Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain

Metastases represent the most common brain tumors in adults. Surgical resection alone results in 45% recurrence and is usually accompanied by radiation and chemotherapy. Adequate chemotherapy delivery to the CNS is hindered by the blood–brain barrier. Efforts at delivering chemotherapy locally to gliomas have shown modest increases in survival, likely limited by the infiltrative nature of the tumor. Temozolomide (TMZ) is first-line treatment for gliomas and recurrent brain metastases. Doxorubicin (DOX) is used in treating many types of breast cancer, although its use is limited by severe cardiac toxicity. Intracranially implanted DOX and TMZ microcapsules are compared with systemic administration of the same treatments in a rodent model of breast adenocarcinoma brain metastases. Outcomes were animal survival, quantified drug exposure, and distribution of cleaved caspase 3. Intracranial delivery of TMZ and systemic DOX administration prolong survival more than intracranial DOX or systemic TMZ. Intracranial TMZ generates the more robust induction of apoptotic pathways. We postulate that these differences may be explained by distribution profiles of each drug when administered intracranially: TMZ displays a broader distribution profile than DOX. These microcapsule devices provide a safe, reliable vehicle for intracranial chemotherapy delivery and have the capacity to be efficacious and superior to systemic delivery of chemotherapy. Future work should include strategies to improve the distribution profile. These findings also have broader implications in localized drug delivery to all tissue, because the efficacy of a drug will always be limited by its ability to diffuse into surrounding tissue past its delivery source.National Institutes of Health (U.S.) (Grant R01 EB006365-06)Brain Science Foundation (Private Grant 106708

Population Structure and Genetic Diversity of Sheep Breeds in the Kyrgyzstan

Sheep are a main livestock species of Kyrgyzstan, a Central Asian country with predominating mountain terrain. The current gene pool of local sheep resources has been forming under diverse climate conditions from the era of the trading caravans of the Great Silk Road, through the Soviet period of large-scale livestock improvements, which was followed by the deep crisis at the end of the 20th century, up to now. However, not much is known about the genetic background and variability of the local sheep populations. Therefore, our aims were to provide a characterization of the population structure and genetic relations within the Kyrgyz sheep breeds and to study their genetic connections with the global sheep breeds using SNP analysis. Samples of the Alai (n = 31), Gissar (n = 30), Kyrgyz coarse wool (n = 13), Aykol (n = 31), and Tien-Shan (n = 24) breeds were genotyped with the OvineSNP50 BeadChip or the Ovine Infinium HD BeadChip (Illumina Inc., USA). The measure of inbreeding based on runs of homozygosity showed a minimum value in the Aykol breed (FROH = 0.034), while the maximum was found in the Alai breed (FROH = 0.071). Short ROH segments (ROH ≤ 4 Mb) were predominant in all breeds. Long ROH segments (ROH > 16 Mb) were absent in the Gissar breed. The Gissar and Aykol breeds had the highest values of the effective population sizes estimated for five generations ago (Ne5 = 660 and 563), whereas the Alai and Kyrgyz coarse wool displayed lower values (Ne5 = 176 and 128, respectively). The synthetic origin of the Aykol breed was clearly evidenced by all analyses applied. Based on the network and admixture analyses of the Kyrgyz and global sheep breeds, the Tien-Shan and the Russian semi-fine wool breeds demonstrated a common ancestry that most likely is due to a contribution of the Lincoln breed. The Gissar, Aykol, and Kyrgyz coarse wool breeds showed a genetic background predominating in sheep populations from Iran and China whereas the Alai demonstrated the different ancestry type. The revealed admixture patterns probably resulted from the exchange and trade during the era of the Great Silk Road, which partly overlapped with historical and archeological findings

Elevated haplotypes frequencies reveal similarities for selection signatures in Western and Russian Simmental populations

This paper shows a straightforward, but surprisingly effective approach to detect genomic regions of importance, illustrated on two Simmental cattle populations. Medium density genomic data of 42 German/Austrian (denoted as “Western“) and 38 Russian Simmental cattle were used to identify the most frequent haplotypes within the two populations. The haplotypes were defined as non-overlapping segments of ten single nucleotide ploymorphisms (SNP). The phasing was done with the SHAPEIT software, with a follow up analysis of haplotypes using the GHap package. Despite the low sample size a number of high frequency haplotypes could be identified across the whole genome. The identified genes residing directly in these high frequency haplotypes were extremely relevant for the dual purpose Simmental cattle. A large part of these genes influenced growth rate and carcass traits, others were relevant for the milk production. A smaller proportion was connected to the reproduction, immune system and cellular processes, with indirect influence on production traits

Deferred Radiotherapy After Debulking of Non-functioning Pituitary Macroadenomas: Clinical Outcomes

