[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

SF-010-4 Distant metastasis occurs late during the genetic evolution of pancreatic cancer

The super family of glutathione S-transferases (GSTs) is composed of multiple isozymes with significant evidence of functional polymorphic variation. Over the last three decades, data from cancer studies have linked aberrant expression of GST isozymes with the development and expression of resistance to a variety of chemicals, including cancer drugs. This review addresses how differences in the human GST isozyme expression patterns influence cancer susceptibility, prognosis and treatment. In addition to the well-characterized catalytic activity, recent evidence has shown that certain GST isozymes can regulate mitogen-activated protein kinases or can facilitate the addition of glutathione to cysteine residues in target proteins (S-glutathionylation). These multiple functionalities have contributed to the recent efforts to target GSTs with novel small molecule therapeutics. Presently, at least two drugs are in late-stage clinical testing. The evolving functions of GST and their divergent expression patterns in individuals make them an attractive target for drug discovery.

Glutathione S-transferase polymorphisms: cancer incidence and therapy

Context Continuing advances in genotyping technologies and the inclusion of DNA collection in observational studies have resulted in an increasing number of genetic association studies. Objective To evaluate the overall progress and contribution of candidate gene association studies to current understanding of the genetic susceptibility to cancer. Data Sources We systematically examined the results of meta-analyses and pooled analyses for genetic polymorphisms and cancer risk published through March 2008. Study Selection We identified 161 meta-analyses and pooled analyses, encompassing 18 cancer sites and 99 genes. Analyses had to meet the following criteria: include at least 500 cases, have cancer risk as outcome, not be focused on HLA antigen genetic markers, and be published in English. Data Extraction Information on cancer site, gene name, variant, point estimate and 95% confidence interval (CI), allelic frequency, number of studies and cases, tests of study heterogeneity, and publication bias were extracted by 1 investigator and reviewed by other investigators. Results These 161 analyses evaluated 344 gene-variant cancer associations and included on average 7.3 studies and 3551 cases (range, 508-19 729 cases) per investigated association. The summary odds ratio (OR) for 98 (28%) statistically significant associations (P value −14 ), NAT2 slow acetylator and bladder cancer (OR, 1.46; 95% CI, 1.26-1.68; P = 2.5 × 10 −7 ), MTHFR C677T and gastric cancer (OR, 1.52; 95% CI, 1.31-1.77; P = 4.9 × 10 −8 ), and GSTM1 null and acute leukemia (OR, 1.20; 95% CI, 1.14-1.25; P = 8.6 × 10 −15 ). When the OR used to determine statistical power was lowered to 1.2, 2 of the 4 noteworthy associations remained so: GSTM1 null with bladder cancer and acute leukemia. Conclusion In this review of candidate gene association studies, nearly one-third of gene-variant cancer associations were statistically significant, with variants in genes encoding for metabolizing enzymes among the most consistent and highly significant associations.

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Genetic Susceptibility to Cancer: The Role of Polymorphisms in Candidate Genes

After the 1918 flu pandemic, the world is again facing a similar situation. However, the advancement in medical science has made it possible to identify that the novel infectious agent is from the coronavirus family. Rapid genome sequencing by various groups helped in identifying the structure and function of the virus, its immunogenicity in diverse populations, and potential preventive measures. Coronavirus attacks the respiratory system, causing pneumonia and lymphopenia in infected individuals. Viral components like spike and nucleocapsid proteins trigger an immune response in the host to eliminate the virus. These viral antigens can be either recognized by the B cells or presented by MHC complexes to the T cells, resulting in antibody production, increased cytokine secretion, and cytolytic activity in the acute phase of infection. Genetic polymorphism in MHC enables it to present some of the T cell epitopes very well over the other MHC alleles. The association of MHC alleles and its downregulated expression has been correlated with disease severity against influenza and coronaviruses. Studies have reported that infected individuals can, after recovery, induce strong protective responses by generating a memory T-cell pool against SARS-CoV and MERS-CoV. These memory T cells were not persistent in the long term and, upon reactivation, caused local damage due to cross-reactivity. So far, the reports suggest that SARS-CoV-2, which is highly contagious, shows related symptoms in three different stages and develops an exhaustive T-cell pool at higher loads of viral infection. As there are no specific treatments available for this novel coronavirus, numerous small molecular drugs that are being used for the treatment of diseases like SARS, MERS, HIV, ebola, malaria, and tuberculosis are being given to COVID-19 patients, and clinical trials for many such drugs have already begun. A classical immunotherapy of convalescent plasma transfusion from recovered patients has also been initiated for the neutralization of viremia in terminally ill COVID-19 patients. Due to the limitations of plasma transfusion, researchers are now focusing on developing neutralizing antibodies against virus particles along with immuno-modulation of cytokines like IL-6, Type I interferons (IFNs), and TNF-α that could help in combating the infection. This review highlights the similarities of the coronaviruses that caused SARS and MERS to the novel SARS-CoV-2 in relation to their pathogenicity and immunogenicity and also focuses on various treatment strategies that could be employed for curing COVID-19.

