Journal of the Medical Sciences (Berkala ilmu Kedokteran)
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One Step Nucleic Acid Amplification (OSNA) Study in Indonesia
No full textABSTRACTSentinel lymph node (SLN) is defined as the first of a few selected lymphatic nodes, into which lymphatic fluid from a primary tumor drains. Streamlined processing of sentinel lymph nodes (SLN) for detection of lymph node metastasis involves the able command over methodical blocks of SLN identification, surgical removal of SLN and SLN analysis. One Step Nucleic Acid Amplification (OSNA) method, which relies on CK19 mRNA expression to detect intraoperatively lymph node metastases in breast cancer cases, emerged as a plausible alternative to the current gold standard that uses histopathological node analysis. Sixty selected axillary sentinel lymph nodes from thirty breast cancer patients. Sentinel lymph nodes were directly bi-halved after collection using customized lymph node cutting device (Sysmex), or scalpel. The first halves were subjected to histopathological examination and were stored in specimen containers containing fresh formaldehyde prior to processing. The adjacent halves were weighed to comply with the required mass by OSNA detection in the range of 50 – 600 mg and wrapped in clean foils for storage in -80°C prior to OSNA analysis. 60 SLNs were same diagnosis using both methods. 25 SLNs were negative and 25 SLNs were positive using both methods. 3 SLNs were positive on OSNA but negative on histology. Other 7 SLNs were negative on OSNA but positive on histology, and these 1 nodes contained only micrometastasis lesion. These results suggest that OSNA is a useful for detecting SLNs metastasis, but a copy number of CK19 might be an indepedent factor from prediction and prognosis of breast cancer.
Mitochondrial Genetics and Cancer
No full textThe first modern human, the Mitochondrial Eve, was traced back to Africa about 200,000 years ago, based on the variation in the mitochondrial DNA (mtDNA). An eruption of a super volcano, Mount Toba, in Sumatra 70,000 years ago may have led to a 'nuclear winter', followed by a 1,000-year ice age. This cold snap would have made life difficult; genetic evidence indicated a sharp reduction in population size around this time, reaching approximately 10,000 individuals. Once the climate started to improve, our ancestors recovered from this near-extinction event. The population expanded, and some courageous explorers ventured beyond Africa. Around 50,000 years ago some of these brave ancestors had successfully crossed the globe to South East Asia and Australia. Some of them settled in the Indonesian archipelago, forming the first settlement of prehistoric Indonesia. The second migration happened around 10,000 years ago, where a group of hunter-gatherers followed the now-submerged river systems that once ran from mainland Asia between the modern islands of Sumatera, Java, and Borneo. Then, around 4,000 years ago the third group of ancestors arrived. This agricultural community brought along their culture of pottery, plant cultivation, and animal domestication, co-inciding with the vast spread of Austronesian languages. Therefore, it is likely that the Indonesian archipelago hosts a wide range of linguistic, ethnic and genetic diversity.1 Nowadays, the modern Indonesia is home to around 700 ethnic populations, each with distinct cultural and linguistic characteristics, representing vast genome diversity.Our ancestors’ decision to embark on a sea travel and take on its related lifestyle has influenced the development of susceptibility and resistance to various diseases observed today. During the prolonged travel, our ancestors were subjected to changes in global climate and geographic dynamic, which strongly influenced and shaped the genetic background of modern humans, including the mtDNA genome. Mitochondria, a well-adapted endosymbiotic intracellular organelles, became efficient for energy production through-out the course of evolution. They are critical for survival and proliferation of living organisms under aerobic conditions and produce ATP through oxidative phosphorylation (OXPHOS). Adaptation to new environments that favor beneficial traits may have caused genetic risk differences that influence the crucial function of the mitochondria, consequently affecting many function in the cell.2 The altered function of the mitochondria might act as an important factor for disease susceptibility across many human populations, i.e. mtDNA variation that grouped together forming a certain type/group (the mtDNA haplogroup) was reported to modulate cancer susceptibility3-5 and resistance6 in Chinese population.Cancer cells are characterized in general by a decrease of mitochondrial respiration and OXPHOS, a consequence