Background: To describe the outcome for a cohort of patients with non-functioning pituitary macroadenomas (NFPMA), managed by debulking surgery with radiation therapy delayed until progression.Methods: Two hundred and sixty-seven patients were treated surgically for pituitary tumors at our institution between 1997 and 2005. One hundred and twenty-six patients met the inclusion criteria of NFPMA. They were followed for at least 2 years.Results: At presentation, 58% of patients had objectively decreased visual function, 66% had endocrine abnormalities, and 46% had headaches. Of the entire cohort, 75% of tumors abutted the optic chiasm and 87% had suprasellar extension. Over a median follow up of 112 months from surgery, 52% of patients had evidence of radiographic tumor progression, and 39% required additional treatment. There was a significant difference freedom from progression and in the number of patients receiving additional treatment with preoperative adenoma size of < 2 vs. ≥2 cm (p < 0.05).Conclusion: Close observation with radiation therapy delayed until the time of progression is an appropriate option for patients presenting with initial adenoma size < 2 cm, and can be considered for those with initial sizes up to 4 cm, as the majority of patients do not require further intervention for 10 or more years, thereby meaningfully postponing the risks of radiotherapy

Overall survival in malignant glioma is significantly prolonged by neurosurgical delivery of etoposide and temozolomide from a thermo-responsive biodegradable paste

Purpose: High-grade glioma (HGG) treatment is limited by the inability of otherwise potentially efficacious drugs to penetrate the blood brain barrier. We evaluate the unique intra-cavity delivery mode and translational potential of a blend of poly(DL-lactic acid-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) paste combining temozolomide and etoposide to treat surgically resected HGG. Experimental Design: To prolong stability of temozolomide pro-drug, combined in vitro drug release was quantitatively assessed from low pH-based PLGA/PEG using advanced analytical methods. In vitro cytotoxicity was measured against a panel of HGG cell lines and patient-derived cultures using metabolic assays. In vivo safety and efficacy was evaluated using orthotopic 9L gliosarcoma allografts, previously utilized pre-clinically to develop Gliadel®. Results: Combined etoposide and temozolomide in vitro release (22 and 7 days respectively) was achieved from a lactic acid-based PLGA/PEG paste, used to enhance stability of temozolomide prodrug. HGG cells from central-enhanced regions were more sensitive to each compound relative to primary lines derived from the HGG invasive margin. Both drugs retained cytotoxic capability upon release from PLGA/PEG. In vivo studies revealed a significant overall survival benefit in post-surgery 9L orthotopic gliosarcomas treated with intra-cavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histological confirmation of disease-free brain. Conclusions: The significant survival benefit of intra-cavity chemotherapy demonstrates clinical applicability of PLGA/PEG paste-mediated delivery of temozolomide and etoposide adjuvant to radiotherapy. PLGA/PEG paste offers a future platform for combination delivery of molecular targeted compounds

Population structure and genetic diversity of 25 Russian sheep breeds based on whole-genome genotyping

Background: Russia has a diverse variety of native and locally developed sheep breeds with coarse, fine, and semi-fine wool, which inhabit different climate zones and landscapes that range from hot deserts to harsh northern areas. To date, no genome-wide information has been used to investigate the history and genetic characteristics of the extant local Russian sheep populations. To infer the population structure and genome-wide diversity of Russian sheep, 25 local breeds were genotyped with the OvineSNP50 BeadChip. Furthermore, to evaluate admixture contributions from foreign breeds in Russian sheep, a set of 58 worldwide breeds from publicly available genotypes was added to our data. Results: We recorded similar observed heterozygosity (0.354-0.395) and allelic richness (1.890-1.955) levels across the analyzed breeds and they are comparable with those observed in the worldwide breeds. Recent effective population sizes estimated from linkage disequilibrium five generations ago ranged from 65 to 543. Multi-dimensional scaling, admixture, and neighbor-net analyses consistently identified a two-step subdivision of the Russian local sheep breeds. A first split clustered the Russian sheep populations according to their wool type (fine wool, semi-fine wool and coarse wool). The Dagestan Mountain and Baikal fine-fleeced breeds differ from the other Merino-derived local breeds. The semi-fine wool cluster combined a breed of Romanian origin, Tsigai, with its derivative Altai Mountain, the two Romney-introgressed breeds Kuibyshev and North Caucasian, and the Lincoln-introgressed Russian longhaired breed. The coarse-wool group comprised the Nordic short-tailed Romanov, the long-fat-tailed outlier Kuchugur and two clusters of fat-tailed sheep: the Caucasian Mountain breeds and the Buubei, Karakul, Edilbai, Kalmyk and Tuva breeds. The Russian fat-tailed breeds shared co-ancestry with sheep from China and Southwestern Asia (Iran). Conclusions: In this study, we derived the genetic characteristics of the major Russian local sheep breeds, which are moderately diverse and have a strong population structure. Pooling our data with a worldwide genotyping set gave deeper insight into the history and origin of the Russian sheep populations

Rapid copper acquisition by developing murine mesothelioma: Decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration

Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an antiangiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4+ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes

Highlights of children with Cancer UK’s workshop on drug delivery in paediatric brain tumours

The first Workshop on Drug Delivery in Paediatric Brain Tumours was hosted in London by the charity Children with Cancer UK. The goals of the workshop were to break down the barriers to treating central nervous system (CNS) tumours in children, leading to new collaborations and further innovations in this under-represented and emotive field. These barriers include the physical delivery challenges presented by the blood–brain barrier, the underpinning reasons for the intractability of CNS cancers, and the practical difficulties of delivering cancer treatment to the brains of children. Novel techniques for overcoming these problems were discussed, new models brought forth, and experiences compared

Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors

Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof