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In Vivo (Athens, Greece) 2024Hypertension occurs frequently in patients taking pazopanib. Therefore, this study aimed to clarify the predictive factors for pazopanib-induced hypertension.
BACKGROUND/AIM
Hypertension occurs frequently in patients taking pazopanib. Therefore, this study aimed to clarify the predictive factors for pazopanib-induced hypertension.
PATIENTS AND METHODS
In total, 47 patients who started pazopanib treatment for renal cell carcinoma or soft tissue sarcoma during hospitalization at Kurume University Hospital from November 2012 to February 2020 were included in the study. Patient background factors associated with pazopanib-induced hypertension were analyzed using a logistic regression model. Subsequently, a time-dependent receiver operating characteristic (ROC) analysis was performed to evaluate changes in the predictive performance of predictors of pazopanib-induced hypertension over time.
RESULTS
Logistic regression analysis showed that total bilirubin (t-bil) and sex are predictors of pazopanib-induced hypertension, along with systolic blood pressure (SBP) before pazopanib introduction. Additionally, evaluation of area under the curve (AUC) changes over time during the first 20 days of pazopanib treatment using time-dependent ROC showed that the AUC tended to be higher in the first half for SBP and in the second half for t-bil. Moreover, models including these two factors (SBP+t-bil and SBP+t-bil+sex) maintained a higher AUC from the early to late stages of the treatment period.
CONCLUSION
Total bilirubin and sex can serve as predictors of pazopanib-induced hypertension. Total bilirubin may contribute to the prediction of the development of hypertension after day 5.
Topics: Indazoles; Humans; Pyrimidines; Male; Female; Hypertension; Sulfonamides; Middle Aged; Aged; ROC Curve; Angiogenesis Inhibitors; Adult; Carcinoma, Renal Cell; Risk Factors; Blood Pressure; Aged, 80 and over; Kidney Neoplasms; Prognosis
PubMed: 38936947
DOI: 10.21873/invivo.13643 -
In Vivo (Athens, Greece) 2024We evaluated the usefulness of prophylactic mini-tracheostomy (PMT) and perioperative administration of tazobactam/piperacillin (TAZ/PIPC) in high-risk patients after...
BACKGROUND/AIM
We evaluated the usefulness of prophylactic mini-tracheostomy (PMT) and perioperative administration of tazobactam/piperacillin (TAZ/PIPC) in high-risk patients after esophagectomy.
PATIENTS AND METHODS
We retrospectively studied 89 consecutive high-risk patients who underwent esophagectomy for esophageal cancer between January 2013 and December 2021. We defined patients with two or more of the following factors as high risk: age ≥70 years, performance status ≥1, respiratory dysfunction, liver dysfunction, cardiac dysfunction, renal dysfunction, diabetes mellitus, albumin <3.5 g/dl, and Brinkman index >600. Standard management was administered to the first 50 patients (standard group). PMT and TAZ/PIPC were administered to the next 39 patients (combination group). Patient characteristics and short-term outcomes were compared before and after propensity-score matching.
RESULTS
Before propensity-score matching, 24-hour urine creatinine clearance, retrosternal route, 3-field lymph node dissection, and open abdominal approach were more common, postoperative pneumonia (13% vs. 36%, p=0.045) and complications of grade ≥3b (2.6% vs. 22%, p=0.01) were less frequent, and the postoperative hospital stay was shorter (median: 23 vs. 28 days, p=0.022) in the combination group than in the standard group. In propensity-score matching, patient characteristics, except for 24-h creatinine clearance and reconstructive route, were matched for 23 paired patients. Postoperative pneumonia (8.7% vs. 39%, p=0.035) and complications of grade ≥3b (0% vs. 26%, p=0.022) were less frequent and postoperative hospital stay was shorter (median: 22 vs. 25 days, p=0.021) in the combination group than in the standard group.
CONCLUSION
PMT with TAZ/PIPC can potentially prevent postoperative pneumonia in high-risk patients after esophagectomy.
Topics: Humans; Male; Female; Aged; Esophagectomy; Esophageal Neoplasms; Pneumonia; Piperacillin, Tazobactam Drug Combination; Middle Aged; Postoperative Complications; Anti-Bacterial Agents; Retrospective Studies; Risk Factors
PubMed: 38936906
DOI: 10.21873/invivo.13630 -
In Vivo (Athens, Greece) 2024To date, therapeutic options for T-cell acute lymphoblastic leukemia (T-ALL) remain very limited. This study evaluated the efficacy of monotherapies and combination...
