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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 -
PLoS Neglected Tropical Diseases Jun 2024Lymphatic filariasis (LF) remains a significant global issue. To eliminate LF as a public health problem, the World Health Organization (WHO) recommends multiple rounds...
BACKGROUND
Lymphatic filariasis (LF) remains a significant global issue. To eliminate LF as a public health problem, the World Health Organization (WHO) recommends multiple rounds of mass drug administration (MDA). In certain scenarios, including when elimination targets have not been met with two-drug MDA, triple-drug MDA (using ivermectin, diethylcarbamazine and albendazole) is recommended. In this study, we report on antigen (Ag) and microfilaria (Mf) prevalence in eight primary sampling units (PSUs) in Samoa 4.5 years after one round of triple-drug MDA.
METHODOLOGY
In 2023, community surveys were conducted in eight PSUs that had been surveyed previously in 2018 (between 1.5 and 3.5 months post triple-drug MDA) and 2019 (six to eight-months post triple-drug MDA). Fifteen houses were randomly selected in each PSU with household members aged ≥ 5 years invited to participate. Blood samples were tested for Ag and Mf.
PRINCIPAL FINDINGS
Ag-positive participants were observed in six of the eight PSUs, and Ag prevalence was significantly above the 1% threshold in four PSUs. The presence of Mf-positive participants in five PSUs confirms the presence of residual active infections.
CONCLUSIONS/SIGNIFICANCE
This study provides evidence of persistent LF transmission in Samoa 4.5 years after one round of triple-drug MDA, confirming that one round was insufficient for interruption of transmission in this setting. Our findings highlight the negative impact of delaying MDA rounds, for example, due to public health emergencies.
Topics: Elephantiasis, Filarial; Humans; Mass Drug Administration; Albendazole; Samoa; Diethylcarbamazine; Ivermectin; Male; Female; Adult; Filaricides; Middle Aged; Adolescent; Animals; Young Adult; Child; Prevalence; Antigens, Helminth; Drug Therapy, Combination; Child, Preschool; Wuchereria bancrofti; Aged
PubMed: 38935622
DOI: 10.1371/journal.pntd.0012236 -
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 -
Medicina (Kaunas, Lithuania) Jun 2024: Malaria continues to be a significant global health challenge. The efficacy of artemisinin-based combination therapies (ACTs) has declined in many parts of the Greater...
: Malaria continues to be a significant global health challenge. The efficacy of artemisinin-based combination therapies (ACTs) has declined in many parts of the Greater Mekong Subregion, including Vietnam, due to the spread of resistant malaria strains. This study was conducted to assess the efficacy of the Dihydroartemisinin (DHA)-Piperaquine (PPQ) regimen in treating uncomplicated malaria and to conduct molecular surveillance of antimalarial drug resistance in Binh Phuoc and Dak Nong provinces. : The study included 63 uncomplicated malaria falciparum patients from therapeutic efficacy studies (TES) treated following the WHO treatment guidelines (2009). Molecular marker analysis was performed on all 63 patients. Methods encompassed Sanger sequencing for mutations and quantitative real-time PCR for the gene. : This study found a marked decrease in the efficacy of the DHA-PPQ regimen, with an increased rate of treatment failures at two study sites. Genetic analysis revealed a significant presence of mutations and amplifications, indicating emerging resistance to artemisinin and its partner drug. : The effectiveness of the standard DHA-PPQ regimen has sharply declined, with rising treatment failure rates. This decline necessitates a review and possible revision of national malaria treatment guidelines. Importantly, molecular monitoring and clinical efficacy assessments together provide a robust framework for understanding and addressing detection drug resistance in malaria.
Topics: Humans; Artemisinins; Quinolines; Vietnam; Antimalarials; Malaria, Falciparum; Male; Female; Adult; Plasmodium falciparum; Drug Resistance; Adolescent; Middle Aged; Drug Therapy, Combination; Young Adult; Protozoan Proteins; Real-Time Polymerase Chain Reaction; Mutation; Piperazines
PubMed: 38929629
DOI: 10.3390/medicina60061013 -
Biomolecules May 2024BUB1 is overexpressed in most human solid cancers, including breast cancer. Higher BUB1 levels are associated with a poor prognosis, especially in patients with...
