Receptor Analogues Research Articles

240 Nutritional Intervention to Improve Carbohydrate Utilization and gut Health in Pigs

Abstract In swine production, using feed antibiotics as antimicrobial growth promotants has been reduced; thus, feed alternatives to manage gut health are required. Dietary fiber, resistant starch, oligosaccharides, and exopolysaccharides are carbohydrate structures and are nutritional tools that may enhance gut health in pigs. Dietary carbohydrates may have a role to alleviate diarrheal diseases including in pigs post-weaning but also reduce constipation in sows. Antibiotics are hypothesized to influence gut health via modulation of intestinal microbial profiles; fermentation and intestinal inflammation are considered important mechanisms. Dietary fiber sources differ in 2 key properties: fermentability and solubility. Rapid fermentation of fiber and oligosaccharides is associated with changes in microbial profiles and increased metabolite production. Recently, microbial composition was hypothesized to be less important and combined output of metabolites should be the focus. Fiber properties may also manipulate retention time and physico-chemical properties of the undigested residue; hence, non-fermentable insoluble fiber may prevent constipation in sows. Starch is mostly digested and absorbed as glucose. However, resistant starch is not digested and acts as insoluble but fermentable fiber and has unique properties, because it specifically increases intestinal abundance of bifidobacteria, which are associated with improved gut health. Using crop breeding, feed processing, and feed additives, the structure of fiber and starch can be altered thereby changing its degradation kinetics and affecting its utilization as energy source and its prebiotic activity. Finally, exopolysaccharides from Limosilactobacillus reuteri and unique oligosaccharides may serve as receptor analogues for pathogenic bacteria, e.g., enterotoxigenic Escherichia coli (ETEC). These receptor analogues block lectin domains of bacterial adhesins and thus prevent adherence of pathogens to the gut wall, thereby avoiding initiation of post-weaning diarrhea. In conclusion, dietary carbohydrates are important energy sources but may also provide important solutions to maintain gut health in pigs.

Four weeks treatment with the GLP-1 receptor analogue liraglutide lowers liver fat and concomitantly circulating glucagon in individuals with overweight.

We investigated the effect of pharmacologically induced weight loss on markers of glucagon resistance in individuals with overweight during treatment with the glucagon-like peptide-1 receptor agonist liraglutide. We performed an open-label study in 14 men with overweight (age 38 ± 11 years, BMI 32 ± 4 kg/m2) without simultaneously diabetes. Subjects were treated with liraglutide, initiated and titrated with 0.6 mg/day/week to reach the final dose of 3.0 mg/day. Subjects were examined at baseline, during titration (Week 4), after 2 weeks of steady state (Week 6) of final dosing of liraglutide and 3 weeks after discontinuation of liraglutide (follow-up). Study participants lost 3.3 ± 1.9 kg (3%) total body weight during the first 4 weeks of treatment with liraglutide. Simultaneously, liver fat content decreased from 12.4 ± 11.6% to 10.2 ± 11.1%, p = 0.025, whereas fat content in the spleen and subcutaneous tissue was unaltered. Markers of glucagon resistance, including plasma glucagon and the glucagon-alanine-index, also decreased significantly during treatment, but total and individual plasma amino acid concentrations did not. Insulin resistance (HOMA-IR) was unchanged during treatment, whereas insulin clearance increased. Treatment with the GLP-1 receptor analogue liraglutide decreased liver fat content, and simultaneously attenuated glucagon concentrations and the glucagon-alanine index in individuals with overweight without diabetes.

