Search Results (275)

Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD⁺) hydrolase involved in axonal degeneration and neuronal cell death. SARM1 plays a pivotal role in triggering the neurodegenerative processes that underlie peripheral neuropathies, traumatic brain injury, and neurodegenerative diseases. Importantly, SARM1 knockdown or knockout prevents the degeneration; as a result, SARM1 has been attracting attention as a potent therapeutic target. In recent years, the development of several SARM1 inhibitors derived from synthetic chemical compounds has been reported; however, no dietary ingredients with SARM1 inhibitory activity have been identified. Therefore, we here focused on dietary ingredients and found that carnosol, an antioxidant contained in rosemary, inhibits the NAD⁺-cleavage activity of SARM1. Purified carnosol inhibited the enzymatic activity of SARM1 and suppressed neurite degeneration and cell death induced by the anti-cancer medicine vincristine (VCR). Carnosol also inhibited VCR-induced hyperalgesia symptoms, suppressed the loss of intra-epidermal nerve fibers in vivo, and reduced the blood fluid level of phosphorylated neurofilament-H caused by an axonal degeneration event. These results indicate that carnosol has a neuroprotective effect via SARM1 inhibition in addition to its previously known antioxidant effect via NF-E2-related factor 2 and thus suppresses neurotoxin-induced peripheral neuropathy. Full article

A quinoline unit is present in many natural products and is an attractive pharmacophore for the development of clinical drugs, including antineoplastics. The title compound (QN) was synthesized via the condensation reaction between quinoline-2-carboxaldehyde and 2-nitrobenzhydrazide. QN’s structure was examined by X-ray diffraction and features extensive stacking interactions in the crystal. The compound is weakly toxic to HepG2 cells, with an IC₅₀ exceeding 400 μM for 48 h exposure. QN at 50 μM, with the dose reduction index in the range of 1.9–4.4, potentiated the cytotoxicity of several clinical chemotherapeutic drugs, including doxorubicin and other topoisomerase inhibitors, vincristine, and carboplatin, but not cisplatin or 5-fluorouracil. The calculated ADME parameters predict satisfactory drug-like properties for QN. Full article

Canine transmissible venereal tumor (CTVT) is a contagious neoplasm with low metastatic potential, primarily affecting free-roaming and stray dogs. Despite its global presence, epidemiological data from some regions remain limited. This study employed a retrospective observational design and analyzed 131 CTVT cases diagnosed via cytology or histopathology at a veterinary teaching hospital in Belo Horizonte, Brazil, aiming to describe the anatomical distribution, treatment outcomes, and epidemiological patterns. Most affected dogs were mixed-breed (70.2%) and female (61.1%), with a median age of 4.5 years. Genital involvement was most common (87.0%), followed by cutaneous (10.7%), nasal (6.1%), and oral (4.6%) tumors. Concurrent tumor locations included genital-cutaneous (5.3%) and oronasal (3.1%). Females had more genital cases, while males were more likely to present cutaneous and nasal CTVT, with 5.2 times greater odds for nasal tumors (OR = 5.2; 95% CI = 1.2–25.9). Purebred dogs also had increased odds of nasal involvement (OR = 8.2; 95% CI = 1.9–40.7). Vincristine chemotherapy was effective, and the number of sessions required for a complete response was not associated with clinical presentation, breed or size. These findings highlight the varied presentations of CTVT and reinforce the need for clinical awareness of non-genital forms. Full article

Objectives: ABCB1-mediated multidrug resistance (MDR) compromises chemotherapy efficacy in colorectal cancer (CRC). Despite decades of research, no selective ABCB1 inhibitor has achieved clinical success. This study investigates ML210 as a novel ABCB1-specific inhibitor to reverse ABCB1-driven MDR. Methods: Cytotoxicity assays (MTT) were performed on ABCB1-overexpressing HCT-8/V and ABCG2-overexpressing S1-M1-80 CRC cells. Drug accumulation (doxorubicin/mitoxantrone) was quantified via flow cytometry, and cell cycle effects were analyzed using propidium iodide staining. Molecular docking utilized the ABCB1 crystal structure. Results: ML210 selectively reversed ABCB1-mediated resistance to doxorubicin and vincristine in HCT-8/V cells, enhancing intracellular drug accumulation without affecting ABCG2 activity. It induced cell cycle arrest in ABCB1-overexpressing cells and did not alter ABCB1 protein expression. Molecular docking revealed stable binding of ML210 within the ABCB1 substrate pocket through hydrophobic interactions and hydrogen bonding. Conclusions: ML210 is a selective ABCB1 inhibitor that circumvents MDR via direct transport blockade, offering a targeted strategy against ABCB1-mediated chemoresistance in CRC. Its specificity for ABCB1 over ABCG2 highlights potential clinical advantages. Full article

