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BioRxiv : the Preprint Server For... Jun 2024While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life....
While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by has the potential to diminish unwanted effects of fumarates while retaining efficacy.
PubMed: 38915544
DOI: 10.1101/2024.06.10.598291 -
RSC Advances Jun 2024Synergistic photodynamic therapy (PDT) with other therapeutic modalities can enhance the therapeutic efficacy of tumor treatment and reduce the adverse effects...
Synergistic photodynamic therapy (PDT) with other therapeutic modalities can enhance the therapeutic efficacy of tumor treatment and reduce the adverse effects associated with drug leakage and off-target accumulation. However, shaping combined strategies for synergistic therapy remains challenging. Herein, we developed versatile hybrid liposomes self-assembled from Ce6-lipid conjugates and loaded with the chemo drug doxorubicin (DOX) and ferroptosis inducer FeO nanoparticles for synergistic PDT/chemo/ferroptosis therapy. Abundant ROS are generated by PDT upon 650 nm light irradiation, FeO-mediated Fenton reaction, and DOX-induced apoptosis. Furthermore, amplifying oxidative stress in cancer cells to disrupt cellular redox homeostasis could accelerate tumor cell death through oxidative damage to lipids, proteins, and DNA. Overall, this work highlights liposome-based therapeutic nanoformulations, thus offering a breakthrough redox homeostasis-based synergistic PDT/chemo/ferroptosis therapy for lung cancer.
PubMed: 38915327
DOI: 10.1039/d4ra03361b -
RSC Advances Jun 2024Development of new effective EGFR-targeted antitumor agents is needed because of their clinical significance. A new series of imidazolone-sulphonamide-pyrimidine hybrids...
Development of new effective EGFR-targeted antitumor agents is needed because of their clinical significance. A new series of imidazolone-sulphonamide-pyrimidine hybrids was designed and synthesized as modified analogs of some reported EGFR inhibitors. The cytotoxic activity of all the synthesized hybrids was investigated against the breast MCF-7 cancerous cell line using doxorubicin (Dox) as a positive control. 4-(Furan-2-ylmethylene)imidazolone-sulphonamide-pyrimidine 6b had the best potent activity against MCF-7 cells with IC result of 1.05 μM, which was better than Dox (IC = 1.91 μM). In addition, mechanistic studies revealed the ability of compounds 5g, 5h and 6b to inhibit EGFR kinase. Cell cycle analysis revealed that compound 6b can halt MCF-7 cells at the G1 phase with a concomitant decrease in cellular percentage at the S and G2/M phases. This compound produced a noticeable rise in the proportion of apoptotic cells with regard to the untreated control. Furthermore, the effects of hybrid 6b on the expression levels of pro-apoptotic Bax and pro-survival Bcl2 were assessed. The results showed that this compound upregulated the level of Bax expression as well as declined the expression value of Bcl-2 with regard to the untreated control.
PubMed: 38915323
DOI: 10.1039/d4ra03157a -
Journal of Hematopathology Jun 2024Quadruple-hit lymphomas are extremely rare non-Hodgkin lymphomas with a reported dismal prognosis in the few reported cases. A "quadruple hit" has been defined by the...
Quadruple-hit lymphomas are extremely rare non-Hodgkin lymphomas with a reported dismal prognosis in the few reported cases. A "quadruple hit" has been defined by the presence of concurrent MYC, BCL2, BCL6, and CCND1 chromosomal rearrangements. We report a new case of a quadruple hit lymphoma in a 73-year-old Hispanic man who presented with an enlarging left-sided neck mass. Computed tomography showed a 1.9-cm mass in left the tonsil with bulky cervical lymphadenopathy. The presence of all four chromosomal rearrangements can reportedly occur with disease progression in both diffuse large B-cell lymphomas and mantle cell lymphomas. Further characterization of the tumor by next-generation sequencing may be of benefit to delineate between these two possibilities. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing were used to confirm and classify the diagnosis. Histologic sections of the cervical lymph node demonstrated an atypical lymphoid infiltrate with large and pleomorphic cells, which were positive for CD20, CD10, BCL1 (Cyclin D1), BCL2, BCL6, and cMYC and negative for CD5 and SOX11 on immunohistochemistry with a Ki-67 proliferative index of 70%. FISH demonstrated MYC, BCL2, BCL6, and CCND1 rearrangements and the diagnosis of high-grade B-cell lymphoma with MYC, BCL2, BCL6, and CCND1 was rendered. Our patient was treated with dose adjusted etoposide, doxorubicin, cyclophosphamide, prednisone, and rituximab chemotherapy and has been in remission for 20 months.
