Anaplastic Carcinoma Thyroid - A Review on the Management of this Aggressive Cancer.

Anaplastic carcinoma thyroid is an aggressive malignancy with very poor survival rate. In this study, we reviewed the records of 34 patients with anaplastic carcinoma thyroid in our centre and we divided them into groups T4a, T4b, and T4c. The case records were reviewed for presentation, diagnosis, treatment and follow-up and we analysed the data using statistical methods. The median age group was 65 years with 22 women and 12 men. There were 16 patients (47%) with a history of thyroid swelling of more than 2 years duration. Of these 16 patients 6 were found to be in T4a group. There were 6 patients in T4a, 14 each in T4b and T4c. All the patients in T4a group were operated and completed multimodal management. The group with T4a had the best prognosis with a mean survival of 1 year. The patients with extracapsular disease (T4b) completed chemotherapy along with radiotherapy. These patients had a mean survival of 6 months. Only 2 patients in metastatic group completed the course of chemotherapy with radiotherapy. The other 12 patients died during the course of treatment due to respiratory failure. The mean survival in this group was a dismal 15 days. On univariate analysis metastatic disease, extracapsular disease, size more than 5 cm and involvement of lymph nodes were the reasons for incomplete treatment and hence markers of worst prognosis. There are 47% of the patients with prior history of thyroid swelling which gives us time to identify and manage thyroid swellings with propensity to undergo anaplastic transformation.

Uterine Sarcoma: The Indian Scenario.

Uterine sarcomas are rare, highly malignant tumours comprising < 1 % of all gynaecologic malignancies. To evaluate clinical presentation, histolopathologic pattern and outcome of uterine sarcomas presenting to a tertiary referral centre over an 8 year period (2004-2012). All histologically proven uterine sarcomas were retrospectively analysed. Clinical presentation, histology, treatment and outcome were analysed. Mean age was 42 years. Predominant histopathology was endometrial stromal sarcoma (n = 13); 9 were low grade, carcinosarcoma (n = 8) and leiomyosarcoma (n = 2). Fourteen patients had Stage I disease, 3 Stage II, 4 Stage III and 2 were Stage IV at presentation. Patients with disease confined to uterus received no adjuvant treatment (61 %). Of these, 11 were endometrial stromal sarcoma (7 were low grade) and 3 were carcinosarcomas. Four patients received adjuvant EBRT following hysterectomy (17 %). Two patients who presented with metastases received palliative chemotherapy. Mean follow-up period was 46 months (0-86 months). Eleven patients (47 %) developed disease recurrence. Seven (30 %) had local recurrence, while 4 (17 %) developed pulmonary metastases. A total of eight patients died and all deaths were within 1 year of recurrence. The only prognostic factor that correlated with survival was the stage of disease at diagnosis.

Keratosis follicularis spinulosa decalvans: a rare cause of scarring alopecia in two young Indian girls.

Keratosis follicularis spinulosa decalvans (KFSD) is an X-linked xenodermatosis characterized by scarring alopecia and follicular hyperkeratosis. This condition mainly affects males with females being carriers and will have milder symptoms. We present two sisters with severe form of KFSD, progressing to scarring alopecia.

Separation, folding and shearing of graphene layers during wedge-based mechanical exfoliation.

We report, using molecular dynamics simulation studies, how and under what conditions graphene layers separate, fold and shear during a wedge-based mechanical exfoliation machining technique to produce few-layer graphene. Our previously reported experimental results using this novel technique have shown clear evidence of few-layer graphene being subjected to such phenomena. Molecular simulations of initial wedge engagement show that the entry location of the wedge tip vis-á-vis the nearest graphene layer plays a key role in determining whether layers separate or fold and which layers and how many of them fold. We also show that depending on this entry location several successive layers beneath the wedge undergo significant elastic bending, consuming energies requiring large vertical forces to be imposed by the moving wedge. The layer separation force itself is seen to be minimal and consistent with breaking up of van der Waals interactions. In addition, shearing of layers occurs mainly during wedge exit and depends largely on the wedge speed and also its depth of insertion. Understanding the conditions at which this separation, folding and shearing of the graphene layers takes place, one can control or tune the wedge-based exfoliation technique for particular kinds of graphene layers.

