第3卷，第2期

Human gene therapy has made significant advances in less than two decades. Within this short period of time, gene therapy has proceeded from the conceptual stage to technology development and laboratory research, and finally to clinical trials for the treatment of a variety of deadly diseases. Cardiovascular disease, cancer, and stroke are leading causes of death worldwide. Despite advances in medical, interventional, radiation and surgical treatments, the mortality rate remains high, and the need for novel therapies is great. Gene therapy provides an efficient approach to disease treatment. Notable advances in gene therapy have been made for genetic disorders, including severe combined immune deficiency, chronic granulomatus disorder, hemophilia and blindness, as well as for acquired diseases, including cancer and neurodegenerative and cardiovascular diseases. However, lack of an ef ficient delivery system to target cells as well as the difficulty of sustained expression of transgenes has hindered advancements in gene therapy. Ultrasound targeted microbubble destruction (UTMD) is a promising approach for target-specific gene delivery, and it has been successfully investigated for the treatment of many diseases in the past decade. In this paper, we review UTMD-mediated gene delivery for the treatment of cardiovascular diseases, cancer and stroke.

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Duchenne muscular dystrophy (DMD) is a progressive muscle degenerative disease affecting one out of 3500 male births. Patients usually succumb to the disease by age 25. It has been shown that skipping exons of the DMD gene that contain disease-causing mutations from the pre-mRNA can result in a shortened, but functional, dystrophin protein that could bring clinical benefits to patients. A recent breakthrough has been reported in Science by three groups who demonstrated that genetically deleting exon 23 by gene editing can restore the expression of dystrophin (albeit a shortened version) and improve the muscle function in a mouse model of DMD.

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The majority of clinical blindness is caused by a loss of transparency of the lens and cornea, largely due to cataracts and corneal injuries. The most common treatment used to restore the transparency is surgical removal of the damaged tissues, followed by transplantation of donated corneal tissue or an artificial lens. However, these therapies are not without limitations or untoward effects. Unraveling the intricate regulatory signals required for cornea and lens development has made it possible to harness the lineage growth potential of stem cells for cornea repair and lens regeneration, as showcased in two recent studies published in the March 17th issue of Nature.

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It is well known that with increasing age, the risk of acquiring certain age-related diseases e such as diabetes, cancer, cardiovascular disease and neurodegenerative diseases, increases. Several theories have been proposed to explain the reason why ageing leads to higher susceptibility to disease. Over time, many of these theories have been proven wrong. Currently, the two theories holding the interest of researchers in this field are the oxidative damage theory and hyperfunction theory of ageing. The former is an old theory which explains that ageing is as a result of oxidative damage (to macromolecular components of the cell) by reactive oxygen species produced as a normal part of metabolism. The hyperfunction theory is a much newer theory which explains that ageing is as a result of the unnecessary and unwanted continuation of certain metabolic processes at old age. In this review, we discuss the mechanisms which underlie the development of age-related cancer. We also discuss the aforementioned theories of ageing. We conclude by explaining the opposing views of proponents of both theories and provide a new viewpoint by revealing a point of synergy in the two theories.

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Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by de ficiency of phenylalanine hydroxylase (PAH). The major molecular defects causing PKU are missense mutations of PAH gene. Large deletions of exon 5 (EX5del955 and EX5del4232ins) were first reported by the Czech study and were later found also in the Polish, Slovak, Slovenian and Italian PKU-patients. These observations demonstrate the existence of a common subset of this mutation predominantly among Central European populations of Slavic descent. That is why we suggest that EX5del1955 and EX5del4232ins268 mutations might be frequent causes of PKU in Ukrainian patients. EX5del955 and EX5del4232ins268 mutations were analyzed in 106 unrelated PKU patients negative for PAH gene mutations on one or both alleles from our previous analysis. The simultaneous detection of EX5del4232ins268 and EX5del955 mutations was performed by PCR amplification of mutant alleles. EX5del955 mutation was not detected in the Ukrainian patients. This relative alleles frequency of EX5del4232ins268 mutation in the Ukrainian PKU population was determined as 1,66%. Our findings can be the one more evidence of Central European Slavic origin of EX5del4232ins268 mutation, suggested previously. This finding is important for the improvement of DNA diagnosis necessary for the management of PKU patients from Ukraine.

