Re-188 lipiodol in hepatocellular carcinoma with portal vein thrombosis: a pilot study using novel chelating agent N-DEDC and its comparison with (A)HDD.

OBJECTIVE: Hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) have limited therapeutic options, Re-188 lipiodol transarterial therapy being one of them. We aimed to assess the safety and efficacy of Re-188 lipiodol exclusively in HCC with PVT as well as to compare two chelating agents for the synthesis of Re-188 lipiodol: novel bis-(diethyldithiocarbamato) nitrido (N-DEDC) with existing acetylated 4-hexadecyl 1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol [(A)HDD]. METHODS: Patients with radiological diagnosis of HCC with PVT having Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and Child Pugh score (PS) A or B were recruited. Patients received an empirical dose of transarterial Re-188 lipiodol, labelled with (A)HDD or N-DEDC. Radiological response on MRI (modified response evaluation criteria in solid tumors), biochemical response with serum alpha fetoprotein and clinical response with ECOG PS was assessed at three months and survival was estimated at the end of the study. RESULTS: Fifteen therapies were performed in 14 patients with a median age of 62 years (range: 41-70 years). Eight therapies were with Re-188 (A)HDD lipiodol and seven with Re-188 N-DEDC lipiodol. Overall mean injected dose was 2.6 ±â€…0.37 GBq. Radiological objective response rate was 31% and disease control rate was 85%. Mean overall survival was 14.21 months and mean progression free survival was 10.23 months. Percentage survival assessed at 3, 6 and 9 months was 93%, 64% and 57%, respectively. Safety parameters, response and survival outcome were comparable for (A)HDD and N-DEDC groups. CONCLUSION: Transarterial Re-188 lipiodol in HCC with PVT is safe and effective in disease control as well as improving survival outcome. Additionally, cost-effective and high-yielding novel agent N-DEDC appears to be a comparable alternative to (A)HDD for the same.

Non-invasive Coronary Artery Disease Screening Based on Electrocardiogram Characteristics and Clinical Risk Factors.

Coronary artery disease (CAD), an acute and life-threatening cardiovascular disease, is a leading cause of mortality and morbidity worldwide. Coronary angiography, the principal diagnostic tool for CAD, is invasive, expensive, and requires a lot of skilled effort. The current study aims to develop an automated and non-invasive CAD detection model and improve its performance as closely as possible to clinically acceptable diagnostic sensitivity. Electrocardiogram (ECG) characteristics are observed to be altered due to CAD and can be studied to develop a screening tool for its detection. The subject's clinical information can help broadly identify the high-cardiac-risk population and serve as a primary step in diagnosing CAD. This paper presents an approach to automatically detect CAD based on clinical data, morphological ECG features, and heart rate variability (HRV) features extracted from short-duration Lead-II ECG recordings. A few popular machine-learning classifiers, including support vector machine (SVM), random forest (RF), K-nearest neighbours (KNN), Gaussian Naïve Bayes (GNB), and multi-layer perceptron (MLP), are trained on the extracted feature space, and their performance is evaluated. Classifiers built by integrating clinical data and features extracted from ECG recordings demonstrated better performance than those built on each feature set separately, and the RF classifier outperforms other considered machine learners and reports an average testing accuracy of 94% and a G-mean score of 92% with a 5-fold cross-validation training accuracy of 95(± 0.04)%.Clinical relevance- The proposed method uses a brief, single-lead ECG recording and performs similarly to current clinical practices in an explainable manner. This makes it suitable for deployment via wearable technology (like smart watch gadgets) and telemonitoring, which may facilitate an earlier and more widespread CAD diagnosis.

Automated Myocardial Infarction Screening Using Morphology-Based Electrocardiogram Biomarkers.

