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Transplantation and Cellular Therapy Nov 2023Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative strategy for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The prediction of...
Myeloablative Dose of Busulfan and Fludarabine Combined with In Vivo T Cell Depletion Is Safe and Effective Conditioning for Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative strategy for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The prediction of transplantation-related mortality (TRM) using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and an arbitrary upper age limit of 55 years for administering myeloablative conditioning (MAC) are common strategies to ensure a safe procedure. The use of reduced-toxicity conditioning regimens is an additional approach to providing safe and effective myeloablation. Herein we report the outcome of AML and MDS patients conditioned with fludarabine and a myeloablative dose of busulfan (FB4) stratified by age and HCT-CI score. The primary objective was overall survival (OS) for patients age ≥55 years. Secondary objectives were total OS, TRM, graft-versus-host disease (GVHD), and GVHD, relapse-free survival (GRFS). The 2 year OS was 72% in patients age <55 and 51% in patients age ≥55. In patients age ≥55 with an HCT-CI <2, the estimated 2 year OS was 64%, with median OS not reached. In those with HCT-CI ≥2, the 2-year OS was 43%, with a median OS of 14 months. The total cumulative incidence of relapse was 30% regardless of age or HCT-CI score. FB4 conditioning regimen offers a high rate of prolonged remission with a relapse rate similar to that reported in previous studies. These positive outcomes suggest that this conditioning platform can be offered to patients age ≥55 years in the absence of comorbidities, and that age should not be the sole determinant of conditioning intensity.
Topics: Humans; Middle Aged; Busulfan; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Graft vs Host Disease; Recurrence; T-Lymphocytes
PubMed: 37579918
DOI: 10.1016/j.jtct.2023.08.012 -
Molecular and Cellular Endocrinology Apr 2024In hyperparathyroidism (hyperPTH), excessive amounts of PTH are secreted, interfering with calcium regulation in the body. Several drugs can control the disease's side...
In hyperparathyroidism (hyperPTH), excessive amounts of PTH are secreted, interfering with calcium regulation in the body. Several drugs can control the disease's side effects, but none of them is an alternative treatment to surgery. Therefore, new drug candidates are necessary. In this study, three computationally repositioned drugs, DG 041, IMD 0354, and cucurbitacin I, are evaluated in an in vitro model of hyperPTH. First, we integrated publicly available transcriptomics datasets to propose drug candidates. Using 3D spheroids derived from a single primary hyperPTH patient, we assessed their in vitro efficacy. None of the proposed drugs affected the viability of healthy cell control (HEK293) or overactive parathyroid cells at the level of toxicity. This behavior was attributed to the non-cancerous nature of the parathyroid cells, establishing the hyperPTH disease model. Cucurbitacin I and IMD 0354 exhibited a slight inverse relationship between increased drug concentrations and cell viability, whereas DG 041 increased viability. Based on these results, further studies are needed on the mechanism of action of the repurposed drugs, including determining the effects of these drugs on cellular PTH synthesis and secretion and on the metabolic pathways that regulate PTH secretion.
Topics: Humans; Parathyroid Hormone; Calcium; Drug Repositioning; HEK293 Cells; Hyperparathyroidism, Primary; Acrylamides; Benzamides; Sulfones; Triterpenes
PubMed: 38228226
DOI: 10.1016/j.mce.2024.112159 -
Environmental Research Dec 2023Leakage of fire-fighting foam from an airfield caused contamination of the drinking water supplied to a third of the population in Ronneby, resulting in very high serum...
BACKGROUND
Leakage of fire-fighting foam from an airfield caused contamination of the drinking water supplied to a third of the population in Ronneby, resulting in very high serum levels of predominantly perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS). The results of studies investigating the association between exposure to perfluorinated alkyl substances (PFAS) and pregnancy complications are inconsistent, and studies at high exposures of PFOS and PFHxS are lacking.
