Tag: pubmed

Phys Chem Chem Phys. 2024 Jul 9. doi: 10.1039/d4cp02116a. Online ahead of print.

ABSTRACT

A trajectory surface hopping approach, which uses machine learning to speed up the most time-consuming steps, has been adopted to investigate the exciton transfer in light-harvesting systems. The present neural networks achieve high accuracy in predicting both Coulomb couplings and excitation energies. The latter are predicted taking into account the environment of the pigments. Direct simulation of exciton dynamics through light-harvesting complexes on significant time scales is usually challenging due to the coupled motion of nuclear and electronic degrees of freedom in these rather large systems containing several relatively large pigments. In the present approach, however, we are able to evaluate a statistically significant number of non-adiabatic molecular dynamics trajectories with respect to exciton delocalization and exciton paths. The formalism is applied to the Fenna-Matthews-Olson complex of green sulfur bacteria, which transfers energy from the light-harvesting chlorosome to the reaction center with astonishing efficiency. The system has been studied experimentally and theoretically for decades. In total, we were able to simulate non-adiabatically more than 30 ns, sampling also the relevant space of parameters within their uncertainty. Our simulations show that the driving force supplied by the energy landscape resulting from electrostatic tuning is sufficient to funnel the energy towards site 3, from where it can be transferred to the reaction center. However, the high efficiency of transfer within a picosecond timescale can be attributed to the rather unusual properties of the BChl a molecules, resulting in very low inner and outer-sphere reorganization energies, not matched by any other organic molecule, e.g., used in organic electronics. A comparison with electron and exciton transfer in organic materials is particularly illuminating, suggesting a mechanism to explain the comparably high transfer efficiency.

PMID:38979564 | DOI:10.1039/d4cp02116a

Oncol Lett. 2024 Jun 26;28(2):401. doi: 10.3892/ol.2024.14534. eCollection 2024 Aug.

ABSTRACT

Transcatheter arterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and camrelizumab (collectively: T-T-C) is a novel treatment strategy for unresectable hepatocellular carcinoma (HCC). The present systematic review and meta-analysis aimed to evaluate the efficacy and safety of T-T-C compared with TACE combined with TKIs only (T-T) in the treatment of patients with unresectable HCC. A systematic literature search was conducted on T-T and T-T-C using PubMed, Embase and the Cochrane Library. Data regarding the clinical outcome, including overall survival (OS), progression-free survival (PFS), tumor response and adverse events (AEs), were independently extracted and analyzed by two researchers using standardized protocols. In total, 7 cohort studies, including 1,798 patients (T-T-C, 838; T-T, 960), were included in the meta-analysis. The results of the present study demonstrated that the T-T-C group had significantly prolonged OS [hazard ratio (HR), 0.38; 95% confidence interval (CI), 0.29-0.50; I²=61.5%; P=0.016)] and PFS (HR, 0.37; 95% CI, 0.30-0.46; I²=44.5%; P=0.109), and showed significantly higher objective response rates [risk ratio (RR), 0.82; 95% CI, 0.69-0.96; I²=25.1%; P=0.237)] and slightly higher disease control rates without a significant difference (RR, 0.96; 95% CI, 0.89-1.03; I²=0.0%; P=0.969). In addition, grade 3/4 AEs were more common in the T-T group, including hypertension (RR, 1.15; 95% CI, 0.85-1.56), vomiting or nausea (RR, 0.88; 95% CI, 0.44-1.76) and pain (RR, 0.74; 95% CI, 0.45-1.21); however, these results were not statistically significant. In conclusion, compared with T-T combination therapy, T-T-C demonstrated a notable advantage in terms of OS, PFS, ORR and DCR in patients with unresectable HCC. For manageable AEs, although the results were not statistically significant, the incidence of AEs in the T-T group was higher than that in the T-T-C group in terms of event probability.

PMID:38979553 | PMC:PMC11228926 | DOI:10.3892/ol.2024.14534

Oncol Lett. 2024 Jun 26;28(2):399. doi: 10.3892/ol.2024.14532. eCollection 2024 Aug.