An insight into differential protein abundance throughout Leishmania donovani promastigote growth and differentiation

Leishmania donovani causes anthroponotic visceral leishmaniasis, responsible for about 50,000 annual deaths worldwide. Current therapies have considerable side effects. Drug resistance has been reported and no vaccine is available nowadays. The development of undifferentiated promastigotes in the sand fly vector’s gut leads to the promastigote form that is highly infective to the mammalian host. Fully differentiated promastigotes play a crucial role in the initial stages of mammalian host infection before internalization in the host phagocytic cell. Therefore, the study of protein levels in the promastigote stage is relevant for disease control, and proteomics analysis is an ideal source of vaccine candidate discovery. This study aims to get insight into the protein levels during the differentiation process of promastigotes by 2DE-MALDI-TOF/TOF. This partial proteome analysis has led to the identification of 75 proteins increased in at least one of the L. donovani promastigote differentiation and growth phases. This study has revealed the differential abundance of said proteins during growth and differentiation. According to previous studies, some are directly involved in parasite survival or are immunostimulatory. The parasite survival–related proteins are ascorbate peroxidase; cystathionine β synthase; an elongation factor 1β paralog; elongation factor 2; endoribonuclease L-PSP; an iron superoxide dismutase paralog; GDP-mannose pyrophosphorylase; several heat shock proteins—HSP70, HSP83-17, mHSP70-rel, HSP110; methylthioadenosine phosphorylase; two thiol-dependent reductase 1 paralogs; transitional endoplasmic reticulum ATPase; and the AhpC thioredoxin paralog. The confirmed immunostimulatory proteins are the heat shock proteins, enolase, and protein kinase C receptor analog. The potential immunostimulatory molecules according to findings in patogenic bacteria are fructose-1,6-diphophate aldolase, dihydrolipoamide acetyltransferase, isocitrate dehydrogenase, pyruvate dehydrogenase E1α and E1β subunits, and triosephosphate isomerase. These proteins may become disease control candidates through future intra-vector control methods or vaccines.

A briefly overview of the research progress for the abscisic acid analogues.

Abscisic acid (ABA) is an important plant endogenous hormone that participates in the regulation of various physiological processes in plants, including the occurrence and development of somatic embryos, seeddevelopment and dormancy. ABA is called “plant stress resistance factor”, while with the limitation of the rapid metabolic inactivation and photoisomerization inactivation of ABA for its large-scale use. Understanding the function and role of ABA in plants is of great significance to promote its application. For decades, scientists have conducted in-depth research on its mechanism of action and signaling pathways, a series of progress were achieved, and hundreds of ABA analogues (similar in structure or function) have been synthesized to develop highly active plant growth regulators and tools to elucidate ABA perception. In this review, we summarize a variety of ABA analogues, especially the ABA receptor analogues, and explore the mechanisms of ABA action and catabolism, which will facilitate the development of novel ABA analogues with high biological activities.

JET LAG SYNDROME: CURRENT INSIGHT AND REVIEW OF THE SCIENTIFIC LITERATURE

The jet lag syndrome is a phenomenon of modern social life that occurs due to a mismatch between the body's natural circadian rhythm and the external environment due to rapid travel across multiple time zones. Jet lag syndrome symptoms are primarily related to sleep disturbance, interfering with travellers' social life and vocational performance. The symptoms usually last for a few days but can be for a week depending upon the changes in time zones. During the jet lag, abrupt shifts in the environmental light-dark cycle temporarily desynchronize the suprachiasmatic nucleus (SCN) of the hypothalamus downstream oscillatory networks from each other, resulting in increased sleepiness and impaired daytime functioning. Eastward travel is associated with a longer duration of jet lag than westward travel. Polysomnographic data show that jet lag results in changes in sleep-wake timing and different aspects of sleep architecture. This circadian misalignment can lead to a cluster of symptoms, including signicant metabolic, cardiovascular, psychiatric, and neurological impairments.[1] Light is the major entrainment factor for the circadian clock, and timed bright light exposure at the appropriate portion of the light-dark cycle is the principal non-pharmacological approach. Nutraceuticals and pharmacological therapies include melatonin, melatonin receptor analogues (agonists), non-benzodiazepine hypnotic agents, caffeine, diphenhydramine (e.g., Benadryl, McNeil; Aler-Dryl, Reese), and armodanil. The awareness about the jet lag syndrome, planned sleep schedule before departure and phase resetting by exposure to light or medication can help travellers overcome this condition. New research suggests that modication of clock function via genetic manipulation may one day have clinical applications.[2] The current perspective of the COVID-19 pandemic resulted in many countries imposing a lockdown, reducing sunlight exposure and altering daily social schedules. Therefore, it essentially leads to changing 'time zones' without actually travelling across time zones, causing social jet lag.[3]

