathologists' annotation of region of interests or selection of image patches on whole-slide images (WSI). We developed an end-to-end Vision Transformer (ViT) - based deep learning architecture for brain tumor WSI analysis, yielding a highly interpretable deep-learning model, ViT-WSI. Based on the principle of weakly supervised machine learning, ViT-WSI accomplishes the task of major primary brain tumor type and subtype classification. Using a systematic gradient-based attribution analysis procedure, ViT-WSI can discover diagnostic histopathological features for primary brain tumors. Furthermore, we demonstrated that ViT-WSI has high predictive power of inferring the status of three diagnostic glioma molecular markers, IDH1 mutation, p53 mutation, and MGMT methylation, directly from H&E-stained histopathological images, with patient level AUC scores of 0.960, 0.874, and 0.845, respectively.

Response of human epidermal growth factor receptor 2-positive colorectal cancer to lapatinib monotherapy: A case report.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) amplification is a molecular driver for a subset of colorectal cancers (CRCs) and one of the major causes of anti-epidermal growth factor receptor (EGFR) treatment failure. Compared to dual anti-HER2 treatments, which have been shown to be effective in HER2-positive metastatic CRC patients, single-agent anti-HER2 therapy is rarely used to treat CRC. CASE SUMMARY: Herein, we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA (ctDNA) testing by next-generation sequencing following the failure of two lines of therapy. Subsequently, the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo. Moreover, serial ctDNA detection was used to monitor the efficacy of lapatinib. The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response. However, a high level of HER2 amplification was detected again at the time of disease progression. Finally, a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression, which may explain the acquired resistance to lapatinib. CONCLUSION: This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy. It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.

Dual Drug Backboned Shattering Polymeric Theranostic Nanomedicine for Synergistic Eradication of Patient-Derived Lung Cancer.

Most of the current nanoparticle-based therapeutics worldwide failing in clinical trials face three major challenges: (i) lack of an optimum drug delivery platform with precise composition, (ii) lack of a method of directly monitoring the fate of a specific drug rather than using any other labelling molecules as a compromise, and (iii) lack of reliable cancer models with high fidelity for drug screen and evaluation. Here, starting from a PP2A inhibitor demethylcantharidin (DMC) and cisplatin, the design of a dual sensitive dual drug backboned shattering polymer (DDBSP) with exact composition at a fixed DMC/Pt ratio for precise nanomedicine is shown. DDBSP self-assembled nanoparticle (DD-NP) can be triggered intracellularly to break down in a chain-shattering manner to release the dual drugs payload. Moreover, DD-NP with extremely high Pt heavy metal content in the polymer chain can directly track the drug itself via Pt-based drug-mediated computer tomography and ICP-MS both in vitro and in vivo. Finally, DD-NP is used to eradicate the tumor burden on a high-fidelity patient-derived lung cancer model for the first time.

Enhancing Therapeutic Efficacy of Cisplatin by Blocking DNA Damage Repair.

Self-repair of nuclear DNA damage is the most known reason that leads to drug resistance of cancer tissue and limited therapeutic efficacy of anticancer drugs. Inhibition of protein phosphatase 2A (PP2A) would block DNA damage-induced defense of cancer cells to suppress DNA repair for enhanced cancer treatment. Here, we combined a PP2A inhibitor LB (4-(3-carboxy-7-oxa-bicyclo[2.2.1]heptane-2-carbonyl) piperazine-1-carboxylic acid tert-butyl ester) and the DNA damage chemotherapeutic drug cisplatin through a simple physical superposition. The two drugs administrated at a ratio of 1:1 exhibited an optional synergistic antitumor efficacy in vitro and in vivo. LB was demonstrated to specifically activate the protein kinase B (Akt) and mitogen-activated protein kinases (MAPK) signaling pathways by PP2A inhibition to overcome cell cycle arrest caused by cisplatin-induced DNA damage.

Overcoming tumor resistance to cisplatin through micelle-mediated combination chemotherapy.

The main obstacles to cancer therapy are the inability to target cancer cells and the acquired drug resistance after a period of chemotherapy. Reduced drug uptake and DNA repair are the two main mechanisms involved in cisplatin resistance. In the present investigation, canthaplatin, a Pt(iv) pro-drug of cisplatin and a protein phosphatase 2A (PP2A) inhibitor (4-(3-carboxy-7-oxa-bicyclo[2.2.1]heptane-2-carbonyl)piperazine-1-carboxylic acid tert-butyl ester), was designed and delivered using PEG-b-PLGA micelles for combination chemotherapy. Polymer/canthaplatin micelles facilitated the delivery of the drug into cancer cells through endocytosis and diminished DNA repair by PP2A inhibition, resulting in enhanced anti-tumor efficiency and excellent reversal ability of tumor resistance to cisplatin both in vitro and in vivo. Additionally, the polymer/canthaplatin micelles could prolong drug residence in the blood and decrease the side effects when compared to cisplatin.

