Experimental oncology最新文献

Background: Acute lymphoblastic leukemia has an intimate physical relationship with nonmalignant bone marrow stromal cells. We have recently demonstrated that stromal cells contribute to the survival of leukemia cells and that there is a bidirectional transfer of intracellular material between them. Understanding the mechanisms of stromal support of leukemia may provide insights into new therapies.

Aim: To test the hypothesis that gap junctions are formed between acute lymphoblastic leukemia cells and nonmalignant stromal cells, and that gap junction function is essential for the survival of leukemia cells.

Materials and methods: We employed a well-characterized in vitro model of human bone marrow stromal cells and primary human B lymphoblastic leukemia cells and measured leukemia cell survival in coculture using flow cytometry. We measured the effects of gap junction antagonist peptides, carbenoxolone (a drug known to interfere with the gap junction function), and several leukemia chemotherapy drugs including methotrexate upon leukemia cell survival.

Results: We demonstrated that stromal cells need to be alive and metabolically active to keep leukemia cells alive. Physical contact between stromal and leukemia cells leads to an increase in gap junction proteins in leukemia cells. Gap junction inhibitory peptides impaired leukemia cell survival as did carbenoxolone, a nonpeptide inhibitor of the gap junction function. Stromal cell survival was not affected. We observed a very modest enhancement of methotrexate antileukemia activity by low-dose carbenoxolone but no significant interactions with dexamethasone, vincristine, mercaptopurine, or doxorubicin.

Conclusion: These studies demonstrate that acute lymphoblastic cell survival is impaired by interference with the gap junction function. The development of drugs targeting gap junctions may provide a novel approach to the therapy of acute lymphoblastic leukemia.

Background: Oral squamous cell carcinoma (OSCC), the 13th most common type of cancer, claimed 364,339 lives in 2020. Researchers have established a strong correlation between early detection and better prognosis for this type of cancer. Tissue biopsy, the most common diagnostic method used by doctors, is both expensive and time-consuming. The recent growth in using transfer learning methodologies to aid in medical diagnosis, along with the improved 5-year survival rate from early diagnosis serve as motivation for this study. The aim of the study was to evaluate an innovative approach using transfer learning of pre-trained classification models and convolutional neural networks (CNN) for the binary classification of OSCC from histopathological images.

Materials and methods: The dataset used for the experiments consisted of 5192 histopathological images in total. The following pre-trained deep learning models were used for feature extraction: ResNet-50, VGG16, and InceptionV3 along with a tuned CNN for classification.

Results: The proposed methodologies were evaluated against the current state of the art. A high sensitivity and its importance in the medical field were highlighted. All three models were used in experiments with different hyperparameters and tested on a set of 126 histopathological images. The highest-performance developed model achieved an accuracy of 0.90, a sensitivity of 0.97, and an AUC of 0.94. The visualization of the results was done using ROC curves and confusion matrices. The study further interprets the results obtained and concludes with suggestions for future research.

Conclusion: The study successfully demonstrated the potential of using transfer learning-based methodologies in the medical field. The interpretation of the results suggests their practical viability and offers directions for future research aimed at improving diagnostic precision and serving as a reliable tool to physicians in the early diagnosis of cancer.

Background: The combination of temozolomide (TMZ) and paclitaxel (PTX) is the most commonly used chemotherapy regimen for glioblastoma, but there is no specific treatment for neuroblastoma due to the acquired multidrug resistance. Approximately half of treated glioblastoma patients develop resistance to TMZ and experience serious side effects. Melatonin (MEL), a multifunctional hormone long known for its antitumor effects, has a great advantage in combination cancer therapy thanks to its ability to affect tumors differently than normal cells.

Aim: This study aims to evaluate the in vitro inhibitory effects of MEL in combination with TMZ on cancer cell viability and to elucidate the underlying mechanisms in the glioblastoma and neuroblastoma cell lines.

Materials and methods: C6 (Rattus norvegicus) and N1E-115 (Mus musculus) cancer cell lines and C8-D1A (mice) healthy cell lines were used. Cell proliferation was evaluated using the MTT test. IC50 values were determined by probit analysis. Two concentrations of TMZ (IC50 and 1/2 IC50) were used to induce cytotoxicity in the C6 and N1E-115 cell lines, both alone and in combination with PXT and MEL (all at IC50). The viable, dead, and apoptotic cells were determined by image-based cytometry using Annexin V/PI staining. The gene expression related to signaling pathways was assessed by the quantitative reverse transcription polymerase chain reaction (qRT-PCR), and key proteins were identified by the Western blot analysis.