BUB1 is overexpressed in most human solid cancers, including breast cancer. Higher BUB1 levels are associated with a poor prognosis, especially in patients with triple-negative breast cancer (TNBC). Women with TNBC often develop resistance to chemotherapy and radiotherapy, which are still the mainstay of treatment for TNBC. Our previous studies demonstrated that a BUB1 kinase inhibitor (BAY1816032) reduced tumor cell proliferation and significantly enhanced radiotherapy efficacy in TNBC. In this study, we evaluated the effectiveness of BAY1816032 with a PARP inhibitor (olaparib), platinum agent (cisplatin), and microtubule poison (paclitaxel) alone or in combination with radiotherapy using cytotoxicity and clonogenic survival assays. BUB1 inhibitors sensitized BRCA1/2 wild-type SUM159 and MDA-MB-231 cells to olaparib, cisplatin, and paclitaxel synergistically (combination index; CI < 1). BAY1816032 significantly increased the radiation sensitization of SUM159 and MDA-MB-231 by olaparib, cisplatin, or paclitaxel at non-toxic concentrations (doses well below the IC concentrations). Importantly, the small molecular inhibitor of BUB1 synergistically (CI < 1) sensitized the BRCA mutant TNBC cell line HCC1937 to olaparib. Furthermore, the BUB1 inhibitor significantly increased the radiation enhancement ratio (rER) in HCC1937 cells (rER 1.34) compared to either agent alone (BUB1i rER 1.19; PARPi rER 1.04). The data presented here are significant as they provide proof that inhibition of BUB1 kinase activity sensitizes TNBC cell lines to a PARP inhibitor and radiation, irrespective of BRCA1/2 mutation status. Due to the ability of the BUB1 inhibitor to sensitize TNBC to different classes of drugs (platinum, PARPi, microtubule depolarization inhibitors), this work strongly supports the role of BUB1 as a novel molecular target to improve chemoradiation efficacy in TNBC and provides a rationale for the clinical evaluation of BAY1816032 as a chemosensitizer and chemoradiosensitizer in TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Cell Line, Tumor; Phthalazines; Cisplatin; Piperazines; Paclitaxel; Protein Serine-Threonine Kinases; Female; Antineoplastic Agents; Cell Proliferation; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; BRCA1 Protein
PubMed: 38927028
DOI: 10.3390/biom14060625 -
Journal of the International AIDS... Jun 2024Outside of pregnancy, evidence shows that persons with HIV initiating or switching to dolutegravir (DTG)-based antiretroviral therapy (ART) experience greater weight...
INTRODUCTION
Outside of pregnancy, evidence shows that persons with HIV initiating or switching to dolutegravir (DTG)-based antiretroviral therapy (ART) experience greater weight gain compared to those on other ART classes. However, there are few data on the impact of DTG-based ART on gestational weight gain (GWG) in sub-Saharan Africa where HIV is most common. According to the National Academy of Medicine (NAM), GWG below and above NAM guidelines is associated with adverse birth outcomes. Therefore, the objective of this study was to describe GWG by HIV status and ART regimen, and examine the associations with adverse birth outcomes.
METHODS
We enrolled pregnant women with HIV (WHIV) and without HIV (≥18 years) in a peri-urban primary healthcare facility in Cape Town, South Africa between 2019 and 2022. GWG was study-measured at 24-28 (baseline) and 33-38 weeks gestation and converted to GWG rate (kg/week) in accordance with NAM guidelines. GWG z-scores were generated using the INTEGROWTH-21 and US standards to account for differing lengths of gestation. Birth outcome data were obtained from medical records. Associations of GWG z-score with adverse birth outcomes were assessed using multivariable linear or log-binomial regression.
