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Science Advances Jun 2024Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells....
Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD synthesis and oxidative phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance.
Topics: Tryptophan; Humans; Drug Resistance, Neoplasm; Neoplastic Stem Cells; Pancreatic Neoplasms; Cell Line, Tumor; Animals; Mice; Gene Expression Regulation, Neoplastic; Carcinoma, Pancreatic Ductal; Gemcitabine; Deoxycytidine; RNA-Binding Proteins; Indoleamine-Pyrrole 2,3,-Dioxygenase
PubMed: 38896624
DOI: 10.1126/sciadv.adj8650 -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2024A portfolio of six modified 2'-deoxyribonucleoside triphosphate (dNTP) derivatives derived from 5-substituted pyrimidine or 7-substituted 7-deazapurine bearing different...
A portfolio of six modified 2'-deoxyribonucleoside triphosphate (dNTP) derivatives derived from 5-substituted pyrimidine or 7-substituted 7-deazapurine bearing different carbohydrate units (d-glucose, d-galactose, d-mannose, l-fucose, sialic acid and N-Ac-d-galactosamine) tethered through propargyl-glycoside linker was designed and synthesized via the Sonogashira reactions of halogenated dNTPs with the corresponding propargyl-glycosides. The nucleotides were found to be good substrates for DNA polymerases in enzymatic primer extension and PCR synthesis of modified and hypermodified DNA displaying up to four different sugars. Proof of concept binding study of sugar-modified oligonucleotides with concanavalin A showed positive effect of avidity and sugar units count.
PubMed: 38896019
DOI: 10.1002/chem.202402318 -
International Journal of Molecular... May 2024The genome is continuously exposed to a variety of harmful factors that result in a significant amount of DNA damage. This article examines the influence of a...
The genome is continuously exposed to a variety of harmful factors that result in a significant amount of DNA damage. This article examines the influence of a multi-damage site containing oxidized imino-allantoin (Ia) and 7,8-dihydro-8-oxo-2'-deoxyguanosine (dG) on the spatial geometry, electronic properties, and ds-DNA charge transfer. The ground stage of a d[AIaAGA]*d[TCTCT] structure was obtained at the M06-2X/6-D95**//M06-2X/sto-3G level of theory in the condensed phase, with the energies obtained at the M06-2X/6-31++G** level. The non-equilibrated and equilibrated solvent-solute interactions were also considered. Theoretical studies reveal that the radical cation prefers to settle on the G moiety, irrespective of the presence of Ia in a ds-oligo. The lowest vertical and adiabatic ionization potential values were found for the G:::C base pair (5.94 and 5.52 [eV], respectively). Conversely, the highest vertical and adiabatic electron affinity was assigned for IaC as follows: 3.15 and 3.49 [eV]. The charge transfers were analyzed according to Marcus' theory. The highest value of charge transfer rate constant for hole and excess electron migration was found for the process towards the GC moiety. Surprisingly, the values obtained for the driving force and activation energy of electro-transfer towards IaC located this process in the Marcus inverted region, which is thermodynamically unfavorable. Therefore, the presence of Ia can slow down the recognition and removal processes of other DNA lesions. However, with regard to anticancer therapy (radio/chemo), the presence of Ia in the structure of clustered DNA damage can result in improved cancer treatment outcomes.
Topics: Oxidation-Reduction; Allantoin; DNA; 8-Hydroxy-2'-Deoxyguanosine; DNA Damage; Thermodynamics; Models, Molecular
PubMed: 38892152
DOI: 10.3390/ijms25115962 -
International Journal of Molecular... May 2024Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine...
Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine lies in the absence of a hydroxyl group at the 3' position of the ribose ring. Upon administration, cordycepin can undergo an enzymatic transformation in specific tissues, forming cordycepin triphosphate. In this study, we conducted a comprehensive analysis of the structural features of cordycepin and its derivatives, contrasting them with endogenous purine-based metabolites using chemoinformatics and bioinformatics tools in addition to molecular dynamics simulations. We tested the hypothesis that cordycepin triphosphate could bind to the active site of the adenylate cyclase enzyme. The outcomes of our molecular dynamics simulations revealed scores that are comparable to, and superior to, those of adenosine triphosphate (ATP), the endogenous ligand. This interaction could reduce the production of cyclic adenosine monophosphate (cAMP) by acting as a pseudo-ATP that lacks a hydroxyl group at the 3' position, essential to carry out nucleotide cyclization. We discuss the implications in the context of the plasticity of cancer and other cells within the tumor microenvironment, such as cancer-associated fibroblast, endothelial, and immune cells. This interaction could awaken antitumor immunity by preventing phenotypic changes in the immune cells driven by sustained cAMP signaling. The last could be an unreported molecular mechanism that helps to explain more details about cordycepin's mechanism of action.
Topics: Deoxyadenosines; Humans; Neoplasms; Cyclic AMP; Molecular Dynamics Simulation; Adenosine Triphosphate; Signal Transduction; Computer Simulation; Adenylyl Cyclases
PubMed: 38891880
DOI: 10.3390/ijms25115692 -
AIDS Research and Therapy Jun 2024Scholars recommend providing migrants living with HIV (MLWH) with free treatment, rapidly, once linked to care to optimize their HIV-related experiences and health...
BACKGROUND
Scholars recommend providing migrants living with HIV (MLWH) with free treatment, rapidly, once linked to care to optimize their HIV-related experiences and health outcomes. Quantitative evaluations of patient-reported measures for MLWH in such models are necessary to explore the viability of these recommendations.
METHODS
Within a 96-week prospective cohort study at a multidisciplinary HIV clinic, participants received bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for free and rapidly following care linkage. Eight patient-reported measures were administered at weeks 4, 24, and 48: (1) mMOS-SS to measure perceived social support; (2) IA-RSS to measure internalized stigma; (3) K6 to measure psychological distress; (4) PROMIS to measure self-efficacy with treatment taking; (5) G-MISS to measure perceived compliance with clinicians' treatment plans; (6) HIVTSQ to measure treatment satisfaction; (7) CARE to measure perceived provider empathy; and (8) PRPCC to measure perceived clinician cultural competence. Linear mixed modelling with bootstrapping was conducted to identify significant differences by sociodemographics and time.
RESULTS
Across weeks 4, 24, and 48, results suggest that MLWH enrolled in this study experienced moderate levels of social support; elevated levels of HIV-related stigma; moderate levels of distress; high self-efficacy with daily medication self-management; great compliance with clinicians' treatment plans; high treatment satisfaction; high perceived empathy; and high perceived cultural competence. Experience of social support (i.e., mMOS-SS scores) differed significantly by birth region. Experience of HIV-related stigma (i.e., IA-RSS scores) differed significantly by birth region, age, and language. Experience of distress (i.e., K6 scores) differed significantly by sexual orientation. Experience of treatment satisfaction (i.e., HIVTSQ scores) differed significantly by birth region and age. No significant differences were identified by time for any measure.
CONCLUSION
Overall, participants expressed positive experiences around treatment and care, alongside comparably lower perceptions of social support, internalized stigma, and distress, potentially underscoring a need to embed targeted, well-funded, and accessible mental health support within HIV care models.
Topics: Humans; HIV Infections; Male; Patient Reported Outcome Measures; Female; Adult; Prospective Studies; Anti-HIV Agents; Social Stigma; Middle Aged; Transients and Migrants; Social Support; Heterocyclic Compounds, 4 or More Rings; Tenofovir; Emtricitabine; Piperazines; Medication Adherence; Pyridones; Drug Combinations; Patient Satisfaction; Young Adult; Self Efficacy; Amides; Heterocyclic Compounds, 3-Ring
PubMed: 38890671
DOI: 10.1186/s12981-024-00632-5 -
Pancreas Jul 2024We sought to investigate whether the addition of nimotuzumab to gemcitabine would improve the treatment efficacy of advanced pancreatic cancer.
OBJECTIVE
We sought to investigate whether the addition of nimotuzumab to gemcitabine would improve the treatment efficacy of advanced pancreatic cancer.
METHODS
This retrospective analysis involved a total of 98 hospitalized patients harboring advanced pancreatic cancer. Depending on the specific treatment, patients were divided into study groups and control groups. The clinical efficacy, adverse reactions, and follow-up results of the 2 groups were compared, and the physical status, CA724, CA19-9, and CEA levels before and after treatment were monitored and recorded.
RESULTS
After treatment, PR ratio, SD ratio, ORR, and DCR in the study group were significantly higher than those in the control group, and PD ratio was significantly lower than that in the control group (P < 0.05) the KPS score after treatment in the study group was markedly higher than that of the control group (P < 0.05). After treatment, however, significantly lower levels of the 3 indicators were observed when compared with the control group (P < 0.05).
CONCLUSION
Our study highlights a more superior combined efficacy of nimotuzumab and gemcitabine than the control regimen, exhibiting improved survival and reduced levels of CA724, CA19-9, and CEA in patients with advanced pancreatic cancer.
Topics: Humans; Pancreatic Neoplasms; Gemcitabine; Deoxycytidine; Male; Female; Antibodies, Monoclonal, Humanized; Retrospective Studies; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Adult; Carcinoembryonic Antigen; CA-19-9 Antigen; Aged, 80 and over; Antigens, Tumor-Associated, Carbohydrate
PubMed: 38888842
DOI: 10.1097/MPA.0000000000002328 -
Bioorganic & Medicinal Chemistry Letters Sep 2024For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl...