Autologous graft-versus-host disease: harnessing anti-tumor immunity through impaired self-tolerance.

The absence of a graft-versus-malignancy (GVM) effect may be responsible for the higher relapse rate seen after autologous hematopoietic cell transplantation (auto-HCT) compared with allogeneic hematopoietic cell transplantation (allo-HCT). Acute GVHD developing after allo-HCT, however, is associated with significant morbidity and mortality. An autoimmune syndrome similar to acute GVHD has been reported to occur after auto-HCT and has been termed the 'auto-aggression' syndrome or autologous GVHD (auto-GVHD). Auto-GVHD tends to be milder than classical GVHD, most commonly involves the skin (rarely the gastrointestinal tract, liver or both) and often is self-limited. Auto-GVHD has been reported to occur both spontaneously and in subjects receiving post transplant immune modulation with CsA, IFN-gamma or the combination. The development of auto-GVHD depends upon the derangement of self tolerance either through administration of post transplant CsA, depletion of regulatory T cells following the preparative chemoradiotherapy or both. Self-reactive CD8(+) T cells paradoxically are able to recognize a self peptide antigen presented by MHC class II molecules and appear to mediate the syndrome. Many clinical trials have been performed using CsA with or without IFN-gamma in an attempt to induce auto-GVHD. While many patients do indeed develop the syndrome, any associated anti-tumor effect remains questionable to date. New strategies to exploit auto-GVHD and enhance a GVM effect such as through the depletion of regulatory T cells or through use of newer immunomodulatory agents may improve the efficacy of auto-HCT.

SEGE: A database on 'intron less/single exonic' genes from eukaryotes.

UNLABELLED: Eukaryotes have both 'intron containing' and 'intron less' genes. Several databases are available for 'intron containing' genes in eukaryotes. In this note, we describe a database for 'intron less' genes from eukaryotes. 'Intron less' eukaryotic genes having prokaryotic architecture will help to understand gene evolution in a much simpler way unlike 'intron containing' genes. AVAILABILITY: SEGE is available at http://intron.bic.nus.edu.sg/seg/ CONTACT: mmeena@ntu.edu.sg

APBioNet: the Asia-Pacific regional consortium for bioinformatics.

Bioinformatics and computational biology, along with the related fields of genomics, proteomics, functional genomics and systems biology are new wave scientific disciplines that harness composite computational power across networks to advance biological knowledge at the most basic level and to direct traditional laboratory-based research efforts in the biomedical sciences. 'Fostering the growth of bioinformatics and allied disciplines in the Asia-Pacific region' is the motto of the first regional bioinformatics society, the Asia-Pacific Bioinformatics Network (APBioNet). APBioNet addresses the issues of hardware, software, databases and networks pertaining to bioinformatics, with the additional layer of pertinent education, training and research. Recent milestones achieved include hosting an international bioinformatics symposium in Asia and setting up large-scale regional grid-computing projects.

Rapid formation of left atrial appendage thrombus after unsuccessful cardioversion of atrial fibrillation.

The acute effect of failed attempts of cardioversion on left atrial (LA) and left atrial appendage (LAA) functions are generally considered benign and no adverse effects have been reported. We report on a subject who had rapid formation of a fresh, mobile thrombus in the LAA despite unsuccessful cardioversion and therapeutic anticoagulation.

Endothelial function in patients with chronic heart failure.

Congestive heart failure is characteristically associated with systemic vasoconstriction and impaired vasodilatory capacity, leading to decreased peripheral perfusion. Factors identified as possible causes of reduced vasodilatory capacity include activation of the sympathetic nervous system and the renin-angiotensin system, vascular stiffness due to increased sodium and fluid retention, and structural vascular changes. More recently, the role of the endothelium as a mediator of vasoregulation and tissue perfusion has been recognized.

BioJAKE: a tool for the creation, visualization and manipulation of metabolic pathways.

The BioJAKE program has been created for the visualization, creation and manipulation of metabolic pathways. It has been designed to provide a familiar and easy-to-use interface while still allowing for the input and manipulation of complex and detailed metabolic data. In recognition of the detailed and diverse sources of data available across the Internet, it also provides a mechanism by which remote database queries can be stored and performed with respect to individual molecules within a pathway. This remote database access functionality is offered in addition to comprehensive local database creation, management and querying capability. The program has been developed in Java so as to provide for platform independence and maximum extendibility.

