Novel hybrid compounds of sclareol and doxorubicin as potential anticancer nanotherapy for glioblastoma.

Two novel hybrid compounds, CON1 and CON2, have been developed by combining sclareol (SC) and doxorubicin (DOX) into a single molecular entity. These hybrid compounds have a 1:1 molar ratio of covalently linked SC and DOX. They have demonstrated promising anticancer properties, especially in glioblastoma cells, and have also shown potential in treating multidrug-resistant (MDR) cancer cells that express the P-glycoprotein (P-gp) membrane transporter. CON1 and CON2 form nanoparticles, as confirmed by Zetasizer, transmission electron microscopy (TEM), and chemical modeling. TEM also showed that CON1 and CON2 can be found in glioblastoma cells, specifically in the cytoplasm, different organelles, nucleus, and nucleolus. To examine the anticancer properties, the U87 glioblastoma cell line, and its corresponding multidrug-resistant U87-TxR cell line, as well as patient-derived astrocytoma grade 3 cells (ASC), were used, while normal human lung fibroblasts were used to determine the selectivity. CON1 and CON2 exhibited better resistance and selectivity profiles than DOX, showing less cytotoxicity, as evidenced by real-time cell analysis, DNA damage determination, cell death induction, mitochondrial respiration, and mitochondrial membrane depolarization studies. Cell cycle analysis and the ß-galactosidase activity assay suggested that glioblastoma cells die by senescence following CON1 treatment. Overall, CON1 and CON2 showed great potential as they have better anticancer features than DOX. They are promising candidates for additional preclinical and clinical studies on glioblastoma.

Economic implications of autonomous adaptation of firms and households in a resource-rich coastal city.

Climate change intensifies the likelihood of extreme flood events worldwide, amplifying the potential for compound flooding. This evolving scenario represents an escalating risk, emphasizing the urgent need for comprehensive climate change adaptation strategies across society. Vital to effective response are models that evaluate damages, costs, and benefits of adaptation strategies, encompassing non-linearities and feedback between anthropogenic and natural systems. While flood risk modeling has progressed, limitations endure, including inadequate stakeholder representation and indirect risks such as business interruption and diminished tax revenues. To address these gaps, we propose an innovative version of the Climate-economy Regional Agent-Based model that integrates a dynamic, rapidly expanding agglomeration economy populated by interacting households and firms with extreme flood events. Through this approach, feedback loops and cascading effects generated by flood shocks are delineated within a socio-economic system of boundedly-rational agents. By leveraging extensive behavioral data, our model incorporates a risk layering strategy encompassing bottom-up and top-down adaptation, spanning individual risk reduction to insurance. Calibrated to resemble a research-rich coastal megacity in China, our model demonstrates how synergistic adaptation actions at all levels effectively combat the mounting climate threat. Crucially, the integration of localized risk management with top-down approaches offers explicit avenues to address both direct and indirect risks, providing significant insights for constructing climate-resilient societies.

Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells.

BACKGROUND: Glioblastoma (GBM) highly expresses Src tyrosine kinase involved in survival, proliferation, angiogenesis and invasiveness of tumor cells. Src activation also reduces reactive oxygen species (ROS) generation, whereas Src inhibitors are able to increase cellular ROS levels. METHODS: Pro-oxidative effects of two pyrazolo[3,4-d]pyrimidine derivatives-Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306-were investigated in human GBM cells U87 and patient-derived GBM-6. ROS production and changes in mitochondrial membrane potential were assessed by flow cytometry. The expression levels of superoxide dismutase 1 (SOD1) and 2 (SOD2) were studied by Western blot. DNA damage, cell death induction and senescence were also examined in GBM-6 cells. RESULTS: Si306 and pro-Si306 more prominently triggered ROS production and expression of antioxidant enzymes in primary GBM cells. These effects were followed by mitochondrial membrane potential disruption, double-strand DNA breaks and senescence that eventually led to necrosis. CONCLUSION: Src kinase inhibitors, Si306 and pro-Si306, showed significant pro-oxidative potential in patient-derived GBM cells. This feature contributes to the already demonstrated anti-glioblastoma properties of these compounds in vitro and in vivo and encourages clinical investigations.

Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo.

Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood-brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.

Flood risk management in Sint Maarten - A coupled agent-based and flood modelling method.