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Human Epidermal Growth Factor Receptor type 2 (HER2) gene amplification and/or protein overexpression is observed in patients suffering from HER2+ breast cancer. This subtype of breast cancer has improved prognosis due to availability of anti-HER2 therapy. However, drug resistance and tumor recurrence still remains a major concern. Cancer Stem Cells (CSCs) are believed to constitute the subset of cell population that is resistant to drug treatment and possesses characteristics of stem cells. CSCs enable the tumors to thrive despite major insults. This review provides a comprehensive idea about the concept of CSCs in context of HER2+ breast cancer by providing the description of the markers that are used for the identification of CSCs and by elucidating the signaling pathways that are associated with HER2+ breast CSCs. Furthermore, the review also describes the interaction of HER2 with those signaling pathways and the future of targeting CSCs in HER2+ breast cancer.

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Estrogen and estrogen receptor-alpha (ER) signaling are important factors in the pathogenesis and treatment of ER-positive breast cancers. Therefore targeted therapies against ER, known as endocrine therapies, are widely used in the treatment of ER-positive breast cancers. While these therapies have shown great success, de novo and acquired resistance are common. The approach to the problem of endocrine therapy resistance is twofold: identify the mechanisms of resistance and develop alternative treatments to overcome these mechanisms. This review focuses on the progress and integration of these two aspects of resolving endocrine therapy resistance in ER-positive breast cancer patients.

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Although genes contribute to colorectal cancer, the gut microbiota are an important player. Accumulating evidence suggests that chronic infection and the ensuing in flammation contributes to tumor initiation and tumor progression. A variety of bacterial species and tumor-promoting virulence mechanisms have been investigated. Significant advances have been made in understanding the composition and functional capabilities of the gut microbiota and its roles in cancer. In the current review, we discuss the novel roles of microbiota in the progression of colon cancer. Although microbiota technically include organisms other than bacteria e.g., viruses and fungi, this review will primarily focus on bacteria. We summarize epidemiological studies of human microbiome and colon cancer. We discuss the progress in the scientific understanding of the interplay between the gut microbiota, barrier function, and host responses in experimental models. Further, we discuss the potential application in prevention, diagnosis, and therapy of colon cancer by targeting microbiota. We discuss the challenges lie ahead and the future direction in studying gut microbiome in colon cancer to close the gap between the basic sciences and clinical application.

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The attenuated anaerobic bacterium Clostridium novyi-NT (C. novyi-NT) is known for its ability to precisely germinate in and eradicate treatment-resistant hypoxic tumors in various experimental animal models and spontaneously occurring canine sarcomas. In this article, we review the therapeutic and toxicologic aspects of C.novyi-NT therapy, key challenges and limitations, and promising strategies to optimize its performance via recombinant DNA technology and immunotherapeutic approaches, to establish C.novyi-NT as an essential tool in cancer therapy.

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Osteosarcoma is a primary bone tumor that affects children and young adults. The estrogen metabolite 2-methoxyestradiol (2-ME) induces cell death in osteosarcoma cells. To determine whether 2-ME actions involve the control of protein synthesis, we studied the effect of 2-ME on eukaryotic initiation factor 4E (eIF4E) and eIF4E-binding protein 1 (4E-BP1) in MG63 osteosarcoma cells. Our results show that 2-ME treatment increases the association of eIF4E with 4E-BP1 in osteosarcoma cells. Also, 2-ME decreases the binding of eIF4E protein to 7-methyl-guanosine cap structure, indicating that 2-ME treatment results in the inhibition of translational initiation. These findings are further supported by the inhibition of protein synthesis in 2-ME-treated osteosarcoma cells. Taken together, our studies show that 2-ME-mediated antitumor effects in osteosarcoma cells involve the regulation of protein synthesis, and translational machinery could serve as a target in the treatment of osteosarcoma.

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Genetic, environmental and demographic factors contribute to the development of essential hypertension. Genetic polymorphism of Rennin-angiotensin-aldosterone system (RAAS) has been extensively studied to determine the genetic susceptibility to hypertension. The insertion/deletion (I/D) angiotensin converting enzyme (ACE) polymorphism has been established as a cardiovascular risk factor in some population, but its association with essential hypertension is controversial. This study sought to determine the association of I/D polymorphism of the ACE gene in south Indian essential hypertensive subjects. A total of 208 clinically diagnosed essential hypertensive patients without any associated diseases and 220 healthy control subjects were included in this study. Distribution and allelic frequency of Insertion (I) and Deletion (D) polymorphism at the 287 base pair Alu repeat sequence in the intron 16 of ACE gene were analyzed. The distribution of II, ID, DD genotypes of ACE gene was 28.3%, 32.6% and 38.9% respectively in essential hypertensive patients and to 53.6%, 26.3% and 20% in controls. The allele frequency for D allele is 0.58 in essential hypertension as compared to 0.34 of control subjects. The genotype and allele frequency of ACE gene polymorphism is significantly differed in patients when compared to controls. In conclusion, the I/D polymorphism of ACE gene is associated with Indian essential hypertension.

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