ABSTRACT

von Willebrand Factor (VWF) is well recognized for being dysregulated in various malignancies and has emerged as a potential biomarker for cancer detection. The present meta-analysis aimed to elucidate the association between plasma VWF and the incidence and metastasis of cancer. For this purpose, a comprehensive search was conducted across multiple databases from their inception until March 3, 2023. This culminated in the selection of 15 original studies on various types of cancer, including a collective sample of 1,403 individuals. The standardized mean difference (SMD) and 95% confidence intervals (CIs) were employed as statistical parameters to determine the association between plasma VWF and the incidence and metastasis of cancer. These were estimated using a random-effects model. The pooled data revealed that the plasma VWF levels of patients with cancer were significantly elevated compared with those of healthy controls (SMD, 0.98; 95% CI, 0.59-1.36), and a significant association was observed between plasma VWF levels and cancer metastasis (SMD, 0.69; 95% CI, 0.33-1.06). The symmetry of the Begg’s funnel plots indicated that no significant bias was present in the analyses of VWF in cancer and its metastasis. In summary, the results of the present meta-analysis support the hypothesis that increased plasma VWF levels may serve as a biomarker for cancer and metastatic progression.

PMID:38979552 | PMC:PMC11228924 | DOI:10.3892/ol.2024.14532

Glob Reg Health Technol Assess. 2024 Jul 3;11:161-168. doi: 10.33393/grhta.2024.3042. eCollection 2024 Jan-Dec.

ABSTRACT

BACKGROUND: Administrative burdens have been identified as a major issue impacting patient care, professional practice, and the overall efficiency of healthcare systems. The aim of this study is to assess the administrative burden faced by Italian hematologists.

METHODS: A cross-sectional survey that included both closed-ended quantitative questions and open-ended free text answer options was administered to 1,570 hematologists working with malignancies and members of Italian GIMEMA Foundation – Franco Mandelli ONLUS and the Italian Linfomi Foundation (FIL). The survey was conducted online from May 24 to June 30, 2023. Descriptive statistics were computed for the quantitative data to clearly summarize the responses and descriptive analysis of free text responses was carried out.

RESULTS: Surveyed hematologists spend an average of 47.07% of their time on administrative tasks, with 63.22% (n = 110) of respondents reporting spending at least half of their time on these activities. More than half (57.47%, n = 100) reported that “Patient care” is the medical task most affected by a lack of time. Additionally, 55.17% (n = 96) reported experiencing burnout in the past 6 months, with filling out “Forms” being identified as the top contributing administrative task by 27.59% (n = 48) of respondents, followed by “Scheduling” (24.71%, n = 43) and “Managing IT system failures” (21.84%, n = 38). Nearly half of the surveyed hematologists (45.40%, n = = 79) identified patient care as the top priority requiring more time.

CONCLUSIONS: The study confirms that the administrative workload of hematologists has a significant impact on patient care, communication, and burnout risk, reducing the time available for patient care, leading to exhaustion and concern about clinical errors.

PMID:38979549 | PMC:PMC11228512 | DOI:10.33393/grhta.2024.3042

Front Cell Infect Microbiol. 2024 Jun 24;14:1309529. doi: 10.3389/fcimb.2024.1309529. eCollection 2024.

ABSTRACT

BACKGROUND: Early prediction of prognosis may help early treatment measures to reduce mortality in critically ill coronavirus disease (COVID-19) patients. The study aimed to develop a mortality prediction model for critically ill COVID-19 patients.

METHODS: This retrospective study analyzed the clinical data of critically ill COVID-19 patients in an intensive care unit between April and June 2022. Propensity matching scores were used to reduce the effect of confounding factors. A predictive model was built using logistic regression analysis and visualized using a nomogram. Calibration and receiver operating characteristic (ROC) curves were used to estimate the accuracy and predictive value of the model. Decision curve analysis (DCA) was used to examine the value of the model for clinical interventions.

RESULTS: In total, 137 critically ill COVID-19 patients were enrolled; 84 survived, and 53 died. Univariate and multivariate logistic regression analyses revealed that aspartate aminotransferase (AST), creatinine, and myoglobin levels were independent prognostic factors. We constructed logistic regression prediction models using the seven least absolute shrinkage and selection operator regression-selected variables (hematocrit, red blood cell distribution width-standard deviation, procalcitonin, AST, creatinine, potassium, and myoglobin; Model 1) and three independent factor variables (Model 2). The calibration curves suggested that the actual predictions of the two models were similar to the ideal predictions. The ROC curve indicated that both models had good predictive power, and Model 1 had better predictive power than Model 2. The DCA results suggested that the model intervention was beneficial to patients and patients benefited more from Model 1 than from Model 2.

CONCLUSION: The predictive model constructed using characteristic variables screened using LASSO regression can accurately predict the prognosis of critically ill COVID-19 patients. This model can assist clinicians in implementing early interventions. External validation by prospective large-sample studies is required.

PMID:38979512 | PMC:PMC11228157 | DOI:10.3389/fcimb.2024.1309529

RSC Adv. 2024 Jul 8;14(30):21432-21438. doi: 10.1039/d4ra02345e. eCollection 2024 Jul 5.

