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Prostate-specific membrane antigen (PSMA) is a glycoprotein present in the prostate, that is overexpressed in prostate cancer (PCa). Recently, PSMA-directed radiopharmaceuticals have been developed, allowing the pinpointing of tumors with the Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging techniques. The aim of the present work was to standardize and validate an automatic synthesis module-based radiolabeling protocol for [68Ga]Ga-PSMA-11, as well as to produce a radiopharmaceutical for PET imaging of PCa malignancies. [68Ga]Ga-PSMA-11 was evaluated to determine the radiochemical purity (RCP), stability in saline solution and serum, lipophilicity, affinity to serum proteins, binding and internalization to lymph node carcinoma of the prostate (LNCaP) cells, and ex vivo biodistribution in mice. The radiopharmaceutical was produced with an RCP of 99.06 ± 0.10%, which was assessed with reversed-phase high-performance liquid chromatography (RP-HPLC). The product was stable in saline solution for up to 4 h (RCP > 98%) and in serum for up to 1 h (RCP > 95%). The lipophilicity was determined as −3.80 ± 0.15, while the serum protein binding (SPB) was <17%. The percentages of binding to LNCaP cells were 4.07 ± 0.51% (30 min) and 4.56 ± 0.46% (60 min), while 19.22 ± 2.73% (30 min) and 16.85 ± 1.34% (60 min) of bound material was internalized. High accumulation of [68Ga]Ga-PSMA-11 was observed in the kidneys, spleen, and tumor, with a tumor-to-contralateral-muscle ratio of >8.5 and a tumor-to-blood ratio of >3.5. In conclusion, an automatic synthesis module-based radiolabeling protocol for [68Ga]Ga-PSMA-11 was standardized and the product was evaluated, thus verifying its characteristics for PET imaging of PCa tumors in a clinical environment.

Radiolabeled peptides with high specificity for overexpressed receptors in tumor cells hold great promise for diagnostic and therapeutic applications. In this work, we aimed at comparing the radiolabeling efficiency and biological properties of two different RGD analogs: GRGDYV and GRGDHV, labeled with iodine-131 (131I) and technetium-99m-tricarbonyl complex [99mTc][Tc(CO)3]+. Additionally, we evaluated their interaction with the αvβ3 integrin molecule, overexpressed in a wide variety of tumors, including glioblastoma. Both peptides were chemically synthesized, purified and radiolabeled with 131I and [99mTc][Tc(CO)3]+ using the chloramine-T and tricarbonyl methodologies, respectively. The stability, binding to serum proteins and partition coefficient were evaluated for both radioconjugates. In addition, the binding and internalization of radiopeptides to rat C6 glioblastoma cells and rat brain homogenates from normal animals and a glioblastoma-induced model were assessed. Finally, ex vivo biodistribution studies were carried out. Radiochemical yields between 95–98% were reached for both peptides under optimized radiolabeling conditions. Both peptides were stable for up to 24 h in saline solution and in human serum. In addition, the radiopeptides have hydrophilic characteristics and a percentage of binding to serum proteins around 35% and 50% for the [131I]I-GRGDYV and [99mTc]Tc(CO)3-GRGDHV fragments, respectively. Radiopeptides showed the capacity of binding and internalization both in cell culture (C6) and rat brain homogenates. Biodistribution studies corroborated the results obtained with brain homogenates and confirmed the different binding characteristics due to the exchange of radionuclides and the presence of the tricarbonyl complex. Thereby, the results showed that both radiopeptides might be considered for future clinical applications.