Real-life effects of adding weekly subcutaneous semaglutide to insulin for the treatment of type 2 diabetes mellitus

ObjectivesThis work aims to determine the real-life anthropometric and analytical benefits of adding subcutaneous semaglutide to previous insulin treatment in patients with type 2 diabetes. MethodsThis is a descriptive, retrospective, open-label study describing the clinical and anthropometric characteristics of 117 patients diagnosed with type 2 diabetes followed-up on in the Endocrinology and Nutrition outpatient clinic of the Hospital Universitario Central de Asturias for 53 weeks after starting treatment with subcutaneous semaglutide (October–December 2019). All patients were on previous insulin treatment with or without oral antidiabetics. ResultsOf the 117 initial patients, 17 did not complete the study due to adverse effects (nausea, vomiting), the physician’s decision, or loss to follow-up. Twelve months (week 53) after starting semaglutide, there was a decrease in HbA1c of 0.74% (95% CI 0.59–1.14, p < 0.05) as well as 3.61 kg of weight loss (95% CI 2.30–4.92, p < 0.05) and a decline in total insulin of 15.88 IU (95% CI 10.98–20.74, p < 0.05) from baseline figures. In patients without prior GLP-1 receptor analogs (GLP-1ra), the effect in terms of a reduction in HbA1c, weight, and the total insulin dose was statistically significant. However, in patients pre-treated with GLP-1ra only had improvements in terms of weight loss. No serious adverse events were observed. ConclusionsThe addition of subcutaneous semaglutide to prior insulin treatment with or without oral antidiabetics safely led to a decrease in HbA1c, weight, and the insulin dose. This effect is greater in GLP-1ra naive patients.

Efectos en vida real de la adición de semaglutida subcutánea semanal al tratamiento con insulina en diabetes mellitus tipo 2

ObjectivesThis work aims to determine the real-life anthropometric and analytical benefits of adding subcutaneous semaglutide to previous insulin treatment in patients with type 2 diabetes. MethodsThis is a descriptive, retrospective, open-label study describing the clinical and anthropometric characteristics of 117 patients diagnosed with type 2 diabetes followed-up on in the Endocrinology and Nutrition outpatient clinic of the Hospital Universitario Central de Asturias for 53 weeks after starting treatment with subcutaneous semaglutide (October-December 2019). All patients were on previous insulin treatment with or without oral antidiabetics. ResultsOf the 117 initial patients, 17 did not complete the study due to adverse effects (nausea, vomiting), the physician's decision, or loss to follow-up.Twelve months (week 53) after starting semaglutide, there was a decrease in HbA1c of 0.74% (95% CI 0.59-1.14, p<0.05) as well as 3.61kg of weight loss (95% CI 2.30-4.92, p<0.05) and a decline in total insulin of 15.88 IU (95% CI 10.98-20.74, p<0.05) from baseline figures. In patients without prior GLP-1 receptor analogs (GLP-1ra), the effect in terms of a reduction in HbA1c, weight, and the total insulin dose was statistically significant. However, in patients pre-treated with GLP-1ra only had improvements in terms of weight loss. No serious adverse events were observed. ConclusionsThe addition of subcutaneous semaglutide to prior insulin treatment with or without oral antidiabetics safely led to a decrease in HbA1c, weight, and the insulin dose. This effect is greater in GLP-1ra naive patients.

