PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells

We determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill medulloblastoma cells. In medulloblastoma cells PDE5 inhibitors interacted in a greater than additive fashion with vincristine/etoposide/cisplatin to cause cell death. Knockdown of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of dominant negative caspase 9 did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with the PDE5 inhibitor sildenafil. Overexpression of BCL-XL and c-FLIP-s suppressed individual and combination drug toxicities. Knockdown of CD95 or FADD suppressed drug combination toxicity. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy which was maximal at ~12 h post-treatment, and in a cell type-dependent manner knockdown of Beclin1 or ATG5 either suppressed or enhanced drug combination lethality. PDE5 inhibitors enhanced the induction of chemotherapy-induced DNA damage in a nitric oxide synthase-dependent fashion. In conclusion, our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for medulloblastoma represents a possible novel modality for future treatment of this disease.     

Integrating pathomics with radiomics and genomics for cancer prognosis: A brief review

In the last decade, the focus of computational pathology research community has shifted from replicating the pathological examination for diagnosis done by pathologists to unlocking and discovering “sub-visual” prognostic image cues from the histopathological image. While we are getting more knowledge and experience in digital pathology, the emerging goal is to integrate other-omics or modalities that will contribute for building a better prognostic assay. In this paper, we provide a brief review of representative works that focus on integrating pathomics with radiomics and genomics for cancer prognosis. It includes: correlation of pathomics and genomics; fusion of pathomics and genomics; fusion of pathomics and radiomics. We also present challenges, potential opportunities, and avenues for future work.     

Cancer targeting potential of some ligand-anchored poly(propylene imine) dendrimers: a comparison

The present investigation was aimed at developing and comparing the cancer-targeting potential of ligand-anchored dendrimers. Folate-, dextran-, and galactose-anchored poly(propylene imine) dendrimers were synthesized and characterized. Dendritic formulations were evaluated for ex vivo cytotoxicity on HeLa and SiHa cell lines. Flow cytometry studies were performed on the HeLa cell line. An ex vivo MTT assay on HeLa cells indicated IC(50) values of 0.05, 0.2, 0.8, and 0.08 μM for folate, dextran, and galactose formulations, and for free paclitaxel (PTX), respectively. An analogous observation was carried out in SiHa cells, where IC(50) values of 0.6, 0.8, 10, and 6 μM were observed by folate, dextran, and galactose formulations, and free PTX, respectively. The outcome of the MTT assay and flow cytometry suggested the order of targeting potential of various ligands under investigation as folate > dextran > galactose. The outcome is deemed to be of scientific value and is believed to assist drug delivery scientists during selection of targeting ligands. FROM THE CLINICAL EDITOR: The cancer targeting potential of folate, dextran and galactose functionalized polypropyleneimine (PPI) dendrimers was studied by this group of investigators, reporting the order of targeting potential as folate > dextran > galactose.     

LC–MS/MS method for simultaneous analysis of cladrin and equol in rat plasma and its application in pharmacokinetics study of cladrin

A rapid and selective LC–MS/MS method for simultaneous analysis of cladrin and equol in female rat plasma has been developed and validated. The chromatographic separation was carried out on RP18 column, and MS/MS analysis was performed in triple quadrupole mass spectrometer with electrospray ionization. The method was linear for the concentration range from 7.8 to 1000 ng/ml for cladrin and 3.9 to 1000 ng/ml for equol. The intra-day and inter-day accuracy and precision of the method were within the acceptable limits. The validated LC–MS/MS method was successfully applied for the pharmacokinetics study of cladrin at 10 mg/kg in female S.D. rats.     

Stereotactic radiosurgery for four or more intracranial metastases

PURPOSE: To evaluate the outcomes after a single stereotactic radiosurgery procedure for the care of patients with 4 or more intracranial metastases. METHODS AND MATERIALS: Two hundred five patients with primary malignancies, including non-small-cell lung carcinoma (42%), breast carcinoma (23%), melanoma (17%), renal cell carcinoma (6%), colon cancer (3%), and others (10%) underwent gamma knife radiosurgery for 4 or more intracranial metastases at one time. The median number of brain metastases was 5 (range, 4-18) with a median total treatment volume of 6.8 cc (range, 0.6-51.0 cc). Radiosurgery was used as sole management (17% of patients), or in combination with whole brain radiotherapy (46%) or after failure of whole brain radiotherapy (38%). The median marginal radiosurgery dose was 16 Gy (range, 12-20 Gy). The mean follow-up was 8 months. RESULTS: The median overall survival after radiosurgery for all patients was 8 months. The 1-year local control rate was 71%, and the median time to progressive/new brain metastases was 9 months. Using the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) classification system, the median overall survivals for RPA classes I, II, and III were 18, 9, and 3 months, respectively (p < 0.00001). Multivariate analysis revealed total treatment volume, age, RPA classification, and marginal dose as significant prognostic factors. The number of metastases was not statistically significant (p = 0.333). CONCLUSION: Radiosurgery seems to provide survival benefit for patients with 4 or more intracranial metastases. Because total treatment volume was the most significant predictor of survival, the total volume of brain metastases, rather than the number of metastases, should be considered in identifying appropriate radiosurgery candidates.     

