Exploitation of Gene Expression and Cancer Biomarkers in Paving the Path to Era of Personalized Medicine

Cancer therapy agents have been used extensively as cytotoxic drugs against tissue or organ of a specific type of cancer. With the better understanding of molecular mechanisms underlying carcinogenesis and cellular events during cancer progression and metastasis, it is now possible to use targeted therapy for these molecular events. Targeted therapy is able to identify cancer patients with dissimilar genetic defects at cellular level for the same cancer type and consequently requires individualized approach for treatment. Cancer therapy begins to shift steadily from the traditional approach of ‘‘one regimen for all patients" to a more individualized approach, through which each patient will be treated specifically according to their specific genetic defects. Personalized medicine accordingly requires identification of indicators or markers that guide in the decision making of such therapy to the chosen patients for more effective therapy. Cancer biomarkers are frequently used in clinical practice for diagnosis and prognosis, as well as identification of responsive patients and prediction of treatment response of cancer patient. The rapid breakthrough and development of microarray and sequencing technologies is probably the main tool for paving the way toward ‘‘individualized biomarker-driven cancer therapy" or ‘‘personalized medicine". In this review, we aim to provide an updated knowledge and overview of the current landscape of cancer biomarkers and their role in personalized medicine, emphasizing the impact of genomics on the implementation of new potential targeted therapies and development of novel cancer biomarkers in improving the outcome of cancer therapy.     

PKCα translocation from mitochondria to nucleus is closely related to induction of apoptosis in gastric cancer cells

PKCs have been implicated in the regulation of cellular differentiation, proliferation, apoptosis and signal transduction. It was demonstrated in this study that PKCa was located both at mitochondria and in cytosol in gastric cancer cell line BGC-823. Treatment of cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in the translocation of PKCa from both mitochondria and cytosol to nucleus as clearly shown by laser-scanning-confocal microscopy, while the protein level of PKCa was not changed by TPA treatment as detected by Western blot. The results also revealed that TPA-induced translocation of PKCa was in close association with apoptosis induction, and such association was further affirmed by other experiments where various apoptotic stimuli and specific inhibitors of PKC were used. Taken together, these findings indicate that translocation of PKCa from both mitochondria and cytosol to nucleus in gastric cancer cell is accompanied by induction of apoptosis, and may imply a new mechanism of th     