BACKGROUND/AIM
To date, therapeutic options for T-cell acute lymphoblastic leukemia (T-ALL) remain very limited. This study evaluated the efficacy of monotherapies and combination therapies including a selective BCL-2 inhibitor for T-ALL cell lines, namely Jurkat, CCRF-CEM, and Loucy.
MATERIALS AND METHODS
Loucy is an early T-precursor ALL (ETP-ALL) cell line characterized by an immature phenotype, whereas Jurkat and CCRF-CEM are late T-cell progenitor ALL (LTP-ALL) cell lines. Monotherapy was conducted with venetoclax, cytarabine, bendamustine, or azacytidine, whereas combination therapy was performed with venetoclax plus cytarabine, venetoclax plus bendamustine, or venetoclax plus azacytidine. Cell viability assay was conducted after 48 h using Trypan blue and the 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). Statistical analysis for evaluating synergistic interactions between anticancer drugs was performed by using the SynergyFinder Plus and drc R package.
RESULTS
Adding venetoclax to cytarabine, bendamustine, or azacitidine achieved an additive effect, with Loewe synergic scores ranging from -10 to 10 in Jurkat and CCRF-CEM. Conversely, the combination of venetoclax and cytarabine displayed an additive effect (Loewe synergic score: 8.45 and 5.82 with MTS and Trypan blue assays, respectively), whereas venetoclax plus bendamustine or azacitidine exhibited a synergistic effect (Loewe synergic score >10 with MTS assay) in Loucy. Remarkably, the Bliss/Loewe score revealed that the combination of venetoclax and bendamustine was the most synergistic, yielding a score of 13.832±0.55.
CONCLUSION
The combination of venetoclax and bendamustine demonstrated the greatest synergistic effect in suppressing ETP-ALL cell proliferation. Further studies are warranted to determine the mechanisms for the synergism between venetoclax and bendamustine in high-risk T-ALL.
Topics: Humans; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides; Drug Synergism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Jurkat Cells; Apoptosis; Cell Proliferation
PubMed: 38936885
DOI: 10.21873/invivo.13624 -
Journal of Molecular Biology Jun 2024Assessing membrane protein stability is among the major challenges in protein science due to their inherent complexity, which complicates the application of conventional...
The structural stability of membrane proteins revisited: Combined thermodynamic and spectral phasor analysis of SDS-induced denaturation of a thermophilic Cu(I)-transport ATPase.
Assessing membrane protein stability is among the major challenges in protein science due to their inherent complexity, which complicates the application of conventional biophysical tools. In this work, sodium dodecyl sulfate-induced denaturation of AfCopA, a Cu(I)-transport ATPase from Archaeoglobus fulgidus, was explored using a combined model-free spectral phasor analysis and a model-dependent thermodynamic analysis. Decrease in tryptophan and 1-anilino-naphthalene-8-sulfonate fluorescence intensity, displacements in the spectral phasor space, and the loss of ATPase activity were reversibly induced by this detergent. Refolding from the SDS-induced denatured state yields an active enzyme that is functionally and spectroscopically indistinguishable from the native state of the protein. Phasor analysis of Trp spectra allowed us to identify two intermediate states in the SDS-induced denaturation of AfCopA, a result further supported by principal component analysis. In contrast, traditional thermodynamic analysis detected only one intermediate state, and including the second one led to overparameterization. Additionally, ANS fluorescence spectral analysis detected one more intermediate and a gradual change at the level of the hydrophobic transmembrane surface of the protein. Based on this evidence, a model for acquiring the native structure of AfCopA in a membrane-like environment is proposed.
PubMed: 38936696
DOI: 10.1016/j.jmb.2024.168689 -
Toxicology and Applied Pharmacology Jun 2024To identify pathway perturbations and examine biological modes of action (MOAs) for various perfluoroalkyl substances, we re-analyzed published in vitro gene expression...
