Forcing dividing cancer cells to die; low‐dose drug combinations to prevent spindle pole clustering

Mitosis, under the control of the microtubule-based mitotic spindle, is an attractive target for anti-cancer treatments, as cancer cells undergo frequent and uncontrolled cell divisions. Microtubule targeting agents that disrupt mitosis or single molecule inhibitors of mitotic kinases or microtubule motors kill cancer cells with a high efficacy. These treatments have, nevertheless, severe disadvantages: they also target frequently dividing healthy tissues, such as the haematopoietic system, and they often lose their efficacy due to primary or acquired resistance mechanisms. An alternative target that has emerged in dividing cancer cells is their ability to “cluster” the poles of the mitotic spindle into a bipolar configuration. This mechanism is necessary for the specific survival of cancer cells that tend to form multipolar spindles due to the frequent presence of abnormal centrosome numbers or other spindle defects. Here we discuss the recent development of combinatorial treatments targeting spindle pole clustering that specifically target cancer cells bearing aberrant centrosome numbers and that have the potential to avoid resistance mechanism due their combinatorial nature.

     

Hypothyroidism during treatment with tyrosine kinase inhibitors

Tyrosine kinase inhibitors are relatively new targeted therapy drugs used for the treatment of metastatic clear cell kidney carcinoma, gastrointestinal stromal tumours, thyroid carcinoma and pancreatic neuroendocrine tumours during the progression of the disease. Hypothyroidism or thyroid dysfunction is often a side effect of this treatment. Therefore, monitoring of thyroid hormone levels before the beginning and during the treatment of tyrosine kinase inhibitors is a necessity. Hypothyroidism correlates with objective response to the treatment. Sunitinib. This is the most described tyrosine kinase inhibitor which causes hypothyroidism. The mechanism of hypothyroidism is still unclear. Sorafenib. Symptoms of hypothyroidism occur in 18% of patients treated with sorafenib due to metastatic renal cell carcinoma. Imatinib. Hypothyroidism is one of the most frequent side effects of the treatment. Emergent tracheotomy was necessary due to larynx swelling during marked hypothyroidism. Motesanib. Hypothyroidism or increased TSH level is diagnosed in 22% to 69% of patients with metastatic differentiated or medullary thyroid carcinomas. The management of patients with thyroid dysfunction and related symptoms such as fatigue is undoubtedly a challenge to an oncologist.     

Multiple sclerosis - remyelination failure as a cause of disease progression

Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system (CNS) that affects worldwide about 2.5 million people. The morphological correlates of the disease are multiple lesions in brain and spinal cord which are characterized by demyelination, inflammation, gliosis and axonal damage. The underlying cause for the permanent neurological deficits in MS patients is axonal loss. Demyelinated axons are prone to damage due to the lack of trophic support by myelin sheaths and oligodendrocytes, as well as the increased vulnerability to immune mediated attacks. Remyelination occurs, but especially in chronic lesions is frequently limited to a small rim at the lesion border. Current treatment strategies are based on anti-inflammatory or immunomodulatory drugs and have the potential to reduce the numbers of newly evolving lesions, although as yet no treatment strategy exists to influence or prevent the progressive disease phase. Therefore, the development of neuroprotective treatment options, such as the promotion of endogenous remyelination is an attractive strategy. A prerequisite for the development of such new treatments is the understanding of the mechanisms leading to remyelination and the reasons for insufficient endogenous repair in chronic MS. This review will therefore provide an overview of the current concepts regarding remyelination in the rodent and human CNS. We will also summarize a selected number of inhibitory pathways and non-disease related factors which may contribute to remyelination failure in chronic MS.     

