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Molecular Pharmaceutics Jun 2024Very late antigen-4 (VLA-4) is a transmembrane integrin protein that is highly expressed in aggressive forms of metastatic melanoma. A small-molecule peptidomimetic,...
Very late antigen-4 (VLA-4) is a transmembrane integrin protein that is highly expressed in aggressive forms of metastatic melanoma. A small-molecule peptidomimetic, LLP2A, was found to have a low pM affinity binding to VLA-4. Because LLP2A itself does not inhibit cancer cell proliferation and survival, it is an ideal candidate for the imaging and delivery of therapeutic payloads. An analog of [Lu]Lu-labeled-LLP2A was previously investigated as a therapeutic agent in melanoma tumor-bearing mice, resulting in only a modest improvement in tumor growth inhibition, likely due to rapid clearance of the agent from the tumor. To improve the pharmacokinetic profile, DOTAGA-PEG-LLP2A with a 4-(-iodophenyl)butyric acid (pIBA) albumin binding moiety was synthesized. We demonstrate the feasibility of this albumin binding strategy by comparing in vitro cell binding assays and in vivo biodistribution performance of [Lu]Lu-DOTAGA-PEG4-LLP2A ([Lu]Lu-) to the albumin binding [Lu]Lu-DOTAGA-pIBA-PEG-LLP2A ([Lu]Lu-). In vitro cell binding assay results for [Lu]Lu- and [Lu]Lu- showed values of 0.40 ± 0.07 and 1.75 ± 0.40 nM, with similar values of 200 ± 6 and 315 ± 15 fmol/mg, respectively. In vivo biodistribution data for both tracers exhibited specific uptake in the tumor, spleen, thymus, and bone due to endogenous expression of VLA-4. Compound [Lu]Lu- exhibited a much longer blood circulation time compared to [Lu]Lu-. The tumor uptake for [Lu]Lu- was highest at 1 h (∼15%ID/g) and that for [Lu]Lu- was highest at 4 h (∼23%ID/g). Significant clearance of [Lu]Lu- from the tumor occurs at 24 h (<5%ID/g) while[Lu]Lu- is retained for greater than 96 h (∼10%ID/g). An efficacy study showed that melanoma tumor-bearing mice receiving compound [Lu]Lu- given in two fractions (2 × 14.8 MBq, 14 days apart) had a greater median survival time than mice administered a single 29.6 MBq dose of compound [Lu]Lu-, while a single 29.6 MBq dose of [Lu]Lu- imparted hematopoietic toxicity. The in vitro and in vivo data show addition of pIBA to [Lu]Lu-DOTAGA-PEG-LLP2A slows blood clearance for a higher tumor uptake, and there is potential of [Lu]Lu- as a theranostic in fractionated administered doses.
Topics: Animals; Lutetium; Mice; Radioisotopes; Tissue Distribution; Cell Line, Tumor; Melanoma; Humans; Radiopharmaceuticals; Melanoma, Experimental; Female; Integrin alpha4beta1; Albumins; Peptides; Theranostic Nanomedicine; Mice, Inbred C57BL; Dipeptides; Phenylurea Compounds
PubMed: 38680059
DOI: 10.1021/acs.molpharmaceut.4c00095 -
Therapeutic Apheresis and Dialysis :... Apr 2024Acute hypertriglyceridemia is considered a category III indication for plasmapheresis. The use of plasma as replacement fluid (RF) has been suggested to replace the...
INTRODUCTION
Acute hypertriglyceridemia is considered a category III indication for plasmapheresis. The use of plasma as replacement fluid (RF) has been suggested to replace the consumed lipoprotein lipase. Heparin when used as an anticoagulant could possibly release lipoprotein lipase, thereby increasing triglyceride clearance.
METHODS
The impact of RF (albumin vs fresh frozen plasma (FFP) and anticoagulant (ACD-A vs. heparin) on triglycerides following plasmapheresis in 27 patients with severe hypertriglyceridemia (SHTG) was investigated. A paired study of four patients with recurrent SHTG was conducted, evaluating continuous (Optia) versus intermittent flow plasmapheresis (Haemonetics).