Disaster risk reduction is a major concern of small island developing states. Measures to reduce risk should not only be based on the magnitude of physical hazard, but also on the exposure and vulnerability of communities. In this article, we examine flood risk management policies in the Caribbean island of Sint Maarten using coupled agent-based and flood models. The agent-based model is used to model actors' behaviour in relation to urban building development and policies that are designed to reduce flood hazard and communities' vulnerability and exposure. The policies considered in the model are a Beach Policy, a Building and Housing Ordinance, a Flood Zoning policy and hazard mitigation structural measures. The flood model is used to simulate coastal and pluvial floods on the island. Agent behaviour such as building new houses and implementing hazard reduction measures affect the flood model as these actions affect the rainfall-runoff process. The flood maps generated from the updated flood model simulations are then used to assess the impact and update agents' attributes and behaviour. The simulations results show that low-lying areas are populated, which increases the exposure, and the number of vulnerable houses is also high. Hence, out of the four policies, implementing hazard reduction measures is the most important. Reducing the flood hazard by widening existing drainage channels, constructing new ones and building dykes as coastal flood defence would reduce the hazard, hence reducing the number of flooded houses. As it affects all households on the island, the Building and Housing Ordinance is an important policy to reduce vulnerability. In general, the coupled model outputs can be used to inform policy decision making and provide insights to policymakers on the island.

SOX3 can promote the malignant behavior of glioblastoma cells.

PURPOSE: Glioblastoma is the most common and lethal adult brain tumor. Despite current therapeutic strategies, including surgery, radiation and chemotherapy, the median survival of glioblastoma patients is 15 months. The development of this tumor depends on a sub-population of glioblastoma stem cells governing tumor propagation and therapy resistance. SOX3 plays a role in both normal neural development and carcinogenesis. However, little is known about its role in glioblastoma. Thus, the aim of this work was to elucidate the role of SOX3 in glioblastoma. METHODS: SOX3 expression was assessed using real-time quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry. MTT, immunocytochemistry and Transwell assays were used to evaluate the effects of exogenous SOX3 overexpression on the viability, proliferation, migration and invasion of glioblastoma cells, respectively. The expression of Hedgehog signaling pathway components and autophagy markers was assessed using RT-qPCR and Western blot analyses, respectively. RESULTS: Higher levels of SOX3 expression were detected in a subset of primary glioblastoma samples compared to those in non-tumoral brain tissues. Exogenous overexpression of this gene was found to increase the proliferation, viability, migration and invasion of glioblastoma cells. We also found that SOX3 up-regulation was accompanied by an enhanced activity of the Hedgehog signaling pathway and by suppression of autophagy in glioblastoma cells. Additionally, we found that SOX3 expression was elevated in patient-derived glioblastoma stem cells, as well as in oncospheres derived from glioblastoma cell lines, compared to their differentiated counterparts, implying that SOX3 expression is associated with the undifferentiated state of glioblastoma cells. CONCLUSION: From our data we conclude that SOX3 can promote the malignant behavior of glioblastoma cells.

From Ataxia to Diagnosis of Askin Tumor - a Case Report.

Peripheral primitive neuroectodermal tumors (pPNET) are a group of extremely rare, aggressive, malignant tumors that are most often found in the thorax (Askin tumor), abdomen, pelvis, extremities and less frequently in the head and neck. The most important prognostic factor is the stage of the tumor. Significant progress both in surgery and in neoadjuvant and adjuvant chemotherapy and radiotherapy, as well as the improvement in diagnosis by cytogenetic and immunohistochemical analysis, should improve the survival rate. We report a case of a 14-year-old girl, with ataxic gait, cardiopulmonary compensated, without respiratory symptoms, who was referred to our hospital for further examination and treatment of newly discovered tumor of the left hemithorax. After a detailed radiological and laboratory investigation, next step was an extensive thoraco-neurosurgical surgery. After histopathological, cytological and molecular analysis, a diagnosis of Askin tumor was made.

Positron emission tomography-computed tomography and 4-hydroxynonenal-histidine immunohistochemistry reveal differential onset of lipid peroxidation in primary lung cancer and in pulmonary metastasis of remote malignancies.

