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It is well accepted that fractional-order calculus yields a more accurate description of complex physical processes compared to integer-order one. So, fractional-order modelling is getting a good attention in the process industry. On the other hand, to meet design goals accurately, control designers prefer fractional-order controllers over integer-order ones due to the availability of more parameters. However, the design of such controllers are complex. More often, the design faces the challenge in real-time implementations, and the problem is circumvented by higher order approximations of fractional-order operators. In the presented work, three methods for integer-order Proportional–Integral–Derivative (PID) controller design are proposed based on Frequency Loop-Shaping (FLS) and Internal Model Control (IMC). To prove the efficacy of the presented control law, simulations are conducted and included along with a performance measure based on ISE (Integral of Square Error), ITAE (Integral of Time Absolute Error) and IAE (Integral of Absolute Error). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

To achieve good servo and regulatory responses, a generalized fractional-order tilt-integral-derivative (FOTID) control is developed in this study for time-delayed fractional-order processes. To enhance the closed-loop robustness, the controller parameters are calculated based on maximum sensitivity (Ms). To check the performance and robustness of the suggested control law, several case studies on industrial processes like DC servo systems, Level-loop, Bio-reactors, Fuel cells and CSTR are performed and compared with existing designs. The robustness of the proposed controller is analysed by employing 20 percent perturbation in plant parameters. Lastly, a comparison of the closed-loop response on different error indices is included. [ABSTRACT FROM AUTHOR]

In many industrial processes, e.g. temperature and level control, chemical reactors can be classified as a variant of integrating plus time-delay system. Controlling these processes is a difficult task due to open-loop instability, which consists of time-delay and unbounded output for bounded input. 1DOF PID control always leads to a large overshoot in set-point tracking for IPTD processes. In a 2DOF PID structure, tuning the set-point weights and the controller parameters is important to achieve good tracking and disturbance rejection properties. But tuning the set-point weights and the parameters of the cascade-feedback controller together is a difficult task. Usually, predetermined values for set-points are chosen, and a controller design is followed. In the present work, an alternative simple approach to obtain controller parameters along with set-point weights is presented which are tuned to yield good tracking and load–disturbance rejection. Explicit controller parameters for different classes of integrating processes are obtained using gain-margin, phase-margin, and inverse plant model which can also be used for controller auto-tuning. To validate the effectiveness of the proposed controller, simulation comparisons with some recently developed methods are included. Moreover, the experimental validation of the proposed controller on a temperature control plant is also presented. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A dual-degree of freedom (dual-DOF) propor-tional-integral proportional-derivative (PI-PD) controller is developed for integrating-type chemical processes with delay. The interior-loop PD controller is designed based on user-defined gain and phase margin. For designing the external-loop PI controller, the moment-matching method is augmented with maximum sensitivity specifications. The suggested design is suitable for chemical processes like continuously stirred tank reactors, boiler steam drums, heat exchangers and distillation columns. Using benchmark models of the aforementioned processes, the closed-loop system outputs and control signals are compared to vindicate the primacy of the suggested dual-DOF PI-PD controller. To study the performance-robustness trade-off of this design, rigorous perturbation analysis is also carried out. The performance improvement achieved by the suggested dual-DOF PI-PD controller is also quantitatively compared with contemporary works. [ABSTRACT FROM AUTHOR]

A wrap-faced embankment model on soft clay soil subjected to earthquake motion was investigated in this study. The study was conducted both experimentally using a shaking table and numerically using PLAXIS 3D software. The amplification of acceleration, displacement, pore water pressure, and strain response were measured while varying input accelerations and surcharge pressures. Time histories of the Kobe record of the 1995 Hanshin earthquake were used as the input seismic motion. The input acceleration was 0.05 g, 0.1 g, 0.15 g, and 0.2 g, and different surcharge pressures were 0.70 kPa, 1.12 kPa, and 1.72 kPa with relative density of Sylhet sand fixed to 48%. The output data from the shaking table tests and the numerical analysis performed through the PLAXIS 3D software were compared, and these findings were also compared with some earlier similar studies. The acceleration amplification, displacement, pore water pressure, and strain (%) changed along the elevation of the embankment and acceleration response increased with the increase in base acceleration. The increase was more noticeable at higher elevations. These findings enrich the knowledge of predicting the dynamic behavior of wrap-faced embankments and enable the design parameters to be adjusted more accurately. [ABSTRACT FROM AUTHOR]

Chemical reactors, heat exchangers, level-loops, and distillation columns are commonly encountered in the chemical process industry, and these are having a significant role in the functioning of any chemical process. For the smooth and efficient functioning of any such process, a robust control law design is an important work to be considered. In this paper, a modified 2DOF robust PID control law has been developed to ensure satisfactory performance in both the step and ramp type references and disturbances. Controller parameters are derived with Maximum sensitivity, Gain, and Phase margin specifications. Case studies with different chemical processes like CSTR, distillation column, heat exchangers, and boiler drum level-loop are included for both the nominal and perturbed cases. Lastly, a performance comparison of ISE (Integral of square error), ITAE (Integral time absolute error), IAE (Integral absolute error), and Total variation (TV) of the control signal is also included. [ABSTRACT FROM AUTHOR]

A novel water soluble fluorescent compound methylated polycyclic benzimidazolium ion 4 based on benzimidazolium ion (85 % yield) for the response of Fe3+ has been demonstrated for the first time due to its excellent photophysical properties. The molecule is highly sensitive and selective towards Fe3+. A dramatic fluorescence switch on‐off‐on has been observed during interchange from Fe3+ to EDTAand the detection limit is 15.8 nM (3σ method) for Fe3+ ions. The compound 4 exhibits excellent antimicrobial and anti‐biofilm activities against E.cloacae and S.aureus. Cell imaging and mammalian cell cytotoxicity were also investigated. The synthesized molecule exhibits selective activity toward gram‐positive bacteria than gram‐negative ones among six different bacterial species. [ABSTRACT FROM AUTHOR]

The article offers information on pediatric-patient perspectives on plain language summaries (PLS). It further discusses PLS coincided with a larger, patient-centric paradigm shift in the clinical research enterprise; well-established ethical mandates calling for sharing research results, as well as industry commitments and global good clinical research practice (GCP); and considerations for returning results to pediatric participants.