JINKENITES——A STRANGE FOSSIL FROM EARLIEST CAMBRIAN IN W. HUBEI

A strange fossil described and illustrated in the present paper was collected by the writer in 1978 from the Huangshandong Member of the Lower Cambrian Tongying Formation in western Hubei. The material was preserved in greyish brown phosphoritic dolomites in association with elements of the Yangtze Micromolluscan Fauna, such as Tchangsichiton notabilus Yu and Sinuconus clypeus, Yu of Class Polyplacophora; Yangtzemerisma rarum Yu and Y.? cancellatum Yu of Class Merismoconchia; Yangtzeconus priscus Yu, Huangshandongoconus pileus Yu, Obtusoconus paucicostatus Yu, O. rostriptutea (Qian) and Spatuloconus rudis Yu of Class Monoplacophora; Bemella simplex Yu, Latouchlla of. memmorabilis Missarzhevsky, L. sanxiaesis Yu and L. lauta Yu of Class uncertain; Archaeospira ornata Yu, A. imbricata Yu and Cambrospira sinensis Yu of Class Gastropoda; Heraultipegma yunnanense He et Yang of Class Rostroconcbia: hyolithids and some other uncertain skeletal fossils. Although the systematic position of this peculiar fossil is unknown at present, it is inferred that this genus may be one of the typical primitive animal groups based on the characters of the shell and the spe cial spines. The shell is bilaterally symmetrical, elliptical in apical view; the dorsal side is roundly convex with three different forms of dorsal spines and several pairs of marginal spines on the anterior margin. Judged from the general morphological characters of the bilaterally symmetrical shell, these lower animals, generally speaking, have adapted themselves readily to different circumstances, and reduced resistance to any directional movement necessary for varied physiological activities. As to the function of the shell’s characteristics, the narrowly rounded side may serve as the anterior. Such a model of the body helps these animals go on with their benthonic creeping or swimming life. On the other hand, the dorsal spines are different from each other in shape, size, mode of arrangement and in number; especially, the end of the hook-shaped spines is generally curved outward, while the geniculate spines are oblique outward, and curved posteriorly all of a sudden. These structures of mechanism also provide us with the evidence that the narrowly rounded side serves as the anterior, while the opposite end as the posterior.It is of particular interest that this genus is somewhat similar to Phylum Mollusca, especially to the tryblidiids of Class Monoplacophora, in some morphological characters, such as: 1) the bilateral symmetry of the shell, 2) the outline elliptical in apical view and cap shaped in lateral view and 3) the dorsal side generally roundly convex. After careful study, it has been found that since this genus is strikingly different from monoplacopharans, may be it belongs to another interesting group of skeletal fossils. The reasons for this are: 1) in the former, there are many pairs of marginal spines on the anterior margin, while in monoplacophorans, no marginal spines can be seen; and 2) in this genus, the sculptures are different from each other in different areas, not only in shape and number, but also in the mode of arrangement, whereas in monoplacophorans, they are identical with each other in the same type and shape. Judged from the different forms of dorsal sculptures, this genus is comparatively similar to such uncertain shelly fossils as Lepidites Zhong, 1977 emend. Yu, 1987 and Xiadongoconus Yu, 1979 from the same horizon in the Yangtze Region of China, but differs from the latter two genera in the presence of marginal spines on the anterior margin. In addition, this new genus also differs from brachiopods and other skeletal fossils in the peculiar type of the shell. According to the above comparison, this genus is entirely different from all the classes of Phylum Mollusca, possibly representing another interesting group of skeletal fossils. It is impossible to determine the exact taxonomic position of this genus until more materials are available.     

Detection of clustered DNA lesions: Biological and clinical applications

Humans are daily exposed to background radiation and various sources of oxidative stress. My research has focused in the last 12 years on the effects of ionizing radiation on DNA, which is considered as the key target of radiation in the cell. Ionizing radiation and endogenous cellular oxidative stress can also induce closely spaced oxidatively induced DNA lesions called "clusters" of DNA damage or locally multiply damage sites, as first introduced by John Ward. I am now interested in the repair mechanisms of clustered DNA damage, which is considered as the most difficult for the cell to repair. A main part of my research is devoted to evaluating the role of clustered DNA damage in the promotion of carcinogenesis in vitro and in vivo . Currently in my laboratory, there are two main ongoing projects. (1) Study of the role of BRCA1 and DNA-dependent protein kinase catalytic subunit repair proteins in the processing of clustered DNA damage in human cancer cells. For this project, we use several tumor cell lines, such as breast cancer cell lines MCF-7 and HCC1937 (BRCA1 deficient) and human glioblastoma cells MO59J/K; and (2) Possible use of DNA damage clusters as novel cancer biomarkers for prognostic and therapeutic applications related to modulation of oxidative stress. In this project human tumor and mice tissues are being used.     

PKCa translocation from mitochondria to nucleus is closely related to induction of apoptosis in gastric cancer cells

PKCs have been implicated in the regulation of cellular differentiation, proliferation, apoptosis and signal transduction. It was demonstrated in this study that PKCα was located both at mitochondria and in cytosol in gastric cancer cell line BGC-823. Treatment of cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in the translocation of PKCα from both mitochondria and cytosol to nucleus as clearly shown by laser-scanning-confocal microscopy, while the protein level of PKCα was not changed by TPA treatment as detected by Western blot. The results also revealed that TPA-induced translocation of PKCα was in close association with apoptosis induction, and such association was further affirmed by other experiments where various apoptotic stimuli and specific inhibitors of PKC were used. Taken together, these findings indicate that translocation of PKCα from both mitochondria and cytosol to nucleus in gastric cancer cell is accompanied by induction of apoptosis, and may imply a new mechanism of the potential linking between cell apoptosis and PKCα translocation.     

