To investigate the prophylactic effect of compression therapy against chemotherapy-induced peripheral neuropathy (CIPN) through meta-analytic evaluation.

The persistence of drug resistance and relapses post-remission in B-chronic lymphocytic leukemia (B-CLL) underscores the exploration of novel therapeutic interventions. Given the pivotal role of autophagy in cancer cell resistance to apoptosis, this study aims to investigate the therapeutic potential of Berberine in modulating autophagy function associated with drug resistance in B-CLL. Peripheral blood mononuclear cells (PBMCs) from 10 CLL patients and 5 healthy individuals were treated with Berberine and Idelalisib (as a control). Flow cytometry analysis was employed to assess the protein expression levels of Beclin1, indicative of autophagy function, and high mobility group protein 1 (HMGB1), serving as an internal control for drug resistance. Furthermore, qRT-PCR was utilized to measure the expression levels of drug resistance markers including Beclin1, HMGB1, heat shock factor binding protein 1 (HSBP1), and receptor for advanced glycation end products (RAGE). Our findings revealed that Berberine exhibited a dual suppressive effect on Beclin1 and HMGB1 levels compared to the control drug. Moreover, Berberine downregulated the expression of the primary HMGB1 receptor, RAGE, in PBMCs from CLL patients. Notably, no significant alteration was observed in HSBP1 expression, a mediator of autophagy induction, upon Berberine treatment. These findings suggest that Berberine may target specific mechanisms associated with autophagy-mediated drug resistance, underscoring its therapeutic potential in B-CLL. Further clinical trials are warranted to validate the therapeutic efficacy of Berberine in B-CLL.

Many metastatic clear cell renal cell carcinomas (ccRCC) are resistant to immune checkpoint inhibitor therapies, however the mechanisms underlying sensitivity or resistance remain incompletely characterised. We demonstrate that ccRCCs in the Vhl/Trp53/Rb1 mutant mouse model are resistant to combined anti-PD-1/anti-CTLA-4 therapy alone and in combination with additional therapeutic agents that reflect current ccRCC clinical trials. However, in some animals in vivo checkpoint therapy allowed isolated splenic T cells to recognise cultured ccRCC cells from the same animal, implicating the tumour microenvironment in suppression of T cell activation. We identified putative immunosuppressive myeloid cell populations with features similar to myeloid cells in the microenvironment of human ccRCC. The expression patterns of immune checkpoint ligands in both the mouse model and in human ccRCC suggests that several checkpoint systems other than PD-1 and CTLA-4 are likely to represent the dominant T cell suppressive forces in ccRCC. Our findings characterise an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance and pave the way for a systematic functional dissection of the identified potential molecular barriers to effective immune therapy of ccRCC.

Bladder cancer is the most common malignant tumor of the urinary tract. In this study, 90 lupane triterpene derivatives, previously synthesized in the laboratory, were systematically evaluated for their potential effects against bladder cancer by cytotoxicity screening against five urinary tumor cell lines. Bioinformatics and molecular dynamics methods were used to investigate the mechanism of action of compound 27 in depth. Most of the derivatives effectively inhibited tumor cell growth, and structure-activity relationship analysis revealed that introducing an indole moiety significantly enhanced the biological activity. The peak activity was reached when the dibromoalkyl chain length was C = 5 (IC50 = 1.121 μM). By integrating transcriptomic data and TCGA findings, we identified 11 key targets, among which DUSP5 and SCG2 showed significant differential expression. Further analysis revealed meaningful insights into the clinical association, 10-year survival prognosis, and immune infiltration. The present study further clarified the effects of compound 27 on the expression of DUSP5 and SCG2 in tumor cells after treatment by a combination of RNA-seq and RT-qPCR. Molecular docking confirmed the stable binding of compound 27 to DUSP5, which was confirmed by molecular dynamics simulations. Compound 27 inhibited bladder cancer progression by upregulating DUSP5 expression and negatively regulating the p38 MAPK pathway, modulating the immune response and promoting apoptosis.