Ischemic heart disease (IHD), a critical and dreadful cardiovascular disease, is a leading cause of death globally. The steady progress of IHD leads to an irreversible condition called myocardial infarction (MI). The detection of MI can be done by observing the altered electrocardiogram (ECG) characteristics. Often, automated ECG analysis is preferred in place of visual inspection to reduce time and ensure reliable detection even when the recording quality is not very good. This paper presents an automated approach to classify recent MI, past MI, and normal sinus rhythm (NSR) classes based on the morphological features of the ECG. In clinical practice, a standard 12-lead ECG setup is typically employed to identify MI. However, acquiring a 12-lead ECG is not always convenient. Hence, in this study, we have explored the possibility of using a minimal number of ECG leads by deriving the augmented limb leads using leads I and II. A well-known and widely used ensemble machine learning tool, the random forest (RF) classifier is trained using features extracted from the derived augmented limb leads and their combinations. An RF classifier built using features extracted from all limb leads has outperformed classifiers built on combinations of them with five-fold cross-validation training accuracy of 97.9 (±0.008) % and testing accuracy of 98 %.Clinical relevance- As high sensitivity is reported in identifying recent MI and past MI classes, the proposed approach is suitable for preventative healthcare applications since it is less likely that subjects with recent or past MI will be misclassified. Due to its low computational complexity, better interpretability, and comparable performance to the state-of-the-art results, the proposed approach can be employed in clinical and cardiac health screening applications. It also has the potential to be employed in remote monitoring with mobile and wearable devices because it is built on features extracted from only lead I and II ECG recordings.

Comparison of 99m Tc-methylenediphosphonate and 68 Ga-BPAMD PET/computed tomography imaging in bone metastasis.

OBJECTIVE: Bone is considered as the third most common site of metastases, besides lung and liver. Early detection of skeletal metastases aids in better management of skeletal-related events. In the present study cold kit-based 2,2 ' ,2 '' -(10-(2-((diphosphonomethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (BPAMD) was labeled with 68 Ga. The radiolabeling parameters and clinical evaluation in patients with suspected bone metastases were compared with routinely used 99m Tc-methylenediphosphonate ( 99m Tc-MDP). METHODOLOGY: The kit components of MDP were incubated with at room temperature for 10 min, followed by radiochemical purity testing using thin-layer chromatography. For radiolabeling of BPAMD, the cold kit components reconstituted in 400 µL of HPLC grade water were transferred and incubated with 68 GaCl 3 in the reactor vessel of the fluidic module at 95°C for 20 min. Radiochemical yield and purity were determined with instant thin-layer chromatography using 0.5 M sodium citrate as mobile phase. For clinical evaluation, patients ( n = 10) with suspected bone metastases were enrolled. 99m Tc-MDP and 68 Ga-BPAMD scans were performed on two different days in random order. Imaging outcomes were noted and compared. RESULTS: Radiolabeling of both tracers is facile using cold kit, although BPAMD requires heating. The radiochemical purity was observed to be greater than 99% for all preparations. Both MDP and BPAMD detected skeletal lesions; however, additional lesions were detected in total of seven patients which were not visualized clearly on 99m Tc-MDP scan. CONCLUSION: BPAMD can be easily tagged with 68 Ga using cold kits. The radiotracer is suitable and efficient for detection of bone metastases using PET/computed tomography.

Simulating Stenotic Conditions of the Coronary Artery in a Lumped Parameter Model of the Cardiovascular System.

Coronary flow control mechanisms maintain the average coronary blood flow (CBF) at 4% of the cardiac output (CO) in normal adults, with no prior diagnosis of coronary artery disease (CAD), under resting conditions. This paper explores a pulsatile sixth order lumped parameter (LP) model of the cardiovascular system (CVS) which utilizes the average CBF approximated from CO along with arterial blood pressure (ABP) waveform to estimate the coronary microvascular resistance using non-linear least square optimization technique. The CVS model includes a third order model of the coronary vascular bed and is shown to achieve phasic coronary flow. The coronary epicardial resistance is varied to emulate different degrees of stenosis and achieve realistic behavior of coronary microvascular resistance under these conditions.

