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The purinergic P2X ligand-gated ion channel 7 receptor (P2X7R) plays a critical role in various inflammatory processes and other diseases. Fast determination of compounds P2X7R binding potency and discovery of a promise PET radiotracer for imaging P2X7R require a P2X7R suitable radioligand for radioactive competitive binding assay. Herein, we designed and synthesized thirteen new P2X7R ligands and determined the in vitro binding potency. The fluorescence screening assay identified the iodide compound 1c with high potency and specificity toward P2X7R with an IC 50 of 0.25 ± 0.05 nM. Therefore, 1c was 125 I-labeled to afford [ 125 I]1c with a good radiochemical yield (44 ± 12 %, n = 3) and high radiochemical purity (>95 %). Radioligand saturation binding assay showed that [ 125 I]1c specifically bound to human P2X7R with high affinity (K d  = 1.68 nM and B max  = 94 fmol/mg). A radioactive high throughput binding assay using [ 125 I]1c for our new compounds demonstrated that the imidazole compounds 1b, 1c, and 1d exhibited high inhibition for >70 %, while the analogues of GSK314181A exhibited low inhibition for <35 %. In addition, our radioligand competitive binding assays using [ 125 I]1c demonstrated that 1b, 1c, and 1d have high potency with IC 50 values of 7.91 ± 0.22, 7.06 ± 1.68, and 7.16 ± 0.41 nM toward P2X7R, respectively.Together, compounds 1b, 1c, and 1d are highly potent for P2X7R, and [ 125 I]1c has great potential to be a radioligand for screening P2X7R binding potency of the new compounds and investigating the P2X7R expression in animal models of human disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Optimal conditions for blood collection for circulating tumor DNA (ctDNA) are still being developed. Although both Streck and EDTA tubes are commonly used, their ability to stabilize ctDNA as a function of time and temperature post-collection has not been thoroughly studied. Additionally, the potential utility of CellSave tubes (commonly used for circulating tumor cell) for ctDNA measurements has not been studied., Design and Methods: Blood was collected into Streck, EDTA, and CellSave tubes from ten patients with metastatic breast cancer enrolled in the MI-ONCOSEQ tumor sequencing program at the University of Michigan and kept either on ice or at room temperature until plasma isolation. Plasma was processed after 2, 6, and 48h post-collection. We used droplet digital PCR (ddPCR) to quantify plasma ctDNA and wild-type DNA for six patients who had tumor tissue mutations represented in commercially available ddPCR assays., Results: ctDNA abundance was similar and stable for up to 6h in all tube types, and there was no effect of storage temperature on the yield for Streck and EDTA tubes. After 48h, however, one out of four patients with detectable ctDNA showed a ~50% decline in ctDNA in the EDTA tube, and three out of six patients showed a 2-3-fold increase in wild-type DNA in the EDTA tube., Conclusions: Streck, EDTA, and CellSave tubes showed similar performance in preserving ctDNA for up to 6h before plasma isolation. Streck and CellSave tubes more consistently stabilized ctDNA and wild-type DNA at 48h than EDTA tubes., (Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Purinergic signalling in the brain is becoming an important focus in the study of CNS health and disease. Various purinergic receptors are found to be present in different brain cells in varying extent, which get activated upon binding of ATP or its analogues. Conventionally, ATP was considered only as a major metabolic fuel of the cell but its recognition as a neurotransmitter in early 1970s, brought meaningful insights in neuron glia crosstalk, participating in various physiological functions in the brain. P2X7R, a member of ligand gated purinergic receptor (P2X) family, is gaining attention in the field of neuroscience because of its emerging role in broad spectrum of ageing and age related neurological disorders. The aim of this review is to provide an overview about the structure and function of P2X7R highlighting its unique features which distinguish it from the other members of its family. This review critically analyzes the literature mentioning the details about the agonist and antagonist of the P2X7R. It also emphasizes the advancements in understanding the dual role of P2X7R in brain development and disorders inviting meaningful insights about its involvement in Alzheimer's disease, Huntington's disease, Multiple Sclerosis, Neuropathic pain, Spinal Cord Injury and NeuroAIDS. Exploring the roles of P2X7R in detail is critical to identify its therapeutic potential in the treatment of acute and chronic neurodegenerative diseases. Moreover, this review also helps to raise more interest in the neurobiology of the purinergic receptors and thus providing new avenues for future research., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Cholecystokinin and Gastrin are amongst the first gastrointestinal hormone discovered. In addition to classical actions (contraction of gallbladder, growth and secretion in the stomach and pancreas), these also act as growth stimulants for gastrointestinal malignancies and cell lines. Growth of these tumours is inhibited by antagonists of the cholecystokinin and gastrin receptors. These receptors provides most promising approach in clinical oncology and several specific radiolabelled ligands have been synthesized for specific tumour targeting and therapy of tumours overexpressing these receptors. Therefore, definition of the molecular structure of the receptor involved in the autocrine/paracrine loop may contribute to novel therapies for gastrointestinal cancer. Hence, this review tries to focus on the role and distribution of these hormones and their receptors in gastrointestinal cancer with a brief talk about the clinical trial using available agonist and antagonist in gastrointestinal cancers., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Advanced gastric cancer carries a very poor prognosis when the tumor becomes unresectable. Even with the best currently available chemotherapy regimens the survival rate remains dismal. A recent breakthrough in the treatment paradigm has been the approval of trastuzumab, a monoclonal antibody, in HER2-positive metastatic gastric cancer. A large number of trials are underway