Endocannabinoids, which are present throughout the central nervous system (CNS), can activate cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n = 56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120 mg) were compared with placebo and nabilone (3 and 6 mg). The primary endpoint was the peak effect (E_max) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Lenabasum was safe and well tolerated. Compared with placebo, a 20-mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120 mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3 mg and 6 mg, a medication currently approved by the US Food and Drug Administration (FDA). At a target therapeutic dose (20 mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120 mg) did elicit subjective ratings of Drug Liking compared with placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared with 3 mg and 6 mg nabilone, lenabasum does have abuse potential and should be used cautiously in clinical settings.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB₁)-selective, cannabinoid receptor type 2 (CB₂)-selective, and CB₁/CB₂ mixed agonists in the cisplatin CIPN model, using both male and female mice. CB₁ selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB₂ agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB₁ selective agonism decreasing plasma estradiol while CB₂ selective agonism increased plasma estradiol. Chronic administration of a mixed CB₁/CB₂ agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB₂ acting compound while selective CB₁ agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects.

Oxidative stress, fibrosis, and inflammasome activation from advanced glycation end product (AGE)–receptor of advanced glycation end product (RAGE) interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of β-caryophyllene (BCP) on activating cannabinoid type 2 receptors (CB2Rs) against diabetic complication, mainly cardiomyopathy and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding a high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dose of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance and insulin resistance and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found to be associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NADPH oxidase 4 and activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2–related factor 2 (Nrf2) signaling. Also, BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition in DCM mice by inhibiting transforming growth factor β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) signaling. Further, BCP treatment suppressed nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate a CB2R-dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2R antagonist. AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP demonstrated the potential to protect the myocardium and pancreas of DCM mice mediating CB2R-dependent mechanisms.

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7–10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain.

There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa. The two most abundant cannabinoids (⁹-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). Although the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials. In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC.

Chronic hypertension leads to injury and fibrosis in major organs. Fibroblast activation protein (FAP) is one of key molecules in tissue fibrosis, and ⁶⁸Ga-labeled FAP inhibitor-46 (FAPI46) PET is a recently developed method for evaluating FAP. The aim of this study was to evaluate FAP expression and fibrosis in a hypertension model and to test the feasibility of ⁶⁸Ga-FAPI46 PET in hypertension. Methods: Hypertension was induced in mice by angiotensin II infusion for 4 wk. ⁶⁸Ga-FAPI46 biodistribution studies and PET scanning were conducted at 1, 2, and 4 wk after hypertension modeling, and uptake in the major organs was measured. The FAP expression and fibrosis formation of the heart and kidney tissues were analyzed and compared with ⁶⁸Ga-FAPI46 uptake. Subgroups of the hypertension model underwent angiotensin receptor blocker administration and high-dose FAPI46 blocking, for comparison. As a preliminary human study, ⁶⁸Ga-FAPI46 PET images of lung cancer patients were analyzed and compared between hypertension and control groups. Results: Uptake of ⁶⁸Ga-FAPI46 in the heart and kidneys was significantly higher in the hypertension group than in the sham group as early as week 1 and decreased after week 2. The uptake was specifically blocked in the high-dose blocking study. Immunohistochemistry also revealed FAP expression in both heart and kidney tissues. However, overt fibrosis was observed in the heart, whereas it was absent from the kidneys. The angiotensin receptor blocker–treated group showed lower uptake in the heart and kidneys than did the hypertension group. In the pilot human study, renal uptake of ⁶⁸Ga-FAPI46 significantly differed between the hypertension and control groups. Conclusion: In hypertension, FAP expression is increased in the heart and kidneys from the early phases and decreases over time. FAP expression appears to represent fibrosis activity preceding or underlying fibrotic tissue formation. ⁶⁸Ga-FAPI46 PET has potential as an effective imaging method for evaluating FAP expression in progressive fibrosis by hypertension.