The Aim of the study was to reveal if PET-CT analysis of primary and of secondary lung cancer could be related to the onset of lipid peroxidation in cancer and in surrounding non-malignant lung tissue. METHODS: Nineteen patients with primary lung cancer and seventeen patients with pulmonary metastasis were involved in the study. Their lungs were analyzed by PET-CT scanning before radical surgical removal of the cancer. Specific immunohistochemistry for the major bioactive marker of lipid peroxidation, 4-hydroxynonenal (HNE), was done for the malignant and surrounding non-malignant lung tissue using genuine monoclonal antibody specific for the HNE-histidine adducts. RESULTS: Both the intensity of the PET-CT analysis and the HNE-immunohistochemistry were in correlation with the size of the tumors analyzed, while primary lung carcinomas were larger than the metastatic tumors. The intensity of the HNE-immunohistochemistry in the surrounding lung tissue was more pronounced in the metastatic than in the primary tumors, but it was negatively correlated with the cancer volume determined by PET-CT. The appearance of HNE was more pronounced in non-malignant surrounding tissue than in cancer or stromal cells, both in case of primary and metastatic tumors. CONCLUSIONS: Both PET-CT and HNE-immunohistochemistry reflect the size of the malignant tissue. However, lipid peroxidation of non-malignant lung tissue in the vicinity of cancer is more pronounced in metastatic than in primary malignancies and might represent the mechanism of defense against cancer, as was recently revealed also in case of human liver cancer.

Adult Brainstem Gliomas: Retrospective Analysis of 51 Patients.

AIM: Brainstem gliomas (BSG) constitute less than 2% of brain tumors in adults. Therapeutic options are limited and BSG are associated with a high morbidity and mortality. MATERIAL AND METHODS: We reviewed the records of 51 patients with BSG treated at the Institute of Neurosurgery, Clinical Center of Serbia in Belgrade between 1998 and 2012. We recorded demographic and clinical variables as well as radiological findings and survival. RESULTS: Of the 51 patients, 62.7% were male and 37.3% were female. The mean age was 30.6±19.3 years. High grade glioma (Astrocytoma grade III and IV) was most common at the age of 38.2±17.9 years (t=.481, p=0.017) while low grade glioma (Astrocytoma grade I and II) was common in younger age as 25.4±17.4 years (X2=4.013; p=0.045), with localization in the pons (X2=5.299; p=0.021) and exophytic presentation (X2=3.862; p=0.049). Ataxia, as initial symptom, was a predictor of poor outcome (HR:5.546, p=0.012). CONCLUSION: Due to its specific localization, BSG present a major challenge for neurosurgery, because of the necessity of safe approach for radical resection. Histological verification of BSG determines the need for additional therapeutic procedures such as radiotherapy and chemotherapy. Benefit from correct diagnosis is reflected in the avoidance of potentially adverse effects of treatment.

The case of synchronous occurrence of primary adenocarcinoma and squamous cell carcinoma in the same lobe of the lung.

Synchronous occurrence of multiple lung cancers in the same lobe of the lung is very rare. Most of the tumors diagnosed in this way have the same histologic type. With imaging methods it is difficult to determine if the multiple lung lesions present hematogenous spread of lung cancer (or cancer from other origin) or these lesions present the second primary lung cancer. We report a rare and unusual case of synchronous occurrence of primary adenocarcinoma and squamous cell carcinoma in the same lobe of the lung. Our case demonstrates that in case of synchronous occurrence of multiple lung lesions each lesion should be sampled and histologic type of every lesion should be determined so the further treatment can be planned accordingly.

Determination of Predictive Anatomic Parameters for Bleeding of Brain Arteriovenous Malformations by Multidetector CT Angiography.

Patients with brain arteriovenous malformation (AVM) have a certain risk to bleed, and the goal of this study was to examine the effect of radiological and clinical predictive characteristics of AVM hemorrhage using multidetector computed tomographic (MDCT) angiography. The study included a series of 57 patients, mean age 35.46 years, who were diagnosed during their hospitalization at Clinical Department of Neurosurgery, Clinical Center of Serbia, in the period from January 2008 to March 2016. In all patients, the diagnosis was made using MDCT angiography. Two groups of patients were observed. The first group included patients who did not initially present with hemorrhage, while the second group initially presented with hemorrhage. Both groups were treated with medical therapy or a combination of medical therapy with embolization/surgery/radiotherapy. Deep venous drainage (p<0.05), combined arterial supply from different basins (p<0.05) with a length <60 mm, venous dilatation present in the drainage vein (p<0.01), and the angle of casting sup-ply arteries in the nidus (p<0.01) carry a risk of repeated bleeding. In the group of patients who had initial hemorrhage, the mean value of the casting angle size was 130°, while in the group that did not have initial bleeding the mean value of the measured angle size was 103.81° with standard deviation of 17.21° (p<0.01). In conclusion, AVMs with deep venous drainage from the carotid and vertebrobasilar basin, the length of the feeding arteries <60 mm, the angle of the casting feeding arteries in the nidus ≥130° and dilatation and/or venous aneurysm of drainage vessel are predictive for clinical presenting by hemorrhage.