A polymer-(multifunctional single-drug) conjugate for combination therapy.

Combination therapy based on polymer-drug conjugates is one of the exciting developments in polymeric drug delivery systems. A single polymer carrier with two or more drugs attached is advantageous because it provides a platform for synergistic agent action. To expand the concept of combination therapy using a single polymer-drug conjugate, we report a polymer-(multifunctional single-drug) conjugate strategy, in which three different drugs (platinum, azidyl radical and DMC) and two different types of therapies are rationally integrated and then conjugated to an amphiphilic block copolymer. When this polymer-(multifunctional single-drug) conjugate is internalized by cancer cells via endocytosis, the three integrated drugs are expected to be activated and execute therapeutic functions in a sequential fashion under extracellular (UVA irradiation) and intracellular (endosomes/lysosomes) environments to amplify the signals of cancer treatment, especially in cisplatin-resistant cancer cells.

A dextran-platinum(iv) conjugate as a reduction-responsive carrier for triggered drug release.

Reduction-responsive nano-carriers have been confirmed to be promising for intracellular drug delivery. To develop multifunctional polymer-based drug delivery system, a novel dextran-Pt(iv) conjugate was synthesized by conjugating Pt(iv) to the side chains of the hydrophilic dextran and used for doxorubicin (DOX) delivery. Pt(iv) conjugation could change the hydrophilicity of dextran, leading to the self-assembly of dextran-Pt(iv) conjugates with different morphologies. Pt(iv) segments served as the key components in assembly formation and as the antitumor prodrug. Under a reductive environment, Pt(iv) was found to be reduced to its active Pt(ii) form and cleaved from dextran, shifting the hydrophilic-hydrophobic balance of the dextran-Pt(iv) conjugate. The collapse of the assembly structure due to the partial or complete recovery of the hydrophilicity of dextran led to triggered release of DOX. The DOX-loaded dextran-Pt(iv) conjugate obtained by combining the released hydrophobic DOX and recovered hydrophilic Pt(ii), was found to be very effective as an antitumor agent as demonstrated in in vitro cytotoxicity evaluations. This DOX-loaded dextran-Pt(iv) conjugate system provided a new strategy to trigger the release of hydrophobic and hydrophilic drugs at the same time via single reduction-responsive control to provide an enhanced anti-tumor effect.

Correlation of macrophage inflammatory protein-2 expression and brain edema in rats after intracerebral hemorrhage.

Brain edema is one of the most frequent and serious complications of intracerebral hemorrhage (ICH), but its underlying mechanism remains largely unknown. In order to understand whether inflammatory mediators released from the blood after cerebral hemorrhage plays a role in brain edema, we investigated the dynamic change of the inflammatory mediator macrophage inflammatory protein-2 (MIP-2) in rat brain after ICH. Our results indicate that the expression of MIP-2 increases 2 hours and peaks 2 days after ICH. The expression of MIP-2 correlates with NF-kappaB activation and brain water content. These results suggest that MIP-2 expression may play an important role in the development of brain edema after ICH in rats.

The expression and the role of protease nexin-1 on brain edema after intracerebral hemorrhage.

Brain edema is one of the most frequent and serious complications of intracerebral hemorrhage (ICH), but how the ICH cause brain edema is unknown. Our studies were designed to investigate the regulation and distribution of protease nexin-1 (PN-1), thrombin and aquaporin-4 (AQP-4) in brain edema after ICH in rat and human brain in vivo. Our result showed that the severity of cerebral edema resulted from an acute stage of ICH. The PN-1-thrombin system modulated cerebral edema after ICH. Thrombin and AQP-4 increased to aggregate cerebral edema after ICH. In order to control the deleterious effect of thrombin's overexpression, PN-1 appeared quickly and abundantly to inhibit thrombin and lessen the cerebral edema. PN-1 was distributed in neurons and glial cells of cerebral cortex, hippocampus, thalamencephalon, basal ganglia, cerebellum and circum-encephalocoele in rat and human brain. The expression of AQP-4 is different between human and rat. Thus, we demonstrated that the animal experimental approach was, however, not sufficient by itself and needed to be corroborated by observations on human brains.