Normal and Abnormal Classification of Electrocardiogram: A Primary Screening Tool Kit.

Cardiovascular diseases (CVDs) are one of the principal causes of death. Cardiac arrhythmia, a critical CVD, can be easily detected from an electrocardiogram (ECG) recording. Automated ECG analysis can help clinicians to identify arrhythmia and prevent untimely death. This paper presents a simple model to classify the ECG recordings into two classes: Normal and Abnormal based on morphological and heart rate variability (HRV) features. Before feature extraction, Signal quality analysis (SQA) is performed to abandon poor quality ECG signals. Several machine-learning classifiers such as Support Vector Machine (SVM), Adaboost (AB), Random Forest (RF), Extra-Tree Classifier (ET), Decision Tree (DT), Artificial Neural Network (ANN), K-Nearest Neighbors (KNN), Logistic Regression (LR), Naïve Bayes (NB), and Gradient Boosting (GB) are explored on the extracted feature space. To enhance the study, few feature selection algorithms such as F test, Least Absolute Shrinkage and Selection Operator (LASSO), and Minimal Redundancy Maximal Relevance (mRMR) algorithms are also applied and the outcomes of each algorithm along with the considered classifiers are analyzed and compared. The proposed algorithm is validated on 2648 Normal and 2518 Abnormal ECG recordings. The accuracy of our best classifier is found to be 95.25 %. It is anticipated that the proposed model will be helpful as a primary and mass screening tool kit in clinical settings.

Morphological Event Based Signal Quality Assessment of Electrocardiogram.

ECG signals acquired from mobile devices by unskilled users are corrupted with several noises. Poor signal quality may result in an increased number of false alarms, degrading diagnostic performance, and increasing the burden on the doctors in decoding the information for further clinical intervention. So, it is necessary to assess the quality of the signals before doing any further processing. This paper presents a method for accessing the reliability of ECG signals obtained from wearable sensors. A morphological event-based quality assessment method is proposed where a signal will be classified as GOOD/BAD. Results show that our method can achieve an accuracy = 92 % with sensitivity = 0.98 and specificity = 0.59.

Genome-wide in silico characterization and stress induced expression analysis of BcL-2 associated athanogene (BAG) family in Musa spp.

Programmed cell death (PCD) is a genetically controlled process for the selective removal of damaged cells. Though understanding about plant PCD has improved over years, the mechanisms are yet to be fully deciphered. Among the several molecular players of PCD in plants, B cell lymphoma 2 (Bcl-2)-associated athanogene (BAG) family of co-chaperones are evolutionary conserved and regulate cell death, growth and development. In this study, we performed a genome-wide in silico analysis of the MusaBAG gene family in a globally important fruit crop banana. Thirteen MusaBAG genes were identified, out of which MusaBAG1, 7 and 8 genes were found to have multiple copies. MusaBAG genes were distributed on seven out of 11 chromosomes in banana. Except for one paralog of MusaBAG8 all the other 12 proteins have characteristic BAG domain. MusaBAG1, 2 and 4 have an additional ubiquitin-like domain whereas MusaBAG5-8 have a calmodulin binding motif. Most of the MusaBAG proteins were predicted to be localized in the nucleus and mitochondria or chloroplast. The in silico cis-regulatory element analysis suggested regulation associated with photoperiodic control, abiotic and biotic stress. The phylogenetic analysis revealed 2 major clusters. Digital gene expression analysis and quantitative real-time RT-PCR depicted the differential expression pattern of MusaBAG genes under abiotic and biotic stress conditions. Further studies are warranted to uncover the role of each of these proteins in growth, PCD and stress responses so as to explore them as candidate genes for engineering transgenic banana plants with improved agronomic traits.

Camptothecin enhances 131I-rituximab-induced G1-arrest and apoptosis in Burkitt lymphoma cells.