Tinospora cordifolia, a safety evaluation

Tinospora cordifolia is one of the indispensable medicinal plants used in veterinary folk medicine/Ayurvedic system of medicine for the treatment of diverse diseases and recommended for improving the immune system by means of body resistance. In the current study, we evaluated the genotoxic risk of the aqueous extract of T. cordifolia (TC) in a battery of four different genotoxicity tests viz., Ames, in vitro chromosome aberration (CA), rodent bone marrow micronucleus (MN), and Comet assay. Experimental results confirmed that in Ames test up to 5000 μg/plate of TC did not exhibit any mutagenic effect in Salmonella typhimurium mutant strains (TA97a, TA98, TA100, TA102, and TA1535). In CA assay, TC was not clastogenic to human peripheral blood lymphocytes up to a concentration of 3000 μg/ml. In MN and Comet assays, TC was pre-treated for 7 days at three dose levels (150, 200 and 250 mg/kg body weight) orally to male Balb/c mice. The results showed that TC treatment did not display clastogenicity and DNA damaging effect in bone marrow erythrocytes and peripheral blood lymphocytes respectively.     

FAMOUS研究：法莫替丁对阿司匹林所致胃肠粘膜损害的预防作用

背景及目的：抑制聚腺苷二磷酸酯核糖聚合酶（PARP）可致某些肿瘤细胞DNA修复障碍,促进肿瘤细胞凋亡,是治疗肿瘤的潜在方法,特别是对于BRCA1或BRCA2基因突变患者。Olaparib（AZD2281）为一种新型的口服PARP抑制剂,本研究对olaparib的有效性及安全性进行了临床评价。     

Acrolein activates matrix metalloproteinases by increasing reactive oxygen species in macrophages

Acrolein is a ubiquitous component of environmental pollutants such as automobile exhaust, cigarette, wood, and coal smoke. It is also a natural constituent of several foods and is generated endogenously during inflammation or oxidation of unsaturated lipids. Because increased inflammation and episodic exposure to acrolein-rich pollutants such as traffic emissions or cigarette smoke have been linked to acute myocardial infarction, we examined the effects of acrolein on matrix metalloproteinases (MMPs), which destabilize atherosclerotic plaques. Our studies show that exposure to acrolein resulted in the secretion of MMP-9 from differentiated THP-1 macrophages. Acrolein-treatment of macrophages also led to an increase in reactive oxygen species (ROS), free intracellular calcium ([Ca²⁺]_i), and xanthine oxidase (XO) activity. ROS production was prevented by allopurinol, but not by rotenone or apocynin and by buffering changes in [Ca²⁺]_I with BAPTA-AM. The increase in MMP production was abolished by pre-treatment with the antioxidants Tiron and N-acetyl cysteine (NAC) or with the xanthine oxidase inhibitors allopurinol or oxypurinol. Finally, MMP activity was significantly stimulated in aortic sections from apoE-null mice containing advanced atherosclerotic lesions after exposure to acrolein ex vivo. These observations suggest that acrolein exposure results in MMP secretion from macrophages via a mechanism that involves an increase in [Ca²⁺]_I, leading to xanthine oxidase activation and an increase in ROS production. ROS-dependent activation of MMPs by acrolein could destabilize atherosclerotic lesions during brief episodes of inflammation or pollutant exposure.     

Counteraction by glutathione and selenium of the prooxidant effect of alloxan in erythrocytes in vitro

Alloxan produces reactive oxygen species which cause injury to the insulin-producing β-cells of the pancreas. The action of alloxan in the production of free radicals was studied in vitro using rat erythrocytes. Alloxan increased lipid peroxidation (LPO) and decreased the activities of the antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase in the erythrocytes. Treatment with glutathione (GSH) and/or selenium along with alloxan was able to decrease LPO and increase the activities of the antioxidant enzymes in the erythrocytes. The results suggest that GSH and selenium both counteract the prooxidant effect of alloxan in rat erythrocytes.