A reduced cost four-component relativistic unitary coupled cluster method for atoms and molecules.

We present a four-component relativistic unitary coupled cluster method for atoms and molecules. We have used commutator-based non-perturbative approximation using the "Bernoulli expansion" to derive an approximation to the relativistic unitary coupled cluster method. The performance of the full quadratic unitary coupled-cluster singles and doubles method (qUCCSD), as well as a perturbative approximation variant (UCC3), has been reported for both energies and properties. It can be seen that both methods give results comparable to those of the standard relativistic coupled cluster method. The qUCCSD method shows better agreement with experimental results due to the better inclusion of relaxation effects. The relativistic UCC3 and qUCCSD methods can simulate the spin-forbidden transition with easy access to transition properties. A natural spinor-based scheme to reduce the computational cost of relativistic UCC3 and qUCCSD methods has been discussed.

[64Cu]Copper chloride PET-CT: a comparative evaluation of fasting and non-fasting states in patients of prostate carcinoma.

Altered copper metabolism in cancer has been linked to increased intracellular copper uptake mediated by human copper transporter 1, with [64Cu]Cu2+ as a potential biomarker for cancer theranostics. [64Cu]CuCl2 PET-CT though explored in various malignancies, a lack of standardized protocol exists, particularly regarding fasting status before imaging. This analysis aimed to evaluate the requirement of fasting for [64Cu]CuCl2 PET-CT along with temporal changes in physiological organ uptake in delayed scans. A total of 26 patients of prostate carcinoma who underwent [64Cu]CuCl2 PET-CT imaging were divided into two groups: (1) nonfasting (n = 12) and (2) fasting (n = 14). The nonfasting group received an average dose of 350 MBq, while the fasting group received 300 MBq of [64Cu]CuCl2, and PET-CT images acquired approximately 60-90 min (1 h image) and 3-3.5 h (delayed image) after intravenous injection of the tracer. An experienced nuclear medicine physician evaluated the images for qualitative assessment between the groups. Multiple spherical regions of interest were placed at sites of physiological organ uptake of the tracer and over the diseased lesions to measure the mean SUVmax. No significant difference was observed in the qualitative assessment of the images between the two groups (except for a slight predilection towards more hepatic tracer retention observed in the fasting group), including in the delayed images. The liver demonstrated the highest tracer uptake in all patients, with a mean SUVmax of 21.5 in the fasting group and 19.7 in the nonfasting group, showing no significant difference (P = 0.32). The kidneys, intestines, and salivary glands also showed similar trends of tracer uptake in both groups. The study illustrated that the fasting or nonfasting status did not affect image quality or semiquantitative measurements significantly in physiological organs and diseased lesions in patients with carcinoma prostate.

Post-GWAS functional analyses of CNTNAP5 suggests its role in glaucomatous neurodegeneration.

Primary angle closure glaucoma (PACG) affects more than 20 million people worldwide, with an increased prevalence in south-east Asia. In a prior haplotype-based GWAS, we identified a novel CNTNAP5 genic region, significantly associated with PACG. In the current study, we have extended our perception of CNTNAP5 involvement in glaucomatous neurodegeneration in a zebrafish model, through investigating phenotypic consequences pertinent to retinal degeneration upon knockdown of cntnap5 by translation-blocking morpholinos. While cntnap5 knockdown was successfully validated using an antibody, immunofluorescence followed by western blot analyses in cntnap5-morphant (MO) zebrafish revealed increased expression of acetylated tubulin indicative of perturbed cytoarchitecture of retinal layers. Moreover, significant loss of Nissl substance is observed in the neuro-retinal layers of cntnap5-MO zebrafish eye, indicating neurodegeneration. Additionally, in spontaneous movement behavioural analysis, cntnap5-MO zebrafish have a significantly lower average distance traversed in light phase compared to mismatch-controls, whereas no significant difference was observed in the dark phase, corroborating with vision loss in the cntnap5-MO zebrafish. This study provides the first direct functional evidence of a putative role of CNTNAP5 in visual neurodegeneration.