RESULTS
Shorter procedures positively impacted triglycerides (TG) drop post-sessions p < 0.05. In albumin sessions, patients who used heparin demonstrated significantly greater drop in TG and required less sessions than did those with citrate p < 0.05. In heparin sessions, patients who used albumin demonstrated significantly greater drop in triglycerides and required less sessions than did those with FFP p < 0.05. Three of six patients who used FFP and heparin showed a triglyceride drop of 11.7% following three sessions and a 50% drop with one albumin session. Compared with Haemonetics, Optia removed comparable volumes of plasma in less time, processing smaller blood volumes and using less citrate p < 0.05. Patients demonstrated significantly lower drop in TG and required more sessions with Haemonetics than they did with Optia p < 0.05.
CONCLUSION
Shorter procedure was the main predictor for effective TG clearance. This can be achieved by continuous apheresis technology, particularly when using albumin as RF. TG removal via Optia seems to be optimized by using heparin.
PubMed: 38676441
DOI: 10.1111/1744-9987.14134 -
International Journal of Molecular... Apr 2024Designed ankyrin repeat protein (DARPin) G3 is an engineered scaffold protein. This small (14.5 kDa) targeting protein binds with high affinity to human epidermal growth...
Designed ankyrin repeat protein (DARPin) G3 is an engineered scaffold protein. This small (14.5 kDa) targeting protein binds with high affinity to human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in several cancers. The use of the DARPin G3 for radionuclide therapy is complicated by its high renal reabsorption after clearance via the glomeruli. We tested the hypothesis that a fusion of the DARPin G3 with an albumin-binding domain (ABD) would prevent rapid renal excretion and high renal reabsorption resulting in better tumour targeting. Two fusion proteins were produced, one with the ABD at the C-terminus (G3-ABD) and another at the N-terminus (ABD-G3). Both variants were labelled with Lu. The binding properties of the novel constructs were evaluated in vitro and their biodistribution was compared in mice with implanted human HER2-expressing tumours. Fusion with the ABD increased the retention time of both constructs in blood compared with the non-ABD-fused control. The effect of fusion with the ABD depended strongly on the order of the domains in the constructs, resulting in appreciably better targeting properties of [Lu]Lu-G3-ABD. Our data suggest that the order of domains is critical for the design of targeting constructs based on scaffold proteins.
Topics: Animals; Female; Humans; Mice; Albumins; Ankyrin Repeat; Cell Line, Tumor; Lutetium; Protein Binding; Protein Domains; Radioisotopes; Radiopharmaceuticals; Receptor, ErbB-2; Recombinant Fusion Proteins; Tissue Distribution; Molecular Targeted Therapy
PubMed: 38673831
DOI: 10.3390/ijms25084246 -
Biomedicines Mar 2024Cadmium (Cd) is a metal with no nutritional value or physiological role. However, it is found in the body of most people because it is a contaminant of nearly all food... (Review)
Review
Cadmium (Cd) is a metal with no nutritional value or physiological role. However, it is found in the body of most people because it is a contaminant of nearly all food types and is readily absorbed. The body burden of Cd is determined principally by its intestinal absorption rate as there is no mechanism for its elimination. Most acquired Cd accumulates within the kidney tubular cells, where its levels increase through to the age of 50 years but decline thereafter due to its release into the urine as the injured tubular cells die. This is associated with progressive kidney disease, which is signified by a sustained decline in the estimated glomerular filtration rate (eGFR) and albuminuria. Generally, reductions in eGFR after Cd exposure are irreversible, and are likely to decline further towards kidney failure if exposure persists. There is no evidence that the elimination of current environmental exposure can reverse these effects and no theoretical reason to believe that such a reversal is possible. This review aims to provide an update on urinary and blood Cd levels that were found to be associated with GFR loss and albuminuria in the general populations. A special emphasis is placed on the mechanisms underlying albumin excretion in Cd-exposed persons, and for an accurate measure of the doses-response relationships between Cd exposure and eGFR, its excretion rate must be normalised to creatinine clearance. The difficult challenge of establishing realistic Cd exposure guidelines such that human health is protected, is discussed.
PubMed: 38672074
DOI: 10.3390/biomedicines12040718 -
Kidney360 Jun 2024
Topics: Humans; Nephrosis, Lipoid; Recurrence; Serum Albumin; Male; Female
PubMed: 38662239
DOI: 10.34067/KID.0000000000000451 -
Surgical Case Reports Apr 2024Spontaneous clearance of chronic hepatitis C virus (HCV) is rare in adults. A T-lymphocyte response is thought to be involved in HCV-RNA clearance. Splenectomy...