Parkinson’s disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to alteration of the integrity of dopaminergic transporters (DATs). In recent years, some radiopharmaceuticals have been used in the clinic to evaluate the integrity of DATs. These include tropane derivatives such as radiolabeled β-CIT and FP-CIT with iodine-123 (123I), and TRODAT-1 with metastable technetium-99 (99mTc). Radiolabeling of β-CIT with radioactive iodine is based on electrophilic radioiodination using oxidizing agents, such as Chloramine T or Iodo-Gen®. For the first time, the present work performed a comparative study of the radiolabeling of β-CIT with iodine-131 (131I), using either Chloramine T or Iodo-Gen® as oxidizing agents, in order to improve the radiolabeling process of β-CIT and to choose the most advantageous oxidizing agent to be used in nuclear medicine. Both radiolabeling methods were similar and resulted in high radiochemical yield (> 95%), with suitable 131I-β-CIT stability up to 72 h. Although Chloramine T is a strong oxidizing agent, it was as effective as Iodo-Gen® for β-CIT radiolabeling with 131I, with the advantage of briefer reaction time and solubility in aqueous medium.

Radiolabeled peptides with high specificity for overexpressed receptors in tumor cells hold great promise for diagnostic and therapeutic applications. In this work, we aimed at comparing the radiolabeling efficiency and biological properties of two different RGD analogs: GRGDYV and GRGDHV, labeled with iodine-131 (131I) and technetium-99m-tricarbonyl complex [99mTc][Tc(CO)3]+. Additionally, we evaluated their interaction with the αvβ3 integrin molecule, overexpressed in a wide variety of tumors, including glioblastoma. Both peptides were chemically synthesized, purified and radiolabeled with 131I and [99mTc][Tc(CO)3]+ using the chloramine-T and tricarbonyl methodologies, respectively. The stability, binding to serum proteins and partition coefficient were evaluated for both radioconjugates. In addition, the binding and internalization of radiopeptides to rat C6 glioblastoma cells and rat brain homogenates from normal animals and a glioblastoma-induced model were assessed. Finally, ex vivo biodistribution studies were carried out. Radiochemical yields between 95-98% were reached for both peptides under optimized radiolabeling conditions. Both peptides were stable for up to 24 h in saline solution and in human serum. In addition, the radiopeptides have hydrophilic characteristics and a percentage of binding to serum proteins around 35% and 50% for the [131I]I-GRGDYV and [99mTc]Tc(CO)3-GRGDHV fragments, respectively. Radiopeptides showed the capacity of binding and internalization both in cell culture (C6) and rat brain homogenates. Biodistribution studies corroborated the results obtained with brain homogenates and confirmed the different binding characteristics due to the exchange of radionuclides and the presence of the tricarbonyl complex. Thereby, the results showed that both radiopeptides might be considered for future clinical applications.Radiolabeled peptides with high specificity for overexpressed receptors in tumor cells hold great promise for diagnostic and therapeutic applications. In this work, we aimed at comparing the radiolabeling efficiency and biological properties of two different RGD analogs: GRGDYV and GRGDHV, labeled with iodine-131 (131I) and technetium-99m-tricarbonyl complex [99mTc][Tc(CO)3]+. Additionally, we evaluated their interaction with the αvβ3 integrin molecule, overexpressed in a wide variety of tumors, including glioblastoma. Both peptides were chemically synthesized, purified and radiolabeled with 131I and [99mTc][Tc(CO)3]+ using the chloramine-T and tricarbonyl methodologies, respectively. The stability, binding to serum proteins and partition coefficient were evaluated for both radioconjugates. In addition, the binding and internalization of radiopeptides to rat C6 glioblastoma cells and rat brain homogenates from normal animals and a glioblastoma-induced model were assessed. Finally, ex vivo biodistribution studies were carried out. Radiochemical yields between 95-98% were reached for both peptides under optimized radiolabeling conditions. Both peptides were stable for up to 24 h in saline solution and in human serum. In addition, the radiopeptides have hydrophilic characteristics and a percentage of binding to serum proteins around 35% and 50% for the [131I]I-GRGDYV and [99mTc]Tc(CO)3-GRGDHV fragments, respectively. Radiopeptides showed the capacity of binding and internalization both in cell culture (C6) and rat brain homogenates. Biodistribution studies corroborated the results obtained with brain homogenates and confirmed the different binding characteristics due to the exchange of radionuclides and the presence of the tricarbonyl complex. Thereby, the results showed that both radiopeptides might be considered for future clinical applications.