Targeting Breast Cancer Using 177 Lu-Labeled Trastuzumab and Trastuzumab Fragment : First-in-Human Clinical Experience.

PURPOSE: A monoclonal antibody, trastuzumab, is used for immunotherapy for HER2-expressing breast cancers. Large-sized antibodies demonstrate hepatobiliary clearance and slower pharmacokinetics. A trastuzumab fragment (Fab; 45 kDa) has been generated for theranostic use. PATIENTS AND METHODS: Fab was generated by papain digestion. Trastuzumab and Fab have been radiolabelled with 177 Lu after being conjugated with a bifunctional chelating. The affinity and target specificity were studied in vitro. The first-in-human study was performed. RESULTS: The bifunctional chelating agent conjugation of 1-2 molecules with trastuzumab and Fab was detected at the molar ratio 1:10 in bicarbonate buffer (0.5 M, pH 8) at 37°-40°C. However, 2-3 molecules of bifunctional chelating agent were conjugated when DMSO in PBS (0.1 M, pH 7) was used as a conjugation buffer at a molar ratio of 1:10. The radiolabelling yield of DOTA-conjugated Fab and trastuzumab at pH 5, 45°C to 50°C, with incubation time 2.5-3 hours was 80% and 41.67%, respectively. However, with DOTAGA-conjugated trastuzumab and Fab, the maximum radiolabelling yield at pH 5.5, 37°C, and at 2.5-3 hours was 80.83% and 83%, respectively. The calculated K d of DOTAGA Fab and trastuzumab with HER2-positive SKBR3 cells was 6.85 ± 0.24 × 10 -8 M and 1.71 ± 0.10 × 10 -8 M, respectively. DOTAGA-Fab and trastuzumab showed better radiolabelling yield at mild reaction conditions.177 Lu-DOTAGA-Fab demonstrated higher lesion uptake and lower liver retention as compared with 177 Lu-DOTAGA-trastuzumab. However, 177 Lu-DOTAGA-Fab as compared with 177 Lu-DOTAGA-trastuzumab showed a relatively early washout (5 days) from the lesion. CONCLUSIONS: 177 Lu-DOTAGA-Fab and trastuzumab are suitable for targeting the HER2 receptors.

ZnAl2O4:Er3+ Upconversion Nanophosphor for SPECT Imaging and Luminescence Modulation via Defect Engineering.

This work reports an "all-in-one" theranostic upconversion luminescence (UCL) system having potential for both diagnostic and therapeutic applications. Despite considerable efforts in designing upconversion nanoparticles (UCNPs) for multimodal imaging and tumor therapy, there are few reports investigating dual modality SPECT/optical imaging for theranostics. Especially, research focusing on in vivo biodistribution studies of intrinsically radiolabeled UCNPs after intravenous injection is of utmost importance for the potential clinical translation of such formulations. Here, we utilized the gamma emission from 169Er and 171Er radionuclides for the demonstration of radiolabeled ZnAl2O4:171/169Er3+ as a potent agent for dual-modality SPECT/optical imaging. No uptake of radio nanoformulation was detected in the skeleton after 4 h of administration, which evidenced the robust integrity of ZnAl2O4:169/171Er3+. Combining the therapeutics using the emission of ß- particulates from 169Er and 171Er will be promising for the radio-theranostic application of the synthesized ZnAl2O4:169/171Er3+ nanoformulation. Cell toxicity studies of ZnAl2O4:1%Er3+ nanoparticles were examined by an MTT assay in B16F10 mouse melanoma cell lines, which demonstrated good biocompatibility. In addition, we explored the mechanism of UCL modulation via defect engineering by Bi3+ codoping in the ZnAl2O4:Er3+ upconversion nanophosphor. The UCL color tuning was successfully achieved from the red to the green region as a function of Bi3+ codoping concentrations. Further, we tried to establish a correlation of UCL tuning with the intrinsic oxygen and cation vacancy defects as a function of Bi3+ codoping concentrations with the help of electron paramagnetic resonance (EPR) and positron annihilation lifetime spectroscopy (PALS) studies. This study contributes to building a bridge between nature of defects and UC luminescence that is crucial for the design of advanced UCNPs for theranostics.

177 Lu-Microspheres Selective Intra-arterial Radionuclide Therapy : A Facile and Biocompatible Permanent Micro-Seed Implants for Unresectable Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis. Surgical resection is limited. Selective intra-arterial radionuclide therapy (SIRT) emerged as a potential cure for intermediate HCC with portal vein thrombosis. We report a pilot study of a 48-year-old man with recurrent HCC who underwent 177 Lu-microsphere SIRT (2.2 GBq) in segment III. Posttherapy SPECT/CT images (24 hours to 3 months) demonstrated excellent localization and prolonged retention within the tumor. Pre- and 3-month post-SIRT CECT showed a notable decrease in arterial enhancement and tumor size. Time-activity curve of the standard and the lesion demonstrated similar decay pattern indicating that 177 Lu-microspheres act as permanent implant.

Synthesis, Quality Control, and Bench-to-Bed Translation of a New [68Ga]Ga-Labeled NOTA-Conjugated Bisphosphonate for Imaging Skeletal Metastases by Positron Emission Tomography.

Background: Early detection of skeletal metastasis is of great interest to determine the prognosis of cancer. Positron emission tomography-computed tomography (PET-CT) imaging provides a better temporal and spectral resolution than single photon emission computed tomography-computed tomography (SPECT-CT) imaging, and hence is more suitable to detect small metastatic lesions. Although [18F]NaF has been approved by U.S. FDA for a similar purpose, requirement of a medical cyclotron for its regular formulation restricts its extensive utilization. Efforts have been made to find suitable alternative molecules that can be labeled with 68Ga and used in PET-CT imaging. Objective: The main objective of this study is to synthesize and evaluate a new [68Ga]Ga-labeled NOTA-conjugated geminal bisphosphonate for its potential use in early detection of skeletal metastases using PET-CT. Methods: The authors performed a multistep synthesis of a new NOTA-conjugated bisphosphonic acid using thiourea linker and radiolabeled the molecule with 68Ga. The radiolabeled formulation was evaluated for its in vitro stability, affinity for hydroxyapatite (HA) particles, preclinical biodistribution in animal models, and PET-CT imaging in patients. Results: The bifunctional chelator (NOTA)-conjugated bisphosphonate was synthesized with 97.8% purity and radiolabeled with 68Ga in high yield (>98%). The radiolabeled formulation was found to retain its stability in vitro to the extent of >95% up to 4 h in physiological saline and human serum. The formulation also showed high affinity for HA particles in vitro with Kd = 907 ± 14 mL/g. Preclinical biodistribution studies in normal Wistar rats demonstrated rapid and almost exclusive skeletal accumulation of the complex. PET-CT imaging in a patient confirmed its ability to detect small metastatic skeletal lesions. Conclusions: The newly synthesized [68Ga]Ga-labeled NOTA-conjugated bisphosphonate is a promising radiotracer for PET-CT imaging for skeletal metastases.

Cancer Brachytherapy at the Nanoscale: An Emerging Paradigm.

Brachytherapy is an established treatment modality that has been globally utilized for the therapy of malignant solid tumors. However, classic therapeutic sealed sources used in brachytherapy must be surgically implanted directly into the tumor site and removed after the requisite period of treatment. In order to avoid the trauma involved in the surgical procedures and prevent undesirable radioactive distribution at the cancerous site, well-dispersed radiolabeled nanomaterials are now being explored for brachytherapy applications. This emerging field has been coined "nanoscale brachytherapy". Despite present-day advancements, an ongoing challenge is obtaining an advanced, functional nanomaterial that concurrently incorporates features of high radiolabeling yield, short labeling time, good radiolabeling stability, and long tumor retention time without leakage of radioactivity to the nontargeted organs. Further, attachment of suitable targeting ligands to the nanoplatforms would widen the nanoscale brachytherapy approach to tumors expressing various phenotypes. Molecular imaging using radiolabeled nanoplatforms enables noninvasive visualization of cellular functions and biological processes in vivo. In vivo imaging also aids in visualizing the localization and retention of the radiolabeled nanoplatforms at the tumor site for the requisite time period to render safe and effective therapy. Herein, we review the advancements over the last several years in the synthesis and use of functionalized radiolabeled nanoplatforms as a noninvasive substitute to standard brachytherapy sources. The limitations of present-day brachytherapy sealed sources are analyzed, while highlighting the advantages of using radiolabeled nanoparticles (NPs) for this purpose. The recent progress in the development of different radiolabeling methods, delivery techniques and nanoparticle internalization mechanisms are discussed. The preclinical studies performed to date are summarized with an emphasis on the current challenges toward the future translation of nanoscale brachytherapy in routine clinical practices.

Normal physiological distribution and tumor localization of 64 CuCl 2 in different human malignancies along with semiquantitative scoring: a comparative evaluation with 18 Fluorodeoxyglucose ( 18 FDG) PET-CT.

OBJECTIVE: This study aimed to explore 64-Copper-Chloride ( 64 CuCl 2 ) PET-CT in various malignancies and demonstrate a head-to-head comparison of uptake on 64 CuCl 2 PET/computed tomography (CT) and 18 fluorodeoxyglucose ( 18 FDG)-PET/CT scans for different malignancies, with an emphasis on 18 FDG nonavid malignancies. METHODS: Fifty-three patients diagnosed with various biopsy-proven malignancies (except prostate cancer) were recruited in this prospective study. All the patients underwent both 64 CuCl 2 PET/CT and 18 FDG-PET/CT. 64 CuCl 2 PET/CT was acquired at 1, 3 and 24 h time points. We studied the physiological biodistribution of 64 CuCl 2 in the various organs, corroborated the uptake of 64 CuCl 2 with various types of malignancies and comparison of their uptake with 18 FDG-PET/CT and their correlation with each other in various lesions. RESULTS: The biodistribution study showed that the liver concentrated 64 CuCl 2 the most out of all the organs, followed by the pancreas and large intestine. Liver and intestinal activity increased subsequently with delayed imaging, and the washout of 64 CuCl 2 was noted in the pancreas in delayed images and followed a hepatobiliary excretion of tracer over a period of time. In lesion-wise analysis, it was noted that the primary neuroendocrine tumor, melanoma and renal/urothelial malignancy group showed more uptake of 64 CuCl 2 , than that in metastasis and vice-versa was noted in lung and soft tissue malignancies. Comparing it with 18 FDG, it was seen that FDG showed more uptake in lesions and showed no significant correlation (Kappa value: 0.089) with the uptake of 64 CuCl 2 in the lesion-wise comparison. CONCLUSION: 64 CuCl 2 PET/CT did not show any added advantage over 18 FDG-PET/CT in the evaluation of the studied malignancies, both primary and their metastasis. Biodistribution studies showed the liver as the organ with maximum uptake, which implies it may hinder the detection of abdominal or hepatic involvement of the disease.

Brachytherapy at the nanoscale with protein functionalized and intrinsically radiolabeled [169Yb]Yb2O3 nanoseeds.

PURPOSE: Classical brachytherapy of solid malignant tumors is an invasive procedure which often results in an uneven dose distribution, while requiring surgical removal of sealed radioactive seed sources after a certain period of time. To circumvent these issues, we report the synthesis of intrinsically radiolabeled and gum Arabic glycoprotein functionalized [169Yb]Yb2O3 nanoseeds as a novel nanoscale brachytherapy agent, which could directly be administered via intratumoral injection for tumor therapy. METHODS: 169Yb (T½ = 32 days) was produced by neutron irradiation of enriched (15.2% in 168Yb) Yb2O3 target in a nuclear reactor, radiochemically converted to [169Yb]YbCl3 and used for nanoparticle (NP) synthesis. Intrinsically radiolabeled NP were synthesized by controlled hydrolysis of Yb3+ ions in gum Arabic glycoprotein medium. In vivo SPECT/CT imaging, autoradiography, and biodistribution studies were performed after intratumoral injection of radiolabeled NP in B16F10 tumor bearing C57BL/6 mice. Systematic tumor regression studies and histopathological analyses were performed to demonstrate therapeutic efficacy in the same mice model. RESULTS: The nanoformulation was a clear solution having high colloidal and radiochemical stability. Uniform distribution and retention of the radiolabeled nanoformulation in the tumor mass were observed via SPECT/CT imaging and autoradiography studies. In a tumor regression study, tumor growth was significantly arrested with different doses of radiolabeled NP compared to the control and the best treatment effect was observed with ~ 27.8 MBq dose. In histopathological analysis, loss of mitotic cells was apparent in tumor tissue of treated groups, whereas no significant damage in kidney, lungs, and liver tissue morphology was observed. CONCLUSIONS: These results hold promise for nanoscale brachytherapy to become a clinically practical treatment modality for unresectable solid cancers.

[90Y]Yttria Alumino Silicate Glass Microspheres: A Biosimilar Formulation to "TheraSphere" for Cost-Effective Treatment of Liver Cancer.

Background: Selective internal radiation therapy (SIRT) using a suitable ß--emitting radionuclide is a promising treatment modality for unresectable liver carcinoma. Yttrium-90 (90Y) [T1/2 = 64.2 h, Eß(max) = 2.28 MeV, no detectable γ-photon] is the most preferred radioisotope for SIRT owing to its favorable decay characteristics. Objective: The present study describes indigenous development and evaluation of intrinsically radiolabeled [90Y]yttria alumino silicate ([90Y]YAS) glass microsphere, a formulation biosimilar to "TheraSphere" (commercially available, U.S. FDA-approved formulation), for SIRT of unresectable liver carcinoma in human patients. Methods: YAS glass microspheres of composition 40Y2O3-20Al2O3-40SiO2 (w/w) and diameter ranging between 20 and 36 µm were synthesized with almost 100% conversion efficiency and >99% sphericity. Intrinsically labeled [90Y]YAS glass microspheres were produced by thermal neutron irradiation of cold YAS glass microspheres in a research reactor. Subsequent to in vitro evaluations and in vivo studies in healthy Wistar rats, customized doses of [90Y]YAS glass microspheres were administered in human patients. Results: [90Y]YAS glass microspheres were produced with 137.7 ± 8.6 MBq/mg YAS glass (∼6800 Bq per microsphere) specific activity and 99.94% ± 0.02% radionuclidic purity at the end of irradiation. The formulation exhibited excellent in vitro stability in human serum and showed >97% retention in the liver up to 7 d post-administration when biodistribution studies were carried out in healthy Wistar rats. Yttrium-90 positron emission tomography scans recorded at different time points post-administration of customized dose of [90Y]YAS glass microspheres in human patients showed near-quantitative retention of the formulation in the injected lobe. Conclusions: The study confirmed the suitability of indigenously prepared [90Y]YAS glass microspheres for clinical use in the treatment of unresectable hepatocellular carcinoma.

Identification of a shared, common haplotype segregating with an SGCB c.544 T > G mutation in Indian patients affected with sarcoglycanopathy.