In this work, a systematic design method for a compact 5-pole Butterworth transverse resonance low pass filter (TR-LPF), in 0.15 μm Gallium Arsenide process, with wide rejection bandwidth (RBW), is presented. The circuit model of TR-LPF and closed-form expressions are provided to appreciate the design process. The fabricated TR-LPF has a cut-off frequency of 10.5 GHz, an insertion loss of 0.4 dB, and the return loss is better than 20 dB. The 20 dB, 30 dB, and 40 dB deep rejection bandwidths (RBWs), across 50 GHz, 45.5 GHz, and 17 GHz respectively, are obtained. The novel use of stubs and spur resonators, within stubs; provides the deep and wide RBW. The compactness of the TR-LPF is realized by the 'C'-and 'Z'-shaped folding of stubs. The dimension of the filter is approximately 0.11 λ g × 0.079 λ g. [ABSTRACT FROM AUTHOR]

The freshwater aquifers of the Indo-Gangetic plains support rich biodiversity which is under the threat of arsenic contamination. The filter feeding bivalve mollusc Lamellidens marginalis is a sessile and sentinel resident of these freshwater habitats. In the present study, the classical cell behaviours of adhesion and aggregation were monitored in the circulating haemocytes of the freshwater bivalve under the exposure of sodium arsenite (NaAsO 2) at sublethal concentrations in controlled laboratory conditions for a maximum time-span of sixteen days. The toxic metalloid significantly inhibited non-self adhesion, inter-haemocyte interactions and haemocyte aggregation in a dose and time dependent manner. The natural occurrence of the filopods on the haemocytes was significantly diminished in the bivalves exposed to the inorganic arsenite. Moreover, a significant fall in the kinetics of phagocytosis index and haemocyte adhesion was observed under the in vitro exposure to NaAsO 2. Compromised non-self adhesion, cell-cell aggregation and phagocytosis of non-self particles by the bivalve haemocytes probably indicate susceptible immunological status of the bivalve. Such vulnerable immunity of the bivalve probably signifies the nature of imminent threat to the freshwater ecosystem as a whole under inorganic arsenite exposure. The findings would be helpful to design bivalve haemocyte based inexpensive biomonitoring tool to assess the health of freshwater ecosystem under potential arsenic threat. • Bivalve Lamellidens marginalis exposed to sublethal concentrations of NaAsO 2. • Haemocyte adhesion and aggregation inhibited dose and time dependently. • Proportion of haemocytes with filopods declined. • Phagocytic index (PI) and haemocyte adhesion inhibited dose dependently (in vitro). • Cell adhesion and PI assays are proposed for biomonitoring of aquatic ecosystem. [ABSTRACT FROM AUTHOR]

Glaucoma is a heterogeneous group of optic neuropathies and is one of the leading causes of irreversible blindness worldwide. Primary angle closure glaucoma (PACG) is a major subtype, prevalent mostly in east and south Asia, where occludable anterior chamber angle is considered as a primary risk factor, which in turn could be responsible for high intraocular pressure (IOP) and subsequent neurodegeneration of retinal ganglion cells. Clinically, IOP is considered as a major risk factor for glaucoma and viewed as an important endophenotype to promote the disease severity. To investigate the comprehensive genomic insights, we conducted a genomewide association study (GWAS) on IOP in individuals with occludable angle (< 15 degrees), thus anatomically predisposed to PACG. After performing GWAS on IOP, we identified 25 genomewide suggestive significant loci (P < 1e−05, n = 240) of which, six were in complete linkage disequilibrium with the ABCA4 genic region. We successfully replicated the most significant discovery, SNPs of ABCA4 (rs2065712) in a separate cohort of 89 individuals (P =1.16e−09). We identified multiple SNPs in ABCA4 to be associated with IOP. Also, we obtained genes harbouring significantly associated SNPs, included in relevant biological pathways that could potentially be involved in IOP variation and glaucomatous neurodegeneration. [ABSTRACT FROM AUTHOR]

Bauhinia acuminata Linn. (Caesalpiniaceae) is a common ornamental plant which has been evaluated for its possible antioxidant properties qualitatively through TLC bioautography and quantitatively through some in vitro testing models including ABTS radical scavenging assay, inhibition of lipid peroxidation etc. The methanolic extract of the leaves revealed to possess chiefly alkaloids and flavonoids and shown significant antioxidant activity by all the methods performed having the best or lowest IC50 value of 91.9 µg/ml in DPPH method. Total phenolic and total flavonoid content were found to be 144.90 ± 4.82 mg gallic acid equivalent/gram dry extract and 114.36 ± 2.80 mg quercetin equivalent/gram dry extract respectively. Ascorbic acid or Trolox was used as standard in different models. [ABSTRACT FROM AUTHOR]

Primary angle closure glaucoma (PACG) is one of the major causes of blindness worldwide. The underlying genetic aetiology is complex in nature and molecular mechanism remains elusive. Here, we identify genomic alterations using haplotype-based genome-wide association study in 148 PACG and 92 anatomically predisposed non-glaucomatous individuals. Logistic regression was performed on each common haplotype (within blocks of 3–8 SNPs) across the genotype and a total of 59 SNPs were found below genome wide suggestive threshold (p<1e−05). We found majority of these SNPs (n = 13) are located in CNTNAP5 genic region. The prioritized rs780010 of CNTNAP5 is also significantly associated with Cup to Disc ratio, which is a clinical parameter directly correlated with glaucomatous neurodegeneration. We further validated rs780010, present in all the significant haplotype blocks with p-value = 2.131e−06 (discovery phase), in a separate replication cohort (PACG, n = 50; control, n = 39) and observed significant association (p = 0.012, per G allele OR = 2.3079; 95% CI: 1.23–4.33). Bioinformatics analyses also suggested neuronal expression of CNTNAP5 with active chromatin structure. KEGG pathway analysis indicates towards pathways related to apoptosis and neurodegeneration. Overall, these results not only indicate a strong genetic association of CNTNAP5 locus with PACG but also suggest its potential involvement in glaucomatous neurodegeneration. [ABSTRACT FROM AUTHOR]

The main objective of this research was to model the zonation of wrap faced embankment on soft clay foundation, by applying a shake table test. Also, to investigate the dynamic behaviors of clay soil, such as acceleration amplification, displacement and pore water pressure of wrap faced embankment. This was done with respect to changes in frequencies of 1 Hz, 3 Hz, 5 Hz, 10 Hz, 12 Hz and 15 Hz respectively. Constant acceleration (0.1 g) and surcharge (19 Kg) were applied by using a laminar box, placed on a shake table testing machine. The main elements of this research were the laboratory test, which was used for preparing reconstitute soil samples, and wrap faced embankment with frequency arrangement. After applying all test parameters, dynamic parameters were increased by rise in elevation with respect to frequency. The result shows that the maximum dynamic parameters were found at the frequency of 10 Hz. It is beneficial to the relative performances of the wrap faced embankment, which is the updated design parameter. [ABSTRACT FROM AUTHOR]