ABSTRACT

In the technical route for the synthesis of avanafil, 1-ethyl-(3-dimethylaminopropyl)carbamyldiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT) are used as reactive acid-amine binding agents. HOBT contains trace amounts of hydrazine residue, and there is a risk of introducing potentially mutagenic impurities with hydrazide-containing structures. The potentially genotoxic impurities E (Imp-E) and F (Imp-F) of avanafil with altering hydrazide-structure were synthesized by chemical method; subsequently, the impurities were evaluated and classified according to ICH M7 guidelines. Two complementary quantitative structure-activity relationship (QSAR) evaluation systems (Derek and Sarah) based on expert rules and statistics were used to preliminarily predict the genotoxicity of Imp-E and Imp-F, and the prediction result of E was suspected to be positive. In the Ames test of Imp-E and Imp-F, in the dose range of 62.5-1000 μg per plate, with or without the presence of metabolic activation system S9, the number of revertant colonies did not exceed 2 times the number of colonies in the solvent control group and did not show a dose-response relationship, and the test results were negative. Imp-E and Imp-F were determined to be negative for genotoxicity, which could be controlled as class 5 in ICH M7, that is, non mutagenic impurity.

PMID:38979469 | PMC:PMC11228755 | DOI:10.1039/d4ra02345e

Front Immunol. 2024 Jun 24;15:1402018. doi: 10.3389/fimmu.2024.1402018. eCollection 2024.

ABSTRACT

AIM: To investigate the efficacy and safety of combining Recombinant Human Endostatin Injection (marketed as Endo) with anti-PD-1 in elderly patients aged 80 and above with non-small cell lung cancer (NSCLC).

METHODS: Retrospective analysis of 181 patients with NSCLC aged 80 and above treated in the Department of Respiratory and Critical Care Medicine at Chaohu Hospital, affiliated with Anhui Medical University, from June 2019 to January 2024. Patients who received at least one cycle of combined Endo with anti-PD-1 were included based on inclusion criteria. Clinical and pathological data were collected, including complete blood count, liver and kidney function, electrocardiogram, coagulation function, thyroid function, cardiac enzymes, and whole-body imaging. Adverse events were recorded with a final follow-up on January 25, 2024. The primary endpoints were progression-free survival (PFS) and overall survival (OS), with safety as a secondary endpoint.

RESULTS: This study involved 14 elderly patients with NSCLC aged over 80. Median progression-free survival (mPFS) was 102 days, and median overall survival (mOS) was 311 days. Subgroup analyses based on treatment cycles showed a non-significant 441-day mPFS increase in the long-term group (≥6 cycles, 5 patients) compared to the short-term group (<6 cycles, 9 patients). However, the mOS in the long-term group significantly exceeded the short-term group by 141 days, with statistical significance (P=0.048). Further categorization revealed a 204-day shorter mPFS in the monotherapy maintenance group (Endo or Immunol) compared to the combination maintenance group (Endo combined with Immunol, 441 days). The mOS of the monotherapy maintenance group was longer (686 days) than the combination maintenance group (311 days), but no statistical significance (P= 0.710, 0.920). Throughout the treatment, 77 adverse events were recorded, mainly grade 1-2, with no new treatment-related reactions occurred. Overall, the safety of Endo combined with anti-PD-1 was considered good and manageable.

CONCLUSION: The combination of Endo and anti-PD-1 could be an effective treatment choice for patients with NSCLC aged 80 and above.

PMID:38979430 | PMC:PMC11228178 | DOI:10.3389/fimmu.2024.1402018

Front Immunol. 2024 Jun 10;15:1418717. doi: 10.3389/fimmu.2024.1418717. eCollection 2024.

ABSTRACT

BACKGROUND: A burgeoning body of evidence has substantiated the association between alterations in the composition of the gut microbiota and rheumatoid arthritis (RA). Nevertheless, our understanding of the intricate mechanisms underpinning this association is limited.

METHODS: To investigate whether the gut microbiota influences the pathogenesis of RA through metabolism or immunity, we performed rigorous synthesis analyses using aggregated statistics from published genome-wide association studies (GWAS) using two-sample Mendelian randomization (MR) and mediated MR techniques, including two-step MR and multivariate MR analyses. Subsequently, we conducted in vitro cellular validation of the analyzed Microbial-Cytokine-RA pathway. We determined the optimal culture conditions through co-culture experiments involving concentration and time. Cell Counting Kit-8 (CCK-8) assays were employed to assess cellular viability, and enzyme-linked immunosorbent assays (ELISA) were performed to assess tumor necrosis factor-inducible gene 6 protein (TSG-6) and tumor necrosis factor-α (TNF-α) levels.