of disruptive mtDNA mutations commonly found in cancer cells, and thus one could say that the growth of cancer cells is directly limited by energetics.7 In order to survive, cancer cells must modify their mitochondrial physiology to optimize energy production to their changing environments. There are two types of advantageous mtDNA mutation in cancer cells: mutations that impair OXPHOS and serve to stimulate neoplastic transformation, and those that facilitate cancer cell adaption to changing bioenergetics environments.8 These mtDNA mutations would eventually lead to an enhanced generation of reactive oxygen species (ROS), which can act both as mutagens and cellular mitogens, and contribute directly to cancer progression.7 Therefore, it can be concluded that mitochondrial alterations are critical for cancer initiation, promotion, and metastasis (Fig 1). Figure 1. Integrated mitochondrial paradigm to explain genetic and phenotypic complexities of metabolic and degenerative disease, aging, and cancer.Top three arrows: factors that have impact on mitochondrial OXPHOS robustness, risk for developing disease symptoms. Central oval arrows: pathophysiological basis of disease processes and the basis of disease progression. Lower five arrows: summarized disease categories and phenotypic outcomes of disturbed mitochondrial energy transformation. Bottom arrow: effect of the problematic accumulation of somatic mtDNA mutations resulting in delayed onset and a progressive course of diseases and aging. Right arrow: clinical problems that can result from reduced energy production in the most energetic tissues: the brain, heart, muscle, and kidney. Left arrow: indicates the metabolic effects of mitochondrial dysfunction, which result in the perturbation of the body’s energy balance. Lower right arrow: mitochondrial alterations are critical for cancer initiation, promotion, and metastasis. Lower left arrow: the hypothesized inflammatory and autoimmune responses that may result from chronic introduction of mitochondria’s bacteria-like DNA and N-formylmethionine proteins into the bloodstream.9
R-Peaks Detection Method for Classifying Arrhythmia Disorder
No full textElectrocardiography (ECG) is a non-invasive technique that is used to diagnose heartabnormalities. ECG records all heart activities and represent them using bio electricsignals. Arrhythmia is one of the cardiac disorder that can be detected using ECG.Arrhythmia need to be detected early because of an early symptom of heart diseaseas deadly as coronary heart disease and heart failure. Arrhythmia described using thedifference between the R-peaks based on QRS complex. Therefore, R-peaks detection willbe an important factor that can be used to classify arrhythmia disease. One of the widelyused methods to detect R-peaks is Pan-Tompkins method. Pan-Tompkins method used athreshold value approach to get all location of R-peaks point from the ECG signals. Thisstudy proposed a development based on Pan-Tompkins method by change the thresholdvalue using normalize technique and moving windows approach to get all location ofR-peaks point from the ECG signals. This study uses MIT-BIH arrhythmia dataset. Thismethod can show the R-peaks detection with 99.83% sensitivity and 0.40% total errorrate detection. Hence, this method has potential to be used for classifying arrhythmiadisorder based on the R-peaks point
The Influence of Long-term Diabetes Mellitus on Pain Response in Mice: In Vivo Models of Painful Diabetic Neuropathy (PDN)
No full textABSTRACTPainful diabetic neuropathy (PDN) is a complication of long-term Diabetes Mellitus (DM) characterized by hyperalgesia and allodynia. In streptozotocin (STZ)-induced diabetic mice, higher dose of STZ and lengthen hiperglycemic condition results in better model of PDN. However, higher dose of STZ tend to induce mortality. Evaluate the doses of STZ that caused PDN with less mortality rate and the timing of pain behavior development in mice model of PDN. Balb/c mice were divided into non-diabetic and STZ-induced diabetic group. The doses of STZ were started from 180 mg/kg i.p. Serum glucose levels were measured 7 days after induction. Mice with glucose levels ≥ 200 mg/dl were considered as diabetic. Pain behaviour was determined by four method i.e. hot plate, tail flick test, von Frey fillament and Randall Selitto,measured on week-0 (baseline), 1, 2, 3, 4 and 5. Data were presented as mean±SEM. The mean differences between weeks were evaluated by One-Way ANOVA and the mean differences between two groups by independent t-test. STZ doses 180 mg/kg, 150 mg/kg and 120 mg/kg caused 100% death and STZ 90 mg/kg failed to induce diabetic condition. STZ 110 mg/kg resulted in 0% mortality while it induced diabetes in 100% mice. Latency time toward thermal stimulus decreased to 5.8 s at 1st week after the mice become diabetes (p<0.05) and it was continued decrease until 4th week. The same result was also showed in tail flick test and Randal Selitto. The pain sensitivity determined by von Frey filament decreased to 1.37 g at week 1 (p<0.05) and continued decrease until 5th week. Optimum dose of STZ to induce PDN was 110 mg/kg. Pain behaviour of diabetic group was observed at 1st week after diabetic and continued until 4th week.Keywords: PDN, hot plate, tail flick test, von Frey fillament, Randall Selitt