Enterococci from foods

Enterococci have recently emerged as nosocomial pathogens. Their ubiquitous nature determines their frequent finding in foods as contaminants. In addition, the notable resistance of enterococci to adverse environmental conditions explains their ability to colonise different ecological niches and their spreading within the food chain through contaminated animals and foods. Enterococci can also contaminate finished products, such as fermented foods and, for this reason, their presence in many foods (such as cheeses and fermented sausages) can only be limited but not completely eliminated using traditional processing technologies. Enterococci are low grade pathogens but their intrinsic resistance to many antibiotics and their acquisition of resistance to the few antibiotics available for treatment in clinical therapy, such as the glycopeptides, have led to difficulties and a search for new drugs and therapeutic options. Enterococci can cause food intoxication through production of biogenic amines and can be a reservoir for worrisome opportunistic infections and for virulence traits. Clearly, there is no consensus on the acceptance of their presence in foodstuffs and their role as primary pathogens is still a question mark. In this review, the following topics will be covered: (i) emergence of the enterococci as human pathogens due to the presence of virulence factors such as the production of adhesins and aggregation substances, or the production of biogenic amines in fermented foods; (ii) their presence in foods; (iii) their involvement in food-borne illnesses; (iv) the presence, selection and spreading of antibiotic-resistant enterococci as opportunistic pathogens in foods, with particular emphasis on vancomycin-resistant enterococci.     

Clustering of PubMed abstracts using nearer terms of the domain

Literature search is a process in which external developers provide alternative representations for efficient data mining of biomedical literature such as ranking search results, displaying summarized knowledge of semantics and clustering results into topics. In clustering search results, prominent vocabularies, such as GO (Gene Ontology), MeSH(Medical Subject Headings) and frequent terms extracted from retrieved PubMed abstracts have been used as topics for grouping. In this study, we have proposed FNeTD (Frequent Nearer Terms of the Domain) method for PubMed abstracts clustering. This is achieved through a two-step process viz; i) identifying frequent words or phrases in the abstracts through the frequent multi-word extraction algorithm and ii) identifying nearer terms of the domain from the extracted frequent phrases using the nearest neighbors search. The efficiency of the clustering of PubMed abstracts using nearer terms of the domain was measured using F-score. The present study suggests that nearer terms of the domain can be used for clustering the search results.     

Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration

Background

Primary amenorrhea due to 46,XY disorders of sex differentiation (DSD) is a frequent reason for consultation in endocrine and gynecology clinics. Among the genetic causes of low-testosterone primary amenorrhea due to 46,XY DSD, SRY gene is reported to be frequently involved, but other genes, such as SF1 and WT1, have never been studied for their prevalence.

Methods

We directly sequenced SRY, SF1 and WT1 genes in 15 adolescent girls with primary amenorrhea, low testosterone concentration, and XY karyotype, to determine the prevalence of mutations. We also analyzed the LH receptor gene in patients with high LH and normal FSH concentrations.

Results

Among the 15 adolescents with primary amenorrhea and low testosterone concentration, we identified two new SRY mutations, five new SF1 mutations and one new LH receptor gene mutation. Our study confirms the 10-15% prevalence of SRY mutations and shows the high prevalence (33%) of SF1 abnormalities in primary amenorrhea due to 46,XY DSD with low plasma testosterone concentration.

Conclusions

The genetic analysis of low-testosterone primary amenorrhea is complex as several factors may be involved. This work underlines the need to systematically analyze the SF1 sequence in girls with primary amenorrhea due to 46,XY DSD and low testosterone, as well as in newborns with 46,XY DSD.     

氧化应激研究进展及其在缺血性心肌病发病中的作用

缺血性心肌病（ischemic cardiomyopathy,ICM）是指由于长期心肌缺血导致心肌局限性或弥漫性纤维化,从而产生心脏收缩和（或）舒张功能受损,引起心脏扩大或僵硬、充血性心力衰竭、心律失常等一系列临床表现的临床综合症。大量研究表明,ICM的发病机制与氧化应激密切相关。研究和开发新的抗氧化药物,将为缺血性心肌病的防治提供新的方向和途径。     

Gene Therapy Strategies for Hepatocellular Carcinoma

Summary Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide. Effective therapy to this cancer is currently lacking, creating an urgent need for new therapeutic strategies for HCC. Gene therapy approach that relies on the transduction of cells with genetic materials, such as apoptotic genes, suicide genes, genes coding for antiangiogenic factors or immunomodulatory molecules, small interfering RNA (siRNA), or oncolytic viral vectors, may provide a promising strategy. The aforementioned strategies have been largely evaluated in the animal models with HCC or liver metastasis. Due to the diversity of vectors and therapeutic genes, being used alone or in combination, gene therapy approach may generate great beneficial effects to control the growth of tumors within the liver.     