BACKGROUND
Spontaneous clearance of chronic hepatitis C virus (HCV) is rare in adults. A T-lymphocyte response is thought to be involved in HCV-RNA clearance. Splenectomy reportedly has a beneficial effect on T cell immune function in patients with cirrhosis. To the best of our knowledge, the present report is the first to describe spontaneous clearance of serum HCV-RNA within 1 year after splenectomy in a patient with cirrhosis.
CASE PRESENTATION
A 55-year-old man with HCV cirrhosis was transferred to our institution with advanced pancytopenia, splenomegaly, and gastric varices. He had a 1-year history of ascites, edema, and general fatigue. The patient had a Child-Pugh score of 8 and serological type 1 HCV; the HCV-RNA level was 4.7 log IU/mL. Contrast-enhanced computed tomography showed gastric varices and marked splenomegaly (estimated spleen volume of 2175 mL). Esophagogastroduodenoscopy revealed enlarged gastric varices with no red color sign, and the varices were larger than those 1 year prior. He was diagnosed with decompensated HCV-related liver cirrhosis and portal hypertension. We considered direct-acting antiviral (DAA) therapy; however, DAA therapy was not approved in Japan for patients with decompensated cirrhosis at that time. Hand-assisted laparoscopic splenectomy was performed to improve the worsening portal hypertension. Further, we planned the initiation of DAA therapy after surgery, when such therapy would become available. DAA therapy was approved 1 year after splenectomy. At that time, we measured the HCV-RNA level before the initiation of DAA therapy; unexpectedly, however, serum HCV-RNA was not detectable, and the virus continued to disappear during the following 4 years. His liver function (total bilirubin, albumin, and prothrombin time) and pancytopenia improved during the 5 years postoperatively. The serum aspartate and alanine aminotransferase levels normalized between 1 and 5 years postoperatively. Esophagogastroduodenoscopy showed no change in the gastric varices during the 5 years after surgery. The patient remained asymptomatic and continued to do well.
CONCLUSIONS
We have presented a case of spontaneous clearance of HCV-RNA after splenectomy in a patient with cirrhosis and portal hypertension. Splenectomy may be associated with disappearance of HCV-RNA based on previous reports. More cases should be accumulated and evaluated.
PubMed: 38647617
DOI: 10.1186/s40792-024-01899-6 -
American Journal of Kidney Diseases :... Apr 2024Reasons for transfer from peritoneal dialysis (PD) to hemodialysis (HD) remain incompletely understood. Among incident and prevalent patients receiving PD, we evaluated...
RATIONALE & OBJECTIVE
Reasons for transfer from peritoneal dialysis (PD) to hemodialysis (HD) remain incompletely understood. Among incident and prevalent patients receiving PD, we evaluated the association of clinical factors, including prior treatment with HD, with PD technique survival.
STUDY DESIGN
Retrospective cohort study.
SETTING & PARTICIPANTS
Adults who initiated PD at a Dialysis Clinic, Inc (DCI) outpatient facility between January 1, 2010, and September 30, 2019.
EXPOSURE
The primary exposure of interest was timing of PD start, categorized as PD-first, PD-early, or PD-late. Other covariates included demographics, clinical characteristics, and routine laboratory results.
OUTCOME
Modality switch from PD to HD sustained for more than 90 days.
ANALYTICAL APPROACH
Multivariable Fine-Gray models with competing risks and time-varying covariates, stratified at 9 months to account for lack of proportionality.
RESULTS
Among 5,224 patients who initiated PD at a DCI facility, 3,174 initiated dialysis with PD ("PD-first"), 942 transitioned from HD to PD within 90 days ("PD-early"), and 1,108 transitioned beyond 90 days ("PD-late"); 1,472 (28%) subsequently transferred from PD to HD. The PD-early and PD-late patients had a higher risk of transfer to HD as compared with PD-first patients (in the first 9 months: adjusted hazard ratio [AHR], 1.51 [95% CI, 1.17-1.96] and 2.41 [95% CI, 1.94-3.00], respectively; and after 9 months: AHR, 1.16 [95% CI, 0.99-1.35] and AHR, 1.43 [95% CI, 1.24-1.65], respectively). More peritonitis episodes, fewer home visits, lower serum albumin levels, lower residual kidney function, and lower peritoneal clearance calculated with weekly Kt/V were additional risk factors for PD-to-HD transfer.