using dendritic cells (DCs) in a number of human malignancies and do show a ray of hope in management of these patients. This review attempts to summarize tumor immunology and the current data regarding use of DCs in gastric cancer therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Gallbladder carcinoma (GBC) is the most common type of biliary tract carcinoma and the third commonest digestive tract malignancy in our region. Studies available in literature do not clearly define the molecular genetic mechanisms involved in the pathogenesis of GBC. Most of these studies are limited to protein expression analysis by immunohistochemistry and western blotting, and only a few have been done on mRNA (messenger RNA) and mutation analysis. This review aims to critically analyze all the available evidence on genetic aberrations in gallbladder carcinoma., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Pancreatic fistula (PF), haemorrhage and delayed gastric emptying are some of the common causes of morbidity and PF is the single most important cause of mortality following pancreaticoduodenectomy (PD). Authors, who claim to have reduced leak rates, recommend modifications of the standard technique of pancreaticojejunostomy (PJ) that are often complex and difficult to standardize for wider applications. Most individual studies, multicenter retrospective analysis and certain prospective studies report a lower leak rate with pancreaticogastrostomy (PG) when compared with PJ. However, the only three randomized controlled clinical trials (RCTs) to date have failed to demonstrate the superiority of either technique. Here we discuss the various aspects of pancreaticoenteric anastomosis following pylorus preserving pancreaticoduodenectomy (PPD) and the standard pancreaticoduodenectomy (PD)., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Breast conservation as an additional benefit was beyond the initial expectations of the investigators who pioneered neoadjuvant chemotherapy (NACT). In recent years an increasing number of patients with locally advanced breast cancer (LABC) are being treated with NACT, followed by breast conservation surgery with axillary dissection and radiation as a part of the multimodality management. Breast conservation has not been the standard of care for women with LABC, owing to concerns of increased chances of local recurrence, and possible survival disadvantage and psychological trauma from experiencing a recurrence of malignancy. LABC is still a common form of presentation of breast cancer in developing countries. Strict adherence to treatment protocols and regular follow-ups for years may not be practical for a large majority of patients hailing from the regions most affected by LABC. Defaulters often thus have a heavy price to pay. Hence lies the importance of carefully selecting LABC patients for a breast conservation approach from others that would have a higher risk of locoregional recurrence. Can we extrapolate the lessons learnt in early breast cancer to LABC and offer selected patients with LABC breast conservation therapy? Would the local control and survival results with conservative therapy be comparable to those obtained using mastectomy, or does the increased tumor burden in LABC necessitate ablative surgery in all women? This review aims to address these important questions.

Several randomized prospective studies on breast cancer patients have proved the safety of neoadjuvant chemotherapy. These trials have also demonstrated that tumor down staging does indeed improve the eligibility for breast conservative surgery without increasing local recurrence rates with possibly an improved survival. However, complete pathologic remissions are noted in only 3-30% of patients. About 20% of patients do not benefit from different chemotherapy regimens currently in use and are thus subjected to toxic drugs. This often leads to progression of disease and thereby the surgeon may lose a window of opportunity to obtain durable locoregional control of disease. Identification of predictive markers associated with pathologic complete response can help to distinguish patients with high or low probability of a response to treatment so that an individualized treatment plan can be implemented. It could also streamline the development of new alternative regimens for those who are unlikely to benefit from existing drugs. It is expected that a combination of markers will be more informative than a single one. So far, several factors have been studied as predictors for response to cytotoxic treatment, viz., tumor size, hormone (estrogen and progesterone) receptor status, tumor type and differentiation, HER2/cerB-2, tumor proliferation Ki-67, apoptosis related genes p53, bcl-2 and BAX; certain subgroups of breast cancer, and the latest in this category is gene expression profiling. However, in terms of prediction of drug responsiveness, data reported are still very limited. This review aims to discuss the current relevant literature on the subject.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These form a distinct category of tumors characterized by oncogenic mutations of the KIT receptor tyrosine kinase in a majority of patients. KIT is used not only for diagnosis but also for targeted therapy of GISTs. Imatinib, a tyrosine kinase inhibitor, is widely used in the treatment of advanced and metastatic GISTs and has been recently employed in the neo adjuvant and adjuvant set-up with encouraging results. Certain specific mutations in an exon (such as in exon 9) of the KIT gene result in GISTs that are relatively unresponsive to the Imatinib treatment. New therapeutic agents like Sunitinib have now been approved for the treatment of Imatinib-resistant GIST. This review summarizes the salient features of GIST along with a detailed review of targeted multi-disciplinary approach to the treatment of these special tumors.

Left renal vein hypertension is a most uncommon and rarely a well-documented cause of gross hematuria. We report a case of lateralizing, gross hematuria resulting from left renal vein hypertension in an individual with a history of a prior Whipple procedure. The diagnosis was suspected at the time of renal angiography and proven by renal venography. Complete rapid resolution of the hematuria and hypertension was achieved following placement of a left renal vein stent.