High-risk neuroblastoma remains a clinically challenging pediatric cancer, with an approximate five-year survival rate of ~60%. Frontline therapy for this group of patients includes surgery and intensive chemotherapy that involves combinations of the tubulin inhibitor vincristine with several other chemotherapeutics. Unfortunately, unresponsiveness to therapy and relapse are common, with tumors often displaying resistance to vincristine. Recently, we characterized a novel set of tubulin inhibitors that are distinct from vincristine and bind within the colchicine binding site present on tubulin monomers. Colchicine binding site inhibitors (CBSIs) have gained traction as improved chemotherapeutics due to their potential to overcome tubulin inhibitor-induced resistance. In this study, we investigate the functional impact of CBSI treatment on multiple neuroblastoma cell lines, including those that are vincristine-resistant. We demonstrate that our newly developed compounds are effective at disrupting cell division in non-resistant and resistant cells and have cellular activity against vincristine-resistant cell lines. Interestingly, we find that vincristine-resistant cell lines differ in their ability to undergo apoptotic cell death in response to CBSI treatment. Taken together, these findings provide a solid foundation to further investigate the utility of CBSIs for neuroblastoma treatment, while highlighting the distinct resistance mechanisms that can emerge in these childhood cancers. Full article

Objective: To evaluate treatment outcomes and prognostic factors in patients with ultra-high-risk gestational trophoblastic neoplasia (GTN) compared to those with low-risk and high-risk GTN. Methods: A retrospective review of medical records was conducted for GTN patients treated at Chiang Mai University Hospital, Chiang Mai, Thailand, between January 1999 and December 2019. Overall and risk-specific survival rates were estimated using the Kaplan–Meier method, and prognostic factors were analyzed through univariate and multivariate analyses. Results: During the study period, 160 patients with GTN were identified, including 98 (61.2%) classified as low-risk, 31 (19.4%) as high-risk, and 31 (19.4%) as ultra-high-risk. One patient in the low-risk group and one in the high-risk group underwent hysterectomy without adjuvant chemotherapy due to spontaneous regression of serum β-hCG (human chorionic gonadotropin). Additionally, one patient with ultra-high-risk GTN died before receiving chemotherapy. Among the 97 low-risk GTN patients, 80 (82.5%) were treated with either single-agent methotrexate or actinomycin D. Among the 30 high-risk GTN patients, 20 (66.7%) received EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) as first-line chemotherapy, while 24 (80%) of the 30 ultra-high-risk GTN patients received EMA/CO as first-line treatment. Following first-line chemotherapy and/or salvage treatment, patients with ultra-high-risk GTN had significantly worse outcomes compared with those with low- and high-risk GTN, with remission rates of 63.3%, 96.9%, and 80.0%, respectively (p < 0.01). The five-year overall survival rate for patients with ultra-high-risk GTN was significantly lower than that for patients with low- and high-risk GTN (56% vs. 96% and 80%, respectively; p < 0.001). On multivariable analysis, significant prognostic factors included antecedent term pregnancy (hazard ratio [HR] = 11.50; 95% confidence interval [CI], 3.56–37.22; p < 0.01) and brain metastasis (HR = 4.61; 95% CI, 1.73–12.28; p < 0.01). Conclusions: Ultra-high-risk GTN accounts for only a small proportion of GTN cases but it is associated with poor survival rate and responsible for the majority of GTN-related deaths. Antecedent term pregnancy and brain metastasis were identified as significant prognostic factors. Full article