EFBAT: exact family-based association tests

Background

Previous studies have reported frequent stretches of homozygosity in human subjects but have failed to clarify whether these are due to cytogenetic abnormalities or to autozygosity.

Methods

Trios which had been typed for closely spaced SNPs spanning the genome were studied. Stretches of extended homozygosity were identified in the child members, as were occasions on which the child had been genotyped as not inheriting one parental allele. The number of times such transmission errors occurred within regions of extended homozygosity was compared with the chance expectation.

Results

Transmission errors occurred more rarely in regions of extended homozygosity than would be expected by chance.

Discussion

Regions of extended homozygosity are not generally due to cytogenetic abnormalities such as uniparental isodisomy. They reflect the Mendelian inheritance of haplotypes from a common ancestor. This may have implications for mapping disease genes.     

氧化应激研究进展及其在缺血性心肌病发病中的作用

缺血性心肌病(ischemic cardiomyopathy,ICM)是指由于长期心肌缺血导致心肌局限性或弥漫性纤维化,从而产生心脏收缩和(或)舒张功能受损,引起心脏扩大或僵硬、充血性心力衰竭、心律失常等一系列临床表现的临床综合症。大量研究表明,ICM的发病机制与氧化应激密切相关。研究和开发新的抗氧化药物,将为缺血性心肌病的防治提供新的方向和途径。     

Psychrophilic and psychrotrophic fungi: a comprehensive review

This article reviews the comparative diversity of psychrophilic and psychrotrophic fungi, their adaptability mechanisms for survival and potential applications in biotechnology and pharmaceuticals. Fungi are able to grow and survive at low temperature and exist widely in polar and non-polar habitats. These cold regions are known for very low temperature, high ultra violet-B radiation, frequent freeze and thaw cycles and low water and nutrient availability. Most of the fungi adapt to such harsh conditions by evolving various strategies in their metabolism and physiology. Psychrophilic and psychrotrophic fungi are of importance in biotechnological and pharmaceutical fields due to their diverse characteristics developed or evolved due to their adaptation and survival in extreme environments, like; production of cold-active enzymes, pharmaceutical or bioactive metabolites and exo-polysaccharides, have potential for bioremediation and can also be used as biofertilizer.     

Newly arrived or previously overlooked: is there evidence for climate-driven changes in the distribution of molluscs in the Barents Sea?

In recent years, there have been frequent reports of invertebrate species newly recorded from particular areas of the Northeastern Atlantic, and it has often been suggested that these are the result of changes in species ranges due to recent warming. These suggestions make three assumptions: (1) that we have a good knowledge of the fauna of these areas; (2) that new records of “southern” species are more frequent than new records of “northern” species; (3) that climate change is the only factor affecting species range. I tested these assumptions on published records of 30 benthic molluscan species which have been found alive for the first time in the Russian part of the Barents Sea since 2006. Some of the discussed species are warm-water species and may have extended their ranges northward in response to climate change. However, our baseline knowledge of the molluscan fauna of this area before 2006 is limited by the frequent lack of molluscan specialists to study the available material, by the frequent lack of detailed publication and by changes in sampling and processing methods. New records of “southern” species are in fact not significantly commoner than new records of “northern” species. Also reasons other than climate change for observed changes in species distribution should be considered.     

Age-related variation in primary sexual characters in a passerine with male age-related fertilization success, the bluethroat Luscinia svecica

In passerine species with frequent extrapair mating, young (second calendar year) males often have a lower fertilization success than older (after second calendar year) males. This pattern might be explained by male- or female-driven mechanisms, such as female preference for older males or higher competitive ability of older males. In this study we measured the size of the testes, the seminal glomera and the cloacal protuberance as well as the size and motility of the sperm, in individual bluethroats Luscinia svecica . In this species, nearly all extrapair fertilizations (EPFs) are obtained by older males. We found that the mass of the testes and the seminal glomera were highly positively correlated and that older males had significantly larger testes (38%), seminal glomera (15%) and cloacal protuberance (23%) than young males. In contrast, there was no difference between age groups in average sperm size or sperm motility. Our results are consistent with the idea that higher fertilization success by older males in this species is due to their higher rate of sperm production, allowing larger ejaculates and/or more frequent copulations. Unequal sperm production capacities by young and older males have important implications for the interpretation of paternity patterns in extrapair mating systems.     