BACKGROUND: Rituximab is a chimeric monoclonal antibody against CD20. It is an established immunotherapeutic agent for non-Hodgkin's lymphoma. Even though rituximab has been used in clinics for decades, only 50% of the patients respond to rituximab therapy. To enhance the in vitro effect of rituximab, it was labeled with Iodine-131 (131I) and combined effect of 131I-rituximab and camptothecin (CPT) was studied on a tumor cell line expressing CD20. OBJECTIVE: The aim is to study the magnitude of cell killing and the underlying mechanism responsible for enhancing in vitro therapeutic efficacy. METHODS: Rituximab was labeled with 131I by the iodogen method. Raji cells were pretreated with CPT (250 nM) for an hour followed by 131I-rituximab (0.37 and 3.7 MBq) and incubated for 24 h in a humidified atmosphere of CO2 incubator at 37°C. Subsequently, Raji cells were harvested and thoroughly washed to carry out studies of cellular toxicity, apoptosis, cell cycle, and mitogen-activated protein kinase (MAPK) pathways. RESULTS: Maximal inhibition of cell proliferation and enhancement of apoptotic cell death was observed in the cells treated with the combination of CPT and 131I-rituximab, compared to controls of CPT-treated and 131I-rituximab-treated cells. Raji cells undergo G1 arrest after 131I-rituximab treatment, which leads to apoptosis and was confirmed by the downregulation of bclxl protein. Expression of p38 was decreased while an increase in phosphorylation of p38 was observed in the combination treatment of CPT and 131I-rituximab. CONCLUSIONS: It was concluded from the findings that CPT enhanced 131I-rituximab-induced apoptosis, G1 cell cycle arrest and p38 MAPK phosphorylation in Raji cells.

Facile Synthesis of a Pt(IV) Prodrug of Cisplatin and Its Intrinsically 195mPt Labeled Analog: A Step Closer to Cancer Theranostic.

BACKGROUND AIMS AND OBJECTIVES: Cisplatin is extensively used in chemotherapy for treatment of a broad range of cancers. But its undesired side reactions with biomolecules that lead to severe side effects especially on kidney and nervous system, are limiting its clinical utility. To reduce its side effects, the kinetically inert Pt(IV) prodrug was recognized as an alternative approach from satisfactory results of preliminary experiments. But, its approval as anticancer drug for clinical use requires detailed investigations of its anticancer action and pharmacological pathways by employing its analogue which can be traced by a suitable technique. As a step closer towards translation of Pt(IV)-based prodrug from research to clinical level, a protocol for efficient synthesis of 195mPt-radiolabeled Pt(IV) prodrug was devised. MATERIALS AND METHODS: In order to achieve the aim, we started synthesis from elemental platinum avoiding lengthy steps. The synthesis protocol was standardized on its cold analogue, as [PtCl2(NH3)2(OCOCH2CH2COOH)2] which has been characterized with nuclear magnetic resonance (1H, 13C{1H} and 195Pt{1H}) spectroscopy, microanalyses and cyclic voltammetry. Also, cytotoxicity of [PtCl2(OCOCH2CH2COOH)2(NH3)2] was evaluated against MCF-7 human breast cancer cell lines using cisplatin as test control. RESULTS: Intrinsically, 195mPt-labeled analogue of prodrug was obtained with high radionuclidic and radiochemical purity. It was confirmed by chromatography and γ-ray spectrometry. CONCLUSION: The 195mPt-radiolabeled prodrug was synthesized in a facile manner. It can be utilized in evaluating the mechanism of anticancer action and pharmacokinetics by enabling synergistic use of molecular imaging and targeted drug delivery.

Formulation and clinical translation of [177Lu]Lu-trastuzumab for radioimmunotheranostics of metastatic breast cancer.