Results: MTT assay showed that the combination of TMZ and MEL significantly reduces the viability of both glioblastoma and neuroblastoma cells compared to the vehicle-treated controls. Notably, MEL combined with 1/2 IC50 TMZ showed a significant death rate of cancer cells compared to controls and PTX. According to qRT-PCR data, the TMZ + MEL combination resulted in the upregulation of the genes of antioxidative enzymes (Sod1 and Sod2) and DNA repair genes (Mlh1, Exo1, and Rad18) in both cell lines. Moreover, the levels of Nfkb1 and Pik3cg were significantly reduced following the TMZ + MEL treatment. The combination of MEL with TMZ also enhanced the cell cycle arrest and increased the expression of p53 and pro-apoptotic proteins (Bax and caspase-3), while significantly decreasing the expression of anti-apoptotic protein Bcl-2.

Conclusions: Our findings indicate that the combination of MEL with a low dose of TMZ may serve as an upstream inducer of apoptosis. This suggests the potential development of a novel selective therapeutic strategy as an alternative to TMZ for the treatment of both glioblastoma and neuroblastoma.

Pituitary adenomas that extend to the ventricular system are extremely rare. We present a 5-year natural history of a giant null cell pituitary adenoma with invasion into the cavernous sinus extending to the third ventricle. MRI series that were available could be useful for neurosurgeons, ophthalmologists, and endocrinologists as well as radiologists. Patients with the diagnosis of pituitary adenoma that are certain according to the radiological and clinical examination should be consulted by a neurosurgeon experienced in endoscopic endonasal surgery, a neuroendocrinologist, and an ophthalmologist. The surgery postponement in such cases results in disability and quality of life worsening. At that time, the surgery of giant pituitary adenomas demands high skills, and the risk of postoperative complications is high. The proper treatment modality including earlier surgery seems to be favorable for patient outcome.

Dimethyl sulfoxide (DMSO) is a common solvent in biological and medical research for dissolving water-insoluble compounds and drugs. However, the impact of DMSO goes beyond its primary function. High-throughput and in vitro assays have uncovered various effects of DMSO in mammalian cells. The present article highlights the biological effects of DMSO on normal and cancerous mammalian cells.

Background: The current prognostic markers in oral squamous cell carcinoma (OSCC) have limited accuracy sometimes leading to inappropriate treatment decisions. Identifying new markers would help clinicians tailor treatment plans based on the individual patient risk factors leading to improved survival rates and quality of life.

Aim: To estimate the value of the miRNA expression indicators in saliva as prognostic and predictive markers of the effectiveness of neoadjuvant chemotherapy (NACT).

Materials and methods: The work is based on the results of the examination and treatment of 61 patients with stage II-IV OSCC. The miR-21, miR-155, and miR-375 expression levels in the saliva samples were analyzed by the real-time reverse transcription polymerase chain reaction.

Results: The salivary miR-21 and -155 expression levels in healthy volunteers were 2.49 and 2.84 times lower than in OSCС patients (p < 0.05). The positive association of miR-21 and miR-155 expression levels and the negative correlation of miR-375 expression level with T index by TNM (r = 0.68, r = 0.75, and r = -0.67, respectively) (p < 0.05) and the presence of lymph node metastasis (r = 0.78, r = 0.71, and r = ‒0.59, respectively) (p < 0.05) were found. Patients with good response to NACT had lower miR-21 and -155, and higher miR-375 levels in saliva compared to those with resistant tumors.

Conclusions: Our study suggests that salivary miR-21, miR-155, and miR-375 may be potential biomarkers for the prognosis of cancer course and the response to NACT in OSCC patients.

Background: An important concern in oncological coloproctology is colorectal anastomotic leakage (AL), which occurs in 3.5%-21% of patients. Predicting the occurrence of failure based on the results of laboratory markers can be decisive for the treatment of this complication.

Aim: To improve the early diagnosis of AL by establishing combinations and threshold values of laboratory markers - predictors of the inflammatory process.

Materials and methods: The prospective study, conducted from 2020 to 2023, included 213 rectal cancer patients who underwent low anterior resection after neoadjuvant chemoradiotherapy. The inflammatory biomarkers were assessed before surgery and on the 3rd, 5th, and 7th days of the postoperative period.

Results: AL diagnosed in 25 (11.74%) patients by the grade of severity was as follows: A (radiological) in 7 (3.29%) patients; B (clinical) - 4 (1.88%); C (clinically expressed, peritonitis) - 11 (5.16%), and P (late) - 3 (1.41%) patients. The changes in the laboratory indicators of the inflammatory response such as С-reactive protein (CRP), procalcitonin (PCT), the counts of neutrophils (NEU), lymphocytes (LYM), platelets (PLT), and neutrophil/lymphocyte ratio (NLR) were significant only in B or C AL grades. Among them, only three indicators were identified as significant for predicting AL when assessed 24 h before the onset of this complication, namely LYM (threshold value ≤ 0.97 × 103/mm3, sensitivity 66.7% and specificity 81.3%, p < 0.001); PLT (threshold value > > 257 103/mm3, sensitivity 58.6%, and specificity 86.7%, p < 0.001); and NLR (threshold value > 4.42, sensitivity 58.1%, and specificity 86.7%, p < 0.001). The three-factor model based on these selected indicators was set up, and the prognosis index (Prog) was proposed with the decision threshold Progcrit = 2.23. The sensitivity of the model was 80% (95% CI 51.9%-95.7%), and the specificity - 74.2% (67.6%-80.2%).