PubMed: 38914869
DOI: 10.1007/s12308-024-00593-8 -
BMJ Case Reports Jun 2024Intracardiac lymphomas are exceedingly rare accounting for only 1% of all primary cardiac tumours. Historically, due to their insidious development and non-specific...
Intracardiac lymphomas are exceedingly rare accounting for only 1% of all primary cardiac tumours. Historically, due to their insidious development and non-specific clinical presentation, the diagnosis has been challenging with most cases being confirmed on post-mortem examination. Our case report details the experience of a previously fit and active woman in her 60s who presented with gradual onset exertional dyspnoea. Through a series of multimodal imaging tools (including echocardiogram, cardiac MRI, CT and positron emission tomography-CT) and biopsy, we confirmed the diagnosis of intracardiac diffuse large B-cell lymphoma. Our patient was managed with chemotherapy and went on to demonstrate excellent radiological response with near-complete resolution of the intracardiac mass. Subjectively, our patient reported significant improvement in exercise tolerance within weeks of commencing treatment.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Female; Heart Neoplasms; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Echocardiography; Dyspnea; Magnetic Resonance Imaging; Tomography, X-Ray Computed; Cyclophosphamide; Positron Emission Tomography Computed Tomography; Diagnosis, Differential; Doxorubicin; Biopsy
PubMed: 38914528
DOI: 10.1136/bcr-2023-259242 -
International Journal of Pharmaceutics Jun 2024The potential of camel milk-derived exosomes (CMDE) to enhance the bioavailability of Cannabidiol (CBD) was investigated. CBD-CMDE formulation was prepared using an...
The potential of camel milk-derived exosomes (CMDE) to enhance the bioavailability of Cannabidiol (CBD) was investigated. CBD-CMDE formulation was prepared using an established procedure and its particle size was 138.4 ± 4.37 nm, and CBD entrapment efficiency of 56.56 ± 4.26 %. In-vitro release studies showed release of 78.27 ± 5.37 % and 46.42 ± 4.75 % CBD from CMDE and control CBD formulation respectively in pH 6.8 at 24 hr. The apparent permeability (Papp) of CBD-CMDE was found to be enhanced by 3.95-fold with Papp of 22.9*10 ± 0.34 cm/sec as compared to control CBD formulation with Papp of 5.8*10 ± 0.65 cm/sec in MDCK cells. CBD-CMDE was found to be more potent than CBD in 2D cytotoxicity assay with IC values of 3.6 ± 0.54 µM, 3.88 ± 0.54 µM and 7.53 ± 0.59 µM, 7.53 ± 0.59 µM against Doxorubicin (DOX) resistant MDA-MB-231 and Rapamycin (RM) resistant MDA-MB-468 breast cancer cells respectively. Moreover, 3D spheroids assay results demonstrated CBD-CMDE with IC values of 14 ± 0.85 µM, 15 ± 0.07 µM as compared to CBD alone with IC values of 25 ± 0.93 µM, 34.7 ± 0.08 µM in MDA-MB-231 DOX RT cells and MDA-MB-468 RM RT cells respectively. In-vivo PK studies showed enhanced bioavailability of CBD from CBD-exosomes with AUC of 1350.56 ± 187.50 h.ng/mL as compared to CBD control formulation with AUC of 351.95 ± 39.10 h.ng/mL with a single oral dose of 12 mg/kg. The data indicate that CMDE significantly improved the oral bioavailability of CBD. Overall, CMDE can be used to enhance the oral absorption of poorly bioavailable APIs.
