Impact of ErbB Receptors and Anticancer Drugs against Breast Cancer: A Review.

Human EGFR (epidermal growth factor receptor) family of tyrosine kinase receptors consists of four members, ErbB1-4. Abnormalities in the ErbB family characterize a variety of human cancers, including breast cancer. Tyrosine kinase is recruited by the activated EGFR cell surface receptor, which transmitted signals from the receptor to interact with intracellular signaling pathways and regulate cellular functions and biological processes. Targeting the intracellular signaling pathways has been aided in the drug development that was already in use and more continually being developed. The review article highlights the function of ErbB receptors/ligands, their role in signaling pathways, effective targeted drugs, and a combination of targeted drug strategies in the treatment of breast cancer that could be leading to the novel combination of anticancer drug delivery systems.

Role of Brain Biomarker in Predicting Clinical Outcome in Hypertensive Cerebrovascular Ischemic Stroke.

This study was undertaken to evaluate the role of serum neuron specific enolase (NSE) in prediction of disability and neurological worsening in hypertensive ischemic cerebrovascular stroke. 80 hypertensive ischemic stroke patients diagnosed by a neurologist as per WHO definition along with radiological findings suggestive of cerebrovascular stroke and differentiating from hemorrhagic stroke and 60 controls having essential hypertension coming to hospital because of regular checkup or headache but with no neurological disease were included in the study. Neurological disability was assessed by NIHSS at the time of admission (within 72 h from the onset of stroke) and on 7th day after admission and cases were categorized into mild, moderate and severe disability. Venous blood samples were drawn within 72 h from the onset of symptoms. The samples were processed as per the laboratory protocol. The serum NSE samples were analyzed using an enzyme immunoassay based on the sandwich technique. We observed raised serum NSE in hypertensive ischemic stroke (17.4 ± 5.4 ng/ml) with significant association between different hypertensive groups than in hypertensive controls (9.1 ± 0.75 ng/ml). Greater degree of disability was observed in hypertensive stroke patients with raised serum NSE and hypertensive patients with mean serum NSE level of 22.9 ± 3.6 ng/ml and dyslipidemia had greater probability of neurological worsening as compared to those with mean serum NSE level of 12.7 ± 1.2 ng/ml. Serum NSE levels can serve as a peripheral indicator of neuronal damage and assist in the prediction of disability and clinical outcome in hypertensive cerebrovascular ischemic stroke patients.

Identification and characterization of ErbB4 kinase inhibitors for effective breast cancer therapy.

The overexpression of ErbB4 is associated with aggressive disease biology and reduced the survival of breast cancer patients. We have used ErbB4 receptor as a novel drug target to spearhead the rational drug design. The present study is divided into two parts. In the first part, we have exploited the hidden information inside ErbB4 kinase receptor both at sequence and structural level. PSI-BLAST algorithm is used to search similar sequences against ErbB4 kinase sequence. Top 15 sequences with high identity were selected for finding conserved and variable regions among sequences using multiple sequence alignment. In the second part, available 3 D structure of ErbB4 kinase is curated using loop modeling, and anomalies in the modeled structure is improved by energy minimization. The resultant structure is validated by analyzing dihedral angles by Ramachandran plot analysis. Furthermore, the potential binding sites were detected by using DoGSite and CASTp server. The similarity-search criterion is used for the preparation of our in-house database of drugs from DrugBank database. In total, 409 drugs yet to be tested against ErbB4 kinase is used for screening purpose. Virtual screening results in identification of 11 compounds with better binding affinity than lapatinib and canertinib. Study of protein-ligand interactions reveals information about amino acid residues; Lys726, Thr771, Met774, Cys778, Arg822, Thr835, Asp836 and Phe837 at the binding pocket. The physicochemical properties and bioactivity score calculation of selected compounds suggest them as biological active. This study presents a rich array that assist in expediting new drug discovery for breast cancer.

Study of the Stability of Various Biochemical Analytes in Samples Stored at Different Predefined Storage Conditions at an Accredited Laboratory of India.

BACKGROUND: Storage of serum and other blood products is often necessary in laboratories because of technical issues or to preserve samples for subsequent research purposes. The aim of this study was to determine whether the stability of biochemical analytes is affected by storage conditions. MATERIALS AND METHODS: A total of 17 biochemical analytes in the sera of ten patients were examined following storage. Subsequent to determining the baseline measurements, the serum of each patient was aliquoted and stored at -20°C for 7, 15, and 30 days and then analyzed for stability. The results were compared with the initial analysis measurements obtained from fresh samples. Mean changes compared to baseline (T0) concentrations were evaluated both statistically and clinically. RESULTS: Our results show that sodium, potassium, urea, creatinine, uric acid, total calcium, phosphorus, direct bilirubin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, albumin, cholesterol, and triglyceride levels were stable under all conditions. Serum amylase was the only analyte demonstrating instability following prolonged storage; amylase levels changed significantly (both statistically and clinically) at 7, 15, and 30 days (P < 0.05). CONCLUSION: Most common biochemical analytes, except for amylase, showed adequate stability in serum following 30 days of storage at -20-C. Serum amylase analysis should be conducted on the same day that the sample is received in the laboratory.