Gastrostomy Under Paravertebral Block in High-Risk Patients with Esophageal Cancer - Two Case Reports.

Here we present two cases of gastrostomy insertion via laparotomy in patients with malignant esophageal disease. Patients were ASA (American Society of Anesthesiologists) physical status III and IV. The patients presented as very high risk for general anesthesia, so we decided to use unilateral left sided paravertebral block (PVB) on four thoracic levels along with contralateral local infiltration at the gastrostomy insertion site. We present two cases, one of them a 57-year-old male ASA III patient scheduled for a gastrostomy procedure due to esophageal cancer with infiltration of the trachea. We also present a case of a 59-year-old male patient, ASA IV status, scheduled for the same procedure due to advanced esophageal cancer with a fistula between the left main bronchus and the esophagus and metastases in the left lung. The paravertebral space was identified with the use of an 8 Hertz (Hz) linear ultrasound probe and a nerve stimulator. Paravertebral block was successfully used for insertion of a gastrostomy, thereby enabling adequate anesthesia and perioperative analgesia without hemodynamic or respiratory complications.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio help identify patients with lung cancer, but do not differentiate between lung cancer subtypes.

AIM: To assess the diagnostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in lung cancer (LC). We compared the ratios between healthy participants and all LC patients, as well patients with different pathohistological LC subtypes. METHODS: We retrieved the data on neutrophil, lymphocyte, and platelet levels in 449 patients with different pathohistological LC subtypes (non-small cell LC, small-cell LC, atypical or metastatic LC, neuroendocrine, and sarcomatoid carcinoma) and 47 healthy controls. NLR and PLR were calculated by dividing the absolute number of neutrophils or platelets with the absolute number of lymphocytes. RESULTS: There were significant differences in both NLR and PLR (P<0.001) between all LC patients and the control group, but there were no differences between patients with different LC subtypes. Reciever operating characteristics analysis for NLR showed the optimal cut-off value of 2.71, with a sensitivity of 77.05% and specificity of 87.23%. The optimal cut-off value for PLR was 182.31, with a sensitivity of 51.09% and specificity of 91.49%. CONCLUSION: The results showed that the NLR and PLR may have added value in the early diagnosis of LC, but further research is needed to confirm these results.

Giant Spinal Schwannoma in a 76-year-old Woman--A Case Report.

A schwannoma is a benign nerve sheath tumor composed of Schwann cells. Spinal schwannoma originates from dorsal roots of the spinal cord, causing symptoms due to the compression of neighboring structures. We present a patient with a low back pain and left L2 and L3 radiculopathy. Neuroimaging techniques (CT, MRI) showed a large expansive mass in the left lumbar paraspinal area. The tumor was removed totally by the posterior approach and was verified to originate from the left L2 spinal nerve root. The histopathological examination revealed typical findings of a schwannoma. The pain was resolved promptly after the surgery, however the patient's neurological condition wasn't improved. Surgical treatment was a final treatment, and no additonal therapy was necessary.

Spontaneous Intracerebral Hematoma in Low-Grade Glioma After 14 Years of Follow-Up.

We are reporting the case of a 53-year old woman presenting to our hospital with a hemorrhagic low-grade glioma (LGG). She was admitted to a nearby general hospital where she had presented with aphasia, right hemiplegia and change of mental status. Computer tomography (CT) images showed a left temporo-parietal hemorrhage with mass effect. She was transferred to our hospital neuro-intensive care unit where emergency craniotomy was performed. A tumor with hematoma was removed and further histopathology analysis revealed tumor progression. We reviewed the literature reporting cases of central nervous system tumors hemorrhage and found that these types of events are exquisitely rare in adults with LGG. However these events are possible, suggesting that it should be included in the differential diagnosis of any patient presenting with intracranial hemorrhage. This case raises questions regarding the benefit of early versus late intervention for patients known to have LGG.