Liraglutide treatment attenuates dysfunction-related changes in the cardiac and cerebral microvasculature in streptozotocin-induced diabetic rats

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Background Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon-like peptide-1 receptor analogue, inhibited the reactive oxygen species producing enzyme NOX2 and adhesion molecules in isolated endothelial cells. Here we have studied how Liraglutide affects advanced glycation, NOX expression and inflammatory status of the cardiac and cerebral microvasculature in vivo in diabetic rats. Methods DM was induced in Sprague Dawley rats (n=15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg body weight). 10 control rats remained non-diabetic. From day 9 post-STZ injection, Liraglutide (200 µg/kg bodyweight; n=7) or vehicle (n=8) was injected subcutaneously daily until termination on day 29. The advanced glycation end-product N-ε-(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM-1 and VCAM-1 were subsequently analysed using immunohistochemistry and quantified to compare Liraglutide treatment to placebo. Results DM increased CML, NOX2, ICAM-1 and VCAM-1 in the intramyocardial vasculature, although not significant for NOX2. NOX4 was not significantly increased in the ventricles and absent in the atria. In the cerebral vasculature, CML, NOX2 and NOX4 were significantly increased, but not ICAM-1 and VCAM-1. Liraglutide significantly reduced the DM-associated CML accumulation and expression of NOX2, ICAM-1 and VCAM-1 in the intramyocardial, and CML, NOX2 and NOX4 in the cerebral vasculature. Liraglutide had these effects without changing blood glucose levels or body weight. Conclusions Our study implies that Liraglutide protects the cardiac and cerebral microvasculature against diabetes-induced dysfunction, independent of a blood glucose lowering effect in a type 1 diabetes rat model.

Bioinformatics analysis of adhesin-binding potential and ADME/Tox profile of anti-Helicobacter pylori peptides derived from wheat germ proteins

Anti-adhesive activity of wheat germ-derived peptides, which is considered as one of the promising strategies for preventing Helicobacter pylori infection, was investigated. The underlying mechanism of anti-adhesive action was due to peptides acting as receptor analogues and binding to H. pylori adhesin proteins. However, there is lack of information on the nature and strength of this molecular interaction as well as the participating species and drug-likeness of the food-derived bioactive peptides. In this study, the biostability and ADME/Tox (absorption, distribution, metabolism, excretion and toxicity) profile of the anti-adhesive peptides were analyzed using bioinformatic tools, and their binding potential to H. pylori's adhesins estimated by molecular docking. Binding is facilitated by mostly hydrogen bonding and hydrophobic interaction occurring in the active site of the adhesin proteins with affinities ranging from -6.0 to -7.4 and -6.0 to -7.8 kcal/mol for BabA and SabA, respectively. The results indicate highly possible binding capabilities of the peptides to adhesin proteins. Out of 16 peptides studied, 14 bound in the vicinity of the active site of BabA and SabA whereas two different peptides demonstrated allosteric binding. The most hydrophobic peptide, P210 showed strong binding affinity for both BabA and SabA and, therefore, predicted to be the most promising peptide for further development in the prevention, management and treatment of H. pylori infection. The selected peptides were shown to be non-toxic, and to have high potential of localized effect of interfering with bacterial adherence. This work provides insights into the anti-adhesive mechanism of peptides and new evidence demonstrating bioactive peptides as promising nutraceutical candidates for preventing H. pylori infection.

Haemagglutinin substitutions N125D, D127E, D222G and R223Q improve replicative fitness and vaccine effectiveness of an A/H1N1pdm09 live attenuated influenza vaccine virus by enhancing α-2,6 receptor binding.