Trastuzumab (Herceptin®) is an approved immunotherapeutic agent used for the treatment of metastatic breast cancer over-expressing HER2 antigen receptors. The aim of the present work is to standardize the formulation protocol of [177Lu]Lu-trastuzumab addressing various reaction parameters, evaluating the efficacy of the radiolabeled product by in vitro investigations, scaling-up the preparation for administration in patients and performing preliminary clinical studies in patients suffering from metastatic breast cancer. Trastuzumab was conjugated with a suitable bi-functional chelating agent namely, p-NCS-benzyl-DOTA. On average 6.15 ± 0.92 p-NCS-benzyl-DOTA molecules were observed to be attached to each trastuzumab moiety. [177Lu]Lu-trastuzumab could be prepared with >95% radiochemical purity (% RCP) employing the optimized radiolabeling procedure. In vitro studies revealed the affinity of [177Lu]Lu-trastuzumab towards HER2 +ve cancer cell lines as well as against HER2 protein (K d = 13.61 nM and 11.36 nM, respectively). The value for percentage immunoreactive fraction (% IRF) for [177Lu]Lu-trastuzumab was observed to be 76.92 ± 2.80. Bio-distribution studies in Swiss mice revealed non-specific uptake in the blood, liver, lungs and heart followed by gradual clearance of activity predominantly through the hepatobiliary route. Preliminary clinical studies carried out in 8 cancer patients with immunohistochemically proven HER2 positive metastatic breast cancer revealed preferential localization of [177Lu]Lu-trastuzumab in breast cancer lesions, which was in concordance with [18F]FDG-PET scans recorded earlier in the same patient indicating the potential of the agent towards radioimmunotheranostic applications.

Efficacy and safety of 177Lu-DOTMP in palliative treatment of symptomatic skeletal metastases: a prospective study.

AIMS: Bone-seeking radiopharmaceutical 177Lu-DOTMP with favorable pharmacokinetics in the preclinical studies has been evaluated for its role in reducing bone pain and improving quality of life (QOL) in patients with symptomatic skeletal metastases. METHOD: Patients with painful widespread skeletal metastases documented on 99mTc-MDP bone scintigraphy were intravenously administered 37 MBq/kg of 177Lu-DOTMP. Visual analogue score (VAS), analgesic score, European Cooperative Group of Oncology (ECOG) and the European Organization of Research and Treatment of Cancer QLQ-C30 of all the patients were assessed at baseline and posttherapy follow-up. Adverse effects were graded according to NCI-CTCAE V 5.0. RESULTS: Twenty-seven patients with painful widespread skeletal metastases (men 18; median age 61 years; range: 18-81) were studied for their responses as complete response, partial response, minimal response, no response and pain progression based on VAS and analgesic score. Overall response was seen in 77.8% of patients (complete, partial and minimal in 29.6, 33.3 and 14.8%, respectively) with significant improvement in median VAS and mean analgesic score at 2 months posttherapy from baseline (P < 0.001). The best response was seen in patients with breast cancer (100%) followed by prostate cancer (81%) and lung cancer (28%). Improvement in QOL was noted in 40% of patients, with change in ECOG score from 3.07 ± 0.67 at baseline to 2.6 ± 0.9 at 2 months posttherapy. Grade 2/3 anemia, grade 1/2 leukopenia and grade 1/3 thrombocytopenia were seen in 37, 11.1 and 18.5% patients respectively in the follow-up. CONCLUSION: 177Lu-DOTMP appears to be efficacious treatment for bone pain palliation with improvement in QOL though less effective in patients with lung cancer. The patients had transient mild-moderate hematotoxicity.

An electrochemical technique for fabrication of Mn-54 sources towards characterization of gamma counting nuclear instruments.

