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Yigong Shi- the Spliceosome, A Protein-Directed Metalloribozyme

Posted by star on 2017-09-11 19:42:15
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      The summary was published at this year by Yigong Shi, which provided the currrently important development of the spliceosome.

      The spliceosome was a large RNA-protein complex that catalyzed the removal of introns from nuclear pre-mRNA, named as the ribonucleoprotein machinery. And ribonucleoproteins (RNPs) could mediate key cellular functions, like gene expression and regulation. Although most RNP enzymes were stable in composition and harbor preformed active sites, the spliceosome followed fundamentally different strategies. The spliceosome could provide accurate recognition and flexible splicing during alternative splicing by various compositional and structural dynamics in substrate-dependent complex assembly, catalytic activation, and active site remodeling [1-2].

 

     But its atomic structure had not been resolved for nearly 40 years. However, the yeast spliceosome was come into light in the cryogenic electron microscopy structure now. With the atomic or near-atomic resolutions, the yeast spliceosome was found having four distinct conformational states. At the active site, there were two catalytic metal ions being coordinated by the U6 small nuclear RNA (snRNA). They also catalyzed both the branching reaction and the exon ligation. The fully assembled spliceosome had U5 and U6, along with 30 contiguous nucleotides of U2 at its 5′-end. Prp8 and 16 core protein components supported the rigidity of RNA elements, to maintain the conformation in all structurally characterized spliceosomes. The mobile site was only the sequences downstream of nucleotide 30 of U2 snRNA, which delivered the intron branch site into the close proximity of the 5′......


 

       Human papillomaviruses (HPV) would be detected in 70–80% of oropharyngeal cancers, the incidence of which had reached epidemic proportions. Regarding the status of the viral genome in these cancers, the current paradigm includes three types; one is the episomal viral genome, the other two are respectively the integration between viral genome and the host genome, and the mixture of the second one with the episomal HPV genomes. The last one had been confirmed the mischaracterizing by integrated HPV genomes and consisted of virus–human hybrid episomes. Most of the hybrid episomes are consistent with the replication of original HPV.

 

       According to the data from the Cancer Genome Atlas (TCGA), head and neck cancer was resulted from three types of HPV genome. Combined all the present data, “mixed” tumors were studied and confirmed to be derived from the replicated sequences between the viral and human. As integrated with viral genomes, the interpretation of outcome for HPV-positive patients was muddied. During de-escalation trials which were important for patients at increased risk, result shown that the patients should be the people with truly integrated tumors. More works need to be done in further. In current, researchers had studied on establishing cell lines from head and neck cancers, through the status of the viral genome at very early passage, to ensure that the viral genome would not be integrated by medium-term cell culture. If E2/E5 expression was lack in situ hybridization between E6/E2/E5 RNA and tumor samples, worse clinical outcomes would appear. The HPV and clinical research organizations should open mind about the proposed model and study further.



Paclitaxel is not the life-saving medicine, but probably a

Posted by star on 2017-09-05 23:21:10
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     Paclitaxel (PTX) was widely used as a chemotherapy medication in the front line of several cancers, including ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, cervical cancer, and pancreatic cancer [1]. PTX could interfere with the normal function of microtubules in cell division, which was considered as the most effective and safe medicines on the World Health Organization's List of Essential Medicines [2-4].

 

Fig.1 Crystal structure of paclitaxel

     However, the latest research shown that although reducing tumor size, PTX increased the circulating tumor cells in the blood and enhanced the metastatic burden at the lung, which had been published on the PNAS by Prof. Hai [5]. The study revealed that there were two steps in the process. Firstly, PTX modulated the tumor microenvironment for metastasis at the microvasculature, to help cancer cells entering the blood stream. Then at the metastatic lung, PTX make cancer cells flourish in the tissue microenvironment. Notably, these changes had a great relationship with ATF3 [5].

 

Fig.2 PTX exacerbates breast cancer metastasis in a host-Atf3–dependent manner

 

Fig.3 A model showing how host-Atf3 and PTX affect multiple steps in the metastatic cascade at both the primary tumor site

      ATF3 was a member of the ATF/CREB family of transcription factors, which directly or indirectly altered the expression of a ser......

Genomic Evolution of Breast Cancer Metastasis and Relapse

Posted by star on 2017-09-05 18:05:34
Hits:35

DOI:10.1016/j.ccell.2017.07.005

Breast cancer cells that spread to other parts of the body break off and leave the primary tumor at late stage of disease development, which was found by the scientists from the Wellcome Trust Sanger Institute and their collaborators. The results, which published on Cancer Cell at August 14th this year, were shown that the realistic goal was catching and treating breast cancer before it spreads. It also opened the door for the assumption that drugs would work against breast cancer,even its spread.

It was estimated that 35,000 people in the UK suffered from metastatic breast cancer. The survival rate is poor. Only 15 % of women with breast cancer could survive for five years or more after being diagnosed. The prognosis has not improved in the past 20-30 years.

In this study, scientists investigated that how breast cancer was evolved from the originally to the spreading tumors, or metastasized. It was controversial that whether the breast cancer cells that spread to other parts of the body break off and leave the primary tumor in the breast at early or at late stages of cancer development. The researching team found that most of the genetic changes in the original cells of breast tumor were also present in the metastatic tumors, which revealed that the cancer cells spread in late period of the disease development.

This study was provided a greater chance for patients with breast cancer that the breast cancer at early stage could be cured to get rid of cancer cells spreading to other tissues, such as the lungs, brain and bone.

The whole genome sequencing provides the researchers accurate treatment strategies for different tumor types. For example, a patient with primary breast cancer was relapsed in the ......

CAR-T as A Promising Immunotherapy for Cancer

Posted by star on 2017-09-04 22:23:19
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       Chimeric antigen receptor (CAR) T cells are a kind of immunotherapy, genetically engineered to target an antigen on the tumor cells. The use of CAR therapy in cancer, by adoptive cell transfer, had been approved by the US Food and Drug Administration (FDA) for use against acute lymphoblastic leukaemia. T cells were removed from the patient and modified to express receptors specific to the patient's particular cancer through recognizing and killing the cancer cells.

       For decades, chemotherapy was the first option for the patients with tumor cells, and outcomes were stagnant. Then the anti-CD20 monoclonal antibodies which work differently than chemotherapy were discovered and improved our survival. The immune-chemotherapy had lasted for approximately ten years, until targeted therapies appeared and improved the outcomes of some patients with resistant lymphomas.

 

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