Approximately 5% to 8% of patients with Wilms tumour have bilateral disease. The prevalence of bilateral Wilms tumour (BWT) is higher in individuals with genetic predisposition syndromes than in those without. The goal of therapy is to preserve as much renal tissue as possible without compromising the overall oncological outcomes, utilising neoadjuvant chemotherapy followed by nephron sparing surgery (NSS) if possible. The Children’s Oncology Group (COG) in North America and the International Society of Paediatric Oncology (SIOP) in Europe have developed the main protocols for the treatment of BWT. Both protocols are similar: initial biopsies are not indicated, and they both recommend surgical resection at week 6 or no later than week 12. Chemotherapy includes the use of vincristine and actinomycin-D in both protocols, but the COG approach also includes the use of doxorubicin, which is a cardiotoxic drug with important long-term effects on the cardiac function of childhood cancer survivors. What doxorubicin adds to patients with BWT in terms of radiological tumour response, resectability, long-term renal function and overall survival, is still not very well described and it may be variable depending on the tumour biology. This article describes the current approach for BWT in North America and Europe, focusing on the potential effect that doxorubicin may have on patient outcomes. Full article

Background/Aim: Among NF1-dependent tumors, the most common are optic pathway gliomas (OPGs). The objective of this study was the retrospective analysis of the course, indications for treatment, and effects of therapy for NF1-OPGs. Patients and Methods: We analyzed demographics, clinical and genetic data, imaging and ophthalmological parameters, their impact on therapeutic decisions, and the effectiveness of the therapy in 92 patients. Results: OPGs were unilateral in 55.4% of patients and bilateral in 44.6%. Post-contrast enhancement in MRI was observed in 67.4%. Oncological treatment was required in 16.3% of patients with median age 3.8 years. Factors significant in multivariate analysis contributing to the need of oncological treatment were: amblyopia and proptosis. Factors contributing to amblyopia were: strabismus, proptosis, co-occurrence of epilepsy, bilateral OPGs, and thickness of the optic nerve ≥ 8 mm. The first line of oncological treatment included vincristine + carboplatin or monotherapy with vinblastine. The use of subsequent lines of oncological treatment was necessary in 46.7% patients. Conclusions: The following conclusions, suggest modification of the approach in the management of patients with NF1-OPG, summarize the presented study: (1) perform the first MRI after the age of 1 year, (2) reduce the frequency of follow-up scans in the first year of observation in patients with isolated involvement of intraocular and/or intraorbital segments of the optic nerve, (3) refrain from administering contrast during control MRI examinations of the orbits after OPG diagnosis; (4) in patients with co-occurring psychomotor delay or treated with antiepileptic drugs, do not make decisions about oncological therapy when visual acuity deterioration is observed, without progression in optical coherence tomography (OCT), visual evoked potentials (VEP), and MRI. Full article

Background: Primary pleural lymphoma is a rare disease posing diagnostic and therapeutic challenges. Case presentation: We present a 65-year-old woman with dyspnoea, cough, and asthenia, with no significant past medical history. Chest X-ray and computed tomography showed extensive right pleural effusion. Video-assisted thoracoscopy demonstrated multiple pleural nodules, while pleural fluid analysis revealed a lymphocytic exudate, and finally, a primary pleural lymphoma diagnosis was confirmed by immunohistochemistry analysis in pleural nodules biopsy. Discussion: In this regard, eight cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, dexamethasone, and rituximab were indicated, and after one year of follow-up, complete clinical and radiological remission was observed. Conlusions: We conclude that video-assisted thoracoscopy with an appropriate histopathological examination remains the gold standard for diagnosis, while R-CHOP chemotherapy plus rituximab may represent a highly effective therapeutic choice. Full article

Background: Lymphomas account for approximately 10% of cancers diagnosed during pregnancy, with Hodgkin’s lymphoma being the most common. However, non-Hodgkin lymphomas, including primary mediastinal large B-cell lymphoma (PMBCL), also represent a significant proportion. Both mediastinal lymphomas and pregnancy develop a hypercoagulable state, increasing the risk of venous thromboembolism and massive pulmonary embolism (PE), requiring extracorporeal membrane oxygenation (ECMO). Methods: Clinical data, blood test and imagings have been collected by the medical records of the patient. Results: We present a 25-year-old woman, at 32 weeks of gestation, who presented to the emergency department with progressive dyspnea and asthenia. Echocardiography revealed a hemodynamically significant pericardial effusion and severe right ventricular dysfunction. Given the severity of her condition, she underwent an emergency caesarean section and subsequently a pericardial drainage. A chest computed tomography scan revealed an incidental mediastinal mass along with a massive PE. Despite pericardial drainage, she remained hemodynamically unstable. Since thrombolysis was contraindicated for the recent cesarean section, venoarterial ECMO was initiated. Systemic anticoagulation was guaranteed by heparin, which shifted to argatroban for heparin resistance. The mediastinal mass was also biopsied, and the diagnosis of PMBCL carried out. Cytoreductive chemotherapy was initiated with the COMP-R regimen (i.e., cyclophosphamide, vincristine, methotrexate, prednisone, and rituximab), and the patient progressively improved up to ICU and hospital discharge. Conclusions: This case highlights the challenges in managing a complicated patient requiring early multidisciplinary intervention, which was crucial for stabilizing the patient and optimizing fetal and maternal prognosis. Full article