Long lived sealed radioactive sources are used for the energy calibration and efficiency determination of counting systems used in the nuclear sector. Using a sulphate bath, a facile electrochemical method was developed by electrodeposition of 54Mn on 5 mm (φ) stainless steel substrates for the preparation of 54Mn sources for such uses. Inactive sources prepared under suitable experimental parameters characterized by XRD revealed that manganese is deposited in oxide form. SEM and EDS analyses of electrodeposited surfaces confirmed uniform distribution of elements and the absence of fractures, flaws, and spatial variations. Cyclic voltammetry (CV) scans provided information about the electrochemical processes involved in the deposition process. Uniform distribution of radioactivity on surface of source was ascertained by autoradiography. Swipe tests of the encapsulated sources confirmed negligible removable surface contamination. The 54Mn sources containing up to 185KBq of 54Mn on stainless steel discs were prepared. These sources along with other longer lived sources were supplied to various users as a package of radiation sources for characterization of gamma counting systems over a wide energy range.

Effect of structural variation on tumor targeting efficacy of cationically charged porphyrin derivatives: Comparative in-vitro and in-vivo evaluation for possible potential in PET and PDT.

tetracationic (TMPyP) and tricationic porphyrin (TriMPyCOOHP) derivatives were synthesized, characterized and investigated for binding with DNA by Isothermal Titration Calorimetry as well as by UV-Vis spectroscopy in order to study the effect of structural variation on tumor targeting efficacy of cationically charged porphyrin derivatives. Fluorescence cell imaging studies performed in cancer cell lines corroborated the findings of aforementioned studies. Photocytotoxicity experiments in A549 cell lines revealed relatively higher light dependent cytotoxic effects exerted by TMPyP compared to TriMPyCOOHP. In-vivo experiments in tumor bearing animal model revealed relatively longer retention of 68Ga-TMPyP in tumorous lesion compared to that of 68Ga-TriMPyCOOHP. The study reveals that removal of one of the positive charges of the tetracationic porphyrin derivatives significantly reduces their DNA binding ability and cytotoxicity as well as brings changes in the pharmacokinetic pattern and tumor retention in small animal model.

A standardized polyherbal preparation POL-6 diminishes alcohol withdrawal anxiety by regulating Gabra1, Gabra2, Gabra3, Gabra4, Gabra5 gene expression of GABAA receptor signaling pathway in rats.

BACKGROUND: Alcohol abuse is a major problem worldwide and it affects people's health and economy. There is a relapse in alcohol intake due to alcohol withdrawal. Alcohol withdrawal anxiety-like behavior is a symptom that appears 6-24 h after the last alcohol ingestion. METHODS: The present study was designed to explore the protective effect of a standardized polyherbal preparation POL-6 in ethanol withdrawal anxiety in Wistar rats. POL-6 was prepared by mixing the dried extracts of six plants Bacopa monnieri, Hypericum perforatum, Centella asiatica, Withania somnifera, Camellia sinesis, and Ocimum sanctum in the proportion 2:1:2:2:1:2 respectively. POL-6 was subjected to phytochemical profiling through LC-MS, HPLC, and HPTLC. The effect of POL-6 on alcohol withdrawal anxiety was tested using a two-bottle choice drinking paradigm model giving animals' free choice between alcohol and water for 15 days. Alcohol was withdrawn on the 16th day and POL-6 (20, 50, and 100 mg/kg, oral), diazepam (2 mg/kg) treatment was given on the withdrawal days. Behavioral parameters were tested using EPM and LDT. On the 18th day blood was collected from the retro-orbital sinus of the rats and alcohol markers ALT, AST, ALP, and GGT were studied. At end of the study, animals were sacrificed and the brain was isolated for exploring the influences of POL-6 on the mRNA expression of GABAA receptor subunits in the amygdala and hippocampus. RESULTS: Phytochemical profiling showed that POL-6 contains major phytoconstituents like withaferin A, quercetin, catechin, rutin, caeffic acid, and ß-sitosterol. In-vivo studies showed that POL-6 possesses an antianxiety effect in alcohol withdrawal. Gene expression studies on the isolated brain tissues showed that POL-6 normalizes the GABAergic transmission in the amygdala and hippocampus of the rats. CONCLUSION: The study concludes that POL-6 may have therapeutic potential for treating ethanol-type dependence.