OBJECTIVES
To investigate the association between exposure to high levels of PFAS and gestational hypertension and preeclampsia, and gestational diabetes mellitus.
METHODS
We retrieved data on 27 292 childbirths between 1995 and 2013 from the National Medical Birth Register for women that had a residential address in Blekinge county for at least one year before delivery. Residential history was used as a proxy for exposure by categorizing women into high-, intermediate-, or background exposed based on their residential address during the five-year period before childbirth. Data on confounders were retrieved from administrative registers. The outcomes were defined based on International Classification of Diseases codes. We used logistic regression to estimate odds ratios (OR) for gestational hypertension and preeclampsia, and gestational diabetes mellitus. We also investigated effect modification by fetal sex.
RESULTS
We found no evidence of increased risk of gestational hypertension and preeclampsia (OR 0.80; CI 0.63-1.03), nor gestational diabetes (OR 1.03; CI 0.67-1.58) after high PFAS exposure. There was no effect modification by fetal sex.
DISCUSSION
This was the first study to investigate the association between high exposure to PFOS and PFHxS and pregnancy complications. The results from this study add important knowledge to public health management as new hotspots with high levels of PFAS are continuously discovered.
Topics: Pregnancy; Female; Humans; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Diabetes, Gestational; Drinking Water; Sweden; Alkanesulfonates; Fluorocarbons
PubMed: 37805182
DOI: 10.1016/j.envres.2023.117316 -
Cancer Medicine Feb 2024It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth....
BACKGROUND
It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME-HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME-HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects.
METHODS
We developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME-HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA-MB-231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV-Neu, 4T1, and MDA-MB-231), prostate (PC3) and colon (HCA7) cancer using F-NaF for HAP and F-FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via ex vivo methods.
RESULTS
Within 24 h of adding the small concentration of 1X of NSPS (~7 μM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA-MB-231 cell cultures that contain HAP but ⟨2% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 breast tumors, located in the mammary fat pad, to increase by nearly 10% from baseline before gradually receding back to baseline during the first hour post NSPS administration. in the tumors that contained TME-HAP in mouse models, MMTV-Neu, 4T1, and MDA-MB-231, PC3, and HCA7, there was a significant reduction (p<0.05) in F-Na Fuptake post NSPS treatment as expected; F uptake in the tumor = 3.8 ± 0.5 %ID/g (percent of the injected dose per gram) at baseline compared to 1.8 ±0.5 %ID/g following one-time treatment with 100 mg/kg NSPS. Of similar importance, is that F-FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one-time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p < 0.05) in the mice treated with one-time NSPS. Toxicity showed no evidence of any adverse effects, a finding attributed to the absence of HAP in normal soft tissue and to our therapeutic NSPS having limited penetration to access HAP within skeletal bone.
CONCLUSION
Dissolution of TME-HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.
Topics: Humans; Male; Animals; Mice; Pharmaceutical Preparations; Fluorodeoxyglucose F18; Immunotherapy; Drug-Related Side Effects and Adverse Reactions; Lung Neoplasms; Alkanesulfonates; Glucose; Hydroxyapatites; Tumor Microenvironment
PubMed: 38239047
DOI: 10.1002/cam4.6812 -
Bone Marrow Transplantation Apr 2024Allogeneic hematopoietic stem cell transplantation (HSCT) currently stands as the sole remedy for individuals afflicted with hemophagocytic lymphohistiocytosis (HLH). In...