During 2013–14 and 2015–16, A/H1N1pdm09 live attenuated influenza vaccine (LAIV) viruses replicated inefficiently in primary human nasal epithelial cells (hNEC). This led to reduced vaccine effectiveness (VE) in quadrivalent formulations, mediated by inter-strain competition. By mutating the haemagglutinin (HA) protein, we aimed to enhance hNEC replication of a novel A/H1N1pdm09 vaccine strain to overcome competition and improve VE. Combinations of N125D, D127E, D222G and R223Q substitutions were introduced to the HA protein of A/Slovenia/2903/2015 (A/SLOV15). A/SLOV15 S13, containing all four HA substitutions, produced approximately 1000-fold more virus than parental V1 during hNEC infection. Immunogenicity in ferrets was increased by approximately 10-fold, without compromising yield in eggs or antigenic match to wild-type (wt) reference strains. Despite S13 and V1 being antigenically similar, only S13 protected ferrets from wt virus shedding and fever post-challenge. Crucially, these data suggested that enhanced fitness allowed S13 to overcome inter-strain competition in quadrivalent LAIV (QLAIV). This improved efficacy was later validated by real-world VE data. S13 displayed increased binding avidity to a mammalian-like α-2,6 receptor analogue (6-SLN), relative to V1, while maintaining avian-like 3-SLN avidity. In silico modelling of the HA receptor binding site revealed additional interactions in the S13:6-SLN binding network and a mild increase in 6-SLN binding energy, indicating a possible mechanism for increased α-2,6 receptor-binding avidity. These data confirm that rational HA mutagenesis can be used to optimise hNEC replication and VE for A/H1N1pdm09 LAIV viruses.

68Ga-DOTATOC Embolus Manifestation and Spontaneous Resolution by PET/CT.

68Ga-labeled somatostatin receptor analogs physiologic distribution patterns have become recognizable among nuclear medicine physicians because of the increasing routine clinical use of this modality in the work-up of neuroendocrine tumors. Some pitfalls during 68Ga-labeled somatostatin receptor PET/CT have recently been reported as causes of misdiagnoses. Iatrogenic microembolism as a cause of 18F-FDG embolus is well-established; however, 68Ga-DOTATOC embolus is not well documented in the literature. In the current case, the presence and the spontaneous resolution of the 68Ga-labeled somatostatin receptoranalogs embolus during sequential PET/CT are nicely demonstrated. Awareness of this incidental finding would avoid misdiagnosis and unnecessary investigations.

Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment.

In recent years, important changes have occurred in the field of diabetes treatment. The focus of the treatment of diabetic patients has shifted from the control of blood glucose itself to the overall management of risk factors, while adjusting blood glucose goals according to individualization. In addition, regulators need to approve new antidiabetic drugs which have been tested for cardiovascular safety. Thus, the newest class of drugs has been shown to reduce major adverse cardiovascular events, including sodium-glucose transporter 2 (SGLT2) and some glucagon like peptide 1 receptor (GLP1) analog. As such, they have a prominent place in the hyperglycemia treatment algorithms. In recent years, the role of DPP4 inhibitors (DPP4i) has been modified. DPP4i have a favorable safety profile and anti-inflammatory profile, do not cause hypoglycemia or weight gain, and do not require dose escalation. In addition, it can also be applied to some types of chronic kidney disease patients and elderly patients with diabetes. Overall, DPP4i, as a class of safe oral hypoglycemic agents, have a role in the management of diabetic patients, and there is extensive experience in their use.

Anti-obesity Medications for the Management of Nonalcoholic Fatty Liver Disease.

Obesity is closely associated with nonalcoholic fatty liver disease (NAFLD), a highly prevalent disease without any approved medication. The aim of this review was to summarize the evidence on the effect of anti-obesity medications on NAFLD, especially focusing on hepatic histology. Orlistat and some glucagon-like peptide-1 receptor analogs, including liraglutide and semaglutide, have beneficial effects on hepatic steatosis and inflammation, but not fibrosis. Other anti-obesity medications, including lorcaserin, setmelanotide, phentermine hydrochloric, phentermine/topiramate, and naltrexone/bupropion, have been minimally investigated in NAFLD. Furthermore, medications like sodium-glucose cotransporter-2 inhibitors and farnesoid X receptor have shown beneficial effects in both NAFLD and obesity, but they have not been licensed for either disease. Liraglutide, semaglutide, and orlistat may be currently used in selected patients with obesity and NAFLD. Further research is warranted, since targeting obesity may provide additional benefits on its comorbidities, including NAFLD.