[CANCER PATIENTS FOLLOW-UP ­ CROATIAN SOCIETY FOR MEDICAL ONCOLOGY CLINICAL GUIDELINES Part V: melanoma, sarcomas, central nerve system tumors, lung cancer].

Treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is being managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not being based on prospective studies, yet on the expert's opinion of a precise oncological center or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardize and rationalize the diagnostic procedures' algorithm in follow­up of oncological patients after primary treatment, in patients with melanoma, sarcomas, central nerve system tumors and lung cancer.

Size, edge, and stage of NSCLC determine the release of CYFRA 21-1 in bloodstream.

BACKGROUND: The computed tomography (CT) is the "golden standard" for the assessment of lung cancer progression due to its ability to clearly display the radiomorphologic characteristics. As lung cancer mortality is very high, more comprehensive approaches may be needed for its earlier diagnosis. The research hypothesis was to investigate the relation between the CT morphologic characteristics (size, stage, and edges) of pulmonary lesion and the extent of release of a soluble fragment of cytokeratin 19 being a part of the cytoskeleton of lung epithelial cells. METHODS: This is a retrospective study including 246 pulmonary lesions being diagnosed and subsequently treated at the University Hospital Centre Zagreb, Croatia. The information about the relevant clinical, radiological, and laboratory facts was collected at the time of diagnosis in 164 NSCLC patients, 52 patients with pulmonary metastases, and 30 benign cysts. CYFRA 21-1 was determined by electrochemiluminescence immunoassay. The nonparametric statistical methods were applied. RESULTS: There was a positive correlation between the size and CYFRA 21-1 in NSCLC unlike metastases or cysts (p = 0.0001). The highest values of CYFRA 21-1 were seen in advanced stages of NSCLC and lesions with spiculated edges. CONCLUSIONS: The level of CYFRA 21-1 positively correlates with the greatest size of NSCLC measured by CT. The differences in CYFRA 21-1 according to TNM classification are significant (p = 0.0001): higher values were observed in advanced stages and with tumors having spiculated, lobulated, and poorly defined edges. The combination of CYFRA 21-1 and CT may help articulate the malignancy of pulmonary lesions.

GLIOBLASTOMA MULTIFORME BRAIN TUMORS LOCATED IN THE MOTOR CORTEX--SPECIFIC FINDINGS IN COMPARISON WITH LOW GRADE GLIOMAS OF THE SAME LOCALIZATION: ANALYSIS OF A SIXTY PATIENT SERIES.

The verified presence of a glioblastoma multiforme (GBM) tumor in the motor area of the brain, in a patient lacking preoperative neurological deficit, offers no certainty that the tumor can be radically removed without the possibility of causing postoperative motor deficit. We present a series of 60 patients hospitalized at the Clinical Department of Neurosurgery, Clinical Center of Serbia in Belgrade between October 2011 and February 2015, harboring tumors located within and in the vicinity of the motor zone of the brain. By using Karnofsky's index (KI), the pre- and postoperative conditions of the patients were evaluated. Regarding electrical stimulation of the motor cortex, significantly lower values of the electrical current intensity, frequency, and pulse wave duration (p < 0.01) were needed for triggering motor response in case of GBM tumor compared to a slowly growing tumor (low-grade). Patients with low-grade gliomas (LGG) had statistically significantly higher KI values pre- and postoperatively than patients with GBM (p < 0.01). Using electrical stimulation of the cortex, a higher grade of resection of LGG could be achieved as compared with the group presenting with GBM (χ² = 5.281; df = 1; p < 0.05). Our findings and review of the results reported by other authors underline the necessity of routine application of electrical stimulation of the cerebral cortex in order to identify the primary motor field (M1).

Laparoscopic surgery for large hydatide liver cyst after two previous laparotomies.

Laparoscopic surgery for hepatic echinococcosis is a technically difficult and demanding surgical procedure even for the most experienced abdominal surgeon. Surgery is performed after the conservative treatment with albendazole for 28 days. We report a case of laparoscopic partial pericystectomy with biliostasis and omentoplasty in a patient with two previously open surgeries (laparotomies)--right subcostal laparotomy for acute inflammation of the gallbladder and right pararectal laparotomy for perforated gangrenous appendix. The patient underwent extensive laparoscopic adhesiolysis due to pronounced intra-abdominal adhesions to gain access to a large hydatid cyst with the diameter of 11 cm. Laparoscopic surgery is much less traumatic to the patient with a better cosmetic effect.