Radiolabeled Arg‐Gly‐Asp (RGD) peptide derivatives have immense potential for non‐invasive monitoring of malignancies overexpressing integrin αvβ3 receptors. Easy availability of suitable radiotracers would augment the utility of this class of molecular imaging agents. Towards this, the present article describes the development of an improved lyophilized kit for the routine clinical formulation of [99mTc]Tc complex of HYNIC‐conjugated dimeric cyclic RGD peptide derivative E‐[c(RGDfK)]2 (E = glutamic acid, f = phenyl alanine, K = lysine) without using Sn2+ and systematic evaluation of its efficacy. Five batches of the kits were prepared, and [99mTc]Tc‐HYNIC‐E[c(RGDfK)]2 radiotracer was synthesized with high radiochemical purity (98.6 ± 0.5%) and specific activity (124.8 GBq/μmol) using the kits. Biodistribution studies in C57BL/6 mice bearing melanoma tumor exhibited significant accumulation of the radiotracer in tumor (5.32 ± 0.56 %ID/g at 60 min p.i.), and this uptake was also found to be receptor‐specific by blocking studies. Preliminary human clinical investigations carried out in 10 breast cancer patients revealed high radiotracer uptake in the tumor along with good tumor‐to‐background contrast. The developed kit formulation showed an exceptionally high shelf‐life of at least 18 months. These results demonstrated promising attributes of the developed kit formulation and warrant more extensive clinical investigations. [ABSTRACT FROM AUTHOR]

The emerging concept of intrinsically radiolabeled nanoparticles has the potential to transform the preclinical and clinical studies by improving the in vivo stability and demonstrating minimal alteration in the inherent pharmacokinetics of the nanoparticles. In this paper, a simple and efficient single-step method for clinical scale synthesis of intrinsically radiolabeled 198Au nanoparticles conjugated with cyclic arginine−glycine−aspartate peptide (198AuNP-RGD) is reported for potential use in targeted cancer therapy. Large radioactive doses (>37 GBq) of 198AuNP-RGD were synthesized by reaction of 198Au-HAuCl 4 with cyclic RGD peptide. The synthesized nanoparticles were characterized by various analytical techniques. In vitro cell binding studies were carried out in B16F10 (murine melanoma) cell line. Biodistribution studies were carried out in melanoma tumor bearing C57BL/6 mice to demonstrate the tumor targeting ability of 198AuNP-RGD. The therapeutic efficacy of 198AuNP-RGD was evaluated by carrying out systematic tumor regression studies in melanoma tumor bearing mice after intravenous administration of the radioactive doses. Well dispersed and biocompatible nanoparticles (~12.5 nm diameter) could be synthesized with excellent radiochemical and colloidal stability. In vitro studies exhibited the cell binding affinity and specificity of 198AuNP-RGD towards melanoma cell line. A high uptake of 8.7 ± 2.1%ID/g in the tumor was observed within 4 h post-injection (p.i.). Significant decrease in tumor uptake of 198AuNP-RGD (2.9 ± 0.8%ID/g) at 4 h p.i. on co-injection of a blocking dose of the peptide suggested that tumor localization of the intrinsically radiolabeled nanoparticles was receptor mediated. Administration of 37.0 MBq of 198AuNP-RGD resulted in significant regression of tumor growth with no apparent body weight loss over a period of 15 d. Overall, these promising results demonstrate the suitability of 198AuNP-RGD as an advanced functional nanoplatform for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract Introduction The widespread clinical utilization of 90Y for preparation of target specific radiopharmaceuticals demands development of a facile, efficient and cost-effective method for radiochemical separation of 90Y from 90Sr via 90Sr/90Y generator. In this article, we describe an efficient and facile method for radiochemical separation of 90Y from 90Sr for preparation of radiopharmaceuticals by exploiting the large difference in the solubility product constants (K sp) of Y(OH) 3 and Sr(OH) 2. Methods A two-step radiochemical separation procedure based on selective precipitation of 90Y under alkaline conditions from 90Sr/90Y equilibrium mixture was developed. The 90Y(OH) 3 colloid formed at pH ~ 10 was selectively trapped in 0.22 μm sterile filter and was subsequently retrieved by dissolution in HCl solution. Detailed quality control analyses of obtained 90Y were carried out and its utility towards preparation of different radiopharmaceuticals was assessed. Results Using the same feed solution of 90Sr (3.7 GBq), consistent and repeated separation of 90Y could be achieved in different batches with >85% yield and >99.999% radionuclidic purity. Yttrium-90 obtained from this process was found suitable for preparation of therapeutically relevant doses of three different radiopharmaceutical formulations, namely, 90Y-DOTA-TATE, 90Y-PSMA-617 and 90Y-CHX-A″-DTPA-Cetuximab with >95% radiochemical purity. Conclusions The promising results obtained in this study would facilitate implementation of the developed technique for obtaining 90Y in adequate quantity and of required purity from a centralized radiopharmacy setup. [ABSTRACT FROM AUTHOR]

This article reports the syntheses and evaluation of 68Ga‐ and 153Sm‐complexes of a new DOTA (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid)‐conjugated geminal bisphosphonate, DOTA‐Bn‐SCN‐BP, for their potential uses in the early detection of skeletal metastases by imaging and palliation of pain arising from skeletal metastases, respectively. The conjugate was synthesized in high purity following an easily adaptable three‐step reaction scheme. Gallium‐68‐ and 153Sm‐complexes were prepared in high yield (>98%) and showed excellent in vitro stability in phosphate‐buffered saline (PBS) and human serum. Both the complexes showed high affinity for hydroxyapatite particles in in vitro binding study. In biodistribution studies carried out in normal Wistar rats, both the complexes exhibited rapid skeletal accumulation with almost no retention in any other major organ. The newly synthesized molecule DOTA‐Bn‐SCN‐BP would therefore be a promising targeting ligand for the development of radiopharmaceuticals for both imaging skeletal metastases and palliation of pain arising out of it in patients with cancer when radiolabeled with 68Ga and 153Sm, respectively. A systematic comparative evaluation, however, showed that there was no significant improvement of skeletal accumulation of the 153Sm‐DOTA‐Bn‐SCN‐BP complex over 153Sm‐DOTMP (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetramethylenephosphonic acid) as the later itself demonstrated optimal properties required for an agent for bone pain palliation. [ABSTRACT FROM AUTHOR]

