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BMC Chemistry Jun 2024A new DES (MTPPBr-PHTH-DES) was prepared from a mixture of methyltriphenyl-phosphonium bromide (MTPPBr) and phthalic acid (PHTH). The eutectic point phase diagram showed...
A new DES (MTPPBr-PHTH-DES) was prepared from a mixture of methyltriphenyl-phosphonium bromide (MTPPBr) and phthalic acid (PHTH). The eutectic point phase diagram showed that a one-to-one molar ratio of MTPPBr to PHTH is the optimal molar ratio for the synthesis of new DES. Then, it was characterized with various techniques such as FT-IR, TGA/DTA, densitometer, eutectic point, and NMR and used as a novel acid catalyst in the synthesis of pyrimido[4,5-d]pyrimidines and pyrano[3,2-c]chromes in solvent-free condition. Short reaction time, low temperature, high efficiency, green condition, and easy recycling and separation of the DES catalyst are among the most important features of the presented method.
PubMed: 38937816
DOI: 10.1186/s13065-024-01227-x -
Facial Plastic Surgery Clinics of North... Aug 2024Alopecia, a widespread issue affecting both genders, often manifests as androgenetic alopecia, although a thorough examination is needed to rule out other causes. This... (Review)
Review
Alopecia, a widespread issue affecting both genders, often manifests as androgenetic alopecia, although a thorough examination is needed to rule out other causes. This chapter focuses on the treatment of androgenetic alopecia. Finasteride and minoxidil, the Food and Drug Administration-approved treatments, offer stability and in some cases improvement in scalp coverage. Platelet-rich plasma exhibits positive results as an off-label alopecia therapy. For eligible individuals, hair transplantation proves effective, using healthy follicular units to restore hair-bearing areas. Multiple options allow for the tailoring of interventions to each patient.
Topics: Humans; Alopecia; Minoxidil; Finasteride; Platelet-Rich Plasma; 5-alpha Reductase Inhibitors; Male; Female
PubMed: 38936999
DOI: 10.1016/j.fsc.2024.02.006 -
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 -
The Lancet. Oncology Jul 2024Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the... (Randomized Controlled Trial)
Randomized Controlled Trial
Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial.
BACKGROUND
Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma.
METHODS
The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m on day 1, maintenance 1 mg/m on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m per day] and oral temozolomide [150 mg/m per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual.
FINDINGS
Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure).
INTERPRETATION
RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting.
FUNDING
Deutsche Krebshilfe.
Topics: Humans; Temozolomide; Irinotecan; Antineoplastic Combined Chemotherapy Protocols; Male; Female; Neuroblastoma; Child, Preschool; Child; Dasatinib; Adolescent; Neoplasm Recurrence, Local; Infant; Adult; Sirolimus; Young Adult; Germany; Drug Resistance, Neoplasm; Progression-Free Survival
PubMed: 38936379
DOI: 10.1016/S1470-2045(24)00202-X -
Bioorganic Chemistry Jun 2024The antifungal bioactivity potential of the organic extract of silk tree (Albizia kalkora) was investigated in the current study. The crude extracts of A. kalkora and...
The antifungal bioactivity potential of the organic extract of silk tree (Albizia kalkora) was investigated in the current study. The crude extracts of A. kalkora and methanol, n-hexane, chloroform, and ethyl acetate fractions were prepared. The antifungal activity of obtained fractions of A. kalkora was studied at different concentrations ranging from 0.39-50 µg/mL. Dimethyl sulfoxide (DMSO) was taken as a toxicity control, whereas thiophanate methyl (TM) as a positive control. All the fractions significantly reduced the FOL growth (methanolic: 9.49-94.93 %, n-hexane: 11.12-100 %, chloroform: 20.96-91.41 %, and ethyl acetate: 18.75-96.70 %). The n-hexane fraction showed 6.25 µg/mL MIC as compared to TM with 64 µg/mL MIC. The non-polar (n-hexane) fraction showed maximum antifungal bioactivity against FOL in comparison with chloroform, methanol, and ethyl acetate fractions. GC/MS analysis exhibited that the n-hexane fraction contained hexadecanoic acid, 9,12,15-octadecatrienoic acid, 9,12-octadecadienoic acid, bis(2-ethylhexyl) phthalate, methyl stearate, and [1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid. The results of in vitro antifungal inhibition were further reinforced by molecular docking analysis. Five virulence proteins of FOL i.e., pH-responsive PacC transcription factor (PACC), MeaB, TOR; target of rapamycin (FMK1), Signal transducing MAP kinase kinase (STE-STE7), and High Osmolarity Glycerol 1(HOG1) were docked with identified phytocompounds in the n-hexane fraction by GC/MS analysis. MEAB showed maximum binding affinities with zinnimide (-12.03 kcal/mol), HOG1 and FMK1with α-Tocospiro-B (-11.51 kcal/mol) and (-10.55 kcal/mol) respectively, STE-STE7 with docosanoic acid (-11.31 kcal/mol), and PACC with heptadecanoic acid (-9.88 kcal/mol) respectively with strong hydrophobic or hydrophilic interactions with active pocket residues. In conclusion, the n-hexane fraction of the A. kalkora can be used to manage FOL.