RESULTS
Among 292 participants (48% WHIV), median age was 29 years (IQR, 25-33), median pre-pregnancy body mass index (BMI) was 31 kg/m (IQR, 26-36) and 20% were primiparous at baseline. The median weekly rate of GWG was 0.30 kg/week (IQR, 0.12-0.50), 35% had GWG below NAM standards (59% WHIV) and 48% had GWG above NAM standards (36% WHIV). WHIV gained weight more slowly (0.25 vs. 0.37 kg/week, p<0.01) than women without HIV. Weekly rate of GWG did not differ by ART regimen (DTG-based ART 0.25 vs. efavirenz-based ART 0.27 kg/week, p = 0.80). In multivariable analyses, GWG z-score was positively associated with continuous birth weight (mean difference = 68.53 95% CI 8.96, 128.10) and categorical high birth weight of >4000 g (RR = 2.18 95% CI 1.18, 4.01).
CONCLUSIONS
Despite slower GWG among WHIV, nearly half of all women gained weight faster than recommended by the NAM. GWG was positively associated with infant birth weight. Interventions to support healthy GWG in sub-Saharan Africa are urgently needed.
Topics: Humans; Female; Pregnancy; HIV Infections; Adult; South Africa; Prospective Studies; Gestational Weight Gain; Pregnancy Complications, Infectious; Young Adult; Pregnancy Outcome; Infant, Newborn; Pyridones; Oxazines; Anti-HIV Agents; Heterocyclic Compounds, 3-Ring; Piperazines
PubMed: 38926935
DOI: 10.1002/jia2.26313 -
Scientific Reports Jun 2024Optimal pH is essential for efficient cobalt extraction from polymeric membrane systems, with DEHPA used as an extractant for Co(II) at pH < 7, achieving 47%...
Optimal pH is essential for efficient cobalt extraction from polymeric membrane systems, with DEHPA used as an extractant for Co(II) at pH < 7, achieving 47% efficiency. The pH of piperazine as a stripping agent increases to a concentration of 0.48 M, and the extraction efficiency of Co(II) > 80%. Depending on the functional group of (CHN), the optimal pH for separation was 9.8. The study revealed that pKa value was calculated to predict the ideal pH, and its value was 9.73, which is nearly to the pH, since the pH of the strip concentration and the properties of the membrane affect the extraction of cobalt at 30 C. The partition ratio indicates the high distribution of the extract in supported ceramic polymer membrane (SCPM). The ceramic component provides mechanical strength and rigidity to the overall membrane structure, allowing it to withstand high pressures and temperatures during operation Study various factors such as the effect of pH on the ionization of the extract; effect of pH on band ionization; effect of pH on the temperature in the extract, effect of pH on the solute, effect of the band at different pH ranges and a comparison was made between the predictive model and experimental data that was proven through mathematical modeling using the MATLAB program.
PubMed: 38926406
DOI: 10.1038/s41598-024-63854-7 -
PloS One 2024The introduction of antiretroviral therapy (ART) has successfully changed the clinical course of people with HIV, leading to a significant decline in the incidence of...