Lutetium-177-labeled PSMA inhibitor has emerged as a promising modality for targeted therapy of prostate carcinoma. A protocol for regular multidose formulation of ready-to-use 177 Lu-PSMA-617 has been developed based on detailed and systematic radiochemical investigations. The formulation meets the requirements of clinical use and can be shipped to nuclear medicine centres for administration up to 4 days from the date of formulation. The reported protocol would be useful toward facilitating widespread clinical utilization of 177 Lu-PSMA-617 in the management of prostate cancer. [ABSTRACT FROM AUTHOR]

Since the inception of radiation synovectomy, a host of radioactive colloids and microparticles incorporating suitable therapeutic radionuclides have been proposed for the treatment of arthritis. The present article reports the synthesis and evaluation of barium titanate microparticles as an innovative and effective carrier platform for lanthanide radionuclides in the preparation of therapeutic agents for treatment of arthritis. The material was synthesized by mechanochemical route and characterized by X‐ray diffraction, scanning electron microscopy, surface area, and particle size distribution analyses. Loading of lanthanide radionuclides (166Ho, 153Sm, 177Lu, and 169Er) on the microparticles was achieved in high yield (> 95%) resulting in the formulation of loaded particulates with excellent radiochemical purities (> 99%). Radiolanthanide‐loaded microparticles exhibited excellent in vitro stability in human serum. In vitro diethylene triamine pentaacetic acid challenge study indicated fairly strong chemical association of lanthanides with barium titanate microparticles. Long‐term biodistribution studies carried out after administration of 177Lu‐loaded microparticles into one of the knee joints of normal Wistar rats revealed near‐complete retention of the formulation (> 96% of the administered radioactivity) within the joint cavity even 14 days post‐administration. The excellent localization of the loaded microparticles was further confirmed by sequential whole‐body radio‐luminescence imaging studies carried out using 166Ho‐loaded microparticles. [ABSTRACT FROM AUTHOR]

Introduction Thermal neutron activation of 152 Sm [ 152 Sm(n,γ) 153 Sm] using natural or isotopically enriched (by 152 Sm) samarium target is the established route for production of 153 Sm used for preparation of 153 Sm-EDTMP for pain palliation in cancer patients with disseminated bone metastases. However, some long-lived radionuclidic contaminants of Eu, such as, 154 Eu (t ½ = 8.6 y) are also produced during the target activation process. This leads to detectable amount of Eu radionuclidic contaminants in patients' skeleton even years after administration with therapeutic doses of 153 Sm-EDTMP. Further, the presence of such contaminants in 153 Sm raises concerns related to radioactive waste management. The aim of the present study was to develop and demonstrate a viable method for large-scale purification of 153 Sm from radionuclidic contaminants of Eu. Methods A radiochemical separation procedure adopting electroamalgamation approach has been critically evaluated. The influence of different experimental parameters for the quantitative removal radionuclidic contaminants of Eu from 153 Sm was investigated and optimized. The effectiveness of the method was demonstrated by purification of ~ 37 GBq of 153 Sm in several batches. As a proof of concept, 153 Sm-EDTMP was administered in normal Wistar rats and ex vivo γ-spectrometry of bone samples were carried out. Results After carrying out the electrolysis under the optimized conditions, the radionuclidic contaminants of Eu could not be detected in purified 153 Sm solution by γ-spectrometry. The overall yield of 153 Sm obtained after the purification process was > 85%. The reliability of this approach was amply demonstrated in several batches, wherein the performance remained consistent. Ex vivo γ-spectrometry of bone samples of Wistar rats administered with 153 Sm-EDTMP (prepared using electrochemically purified 153 Sm) did not show photo peaks corresponding to radionuclidic contaminants of Eu. Conclusions A viable electrochemical strategy for the large-scale purification of 153 Sm from radionuclidic contaminants of Eu has been successfully developed and demonstrated. [ABSTRACT FROM AUTHOR]

An integral--proportional derivative (I--PD) control strategy for integrating plus time-delay processes is proposed. The proposed scheme consists of an inner PD loop and an outer I-loop for taking care of the servo as well as the regulatory action. Explicit formulas for tuning of the proposed controller are derived in terms of gain margin, phase margin and critical gain. Moreover, pole-placement and frequency loop-shaping design methods are also explored for designing the I--PD controller. Simulation results show the superiority of the proposed I--PD controller over conventional P/PI/PID ones for integrating processes. The design is also validated through experiments on a temperature control process. [ABSTRACT FROM AUTHOR]

An integral–proportional derivative (I–PD) control strategy for integrating plus time‐delay processes is proposed. The proposed scheme consists of an inner PD loop and an outer I‐loop for taking care of the servo as well as the regulatory action. Explicit formulas for tuning of the proposed controller are derived in terms of gain margin, phase margin and critical gain. Moreover, pole‐placement and frequency loop‐shaping design methods are also explored for designing the I–PD controller. Simulation results show the superiority of the proposed I–PD controller over conventional P/PI/PID ones for integrating processes. The design is also validated through experiments on a temperature control process. [ABSTRACT FROM AUTHOR]

Scandium-47 [T½= 3.35 d, Eβ-(max.) = 600 keV, Eγ = 159 keV] is a relatively new radioisotope that holds tremendous potential for use in cancer theranostics. The radioisotope was produced by thermal neutron irradiation of enriched46Ca producing47Ca, which decays by β−emission to47Sc. A viable method based on the selective electroamalgamation of Ca2+ions has been developed for the clinical-scale separation of47Sc from47Ca. The overall yield of47Sc after the separation process was >80% and it was obtained with >99.9% radionuclidic purity in a form suitable for radiopharmaceutical preparation. This strategy holds promise for future clinical translation of this radioisotope. [ABSTRACT FROM AUTHOR]

The present article reports the synthesis and characterization of mesoporous tin oxide (MTO) nanoparticles by a solid-state mechanochemical route. The synthesized material was used as an advanced sorbent material for 68Ge/68Ga radionuclide generator technology. Gallium-68 (t½ = 68 min) obtained from the 68Ge/68Ga generator is an important diagnostic radioisotope which holds tremendous potential in the non-invasive monitoring of various diseases, including cancer, using positron emission tomography (PET). The crystallite size of the MTO nanoparticles was in the range of 6–12 nm with a large surface area of 265 ± 16 m2 g−1, while the mean pore radius was found to be 2.1 ± 0.6 nm. Determination of the zeta-potential of the MTO nanoparticles dispersed in solutions at different pH values aided in understanding the sorption and separation mechanisms, which were based on the surface charge developed on the nanosorbent. The sorption capacity observed under column-flow conditions was 85 ± 5 mg Ge per g of nanosorbent. A clinical-scale 68Ge/68Ga generator (740 MBq) was developed using this nanosorbent. Gallium-68 could be regularly eluted from this generator over a prolonged period of 1 year with ＞70% elution yield and met all the requirements for clinical use. The suitability of 68Ga obtained from it was evaluated in preclinical settings by the preparation of a 68Ga-labeled peptide containing the arginine-glycine-aspartic acid (RGD) motif. To the best of our knowledge, this is the first report on the synthesis of MTO nanoparticles by a mechanochemical route which could be effectively utilized for the routine preparation of clinical-scale 68Ge/68Ga generators. The promising results obtained in this study would facilitate greater implementation of mechanochemistry for the synthesis of nanosorbents for radionuclide generator technology since this method is simple, economical and convenient. [ABSTRACT FROM AUTHOR]