LIMITATIONS
Missing data on dialysis adequacy and residual kidney function, confounded by short PD technique survival.
CONCLUSIONS
Initiating dialysis with PD is associated with greater PD technique survival, though many of those who initiate PD-late in their dialysis course still experience substantial time on PD. Peritonitis, lower serum albumin, and lower Kt/V are risk factors for PD-to-HD transfer that may be amenable to intervention.
PLAIN-LANGUAGE SUMMARY
Peritoneal dialysis (PD) is an important kidney replacement modality with several potential advantages compared with in-center hemodialysis (HD). However, a substantial number of patients transfer to in-center HD early on, without having experienced the quality-of-life and other benefits that come with sustained maintenance of PD. Using retrospective data from a midsize national dialysis provider, we found that initiating dialysis with PD is associated with longer maintenance of PD, compared with initiating dialysis with HD and a later switch to PD. However, many of those who initiate PD-late in their dialysis course still experience substantial time on PD. Peritonitis, lower serum albumin, and lower small protein removal are other risk factors for PD-to-HD transfer that may be amenable to intervention.
PubMed: 38640994
DOI: 10.1053/j.ajkd.2024.03.012 -
Renal Failure Dec 2024To delineate the efficacy and safety profile of hemodiafiltration with endogenous reinfusion (HFR) for uremic toxin removal in patients undergoing maintenance...
OBJECTIVE
To delineate the efficacy and safety profile of hemodiafiltration with endogenous reinfusion (HFR) for uremic toxin removal in patients undergoing maintenance hemodialysis (MHD).
METHODS
Patients who have been on MHD for a period of at least 3 months were enrolled. Each subject underwent one HFR and one hemodiafiltration (HDF) treatment. Blood samples were collected before and after a single HFR or HDF treatment to test uremic toxin levels and to calculate clearance rate. The primary efficacy endpoint was to compare uremic toxin levels of indoxyl sulfate (IS), λ-free light chains (λFLC), and β-microglobulin (β-MG) before and after HFR treatment. Secondary efficacy endpoints was to compare the levels of urea, interleukin-6 (IL-6), P-cresol, chitinase-3-like protein 1 (YKL-40), leptin (LEP), hippuric acid (HPA), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), tumor necrosis factor-α (TNF-α), fibroblast growth factor 23 (FGF23) before and after HFR treatment. The study also undertook a comparative analysis of uremic toxin clearance between a single HFR and HDF treatment. Meanwhile, the lever of serum albumin and branched-chain amino acids before and after a single HFR or HDF treatment were compared. In terms of safety, the study was meticulous in recording vital signs and the incidence of adverse events throughout its duration.
RESULTS
The study enrolled 20 patients. After a single HFR treatment, levels of IS, λFLC, β-MG, IL-6, P-cresol, YKL-40, LEP, HPA, TMAO, ADMA, TNF-α, and FGF23 significantly decreased ( < 0.001 for all). The clearance rates of λFLC, β-MG, IL-6, LEP, and TNF-α were significantly higher in HFR compared to HDF ( values: 0.036, 0.042, 0.041, 0.019, and 0.036, respectively). Compared with pre-HFR and post-HFR treatment, levels of serum albumin, valine, and isoleucine showed no significant difference ( > 0.05), while post-HDF, levels of serum albumin significantly decreased ( = 0.000).
CONCLUSION
HFR treatment effectively eliminates uremic toxins from the bloodstream of patients undergoing MHD, especially protein-bound toxins and large middle-molecule toxins. Additionally, it retains essential physiological compounds like albumin and branched-chain amino acids, underscoring its commendable safety profile.
Topics: Humans; Hemodiafiltration; Pilot Projects; Uremic Toxins; Chitinase-3-Like Protein 1; Interleukin-6; Tumor Necrosis Factor-alpha; Renal Dialysis; Amino Acids, Branched-Chain; Serum Albumin; Cresols; Methylamines
PubMed: 38632963
DOI: 10.1080/0886022X.2024.2338929 -
Renal Failure Dec 2024Renal hypoxia plays a key role in the progression of chronic kidney disease (CKD). Shen Shuai II Recipe (SSR) has shown good results in the treatment of CKD as a common...