The role of gastrin-releasing peptide receptor (GRPR) in various diseases, including cancer, has been extensively studied and has emerged as a promising therapeutic target. In this study, we successfully achieved the use of [²¹²Pb]Pb-DOTAM-GRPR1, comprising the α-particle generator, ²¹²Pb, combined with a GRPR-targeting peptide, GRPR1, in a prostate cancer model. Methods: Pharmacokinetics, toxicity, radiation dosimetry, and efficacy were assessed in GRPR-positive prostate tumor–bearing mice after intravenous administration of [²¹²Pb]Pb-DOTAM-GRPR1 (where DOTAM is 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane). Results: Preclinical studies have shown tumor targeting of up to 5 percent injected dose per gram over 24 h, and optimization of the drug formulation and quantity has led to minimized oxidation and off-target binding, respectively. Particularly, an increase in peptide amount from 28 to 280 ng was shown to reduce off-target uptake, especially at the level of the pancreas, by about 30%. Furthermore, dosimetry studies confirmed the kidney as the dose-limiting organ, and toxicity studies revealed that a nontoxic dose of up to 1,665 kBq could be injected into mice. Efficacy studies indicated a median survival time of 9 wk in the control group, which received only a buffer solution, compared with 19 wk in the group that received 4 injections of 370 kBq at 3-wk intervals. Conclusion: Taken together, these combined data demonstrate the safety, tolerability, and efficacy of [²¹²Pb]Pb-DOTAM-GRPR1, thus warranting further exploration in clinical trials.

The role of somatostatin receptor (SSTR) PET/CT, using ⁶⁸Ga-based tracers or [⁶⁴Cu]Cu-DOTATATE (⁶⁴Cu-DOTATATE), in the management of patients with neuroendocrine neoplasm (NEN) is guided by appropriate use criteria (AUC). In this study, we performed systematic analyses of referral patterns and image findings of routine ⁶⁴Cu-DOTATATE PET/CT scans to support AUC development. Methods: We included all clinical routine ⁶⁴Cu-DOTATATE PET/CT scans performed between April 10, 2018 (start of clinical use), and May 2, 2022, at Copenhagen University Hospital–Rigshospitalet. We reviewed the referral text and image report of each scan and classified the indication according to clinical scenarios as listed in the AUC. Results: In total, 1,290 patients underwent 2,249 ⁶⁴Cu-DOTATATE PET/CT scans. Monitoring of patients with NEN seen both on conventional imaging and on SSTR PET without clinical evidence of progression was the most common indication (defined as "may be appropriate" in the AUC) and accounted for 703 (31.3%) scans. Initial staging after NEN diagnosis ("appropriate" in the AUC) and restaging after curative-intent surgery ("may be appropriate" in the AUC) accounted for 221 (9.8%) and 241 (10.7%) scans, respectively. Selection of patients eligible for peptide receptor radionuclide therapy ("appropriate" in the AUC) and restaging after peptide receptor radionuclide therapy completion ("appropriate" in the AUC) accounted for 95 (4.2%) and 115 (5.1%) scans, respectively. The number of scans performed for indications not defined in the AUC was 371 (16.5%). Image result analysis revealed no disease in 669 scans (29.7%), stable disease in 582 (25.9%), and progression in 461 (20.5%). In 99 of the 461 (21.5%) scans, progression was detected on PET but not on CT. Conclusion: Our study provided real-life data that may contribute to support development of ⁶⁴Cu-DOTATATE/SSTR PET/CT guidelines including AUC. Some scenarios listed as "may be appropriate" in the current AUC were frequent in our data. Monitoring of patients with NEN without clinical evidence of progression was the most frequent indication for ⁶⁴Cu-DOTATATE PET/CT, in which disease progression was detected in more than one third, and a large proportion was visible by PET only. We therefore conclude that this scenario could potentially be classified as appropriate.

Neuroendocrine tumor (NET) metastases to the heart are found in 1%–4% of NET patients and have been reported primarily in the form of individual cases. We investigated the prevalence, clinical characteristics, imaging features, and outcomes of NET patients with cardiac metastases on ⁶⁸Ga-DOTATATE PET/CT. Methods: ⁶⁸Ga-DOTATATE PET/CT of 490 consecutive patients from a single institution were retrospectively reviewed for sites of metastases. The cumulative cardiovascular event rate and overall survival of patients with cardiac NET metastases (CNMs) were compared with those of a control group of metastatic NET patients without cardiac metastases. In patients with CNMs, the cardiac SUV_max with and without normalization to the myocardial background uptake was compared with a separate cohort of 11 patients with active cardiac sarcoidosis who underwent ⁶⁸Ga-DOTATATE PET/CT for research purposes. Results: In total, 270 patients with metastatic NETs were identified, 9 (3.3%) of whom had CNMs. All 9 patients had grade 1–2 gastroenteropancreatic NETs, most commonly from the small intestine (7 patients). The control group consisted of 140 patients with metastatic grade 1–2 gastroenteropancreatic NETs. On Kaplan–Meier analysis, there was no significant difference in the risk of cardiovascular adverse events (P = 0.91 on log-rank test) or mortality (P = 0.83) between the metastatic NET patients with and without cardiac metastases. The degree of cardiac DOTATATE uptake was significantly higher in CNMs than in patients with cardiac sarcoidosis without overlap, in terms of both cardiac SUV_max (P = 0.027) and SUV_max–to–myocardial background ratio (P = 0.021). Conclusion: Routine ⁶⁸Ga-DOTATATE PET/CT can be used to identify CNMs in 3% of patients with metastatic NETs. CNMs do not confer added cardiovascular or mortality risk. A distinguishing feature of CNMs is their high degree of DOTATATE uptake compared with focal myocardial inflammation.