Radiolabeled peptides with high specificity for overexpressed receptors in tumor cells hold great promise for diagnostic and therapeutic applications. In this work, we aimed at comparing the radiolabeling efficiency and biological properties of two different RGD analogs: GRGDYV and GRGDHV, labeled with iodine-131 ( I) and technetium-99m-tricarbonyl complex [ Tc][Tc(CO) ] . Additionally, we evaluated their interaction with the α β integrin molecule, overexpressed in a wide variety of tumors, including glioblastoma. Both peptides were chemically synthesized, purified and radiolabeled with I and [ Tc][Tc(CO) ] using the chloramine-T and tricarbonyl methodologies, respectively. The stability, binding to serum proteins and partition coefficient were evaluated for both radioconjugates. In addition, the binding and internalization of radiopeptides to rat C6 glioblastoma cells and rat brain homogenates from normal animals and a glioblastoma-induced model were assessed. Finally, ex vivo biodistribution studies were carried out. Radiochemical yields between 95-98% were reached for both peptides under optimized radiolabeling conditions. Both peptides were stable for up to 24 h in saline solution and in human serum. In addition, the radiopeptides have hydrophilic characteristics and a percentage of binding to serum proteins around 35% and 50% for the [ I]I-GRGDYV and [ Tc]Tc(CO) -GRGDHV fragments, respectively. Radiopeptides showed the capacity of binding and internalization both in cell culture (C6) and rat brain homogenates. Biodistribution studies corroborated the results obtained with brain homogenates and confirmed the different binding characteristics due to the exchange of radionuclides and the presence of the tricarbonyl complex. Thereby, the results showed that both radiopeptides might be considered for future clinical applications.

Prostate-specific membrane antigen (PSMA) is a glycoprotein present in the prostate, that is overexpressed in prostate cancer (PCa). Recently, PSMA-directed radiopharmaceuticals have been developed, allowing the pinpointing of tumors with the Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging techniques. The aim of the present work was to standardize and validate an automatic synthesis module-based radiolabeling protocol for [68Ga]Ga-PSMA-11, as well as to produce a radiopharmaceutical for PET imaging of PCa malignancies. [68Ga]Ga-PSMA-11 was evaluated to determine the radiochemical purity (RCP), stability in saline solution and serum, lipophilicity, affinity to serum proteins, binding and internalization to lymph node carcinoma of the prostate (LNCaP) cells, and ex vivo biodistribution in mice. The radiopharmaceutical was produced with an RCP of 99.06 ± 0.10%, which was assessed with reversed-phase high-performance liquid chromatography (RP-HPLC). The product was stable in saline solution for up to 4 h (RCP > 98%) and in serum for up to 1 h (RCP > 95%). The lipophilicity was determined as -3.80 ± 0.15, while the serum protein binding (SPB) was <17%. The percentages of binding to LNCaP cells were 4.07 ± 0.51% (30 min) and 4.56 ± 0.46% (60 min), while 19.22 ± 2.73% (30 min) and 16.85 ± 1.34% (60 min) of bound material was internalized. High accumulation of [68Ga]Ga-PSMA-11 was observed in the kidneys, spleen, and tumor, with a tumor-to-contralateral-muscle ratio of >8.5 and a tumor-to-blood ratio of >3.5. In conclusion, an automatic synthesis module-based radiolabeling protocol for [68Ga]Ga-PSMA-11 was standardized and the product was evaluated, thus verifying its characteristics for PET imaging of PCa tumors in a clinical environment.Prostate-specific membrane antigen (PSMA) is a glycoprotein present in the prostate, that is overexpressed in prostate cancer (PCa). Recently, PSMA-directed radiopharmaceuticals have been developed, allowing the pinpointing of tumors with the Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging techniques. The aim of the present work was to standardize and validate an automatic synthesis module-based radiolabeling protocol for [68Ga]Ga-PSMA-11, as well as to produce a radiopharmaceutical for PET imaging of PCa malignancies. [68Ga]Ga-PSMA-11 was evaluated to determine the radiochemical purity (RCP), stability in saline solution and serum, lipophilicity, affinity to serum proteins, binding and internalization to lymph node carcinoma of the prostate (LNCaP) cells, and ex vivo biodistribution in mice. The radiopharmaceutical was produced with an RCP of 99.06 ± 0.10%, which was assessed with reversed-phase high-performance liquid chromatography (RP-HPLC). The product was stable in saline solution for up to 4 h (RCP > 98%) and in serum for up to 1 h (RCP > 95%). The lipophilicity was determined as -3.80 ± 0.15, while the serum protein binding (SPB) was <17%. The percentages of binding to LNCaP cells were 4.07 ± 0.51% (30 min) and 4.56 ± 0.46% (60 min), while 19.22 ± 2.73% (30 min) and 16.85 ± 1.34% (60 min) of bound material was internalized. High accumulation of [68Ga]Ga-PSMA-11 was observed in the kidneys, spleen, and tumor, with a tumor-to-contralateral-muscle ratio of >8.5 and a tumor-to-blood ratio of >3.5. In conclusion, an automatic synthesis module-based radiolabeling protocol for [68Ga]Ga-PSMA-11 was standardized and the product was evaluated, thus verifying its characteristics for PET imaging of PCa tumors in a clinical environment.

As caretakers of the hematopoietic system, hematopoietic stem cells assure a lifelong supply of differentiated populations that are responsible for critical bodily functions, including oxygen transport, immunological protection and coagulation. Due to the far-reaching influence of the hematopoietic system, hematological disorders typically have a significant impact on the lives of individuals, even becoming fatal. Hematopoietic cell transplantation was the first effective therapeutic avenue to treat such hematological diseases. Since then, key use and manipulation of hematopoietic stem cells for treatments has been aspired to fully take advantage of such an important cell population. Limited knowledge on hematopoietic stem cell behavior has motivated in-depth research into their biology. Efforts were able to uncover their native environment and characteristics during development and adult stages. Several signaling pathways at a cellular level have been mapped, providing insight into their machinery. Important dynamics of hematopoietic stem cell maintenance were begun to be understood with improved comprehension of their metabolism and progressive aging. These advances have provided a solid platform for the development of innovative strategies for the manipulation of hematopoietic stem cells. Specifically, expansion of the hematopoietic stem cell pool has triggered immense interest, gaining momentum. A wide range of approaches have sprouted, leading to a variety of expansion systems, from simpler small molecule-based strategies to complex biomimetic scaffolds. The recent approval of Omisirge, the first expanded hematopoietic stem and progenitor cell product, whose expansion platform is one of the earliest, is predictive of further successes that might arise soon. In order to guarantee the quality of these ex vivo manipulated cells, robust assays that measure cell function or potency need to be developed. Whether targeting hematopoietic engraftment, immunological differentiation potential or malignancy clearance, hematopoietic stem cells and their derivatives need efficient scaling of their therapeutic potency. In this review, we comprehensively view hematopoietic stem cells as therapeutic assets, going from fundamental to translational.

Expansins are plant cell wall-loosening proteins involved in adaptive responses to environmental stimuli and various developmental processes. The first genome-wide analysis of the expansin superfamily in the Arachis genus identified 40 members in A. duranensis and 44 in A. ipaënsis , the wild progenitors of cultivated peanut ( A. hypogaea ). These expansins were further characterized regarding their subfamily classification, distribution along the genomes, duplication events, molecular structure, and phylogeny. A RNA-seq expression analysis in different Arachis species showed that the majority of these expansins are modulated in response to diverse stresses such as water deficit, root-knot nematode (RKN) infection, and UV exposure, with an expansin-like B gene ( AraEXLB8 ) displaying a highly distinct stress-responsive expression profile. Further analysis of the AraEXLB8 coding sequences showed high conservation across the Arachis genotypes, with eight haplotypes identified. The modulation of AraEXLB8 expression in response to the aforementioned stresses was confirmed by qRT-PCR analysis in distinct Arachis genotypes, whilst in situ hybridization revealed transcripts in different root tissues according to the stress imposed. The overexpression of AraEXLB8 in soybean ( Glycine max ) composite plants remarkably decreased the number of galls in transformed hairy roots inoculated with RKN. This study improves the current understanding of the molecular evolution, divergence, and gene expression of expansins in Arachis , and provides molecular and functional insights into the role of expansin-like B, the less-studied plant expansin subfamily.

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. The prognosis of patients is very poor, with a median overall survival of ~ 15 months after diagnosis. Cadherin‐3 (also known as P‐cadherin), a cell–cell adhesion molecule encoded by the CDH3 gene, is deregulated in several cancer types, but its relevance in GBM is unknown. In this study, we investigated the functional roles, the associated molecular signatures, and the prognostic value of CDH3/P‐cadherin in this highly malignant brain tumor. CDH3/P‐cadherin mRNA and protein levels were evaluated in human glioma samples. Knockdown and overexpression models of P‐cadherin in GBM were used to evaluate its functional role in vitro and in vivo. CDH3‐associated gene signatures were identified by enrichment analyses and correlations. The impact of CDH3 in the survival of GBM patients was assessed in independent cohorts using both univariable and multivariable models. We found that P‐cadherin protein is expressed in a subset of gliomas, with an increased percentage of positive samples in grade IV tumors. Concordantly, CDH3 mRNA levels in glioma samples from The Cancer Genome Atlas (TCGA) database are increased in high‐grade gliomas. P‐cadherin displays oncogenic functions in multiple knockdown and overexpression GBM cell models by affecting cell viability, cell cycle, cell invasion, migration, and neurosphere formation capacity. Genes that were positively correlated with CDH3 are enriched for oncogenic pathways commonly activated in GBM. In vivo, GBM cells expressing high levels of P‐cadherin generate larger subcutaneous tumors and cause shorter survival of mice in an orthotopic intracranial model. Concomitantly, high CDH3 expression is predictive of shorter overall survival of GBM patients in independent cohorts. Together, our results show that CDH3/P‐cadherin expression is associated with aggressiveness features of GBM and poor patient prognosis, suggesting that it may be a novel therapeutic target for this deadly brain tumor. Here, we identified Cadherin‐3 (CDH3) as a novel oncogene in glioblastoma (GBM). CDH3 affected distinct cancer hallmarks in vitro and was related to increased tumor growth and shorter survival in vivo. Clinically, CDH3 correlated with cancer‐related signatures and was overexpressed in a subset of patients with poor prognosis, thus suggesting that CDH3 could hold a prognostic value for patients with GBM (Scheme drawn with images from Servier Medical Art; https://smart.servier.com/).

Nematodes and drought are major constraints in tropical agriculture and often occur simultaneously. Plant responses to these stresses are complex and require crosstalk between biotic and abiotic signaling pathways. In this study, we explored the transcriptome data of wild Arachis species subjected to drought (A-metaDEG) and the root-knot nematode Meloidogyne arenaria (B-metaDEG) via meta-analysis, to identify core-stress responsive genes to each individual and concurrent stresses in these species. Transcriptome analysis of a nematode/drought bioassay (cross-stress) showed that the set of stress responsive DEGs to concurrent stress is distinct from those resulting from overlapping A- and B-metaDEGs, indicating a specialized and unique response to combined stresses in wild Arachis . Whilst individual biotic and abiotic stresses elicit hormone-responsive genes, most notably in the jasmonic and abscisic acid pathways, combined stresses seem to trigger mainly the ethylene hormone pathway. The overexpression of a cross-stress tolerance candidate gene identified here, an endochitinase-encoding gene ( AsECHI ) from Arachis stenosperma , reduced up to 30% of M. incognita infection and increased post-drought recovery in Arabidopsis plants submitted to both stresses. The elucidation of the network of cross-stress responsive genes in Arachis contributes to better understanding the complex regulation of biotic and abiotic responses in plants facilitating more adequate crop breeding for combined stress tolerance.