Sarcoglycanopathy is the most frequent form of autosomal recessive limb-girdle muscular dystrophies caused by mutations in SGCB gene encoding beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype co-segregating in 14 sarcoglycanopathy cases from 13 unrelated families from south Indian region with the likely pathogenic homozygous mutation c.544 T > G (p.Thr182Pro) in SGCB. Haplotype was reconstructed based on 10 polymorphic markers surrounding the c.544 T > G mutation in the cases and related family members as well as 150 unrelated controls from Indian populations using PLINK1.9. We identified haplotype H1 = G, A, G, T, G, G, A, C, T, G, T at a significantly higher frequency in cases compared to related controls and unrelated control Indian population. Upon segregation analysis within the family pedigrees, H1 is observed to co-segregate with c.544 T > G in a homozygous state in all the pedigrees of cases except one indicating a probable event of founder effect. Furthermore, Identical-by-descent and inbreeding coefficient analysis revealed relatedness among 33 new pairs of seemingly unrelated individuals from sarcoglycanopathy cohort and a higher proportion of homozygous markers, thereby indicating common ancestry. Since all these patients are from the south Indian region, we suggest this region to be a primary target of mutation screening in patients diagnosed with sarcoglycanopathy.

Exploratory analysis of 64 CuCl 2 PET-CT imaging in carcinoma prostate and its comparison with 68 Ga-PSMA-11 and 18 F-FDG PET-CT.

AIM: Exploratory analysis of 64 CuCl 2 PET-CT imaging in patients of carcinoma prostate and its head-to-head comparison with 68 Ga-PSMA-11 and 18 F-FDG PET-CT. METHODS: In this prospective study, 50 patients of biopsy-proven carcinoma prostate belonging to the entire spectrum of disease were evaluated, out of which 21 patients were for initial staging and 29 were for restaging/response evaluation. Both 64 CuCl 2 (early and delayed) and 68 Ga-PSMA-11 PET-CT were undertaken in all patients and 18 F-FDG PET-CT was done in patients whenever possible. All scans were done within a period of 2 weeks, without any interim therapeutic intervention. 64 CuCl 2 PET-CT was acquired at 1 and 3 h. We evaluated the physiological uptake of 64 CuCl 2 , correlated the uptake in primary with disease parameters like Gleason score and serum PSA levels, and compared the detection rates for primary and metastatic disease with 68 Ga-PSMA-11 and 18 F-FDG PET-CT. RESULTS: The detection rates of primary disease were same for both 64 CuCl 2 and 68 Ga-PSMA-11 PET-CT and both agents performed similarly in detecting extra-prostatic disease. There was no statistically significant correlation observed between the uptake of 64 CuCl 2 in the primary lesion with disease parameters. With regard to the evaluation of metastatic disease, the detection rate of 64 CuCl 2 PET-CT was 86% for lymph nodes, 77.3% for skeletal metastases and 80.6% for soft tissue metastases while 68 Ga-PSMA-11 PET-CT performed better with detection rates were 98%, 99% and 85.4%, respectively. In 17 patients where 18 F-FDG PET-CT was available, 64 CuCl 2 PET-CT detected more metastatic disease than 18 F-FDG PET-CT. CONCLUSION: 64 CuCl 2 PET-CT did not show any additional advantage over 68 Ga-PSMA-11 PET-CT in evaluation of local disease or for the assessment of metastatic disease. When compared to 68 Ga-PSMA-11 PET-CT, the absence of urinary bladder and ureteric activity allows better contrast for evaluating local disease, but it does not translate into increased disease detection.

Alpha-induced production and robust radiochemical separation of 43Sc as an emerging radiometal for formulation of PET radiopharmaceuticals.

Scandium-43 is an emerging PET radiometal that was produced by α-particle bombardment on natural CaCO3 target via natCa (α,p) 43Sc and natCa (α,n) 43Ti→43Sc reactions using K-130 cyclotron at VECC. A robust radiochemical procedure based on selective precipitation of 43Sc as Sc(OH)3 was developed for separation of the radioisotope from the irradiated target. The overall yield of the separation process was >85% and it was obtained in a form suitable for preparation of target specific radiopharmaceuticals for PET imaging of cancer.

Biochemical separation of Cetuximab-Fab from papain-digested antibody fragments and radiolabeling with 64Cu for potential use in radioimmunotheranostics.