One-carbon metabolism and breast cancer: an epidemiological perspective

One-carbon metabolism is a network of biological reactions that plays critical role in DNA methylation and DNA synthesis, and in turn, facilitates the cross-talk between genetic and epigenetic processes. Genetic polymorphisms and supplies of cofactors （e.g. folate, vitamins B） involved in this pathway have been shown to influence cancer risk and even survival. In this review, we summarized the epidemiological evidence for one-carbon metabolism, from both genetics and lifestyle aspects, in relation to breast cancer risk. We also discussed this pathway in relation to breast cancer survival and the modulation of one-carbon polymorphism in chemotherapy. Emerging evidence on modulation of DNA methylation by one-carbon metabolism suggests that disruption of epigenome might have been the underlying mechanism. More results are expected and will be translated to guidance to the general population for disease prevention as well as to clinicians for treatment and management of the disease.     

Identification of tumor evolution patterns by means of inductive logic programming

In considering key events of genomic disorders in the development and progression of cancer, the correlation between genomic instability and carcinogenesis is currently under investigation. In this work, we propose an inductive logic programming approach to the problem of modeling evolution patterns for breast cancer. Using this approach, it is possible to extract fingerprints of stages of the disease that can be used in order to develop and deliver the most adequate therapies to patients. Furthermore, such a model can help physicians and biologists in the elucidation of molecular dynamics underlying the aberrations-waterfall model behind carcinogenesis. By showing results obtained some hints about further approach to the hypotheses. on a real-world dataset, we try to give knowledge-driven validations of such     

Beyond tumorigenesis： cancer stem cells in metastasis

The importance of cancer stem cells （CSCs） in tumor-initiation has been firmly established in leukemia and recently reported for a variety of solid tumors. However, the role of CSCs in multistage cancer progression, particularly with respect to metastasis, has not been well-defined. Cancer metastasis requires the seeding and successful colonization of specialized CSCs at distant organs. The biology of normal stem cells and CSCs share remarkable similarities and may have important implications when applied to the study of cancer metastasis. Furthermore, overlapping sets of molecules and pathways have recently been identified to regulate both stem cell migration and cancer metastasis. These molecules constitute a complex network of cellular interactions that facilitate both the initiation of the pre-metastasis niche by the primary tumor and the formation of a nurturing organ microenvironment for migrating CSCs. In this review, we surveyed the recent advances in this dynamic field and propose a unified model of cancer progression in which CSCs assume a central role in both tumorigenesis and metastasis. Better understanding of CSCs as a fundamental component of the metastatic cascade will lead to novel therapeutic strategies against metastatic cancer.     

Role of SKP1-CUL1-F-Box-Protein (SCF) E3 Ubiquitin Ligases in Skin Cancer

Many biological processes such as cell proliferation, differentiation, and cell death depend precisely on the timely synthesis anddegradation of key regulatory proteins. While protein synthesis can be regulated at multiple levels, protein degradation is mainlycontrolled by the ubiquitineproteasome system (UPS), which consists of two distinct steps: (1) ubiquitylation of targeted protein by E1ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase, and (2) subsequent degradation by the 26Sproteasome. Among all E3 ubiquitin ligases, the SCF (SKP1-CUL1-F-box protein) E3 ligases are the largest family and are responsiblefor the turnover of many key regulatory proteins. Aberrant regulation of SCF E3 ligases is associated with various human diseases, such ascancers, including skin cancer. In this review, we provide a comprehensive overview of all currently published data to define a promotingrole of SCF E3 ligases in the development of skin cancer. The future directions in this area of research are also discussed with an ultimategoal to develop small molecule inhibitors of SCF E3 ligases as a novel approach for the treatment of human skin cancer. Furthermore,altered components or substrates of SCF E3 ligases may also be developed as the biomarkers for early diagnosis or predicting prognosis.     