Synthesis and Anticancer Activity of Thiadiazole Containing Thiourea, Benzothiazole and Imidazo[2,1-b][1,3,4]thiadiazole Scaffolds.

BACKGROUND: A great array of nitrogen-containing heterocyclic rings were being extensively explored for their functional versatility in the field of medicine, especially in anticancer research. 1,3,4- thiadiazole is one of such heterocyclic rings with promising anticancer activity against several cancer cell lines, inhibiting diverse biological targets. INTRODUCTION: The 1,3,4-thiadiazole, when equipped with other heterocyclic scaffolds, has displayed enhanced anticancer properties. The thiourea, benzothiazole, imidazo[2,1,b][1,3,4]-thiadiazoles are such potential scaffolds with promising anticancer activity. METHODS: A new series of 5-substituted-1,3,4-thiadiazoles linked with phenyl thiourea, benzothiazole and 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized and tested for invitro anticancer activity on various cancer cell lines. RESULTS: The National Cancer Institute's preliminary anticancer screening results showed compounds 4b and 5b having potent antileukemic activity. Compound 4b selectively showed 32 percent lethality on Human Leukemia-60 cell line. The docking studies of the derivatives on aromatase enzyme (Protein Data Bank: 3S7S) have shown reversible interactions at the active site with good docking scores comparable to Letrozole and Exemestane. Furthermore, the selected derivatives were tested for anticancer activity on HeLa cell line based on the molecular docking studies. CONCLUSION: Compounds 4b and 5b showed effective inhibition equivalent to Letrozole. These preliminary biological screening studies have given positive anticancer activity for these new classes of derivatives. An additional research study like the mechanism of action of the anticancer activity of this new class of compounds is necessary. These groundwork studies illuminate a future pathway for research of this class of compounds enabling the discovery of potent antitumor agents.

Dose-dependent cell cycle arrest and apoptosis in HER2 breast cancer cells by177Lu-CHX-A"-DTPA-Trastuzumab.

BACKGROUND: Trastuzumab is a Food and Drug Administration-approved humanized monoclonal antibody which targets the extracellular domain of human epidermal growth factor receptor 2 (HER2) receptor overexpressed on HER2-positive breast cancer cells. The combination of Lutetium-177 (177 Lu) (t½= 6.7 days, Eßmax497 keV (78.6%) and trastuzumab makes it a suitable targeting agent for radioimmunotherapy. In preclinical and clinical studies,177 Lu-Trastuzumab has proven to be effective for the treatment of HER2-positive malignancies such as breast and ovarian cancer. OBJECTIVES: In this study, we report the mechanism of action of177 Lu-CHX-A"-diethylenetriaminepentaacetic acid (DTPA)-trastuzumab at the cellular and molecular level by performing various in vitro assays in HER2-positive MDA-MB-453 breast cancer cells. MATERIALS AND METHODS: Trastuzumab was conjugated to the bifunctional chelating agent (BFCA) para-isothiocyanatobenzyl-DTPA and radiolabeled with177 Lu. In vitro cell binding studies were carried out in MDA-MB-453 cells to confirm the specificity of the complex toward the receptor. Cellular toxicity, cell cycle, and cell death analysis were also performed for exploring the potential of the radioimmunoconjugate at cellular and molecular level. RESULTS: In vitro cell binding studies showed a maximum binding of 10.7 ± 0.1% which reduced to 2.9 ± 0.1% on coincubation with unlabeled antibody. Our study revealed that the cellular toxicity was dose dependent, and mode of cell death was predominantly by apoptosis. The radioimmunoconjugate retarded the cell in the S phase of cell cycle with two-fold increase in G2/M arrest which justifies the enhanced apoptosis at higher doses. CONCLUSIONS: The study revealed that the formulation can execute a dose-dependent cellular toxicity through induction of apoptosis.