Validation of NMR side-chain conformations by packing calculations.

The precision and accuracy of protein structures determined by nuclear magnetic resonance (NMR) spectroscopy depend on the completeness of input experimental data set. Typically, rather than a single structure, an ensemble of up to 20 equally representative conformers is generated and routinely deposited in the Protein Database. There are substantially more experimentally derived restraints available to define the main-chain coordinates than those of the side chains. Consequently, the side-chain conformations among the conformers are more variable and less well defined than those of the backbone. Even when a side chain is determined with high precision and is found to adopt very similar orientations among all the conformers in the ensemble, it is possible that its orientation might still be incorrect. Thus, it would be helpful if there were a method to assess independently the side-chain orientations determined by NMR. Recently, homology modeling by side-chain packing algorithms has been shown to be successful in predicting the side-chain conformations of the buried residues for a protein when the main-chain coordinates and sequence information are given. Since the main-chain coordinates determined by NMR are consistently more reliable than those of the side-chains, we have applied the side-chain packing algorithms to predict side-chain conformations that are compatible with the NMR-derived backbone. Using four test cases where the NMR solution structures and the X-ray crystal structure of the same protein are available, we demonstrate that the side-chain packing method can provide independent validation for the side-chain conformations of NMR structures. Comparison of the side-chain conformations derived by side-chain packing prediction and by NMR spectroscopy demonstrates that when there is agreement between the NMR model and the predicted model, on average 78% of the time the X-ray structure also concurs. While the side-chain packing method can confirm the reliable residue conformations in NMR models, more importantly, it can also identify the questionable residue conformations with an accuracy of 60%. This validation method can serve to increase the confidence level for potential users of structural models determined by NMR.

Development of software tools at BioInformatics Centre (BIC) at the National University of Singapore (NUS).

There is burgeoning volume of information and data arising from the rapid research and unprecedented progress in molecular biology. This has been particularly affected by the Human Genome Project which is trying to completely sequence three billion nucleotides of the human genome (1),(1a). Other genome sequencing projects are also contributing substantially to this exponential growth in the number of DNA nucleotides and proteins sequenced. The number of journals, reports and research papers and tools required for the analysis of these sequences has also increased. For this the life sciences today needs tools in information technology and computation to prevent degeneration of this data into an inchoate accretion of unconnected facts and figures. The recently formed BioInformatics Centre (BIC) at the National University of Singapore (NUS) provides access to various commonly used computational tools available over the World Wide Web (WWW)--using a uniform interface and easy access. We have also come up with a new database tool. BioKleisli, which allows you to interact with various geographically scattered, heterogeneous, structurally complex and constantly evolving data sources. This paper summarises the importance of network access and database integration to biomedical research and gives a glimpse of current research conducted at BIC.

From sequence to structure to literature: the protocol approach to bioinformation.

Until the recent advent of high-throughput experimental data-acquisition in biology, the computational analysis of the biological data was predominantly on an ad hoc basis--i.e., the application of a given piece of software on the biological data depended on the need of the moment. This "functional approach" often resulted in piecemeal computational analysis with large amount of intervening "dead-time". The present high-throughput availability of experimental biological data requires a more streamlined and integrated "protocol approach". In this work, we illustrate such a user-friendly protocol using a common question frequently faced by a wet-lab bench-biologist--"Now that I have a DNA or protein sequence, what can I do with it using a computer?" As phrased, this question is steeped in the functional approach. In contrast, the protocol approach would re-phrase the same question as "Now that I have a DNA or protein sequence, what can a computer do for me?" Our integrating tool can start with a sequence and build a substantial custom data-warehouse of computationally derived sequence information, structure information and relevant published literature, that is continually updated.

In vivo expression of an alternatively spliced human tumor message that encodes a truncated form of cathepsin B. Subcellular distribution of the truncated enzyme in COS cells.

