Acetylcholinesterase (AChE) is one of the main drug targets for treating Alzheimer\'s disease. This current study relies on multiple molecular modeling approaches to develop new potent inhibitors of AChE. We explored a 2D QSAR study using the statistical method of multiple linear regression based on a set of substituted 5-phenyl-1,3,4-oxadiazole and N-benzylpiperidine analogs, which were recently synthesized and proved their inhibitory activities against acetylcholinesterase (AChE). The molecular descriptors, polar surface area, dipole moment, and molecular weight are the key structural properties governing AChE inhibition activity. The MLR model was selected based on its statistical parameters: R2 = 0.701, R2test = 0.76, Q2CV = 0.638, and RMSE = 0.336, demonstrating its predictive reliability. Randomization tests, VIF tests, and applicability domain tests were adopted to verify the model\'s robustness. As a result, 11 new molecules were designed with higher anti-Alzheimer\'s activities than the model molecule. We demonstrated their improved pharmacokinetic properties through an in silico ADMET study. A molecular docking study was conducted to explore their AChE inhibition mechanisms and binding affinities in the active site. The binding scores of compounds M1, M2, and M6 were (-12.6 kcal/mol), (-13 kcal/mol), and (-12.4 kcal/mol), respectively, which are higher than the standard inhibitor Donepezil with a binding score of (-10.8 kcal/mol). Molecular dynamics simulations over 100 ns were used to validate the molecular docking results, indicating that compounds M1 and M2 remain stable in the active site, confirming their potential as promising anti-AChE inhibitors.

PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro. For this, we studied the effect of IL-6 and type I interferon (IFN) in vitro on human T cells in a mixed leukocyte reaction (MLR) in the absence or presence of PD-1 blockade. While IL-6 reduced IFN-γ secretion by T cells in both the presence and absence of PD-1 blockade, IFN-α specifically reduced the IFN-γ secretion only in the presence of PD-1 blockade. IFN-α reduced T cell proliferation independent of PD-1 blockade and reduced the percentage of cells producing IFN-γ only in the presence of PD-1 blockade. Next we determined the type I IFN score in a cohort of 22 melanoma patients treated with nivolumab. In this cohort, we did not find a correlation between clinical response and type I IFN score, nor between clinical response and IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade. We conclude that IFN-α reduces the effectiveness of PD-1 blockade in vitro, but that in this cohort, type I IFN score in vivo, nor IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade correlated to decreased therapy responses in patients.

UNASSIGNED: Leukocyte parameters are associated with cardiovascular diseases. The aim of the present study was to investigate the role of leukocyte parameters in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) with high thrombus burden (HTB).
UNASSIGNED: A total of 102 consecutive STEMI patients with HTB who underwent PPCI within 12 h from the onset of symptoms between June 2020 and September 2021 were enrolled in this study. In addition, 101 age- and sex-matched STEMI patients with low thrombus burden (LTB) who underwent PPCI within 12 h from the onset of symptoms were enrolled as controls. Leukocyte parameters, such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR), were calculated at the time of admission.
UNASSIGNED: The value of NLR and MLR were significantly higher in the HTB group than in the LTB group (6.24 ± 4.87 vs. 4.65 ± 3.47, p = 0.008; 0.40 ± 0.27 vs. 0.33 ± 0.20, p = 0.038). A cutoff value of >5.38 for NLR had a sensitivity and specificity of 53.9% and 74.3%, respectively, and MLR >0.29 had a sensitivity and specificity of 60.8% and 55.4%, respectively, for determining the STEMI patients with HTB [area under the receiver operating characteristic curve (AUC): 0.603, 95% confidence interval (CI): 0.524-0.681, p = 0.012; AUC: 0.578, 95% CI: 0.499-0.656, p = 0.046]. There was no significant difference of all-cause mortality rate and major adverse cardiac events (MACEs) between the STEMI patients with HTB or with LTB (3.92% in HTB group vs. 2.97% in LTB group, p = 0.712; 10.78% in HTB group vs. 8.91% in LTB group, p = 0.215). Compared with the HTB patients in the low NLR group, C-reactive protein, baseline troponin I, baseline brain natriuretic peptide, and leukocyte parameters, such as white blood cell, neutrophil, lymphocyte, NLR, PLR, and MLR, were also significantly higher in the high NLR group in STEMI patients who underwent PPCI with HTB (18.94 ± 19.06 vs. 35.23 ± 52.83, p = 0.037; 10.99 ± 18.07 vs. 21.37 ± 19.64, p = 0.007; 199.39 ± 323.67 vs. 430.72 ± 683.59, p = 0.028; 11.55 ± 3.56 vs. 9.31 ± 2.54, p = 0.001; 9.77 ± 3.17 vs. 5.79 ± 1.97, p = 0.000; 1.16 ± 0.44 vs. 2.69 ± 1.23, p = 0.000; 9.37 ± 4.60 vs 1.31 ± 2.58, p = 0.000; 200.88 ± 89.90 vs. 97.47 ± 50.99, p = 0.000; 0.52 ± 0.29 vs. 0.26 ± 0.14, p = 0.000, respectively). MACEs and heart failure in the high NLR group were significantly higher than that in the low NLR group of STEMI patients who underwent PPCI with HTB (20.45% vs. 4.25%, p = 0.041; 10.91% vs. 2.13%, p = 0.038).
UNASSIGNED: The value of NLR and MLR were higher in STEMI patients who underwent PPCI with HTB. In STEMI patients who underwent PPCI with HTB, a raised NLR could effectively predict the occurrence of MACEs and heart failure.