In Canada and across the globe, access to PSMA PET/CT is limited and expensive. For patients with biochemical recurrence (BCR) after treatment for prostate cancer, novel strategies are needed to better stratify patients who may or may not benefit from a PSMA PET scan. The role of the free-to-total prostate-specific antigen (PSA) ratio (FPSAR) in posttreatment prostate cancer, specifically in the PSMA PET/CT era, remains unknown. Our aim in this study was to determine the association of FPSAR in patients referred for ¹⁸F-DCFPyL PSMA PET/CT in the BCR setting and assess the correlation between FPSAR and ¹⁸F-DCFPyL PSMA PET/CT positivity (local recurrence or distant metastases). Methods: This prospective study included 137 patients who were referred for ¹⁸F-DCFPyL PSMA PET/CT and had BCR with a total PSA of less than 1 ng/mL after radical prostatectomy (RP) (including adjuvant or salvage radiotherapy). Blood samples were collected on the day of ¹⁸F-DCFPyL PSMA PET/CT. FPSAR was categorized as less than 0.10 or as 0.10 or more. A positive ¹⁸F-DCFPyL PSMA PET/CT scan was defined by a PROMISE classification lesion score of 2 or 3, irrespective of the site of increased tracer uptake (e.g., prostate, pelvic nodes, bone, or viscera). Results: Overall, 137 blood samples of patients with BCR after RP were analyzed to calculate FPSAR. The median age at ¹⁸F-DCFPyL PSMA PET/CT was 68.6 y (interquartile range, 63.0–72.4 y), and the median PSA at ¹⁸F-DCFPyL PSMA PET/CT was 0.3 ng/mL (interquartile range, 0.3–0.6 ng/mL). Eighty-six patients (62.8%) had an FPSAR of less than 0.10, whereas 51 patients (37.2%) had an FPSAR of 0.10 or more. An FPSAR of 0.10 or more was identified as an independent predictor of a positive ¹⁸F-DCFPyL PSMA PET/CT scan, with an odds ratio of 6.99 (95% CI, 2.96–16.51; P < 0.001). Conclusion: An FPSAR of 0.10 or more after RP independently correlated with increased odds of a positive ¹⁸F-DCFPyL PSMA PET/CT scan among BCR post-RP patients. These findings may offer an inexpensive method by which to triage access to ¹⁸F-DCFPyL PSMA PET/CT in jurisdictions where availability is not replete.

Identifying cancer therapy resistance is a key time-saving tool for physicians. Part of chemotherapy resistance includes senescence, a persistent state without cell division or cell death. Chemically inducing senescence with the combination of trametinib and palbociclib (TP) yields several tumorigenic and prometastatic factors in pancreatic cancer models with many potential antibody-based targets. In particular, urokinase plasminogen activator receptor (uPAR) has been shown to be a membrane-bound marker of senescence in addition to an oncology target. Methods: Here, 2 antibodies against murine uPAR and human uPAR were developed as immuno-PET agents to noninvasively track uPAR antigen abundance. Results: TP treatment increased cell uptake both in murine KPC cells and in human MiaPaCa2 cells. In vivo, subcutaneously implanted murine KPC tumors had high tumor uptake with the antimurine uPAR antibody independently of TP in young mice, yet uPAR uptake was maintained in aged mice on TP. Mice xenografted with human MiaPaCa2 tumors showed a significant increase in tumor uptake on TP therapy when imaged with the antihuman uPAR antibody. Imaging with either uPAR antibody was found to be more tumor-selective than imaging with [¹⁸F]FDG or [¹⁸F]F-DPA-714. Conclusion: The use of radiolabeled uPAR-targeting antibodies provides a new antibody-based PET imaging candidate for pancreatic cancer imaging as well as chemotherapy-induced senescence.