Can allelopathically active submerged macrophytes stabilise clear-water states in shallow lakes?

Inhibition of phytoplankton by allelochemicals released by submerged macrophytes is supposed to be one of the mechanisms that contribute to the stabilisation of clear-water states in shallow lakes. The relevance of this process at ecosystem level, however, is debated because in situ evidence is difficult to achieve. Our literature review indicates that allelopathically active species such as Myriophyllum, Ceratophyllum, Elodea and Najas or certain charophytes are among the most frequent submerged macrophytes in temperate shallow lakes. The most common experimental approach for allelopathic interference between macrophytes and phytoplankton has been the use of plant extracts or purified plant compounds. Final evidence, however, requires combination with more realistic in situ experiments. Such investigations have successfully been performed with selected species. In situ allelopathic activity is also influenced by the fact that phytoplankton species exhibit differential sensitivity against allelochemicals both between and within major taxonomic groups such as diatoms, cyanobacteria and chlorophytes. In general, epiphytic species apparently are less sensitive towards allelochemicals than phytoplankton despite living closely attached to the plants and being of key importance for macrophyte growth due to their shading. Light and nutrient availability potentially influence the sensitivity of target algae and cyanobacteria. Whether or not additional stressors such as nutrient limitation enhance or dampen allelopathic interactions still has to be clarified. We strongly propose allelopathy as an important mechanism in the interaction between submerged macrophytes and phytoplankton in shallow lakes based on the frequent occurrence of active species and the knowledge of potential target species. The role of allelopathy interfering with epiphyton development is less well understood. Including further levels of complexity, such as nutrient interference, grazing and climate, will extend this ecosystem-based view of in situ allelopathy.     

Exploring macroevolution using modern and fossil data

Macroevolution, encompassing the deep-time patterns of the origins of modern biodiversity, has been discussed in many contexts. Non-Darwinian models such as macromutations have been proposed as a means of bridging seemingly large gaps in knowledge, or as a means to explain the origin of exquisitely adapted body plans. However, such gaps can be spanned by new fossil finds, and complex, integrated organisms can be shown to have evolved piecemeal. For example, the fossil record between dinosaurs and Archaeopteryx has now filled up with astonishing fossil intermediates that show how the unique plexus of avian adaptations emerged step by step over 60 Myr. New numerical approaches to morphometrics and phylogenetic comparative methods allow palaeontologists and biologists to work together on deep-time questions of evolution, to explore how diversity, morphology and function have changed through time. Patterns are more complex than sometimes expected, with frequent decoupling of species diversity and morphological diversity, pointing to the need for some new generalizations about the processes that lie behind such patterns.     

DNA Sequence Effects on Single Base Deletions Arising during DNA Polymerization in Vitro by Escherichia Coli Klenow Fragment Polymerase

Most single base deletions detected after DNA polymerization in vitro directed by either Escherichia coli DNA polymerase I or its Klenow fragment are opposite Pu in the template. The most frequent study, were previously found to be associated with the consensus template context 5'-PyTPu-3'. In this study, the predictive power of the consensus sequence on single base deletion frequencies was directly tested by parallel comparison of mutations arising in four related DNAs differing by a single base. G, a deletion hotspot within the template context 5'-TTGA-3', was substituted by each of the 3 other bases. Previous studies had shown that deletions opposite the G were frequent but that deletions opposite its neighboring A were never detected. Based on the predictions of the consensus, the substitution of T for G should produce frequent deletions opposite the neighboring A due to its new 5'-TTTA-3' template context. This prediction was fulfilled; no deletions of this A were detected in the other templates. The consensus further predicted that deletions opposite template C would be lower than those opposite either A or G at the same site and this prediction was also fulfilled. The C substitution also produced a new hotspot for 1 bp deletions 14 bp away. The new hotspot depends on quasi-palindromic misalignment of the newly synthesized DNA strand during polymerization; accurate, but ectopically templated synthesis is responsible for this mutagenesis. Mutations templated by quasi-palindromic misalignments have previously been recognized when they produced complex sequence changes; here we show that this mechanism can produce frequent single base deletions. The unique stimulation of misalignment mutagenesis by the C substitution in the template is consistent with the singular ability of C at that site to contribute to extended complementary pairing during the DNA misalignment that precedes mutagenesis.     