Abstract: Development of suitably radiolabeled nanoplatforms for cancer targeting is still at an early stage necessitating a simplified and reliable approach for incorporation of radioisotopes onto nanoparticles with minimal impact on their original biological behavior. In this study, we have developed an one‐pot synthesis protocol for preparation of small sized (4‐5 nm diameter), water soluble, intrinsically radiolabeled 64Cu metal nanoparticles capped within human serum albumin (HSA) scaffold (64Cu‐HSA nanocomposite). Detailed characterization of the as‐synthesized nanoparticles was carried out by various analytical techniques to establish the colloidal and radiochemical stability, biocompatibility and suitability for clinical administration. The biological efficacy of 64Cu‐HSA nanocomposite was demonstrated by biodistribution studies in melanoma tumor bearing C57BL/6 mice, that showed rapid diffusion and accumulation of the radiotracer into tumor and clearance from the biological system by both renal and hepatobiliary routes. The promising results obtained in this study suggest that this strategy could be employed to facilitate clinical translation of a new class of biocompatible radiotracers derived from metal‐based nanoparticles for PET imaging. [ABSTRACT FROM AUTHOR]

Use of bone-seeking radiopharmaceuticals is an established modality in the palliative care of pain due to skeletal metastases. 177Lu-DOTMP is a promising radiopharmaceutical for this application owing to the ideally suited decay properties of 177Lu and excellent thermodynamic stability and kinetic rigidity of the macrocyclic complex. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of clinical doses of 177Lu-DOTMP at hospital radiopharmacy. After extensive radiochemical studies, an optimized strategy for formulation of clinical doses of 177Lu-DOTMP was developed, which involves simple mixing of approximately 3.7 GBq of 177Lu activity as 177LuCl3 solution to an aqueous solution containing 5 mg of DOTMP and 8 mg of NaHCO3. The proposed protocol yielded 177Lu-DOTMP with >98% radiochemical purity, and the resultant formulation showed excellent in vitro stability and desired pharmacokinetic properties in animal model. Preliminary clinical investigations in 5 patients showed specific skeletal accumulation with preferential localization in the osteoblastic lesion sites and almost no uptake in soft tissue or any other major nontarget organ. The developed 'mix-and-use' strategy would be useful for large number of nuclear medicine centers having access to 177Lu activity and would thereby accelerate the clinical translation of 177Lu-DOTMP. [ABSTRACT FROM AUTHOR]

In this study, radiolabeled FAPI-46-F1D (IC SB 50 sb = 157.8 ± 14.5 pM) and FAPI-46-Ibu (IC SB 50 sb = 39.4 ± 16.1 pM) showed enhanced inhibitory activity, while FAPI-46-EB (IC SB 50 sb = 634.3 ± 102.3 pM) and FAP-2286 (IC SB 50 sb = 247.6 ± 71.1 pM) showed reduced or very similar inhibitory activity compared to FAPI-46 (IC SB 50 sb = 247.0 ± 17 pM). The first approach is multimerization of high-affinity FAPI ligands to enhance residence time in FAP-positive tumors [[10]], such as dimeric FAPI ligands that offer better chances of rebinding to their target, with slower off-rates than are seen with their monovalent counterparts [[9]-[11]]. While the potential of these radiolabeled FAPIs as SPECT/PET imaging agents is incontestable, their suitability for therapy is impaired by their short tumor retention leading to suboptimal radiation doses to the tumor [[2], [8]]. [Extracted from the article]

Yttrium-90 obtained from most of the 90 Sr/ 90 Y generators contains 90 Sr impurity above permissible limit for human administration. A protocol has been optimized for formulation of therapeutic dose of 90 Y-DOTA-Tyr 3 -octreotate ( 90 Y-DOTA-TATE) and removal of 90 Sr impurity from it. The radiochemical purity of 90 Y-DOTA-TATE was found to be >98% and it met the requirements for clinical use. The radiopharmaceutical was used in preliminary clinical investigation in patients with neuroendocrine tumors. This promising strategy would aid toward widespread clinical utilization of 90 Sr/ 90 Y generators. [ABSTRACT FROM AUTHOR]

Introduction The commercially available 68 Ge/ 68 Ga generators are generally used in clinical context in conjunction with automated or semi-automated modules for the syntheses of 68 Ga radiopharmaceuticals. It is desirable to develop strategies for the formulation of 68 Ga-radiopharmaceuticals without use of such expensive modules in order to make 68 Ga-based clinical positron emission tomography (PET) more popular and affordable worldwide. Methods An organic matrix based 68 Ge/ 68 Ga generator was used for preparation of clinically relevant doses of four different 68 Ga-based radiopharmaceuticals, namely 68 Ga-DOTA-NOC, 68 Ga-NODAGA-RGD 2 , 68 Ga-PSMA-11 and 68 Ga-BPAMD. Detailed performance evaluation of the generator was carried out over the period of 9 months. The radiolabeling conditions were optimized in a hospital radiopharmacy directly utilizing 68 Ga eluted from the generator without use of any synthesis module. Quality control tests of the radiopharmaceuticals were carried out to assess their suitability for clinical use. The clinical utility of the synthesized radiopharmaceuticals was ascertained by performing PET scans in human patients. Results During the period of evaluation, 68 Ga could be obtained from the generator in 4 mL of 0.05 M HCl with 60–85% elution yield and >99.99% radionuclidic purity. While directly using 68 Ga eluted from the generator, the 68 Ga-based radiopharmaceuticals could be prepared with >95% radiochemical purity and they met all the requirements for clinical administration. The clinical efficacy of the radiopharmaceuticals synthesized was established by PET scans in human patients. The performance of the generator remained consistent over the 9-month period and >100 clinical doses of different radiopharmaceuticals were prepared with excellent reproducibility and clinical effectiveness. Conclusions The promising results obtained in this study would make 68 Ga-radiopharmacy more practical and cost effective in clinical context. To the best of our knowledge, this is the first report on the clinical scale syntheses and utilization of 68 Ga-based radiopharmaceuticals without using any synthesis module. [ABSTRACT FROM AUTHOR]