This single-center, single-arm, phase II trial (ChiCTR2100050057) investigated the ability of ¹⁸F-labeled fibroblast activation protein inhibitor ([¹⁸F]AlF-NOTA-FAPI-04, denoted as ¹⁸F-FAPI) PET/CT to predict the response to neoadjuvant camrelizumab plus chemotherapy (nCC) in locally advanced esophageal squamous cell carcinoma (LA-ESCC). Methods: This study included 32 newly diagnosed LA-ESCC participants who underwent ¹⁸F-FAPI PET/CT at baseline, of whom 23 also underwent scanning after 2 cycles of nCC. The participants underwent surgery after 2 cycles of nCC. Recorded PET parameters included maximum, peak, and mean SUVs and tumor-to-background ratios (TBRs), metabolic tumor volume, and total lesion FAP expression. PET parameters were compared between patient groups with good and poor pathologic responses, and the predictive performance for treatment response was analyzed. Results: The good and poor response groups each included 16 participants (16/32, 50.0%). On ¹⁸F-FAPI PET/CT, the posttreatment SUVs were significantly lower in good responders than in poor responders, whereas the changes in SUVs with treatment were significantly higher (all P < 0.05). SUV_max (area under the curve [AUC], 0.87; P = 0.0026), SUV_peak (AUC, 0.89; P = 0.0017), SUV_mean (AUC, 0.88; P = 0.0021), TBR_max (AUC, 0.86; P = 0.0031), and TBR_mean (AUC, 0.88; P = 0.0021) after nCC were significant predictors of pathologic response to nCC, with sensitivities of 63.64%–81.82% and specificities of 83.33%–100%. Changes in SUV_max (AUC, 0.81; P = 0.0116), SUV_peak (AUC, 0.82; P = 0.0097), SUV_mean (AUC, 0.81; P = 0.0116), and TBR_mean (AUC, 0.74; P = 0.0489) also were significant predictors of the pathologic response to nCC, with sensitivities and specificities in similar ranges. Conclusion: ¹⁸F-FAPI PET/CT parameters after treatment and their changes from baseline can predict the pathologic response to nCC in LA-ESCC participants.

In several malignancies, only a limited number of patients respond to immune checkpoint inhibitors. Predicting and monitoring responses to these inhibitors represent an unmet clinical need. Here, we developed a PET/CT probe targeting granzyme B, [⁶⁸Ga]Ga-NOTA-Gly-Gly-Gly-Ile-Glu-Pro-Asp-CHO (GSI), and aimed to investigate whether it can be used to monitor the effects of immune checkpoint inhibitors early in the course of therapy. Methods: Seventy-two patients with gastric cancer (stages III–IV) were recruited for [⁶⁸Ga]Ga-NOTA-GSI PET/CT imaging after 2 or 3 cycles of the immunotherapy, and 40 patients were included in the final analysis. The SUV_max of primary tumors (SUV_max-t), SUV_max of metastatic lymph nodes (SUV_max-LN), and SUV_max of normal tissues (liver and blood pool) were measured, and their target-to-liver background ratio (TLR) and target-to-blood background ratio (TBR) were denoted for primary tumors as TLR_tumor and TBR_tumor and for metastatic lymph nodes as TLR_LN and TBR_LN, respectively. The treatment responses were assessed within 1 wk after full-course treatment according to RECIST version 1.1. Wilcoxon rank-sum tests were used to compare the PET/CT parameters between responders and nonresponders. Receiver operating characteristic curve analysis was used to assess the diagnostic efficacy of [⁶⁸Ga]Ga-NOTA-GSI PET/CT parameters in identifying responders. Two-tailed P value of less than 0.05 was considered statistically significant. Results: We found that SUV_max-t, TLR_tumor, TBR_tumor, SUV_max-LN, and TBR_LN were higher in responders than in nonresponders (2.49 ± 0.58 vs. 1.55 ± 0.48, P = 0.000; 2.24 ± 0.48 vs. 1.74 ± 0.67, P = 0.007; 1.38 ± 0.43 vs. 0.90 ± 0.23, P = 0.000; 2.24 ± 0.99 vs. 1.42 ± 0.55, P = 0.003; and 1.28 ± 0.68 vs. 0.83 ± 0.32, P = 0.012, respectively). According to receiver operating characteristic curve analysis, the area under the curve for SUV_max-t, TBR_tumor, TLR_tumor, SUV_max-LN, TLR_LN, and TBR_LN was 0.886, 0.866, 0.746, 0.772, 0.648, and 0.731, respectively. The threshold of SUV_max-t was 2.05, and its sensitivity and specificity were 81.0% and 84.2%, respectively. In addition, multivariate logistic regression indicated that TBR_tumor was an independent predictor of treatment response (P = 0.03). Conclusion: Our results indicated that [⁶⁸Ga]Ga-NOTA-GSI PET/CT is a promising tool for predicting early response to combined immunotherapy in gastric cancer patients.