Oxaliplatin, a key chemotherapeutic agent, often induces resistance in colorectal cancer (CRC) treatment, highlighting the urgent need for reliable biomarkers to predict treatment efficacy. In this study, we aimed to identify key genes associated with oxaliplatin resistance in CRC and to evaluate their potential as prognostic biomarkers. Using CRC patient data from the TCGA dataset, we categorized patients into oxaliplatin-resistant and -sensitive groups and conducted differential expression analysis. Key feature genes were identified through univariate Cox analysis, LASSO regression, and stepwise multivariate Cox regression. The predictive value of the identified markers was validated using logistic regression, weighted gene co-expression network analysis (WGCNA), and external validation in GEO cohorts. The tumor microenvironment (TME) was assessed using the MCP-counter algorithm, and CRC cell experiments were performed to evaluate changes in drug sensitivity following oxaliplatin exposure. Based on TCGA CRC data, we constructed a prognostic index derived from a three-gene signature associated with oxaliplatin resistance. This index was significantly correlated with progression-free survival (PFS) in oxaliplatin-resistant CRC patients and showed robust prognostic performance, with AUCs of 0.848 and 0.861 in gastric cancer and pancreatic adenocarcinoma cohorts, respectively. Notably, TNFAIP2 knockout significantly reduced clonogenic ability in CRC cells following oxaliplatin treatment. Our results identify TLE4, TNFAIP2, and ARGLU1 as key contributors to oxaliplatin resistance in CRC. The oxaliplatin resistance-related gene signature (ORGSig) serves as a promising tool for predicting treatment response and prognosis in CRC patients receiving oxaliplatin-based chemotherapy. This signature also offers potential for guiding personalized therapy and overcoming drug resistance in clinical practice.

Liquids irradiated with nonequilibrium atmospheric pressure plasma exert antitumor effects. Here, we produced plasma-activated acetated Ringer (PAA) and plasma-activated sodium acetate (PASA) solutions, each at 1%, 3%, and 5% mass concentrations. We evaluated the antitumor effects of PAA and PASA on gastric cancer (GC). Two GC cell lines (MKN1-Luc and MKN45-Luc) as well as normal human peritoneal mesothelial cells were subjected to cell viability assays using PAA, 1% PASA, 3% PASA, and 5% PASA. To elucidate the functional mechanisms, we examined morphological changes induced by 3% PASA following 10 min of irradiation. To further elucidate the underlying biological processes, we compared the expression of apoptosis-related proteins following the administration of 3% sodium acetate solution without plasma exposure and 3% PASA irradiated for 10 min. Additionally, MKN45-Luc cells were intraperitoneally injected into mice, followed by intraperitoneal administration of acetated Ringer's solution without plasma exposure (control-1 group), 3% sodium acetate solution without plasma exposure (control-2 group), and 3% PASA irradiated for 10 min (treatment group). Peritoneal dissemination was observed using in vivo bioluminescent imaging and laparotomy. PAA and PASA achieved an antitumor effect in a sodium acetate concentration-dependent manner. PAA and 3% PASA caused significantly less damage to normal peritoneal mesothelial cells compared to GC cells at 5 and 10 min of plasma exposure (p < 0.001). Blebs, indicative of apoptosis, were observed at 1.5 h after 3% PASA treatment in GC cells. 3% PASA treatment increased the expression of phosphorylated MKK3/MKK6 and phosphorylated p38 MAPK, suggesting that apoptosis may be mediated through the p38 MAPK pathway. The intraperitoneal administration of 3% PASA significantly reduced the number of peritoneal nodules, and no adverse events were detected. Here we show that PASA exerted an antitumor effect on GC, indicating that the intraperitoneal administration of 3% PASA may serve as a novel treatment for the peritoneal dissemination of GC.