29 Nutritional Interventions for Intestinal Health of Nursery Pigs: Carbohydrates

Abstract In swine production, using feed antibiotics as antimicrobial growth promotants has been reduced; thus, feed alternatives to manage gut health are required to prevent post-weaning diarrhea. Dietary fiber, resistant starch, oligosaccharides, and exopolysaccharides are carbohydrates that together with glycoproteins are nutritional tools that may be part of managing gut health in pigs. Antibiotics are hypothesized to influence gut health via modulation of intestinal microbial profiles; fermentation and intestinal inflammation are considered important mechanisms. Dietary fiber is an alternative, but its sources differ in at least 2 key properties: fermentability and viscosity. Rapid fermentation of fiber and oligosaccharides is associated with changes in microbial profiles and increased metabolite production. Recently, microbial composition was hypothesized to be less important and combined output of metabolites should be the focus. Increased viscosity has been associated with increased gut content of virulence factors that are linked with diarrhea. Fiber properties may also manipulate retention time and physico-chemical properties of the undigested residue. Starch is mostly digested and absorbed as glucose. However, resistant starch is not digested and acts as fermentable fiber but has unique properties, because it specifically increases intestinal abundance of bifidobacteria that are associated with improved gut health. Feed ingredients and some feed additives influence kinetics of fermentation and have prebiotic activity. Their kinetics of fermentation should be quantified so that it can be considered in feed formulation. Finally, exopolysaccharides from Limosilactobacillus reuteri and unique oligosaccharides and glycoprotein may serve as receptor analogues for pathogenic bacteria, e.g., enterotoxigenic Escherichia coli (ETEC). These receptor analogues block lectin domains of bacterial adhesins and thus prevent adherence of pathogens to the gut wall, thereby avoiding initiation of post-weaning diarrhea. In conclusion, dietary fiber and other carbohydrates may be important solutions to maintain gut health when antibiotics are removed as growth promotants from swine feeds.

Variation in Glycemic Outcomes in Focal Forms of Congenital Hyperinsulinism-The UK Perspective.

ContextIn focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic β-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery.ObjectiveWe describe surgical and nonsurgical outcomes of focal CHI in a national cohort.MethodsPatients with focal CHI were retrospectively reviewed at 2 specialist centers, 2003-2018.ResultsOf 59 patients with focal CHI, 57 had heterozygous mutations in ABCC8/KCNJ11 (51 paternally inherited, 6 de novo). Fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography computed tomography scan identified focal lesions in 51 patients. In 5 patients, imaging was inconclusive; the diagnosis was established by frozen section histopathology in 3 patients, a lesion was not identified in 1 patient, and 1 declined surgery. Most patients (n = 56) were unresponsive to diazoxide, of whom 33 were unresponsive or partially responsive to somatostatin receptor analog (SSRA) therapy. Fifty-five patients underwent surgery: 40 had immediate resolution of CHI, 10 had persistent hypoglycemia and a focus was not identified on biopsy in 5. In the 10 patients with persistent hypoglycemia, 7 underwent further surgery with resolution in 4 and ongoing hypoglycemia requiring SSRA in 3. Nine (15% of cohort) patients (1 complex surgical access; 4 biopsy negative; 4 declined surgery) were managed conservatively; medication was discontinued in 8 children at a median (range) age 2.4 (1.5-7.7) years and 1 remains on SSRA at 16 years with improved fasting tolerance and reduction in SSRA dose.ConclusionDespite a unifying genetic basis of disease, we report inherent heterogeneity in focal CHI patients impacting outcomes of both surgical and medical management.