Allogeneic hematopoietic stem cell transplantation (HSCT) currently stands as the sole remedy for individuals afflicted with hemophagocytic lymphohistiocytosis (HLH). In this study, we retrospectively evaluated how pediatric patients with relapsed or refractory (R/R) HLH responded to our institution's cocktail conditioning regimen. The disease was diagnosed according to criteria applicable to patients with familial/genetic, relapsing, or severe/persistent HLH. All donors were HLA haplo-identical family donors. In our cohort, sixty-five patients (P-HLH), including 28 with familial/genetic HLH, 36 with secondary HLH, and 1 with an unknown cause, underwent haplo-identical family donor HSCT. The conditioning regimen consisted of intravenous administration of etoposide (VP-16), busulfan, fludarabine, rabbit anti-human thymocyte globulin (r-ATG), and cyclophosphamide (Cy). Tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GvHD) prevention. We observed that the median time for neutrophil recovery was 11 days (range, 8-24), and for platelet counts to exceed 20 × 10/L, it was 14 days (range, 7-130). There were 5 patients (7.7%) who experienced grades III to IV acute GvHD, and 6 patients (9.2%) developed extensive chronic GvHD. The estimated 3- and 5-year overall survival rates were 78.1% (95% CI, 65.8-84.6%) and 74.9% (95% CI, 61.2-84.4%), respectively. The estimated 3- and 5-year event-free survival rates were 73.5% (95% CI, 60.8-82.6%) and 70.3% (95% CI, 56.4-80.5%), respectively. Our findings demonstrate that our innovative conditioning regimen is both effective and safe, offering valuable insights for healthcare professionals evaluating the merits of existing therapies.
Topics: Humans; Child; Lymphohistiocytosis, Hemophagocytic; Retrospective Studies; Transplantation Conditioning; Graft vs Host Disease; Busulfan; Hematopoietic Stem Cell Transplantation; Etoposide
PubMed: 38287082
DOI: 10.1038/s41409-024-02212-7 -
Transformation process and phytotoxicity of sulfamethoxazole and N4-acetyl-sulfamethoxazole in rice.The Science of the Total Environment Mar 2024Sulfonamide antibiotics, extensively used in human and veterinary therapy, accumulate in agroecosystem soils through livestock manure and sewage irrigation. However, the...
Sulfonamide antibiotics, extensively used in human and veterinary therapy, accumulate in agroecosystem soils through livestock manure and sewage irrigation. However, the interaction between sulfonamides and rice plants remains unclear. This study investigated the transformation behavior and toxicity of sulfamethoxazole (SMX) and its main metabolite, N4-acetyl-sulfamethoxazole (NASMX) in rice. SMX and NASMX were rapidly taken up by roots and translocated acropetally. NASMX showed higher accumulating capacity, with NASMX concentrations up to 20.36 ± 1.98 μg/g (roots) and 5.62 ± 1.17 μg/g (shoots), and with SMX concentrations up to 15.97 ± 2.53 μg/g (roots) and 3.22 ± 0.789 μg/g (shoots). A total of 18 intermediate transformation products of SMX were identified by nontarget screening using Orbitrap-HRMS, revealing pathways such as deamination, hydroxylation, acetylation, formylation, and glycosylation. Notably, NASMX transformed back into SMX in rice, a novel finding. Transcriptomic analysis highlights the involvements of cytochrome P450 (CYP450), acetyltransferase (ACEs) and glycosyltransferases (GTs) in these biotransformation pathways. Moreover, exposure to SMX and NASMX disrupts TCA cycle, amino acid, linoleic acid, nucleotide metabolism, and phenylpropanoid biosynthesis pathways of rice, with NASMX exerting a stronger impact on metabolic networks. These findings elucidate the sulfonamides' metabolism, phytotoxicity mechanisms, and contribute to assessing food safety and human exposure risk amid antibiotic pollution.
Topics: Humans; Sulfamethoxazole; Oryza; Anti-Bacterial Agents; Sulfonamides; Soil; Sulfanilamide
PubMed: 38340847
DOI: 10.1016/j.scitotenv.2024.170857 -
Influenza and Other Respiratory Viruses Jul 2023Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available.
