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ஐ.எஸ்.எஸ்.என்: 1747-0862

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தொகுதி 12, பிரச்சினை 1 (2018)

ஆய்வுக் கட்டுரை

Caspase-Cleaved Cytokeratin 18 as a Potential Molecular Biomarker for Monitoring Chemotherapeutic Response in Breast Cancer Patients

Gemechu Y, Seifu D, Tigneh W and Labisso WL

Background: Breast cancer is one of the most dreadful cancer types, with the highest mortality and morbidity in women in both low and high-income countries. Cytokeratins can be applied as noninvasive, efficient and satisfactory molecular tools to monitor and predict the response to chemotherapy for breast cancer. Objective: This study was intended to explore the potential application of ccCK18 as a molecular biomarker for monitoring and predicting the efficacy of chemotherapy on breast cancer patients. Methodology: A hospital-based prospective study was conducted on 40 breast cancer patients and 38 apparently healthy control individuals in Black Lion Specialized Hospital. Blood samples were obtained from study subjects and control groups before chemotherapy, at 4 and 6 hours after chemotherapy. An ELISA assay was applied to measure plasma caspase-cleaved Cytokeratin 18 (ccCK18). The association between expression of ccCK18 and the tumor metastasis and stages and grades were determined with ELISA. Different biochemical tests were also carried out to investigate the function of liver in relation to ccCK18 level with respect to cancer chemotherapy. Wilcoxon signed rank test, Spearman’s rho test and paired t-test were applied as statistical tools to determine association and correlation among different the study parameters. A p-value of <0.05 was considered as statistically significant. Results: The baseline levels of plasma ccCK-18 were significantly higher in patients with breast cancer than those in the control group (% CI= 95%, p<0.05). The level of ccCK-18 was also significantly increased at 6 hours after chemotherapy (p<0.05). Patients with pT3 tumor size displayed the highest median level compared to other tumor sizes. The ccCK-18 level was observed to be higher among patients with distant metastasis than in nonmetastatic patients. Lactate dehydrogenase (LDH) levels were also elevated at 6 hours, following chemotherapy. Plasma liver function tests (ALT, AST, ALP and total bilirubin) were normal before and after chemotherapy, indicating that there was no major liver damage following chemotherapy. Conclusion: ccCK-18 level in blood could be used as a molecular biomarker for monitoring the disease and predicting the response of patients to breast cancer chemotherapy, particularly in low settings; however, further studies with other protocols are warranted to tailor chemotherapy treatment in a better way.

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Practical Advices About How To Handle Disease Progression During Osimertinib In EGFR-Mutant NSCLC Patients: Is It The Same Old Story? A Mini Review

Cortellini A, Buttitta F, Marchetti A and Ficorella C

After the advent of third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), oncologists are called to face new challenges in everyday management of EGFR mutated non-small-cell-lungcancer (NSCLC) patients. These drugs, in particular Osimertinib (which is the only one currently available), represent an extraordinary innovation. But while raising the bar of expectations, they pose us new challenges. Mechanisms of resistance to Osimertinib are heterogeneous: from a "molecular point of view" they can be categorized in EGFR-dependent and independent ones. In recent years many clinical reports have shown interesting results with target treatments, mainly chosen on the basis of the "molecular resistance". However, in common practice clinicians and patients must face off with the reality and with limited treatment options. It may be helpful to classify different clinical patterns of disease progression during treatment with Osimertinib. Treating a localized progression to a single organ certainly differs from treating a wide dissemination of disease, as well as treating symptomatic progressions differs from treating non-symptomatic ones. This mini-review aims to analyse, with a very practical approach, current options for clinical management of EGFR mutant NSCLC patient at the time of disease progression during Osimertinib, by focusing particularly on maintenance strategies beyond progression.

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Bioorthogonal Chemistry in Biology and Medicine

Chakraborty P

Bioorthogonal chemistry and reactions developed from innovations in chemistry, having their excellent biocompatibility can be applied in various biological reactions. As these reactions, does not interfere with other reactions in the biological system, they can be used as excellent tools for tracking and studying dynamics of various biological processes. In this mini review, only the applications of bioorthogonal chemistry in host-microbe interaction and targeted therapy are discussed.