Estimation of Arterial Blood Pressure Waveform from Photoplethysmogram Signal using Linear Transfer Function Approach.

The primary risk factor of hypertension, is the lack of awareness caused by the unavailability of ubiquitous blood pressure (BP) measurement. In this study, we have investigated the BP estimation using the photoplethysmogram (PPG) signal and a suitable subject-specific mathematical model. The linear transfer function (LTF) technique was used to identify the subject-specific model. Firstly, we tried to identify the model considering arterial blood pressure (ABP) as input and PPG as output, and we achieved an average estimation accuracy (normalized root mean square, NRMSE) of 84.4%. Next, we fitted an inverse model, where ABP is the output, and PPG is the input, and we achieved an average estimation accuracy (NRMSE) of 84.7%. Finallly, We verified that the two identified models mentioned above are inverse of each other. In this study, we have used ABP and PPG signals of 10 (male = 7, female = 3) subjets from the MIMIC II database. The results are quite promising for the use of the PPG in the detection and diagnosis of cardiovascular diseases.

Mitigating artifacts by data driven identification & correction of rotational misalignment in gamma ray computed tomography.

Industrial Computed Tomography (ICT) is a radiation based cross sectional imaging technique that requires a sample to be manipulated precisely in a specific geometry to acquire analytically useful data. Unlike medical CT, industrial CT may require use of gamma radiation from radio-isotopes like Co60, Cs137 etc. having higher energy radiations for penetrating through higher density and thickness of material under inspection. Data acquisition in ICT involves use of a mechanical manipulator to rotate either the specimen or the source and detectors assembly in circular and linear geometry. Misalignment in mechanical set-up leads to significant artifacts in CT image. The effects may be even more pronounced in data acquired with discrete detector as against Linear Detector Array (LDA) because of certain built-in mechanical integrity associated with LDA. This paper discusses cross correlation based software correction method for combination of gamma ray source and NaI (Tl) scintillation detector based transmission ICT system in parallel beam CT geometry. The proposed correction does not require calibration of the set-up and any prior knowledge of the sample geometry or composition. This data driven correction yields improved CT reconstruction with limited data. The method is demonstrated with a mathematical simulation and applied to experimental data for validation.

Clinical evaluation of kit based Tc-99m-HYNIC-RGD2 for imaging angiogenesis in breast carcinoma patients.

BACKGROUND: Radiolabeled RGD peptide can be used for noninvasive in vivo imaging of αvß3 integrin receptors leading to early detection of tumor cells and hence improving the clinical outcomes. In the present study single vial kit based HYNIC RGD2 was radiolabeled with Tc-99m and evaluated in patients with breast carcinoma. METHODS: Radiolabeling was performed via bifunctional chelator method. Tc-99m 1110-2960 MBq (30-80 mCi) was added to the HYNIC-RGD2 vial. The reaction mixture was heated for 20 minutes at 100°C. After performing the quality checks, whole-body planar imaging was performed in 20 patients at 2-2.5 h post i.v. injection of 555-740 MBq (15-20 mCi) of the radiotracer. RESULTS: Radiolabeling yield of ≥98% was observed in all the formulations. Quality control tests indicated the suitability of radiopharmaceutical for intravenous administration. Physiological uptake of Tc-99m HYNIC-RGD2 was observed in the nasopharynx, salivary glands, liver, spleen, and intestine. Good uptake of radiotracer was observed in breast lesions of 18 patients. Two patients were observed to be negative. Increased uptake was also seen in metastatic sites in two patients and in lymph nodes in three patients. Scintigraphy findings were in corroboration with pathological observations. CONCLUSION: The single vial cold kit based radiolabeling of Tc-99m HYNIC-RGD2 is facile leading to its easy availability. Tc-99m HYNIC-RGD2 is a promising radiopharmaceutical which can be used for the molecular imaging of angiogenesis in breast carcinoma patients.