Uterine serous carcinoma (USC) accounts for 40% of endometrial cancer-related deaths. The standard of care for stages III and IV USC yields a 20%-30% survival at 2 years and a 10%-20% survival at 3-5 years. Recent advances in the second-line treatment of advanced or recurrent USC are rapidly evolving. Targeted therapeutic approaches with the use of lenvatinib plus pembrolizumab, as well as the use of trastuzumab deruxtecan, offer new hope for successful second-line therapies for patients. However, further investigation into novel targeted therapeutic approaches is warranted, given the high burden of disease associated with this aggressive histological subtype. USC shares clinical and genomic similarities with epithelial ovarian cancer, suggesting a correlation with 'BRCAness'. Niraparib, a potent PARP1 and PARP2 inhibitor, was shown to have a positive impact on platinum-sensitive recurrent ovarian cancer, regardless of the presence or absence of BRCA status. Our hypothesis is that patients with stage III, stage IV and platinum-sensitive recurrent USC receiving niraparib maintenance in addition to standard therapy for USC may have an improved progression-free survival.

This study evaluated the clinical characteristics and treatment outcomes of bigger premature infants treated for retinopathy of prematurity (ROP).

Indocyanine green (ICG) demonstrates both photodynamic therapy (PDT) and photothermal therapy (PTT) capabilities but faces challenges including rapid blood clearance, insufficient ROS production, and molecular chaperone-induced thermotolerance. However, highly efficient synchronous targeting delivery of photosensitizer and sensitizer to cancer cells remains a giant challenge due to their significantly different physicochemical properties. To address these limitations, we developed a dual-responsive nano-platform, TCS-βCD@CLRP/PEI-SS@ICG-NPs (I&C-NPs), designed for ICG and chloramphenicol (CLRP) co-delivery and cascade synergetic anti-tumor effect through mitochondrial destruction/photothermal therapy/photodynamic therapy (Mito destruction/PTT/PDT). Mitochondrial-targeted "pocket" cyclodextrin-grafted carboxymethyl chitosan (TCS-βCD) and biodegradable disulfide-grafted polyethyleneimine (PEI-SS) were designed and synthesized. Mitochondrial respiration consumes oxygen in cells like "oxygen consumption for fire", while CLRP, the "fire extinguisher", can inhibit mitochondrial respiration and reduce oxygen consumption. Through multiple intermolecular forces, PEI-SS and TCS-βCD encapsulated ICG with 71.05 % efficiency and CLRP with 78.18 % efficiency, forming I&C-NPs exhibiting 123.5 nm in size and exhibiting a zeta potential of +7.8 mV. These nanoparticles functioned as "On-call firefighter", targeting mitochondria through dual responsiveness to elevated glutathione (GSH) in the tumor microenvironment (TME) and laser-induced photothermal heating. The system achieved GSH-/laser-activated drug release efficiency of >80 % and efficient cascade synergetic anti-tumor efficacy: (1) I&C-NPs target and disrupt the mitochondria of tumor cells, and CLRP acts as a PDT sensitizer to minimize oxygen consumption. (2) The PDT effect can be amplified, generating large amounts of ROS (1.69-fold compared to free ICG) in vivo and showing a reduction of HIF-1α. (3) The production of ROS disrupts heat shock proteins and down-regulates HSP 70 protein expression, decreasing tumor tolerance to hyperthermia and resulting in robust photothermal conversion efficiency. Consequently, GSH-/laser-activated mitochondria-oriented I&C-NPs could co-deliver ICG and CLRP, achieving the cascade synergetic anti-tumor effect of Mito destruction/PTT/PDT with the tumor inhibitory rate > 77 %.