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Donepezil for Constipation in Lewy Body Disease: A Twelve-Month Follow-Up

Lepkowsky CM

Previously, the acetylcholinesterase inhibitor Donepezil was used in a case study to address the symptoms of constipation, obstipation, and impaction in four patients with Lewy Body diseases. In patients with both Parkinson’s disease (PD) and Neurocognitive Disorder with Lewy Bodies (NCDLB), the use of Donepezil led to symptom reduction. After six months, the symptoms of the same patients were reviewed, with no loss of bowel motility nor emergence of new symptoms. After twelve months, another review of symptoms was conducted. The results indicate that Donepezil appears to be effective in reducing the symptoms of constipation, obstipation and impaction over an extended period of treatment.

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BCL6/BCL2 and MYC Alterations Drawing the Gray Zone between Diffuse Large B-cell Lymphoma and Double, Triple Hit Lymphoma

Salamoon M

Diffuse large B-cell lymphoma (DLBCL) Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non- Hodgkin lymphoma that develops from the B-cells in the lymphatic system. Under the microscope, large malignant lymphocytes are seen diffusely throughout the specimen. Diffuse Large B-Cell Lymphoma (DLBCL) accounts for 20– 30% of all lymphoid malignancies. This subtype forms distinct morphological, molecular, and phenotypic variants. Therefore, it is of a great value to classify diffuse large B-cell lymphoma according to gene expression profiling into germinal center B-cell subtype, activated B-cell subtype, and unclassified subtype. The outcomes vary between these subtypes, and the germinal center B-cell subtype has a better outcome with the current standard rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy.

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Fetal Chimerism and Fetal Thymic Transplantation

Bhattacharya N and Sengupta P

Fetal tissue transplantation is an attractive field of modern medicine that can have immense application in treating several refractile conditions. Fetal tissue transplantation is an allogeneic transplantation procedure and like any allogeneic transplantation they contribute towards the formation of a chimera at the cellular and tissue level grossly and can be classified as a macro chimerism. The fetus during the time of pregnancy also takes part in microchimerism through fetomaternal cell trafficking where there is an exchange of the maternal and the fetal cells through the blood-placental barrier. Apart from the creation of a stable chimerism, fetal tissues also play a role in healing. Fetal thymic transplantation is one of the most exciting applications of regenerative medicine which has also been discussed briefly with some case studies.

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Impact of Climatic Fluctuation on Dengue Virus Etiology

Tilwani K, Dave G and Nadurbarkar V

Aedes mosquito-body is the favored habitat for the member of Flaiviridae, the most famous member of the family, formerly known as Dengue virus (DENV). Dengue virus infection induces high fever in human and responsible for associated symptoms like skin rashes. In literature, it has been noted that the onset of dengue fever usually occurs in monsoon and winter seasons, which gradually declines with onset of summer. This season-coordinated trend has suggested positive association towards the climate and proliferation of Dengue virus. To investigate this hypothesis, this study has been proposed. In this study, the date-wise data for Dengue positive cases were obtained from the Government hospitals across Gujarat region. The data were further correlated with the climatic parameters for that date. The investigation suggests the strong correlation between climatic fluctuations. The correlation analysis of obtain data suggests the fluctuations in relative humidity, temperature and pressure during day and night has strong impact. We proposed Poisson regression model and Negative Binomial model for prediction.

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Parkinson’s Disease: A Case Report of Motor Symptoms Resolution Following Antibiotic Treatment for Suspected Bacterial Osteomyelitis

Leheste JR, Gottlieb SF, Biegel CA, Ramos RL, Torres G and Saggio G

Background and case: The vast majority of Parkinson’s disease (PD) cases occur sporadically without any obvious etiological schema. That poses major hurdles to the discovery of effective preventative and treatment strategies. Here we are reporting the case of an 86-year-old Caucasian male, with a 21-year history of PD, who reports complete resolution of PD - related motor symptoms after treatment with antibiotics for suspected bacterial osteomyelitis.
Results: After a right leg injury, the patient was prescribed a ten-day course of ciprofloxacin and a four-week course of dicloxacillin for suspected osteomyelitis. After completion of the antibiotics, the patient reported his pervasive motor symptoms as “completely resolved” which to this day have not returned.
Conclusion: PD is a progressive, mostly idiopathic, neurodegenerative disorder with effective but limited treatment options and without compelling preventative strategies. Here we identify the first case indicating the resolution of PD-linked motor symptoms following an unrelated treatment course with antibiotics. This raises interesting questions about the use of antibiotics in PD and the potential of an etiological bacterial connection. The microbiome signature of PD is a current ‘hot topic’ of investigation and studies need to continue investigating bacteria as a possible causes of PD and antibiotics as effective treatment modalities.