The cardiovascular benefits of GLP1-RAs are related to their positive effect on glycemic control: A meta-regression analysis

Backgrounds and AimsGlucagon-like-peptides 1 receptor analogues (GLP1-RAs) have gained primacy in the management of type 2 diabetes (T2D).However, in contrast to the CVOT conducted with sodium glucose cotransporter-2 inhibitors (SGLT-2i)there was a significant reduction in glycated haemoglobin (HbA1c) in some of the CVOT with GLP1-RA. The aim of this analysis is to explore the possible association between cardiovascular outcome benefits with GLP1-RA and HbA1c reduction. MethodsA Cochrane library based web search yielded 9 eligible citations for this analysis. The analysis was performed using the comprehensive meta-analysis (CMA) software.A meta-regression analysis was performed using HbA1c, weight, and systolic blood pressure reduction as moderators. ResultThe meta-regression analysis was conducted on a pooled population of 64,236 patients. There was a significant heterogeneity associated with the MACE benefits (Q = 16.88, I2: 52.59, df = 7, p = 0.03). Among the moderators selected to explain the variance in true effects, HbA1c reduction was significant (Q = 7.00, P=<0.001, R2:1.0). Additional meta-regression analysis using 0.9% reduction of HbA1c from baseline indicated an association with MACE benefit (95% CI −0.23 to −0.02, P = 0.01, R2: 0.98). ConclusionThe MACE benefits associated with GLP1-RAs are dependent on the reduction of HbA1c levels.

Evaluation of Liver and Renal Toxicity in Peptide Receptor Radionuclide Therapy for Somatostatin Receptor Expressing Tumors: A 2-Year Follow-Up.

BackgroundPeptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin receptor (SSR) analogs is now an established systemic treatment for neuroendocrine tumors (NET). However, more short- and long-term data about renal and hepatotoxicity is needed. Here we present our experience in this clinical scenario.MethodsEighty-six patients with progressive SSR-expressing malignancies underwent PRRT with Lu-177 Dotatate and were followed up for up to 2 years. Laboratory tests were done 1 week before each cycle and every 2 months at follow-up. Hepatic and renal toxicity was determined based on NCI CTCAE V5.0.Results55/86 (64%) patients completed all 4 cycles of PRRT; 18/86 (20.9%) are currently being treated; 13/86 (15.1%) had to discontinue PRRT: 4/13 (31%) due to hematologic toxicity, 9/13 (69%) due to non-PRRT-related comorbidities. Out of the patients who finished treatment, only transient grade 2 toxicities were observed during PRRT: hypoalbuminemia in 5.5% (3/55), and renal toxicity (serum creatinine and estimated glomerular filtration rate) in 1.8% (1/55). No grade 3 or 4 liver and renal toxicity occurred. Patients presenting with impaired liver or renal function prior to PRRT, either improved or had stable findings. No deterioration was observed.ConclusionPeptide receptor radionuclide therapy does not have a negative impact on liver and renal function, even in patients with pre-existing impaired parameters. No grade 3 or 4 hepatic or renal toxicity was identified. Only transient grade 2 hypoalbuminemia in 5.5% and nephrotoxicity in 1.8% of patients were seen during PRRT.

Exotoxin-Targeted Drug Modalities as Antibiotic Alternatives.

The paradigm of antivirulence therapy dictates that bacterial pathogens are specifically disarmed but not killed by neutralizing their virulence factors. Clearance of the invading pathogen by the immune system is promoted. As compared to antibiotics, the pathogen-selective antivirulence drugs hold promise to minimize collateral damage to the beneficial microbiome. Also, selective pressure for resistance is expected to be lower because bacterial viability is not directly affected. Antivirulence drugs are being developed for stand-alone prophylactic and therapeutic treatments but also for combinatorial use with antibiotics. This Review focuses on drug modalities that target bacterial exotoxins after the secretion or release-upon-lysis. Exotoxins have a significant and sometimes the primary role as the disease-causing virulence factor, and thereby they are attractive targets for drug development. We describe the key pre-clinical and clinical trial data that have led to the approval of currently used exotoxin-targeted drugs, namely the monoclonal antibodies bezlotoxumab (toxin B/TcdB, Clostridioides difficile), raxibacumab (anthrax toxin, Bacillus anthracis), and obiltoxaximab (anthrax toxin, Bacillus anthracis), but also to challenges with some of the promising leads. We also highlight the recent developments in pre-clinical research sector to develop exotoxin-targeted drug modalities, i.e., monoclonal antibodies, antibody fragments, antibody mimetics, receptor analogs, neutralizing scaffolds, dominant-negative mutants, and small molecules. We describe how these exotoxin-targeted drug modalities work with high-resolution structural knowledge and highlight their advantages and disadvantages as antibiotic alternatives.