Cathepsin B is a lysosomal cysteine protease whose increased expression is believed to be linked to the malignant progression of tumors. Alternative splicing and the use of alternative transcription initiation sites in humans produce cathepsin B mRNAs that differ in their 5'- and 3'-untranslated ends. Some human tumors also contain cathepsin B-related transcripts that lack exon 3 which encodes the N-terminal signal peptide and 34 of the 62-amino acid inhibitory propeptide. In this study we show that one such transcript, CB(-2,3), which is missing exons 2 and 3, is likely to be a functional message in tumors. Thus, CB(-2,3) was found to be otherwise complete, containing the remainder of the cathepsin B coding sequence and the part of the 3'-untranslated region that is common to all previously characterized cathepsin B mRNAs in humans. Its in vitro translation product can be folded to produce enzymatic activity against the cathepsin B-specific substrate, Nalpha-benzyloxycarbonyl-L-Arg-L-Arg-4-methylcoumaryl-7-amide. Endogenous CB(-2,3) from the metastatic human melanoma cell line, A375M, co-sediments with polysomes, indicating that it engages the eukaryotic translation machinery in these cells. Epitope-tagged forms of the truncated cathepsin B from CB(-2,3) are produced in amounts comparable to the normal protein after transient transfection into COS cells. Immunofluorescence microscopy and subcellular fractionation show this novel tumor form of cathepsin B to be associated with nuclei and other membranous organelles, where it is likely to be bound to the cytoplasmic face of the membranes. This subcellular distribution was different from the lysosomal pattern shown by the epitope-tagged, full-length cathepsin B in COS cells. These results indicate that the message missing exons 2 and 3 is likely to be translated into a catalytically active enzyme, and that alternative splicing (exon skipping) could contribute to the aberrant intracellular trafficking of cathepsin B that is observed in some human cancers.

Integration of bioInformatics tools at the National University of Singapore (NUS).

In the past decade "Big Science" such as the Genome Project has generated an enormous amount of data in the life sciences. Concurrently, the synergy of this project with existing research has quickened the pace of biological discovery. But the major drawback that is beginning to be felt worldwide is the primitive level of organisation in the data accumulated. Without a proper framework or knowledge scaffold to hang and interconnect the various bits of data and information, the national knowledge-to-data ratio is declining rapidly. We are trying to serve a solution to this enigma by providing a World Wide Web (WWW) interface to Biosoftware and at the same time have come up with a database integration tool that can query heterogeneous, geographically scattered and disparate databases simultaneously. In this report we will talk about BioInformatics in general with specific reference to BioInformatics Centre (BIC) at the National University of Singapore.

Protein folding: the endgame.

The last stage of protein folding, the "endgame," involves the ordering of amino acid side-chains into a well defined and closely packed configuration. We review a number of topics related to this process. We first describe how the observed packing in protein crystal structures is measured. Such measurements show that the protein interior is packed exceptionally tightly, more so than the protein surface or surrounding solvent and even more efficiently than crystals of simple organic molecules. In vitro protein folding experiments also show that the protein is close-packed in solution and that the tight packing and intercalation of side-chains is a final and essential step in the folding pathway. These experimental observations, in turn, suggest that a folded protein structure can be described as a kind of three-dimensional jigsaw puzzle and that predicting side-chain packing is possible in the sense of solving this puzzle. The major difficulty that must be overcome in predicting side-chain packing is a combinatorial "explosion" in the number of possible configurations. There has been much recent progress towards overcoming this problem, and we survey a variety of the approaches. These approaches differ principally in whether they use ab initio (physical) or more knowledge-based methods, how they divide up and search conformational space, and how they evaluate candidate configurations (using scoring functions). The accuracy of side-chain prediction depends crucially on the (assumed) positioning of the main-chain. Methods for predicting main-chain conformation are, in a sense, not as developed as that for side-chains. We conclude by surveying these methods. As with side-chain prediction, there are a great variety of approaches, which differ in how they divide up and search space and in how they score candidate conformations.

A structural explanation for the twilight zone of protein sequence homology.

Homology modeling of protein structures as a function of sequence breaks down at the twilight zone limit of sequence identity between the template and target proteins. Our results suggest that protein sequences that have diverged from a common ancestor beyond the twilight zone may adopt side-chain interactions that are very different from those endowed by the ancestral sequence.