Recent advances in the study of HPV-associated carcinogenesis

Human papillomaviruses(HPVs) cause virtually all cervical cancers, the second leading cause of death by cancer among women, as well as other anogenital cancers and a subset of head and neck cancers. Approximately half of women, who develop cervical cancer die from it. Despite the optimism that has accompanied the introduction of prophylactic vaccines to prevent some HPV infections, the relatively modest uptake of the vaccine, especially in the developing world, and the very high fraction of men and women who are already infected, means that HPV-associated disease will remain as a significant public health problem for decades. In this review, we summarize some recent findings on HPV-associated carcinogenesis, such as mi RNAs in HPV-associated cancers, implication of stem cells in the biology and therapy of HPV-positive cancers, HPV vaccines, targeted therapy of cervical cancer, and drug treatment for HPV-induced intraepithelial neoplasias.     

Current status and future perspectives of immunotherapy in bladder cancer treatment

The treatment strategy of bladder cancer has evolved not only through the traditional modalities of surgery and chemotherapy but also by immunotherapy over the past several decades. Immunotherapies such as intravesical Bacillus Calmette-Guérin(BCG)vaccines and immune checkpoint blockades(ICBs) are sometimes used for treating patients with bladder cancer, especially those who develop resistance to conventional first-line treatments such as surgery and chemotherapy. Unfortunately, it is a limited number of individuals that see clinical benefits from this approach, and complicating matters more is that many of these patients suffer severe immune-related adverse events(ir AEs). If current momentum continues to result in improved response rates and managed ir AEs, immunotherapy could be poised to revolutionize the landscape of urothelial carcinoma therapeutics.     

RNA-binding protein QKI regulates contact inhibition via Yes-associate protein in ccRCC

Contact inhibition adjusts organ size to the proper size and ensures the cultured cells growing to a monolayer.By regulating the downstream coordinator YAP,the evolutionarily conserved Hippo transduction pathway attunes cell growth and death in response to cell contact inhibition,polarity,self-renewal,and differentiation.Dysregulation of this pathway is involved in various diseases such as cancer.RNA-binding protein QKI regulates cell proliferation,metabolism,division,and immunity in various cancer models,but its role in cancer cell contact inhibition remains unclear.In this study,we aimed to clarify the relationship between QKI and YAP,and the role of their interaction in cell contact inhibition.We found a lower QKI expression level in sparse condition,whereas a higher expression level in confluent condition by western blot analysis and immunofluorescence assay.QKI knockdown elevated cell proliferation and invasion both in vitro and in vivo.Strikingly,the results of CCK-8 assay,colony formation assay,and transwell assay showed that the phenomenon was in accord with the expression level of pYAP and reverse with YAP.Higher levels of Wnt3a and β-catenin were also found in xenografts of QKI-knockdown clear cell renal cell carcinoma (ccRCC) CAKI-1 cells by western blot analysis and immumohistochemical staining.Finally,a positive correlation between QKI and pYAP was found in clinical specimens by immunohistochemistry.Thus,as a negative regulator of YAP,QKI attuned the cell contact inhibition,leading to inhibition of cancer cell proliferation and invasion through Wnt and GPCR pathway.     

Identifying cancer genes from cancer mutation profiles by cancer functions

It is of great importance to identify new cancer genes from the data of large scale genome screenings of gene mutations in cancers. Considering the alternations of some essential functions are indispensable for oncogenesis, we define them as cancer functions and select, as their approximations, a group of detailed functions in GO (Gene Ontology) highly enriched with known cancer genes. To evaluate the efficiency of using cancer functions as features to identify cancer genes, we define, in the screened genes, the known protein kinase cancer genes as gold standard positives and the other kinase genes as gold standard negatives. The results show that cancer associated functions are more efficient in identifying cancer genes than the selection pressure feature. Furthermore, combining cancer functions with the number of non-silent mutations can generate more reliable positive predictions. Finally, with precision 0.42, we suggest a list of 46 kinase genes as candidate cancer genes which are annotated to cancer functions and carry at least 3 non-silent mutations.     