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Overview of Immune Response During SARS-CoV-2 Infection: Lessons From the Past.

Breast cancer stem cells: a novel therapeutic target.

The objective of the paper was to study the association of polymorphisms of phases I and II xenobiotic metabolizing enzyme genes cytochrome P450 (CYP-4501A1*2A, *2B, *2C and *4 alleles, CYP-4502D6*4 allele), glutathione-S-transferase (GSTM1 and GSTT1 null genotypes) and N-acetyl transferase 2 (NAT2*6B and *7A alleles) with the incidence of acute myeloid leukemia (AML) in an eastern Indian population. Polymerase chain reaction and restriction fragment length polymorphism of genomic DNA from peripheral blood cells were used to detect CYP-450 and NAT2 gene polymorphisms in 110 AML patients and 144 racially and geographically matched normal controls. Polymerase chain reaction was also applied to detect GST gene polymorphisms in both groups. A statistically significant difference between the AML group and the normal group was observed in the case of glutathione-S-transferase M1 null (odds ratio 3.25, 95% confidence interval 1.9-5.58, P<0.001) and N-acetyl transferase 2*6B (odds ratio 3.04, 95% confidence interval 1.79-5.16, P<0.001) genotypes. Combined deficiency of N-acetyl transferase 2 and glutathione-S-transferase M1 genes produced an odds ratio of 11.91 (95% confidence interval 4.06-34.96, P<0.001). The effect of N-acetyl transferase 2*6B (P<0.001) is significant only at ages <or=40. In the population studied, persons with glutathione-S-transferase M1 null genotype and N-acetyl transferase 2*6B allele are at increased risk of developing AML, and the risk is considerably enhanced in persons with both glutathione-S-transferase M1 and N-acetyl transferase 2 deficiency.

Association of cytochrome P450, glutathione S-transferase and N-acetyl transferase 2 gene polymorphisms with incidence of acute myeloid leukemia.

Individualizing breast cancer treatment-The dawn of personalized medicine.

Polymorphisms associated with genes coding for glutathione S-transferase enzymes are known to influence metabolism of different carcinogens and have been associated with incidence of various types of cancer. We have determined the GST M1 and GST T1 'null' genotype frequency in 81 patients with chronic myeloid leukaemia (CML) and 123 racially and geographically matched control individuals by multiplex polymerase chain reaction (PCR). GST M1 null genotype frequencies in CML and controls were 28.4% and 27.7%, respectively. GST T1 null genotype frequencies in CML and controls were 19.8% and 7.3%, respectively. The GST T1 null genotype frequency in CML patients is significantly different from that in controls (odds ratio (OR) 3.12, 95% confidence interval (CI) 1.3-7.45, P=0.008).

Glutathione S-transferase M1 and T1 null genotype frequency in chronic myeloid leukaemia.

Scorpion venom components have multifaceted orientation against bacterial, viral, fungal infections and other neuronal disorders. They can modulate the ion channels (K+, Na+, Cl−, Ca2+) of our body and this concept has been hypothesized in formulating pharmaceuticals. The triumphant achievement of these venom components as formulated anticancer agent in Phase I and Phase II clinical trials allure researchers to excavate beneficial venom components prohibiting DNA replication in malignant tumor cells. This review brings forth the achievements of Science and Technology in classifying the venom components as therapeutics and further application in drug product development.

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Ashis Mukhopadhyay

Papers

Breast cancer stem cells: a novel therapeutic target.

Association of cytochrome P450, glutathione S-transferase and N-acetyl transferase 2 gene polymorphisms with incidence of acute myeloid leukemia.

Individualizing breast cancer treatment-The dawn of personalized medicine.

Glutathione S-transferase M1 and T1 null genotype frequency in chronic myeloid leukaemia.

Scorpion Venom–Toxins that Aid in Drug Development: A Review