Non infectious risk factors in pediatric sensorineural hearing loss
No full textPediatric sensorineural hearing loss can cause delay in speech and daily socialcommunication. The causative factors are infectious or non infecious. The role ofinfectious risk factors in pediatric sensorineral hearing loss has been proven. However,the role of non infectious factors has not been reported, yet. The aim of the study was toevaluate the role of non infectious factors in pediatric sensorineural hearing loss (SNHL).This was a case control study using data collected from outpatients and medical recordsin Dr. Sardjito General Hospital, Yogyakarta from June to December 2015. The inclusioncriteria of case group were children with SNHL and aged 0 – 5 years old, whereasthe inclusion criteria of control group was children with normal hearing and aged 0-5years old. The exclusion criteria were children with history of infectious risk factors andhead trauma. Hearing status were determined by Otoacoustic Emission Testing (OAE)and Brainstem Evoked Response Auditory (BERA), based on a= 5%, b = 20%; ORasumption = 3.0. Sixty two subjects were selected with 31 subjects in each group.Multivariate analysis showed that low birth weight (LBW) (p=0.018; OR=6.553; 95%CI=1.38 – 31.13) and asphyxia (p= 0.041; OR=6.448; 95% CI=1.077 – 38.595)were risk factors, while hyperbilirubinemia (p= 0.382; OR=2.46; 95% CI=0.365 –13.805) and gestation (p=0.876; OR=0.831; 95% CI=0.081 – 8.483) were not riskfactors for pediatric SNHL. In conclusion, LBW and asphyxia are risk factors for pediatricSNHL, whereas prematurity and hyperbilirubinemia are not risk factors
Prevalence and Distribution of Thalassemia Trait Screening
No full textThalassemia is an inherited disorder of autosomal recessive gene caused by decrease or absent production of one or two type of globin chain. This disorder will affect the quality and quantity of blood production. In Indonesia, thalassemia is not concerned as urgency, although it lies in thalassemia belt area. Thalassemia is classified according to the particular globin chain which affected such as α-thalassemia and β-thalassemia. Besides thalassemia, there are variant hemoglobinopathy called HbE. The aim of this study was to assess the prevalence of thalassemia carriers among the volunteer of screening in province DI Yogyakarta from 2012 until 2015. The thalassemia carrier screening was conducted by collaborating with Indonesian Association of Parents of Children with Thalassemia (POPTI) Yogyakarta. The hematological measurement and High-Performance Liquid Chromatography (HPLC) were performed on Prodia Laboratory Yogyakarta. The analysis of carriers prevalence was conducted in Laboratory of Genetics and Breeding, Faculty of Biology, Universitas Gadjah Mada. From 241 volunteers, we found 44 volunteers was diagnosed as β-thalassemia carrier, 30 volunteers as α-thalassemia carrier as well as HbE disorder carrier, and 1 volunteer was diagnosed as α-β-thalassemia carrier. The number of thalassemia carrier shows no significant difference each year. The prevalence of thalassemia carrier was high, even though the distribution is limited by the location where the screening took place.Keywords : Thalassemia trait screening - α-thalassemia - β-thalassemia – HbE – HPL
Proposed Organization of Family Cancer Clinics in Indonesia
No full textAbstractAround 10-15% of breast cancers are associated hereditary and/or familial predisposition. By definition familial breast occurs in two or more first degree relatives within a nuclear pedigree (first or second degree relatives). Hereditary and familial cancer displays different characteristics in the pathological features, clinical course, response to treatment, and outcomes. Therefore, specific consultation and treatment need to be addressed to patients with hereditary or familial predisposition for example the need for rigorous surveillance and preventive treatment including options for preventive surgery. Cancer clinical genetic service is not yet formally available in daily clinical practice in Indonesia. Surgeons usually become the first medical specialist to see cancer patients with familial predisposition, therefore they have to elaborate clinical cancer genetic service under Family Cancer Clinic (FCC). Clinical genetic service within FCC consists of several step-wise tasks including assessment of personal and family history of cancer, personalized cancer risk assessment, review of medical and family history, individual cancer screening and surveillance recommendations, genetic testing if necessary, discussion of benefits and limitations of genetic test, cancer risk reduction options and preventive strategies, and opportunity to participate in research as well as clinical trial. Nation-wide network for FCC is of importance to share knowledge and skill to perform cancer genetic service. Ability to perform genetic test including the interpretation in Indonesia has also been required