METHODS
This was a Phase 2 study of the oral RSV fusion protein inhibitor AK0529 in infants aged 1-24 months, hospitalized with RSV infection. In Part 1, patients ( = 24) were randomized 2:1 to receive a single dose of AK0529 up to 4 mg/kg or placebo. In Part 2, patients ( = 48) were randomized 2:1 to receive AK0529 at 0.5, 1, or 2 mg/kg bid or placebo for 5 days. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modelling. Safety, tolerability, viral load, and respiratory signs and symptoms were assessed daily during treatment.
RESULTS
No safety or tolerability signals were detected for AK0529: grade ≥3 treatment-emergent adverse events occurring in 4.1% of patients in AK0529 and 4.2% in placebo groups, respectively, and none led to death or withdrawal from the study. In Part 2, targeted drug exposure was reached with 2 mg/kg bid. A numerically greater reduction in median viral load with 2 mg/kg bid AK0529 than with placebo at 96 h was observed. A -4.0 (95% CI: -4.51, -2.03) median reduction in Wang Respiratory Score from baseline to 96 h was observed in the 2 mg/kg group compared with -2.0 (95% CI: -3.42, -1.82) in the placebo group.
CONCLUSIONS
AK0529 was well tolerated in hospitalized RSV-infected infant patients. Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and Wang Respiratory Score.
CLINICAL TRIALS REGISTRATION
NCT02654171.
Topics: Child; Infant; Humans; Child, Preschool; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Sulfones; Quinazolines
PubMed: 37502622
DOI: 10.1111/irv.13176 -
Molecular Diversity Aug 2023To discover alternative substances to compounds used to treat many diseases, especially treating Alzheimer's disease (AD) and Parkinson's disease targeting carbonic...
To discover alternative substances to compounds used to treat many diseases, especially treating Alzheimer's disease (AD) and Parkinson's disease targeting carbonic anhydrase (hCA) and acetylcholinesterase (AChE) enzymes, is important. For this purpose, a series of novel bis-ureido-substituted sulfaguanidine (SG1-4) and sulfisoxazole (SO1-4) derivatives were synthesized, and their inhibitory capacities were screened against hCA isoenzymes (hCA I and II) and AChE. Possible binding mechanisms of inhibitors to the active site were elucidated by in silico studies, and the results were supported by in vitro results. Moreover, the percent radical scavenging capacities of the derivatives were also evaluated. The derivatives (SG1-4 and SO1-4) were more effective against hCAs compared to standard drug acetazolamide (K values of 98.28-439.17 nM for hCA I and II, respectively) and exhibited the highest inhibition with the Ks in the ranges of 2.54 ± 0.50-41.02 ± 7.52 nM for hCA I, 11.20 ± 2.97-67.14 ± 13.58 nM for hCA II, and 257.60 ± 27.84-442.60 ± 52.13 nM for AChE. Also, compounds SG1 and SO1 also showed ABTS radical scavenging activity at the rate of 70% and 78%, respectively. These results will contribute to the literature for the rational design and synthesis of new potent and selective inhibitors targeting hCAs and AChE with multifunctional effects such as radical scavenging as well as inhibition. This study focused on the synthesis and inhibitory effects of bis-ureido-substituted sulfaguanidine (SG1-4) and sulfisoxazole (SO1-4) derivatives against human hCA I and II isoforms and AChE. In order to test synthesized derivatives' free radical scavenging potentials were the DPPH and ABTS assays. In silico studies elucidated possible binding mechanisms of inhibitors to the active site.
Topics: Humans; Carbonic Anhydrases; Cholinesterase Inhibitors; Acetylcholinesterase; Sulfisoxazole; Sulfaguanidine; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Structure-Activity Relationship; Molecular Structure
PubMed: 36136229
DOI: 10.1007/s11030-022-10527-0 -
Journal of Pharmaceutical and... Oct 2023Furosemide (FUR) has been used in probe drugs cocktails for in vivo evaluation of the renal transporters OAT1 and OAT3 activities in studies of drug-drug interactions...
Determination of furosemide and its glucuronide metabolite in plasma, plasma ultrafiltrate and urine by HPLC-MS/MS with application to secretion and metabolite formation clearances in non-pregnant and pregnant women.