Antibody gene therapy： an attractive approach for the treatment of cancers and other chronic diseases

Monoclonal antibodies(mAb)have been successfullyapplied to the treatment of chronic diseases,such as cancer,inflammation and immune diseases.With the technicaladvances in antibody engineering,development of smallrecombinant antibody fragments as high affinity therapeu-tics with reduced immunogenicity has become under thespotlight.A popular format of the engineered recombinantantibody fragments is the single-chain fixed-variable(scFv)molecules,in which the VH and VL regions of the parentalantibody are jointed together by a polypeptide linker.ThescFv fragment retains the target specificity and antigen-binding affinity of the intact antibody,and can be geneti-cally designed and produced in large quantity by ectopicallyexpressing both VH and VL regions from a single cDNAin cells.Due to its smaller size,the scFv molecule showsimproved pharmacokinetics in tumor penetration and isbetter tolerated by the host immune system.Despite thesepotential advantages of using scFv molecules for immu-notherapy,especially for chronic diseases such as cancers,the treatment efficacy,however,is often compromised bythe rapid blood clearance and insufficient concentration ofthe infused scFv fragments at the target site.To achievehigh local concentrations in the target tissues,large amountof the recombinant scFv proteins(hundreds milligrams or     

Mechanisms of autophagy and apoptosis: Recent developments in breast cancer cells

Autophagy,the pathway whereby cell components are degraded by lysosomes,is involved in the cell response to environmental stresses,such as nutrient deprivation,hypoxia or exposition to chemotherapeutic agents.Under these conditions,which are reminiscent of certain phases of tumor development,autophagy either promotes cell survival or induces cell death. This strengthens the possibility that autophagy could be an important target in cancer therapy,as has been proposed.Here,we describe the regulation of survival and death by autophagy and apoptosis,especially in cultured breast cancer cells.In particular,we discuss whether autophagy represents an apoptosis-independent process and/or if they share common pathways. We believe that understanding in detail the molecular mechanisms that underlie the relationships between autophagy and apoptosis in breast cancer cells could improve the available treatments for this disease.     

Incidence and management of white grub, Schizonycha ruficollis on seedlings of teak （Tectona grandis Linn, f,）

In investigation was conducted annually from 2002 to 2005 between the second week of May and the end of September on the incidence of scarab beetle, Schizonycha ruficollis （Fabricius） in a teak （Tectona grandis L.f.） nursery at Ramdongari, Nagpur, India. The immature stages, that is white grubs of the scarab beetle damaged 14%-52% of teak seedlings in the nursery beds, whereas the adult of the species, that is scarab beetles, were recorded on three new host trees （ Ziziphus xylopyra, Acacia catechu and A. leucophloea） in addition to the reported hosts such as ziziphus （Z. jujuba and Z. mauritiana）. Beetles of the S. ruficollis started emerging from the nursery beds just after the pre-monsoon showers and continued for 10-18 days. While beetle of S. ruficollis defoliated tree hosts available in the surroundings, the immature stages of the beetle caused major damage by feeding on root systerfls of teak seedlings with symptoms of wilting and mortality in forest nursery beds. The result of chemical and biological treatments for the management of grubs of S. ruficollis in nursery beds indicated phorate 10% granular at the rate of 20 g/m^2 and chlorpyriphos 20% emulsifiable concentrate at the rate of 5.0 mL/m^2 to be effective. Grubs of S. ruficollis have not been recorded previously as a major pest of teak （T. grandis）. This is also the first report on occurrence of S. ruficollis adults on tree hosts such as Z. xylopyra, A. catechu and A. leucophloea. White grubs being pests of economic importance and the toughest insects to manage, information given in this paper on incidence, pest status and management of Schizonycha ruficollis is of importance to researchers and forest nursery managers.