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BMC Public Health Jun 2024Pre-exposure prophylaxis (PrEP) with oral emtricitabine/tenofovir disoproxil (FTC/TDF) proved highly efficient in preventing HIV. Since 09/2019, FTC/TDF-PrEP is covered...
BACKGROUND
Pre-exposure prophylaxis (PrEP) with oral emtricitabine/tenofovir disoproxil (FTC/TDF) proved highly efficient in preventing HIV. Since 09/2019, FTC/TDF-PrEP is covered by health insurances in Germany, if prescribed by licensed specialists. However, methods to longitudinally monitor progress in PrEP implementation in Germany are lacking.
METHODS
Utilizing anonymous FTC/TDF prescription data from 2017-2021, we developed a mathematical model to disentangle HIV-treatment from PrEP prescriptions, as well as to translate PrEP prescriptions into number of PrEP users. We used the model to estimate past- and future PrEP uptake dynamics, to predict coverage of PrEP needs and to quantify the impact of COVID-19 on PrEP uptake on a national and regional level.
RESULTS
We identified significant (p<0.01) decelerating effects of the first- and second COVID-19-lockdown on PrEP uptake in 04/2020 and 12/2020. We estimated 26,159 (CI: 25,751-26,571) PrEP users by 12/2021, corresponding to 33% PrEP coverage of people in need. We projected 64,794 (CI: 62,956-66,557) PrEP users by 12/2030, corresponding to 81% PrEP coverage. We identified profound regional differences, with high PrEP coverage and uptake in metropoles and low coverage in more rural regions.
CONCLUSIONS
Our approach presents a comprehensive solution to monitor and forecast PrEP implementation from anonymous data and highlighted that the COVID-19 pandemic significantly decelerated PrEP uptake in Germany. Moreover, slow PrEP uptake in rural areas indicate that structural barriers in PrEP care, education or information exist that may hamper the goal of ending the AIDS epidemic by 2030.
Topics: Humans; Pre-Exposure Prophylaxis; Germany; HIV Infections; COVID-19; Anti-HIV Agents; Male; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Female; Models, Theoretical; Adult
PubMed: 38918748
DOI: 10.1186/s12889-024-19198-y -
Asian Pacific Journal of Cancer... Jun 2024Capecitabine has been widely prescribed to treat various cancers. The hand foot syndrome (HFS) is the most troublesome adverse effect. Urea cream has been pre-emptively... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
A Randomized Single-Blinded Phase II Trial Comparing Efficacy and Quality of Life of Topical Aloe Vera Gel Plus Urea Cream Versus Urea Cream Alone for Prevention of Hand Foot Syndrome in Cancer Patients Receiving Capecitabine.
INTRODUCTION
Capecitabine has been widely prescribed to treat various cancers. The hand foot syndrome (HFS) is the most troublesome adverse effect. Urea cream has been pre-emptively co-prescribed, even though its efficacy is doubtful. Aloe vera gel with urea cream might potentiate each other. This trial was intended to prove the efficacy of this combination.
MATERIALS AND METHODS
The investigators conducted a randomized single-blinded phase II study. The participants were randomized 1:1 to receive the combination of aloe vera gel and 10% urea cream (n = 30), the experimental A+U arm and 10% urea cream alone (n = 31), the U arm. The sample size was calculated to have 90% power to show the significant 20% reduction in the incidence of HFS grade 2-3 of the combination therapy with alpha level = 0.05. Both the CTCAE criteria version 5 and the dermatology life quality index (DLQI) were assessed to determine the severity of HFS and quality of life, respectively.
RESULTS
Most of the participants had rectal cancer (A+U: 43.3%; U: 41.9%). In the A+U group, 86.7% had grade 0-1 HFS and 13.3% had grade 2-3 HFS. In the U group, 64.5% had grade 0-1 HFS and 35.5% had grade 2-3 HFS (Mann-Whitney U test, p = 0.045). Grade 2-3 HFS was significantly lower in the combination group.
CONCLUSION
Combination of aloe vera gel and 10% urea cream ameliorated the severity of HFS in participants taking capecitabine; however, no significant difference in DLQI between the groups was demonstrated.
Topics: Humans; Capecitabine; Female; Male; Middle Aged; Quality of Life; Hand-Foot Syndrome; Urea; Antimetabolites, Antineoplastic; Single-Blind Method; Plant Preparations; Prognosis; Follow-Up Studies; Adult; Administration, Topical; Aged; Neoplasms; Skin Cream; Aloe
PubMed: 38918684
DOI: 10.31557/APJCP.2024.25.6.2203 -
Organic & Biomolecular Chemistry Jun 2024The purinyl ring contains four embedded nitrogen atoms of varying basicities. Selective utilization of these ring nitrogen atoms can lead to relatively facile remote...