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Discordant Symptoms in Monozygotic Twins with Huntington's Disease, Spinocerebellar Ataxia and other Neurodegenerative and Mendelian Disorders

Burnham K

This is a review of nature (genetics) vs. nurture (environment in several genetically based conditions of the brain and nervous system. In the medical literature on twins similar symptoms and progression of the diseases are described as concordant. Symptoms that differ among identical twins are described as discordant. If a genetic condition like Huntington's disease is 100 percent influenced by genetics, then one would expect all Huntington's symptoms to be concordant. If some symptoms are discordant then they are attributed to the environment. Ways to describe these environmental factors include: non-genetic factors, epigenetics, nurture, stochastic (patterns that can't be predicted), pre and post-natal environment, lifestyle, and nutrition. These environmental factors are slightly different or hugely different even for identical twins. The environmental factors, especially lifestyle and nutrition are the factors most influenced by brain health coaches and complementary and alternative medicine practitioners. The literature supports the idea that even in Mendelian disorders (conditions that are thought of as primarily influenced by genetics) the environment, lifestyle, and nutrition can make large differences in the symptom picture and quality of life.

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Genetic Insights from a Molecular Pathway Analysis on Two Independent Samples of Autistic Patients

Drago A, Calabro M, Crisafulli C and Rasmussen SK

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by limited interest and lacking ability in social interactions, repetitive behavior and dysfunction in social communication. ASD runs in families. Twin studies suggest a strong genetic basis for ASD. The complete definition of a genetic profile at risk for ASD is nevertheless currently lacking.
Methods: NIHM-Autism datasets 3 and 4 (n=1233 and n=2890 respectively) were analyzed. A molecular pathway analysis was conducted. Quality analysis was run as usual (λ values). Plink and R (ReactomePA and Bioconductor packages) served for TDT, association tests and the molecular pathway analysis.
Results and Discussion: The “Adherens junctions’ interactions pathway” and “Axon guidance” were enriched in the first sample, while the “Extracellular matrix organization pathway” was enriched in the second sample. The “Axon guidance pathway” showed a trend for enrichment in the second sample. A trend of significant enrichment was observed for the “NCAM1 molecular pathway” when the severity of autistic symptoms was investigated.
Conclusion: Cell to cell interaction and the cell-matrix interaction may hold the genetic risk for ASD. Both neurodevelopment and immune response (T-cell) rely on those processes and may be involved in the pathophysiology of ASD.

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The Laboratorial Diagnosis for G6PD Deficiency in Multiethnic Population

De Souza Ondei L, Silveira LM, Bonini-Domingos CR, Orlandini LC, Leite AA, Ricci O, and Machado RLD

The deficiency of glucose-6-phosphate dehydrogenase (G6PD) is the most frequent of the causes of hemolytic anemias by enzymopathies. Considering the high prevalence of these alterations and the miscegenated characteristic of the Brazilian population, the objective of this study was to investigate the frequency of this genetic affection, correlating them with the ethnic aspects and with the importance of the methodologies used for the routine laboratory diagnosis. A total of 544 peripheral blood samples collected after informed consent were analyzed from individuals aged 16-65, including 426 blood donors and 118 from individuals in an educational institution. The samples were submitted to the classic laboratory diagnosis methods for G6PD deficiency, with subsequent confirmation by complementary and specific methodologies. For the G6PD deficiency, a frequency of 3.86% was found, with 81.48% of the samples presenting the mutation A-202 (G> A), of African origin. The high frequency of G6PD deficiency reinforces the importance of investigating these hereditary conditions with due laboratory confirmation especially in mixed populations.