To identify pathway perturbations and examine biological modes of action (MOAs) for various perfluoroalkyl substances, we re-analyzed published in vitro gene expression studies from human primary liver spheroids. With treatment times ranging from 10 to 14 days, shorter-chain PFAS (those with 6 or fewer fluorinated carbon atoms in the alkyl chain) showed enrichment for pathways of fatty acid metabolism and fatty acid beta-oxidation with upregulated genes. Longer-chain PFAS compounds, specifically PFOS (perfluorooctane sulfonate), PFDS (perfluorodecane sulfonate), and higher doses of PFOA (perfluorooctanoic acid), had enrichment for pathways involved in steroid metabolism, fatty acid metabolism, and biological oxidation for downregulated genes. Although PFNA (perfluorononanoic acid), PFDA (perfluorodecanoic acid), and PFUnDA (perfluoroundecanoic acid) were more toxic and could only be examined after a 1-day treatment, all three had enrichment patterns similar to those observed with PFOS. With PFOA there were dose-dependent changes in pathway enrichment, shifting from upregulation of fatty acid metabolism and downregulation of steroid metabolism to downregulation of both at higher doses. The response to PFHpS (perfluoroheptanesulfonic acid) was similar to the PFOA pattern at the lower treatment dose. Based on results of transcription factor binding sites analyses, we propose that downregulation of pathways of lipid metabolism by longer chain PFAS may be due to inhibitory interactions of PPARD on genes controlled by PPARA and PPARG. In conclusion, our transcriptomic analysis indicates that the biological MOAs of PFAS compounds differ according to chain length and dose, and that risk assessments for PFAS should consider these differences in biological MOAs when evaluating mixtures of these compounds.
PubMed: 38936668
DOI: 10.1016/j.taap.2024.117013 -
International Journal of Biological... Jun 2024Polyether-ether-ketone (PEEK) is clinically used as a bio-implant for the healing of skeletal defects. However, the osseointegration of clinical-sized bone grafts...
Polyether-ether-ketone (PEEK) is clinically used as a bio-implant for the healing of skeletal defects. However, the osseointegration of clinical-sized bone grafts remains limited. In this study, surface-porous PEEK was created by using a sulfonation method and a metal-polysaccharide complex MgCS was introduced on the surface of sulfonated PEEK to form MgCS@SPEEK. The as-prepared MgCS@SPEEK was found to have a porous surface with good hydrophilicity and bioactivity. This was followed by an investigation into whether MgCS loaded onto sulfonated PEEK surfaces could promote osseointegration and angiogenesis. The in vitro results showed that MgCS@SPEEK had a positive effect on reducing the expression levels of inflammatory genes and promoting osteogenesis and angiogenesis-related genes expression levels. Furthermore, porous MgCS@SPEEK was implanted in critical-sized rat tibiae defects for in vivo evaluation of osseointegration. The microcomputed tomography evaluation results revealed substantial bone formation at 4 and 8 weeks. Collectively, these findings indicate that MgCS@SPEEK could provide improved osseointegration and an attractive strategy for orthopedic applications.
PubMed: 38936580
DOI: 10.1016/j.ijbiomac.2024.133435 -
Chemosphere Jun 2024PER: and polyfluorinated alkyl substances, especially perfluorooctanoic acid and perfluorooctane sulfonic acid (PFOX), have attracted considerable attention lately... (Review)
Review
PER: and polyfluorinated alkyl substances, especially perfluorooctanoic acid and perfluorooctane sulfonic acid (PFOX), have attracted considerable attention lately because of their widespread occurrence in aquatic environment and potential biological toxicity to animals and human beings. The development of economical, efficient, and engineerable adsorbents for removing PFOX in water has become one of the research focuses. This review summarized the recent progress on natural mineral and industrial solid based adsorbent (NM&ISW-A) and removal mechanisms concerning PFOX onto NM&ISW-A, as well as proposed the current challenges and future perspectives of using NM&ISW-A for PFOX removal in water. Kaolinite and montmorillonite are usually used as model clay minerals for PFOX removal, and have been proved to adsorb PFOX by ligand exchange and electrostatic attraction. Fe-based minerals, such as goethite, magnetite, and hematite, have better PFOX adsorption capacity than clay minerals. The adsorbent prepared from industrial solid waste by high temperature roasting has great potential application prospects. Fabricating nanomaterials, amination modification, surfactant modification, fluorination modification, developing versatile composites, and designing special porous structure are beneficial to improve the adsorption performance of PFOX onto NM&ISW-A by enhancing the specific surface area, positive charge, and hydrophobicity. Electrostatic interaction, hydrophobic interaction, hydrogen bond, ligand and ion exchange, and self-aggregation (formation of micelle or hemimicelle) are the main adsorption mechanisms of PFOX by NM&ISW-A. Among them, electrostatic and hydrophobic interactions play a considerable role in the removal of PFOX by NM&ISW-A. Therefore, NM&ISW-A with electrostatic functionalities and considerable hydrophobic segments enables rapid, efficient, and high-capacity removal of PFOX. The future directions of NM&ISW-A for PFOX removal include the preparation and regeneration of engineerable NM&ISW-A, the development of coupling technology for PFOX removal based on NM&ISW-A, the in-depth research on adsorption mechanism of PFOX by NM&ISW-A, as well as the development of NM&ISW-A for PFOX alternatives removal. This review paper would be helpful the comprehensive understanding of NM&ISW-A potential for PFOX removal and the PFOX removal mechanisms, and identifies the gaps for future research and development.