For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl ester (CPE) system used in peptide thioester synthesis, which normally requires basic conditions, for use as an self-immolative linker and release device for a lipid-gemcitabine conjugate. To improve release under physiological conditions for medical application, a methyl group at the α-position of cysteine on the CPE unit was incorporated in anticipation of the Thorpe-Ingold effect. As a result, Ac-Gly-(α-Me)Cys(SH)-Pro-gemcitabine 11 drastically promoted the release of gemcitabine in comparison with Ac-Gly-Cys(SH)-Pro-gemcitabine 10. Furthermore, in the presence of bovine serum albumin and/or 2-mercaptoethanesulfonic acid, the gentle and continuous release of gemcitabine from the lipid-gemcitabine conjugate 16 was achieved. In addition to gemcitabine, this method could allow high clearance drugs, including nucleic acid and prostacyclin derivatives, to maintain their biological activity long enough to become effective.
Topics: Gemcitabine; Deoxycytidine; Lipids; Esters; Drug Liberation; Cysteine; Humans; Molecular Structure; Serum Albumin, Bovine; Animals
PubMed: 38879090
DOI: 10.1016/j.bmcl.2024.129850 -
Cancer Medicine Jun 2024Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated...
BACKGROUND AND AIMS
Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer.
METHODS
To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRAS/LSL-p53/TFF1) were analyzed by immunohistochemistry (IHC). To explore the efficacy of extracellular administration of TFF1, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines, a xenograft mouse model and a transgenic mouse model.
RESULTS
The deficiency of TFF1 was associated with increased EMT of cancer cells in mouse models of pancreatic cancer, KPC. The expression of TFF1 in cancer cells was associated with better survival rate of the patients who underwent chemotherapy, and loss of TFF1 deteriorated the benefit of gemcitabine in KPC mice. Extracellular administration of TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model and resulted in the better survival of KPC mice by inhibiting EMT and cancer stemness.
CONCLUSION
These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.
Topics: Animals; Pancreatic Neoplasms; Trefoil Factor-1; Humans; Mice; Epithelial-Mesenchymal Transition; Neoplastic Stem Cells; Drug Resistance, Neoplasm; Cell Line, Tumor; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays; Gemcitabine; Mice, Transgenic; Female; Male; Cell Proliferation; Deoxycytidine; Apoptosis; Gene Expression Regulation, Neoplastic
PubMed: 38872370
DOI: 10.1002/cam4.7395 -
Cirugia Y Cirujanos 2024In the 1980s in Mexico, that of the «moral renewal», there was the opening to the market and the manifestation of human immunodeficiency virus (HIV) and AIDS. In this...
In the 1980s in Mexico, that of the «moral renewal», there was the opening to the market and the manifestation of human immunodeficiency virus (HIV) and AIDS. In this writing, the historical and therapeutic conditions are related to alleviate the syndrome until the arrival of the first antiretroviral. It is a reconstruction of the events, of which the medical-social, main clinical manifestations and of course the pharmacological therapy, until de the development zidovudina or azidotimidina of AZT, the first antiretroviral to be approved. Nevertheless, in the Mexican context, this event wasn't decisive to significantly change the morbility and the mortality.
Topics: Mexico; Humans; Zidovudine; History, 20th Century; HIV Infections; Anti-HIV Agents; Acquired Immunodeficiency Syndrome
PubMed: 38862119
DOI: 10.24875/CIRU.22000250 -
Luminescence : the Journal of... Jun 2024The goal of the current research was to establish a quick and practical fluorometric technique for trifluridine analysis. The approach relied on the drug's complex...
The goal of the current research was to establish a quick and practical fluorometric technique for trifluridine analysis. The approach relied on the drug's complex formation with the zinc ion to produce a high-fluorescence product. The fluorescence was further enhanced by adding sodium dodecyl sulfate, and it was observed at 450 nm following excitation at 400 nm. With a determination coefficient of 0.9994, the association between emission intensity and trifluridine concentration was linear between 1 and 125 ng mL. The quantitation limit was 0.987 ng mL while 0.333 ng mL was the detection limit. The buffer type, pH and concentration, type of surfactant and concentration, and finally the diluting solvent were among the reaction conditions that were closely examined. With great precision and reliability, the drug in question was quantified using this method in dosage formulations. The proposed method's level of greenness was assessed using two methodologies: the analytical greenness metric (AGREE) and the Green Analytical Procedure Index (GAPI).
Topics: Spectrometry, Fluorescence; Trifluridine; Green Chemistry Technology; Hydrogen-Ion Concentration; Zinc; Sodium Dodecyl Sulfate; Dosage Forms; Limit of Detection
PubMed: 38859746
DOI: 10.1002/bio.4793