Causes of Birth Asphyxia and Trauma

Causes of birth asphyxia and trauma were determined in the 208 most severely affected infants of 10,995 consecutive live births; 159 infants had cerebral disturbances, 39 had fractures and palsies, and 10 had fractures or palsies in addition to cerebral disturbances. Most frequent causes of birth asphyxia and trauma were: prolonged labour, midforceps or breech delivery in full-term infants; abruption placentae, difficult breech delivery, and maternal sedation in premature infants; and unattended precipitate deliveries in immature infants. Asphyxia following normal labour and delivery usually occurred in infants with fetal malnutrition.Improved obstetrical management with more frequent use of Cesarean section delivery might have been of value in preventing much of this fetal injury.Asphyxia and trauma due to complications of delivery were twice as frequent on the ward as on the private service. This may have been due in part to a lower Cesarean section rate on the ward service. A monthly review of birth asphyxia and trauma is recommended to help maintain a high standard of obstetrical practice.     

Hybrid Formulations of Liposomes and Bioadhesive Polymers Improve the Hypotensive Effect of the Melatonin Analogue 5-MCA-NAT in Rabbit Eyes

For the treatment of chronic ocular diseases such as glaucoma, continuous instillations of eye drops are needed. However, frequent administrations of hypotensive topical formulations can produce adverse ocular surface effects due to the active substance or other components of the formulation, such as preservatives or other excipients. Thus the development of unpreserved formulations that are well tolerated after frequent instillations is an important challenge to improve ophthalmic chronic topical therapies. Furthermore, several components can improve the properties of the formulation in terms of efficacy. In order to achieve the mentioned objectives, we have developed formulations of liposomes (150–200 nm) containing components similar to those in the tear film and loaded with the hypotensive melatonin analog 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT, 100 µM). These formulations were combined with mucoadhesive (sodium hyaluronate or carboxymethylcellulose) or amphiphilic block thermosensitive (poloxamer) polymers to prolong the hypotensive efficacy of the drug. In rabbit eyes, the decrease of intraocular pressure with 5-MCA-NAT-loaded liposomes that were dispersed with 0.2% sodium hyaluronate, 39.1±2.2%, was remarkably higher compared to other liposomes formulated without or with other bioadhesive polymers, and the effect lasted more than 8 hours. According to the results obtained in the present work, these technological strategies could provide an improved modality for delivering therapeutic agents in patients with glaucoma.     

Comparative proteomic analysis of cisplatin sensitive IGROV1 ovarian carcinoma cell line and its resistant counterpart IGROV1-R10

Ovarian cancer is one of the leading causes of mortality due to gynaecological cancer. Despite a good response to surgery and initial chemotherapy essentially based on cisplatin (cis-diamino-dichloro-platinum(II) (CDDP)) compounds, late tumour detection and frequent recurrences with chemoresistance acquisition are responsible for poor prognosis. Several mechanisms have been implicated in CDDP resistance but they are not sufficient to exhaustively explain this resistance emergence. We applied a proteomic approach based on 2-DE coupled with MS to identify proteins associated with the chemoresistance process. We first established a proteomic pattern of the CDDP sensitive ovarian cell line IGROV1 using MALDI-TOF-MS and PMF. We then compared this 2-D pattern with that of the CDDP-resistant counterpart IGROV1-R10. Among the 40 proteins identified, cytokeratins 8 and 18 and aldehyde dehydrogenase 1 were overexpressed in IGROV1-R10, whereas annexin IV was down-regulated. These observations have been confirmed by Western blotting. The characterization of such variations could lead to the development of new protein markers or to the establishment of new therapeutic strategies. Moreover, the identification of proteins involved in CDDP resistance in ovarian tumours would be useful in completing our understanding on this complex mechanism.