Conclusion: Based on the routine laboratory predictors used in the complex diagnosis of AL, B or C AL grades may be predicted allowing for the timely effective early diagnosis, medication, and surgical intervention..

Background: The identification of the subgroups with differential treatment effects (DTE) is important for decisionmaking in personalized treatment. The DTE analysis assists in identifying patients who are more likely to benefit from a particular treatment regimen. The aim of the study was to analyze DTE in terms of the survival of glioblastoma (GBM) patients in the groups of standard radiotherapy (SRT) and hypofractionated radiotherapy (HRT) by the multicluster modeling of homogenous groups while retaining the statistical characteristics of the overall primary study cohort.

Patients and methods: The cohort of 159 patients with newly diagnosed GBM stratified according to the radiotherapy regimen (HRT group (n = 110/69.2%); SRT group (n = 49/30.8%)) was evaluated retrospectively. Forty-eight subgroups (multiclusters) were created by enumerating all possible combinations of 5 significant covariates (age, sex, the radicality of the surgical resection, chemotherapy, and Karnofsky performance status) of the Cox model. The DTE for the cancerspecific survival (CSS) within 48 modeled multiclusters were studied by comparing the interpolated Weibull CSS curves according to the Kolmogorov - Smirnov test.

Results: The findings showed that the SRT group was superior to the HRT group by CSS only in 3 of the modeled clusters presenting clinical scenarios with a non-radical tumor resection, no chemotherapy, and low Karnofsky functional status (≤ 70 scores) (Cluster 10: male aged < 60; Cluster 21: female aged ≥ 60; Cluster 22: male aged ≥ 60). Most of the studied clinical variants (45 of 48 multiclusters) did not demonstrate a significant difference when comparing the interpolated Weibull curves of the CSS for the SRT and HRT groups according to the Kolmogorov - Smirnov test (p ≥ 0.05).

Conclusions: We propose a novel multicluster modeling approach that addresses DTE in relatively small samples of GBM patients receiving SRT or HRT. This original analytical method can be taken into consideration while designing new well-powered prospective trials aimed at the subgroup analysis in GBM patients who will be most beneficial from personalized treatment strategies.

Choriocarcinoma is characterized as the most aggressive malignant alternation of gestational trophoblastic neoplasm; however, this illness is a curable malignancy. Although a rarity, this disease affects a female patient's life and causes a fatal condition. Choriocarcinoma is a life-threatening disease since it is initially insidious and can rapidly lead to masive hemorrhage, even death. Choriocarcinoma should be suspected in childbearing-age women with the high-risk scores according to FIGO. The study aims to report a severe case of widespread metastatic choriocarcinoma to optimize the treatment with multiagent chemotherapy and a multidisciplinary cooperation at our center. A G1P0 20-year-old woman was referred to the hospital for suspicion of metastatic choriocarcinoma after self-stopping chemotherapy because of the COVID-19 pandemic. During hospitalization, the tumor metastasized and presented profuse intraabdominal hemorrhage. The patient underwent immediate surgical intervention to control bleeding, and a definitive diagnosis was accurately established by the histopathological examination. After surgery, the EMA/CO regimen was administered as the first line of treatment, despite the patient being in a coma and requiring a ventilator machine. After 6 cycles of the EMA/CO regimen, her serum β-hCG level decreased to 8 mUI/mL, however, her β-hCG concentration was not down to a negative value. Thus, the patient received paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE regimen) for complete remission following 2 cycles. The delays in choriocarcinoma treatment are prognostic factors for worse outcomes, whereas chemotherapy may be considered a suitable treatment even in a patient's coma, thus improving a prognosis substantially.

Oncolytic viruses (OVs) are emerging as novel tools in cancer therapy. Oncolytic virotherapy offers an attractive therapeutic combination of tumor-specific killing and immune co-stimulation, therefore amplifying the host immune response against tumors. Moreover, OVs can be engineered for the expression of different immunostimulatory molecules to optimize and enhance the efficacy of oncolytic virotherapy. The effectiveness of OVs has been demonstrated in many preclinical studies for different types of cancers to achieve the aim of personalized cancer therapy. Human respiratory syncytial virus (RSV), an RNA virus of the Pneumoviridae family causes severe lower respiratory tract infections in infants and immunocompromised individuals. Interestingly, the oncolytic activity of RSV demonstrated in human prostate, hepatocellular, and dermal cancer cells is mostly mediated via apoptotic cell death associated with the impaired NF-κB activation or with the defect of the IFNα/β-induced STAT-1 activation. At the same time, the studies on cervical cancer revealed that RSV infection resulted in autophagy activation and apoptosis through the ROS-BAX and TNF- α-mediated pathways. The rational combinations of OVs, including RSV, with other approaches may benefit patients whose response to conventional therapies is limited. Here, we discuss the oncolytic activity of RSV and its potential use against different types of cancer.