Serum Total Sialic Acid and Highly Sensitive C-reactive Protein: Prognostic Markers for the Diabetic Nephropathy.

BACKGROUND: This study was undertaken to evaluate and establish the role of total sialic acid (TSA) and highly sensitive C-reactive protein (hs-CRP) in type 2 diabetes mellitus (T2DM) and its correlation with complications such as diabetic nephropathy. MATERIALS AND METHODS: One hundred fifty-seven patients with T2DM with nephropathy (DN) and 162 patients of T2DM without nephropathy (DM) along with 165 unrelated age and sex-matched healthy controls were included in the study. Serum glucose (fasting and postprandial) levels, renal profile, and lipid profile were done as per standard protocol. Serum TSA test levels and hs-CRP level were evaluated using thiobarbituric acid assay and immunoturbidimetric method respectively. RESULTS: We observed a higher concentration of serum TSA (82.67 ± 6.63 mg/dl) and hs-CRP (3.2 ± 1.44 mg/L) in diabetic nephropathy than the diabetes mellitus group (73.83 ± 6.90 mg/dl and 2.07 ± 1.32 mg/L, respectively). Both TSA and hs-CRP levels were found significantly correlated with fasting and postprandial blood sugar, hemoglobin A1c, and urine microalbumin levels in both DM and DN groups. Multinomial logistic regression analysis showed that both TSA and hs-CRP was independently associated with diabetic nephropathy. CONCLUSION: High serum TSA and hs-CRP levels may increase the microangiopathic (diabetic nephropathy) complications of T2DM.

Prevalence of extended spectrum beta-lactamase producing uropathogens and their antibiotic resistance profile in patients visiting a tertiary care hospital in central India: Implications on empiric therapy.

CONTEXT: Antimicrobial resistance showed by different uropathogens is one of the barricades that might hinder a successful treatment. Detection of extended spectrum beta-lactamase (ESBL) production among uropathogens is an important marker of endemicity. AIMS: The present prospective study was done to identify the trends of uropathogens, to find the prevalence of ESBL isolates and to study the antibiotic resistance profile of the ESBL and non-ESBL uropathogenic isolates. MATERIALS AND METHODS: This study was conducted in the Department of Microbiology of a teaching tertiary care hospital from July 2013 to September 2013. All the uropathogenic isolates were identified up to species level by conventional methods. The prevalence of potential ESBL producers was explored. Antibiotic resistance test of the urinary isolates was done by disc-diffusion method and the results were interpreted according to Clinical Laboratory Standards Institute-2013 guidelines. RESULTS: A total of 670 urine samples from male and female patients visiting the outpatient department (OPD) and inpatient department (IPD) of our hospital were collected. A significantly higher number of IPD and OPD males (55.1% and 55.5%) were found to be culture positive. Escherichia coli (55.3%) was the most frequently isolated uropathogen followed by Klebsiella pneumoniae (23%). However, strains of Escherichia coli (41.6%) were the highest ESBL producing isolates followed by Pseudomonas aeruginosa (36.1%). ESBL producing isolates were found to be multidrug-resistant when compared to non-ESBL producers. However, excessive drug-resistance among non-ESBL producing isolates can't be ignored. CONCLUSION: Our study confirms a global trend toward increased resistance to beta-lactam antibiotics. We emphasize on the formulation of antibiotic policy for a particular geographical area.

Effect of lipid profile upon prognosis in ischemic and haemorrhagic cerebrovascular stroke.

Stroke is the third major cause of death worldwide. Elevated plasma concentration of low density lipoproteins and low plasma concentration of high density lipoprotein concentration are associated with an increased risk of atherosclerosis and coronary heart disease but the relation between serum lipids, and cerebrovascular disease is less clear. The aim of this study was to investigate the reliability and accuracy of serum lipid profile in assessing the prognosis/neurological worsening in patients with ischemic and hemorrhagic cerebrovascular stroke. The subjects in the present study comprised of 101 healthy controls and 150 cerebrovascular stroke patients (including 90 with ischemic stroke and 60 with intracerebral hemorrhagic stroke). In both the groups fasting lipid profile was determined within 72 h of the stroke. A statistically significant association was observed (p < 0.001) between the parameters of lipid profile of cases and healthy controls, and also with the prognosis of the stroke.

Relation of oxidative stress, zinc and alkaline phosphatase in protein energy malnutrition.