The purinyl ring contains four embedded nitrogen atoms of varying basicities. Selective utilization of these ring nitrogen atoms can lead to relatively facile remote functionalization, yielding modified purinyl motifs that are otherwise not easily obtained. Herein, we report previously undescribed -directed aroylation of 6-arylpurine ribo and the more labile 2'-deoxyribonucleosides. Kinetic isotope analysis as well as reaction with a well-defined dimeric, palladated 9-benzyl 6-arylpurine provided evidence for -directed cyclometallation as a key step, with a plausible rate-limiting C-H bond cleavage. Radical inhibition experiments indicate the likely intermediacy of aroyl radicals. The chemistry surmounts difficulties often posed in the functionalization of polynitrogenated and polyoxygenated nucleosidic structures that possess complex reactivities and a labile glycosidic bond that is more sensitive in the 2'-deoxy substrates.
PubMed: 38916551
DOI: 10.1039/d4ob00689e -
Acta Oncologica (Stockholm, Sweden) Jun 2024Background and purpose: Capecitabine can be used as first-line treatment for advanced breast cancer. However, real-world data on efficacy of capecitabine in this...
UNLABELLED
Background and purpose: Capecitabine can be used as first-line treatment for advanced breast cancer. However, real-world data on efficacy of capecitabine in this setting is sparse. The purpose of the study is to evaluate outcomes of patients with Human Epidermal Growth Factor Receptor (HER2)-normal advanced breast cancer treated with capecitabine monotherapy as first-line treatment.
MATERIAL AND METHODS
The study utilized the Danish Breast Cancer Group (DBCG) database and was conducted retrospectively across all Danish oncology departments. Inclusion criteria were female patients, with HER2-normal advanced breast cancer treated with capecitabine monotherapy as the first-line treatment from 2010 to 2020. The primary endpoints were overall survival (OS) and progression-free survival (PFS).
RESULTS
A total of 494 patients were included. Median OS was 16.4 months (95% confidence interval [CI]: 14.5-18.0), and median PFS was 6.0 months (95% CI: 5.3-6.7). Patients with estrogen receptor (ER)-positive disease had significantly longer OS (median: 22.8 vs. 10.5 months, p < 0.001) and PFS (median: 7.4 vs. 4.9 months, p = 0.003), when compared to ER-negative patients. Stratifying by age, patients under 45 years displayed a median PFS of 4.1 months, while those aged 45-70 years and over 70 years had median PFS of 5.7 and 7.2 months, respectively (p = 0.01).
INTERPRETATION
In this nationwide study, the efficacy of capecitabine as a first-line treatment for HER2-normal advanced breast cancer is consistent with other, mainly retrospective, studies. However, when assessed against contemporary and newer treatments, its effectiveness appears inferior to alternative chemotherapies or targeted therapies.
Topics: Humans; Capecitabine; Female; Retrospective Studies; Breast Neoplasms; Middle Aged; Receptor, ErbB-2; Aged; Adult; Antimetabolites, Antineoplastic; Aged, 80 and over; Denmark; Progression-Free Survival; Receptors, Estrogen
PubMed: 38912829
DOI: 10.2340/1651-226X.2024.38886 -
Journal of Nanobiotechnology Jun 2024Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection...
BACKGROUND
Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection is an important component of successful surgery. With the development of new nanotechnology, more treatment options have been provided for postoperative adjuvant therapy. This study presents an innovative hydrogel system that stimulates tumoricidal immunity after surgical resection of non-small cell lung cancer (NSCLC) and prevents cancer relapse.
RESULTS
The hydrogel system is based on the excellent photothermal conversion performance of single-atom platinum (CN-Pt) along with the delivery and release of the chemotherapy drug, gemcitabine (GEM). The system is coated onto the wound surface after tumor removal with subsequent near-infrared (NIR) photothermal therapy, which efficiently induces necroptosis of residual cancer cells, amplifies the levels of damage-associated molecular patterns (DAMPs), and increases the number of M1 macrophages. The significantly higher levels of phagocytic macrophages enhance tumor immunogenicity and sensitize cancer cells to CD8 + T-cell immunity to control postoperative recurrence, which has been verified using an animal model of postoperative lung cancer recurrence. The CN-Pt-GEM-hydrogel with NIR can also inhibit postoperative wound infection.
CONCLUSIONS
These findings introduce an alternative strategy for supplementing antitumor immunity in patients undergoing resection of NSCLC tumors. The CN-Pt-GEM-hydrogel with the NIR system also exhibits good biosafety and may be adaptable for clinical application in relation to tumor resection surgery, wound tissue filling, infection prevention, and recurrence prevention.
Topics: Animals; Lung Neoplasms; Mice; Deoxycytidine; Hydrogels; Gemcitabine; Humans; Carcinoma, Non-Small-Cell Lung; Necroptosis; Neoplasm Recurrence, Local; Cell Line, Tumor; Immunotherapy; Photothermal Therapy; Wound Infection; Macrophages; Mice, Inbred C57BL; CD8-Positive T-Lymphocytes
PubMed: 38902678
DOI: 10.1186/s12951-024-02568-4 -
Nature Communications Jun 2024Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9...
Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-β and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.
Topics: Pancreatic Neoplasms; Humans; Animals; CRISPR-Cas Systems; Mice; Cell Line, Tumor; Ubiquitin-Specific Proteases; Mutation; Gene Expression Regulation, Neoplastic; Deoxycytidine; Gemcitabine
PubMed: 38902237
DOI: 10.1038/s41467-024-49450-3 -
Journal of Chemical Information and... Jun 2024DNA polymerases (Pols) add incoming nucleotides (deoxyribonucleoside triphosphate (dNTPs)) to growing DNA strands, a crucial step for DNA synthesis. The insertion of...
DNA polymerases (Pols) add incoming nucleotides (deoxyribonucleoside triphosphate (dNTPs)) to growing DNA strands, a crucial step for DNA synthesis. The insertion of correct (vs incorrect) nucleotides relates to Pols' fidelity, which defines Pols' ability to faithfully replicate DNA strands in a template-dependent manner. We and others have demonstrated that reactant alignment and correct base pairing at the Pols catalytic site are crucial structural features to fidelity. Here, we first used equilibrium molecular simulations to demonstrate that the local dynamics at the protein-DNA interface in the proximity of the catalytic site is different when correct vs incorrect dNTPs are bound to polymerase β (Pol β). Formation and dynamic stability of specific interatomic interactions around the incoming nucleotide influence the overall binding site architecture. This explains why certain Pols' mutants can affect the local catalytic environment and influence the selection of correct vs incorrect nucleotides. In particular, this is here demonstrated by analyzing the interaction network formed by the residue R283, whose mutant R283A has an experimentally measured lower capacity of differentiating correct (G:dCTP) vs incorrect (G:dATP) base pairing in Pol β. We also used alchemical free-energy calculations to quantify the G:dCTP →G:dATP transformation in Pol β wild-type and mutant R283A. These results correlate well with the experimental trend, thus corroborating our mechanistic insights. Sequence and structural comparisons with other Pols from the same family suggest that these findings may also be valid in similar enzymes.
PubMed: 38901009
DOI: 10.1021/acs.jcim.4c00696 -
BMJ (Clinical Research Ed.) Jun 2024To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Nab-paclitaxel, cisplatin, and capecitabine versus cisplatin and gemcitabine as first line chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma: randomised phase 3 clinical trial.
OBJECTIVE
To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma.
DESIGN
Phase 3, open label, multicentre, randomised trial.
SETTING
Four hospitals located in China between September 2019 and August 2022.
PARTICIPANTS
Adults (≥18 years) with recurrent or metastatic nasopharyngeal carcinoma.
INTERVENTIONS
Patients were randomised in a 1:1 ratio to treatment with either nab-paclitaxel (200 g/m on day 1), cisplatin (60 mg/m on day 1), and capecitabine (1000 mg/m twice on days 1-14) or gemcitabine (1 g/m on days 1 and 8) and cisplatin (80 mg/m on day 1).
MAIN OUTCOME MEASURES
Progression-free survival was evaluated by the independent review committee as the primary endpoint in the intention-to-treat population.
RESULTS
The median follow-up was 15.8 months in the prespecified interim analysis (31 October 2022). As assessed by the independent review committee, the median progression-free survival was 11.3 (95% confidence interval 9.7 to 12.9) months in the nab-TPC cohort compared with 7.7 (6.5 to 9.0) months in the gemcitabine and cisplatin cohort. The hazard ratio was 0.43 (95% confidence interval 0.25 to 0.73; P=0.002). The objective response rate in the nab-TPC cohort was 83% (34/41) versus 63% (25/40) in the gemcitabine and cisplatin cohort (P=0.05), and the duration of response was 10.8 months in the nab-TPC cohort compared with 6.9 months in the gemcitabine and cisplatin cohort (P=0.009). Treatment related grade 3 or 4 adverse events, including leukopenia (4/41 (10%) 13/40 (33%); P=0.02), neutropenia (6/41 (15%) 16/40 (40%); P=0.01), and anaemia (1/41 (2%) 8/40 (20%); P=0.01), were higher in the gemcitabine and cisplatin cohort than in the nab-TPC cohort. No deaths related to treatment occurred in either treatment group. Survival and long term toxicity are still being evaluated with longer follow-up.
CONCLUSION
The nab-TPC regimen showed a superior antitumoural efficacy and favourable safety profile compared with gemcitabine and cisplatin for recurrent or metastatic nasopharyngeal carcinoma. Nab-TPC should be considered the standard first line treatment for recurrent or metastatic nasopharyngeal carcinoma. Longer follow-up is needed to confirm the benefits for overall survival.
TRIAL REGISTRATION
Chinese Clinical Trial Registry ChiCTR1900027112.
Topics: Humans; Cisplatin; Male; Middle Aged; Female; Gemcitabine; Nasopharyngeal Carcinoma; Deoxycytidine; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Adult; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Paclitaxel; Albumins; Aged; Progression-Free Survival; China; Neoplasm Metastasis
PubMed: 38897625
DOI: 10.1136/bmj-2023-077890 -
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