Engineered Fab fragments of monoclonal antibodies (mAbs) after radiolabeling with suitable radiometals have the potential to play a key role in personalized radioimmunotheranostics of cancer patients. In this study, we have generated Fab fragment of Cetuximab, a mAb targeting epidermal growth factor receptor (EGFR) expression and purified from the Fc and other fragments by ultrafiltration and affinity chromatography. The Cetuximab-Fab was conjugated with a suitable bifunctional chelator and radiolabeled with no-carrier-added (NCA) 64Cu produced via 64Zn (n, p) 64Cu reaction in a nuclear reactor. The radioimmunoconjugate obtained after size exclusion chromatographic separation possessed >95% radiochemical purity and it retained its integrity over at least three half-lives of the radiometal. Biodistribution studies was performed in fibrosarcoma tumor bearing Swiss mice, which demonstrated the explicit need for purification of the Cetuximab-Fab from Fc fragments. Enhanced and rapid tumor uptake with decent tumor-to-background ratio with prolonged retention was observed when radiolabeled purified Cetuximab-Fab was intravenously administered in animal models. Overall, this preclinical study established the pivotal role of separation science and technology to obtain the radioimmunoconjugate with requisite purity in order to demonstrate optimal pharmacokinetics and maximized treatment efficacy.

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.

A robust lyophilized kit for convenient one-step formulation of [68Ga]Ga-DOTA-E-[c(RGDfK)]2 in hospital radiopharmacy for clinical PET imaging.

The present article describes the development of robust lyophilized kit for convenient formulation of [68Ga]Ga-DOTA-E-[c(RGDfK)]2 (E = glutamic acid, R = arginine, G = glycine, D = aspartic acid, f = phenylalanine, K = lysine) radiopharmaceutical for clinical use in non-invasive monitoring of malignancies overexpressing integrin αvß3 receptors. Five batches of the kit were prepared with optimized kit contents, all of which showed high 68Ga-radiolabeling yield (>98%). Pre-clinical evaluation of the [68Ga]Ga-radiotracer in SCID mice bearing FTC133 tumour exhibited significant accumulation in the tumor xenograft. Preliminary human clinical investigation carried out in a 60 year old male patient with metastatic lung cancer revealed high radiotracer uptake in the tumor along with satisfactory target to non-target contrast. The developed kit formulation also showed a long shelf-life of at least 12 months on storage at 0 °C. All these results point towards the promising attributes of the developed kit formulation for convenient preparation of [68Ga]Ga-DOTA-E-[c(RGDfK)]2 for routine clinical use.

A quantitative trait GWAS on lens thickness identifies novel risk loci on PTPRM in the narrow angle individuals susceptible to PACG.

PURPOSE: PACG is one of the leading causes of blindness where lens thickness is a major risk factor for narrow-angle individuals. To our knowledge, no literature has been reported on candidate gene for lens thickness as a quantitative trait (QT). Here, we performed a genome-wide association analysis on lens thickness in the narrow-angle individuals. MATERIALS AND METHODS: We conducted a genome-wide association study (GWAS) in the narrow angle individuals to investigate comprehensive genetic insights on lens thickness. RESULTS: In QT-GWAS, we identified 145 genome-wide suggestive significant loci in the discovery cohort. Subsequently, we observed 13 SNPs that showed statistical significance around the region of PTRRM. Regional association analysis for top significant genotyped variants identified PTPRM as the most likely candidate for increased LT. Integrative bioinformatic analyses confirmed that the associated genomic region has potential regulatory roles for modulating transcription as enhancers. In the replication cohort, the sentinel genotype SNP was further associated significantly (P-value =0.000448) with high LT individuals. In both cohorts, the T allele of rs1941137 in the PTPRM gene indicates as a risk allele for the increased LT. CONCLUSION: In this study, we discovered evidence of a genomic association between chromosomal areas around the PTPRM and increased lens thickness, resulting in a narrow angle. The regulatory components corresponding to PTPRM variations might have a role in the thicker lens. We report that the genomic region near PTPRM, a gene of potential interest, is associated with increased lens thickness.