OBJECTIVE: To determine serum zinc (Zn), total anti-oxidant capacity (TAC), malondialdehyde (MDA), alkaline phosphatase (ALP) and albumin in protein energy malnutrition (PEM) and to analyse the appropriateness of using low weight-for-age for detecting childhood under-nutrition. METHODS: This study comprised 455 children (355 malnourished and 100 normal). They were classified according to the Nutrition Subcommittee of Indian Academy of Pediatrics, Z-Score Classification and Composite Index of Anthropometric Failure. Serum Zn, TAC, MDA, ALP and albumin levels were determined. RESULTS: The serum Zn, TAC, ALP and albumin levels were found to be significantly decreased and MDA levels were significantly increased in malnourished children as compared with control (P < 0.001). CONCLUSION: The significant increase in serum MDA concentration associated with the decrease in serum TAC, Zn and ALP in malnourished children suggest that these children were potentially susceptible to high oxidative stress. Current study also suggest that conventional measures of detecting under-nutrition (low weight-for-age) may be missing out a considerable proportion of undernourished children present in the population.

Correlation of Brain Biomarker Neuron Specific Enolase (NSE) with Degree of Disability and Neurological Worsening in Cerebrovascular Stroke.

Stroke is the third major cause of death and foremost cause of disability worldwide. Cerebrovascular stroke remains largely a clinical diagnosis. The use of biomarkers in diagnosing stroke and assessing prognosis is an emerging and rapidly evolving field. The study aimed to investigate the predictive value of neurobiochemical marker of brain damage (neuron-specific enolase [NSE]) with respect to degree of disability at the time of admission and neurological worsening in acute ischemic stroke patients. We investigated 150 patients with cerebrovascular stroke who were admitted within 72 h of onset of stroke in the Department of Neurology at SAIMS. Venous blood samples were taken after admission and NSE was analyzed by solid enzyme linked immunosorbent assay using Analyzer and microplate reader from Biored: Code 680. In all patients, the neurological status was evaluated by a standardized neurological examination and the National Institutes of Health Stroke Scale on admission and on day 7. Serum NSE concentration was found to significantly correlate with both degree of disability and neurological worsening in acute ischemic stroke cases in the present study. The maximum serum NSE level within 72 h of admission was significantly higher in patients with greater degree of disability at the time of admission. Serum NSE levels were also found to be significantly elevated in patients with bad neurological outcome. Our study showed that serum NSE has high predictive value for determining severity and early neurobehavioral outcome after acute stroke.

Correlation between proinflammatory serum markers: high sensitivity C-reactive protein, interleukin-6 with disability score in acute ischemic stroke.

Stroke being the third leading cause of death and foremost cause of disability, if potential diagnostic utility of blood borne protein biomarkers in predicting acute stroke is established, it would be a substantial adjunct to computerized tomography and magnetic resonance imaging which have their own limitations. This study was done to correlate serum Interleukin 6, high sensitivity C reactive protein at the time of admission with neurological worsening assessed by NIHSS at the time of admission and 7 days after admission. 46 Patients admitted in neurology department SAIMS, Indore with first ever ischemic stroke within 72 h of onset were included in the study. All patients with history of stroke of more than 72 h onset, Infection & peripartum stroke were excluded from the study. Disability scoring was done by NIHSS and their serum samples assayed for hsCRP, IL6 by commercially available quantitative sandwich enzyme-linked immunoadsorbent assay kits. Serum samples of 50 control cases which included healthy volunteers and staff from SAIMS were also analyzed for hsCRP, IL6 for comparative study. A significant correlation was observed between NIHSS scoring and serum hsCRP and IL6 at the time of admission. Patients with initial high serum IL6 and hsCRP also showed significant clinical deterioration as assessed by NIHSS scoring 7 days after admission. Elevated hsCRP and IL6 within 72 h of admission strongly correlated with functional disability in study population in India and may serve as useful adjunct to CT Scan in emergency setting.

Serum zinc and malondialdehyde concentrations and their relation to total antioxidant capacity in protein energy malnutrition.

The aim of present study was to assess the association between serum zinc and oxidant/antioxidant status in children with protein energy malnutrition. Serum zinc, total antioxidant capacity and malondialdehyde were measured spectrophotometrically in 100 children (6 mo to 5 y); out of these, 50 children were malnourished and 50 children served as controls. Serum zinc levels were found to be significantly low in the malnourished (p<0.001). Serum zinc levels in Grade I and Grade II malnourished were 82.7 and 67.7 microg/dL respectively and in Grade III and IV combined was 53.2 microg/dL as compared to 109.5 microg/dL in the control group. These levels were significantly lower in children who had skin lesions than in those without such lesions (p<0.001). Total antioxidant capacity was found to be significantly lowered in malnourished children (Grade I=1.3 mmol/L, Grade II=1.1 mmol/L, Grade III and IV=0.5 mmol/L) as compared to 2.0 mmol/L in the control group (p<0.001). The malondialdehyde concentration in malnourished children was significantly higher (p<0.001) (Grade I=1.6 nmol/mL, Grade II=1.9 nmol/mL, Grade III and IV=2.9 nmol/mL) as compared to 1.3 nmol/mL in controls. Total antioxidant capacity and hypoalbuminaemia were also correlated positively with low serum zinc level. Serum trace element deficiency leading to depleted antioxidant protection may be a contributing factor to the pathophysiology of protein energy malnutrition and replacement of these elements in the management of this condition might be important.