Inositol-requiring enzyme 1α (IRE1α) signaling is one of three arms of the unfolded protein response, playing a vital role in maintaining endoplasmic reticulum homeostasis. Pharmacological modulation of this pathway offers potential therapeutic strategies for various diseases. Molecular glues may regulate protein stability and activity by inducing protein-protein interaction. Here, we find that verteporfin functions as a molecular glue, promoting IRE1α dimerization and activation. Specifically, verteporfin binds to IRE1α, facilitating its dimerization, which relies on the His692 residue. This activation of IRE1α triggers XBP1 splicing and miR-153-mediated downregulation of PTEN, along with AKT phosphorylation. Additionally, we identify the pro-metastasis gene BACH1 as a novel target of miR-153, which is downregulated by IRE1α and verteporfin. While verteporfin inhibits breast cancer cell viability and invasion, its combination with an AKT inhibitor synergistically suppresses breast cancer progression. Our findings establish a mechanistic link between IRE1α and PI3K/AKT signaling, highlighting a possibility for therapeutic intervention.

Cholangiocarcinoma (CCA) often exhibits poor responses to chemotherapy due to mechanisms of chemoresistance (MOCs). The Wnt/β-catenin pathway, hyperactivated in CCA and crucial for cell proliferation, migration, and angiogenesis, may contribute to CCA chemoresistance. This study investigates the role of Wnt/β-catenin in CCA multidrug resistance phenotype and explores the therapeutic potential of combining chemotherapy with Wnt/β-catenin inhibitors.

Obesity is linked to a heightened risk of developing triple-negative breast cancer (TNBC). Obesity-associated triple-negative breast cancer (OA-TNBC) presents limited therapeutic options and is characterized by a poor prognosis. Although Astragaloside IV (ASIV) exhibits anti-tumor properties across different cancers, its effect and mechanisms in OA-TNBC remain unclear.

Angiosarcoma is a rare and aggressive malignancy with limited treatment options. This phase II, multicenter, open-label, single-arm study (AngioCheck) evaluated the efficacy and safety of nivolumab in patients with cutaneous angiosarcoma previously treated with taxane-based chemotherapy.

Cancer remains one of the leading causes of global mortality, necessitating novel therapeutic strategies. Liver X Receptors (LXRα and LXRβ) and the Farnesoid X Receptor (FXR) are nuclear receptors that regulate lipid and cholesterol homeostasis, bile acid metabolism, inflammation, and immune response pathways intricately linked to cellular dysregulation in oncogenesis. Despite their therapeutic potential, these receptors remain underexplored targets in cancer research. This study implements an extensive suite of computational strategies to identify and evaluate potential modulators of LXRα/β and FXR, through virtual screening using resveratrol as the lead scaffold, followed by drug-likeness evaluation and toxicity profiling. Molecular docking (MVD, AutoDock and ML-PLIC) identified C144 (AZD7762), a well-established CHK1 kinase inhibitor, as the top-ranked ligand, demonstrating superior binding affinity and conformational stability via convergent interaction mechanisms. Additionally, reactivity descriptors derived from density functional theory (DFT) and frontier molecular orbital (FMO) analyses further substantiated its favorable electronic properties and chemical stability. Structural pharmacophore mapping using LigandScout confirmed pharmacophoric alignment with receptor active sites, while bioactivity profiles predicted high efficacy. Extensive quantum mechanical analyses (MEP, NBO, Mulliken/NPA, NCI, RDG, ELF, LOL, BSA, HAS) revealed favorable electronic characteristics, stability, charge distribution, and interaction potential. CLC-Pred, biotransformation (RA), pharmacokinetic profiling, molecular dynamics simulations, MM/PBSA and Shermo-based thermodynamic predictions further validated its biostability and systemic compatibility. These findings position C144 (AZD7762) as a promising anticancer candidate targeting LXRα, LXRβ, and FXR pathways. Further optimization and validation through in vitro and in vivo studies are essential for advancing these findings toward clinical application.