PubMed: 38914353
DOI: 10.1016/j.ijpharm.2024.124375 -
Journal of the National Cancer Institute Jun 2024In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab+chemotherapy then adjuvant pembrolizumab significantly improved pathological complete response and event-free...
BACKGROUND
In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab+chemotherapy then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522.
METHODS
Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel+carboplatin then 4 cycles of doxorubicin (or epirubicin)+cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. EORTC QLQ-30 and QLQ-BR23 were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1/cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with ≥60%/80% completion/compliance were assessed using a longitudinal model (no alpha error assigned).
RESULTS
Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab+chemotherapy [N = 762] vs placebo+chemotherapy [N = 383]) in LS mean change from baseline to week 21 in QLQ-C30 GHS/QoL, emotional functioning, and physical functioning were -1.04 (95% CI, -3.46 to 1.38), -0.69 (95% CI, -3.13 to 1.75), and -2.85 (95% CI, -5.11 to - 0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [N = 539] vs placebo [N = 308]) in LS mean change from baseline to week 24 were -0.41 (95% CI, -2.60 to 1.77), -0.60 (95% CI, -2.99 to 1.79), and -1.57 (95% CI, -3.36 to 0.21).
CONCLUSIONS
No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab+chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo+chemotherapy in early-stage TNBC.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT03036488.
PubMed: 38913881
DOI: 10.1093/jnci/djae129 -
Methods in Molecular Biology (Clifton,... 2024Hodgkin lymphoma (HL) is one of the most common lymphomas, with an incidence of 3 per 100,000 persons. Current treatment uses a cocktail of genotoxic agents, including...
Hodgkin lymphoma (HL) is one of the most common lymphomas, with an incidence of 3 per 100,000 persons. Current treatment uses a cocktail of genotoxic agents, including adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), along with or without radiotherapy. This treatment regimen has proved to be efficient in killing cancer cells, resulting in HL patients having a survival rate of >90% cancer-free survival at five years. However, this therapy does not have a specific cell target, and it can induce damage in the genome of non-cancerous cells. Previous studies have shown that HL survivors often exhibit karyotypes characterized by complex chromosomal abnormalities that are difficult to analyze by conventional banding. Multicolor fluorescence in situ hybridization (M-FISH) is a powerful tool to analyze complex karyotypes; we used M-FISH to investigate the presence of chromosomal damage in peripheral blood lymphocytes from five healthy individuals and five HL patients before, during, and one year after anti-cancer treatment. Our results show that this anti-cancer treatment-induced genomic chaos that persists in the hematopoietic stem cells from HL patients one year after finishing therapy. This chromosomal instability may play a role in the occurrence of second primary cancers that are observed in 10% of HL survivors. This chapter will describe a protocol for utilizing M-FISH to study treatment-induced genome chaos in Hodgkin's lymphoma (HL) patients, following a brief discussion.
Topics: Hodgkin Disease; Humans; In Situ Hybridization, Fluorescence; Chromosome Aberrations; Doxorubicin; Genome, Human; Antineoplastic Combined Chemotherapy Protocols; Chromosomal Instability; Lymphocytes; Bleomycin
PubMed: 38913314
DOI: 10.1007/978-1-0716-3946-7_14 -
AMB Express Jun 2024
PubMed: 38913277
DOI: 10.1186/s13568-024-01724-1 -
Cancer Chemotherapy and Pharmacology Jun 2024Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages...
Immunoregulatory cyclophilin a improves low-dose chemotherapy with a modulation of the immune tumor microenvironment in experimental models of melanoma B16 and lymphoma EL4 in vivo.
PURPOSE
Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC.
METHODS
In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo.
RESULTS
Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses.
CONCLUSION
RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.
PubMed: 38913118
DOI: 10.1007/s00280-024-04691-3