PubMed: 38936050
DOI: 10.1016/j.bioorg.2024.107561 -
JCO Precision Oncology Jun 2024Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain genetic variants with standard dosing. We implemented... (Observational Study)
Observational Study
Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase () Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.
PURPOSE
Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain genetic variants with standard dosing. We implemented genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization.
METHODS
In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization.
RESULTS
Of the 757 patients who received genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively ( = .085); 64%, 25%, and 13% were hospitalized ( < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients ( = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups ( < .001), with reactive carriers having the earliest onset and highest incidence.
CONCLUSION
genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.
Topics: Humans; Male; Female; Dihydrouracil Dehydrogenase (NADP); Middle Aged; Hospitalization; Prospective Studies; Genotype; Aged; Fluorouracil; Neoplasms; Antimetabolites, Antineoplastic; Cancer Care Facilities; Adult
PubMed: 38935897
DOI: 10.1200/PO.23.00623 -
JCO Precision Oncology Jun 2024HMGA2::NCOR2 keratin-positive giant cell tumors in children with response to imatinib in an infant.
HMGA2::NCOR2 keratin-positive giant cell tumors in children with response to imatinib in an infant.
Topics: Humans; Imatinib Mesylate; Infant; HMGA2 Protein; Male; Soft Tissue Neoplasms; Female; Keratins; Giant Cell Tumor of Bone; Child; Antineoplastic Agents; Bone Neoplasms; Child, Preschool
PubMed: 38935896
DOI: 10.1200/PO.23.00659 -
PloS One 2024Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account....
Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.
Topics: Animals; Aniline Compounds; Acrylamides; Afatinib; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mice; Humans; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Disease Models, Animal; Xenograft Model Antitumor Assays; ErbB Receptors; Quinazolines; Piperazines; Female; Indoles; Pyrimidines
PubMed: 38935790
DOI: 10.1371/journal.pone.0304914 -
Proceedings of the National Academy of... Jul 2024In 1967, in this journal, Evelyn Witkin proposed the existence of a coordinated DNA damage response in , which later came to be called the "SOS response." We revisited...
In 1967, in this journal, Evelyn Witkin proposed the existence of a coordinated DNA damage response in , which later came to be called the "SOS response." We revisited this response using the replication inhibitor azidothymidine (AZT) and RNA-Seq analysis and identified several features. We confirm the induction of classic Save our ship (SOS) loci and identify several genes, including many of the pyrimidine pathway, that have not been previously demonstrated to be DNA damage-inducible. Despite a strong dependence on LexA, these genes lack LexA boxes and their regulation by LexA is likely to be indirect via unknown factors. We show that the transcription factor "stringent starvation protein" SspA is as important as LexA in the regulation of AZT-induced genes and that the genes activated by SspA change dramatically after AZT exposure. Our experiments identify additional LexA-independent DNA damage inducible genes, including 22 small RNA genes, some of which appear to activated by SspA. Motility and chemotaxis genes are strongly down-regulated by AZT, possibly as a result of one of more of the small RNAs or other transcription factors such as AppY and GadE, whose expression is elevated by AZT. Genes controlling the iron siderophore, enterobactin, and iron homeostasis are also strongly induced, independent of LexA. We confirm that IraD antiadaptor protein is induced independent of LexA and that a second antiadaptor, IraM is likewise strongly AZT-inducible, independent of LexA, suggesting that RpoS stabilization via these antiadaptor proteins is an integral part of replication stress tolerance.
Topics: Escherichia coli; DNA Damage; Gene Expression Regulation, Bacterial; Escherichia coli Proteins; DNA Replication; SOS Response, Genetics; Bacterial Proteins; Serine Endopeptidases
PubMed: 38935560
DOI: 10.1073/pnas.2407832121 -
AIDS (London, England) Jul 2024
Topics: Humans; Female; Pregnancy; Pyridones; HIV Infections; Pregnancy Complications, Infectious; Tenofovir; Anti-HIV Agents; Oxazines; Heterocyclic Compounds, 3-Ring; Lamivudine; Piperazines; Treatment Outcome
PubMed: 38932745
DOI: 10.1097/QAD.0000000000003911