α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential.

The class F of G protein-coupled receptors (GPCRs) consists of 10 Frizzleds (FZD_1–10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched. The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first-class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation, and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to the rapid development of our knowledge about structure-function relationships, providing a great starting point for drug development. Despite the progress, questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems.

BACKGROUND AND PURPOSE:

A cleftlike nonenhancing hypointensity was observed repeatedly in the pituitary gland at the adenohypophysis/neurohypophysis border on contrast-enhanced 3D fat-saturated T1-MPRAGE using clinical 7T MRI. Our primary goal was to assess the prevalence of this finding. The secondary goals were to evaluate the frequency of other incidental pituitary lesions, MRI artifacts, and their effect on pituitary imaging on the contrast-enhanced 3D fat-saturated T1 MPRAGE at 7T.

BACKGROUND AND PURPOSE:

Overuse of CT-based cerebrovascular imaging in the emergency department and inpatient settings, notably CTA of the head and neck for minor and nonfocal neurologic presentations, stresses imaging services and exposes patients to radiation and contrast. Furthermore, such CT-based imaging is often insufficient for definitive diagnosis, necessitating additional MR imaging. Recent advances in fast MRI may allow timely assessment and a reduced need for head and neck CTA in select populations.

BACKGROUND AND PURPOSE:

Periprocedural intracranial hemorrhage is one of common complications after stent placement for symptomatic intracranial atherosclerotic stenosis. This study was conducted to demonstrate predictors and long-term outcomes of periprocedural intracranial hemorrhage after stent placement for symptomatic intracranial atherosclerotic stenosis.

BACKGROUND AND PURPOSE:

Angioplasty and stent placement have been described as a bailout technique in individuals with failed thrombectomy. We aimed to investigate Stent retriever AssIsted Lysis (SAIL) with tirofiban before angioplasty and stent placement.

BACKGROUND AND PURPOSE:

Reocclusion after treatment is a concern in endovascular therapy for isolated intracranial atherothrombotic stroke-related large-vessel occlusion (AT-LVO). However, the optimal endovascular therapy technique for AT-LVO has not yet been investigated. This study evaluated the optimal endovascular therapy technique for AT-LVO in a real-world setting.

SUMMARY:

Vascular inflammation is widely recognized as an important factor in the atherosclerotic process, particularly in terms of plaque development and progression. Conventional tests, such as measuring circulating inflammatory biomarkers, lack the precision to identify specific areas of vascular inflammation. In this context, noninvasive imaging modalities can detect perivascular fat changes, serving as a marker of vascular inflammation. This review aims to provide a comprehensive overview of the key concepts related to perivascular carotid fat and its pathophysiology. Additionally, we examine the existing literature on the association of pericarotid fat with features of plaque vulnerability and cerebrovascular events. Finally, we scrutinize the advantages and limitations of the noninvasive assessment of pericarotid fat.

Patient expectations of receiving antibiotics for common symptoms can trigger unnecessary use. We conducted a survey (n = 564) between January 2020 to June 2021 in public and private primary care clinics in Texas to study the prevalence and predictors of patients’ antibiotic expectations for common symptoms/illnesses. We surveyed Black patients (33%) and Hispanic/Latine patients (47%), and over 93% expected to receive an antibiotic for at least 1 of the 5 pre-defined symptoms/illnesses. Public clinic patients were nearly twice as likely to expect antibiotics for sore throat, diarrhea, and cold/flu than private clinic patients. Lack of knowledge of potential risks of antibiotic use was associated with increased antibiotic expectations for diarrhea (odds ratio [OR] = 1.6; 95% CI, 1.1-2.4) and cold/flu symptoms (OR = 2.9; 95% CI, 2.0-4.4). Lower education and inadequate health literacy were predictors of antibiotic expectations for diarrhea. Future antibiotic stewardship interventions should tailor patient education materials to include information on antibiotic risks and guidance on appropriate antibiotic indications.