Background: Malignant Ectomesenchymoma (MEM) is a rare, aggressive soft tissue neoplasm with both neuroectodermal and mesenchymal differentiation. Congenital cases are extremely uncommon, posing significant diagnostic and therapeutic challenges. Case Presentation: We report a case of a full-term male neonate presenting with a large congenital neck mass and respiratory distress at birth. Imaging revealed a lobulated, heterogeneously enhancing mass in the left submandibular region with a mass effect on the airway. Open biopsy and gross resection on day six of life confirmed MEM with rhabdomyoblastic and neuroectodermal differentiation. Post-surgical staging classified the tumor as Stage I, Clinical Group II. Despite initial chemotherapy with Vincristine, Actinomycin, and Cyclophosphamide (VAC), tumor recurrence was detected at week nine of chemotherapy, necessitating a transition to Vincristine, Irinotecan, and Temozolomide (VIT). Discussion: MEM is an extremely rare neoplasm in infants, particularly in congenital presentations. Diagnosis is challenging due to its mixed histopathological features and broad differential diagnosis, including rhabdomyosarcoma, fibrosarcoma, lymphangioma, and neuroblastoma. Management typically involves multimodal therapy, with surgical resection being the mainstay of treatment. Chemotherapy is often tailored to the tumor’s most aggressive component, though standardized treatment protocols remain undefined. Conclusions: This case highlights the importance of early recognition and a multidisciplinary approach in managing congenital MEM, as a differential diagnosis of soft tissue masses in infants, particularly in the head and neck region. Full article

Background/Objectives: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant dose-limiting side effect of many effective anticancer agents, including vincristine. While CIPN adversely affects both oncological outcomes and the quality of life for cancer patients, the in vivo mechanisms behind CIPN pathology remain largely unknown, and effective treatments have yet to be developed. In this study, we established a novel Drosophila model of CIPN using vincristine to explore the molecular mechanisms underlying this condition. Methods: We assessed the impact of vincristine exposure on thermal nociception in Drosophila larvae using a programmable heat probe. Additionally, we investigated vincristine-induced mitochondrial dysfunction and dendritic abnormalities in class IV dendritic arborization (C4da) neurons with various fluorescent protein markers. Results: We found a dose-dependent increase in thermal hypersensitivity, accompanied by changes in the sensory dendrites of C4da neurons in vincristine-treated fly larvae. Moreover, vincristine significantly enhanced mitochondrial ROS production and mitophagy—a selective autophagy that targets dysfunctional mitochondria—indicating vincristine-induced mitochondrial dysfunction within C4da neurons. Surprisingly, inhibiting the pyruvate dehydrogenase complex (PDH), a key mitochondrial metabolic enzyme complex, effectively rescued the mitochondrial and sensory abnormalities caused by vincristine. Conclusions: Findings from this first Drosophila model of vincristine-induced peripheral neuropathy (VIPN) suggest that mitochondrial dysfunction plays a critical role in VIPN pathology, representing PDH as a potential target for the treatment of VIPN. Full article