Synthesis of intrinsically radiolabeled nanoparticles is an emerging concept in cancer theranostics and is expected to play an imperative role in translating nanotechnology research into the nuclear medicine industry. In order to reduce reliance on cyclotron produced 64Cu (t1/2 = 12.7 h, EC 45%, β+ 17.9%, β- 37.1%) and increase global accessibility of this radioisotope for preclinical and clinical investigations, we have explored the feasibility of using neutron-activated 64Cu produced in research reactors for potential use in cancer theranostics. A viable strategy has been developed for production of 64Cu in medium-flux research reactors and its utilization toward industrial-scale (GBq level) synthesis of intrinsically radiolabeled 64CuS nanoparticles (∼30 nm particle size). The synthesis procedure was easily executable in a hot cell equipped with remotely operable gadgets and 64CuS nanoparticles could be synthesized in a form suitable for clinical administration. The stability of the nanoparticles under physiological conditions was established by detailed in vitro studies in phosphate buffered saline (PBS) and mouse serum media. The biological efficacy of intrinsically radiolabeled 64CuS nanoparticles was studied in C57BL/6 mice bearing melanoma tumors. The results of the biodistribution studies revealed significant tumor uptake (4.64% ± 1.71%ID/g) within 4 h post-injection (where %ID is the percent injected radioactivity dose), with good tumor-to-background contrast. Collectively, the promising results obtained in this study suggest that the concept of intrinsically radiolabeled nanoplatforms can be employed to facilitate widespread utilization of neutron-activated 64Cu in nuclear medicine industry. [ABSTRACT FROM AUTHOR]

The present article reports the synthesis and characterization of mesoporous tin oxide (MTO) nanoparticles by a solid-state mechanochemical route. The synthesized material was used as an advanced sorbent material for 68Ge/68Ga radionuclide generator technology. Gallium-68 (t½ = 68 min) obtained from the 68Ge/68Ga generator is an important diagnostic radioisotope which holds tremendous potential in the non-invasive monitoring of various diseases, including cancer, using positron emission tomography (PET). The crystallite size of the MTO nanoparticles was in the range of 6–12 nm with a large surface area of 265 ± 16 m2 g−1, while the mean pore radius was found to be 2.1 ± 0.6 nm. Determination of the zeta-potential of the MTO nanoparticles dispersed in solutions at different pH values aided in understanding the sorption and separation mechanisms, which were based on the surface charge developed on the nanosorbent. The sorption capacity observed under column-flow conditions was 85 ± 5 mg Ge per g of nanosorbent. A clinical-scale 68Ge/68Ga generator (740 MBq) was developed using this nanosorbent. Gallium-68 could be regularly eluted from this generator over a prolonged period of 1 year with ＞70% elution yield and met all the requirements for clinical use. The suitability of 68Ga obtained from it was evaluated in preclinical settings by the preparation of a 68Ga-labeled peptide containing the arginine-glycine-aspartic acid (RGD) motif. To the best of our knowledge, this is the first report on the synthesis of MTO nanoparticles by a mechanochemical route which could be effectively utilized for the routine preparation of clinical-scale 68Ge/68Ga generators. The promising results obtained in this study would facilitate greater implementation of mechanochemistry for the synthesis of nanosorbents for radionuclide generator technology since this method is simple, economical and convenient. [ABSTRACT FROM AUTHOR]

Targeted radionuclide therapy using 177Lu-labeled peptidomimetic inhibitor of prostate specific membrane antigen (PSMA) viz. PSMA-617 is emerging as one the most effective strategies for management of metastatic prostate cancer, which is one of the leading causes of cancer related death. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of therapeutic dose of 177Lu-PSMA-617 at hospital radiopharmacy using moderate specific activity 177Lu available at an affordable cost. Extensive radiochemical studies were performed to optimize the required [PSMA-617] / [Lu] ratio and other parameters to formulate 7.4 GBq dose of 177Lu-PSMA-617. Based on these, 7.4 GBq therapeutic dose of 177Lu-PSMA-617 was formulated by incubating 160 µg of PSMA-617 with indigenously produced 177LuCl3 (555 GBq/µg specific activity of 177Lu) at 90 °C for 30 min. The radiochemical purity of the formulation was 98.3 ± 0.6% ( n = 7) which was retained to the extent of >95% after 7 d in normal saline at room temperature and >96% after 2 d in human serum at 37 °C. Preliminary clinical studies showed specific targeting of the agent in the lesion sites and similar physiological distribution as in diagnostic 68Ga-PSMA-11 PET scans performed earlier. The developed optimized protocol for formulating therapeutic dose of 177Lu-PSMA-617 could be useful for large number of nuclear medicine therapy clinics across the world having access to moderate specific activity 177Lu at an affordable cost. [ABSTRACT FROM AUTHOR]

Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human-mouse chimeric IgG1 mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (~2.22 GBq) of 90Y-labelled Cetuximab and 177Lu-labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N-[(R)-2-amino-3-(paraisothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N′,N″,N″-pentaacetic acid (CHX-A″-DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 ± 0.27 GBq/mg for 90Y-CHX-A″-DTPA-Cetuximab and 1.14 ± 0.15 GBq/mg for 177Lu-CHX-A″-DTPA-Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both 90Y-CHX-A″-DTPA-Cetuximab and 177Lu-CHX-A″-DTPA-Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24-h post-injection (p.i.) (~16%ID/g) with good tumour-to-background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of 90Y-CHX-A″-DTPA-Cetuximab in tumour-bearing mice. The tumour uptake at 24 h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) or Kala-azar, the second-largest parasitic killer worldwide, is caused by Leishmania donovani. The drugs to treat VL are toxic and expensive. Moreover, their indiscriminate use gave rise to resistant strains. The high rate of parasite proliferation within the host macrophage cells causes pathogenesis. In the proliferative pathway, FRB domain of TOR protein is ubiquitously essential. Although orthologues of mTOR protein are reported in trypanosomatids and Leishmania but therein depth molecular characterization is yet to be done. Considerable protein sequence homology exists between the TOR of kinetoplastidas and mammals. Interestingly, exogenous human FRB domain was shown to block G1 to S transition in mammalian cancer cells. Thus, we hypothesized that expression of human FRB domain would inhibit the proliferation of Leishmania donovani. Indeed, promastigotes stably expressing wild type human FRB domain show 4.7 and 1.5 folds less intra- and extra-cellular proliferations than that of untransfected controls. They also manifested 2.65 times lower rate of glucose stimulated oxygen consumption. The activities of all respiratory complexes were compromised in the hFRB expressing promastigotes. In these cells, depolarized mitochondria were 2-fold more than control cells. However, promastigotes expressing its mutant version (Trp2027-Phe) has shown similar characteristics like untransfected cells. Thus, this study reveals greater insights on the conserved role of TOR in the regulation of the respiratory complexes in L. donovani. The slow growing variant of FRB expressing promastigotes will have great potential to be exploited as a prophylactic agent against leishmaniasis. [Display omitted] • Expression of wild type hFRB domain in the L. donovani promastigotes led to the inactivation of downstream TOR functions. • Wild type hFRB but not the mutant (Trp2027-Phe) results in less infective "proliferation deficient" L. donovani parasites. • Wild type hFRB caused dysfunction in mitochondrial respiration that is in part due to its depolarization in L. donovani. • Mutant hFRB (Trp2027-Phe) expressing promastigotes has shown similar phenotype like untransfected control. [ABSTRACT FROM AUTHOR]

The present study is aimed at carrying out a comparative performance evaluation of different types of 68Ge/68Ga generators to identify the best choice for use in 68Ga-radiopharmacy. Over the 1 year period of evaluation, the elution yields from the CeO2-based and SiO2-based 68Ge/68Ga generators remained almost consistent, in contrast to the sharp decrease observed in the elution yields from TiO2 and SnO2-based generators. The level of 68Ge impurity in 68Ga eluates from the CeO2 and SiO2-based 68Ge/68Ga generator was always <10−3%, while this level increased from 10−3% to 10−1% in case of TiO2 and SnO2-based generators. The level of chemical impurities in 68Ga eluates from CeO2 and SiO2-based 68Ge/68Ga generators was negligibly low (<0.1 ppm) in contrast to the significantly higher level (1-20 ppm) of such impurities in eluates from other two generators. As demonstrated by radiolabeling studies carried out using DOTA-coupled dimeric cyclic RGD peptide derivative (DOTA-RGD2), CeO2-PAN and SiO2-based generators are directly amenable for radiopharmaceutical preparation, whereas the other generators can be only used after post-elution purification of 68Ga eluates. Clinically relevant dose of 68Ga-DOTA-RGD2 was prepared in a hospital radiopharmacy for non-invasive visualization of tumors in breast cancer patients using positron emission tomography. [ABSTRACT FROM AUTHOR]

Introduction With an objective to develop a cost-effective radiochemical formulation for palliation of pain due to skeletal metastases, we have demonstrated a viable method for large-scale production of 45 Ca (t ½ = 163 days, E βmax = 0.3 MeV) using moderate flux research reactor, its purification from radionuclidic impurities adopting electrochemical approach and preclinical evaluation of 45 CaCl 2 . Methods Irradiation parameters were optimized by theoretical calculations for production of 45 Ca with highest possible specific activity along with minimum radionuclidic impurity burden. Based on this, the radioisotope was produced in reactor by irradiation of isotopically enriched (98% in 44 Ca) CaO target at a thermal neutron flux of ~ 1 × 10 14 n.cm − 2 .s − 1 for 4 months. Scandium-46 impurity co-produced along with 45 Ca was efficiently removed adopting an electrochemical separation approach. The bone specificity of 45 CaCl 2 was established by in vitro studies involving its uptake in hydroxyapatite (HA) particles and also evaluating its biodistribution pattern over a period of 2 weeks after in vivo administration in Wistar rats. Results Thermal neutron irradiation of 100 mg of enriched (98% in 44 Ca) CaO target followed by radiochemical processing and electrochemical purification procedure yielded ~ 37 GBq of 45 Ca with a specific activity of ~ 370 MBq/mg and radionuclidic purity > 99.99%. The reliability and reproducibility of this approach were amply demonstrated by process demonstration in several batches. In vitro studies indicated significant uptake of 45 CaCl 2 (up to 65%) in HA particles. In vivo biodistribution studies in Wistar rats showed specific skeletal accumulation (40–46%ID) with good retention over a period of 2 weeks. Conclusions To the best of our knowledge, this is the first study on utilization of 45 CaCl 2 in the context of nuclear medicine. The results obtained in this study hold promise and warrant further investigations for future translation of 45 CaCl 2 to the clinics, thereby potentially enabling a cost-effective approach for metastatic bone pain palliation especially in developing countries. [ABSTRACT FROM AUTHOR]

Introduction The present article demonstrates a ‘mix-and-use’ approach for radiolabeling RGD peptide derivative with 68 Ga, which is easily adaptable in hospital radiopharmacy practice. The radiotracer thus formulated was successfully used for positron emission tomography (PET) imaging of breast cancer in human patients. Methods The conditions for radiolabeling NODAGA-coupled dimeric cyclic RGD peptide derivative [NODAGA-(RGD) 2 ] with 68 Ga were optimized using 68 Ga obtained from a 68 Ge/ 68 Ga generator developed in-house with CeO 2 -PAN composite sorbent as well as from a commercial 68 Ge/ 68 Ga generator obtained from ITG, Germany. Preclinical studies were carried out in C57BL/6 mice bearing melanoma tumors. The radiotracer was prepared in a hospital radiopharmacy using 68 Ga obtained from ITG generator and used for monitoring breast cancer patients by positron emission tomography (PET) imaging. Results 68 Ga-NODAGA-(RGD) 2 could be prepared with high radiolabeling yield (> 98%) and specific activity (~ 50 GBq/μmol) within 10 min at room temperature by mixing 68 Ga with the solution of the peptide conjugate. In vivo biodistribution studies showed significant uptake (5.24 ± 0.39% ID/g) in melanoma tumor at 30 min post-injection, with high tumor-to-background contrast. The integrin α v β 3 specificity of the tracer was corroborated by blocking study. Preliminary clinical studies in locally advanced breast cancer (LABC) patients indicated specifically high tumor uptake (SUV max 10–15) with good contrast. Conclusions This is one of the very few reports which presents preliminary clinical data on use of 68 Ga-NODAGA-(RGD) 2 and the developed ‘mix-and-use’ holds tremendous prospect in clinical PET imaging using 68 Ga. [ABSTRACT FROM AUTHOR]