The introduction of antiretroviral therapy (ART) has successfully changed the clinical course of people with HIV, leading to a significant decline in the incidence of HIV-related neurocognitive disorders. Integrase strand transferase inhibitors (INSTI) are recommended and preferred first-line ART for the treatment of HIV-1 infection in ART-naïve subjects. This type of therapy regimen is expected to have higher CNS penetration, which may bring more cognitive stability or even make significant cognitive improvement in people with HIV. The study aimed to follow up on neurocognitive performance in HIV subjects on two types of INSTI therapy regimens at two-time points, one year apart. The study sample consisted of 61 ART naïve male participants, of which 32 were prescribed raltegravir (RAL) and 29 dolutegravir (DTG). There was no significant difference between subsamples according to the main sociodemographic (age, education level) and clinical characteristics (duration of therapy, nadir CD4 cells level, CD4 cells count, CD8 cells, CD4/CD8 ratio). For neurocognitive assessment, six measures were used: general cognitive ability (MoCA test), verbal fluency (total sum score for phonemic and category fluency), verbal working memory (digit span forward), cognitive capacity (digit span backwards), sustained attention (Color Trail Test 1), and divided attention (Color Trail Test 2). In both therapy groups (RAL and DTG), there was no significant decrease in neurocognitive achievement on all used measures over a one-year follow-up in both therapy groups. A statistically significant interactive effect of time and type of therapy was found on the measure of divided attention-DTG group showed slight improvement, whereas RAL group showed slight decrease in performance. During the one-year follow-up of persons on INSTI-based regimen, no significant changes in cognitive achievement were recorded, which suggests that the existing therapy can have a potentially positive effect on the maintenance of neurocognitive achievement.
Topics: Humans; Male; HIV Infections; Adult; Follow-Up Studies; Cognition; Raltegravir Potassium; HIV Integrase Inhibitors; Middle Aged; Pyridones; Piperazines; Heterocyclic Compounds, 3-Ring; Oxazines; Neuropsychological Tests; HIV-1
PubMed: 38923982
DOI: 10.1371/journal.pone.0306278 -
PloS One 2024In 2019, WHO recommended dolutegravir (DTG) as a backbone for first- and second-line antiretroviral therapy (ART) regimens for people living with HIV (PLHIV). According...
BACKGROUND
In 2019, WHO recommended dolutegravir (DTG) as a backbone for first- and second-line antiretroviral therapy (ART) regimens for people living with HIV (PLHIV). According to the 2018 Uganda's HIV treatment guidelines, patients with viral non-suppression (≥1,000 copies/mL) should receive intensive adherence counseling (IAC) with repeat viral load (VL) within 6 months. This analysis focused on the prevalence and factors associated with viral suppression following IAC among PLHIV on DTG-based regimens (DBRs) with an initial episode of viral non-suppression (VNS) in Uganda.
METHODS
We conducted a retrospective analysis for PLHIV on DBRs with an initial episode of VNS (≥1,000 copies/mL) in Uganda during October 2019-September 2020 who had a follow up VL test result during September 2020-July 2021. Data were abstracted from the Central Public Health Laboratory (CPHL) database, including patient demographics and VL results. Viral non-suppression (VNS) was defined as a VL test result of ≥1,000 copies/mL. We characterized PLHIV on DBRs and used logistic regression models to determine factors associated with VL suppression after an initial episode of VNS.
RESULTS
A total of 564 PLHIV on DBRs with an initial episode of VNS were followed up and 43 were excluded due to missing data. Of the 521, 220 (42.2%) were children (<15 years) and 231 (44.3%) were female. Median age was 28 years (interquartile range [IQR]: 12-43 years), and median duration on DBRs was 12 months (IQR: 6-15 months). Overall, 80.8% (421/521) PLHIV had a suppressed viral load at first follow up testing (children = 74.5% [164/220]; adults = 85.4% [257/301]). Children with initial VL results ≥5,000 copies/mL were less likely to achieve viral suppression at follow up testing compared to those with <5,000 copies/mL (AOR: 0.38; 95% CI: 0.20-0.71; p = 0.002).
CONCLUSIONS
In a programmatic setting, most adults and children suppressed following an initial episode of VNS on DBRs. High rates of suppression after VNS suggest adherence challenges, rather than drug resistance. Continuation of DBRs should be considered before regimen switch.
Topics: Humans; Pyridones; Heterocyclic Compounds, 3-Ring; Female; Uganda; Male; HIV Infections; Adult; Oxazines; Viral Load; Piperazines; Retrospective Studies; HIV Integrase Inhibitors; Adolescent; Young Adult; Middle Aged; Anti-HIV Agents; Child; HIV-1
PubMed: 38923981
DOI: 10.1371/journal.pone.0305129