OBJECTIVE: Exploring the predictive value of NLR, PLR, MLR, and SII for the severity of cervical cancer screening abnormalities in patients.
METHODS: A retrospective analysis was conducted on the data of 324 patients suspected of cervical lesions due to abnormal TCT and/or HPV in our hospital from January 2023 to December 2023, who underwent colposcopy. The pathological results of colposcopic biopsy confirmed that there were 140 cases of chronic cervicitis, which classified as the group without cervical lesions. The cervical lesion group included 184 cases, including 91 cases of LSIL, 71 cases of HSIL, and 22 cases of cervical cancer. Compared the differences in preoperative peripheral blood NLR, PLR, MLR, and SII among different groups of patients, and evaluated their predictive value for the severity of cervical lesions using Receiver Operating Characteristic (ROC) curves.
RESULTS: The levels of NLR, PLR, and SII in the group without cervical lesions were lower than those in the group with cervical lesions (p < 0.05), and there was no statistically significant difference in MLR (p > 0.05). The comparison of NLR among LSIL, HSIL, and cervical cancer groups showed statistically significant differences (p < 0.05), while PLR, MLR, and SII showed no statistically significant differences (p > 0.05). The AUC of peripheral blood NLR, PLR, and SII for predicting cervical lesions were 0.569, 0.582, and 0.572, respectively. The optimal cutoff values were 2.3,176.48, and 603.56. The sensitivity and specificity were 38.6% and 73.6%, 28.8% and 85.7%, 37.5% and 76.4%, respectively. At the same time, the joint testing of the three had the highest efficiency, with sensitivity of 69% and specificity of 45%.
CONCLUSIONS: Although the peripheral blood NLR, PLR, and SII of the cervical lesions patients were higher than those without cervical lesions in cervical cancer screening abnormal patients, the predictive ROC curve discrimination was low. Therefore, it is not recommended to use preoperative peripheral blood inflammatory markers as markers for cervical cancer screening abnormal patient diversion.

OBJECTIVE: To investigate the differences and correlation between blood inflammatory indexes such as monocytes (MONO), lymphocytes (LYM), haemoglobin (HGB), neutrophils (NEU), platelets (PLT), ultrasensitive C-reactive protein, albumin and platelet/lymphocyte ratio (PLR), NEU/LYM ratio (NLR), MONO/LYM ratio (MLR) and clinicopathologic characteristics of patients with non-small cell lung cancer (NSCLC).
METHODS: 187 patients with NSCLC who were first diagnosed in 2017-2023 and 102 with healthy check-ups during the same period (control group) were retrospectively selected as study subjects to compare the differences in inflammatory indexes between the two groups and the levels of inflammatory indexes in NSCLC patients with different clinicopathologic characteristics.
RESULTS: Correlation analysis between blood inflammatory indexes and clinicopathologic features in NSCLC group showed that C-reactive protein, CAR, and PLR values were different in different pathologic types (P<0.05). The values of NEU, MONO, C-reactive protein, MLR, NLR, CAR and albumin were different among various degrees of differentiation (P<0.05). There were differences in LYM, albumin, MLR, NLR, CAR, and C-reactive protein among M stage subgroups (P<0.05). Analysis of the efficacy of early diagnosis of non-small cell lung cancer has been shown, the AUC of NLR was 0.796, sensitivity of 0.679, specificity of 0.176, 95% CI=0.743-0.849 (P<0.001). The AUC of albumin was 0.977, the sensitivity was 0.941, the specificity was 0.941, and 95% CI was 0.959-0.994 (P<0.001).
CONCLUSIONS: Blood inflammatory indexes are closely associated with NSCLC and vary according to pathologic features. Blood inflammatory indices can predict tumor pathologic staging and guide treatment for patients with NSCLC.