Furosemide (FUR) has been used in probe drugs cocktails for in vivo evaluation of the renal transporters OAT1 and OAT3 activities in studies of drug-drug interactions (generally using probenecid as an inhibitor) and drug-disease interactions. The objective of this study was to develop and validate methods for FUR and its glucuronide metabolite (FUR-GLU) analysis in plasma, plasma ultrafiltrate and urine for application in pharmacokinetics studies: a pilot drug-drug interaction study in pregnant women (n = 2), who received a single oral dose of FUR (40 mg) and in another occasion a single oral dose of probenecid (750 mg) before a single oral dose of FUR (40 mg), and in non-pregnant women participants (n = 12), who only received a single oral dose of FUR (40 mg). The samples preparation for FUR in 50 µL of plasma and plasma lysate were carried by acidified liquid-liquid extraction, while 50 µL of urine and 200 µL of plasma ultrafiltrate were simply diluted with the mobile phase. The methods presented linearities in the range of 0.50 - 2500 ng/mL of plasma and plasma lysate, 0.125 - 250 ng/mL of plasma ultrafiltrate, and 50 - 20,000 ng/mL of urine. FUR-GLU methods presented linearities in the range of 0.125 - 250 ng/mL of plasma ultrafiltrate and 50 - 20,000 ng/mL of urine. Precision and accuracy evaluations showed coefficients of variation and relative errors < 15%. In the pregnant women participants, the mean values of FUR CL CL CL and CL were all reduced when probenecid was administered with FUR (8.24 vs 2.89 L/h, 8.15 vs 2.80 L/h, 3.86 vs 1.75 L/h, 48.26 vs 22.10 L/h, respectively). Non-pregnant women presented similar values of FUR CL CL CL to the pregnant women who received FUR only. Finally, FUR fraction unbound (fu) resulted in values of approximately 1% in pregnant women and to 0.22% in non-pregnant women. These developed and validated methods for FUR and FUR-GLU quantification in multiple matrices can allow the further investigation of UGT1A9/1A1 and the fu when FUR is administered as an OAT 1 and 3 in vivo probe.
Topics: Female; Humans; Furosemide; Glucuronides; Chromatography, High Pressure Liquid; Probenecid; Tandem Mass Spectrometry
PubMed: 37634358
DOI: 10.1016/j.jpba.2023.115635 -
Molecular and Biochemical Parasitology Dec 2023Acanthamoeba are known to cause a vision threatening eye infection typically due to contact lens wear, and an infection of the central nervous system. The ability of...
Acanthamoeba are known to cause a vision threatening eye infection typically due to contact lens wear, and an infection of the central nervous system. The ability of these amoebae to switch phenotypes, from an active trophozoite to a resistant cyst form is not well understood; the cyst stage is often resistant to chemotherapy, which is of concern given the rise of contact lens use and the ineffective disinfectants available, versus the cyst stage. Herein, for the first time, a range of raloxifene sulfonate/sulfamate derivatives which target nucleotide pyrophosphatase/phosphodiesterase enzymes, were assessed using amoebicidal and excystation tests versus the trophozoite and cyst stage of Acanthamoeba. Moreover, the potential for cytopathogenicity inhibition in amoebae was assessed. Each of the derivatives showed considerable anti-amoebic activity as well as the ability to suppress phenotypic switching (except for compound 1a). Selected raloxifene derivatives reduced Acanthamoeba-mediated host cell damage using lactate dehydrogenase assay. These findings suggest that pyrophosphatase/phosphodiesterase enzymes may be valuable targets against Acanthamoeba infections.
Topics: Animals; Acanthamoeba castellanii; Raloxifene Hydrochloride; Sulfonic Acids; Trophozoites; Alkanesulfonates; Phosphoric Diester Hydrolases
PubMed: 37562558
DOI: 10.1016/j.molbiopara.2023.111582