PubMed: 38936483
DOI: 10.1016/j.chemosphere.2024.142662 -
International Immunopharmacology Jun 2024Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by diverse clinical manifestations and organ damage. Despite its elusive etiology,...
Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by diverse clinical manifestations and organ damage. Despite its elusive etiology, dysregulated subsets and functions of B cells are pivotal in SLE pathogenesis. Peoniflorin-6'-O-benzene sulfonate (CP-25), an esterification modification of Paeoniflorin, exhibits potent anti-inflammatory and immunomodulatory properties in autoimmune diseases (AID). However, the involvement of CP-25 and its target, GRK2, in SLE development has not been explored. In this study, we demonstrate that both genetic deficiency and pharmacological inhibition of GRK2 attenuate autoantibodies production, reduce systemic inflammation, and mitigate histopathological alterations in the spleen and kidney in the pristane-induced mouse SLE model. Importantly, our findings highlight that both genetic deficiency and pharmacological inhibition of GRK2 suppress plasma cells generation and restore dysregulated B-cell subsets by modulating two crucial transcription factors, Blimp1 and IRF4. Collectively, targeting GRK2 with CP-25 emerges as a promising therapeutic approach for SLE.
PubMed: 38936060
DOI: 10.1016/j.intimp.2024.112557 -
The Journal of Organic Chemistry Jun 2024A nickel-catalyzed direct sulfonylation of alkenes with sulfonyl chlorides has been developed using 1,10-phenanthroline-5,6-dione as the ligand. Unactivated alkenes and...
A nickel-catalyzed direct sulfonylation of alkenes with sulfonyl chlorides has been developed using 1,10-phenanthroline-5,6-dione as the ligand. Unactivated alkenes and styrenes including 1,1-, 1,2-disubstituted alkenes can be subjected to the protocol, and a wide range of vinyl sulfones was obtained in high to excellent yields with good functional group compatibility. Notably, the process did not allow the desulfonylation of sulfonyl chloride or chlorosulfonylation of alkenes. Radical-trapping experiment supported that a sulfonyl free-radical was likely produced and triggered subsequent transformation in the process.
PubMed: 38935873
DOI: 10.1021/acs.joc.4c00094 -
The Journal of Organic Chemistry Jun 2024-Alkoxyphthalimides, one kind of phthalimide derivative, have great importance in synthesis, mainly used as free radical precursors. While the phthalimide unit, for a...
-Alkoxyphthalimides, one kind of phthalimide derivative, have great importance in synthesis, mainly used as free radical precursors. While the phthalimide unit, for a long time, was treated as part of the waste stream. Construction of C-N bonds has always been a hot spot, especially in reductive cross-coupling. Herein, a nickel-catalyzed reductive cross-coupling reaction of -methoxyphthalimides with alkyl halides is described, where -methoxyphthalimides serve as nitrogen electrophiles. This tactic provides a new approach to construct C-N bonds under mild neutral conditions. Alkyl chlorides, bromides, iodides, and sulfonates are all fit to this transformation. Moreover, the reaction could tolerate a broad substrate scope, especially base-sensitive functional groups (boron or silicon groups), as well as competitive nucleophilic groups (phenols and amides), which are incompatible with traditional Gabriel synthesis under basic conditions, demonstrating a complementary role of this work to Gabriel synthesis.
PubMed: 38935867
DOI: 10.1021/acs.joc.4c00871