Missing or inaccessible lung function measurements, gathered over time, have the potential to stagnate or impair clinical care decisions being made. This jeopardises patient safety and often contributes to excessive resource utilisation. Data integration is fundamental to clinical decision-making and entails amalgamating lung function data from multiple sources in a user-friendly format. Despite this, current systems for recording lung function data are suboptimal, with copious gaps in the clinical picture arising from missing or inaccessible lung function measurements. This article discusses the importance of data integration for lung function, with a call to action for key stakeholders involved in the performance, management and interpretation of such tests.

Advancements in immunotherapy in the perioperative setting have revolutionised the treatment of resectable nonsmall cell lung cancer (NSCLC). Here we present the methodology and results of the clinical trial CheckMate 816 demonstrating the benefit of neoadjuvant therapy with nivolumab plus chemotherapy compared with chemotherapy alone. Furthermore, this article discusses the implications for future practice in resectable NSCLC and the need for future research.

The driverless vehicles still can't take L.A.'s notorious highways.

Tim Miller hopes Amazon's anthology series will help viewers appreciate the "blood, sweat, and tears" Firewalk Studios put into the scrapped game.

There has been fallout. Speaker Nathan Cooper is said to have decreed guests will never again be seated inside the legislative chamber.

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HARI SREENIVASAN: The desire of the Kurds along Iraq’s northern border to govern themselves is receiving more resistance from Iraq’s central government. Iraqi army forces are demanding Kurdish troops withdraw from oil fields and military bases around Kirkuk, a city in the Kurdistan region that voted for independence last month. Kirkuk also has 10% of Iraq’s known oil reserves. Washington Post’s Loveday Morris is in Baghdad covering this standoff joins me now via Skype. First of all the significance of this. Why is it so important?

LOVEDAY MORRIS: There’s been a longtime conflict between Baghdad and Kurdistan over these disputed territories. Most significant of which is Kirkuk because of the oil reserves. But the referendum last month has really sharpened these disputes because you have Baghdad opposing independence and so it feels like they have to restate its territorial claims these areas. So that’s why we’re seeing a lot of tension right now.

HARI SREENIVASAN: And just to give people a little bit of a brief timeline – Iraqi forces control this area for a while and then in June ISIS took over the area and now it’s kind of back in Kurdish hands?

LOVEDAY MORRIS: Right. So in June 2014 Iraq lost control of a lot of the areas and we have this huge collapse in the face of an ISIS offensive. Over 100,000 soldiers fled and Kurdish forces moved in some of these areas – some of them maybe took from ISIS and others just moved into into the vacuum. And so Iraqi forces have been in these areas since June 2014. And that’s their main demand that they return to the areas.

HARI SREENIVASAN: What’s the likelihood that this standoff right now turns violent? Into some sort of a civil war?

LOVEDAY MORRIS:: I think at this point both sides don’t want violence. Al-Abadi, the prime minister, is really trying to defuse the situation by saying there’s going to be no military attack. But at the same time there is this buildup of forces so that I think they are trying to, in a way, intimidate the Kurds to withdraw from some areas but they don’t want to see a fight per say. But in this really tense situation there can be a small spark and things can turn violent quite easily.

HARI SREENIVASAN: Thank you.

The post Iraqi, Kurdish forces in standoff, weeks after Kurdish vote for independence appeared first on PBS NewsHour.

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Ministers must follow the UK Government and extend rates relief for businesses in Scotland, Anas Sarwar has said.

International numbers are on the up but not everything in tourism is rosy

A new Nordic-style Open Kindergarten will be trialled in part of Scotland ahead of a potential roll-out across the country.

The flats are described as the first new homes on the Scottish town's High Street 'in living memory'

Family business Graham’s Family Dairy has secured a multinational listing

The accountancy firm has opened a new office in the Scottish town

The plane is hailed as 'one of the most advanced aircraft available on the market'

Scotland was second out of 12 UK nations and regions on one key measure

Motorists have been urged to plan ahead with a major bridge due to close for work is carried out.  

A Scottish distillery has hailed the opening of a new 'dining destination' amid an expansion push.

Health Secretary Neil Gray will address concerns around his use of a ministerial car to attend football games at Hampden.

A film about a campaign to ban greyhound racing in Scotland has won an animal welfare award at a ceremony in London.

The concierge team at The Balmoral have helped raise awareness for a special event to raise money for charity in memory of Scotland legend Doddie Weir.