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Bio-Nanotechnology and its Role in Agriculture and Food Industry

Thakur S, Thakur S and Kumar R

Bulk material is divided into small size particles with one or more dimensions in the nanometer range or even smaller, the individual particles exhibit unexpected properties which are different from those of the bulk material. Due to distinct properties of nanomaterials like improved plant disease resistance, detect the mycotoxins in food, efficient nutrient utilization and enhanced plant growth. Bio-Nanotechnology combines biological principles with physical and chemical approaches to produce nano-size particles with specific functions. It also represents an economic substitute for chemical and physical methods of nanoparticles formation. Metal nanoparticles exhibit good anti-pathogenic, anti-bacterial, and anti-fungal activities due to electrostatic interaction of nanoparticles with bacterial cell membrane and their accumulation in cytoplasm. Nano-fertilizers may contain zinc, silica, iron and titanium dioxide, gold nano-rods, core shell QDs, etc. The carbon nanotubes and nanoparticles of silver, zinc oxide, etc can be really helpful in remediating the plant growth by ensuring that the nutrients are utilized optimally by the plants. Nanoscale biomaterials can take part in pathogen detection as well as helps in nanoscale purification systems for improved food quality. Some important aspects covered such as nano-additives, intelligent packaging, control and nutraceuticals delivery, nano-coding of plastics and paper materials and nano-encapsulation and target delivery. Nanoparticles have been effectively entrenched in the packaging materials for making food storage, thus minimizing pathogenic growth on stored foodstuffs. The bio-nanotechnology is a forward-looking process and acts as an agricultural biosecurity.

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Possible Implication of RNF135 in High Type 1 Neurofibromatosis Tumoral Risk

Schwartz M, Heide S, Benzarti A, Rordriguez D, Marzin P, Ader F, Larbi-Messaoud S, Belhous K, Keren B, Whalen S, Chantot-Bastaraud S and Jean-Pierre S

Background: Recurrent type 1 and 2 microdeletions of NF1 (neurofibromatosis, type 1) gene leads to a more severe phenotype than heterozygous point mutations. The associated deletion of RNF135 (Ring Finger protein 135), a flanking NF1 gene, is known to be responsible for the childhood overgrowth syndrome but its implication in tumoral severity has never been proven.
Methods and Results: A Single Nucleotide Polymorphisms array (715K) was performed in a patient with a very severe form of type 1 neurofibromatosis, as revealed by massive cervico-mediastinal plexiform neurofibromas. It showed a small 126kb atypical deletion encompassing only RNF135 and the first exon of NF1.
Conclusion: This observation highlights the possible role of RNF135 in tumoral severity in type 1 neurofibromatosis caused by recurrent type 1 and type 2 microdeletions.

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A Modern Approach to the Molecular Diagnosis of Inherited Bleeding Disorders

José María Bastida, Veronica Palma-Barqueros, Maria Luisa Lozano, Rocío Benito, Vicente Vicente, Jesús María Hernández-Rivas, José Rivera and José Ramón González-Porras

Diagnosis of inherited bleeding disorders (IBDs) requires careful evaluation of patients’ clinical features and assessment of bleeding with the appropriate tools. Definitive diagnosis can be achieved by platelet functional assays for some disorders, but, in most cases, these tests are not sufficiently sensitive or specific. Moreover, tests are hindered by the need for relatively large samples of fresh blood. Identifying the underlying molecular defect not only facilitates a definitive diagnosis of an IBD, but may also help with the clinical prognosis, and enable genetic counseling. Until recently, molecular diagnosis has relied on Sanger sequencing of single or small numbers of candidate genes that are already known to cause some inherited platelet disorders. High-throughput sequencing (HTS) technologies have revolutionized molecular diagnosis of human disease, since they allow simultaneous, rapid and affordable investigation of multiple genes. HTS is being widely implemented and is rapidly improving the molecular characterization of IBDs in routine clinical practice.

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Immune Checkpoints of CD8+ T Cells in Acute Myeloid Leukemia

Yang J, Liu G, Zhou M, Cheng J, Chen Q and Shen E

Acute myeloid leukemia (AML) is one of the most common types of hematopoietic malignancy in the adults. Induction chemotherapy followed by post-remission is the general treatment for AML patients with high relapse rate and poor prognosis, which is often related to the CD8+ T cell immune status of the AML patients. Herein, we will make a mini review of phenotype-immune checkpoints expression and function of CD8+ T cells in AML based on our data and other groups, and this might indicate the application of immune checkpoints blockade alone or in combination in AML treatment.