Drug efflux mediated by transporter proteins is one of the major mechanisms conferring multidrug resistance (MDR) to antimicrobial agents in bacteria and to chemotherapeutics in cancer cells. Therefore, the development or identification of efflux modulators represents a promising strategy to overcome the resistant phenotype. Various chemical compounds have been tested in experimental studies as reversal agents either in combination with antimicrobial or anticancer drugs and have shown sensitizing activity in resistant bacteria or cancer cell lines. Owing to the common resistance mechanisms exhibited by bacteria and cancer cells, the identification of chemical agents with dual reversal activity offers a strategy to simultaneously combat antibacterial and cancer multidrug resistance.

The dense extracellular matrix (ECM) of stroma-rich solid tumors acts as a significant barrier to effective chemotherapy by hindering drug penetration. In this study, a supramolecular hydrogel was successfully developed, enabling the codelivery and sequential release of hydrophilic and lipophilic drugs designed to target the ECM. The hydrogel is easy to prepare, has self-healing properties and excellent biocompatibility. Upon administration, the hydrogel first releases pirfenidone to inhibit collagen production, weakening the ECM, followed by the release of paclitaxel, which improves tumor penetration. The effectiveness of this sequential drug delivery system was validated in both oral squamous cell carcinoma and pancreatic cancer models, a classic example of a tumor with abundant ECM. In vitro experiments showed controlled sequential release profiles, whereas in vivo experiments using cell-derived and patient-derived xenograft models revealed that the hydrogel was more effective at tumor suppression compared to traditional methods. Single administration of the hydrogel led to long-term localized drug release, maintaining higher concentrations of chemotherapeutic agents in the tumor tissue and effectively reducing the tumor volume. This study provided a promising strategy to enhance chemotherapy in ECM-dense tumors, offering an efficient and minimally invasive method for localized, sustained-release cancer therapy.

This study reports the multifunctional potential of gold nanoparticles (AuNPs) biosynthesized by using Salvia splendens leaf extract (SSLE). The biosynthesized AuNPs were characterized by UV-Visible spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering, followed by the assessment of their anti-cancer, anti-oxidant, anti-inflammatory and anti-bacterial potentials. The biosynthesized SSLE-AuNPs showed a characteristic absorbance peak at 559 nm that corresponds to the surface plasmon resonance (SPR) band of the AuNPs. The zeta potential of SSLE-AuNPs was estimated to be ‒ 21 ± 1.9 mV, and TEM analysis confirmed the particles to be spherical with an average size of 94.8 ± 5.1 nm. The SSLE-AuNPs exhibited dose-dependent antioxidant activity, with IC50 values of 218.5 ± 4.2 µg/mL (DPPH) and 185.3 ± 3.7 µg/mL (ABTS), compared to ascorbic acid (32.1 ± 1.8 µg/mL and 28.6 ± 1.5 µg/mL, respectively. In addition, SSLE-AuNPs exerted potent anti-bacterial effect against Staphylococcus aureus (MIC50 68 ± 2.1 μg/mL) and Klebsiella pneumoniae (MIC50 82 ± 2.3 μg/mL), which was comparable to that of the standard antibacterial agent, tetracycline. Moreover, SSLE-AuNPs induced significant reduction in cellular viability of A549 cells at concentrations of 100, 200 and 400 μg/mL, respectively (p < 0.001). Such cytotoxic potential of SSLE-AuNPs was accompanied by considerable instigation of nuclear fragmentation and condensation, caspase activation, and ROS generation in A549 cells. Furthermore, in vitro studies highlighted the anti-inflammatory potential of SSLE-AuNPs on murine alveolar macrophages (J774A.1) via deflating inflammatory mediators such as the proinflammatory cytokines. To sum up, the present findings have substantiated the antioxidant, antibacterial, anticancer and antiphlogistic properties of SSLE-AuNPs, paving the way for subsequent investigations into green synthesized nano-formulations.