RESULTS: Our univariable MR results confirmed 15 microbial traits, 7 metabolites and 2 cytokines that may be causally associated with RA (P _FDR < 0.05). Mediation analysis revealed that microbial traits influence the risk of RA through metabolite or cytokine (proportion mediated: 7.75% – 58.22%). In vitro experiments demonstrated that TSG-6 was highly expressed in the Subdoligranulum variabile treatment group and was correlated with decreased RA severity (reduced TNF-α expression). Silencing the TSG-6 gene significantly increased TNF-α expression, regardless of treatment with S. variabile. Additionally, S. variabile-secreted exosomes exhibited the same effect.

CONCLUSION: The results of this study suggest that S. variabile has the potential to promote TSG-6 secretion, thereby reducing RA inflammation.

PMID:38979426 | PMC:PMC11229780 | DOI:10.3389/fimmu.2024.1418717

Front Immunol. 2024 Jun 24;15:1405348. doi: 10.3389/fimmu.2024.1405348. eCollection 2024.

ABSTRACT

BACKGROUND: Antiretroviral therapy (ART) for HIV-1 treatment has improved lifespan but requires lifelong adherence for people living with HIV (PLWH), highlighting the need for a cure. Evaluation of potential cure strategies requires analytic treatment interruption (ATI) with close monitoring of viral rebound. Predictive biomarkers for HIV-1 rebound and/or duration of control during ATI will facilitate these HIV cure trials while minimizing risks. Available evidence suggests that host immune, glycomic, lipid, and metabolic markers of inflammation may be associated with HIV-1 persistence in PLWH who are treated during chronic HIV-1 infection.

METHODS: We conducted post-hoc analysis of HIV controllers who could maintain low levels of plasma HIV-1 without ART in a phase 1b vesatolimod trial. Baseline and pre-ATI levels of immune, glycomic, lipidomic, and metabolomic markers were tested for association with ATI outcomes (time of HIV-1 rebound to 200 copies/mL and 1,000 copies/mL, duration of HIV-1 RNA ≤400 copies/mL and change in intact proviral HIV-1 DNA during ATI) using Spearman’s correlation and Cox proportional hazards model.

RESULTS: Higher levels of CD69+CD8+ T-cells were consistently associated with shorter time to HIV-1 rebound at baseline and pre-ATI. With few exceptions, baseline fucosylated, non-galactosylated, non-sialylated, bisecting IgG N-glycans were associated with shorter time to HIV rebound and duration of control as with previous studies. Baseline plasma MPA and HPA binding glycans and non-galactosylated/non-sialylated glycans were associated with longer time to HIV rebound, while baseline multiply-galactosylated glycans and sialylated glycans, GNA-binding glycans, NPA-binding glycans, WGA-binding glycans, and bisecting GlcNAc glycans were associated with shorter time to HIV rebound and duration of control. Fourteen bioactive lipids had significant baseline associations with longer time to rebound and duration of control, and larger intact proviral HIV-1 DNA changes; additionally, three baseline bioactive lipids were associated with shorter time to first rebound and duration of control.

CONCLUSION: Consistent with studies in HIV non-controllers, proinflammatory glycans, lipids, and metabolites were generally associated with shorter duration of HIV-1 control. Notable differences were observed between HIV controllers vs. non-controllers in some specific markers. For the first time, exploratory biomarkers of ATI viral outcomes in HIV-controllers were investigated but require further validation.

PMID:38979421 | PMC:PMC11229794 | DOI:10.3389/fimmu.2024.1405348

Front Immunol. 2024 Jun 24;15:1394123. doi: 10.3389/fimmu.2024.1394123. eCollection 2024.

ABSTRACT

OBJECTIVE: To evaluate the cardiovascular safety of anticancer drug immune checkpoint inhibitors (ICIs) used in patients with malignant tumors.

METHODS: Four clinical research databases that have been completed since their establishment were searched, and the odds ratios and 95% confidence intervals of each indicator were statistically calculated.

RESULTS: 62 randomized controlled trial and controlled trials were included. In single drug treatment ICIs group, the overall risk of cardio cerebral Vascular disease at all levels was higher than that in the placebo/chemotherapy group. Especially in all grades of Myocarditis and above grade 3 compared with normal controls, except for pericardial lesions, other indicators have no obvious side effects.

CONCLUSION: Single drug use of an anti-tumor ICIs may increase cardiovascular side effects risk in cancer patients, so we need to strengthen monitoring, identification and management, and timely intervention to manage ICI induced adverse events.

PMID:38979409 | PMC:PMC11228135 | DOI:10.3389/fimmu.2024.1394123