Long-acting amylin analogues for the management of obesity.

To summarize recent developments of long-acting amylin analogues for the treatment of obesity and to outline their mode of action. Amylin is a pancreatic hormone acting to control energy homeostasis and body weight. Activity at the calcitonin and amylin receptors in the area postrema seems to - at least partly - be responsible for these effects of amylin. Both preclinical and early-stage clinical studies investigating long-acting amylin receptor analogues demonstrate beneficial effects on body weight in obesity. Cagrilintide, a novel amylin analogue suitable for once-weekly administration, is in phase II clinical development and has shown promising body weight reducing effects alone and in combination with the glucagon-like peptide 1 receptor agonist semaglutide. Long-acting amylin analogues have emerged as a possible pharmacotherapy against obesity, but more studies are needed to support the utility and long-term effects of this strategy in relevant populations.

Detection of Bone Metastases by 68Ga-DOTA-SSAs and 18F-FDG PET/CT: A Two-Center Head-to-Head Study of Gastroenteropancreatic Neuroendocrine Neoplasms.

This study aimed to assess the efficacy of dual-tracer [68Ga-DOTA-somatostatin receptor analogs (SSAs) and 18F-fluorodeoxyglucose (FDG)] positron emission tomography/computed tomography (PET/CT) imaging for detecting bone metastases (BMs) in patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). We retrospectively enrolled 74 GEP-NEN patients with BMs from two centers, who underwent dual-tracer PET/CT from January 2014 to March 2021. We compared and analyzed effectiveness of the dual PET/CT imaging techniques on the BMs, based on 18F-FDG and 68Ga-DOTA-SSAs. Specifically, we analyzed the imaging results using χ 2 tests for classification variables, paired-sample tests for number of BMs, Wilcoxon's signed rank test for number of lesions, and the Kruskal-Wallis test for standard uptake value (SUV) ratio comparison. The correlation of dual-tracer SUVmax with Ki-67 index was analyzed by Spearman's correlation coefficient. The detection efficiencies of dual-tracer PET/CT imaging in patients with different pathologies showed discordant for detecting liver metastases and BMs in group neuroendocrine tumor (NET) G3, 68Ga-DOTA-SSAs was better at detecting BMs for NET G3 (P=0.049 for SUVT/B and P=0.026 for the number of metastatic lesions). In addition, statistical significance was found among osteogenesis group, osteolysis group, and the no-change group (for bone SUVT/B value detected by 18F-FDG and Ki-67 index, osteogenesis group < osteolysis group; for bone SUVT/B detected by 68Ga-DOTA-SSAs, osteogenesis group > the no-change group). What is more, liver and bone SUVmax and Ki-67 index were positively correlated in 18F-FDG imaging (P < 0.001 for liver; P=0.002 for bone), and negatively correlated in 68Ga-DOTA-SSAs imaging (P < 0.001 for liver; P=0.039 for bone). 68Ga-DOTA-SSAs was superior to 18F-FDG for detecting BMs in NET G1/G2 (well and moderately differentiated NETs), as well as in NET G3 (poorly differentiated NETs). Relatively good differentiation was observed in the osteogenesis group. In addition, dual-tracer PET/CT imaging results were observably correlated with tumor differentiation.