Patients with disseminated metastatic disease from breast cancer are likely to have liver involvement in >50% of cases at some point during disease progression. These patients have a poor prognosis; and, when treated with the standard of care systemic therapy they have a median survival of <9-months. Increasing survival in breast cancer patients will likely require the administration of better therapies that are specifically targeted to treat distant metastases. One approach to increasing treatment efficacy for breast cancer liver metastases is through the application locoregional therapies. Locoregional therapies are an appealing interventional approach for breast cancer patients with liver metastases since these tumor lesions are accessible via minimally invasive procedures that can be administered using either ultrasound or CT imaging. Current locoregional therapies to treat breast cancer liver metastases are non-specific and have not produced significant increases in survival. The goal of this study was to design and test a targeted locoregional therapeutic intervention for breast cancer liver metastases. The lead candidate, a fixed-dose small-molecule drug called MBC-005, was tested in vitro and then the efficacy was evaluated in a BALB/c mouse liver metastases model. A novel formulation of N-allyl noroxymorphone hydrochloride incorporated into an alginate-based gel overcomes many of the limitations associated with the administration of small-molecule drugs, which include solubility, off-target toxicity, and enzymatic degradation. In vitro results demonstrated that MBC-005 mediated its anti-tumorigenic effect through a p21-dependent mechanism via a novel molecular pathway, in which N-allyl noroxymorphone component of MBC-005 stimulated the opioid growth factor receptor to increase p21 expression. Intratumoral administration of MBC-005 increased survival 3.9-fold in mice and significantly decreased tumor volume 4-fold. While many cytotoxic therapies increase p21 expression as a response to DNA damage, MBC-005 increased p21 expression independent cytotoxic DNA damage. MBC-005 did not induce off-target toxicity; and, as such, would be amenable to multiple rounds of administration. Nevertheless, it is notable that the positive effects of MBC-005 treatment on increasing survival and decreasing tumor volume in mice was achieved using a single dose.

Despite advancements in treatment for B-cell non-Hodgkin lymphoma (B-NHL) in recent decades, many patients still relapse or are refractory to treatment, which represents a high unmet medical need. Novel CD20 × CD3 T-cell-engaging bispecific antibodies (bsAbs) have created a new paradigm for the treatment of B-NHL. Pivotal studies of four CD20 × CD3 bsAbs, mosunetuzumab, glofitamab, epcoritamab, and odronextamab, as monotherapy, have demonstrated robust responses with generally manageable safety profiles in patients with relapsed or refractory follicular lymphoma and diffuse large B-cell lymphoma after ≥ 2 lines of systemic therapy. These agents have presented unique challenges (e.g., cytokine release syndrome [CRS]), which have required different strategies to overcome. This review provides a comprehensive overview of the clinical development of these four CD20 × CD3 bsAbs that have been investigated for the treatment of B-NHL, with a specific focus on translational assessments to select starting doses in first-in-human studies, management of CRS, application of modeling and simulation approaches to aid dose escalation and optimization/selection, and strategies used in the design of phase I-III clinical trials. By highlighting learnings and experiences from these four bsAbs assessed, which have not been summarized collectively elsewhere, we aim to promote more efficient study design for novel bsAbs in B-NHL in the future.

Lung cancer is a leading cause of cancer deaths worldwide and new therapeutic approaches are needed. This study investigates the efficacy of a new zinc oxide-based nanomedicine in a mouse model of heterotopic lung cancer. C57BL/6 mouse model with Lewis lung carcinoma (LL2) cells was used. The mice were treated with different doses of nanodrug, cisplatin, or phosphate-buffered saline. Tumor growth, metastasis, markers for oxidative stress, and immune responses, in particular the infiltration of CD8+ T cells, were examined. The nanodrug significantly reduced tumor size, inhibited metastasis, and improved survival compared to the control group. Moreover, no significant toxic effect was observed in hematological, biochemical and histopathological analyses. Furthermore, the nanodrug altered the tumor microenvironment in favor of immune system activation by modulating the level of oxidative stress and increasing CD8+ cell infiltration. The results show that this new nanomedicine may be a candidate for an effective treatment for lung cancer.