Vincristine (VCR) is a chemotherapeutic agent classified as a vinca alkaloid. Royal jelly (RJ) is a significant bee product produced by worker bees, characterized by its high protein content. This study aims to investigate the protective effects of RJ against VCR-induced liver damage. VCR was intraperitoneally administered at a dose of 0.1 mg/kg body weight (b.w.) and RJ was orally administered at doses of 150 and 300 mg/kg b.w. Both treatments were applied to the rats on days 1–6 and 9–14. The composition of RJ was analyzed using LC-MS/MS, revealing the presence of 15 different phytochemical compounds with strong antioxidant properties. Serum samples obtained from the rats were analyzed for ALT, ALP, and AST levels. While these enzyme levels were significantly elevated in the VCR group, a notable reduction was observed following RJ administration. Additionally, SOD, CAT, GPx, and GSH antioxidant parameters, along with MDA levels, were evaluated in liver tissue samples. The results indicated a decrease in SOD, CAT, GPx, and GSH activities/levels and an increase in MDA levels in the VCR group. Furthermore, ELISA was used to assess JAK2, STAT3, and mTOR/PI3K/AKT signaling pathways. VCR administration led to a decrease in mTOR/PI3K/AKT levels and an increase in JAK2 and STAT3 levels. In addition, the mRNA transcription levels of inflammation (NF-κB, TNF-α, and IL-1β), endoplasmic reticulum (ER) stress (IRE-1, GRP78, PERK, and ATF-6), and autophagy markers (LC3A and LC3B) were examined. A significant increase in inflammation, ER stress, and autophagy-related markers was observed in the VCR-treated group. Lastly, the protein expression levels of Bax, Bcl-2, Caspase-3, and NF-κB were evaluated. VCR treatment increased Bax, Caspase 3, and NF-κB levels, whereas Bcl-2 levels were decreased. However, following RJ administration, all these parameters were reversed, demonstrating significant improvements. In conclusion, these findings suggest that RJ may exert a protective effect against VCR-induced liver damage. Full article

The current standard of care for treatment of intermediate–large B-cell lymphoma in dogs is a CHOP-based chemotherapy protocol. On-protocol disease progression is reported to be temporally associated with cyclophosphamide administration. The objectives of this prospective pilot clinical trial were to describe the adverse event profile and identify early signal of efficacy of a novel cyclophosphamide-free chemotherapy protocol consisting of temozolomide, doxorubicin, vincristine, and prednisone (THOP) as first-line treatment in dogs with diffuse large cell B-cell lymphoma. Treatment-naïve dogs with intermediate–large B-cell lymphoma were enrolled. THOP was administered as a three-week cycle for five cycles. Fourteen dogs were enrolled. All dogs achieved complete remission with a median time to progression (TTP) of 269 days and a median survival of 433 days. There were five grade III and four grade IV hematologic toxicities reported; one grade III gastrointestinal toxicity was observed. THOP appears to be well tolerated and an effective first-line protocol for the treatment of intermediate–large B-cell lymphoma in dogs. Full article

Plant extracts are increasingly becoming an answer to expensive, high-dose, synthesized chemotherapy, with milder side effects and easier accessibility. Many botanical plants contain active ingredients, such as terpenoids and alkaloids, which may combat cancer; however, studies need to be performed to test whether they are solely effective enough and whether the extracted compounds are selective for the tumor itself. Many chemotherapy drugs were initially of botanical origin, such as vincristine from Catharanthus roseus and paclitaxel from the Taxus baccata tree. The objective of this review is to assess the mechanisms of herbal therapeutics in their role against malignancy. Ajwa, curcumin, ginseng, lycopene, and ursolic acid were all respectively evaluated in the paper for their prevalent properties, their method of extraction, notable usage in medicine, which pathways they activate, and whether the transductions can disrupt cancer formation or proliferation. The findings from the review demonstrated that all the therapeutics exhibited pro-apoptotic behavior, Ajwa and curcumin exerted cell cycle arrest upon neoplasms, and Ajwa, curcumin, and lycopene showed anti-metastatic behavior. Most extracts were tested on colorectal cancer, and the pathways most commonly applied were through BAX/Bcl2 and endoproteases, such as caspase-3 and caspase-9, indicating predominantly mitochondrial apoptosis. In addition, cell cycle arrest was noted to occur during the G2/M phase via Wnt/β-catenin in both curcumin and ginseng, independently of the Wnt/β-catenin pathway in Ajwa constituents, reducing cell viability. All of these studies were demonstrated in vitro within varieties of single cell cultures, which did not take into account bioavailability nor properly demonstrate the tumor microenvironment, which may not yield the same results in vivo. Clinical trials need to be undergone to appropriately test effective dosages, as if a compound is strongly pro-apoptotic, it may not be selective just to tumor cells but also to healthy cells, which may impair their functions. Full article