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Using Visual Representations to Present the Pattern of International Co-Author Collaboration in the Field of Molecular and Genetic Research

Chien TW, Chang Y, Chow JC and Chou W

Objective: The pattern of international co-author collaboration in molecular and genetic research remains unclear. We collected data from Medline and report the results with graphical presentations using Google maps and social network analysis (SNA).
Methods: Downloading 6,732 abstracts on December 13, 2017 from the Medline library with keywords of Molecular (Title) AND Genetic (Title), we reported following features: (1) nation and journal distribution; (2) main keywords frequently presented in papers; (3) the eminent author and key indicators in SNA. We programmed Microsoft Excel VBA to organize data. Google Maps and SNA Pajek were used for displaying results in molecular and genetic research.
Results: We found that (1) the most number of nations are from U.S. (1622,31.88%), China (361, 7.10%), and Japan (356, 7.00%);(2) the most number of journals is Genetika (103, 1.53%); (3) two clusters of RT-PCR and genetic association earn the highest cluster coefficient; (4) the eminent with the highest cluster coefficient is J Barhanin from Italy.
Conclusion: Social network analysis provides wide and deep insight with the relationships among entities of interest. The results drawn by Google maps can be offered to readers for future submission to journals.

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Antimicrobial Effect of Plant Oils against Some Bacterias Izolated from Patients Samples

Balkan CE, Kordali S and Bozhüyük AU

Aim:  The aim of present study was to compare the antibacterial potential of Thymus sipyleus boiss. subsp. sipyleus boiss. var. sipyleus L.  (Thymol and camphor both tested), Satureja thymbra L. and Origanum onites L. by Kirby Bauer disc diffusion method.
Methods: We isolated Enterococcus spp., E. coli, Morgonella morganii, Pseudomonas aeruginosa, MSSA, Klebsiella pneumonia and Proteus mirabilis from different patient samples. The antibacterial activity of each oils was evaluated by the Kirby Bauer disc diffusion method.
Results: Proteus mirabilis were the most susceptible bacteria against essential oils, followed by Klebsiella pneumonia and Morganella morganii. Pseudomonas aeruginosa did not show susceptibility to any oil.
Conclusion: The essential oils of the T. sipyleus, O. onites and S. thymbra were especially very effective against the resistant strains such as Enterococcus spp. and Klebsiella pneumonia. In this group the maximum antimicrobial activity was observed with the essential oils of Origanum onites and Satureja thymbra. We think that these oils can be proposed in treatment process as an alternative application structures in the future.

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Neutrophil to Lymphocyte Ratio and Red Blood Cell Distribution Width Levels in Preterm vs. Term Births

Melissa CL, Aaron HG, Jonathan HBS, Angel GR and James A

Objective: Despite its broad etiology, preterm labor has been firmly linked to inflammatory/infectious processes. However, very few cases of preterm birth are preceded by acute signs and symptoms of clinical infection. Many studies have found neutrophil-to-lymphocyte ratio and red blood cell distribution width to be elevated in cases of subclinical infections. We performed a retrospective study to compare the levels of these two markers in preterm vs. term births.
Material and methods: Patient information was obtained retrospectively. Preterm and term birth patients were captured from our database during a three-year period. Neutrophil-to-lymphocyte ratio and red blood cell distribution width in the first trimester and on admission to labor and delivery was obtained. A sample size of 130 per group was required to find a 20% difference with 80% power (standard deviation=3.2). p-values less than 0.05 were considered significant.
Results: The preterm birth group contained 137 patients with an average gestational age of 32.4 ± 4.1 weeks and the term birth group included 145 patients with an average gestational age of 39.2 ± 1.1 weeks. The neutrophilto- lymphocyte ratio at the time of delivery was found to be higher in the preterm birth group (5.9 ± 5.1 vs. 4.6 ± 3.2, p=0.007).
Red blood cell distribution width at delivery did not differ between groups (13.6 ± 0.9, 13.9 ± 1.8, p=0.09). Subgroup analysis of preterm patients with preterm premature rupture of membranes (n=52) or gestational age <35 weeks (n=72) did not result in significant difference when compared to term patients.
Conclusion: Neutrophil-to-lymphocyte ratio was significantly elevated in preterm birth patients when compared to term patients. No statistically significant difference in red blood cell distribution width was found between groups.

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