Shen Shuai II recipe improves renal hypoxia to attenuate renal injury in 5/6 renal ablation/infarction rats and effect evaluation using blood oxygenation level-dependent functional magnetic resonance imaging.
Renal hypoxia plays a key role in the progression of chronic kidney disease (CKD). Shen Shuai II Recipe (SSR) has shown good results in the treatment of CKD as a common herbal formula. This study aimed to explore the effect of SSR on renal hypoxia and injury in CKD rats. Twenty-five Wistar rats underwent 5/6 renal ablation/infarction (A/I) surgery were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + losartan (LOS), and 5/6 (A/I) + SSR groups. Another eight normal rats were used as the Sham group. After 8-week corresponding interventions, blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) was performed to evaluate renal oxygenation in all rats, and biochemical indicators were used to measure kidney and liver function, hemoglobin, and proteinuria. The expression of fibrosis and hypoxia-related proteins was analyzed using immunoblotting examination. Renal oxygenation, evaluated by BOLD-fMRI as cortical and medullary T2* values (COT2* and MET2*), was decreased in 5/6 (A/I) rats, but increased after SSR treatment. SSR also downregulated the expression of hypoxia-inducible factor-1α (HIF-1α) in 5/6 (A/I) kidneys. With the improvement of renal hypoxia, renal function and fibrosis were improved in 5/6 (A/I) rats, accompanied by reduced proteinuria. Furthermore, the COT2* and MET2* were significantly positively correlated with the levels of creatinine clearance rate (Ccr) and hemoglobin, but negatively associated with the levels of serum creatinine (SCr), blood urea nitrogen (BUN), serum cystatin C (CysC), serum uric acid (UA), 24-h urinary protein (24-h Upr), and urinary albumin:creatinine ratio (UACR). The degree of renal oxygenation reduction is correlated with the severity of renal injury in CKD. SSR can improve renal hypoxia to attenuate renal injury in 5/6 (A/I) rats of CKD.
Topics: Rats; Animals; Creatinine; Uric Acid; Rats, Sprague-Dawley; Rats, Wistar; Kidney; Renal Insufficiency, Chronic; Ischemia; Infarction; Hypoxia; Fibrosis; Proteinuria; Magnetic Resonance Imaging; Hemoglobins
PubMed: 38622926
DOI: 10.1080/0886022X.2024.2338565 -
Frontiers in Pharmacology Apr 2024Cancer is a leading cause of death worldwide. Several targeted anticancer drugs entered clinical practice and improved survival of cancer patients with selected tumor...
Cancer is a leading cause of death worldwide. Several targeted anticancer drugs entered clinical practice and improved survival of cancer patients with selected tumor types, but therapy resistance and metastatic disease remains a challenge. A major class of targeted anticancer drugs are therapeutic antibodies, but their use is limited to extracellular targets. Hence, alternative binding scaffolds have been investigated for intracellular use and better tumor tissue penetration. Among those, monobodies are small synthetic protein binders that were engineered to bind with high affinity and selectivity to central intracellular oncoproteins and inhibit their signaling. Despite their use as basic research tools, the potential of monobodies as protein therapeutics remains to be explored. In particular, the pharmacological properties of monobodies, including plasma stability, toxicity and pharmacokinetics have not been investigated. Here, we show that monobodies have high plasma stability, are well-tolerated in mice, but have a short half-life due to rapid renal clearance. Therefore, we engineered monobody fusions with an albumin-binding domain (ABD), which showed enhanced pharmacological properties without affecting their target binding: We found that ABD-monobody fusions display increased stability in mouse plasma. Most importantly, ABD-monobodies have a dramatically prolonged half-life and are not rapidly excreted by renal clearance, remaining in the blood significantly longer, while not accumulating in specific internal organs. Our results demonstrate the promise and versatility of monobodies to be developed into future therapeutics for cancer treatment. We anticipate that monobodies may be able to extend the spectrum of intracellular targets, resulting in a significant benefit to patient outcome.
PubMed: 38617793
DOI: 10.3389/fphar.2024.1393112