Dopamine (DA) and serotonin (SRT) are monoamine neurotransmitters that play a key role in regulating the central and peripheral nervous system. Their impaired metabolism has been implicated in several neurological disorders, such as Parkinson’s disease and depression. Consequently, it is imperative to monitor changes in levels of these low-abundant neurotransmitters and their role in mediating disease. For the first time, a rapid, specific and sensitive isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of DA and SRT in the nematode Caenorhabditis elegans ( C. elegans ). This model organism offers a unique approach for studying the effect of various drugs and environmental conditions on neurotransmitter levels, given by the conserved DA and SRT biology, including synaptic release, trafficking and formation. We introduce a novel sample preparation protocol incorporating the usage of sodium thiosulfate in perchloric acid as extraction medium that assures high recovery of the relatively unstable neurotransmitters monitored. Moreover, the use of both deuterated internal standards and the multiple reaction monitoring (MRM) technique allows for unequivocal quantification. Thereby, to the best of our knowledge, we achieve a detection sensitivity that clearly exceeds those of published DA and SRT quantification methods in various matrices. We are the first to show that exposure of C. elegans to the monoamine oxidase B (MAO-B) inhibitor selegiline or the catechol- O -methyltransferase (COMT) inhibitor tolcapone, in order to block DA and SRT degradation, resulted in accumulation of the respective neurotransmitter. Assessment of a behavioral output of the dopaminergic system (basal slowing response) corroborated the analytical LC-MS/MS data. Thus, utilization of the C. elegans model system in conjunction with our analytical method is well-suited to investigate drug-mediated modulation of the DA and SRT system in order to identify compounds with neuroprotective or regenerative properties. [ABSTRACT FROM AUTHOR]

Manganese (Mn) is an essential heavy metal that is naturally found in the environment. Daily intake through dietary sources provides the necessary amount required for several key physiological processes, including antioxidant defense, energy metabolism, immune function and others. However, overexposure from environmental sources can result in a condition known as manganism that features symptomatology similar to Parkinson's disease (PD). This disorder presents with debilitating motor and cognitive deficits that arise from a neurodegenerative process. In order to maintain a balance between its essentiality and neurotoxicity, several mechanisms exist to properly buffer cellular Mn levels. These include transporters involved in Mn uptake, and newly discovered Mn efflux mechanisms. This review will focus on current studies related to mechanisms underlying Mn import and export, primarily the Mn transporters, and their function and roles in Mn-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

PSMA theranostics: review of the current status of PSMA-targeted imaging and radioligand therapy. Astatine-211 for PSMA-targeted -radiation therapy of micrometastatic prostate cancer: a sustainable approach towards precision oncology Biodistribution and dosimetry for combined [177Lu]Lu-PSMA-I&T/[225Ac]Ac-PSMA-I&T therapy using multi-isotope quantitative SPECT imaging. Several peptidomimetic inhibitors of PSMA (such as PSMA-11, PSMA-617, PSMA I&T, MIP-1095, DCFPyL, etc.) typically having a Glu-ureido component that serves as the PSMA binding motif have been designed and translated for routine clinical use [[4], [7]-[9]]. [Extracted from the article]

Introduction The scope of using no carrier added (NCA) 90 Y [T 1/2 = 64.1 h, E β(max) = 2.28 MeV] obtained from 90 Sr/ 90 Y generator in radiation synovectomy (RSV) is widely accepted. In the present study, the prospect of using 90 Y produced by (n,γ) route in a medium flux research reactor for use in RSV was explored. Methods Yttrium-90 was produced by thermal neutron irradiation of Y 2 O 3 target at a neutron flux of ~ 1 × 10 14 n/cm 2 .s for 14 d. The influence of various experimental parameters were systematically investigated and optimized to arrive at the most favorable conditions for the formulation of 90 Y labeled hydroxyapatite (HA) using HA particles of 1–10 μm size range. An optimized kit formulation strategy was developed for convenient one-step compounding of 90 Y-HA, which is easily adaptable at hospital radiopharmacy. The pre-clinical biological evaluation of 90 Y-HA particles was studied by carrying out biodistribution and bioluminiscence imaging studies in Wistar rats. The first clinical investigation using the radiolabeled preparation was performed on a patient suffering from chronic arthritis in knee joint by administering 185 MBq 90 Y-HA formulated at the hospital radiopharmacy deploying the proposed strategy. Results Yttrium-90 was produced with a specific activity of 851 ± 111 MBq/mg and radionuclidic purity of 99.95 ± 0.02%. 90 Y-labeled HA particles (185 ± 10 MBq doses) were formulated in high radiochemical purity (> 99%) and excellent in vitro stability. The preparation showed promising results in pre-clinical studies carried out in Wistar rats. The preliminary results of the first clinical investigation of 90 Y-HA preparation in a patient with rheumatoid arthritis in knee joints demonstrated the effectiveness of the formulation prepared using 90 Y produced via (n,γ) route in the management of the disease. Conclusion The studies revealed that effective utilization of 90 Y produced via (n,γ) route in a medium flux research reactor coupled with the developed strategy of using HA kits for convenient formulation of 90 Y-HA at the hospital radiopharmacy can contribute to sustainable growth in the clinical utilization of 90 Y in RSV in the foreseeable future. [ABSTRACT FROM AUTHOR]

Peptide receptor radionuclide therapy (PRRT) is a site-directed targeted therapeutic strategy that specifically uses radiolabeled peptides as biological targeting vectors designed to deliver cytotoxic levels of radiation dose to cancer cells, which overexpress specific receptors. Interest in PRRT has steadily grown because of the advantages of targeting cellular receptors in vivo with high sensitivity as well as specificity and treatment at the molecular level. Recent advances in molecular biology have not only stimulated advances in PRRT in a sustainable manner but have also pushed the field significantly forward to several unexplored possibilities. Recent decades have witnessed unprecedented endeavors for developing radiolabeled receptor-binding somatostatin analogs for the treatment of neuroendocrine tumors, which have played an important role in the evolution of PRRT and paved the way for the development of other receptor-targeting peptides. Several peptides targeting a variety of receptors have been identified, demonstrating their potential to catalyze breakthroughs in PRRT. In this review, the authors discuss several of these peptides and their analogs with regard to their applications and potential in radionuclide therapy. The advancement in the availability of combinatorial peptide libraries for peptide designing and screening provides the capability of regulating immunogenicity and chemical manipulability. Moreover, the availability of a wide range of bifunctional chelating agents opens up the scope of convenient radiolabeling. For these reasons, it would be possible to envision a future where the scope of PRRT can be tailored for patient-specific application. While PRRT lies at the interface between many disciplines, this technology is inextricably linked to the availability of the therapeutic radionuclides of required quality and activity levels and hence their production is also reviewed. [ABSTRACT FROM AUTHOR]