Management of hereditary breast cancer: Surgeon's perspective
No full textMutations due to hereditary related genes such as BRCA1, BRCA2, TP53 and PTEN confer greater risk of developing breast cancer and for BRCA mutations, also ovarian cancer. The risk assessment based on genetic testing allows options of high risk surveillance, prevention and may now also guide use of specific therapies for treatment such as targeted therapies and use of platinum base chemotherapy. The choice of management, once an individual has been found to carry the BRCA mutation may also vary. Moreover the availability of genetic testing, method of testing such as the transition into the use of Next Generation Sequencing techniques has also increased options of clinicians to the choice of testing.Breast Surgeons are most likely to be the first person who encounters the first presentation of a breast cancer patient. It is important for breast surgeons to be actively involved in the referrals of patients for genetic testing and subsequently planning of the management of such high risk individuals in a multidisciplinary setting. Basic principles of genetic testing and choice of management will be discussed in reference to the surgeon’s perspectives. Keywords: mutations, BRCA1. BRCA2. TP53, PTEN, NGS, multidisciplinary settin
A Comprehensive Exploration of Java Man: Bio-Cultural Evolution from Homo erectus to Homo sapiens
No full textABSTRACTAn overlap of time period between Homo erectus and Homo sapiens has not been confirmed. In the history of man, there have been two missing links: one between man and ape, and one between progressive Homo erectus and archaic Homo sapiens. Specimen dating on Java Man has been discrepant among research groups, and the use of molecular biology in ancient specimens has been a novelty. This study intends to use fossilised specimens, to harvest DNA to be sequenced for ribosomal DNA analysis for comparative phylogeny among ancient and modern man and other hominids. Dental calculus will be analysed to identify starch, carbohydrate, and protein to illustrate paleo dietary pattern. Soil samples will be examined for pollen and phytoliths to elaborate on ancient ecosystem. Blood samples will be procured from indigenous people along the riverflow region of Bengawan Solo to analyse modern human DNA. We hope that we may reconstruct the evolution pathway, construct the phylogenetic tree between ancient and modern hominids, and discover the uniqueness of Homo sapiens sapiens.Keywords: Java Man, Ribosomal DNA, Hominid Phylogenetic
DNA extraction, Polymerase Chain Reaction, and Sequencing : Workshop in Clinical Genetics
No full textAbstractDNA extraction, Polymerase Chain Reaction (PCR), and Sequencing are basic methods in molecular biology and genetics. Those there are routinely performed as basic methods in genetic research and currently also for diagnostic lab especially for pathology and human genetics. With the advance in the genetics and clinical service for cancer management, mutation analysis is very important not only for diagnosis but also for prediction of therapeutic response. Detection of KRAS, BRAF, EGFR, and c-KIT mutations is presently performed in almost every molecular pathology lab as part of daily clinical service in cancer management. In this workshop we will discuss tips and tricks for those three basic lab methods. How to improve amount and purity of DNA extraction from blood and tissues, how to avoid DNA degradation during the procedure and storage, how to perform PCR, factors and substance that inhibit polymerases during PCR, how to design effective primer pairs, and how basic theory for sequencing, and interpretation of sequencing will be discussed. Although it has been widely discussed, this workshop is especially important for clinicians who previous do not have hands-on laboratory experience. In addition, number of labs with ability to perform and serve basic genetic and molecular analysis are still limited in Indonesia. With this workshop, we expect to improve knowledge and skill in DNA extraction, PCR, and Sequencing.Keywords : DNA, PCR, sequencin