OBJECTIVE: To investigate the relationship between preoperative inflammatory markers and recurrence of CIN after loop electrosurgical excision procedure (LEEP).
METHODS: A retrospective historical cohort study was conducted at gynecologic oncology unit, Bhumibol Adulyadej Hospital, Royal Thai Air Force, Thailand. Data was collected from medical records of CIN cases from year 2016 to 2021. Inclusion criteria were subjects who were diagnosed of CIN and underwent LEEP with pathologic confirmation and followed up for two years (at 6 months, 1 year, and 2 years). Preoperative complete blood count (CBC) was obtained within one month for calculation as systemic inflammatory values.
RESULTS: One hundred and ten cases of CIN were enrolled. Mean age of participants was 48.1 years old. Three-fourths (83/110) of the participants had histological confirmation as CIN2/3. Sixteen (18/110) and twenty (22/110) percentage of cases had recurrence of disease at 1 and 2 years, respectively. Monocytes /lymphocytes ratio (MLR) and systemic inflammation response index (SIRI) could predict recurrence of CIN within 2 years. MLR more than 0.16 and SIRI more than 0.57 gave the sensitivity and negative predictive value (NPV) at percentage of 77.3/ 81.8 and 91.8/ 90.2, respectively. Combination of MLR and SIRI had sensitivity and NPV at 90.5 and 95.4 percent, respectively. MLR and SIRI could not predict marginal involvement, glandular involvement, and LEEP confirmed CIN 2/3.
CONCLUSIONS: Pretreatment MLR and SIRI were statistically significant in predicting the recurrence in CIN after post LEEP procedure within 2 years follow up.

BACKGROUND: Inhibiting receptor-tyrosine-kinase (RTK) signalling pathways has emerged as a key focus of novel cancer therapy development. Vascular endothelial growth factor receptor (VEGFR) is a member of the RTK family and is required for vasculogenesis and angiogenesis. Because VEGFR 2 is the subtype responsible for cellular angiogenesis and vasculogenesis, blocking it will impair tumour cell blood supply, reducing their development, proliferation, and metastasis.
OBJECTIVE: The aim of this study is to obtain an optimised pharmacophore as a VEGFR2 inhibitor using QSAR investigations. This aids in determining the link between structure and activity in new chemical entities (NCEs).
METHODS: The multi-linear regression approach (MLR) method was utilised to generate the QSAR Model using the programme QSARINS v.2.2.4.
CONCLUSIONS: For 2D QSAR, the best models produced has correlation coefficients of R2= 0.9396. The 3D-QSAR model obtained with R2= 0.9121 and Q2 = 0.8377. Taking docking observations, pharmacological behaviour, and toxicity analyses into account, most of the derivatives demonstrated VEGFR2 inhibitory competence.
CONCLUSIONS: According to QSAR studies, more electron-donating groups on the benzene ring linked to the isoxazole were shown to be necessary for activity. In molecular docking studies, most compounds have shown stronger affinity for the crucial amino acids Cys:919, Asp:1046, and Glu:885, which are found in typical drugs. All NCEs passed the Lipinski screening.

BACKGROUND: Periprosthetic joint infection (PJI) is a devastating complication that develops after total joint arthroplasty (TJA), whose incidence is expected to increase over the years. Traditionally, surgical treatment of PJI has been based on algorithms, where early infections are preferably treated with debridement, antibiotics, and implant retention (DAIR) and late infections with two-stage revision surgery. Two-stage revision is considered the \"gold standard\" for treatment of chronic prosthetic joint infection (PJI) as it enables local delivery of antibiotics, maintenance of limb-length and mobility, and easier reimplantation. Many studies have attempted to identify potential predicting factors for early diagnosis of PJI, but its management remains challenging. In this observational retrospective study, we investigated the potential role of inflammatory blood markers (neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic inflammatory index (SII), systemic inflammatory response index (SIRI), and aggregate index of systemic inflammation (AISI)) as prognostic factors in two-stage exchange arthroplasty for PJI.
METHODS: A single-center retrospective analysis was conducted, collecting clinical data and laboratory parameters from patients submitted to prosthetic explantation (EP) for chronic PJI. Laboratory parameters (PCR, NLR, MLR, PLR, SIRI, SII, and AISI) were evaluated at the explantation time; at 4, 6, and 8 weeks after surgery; and at reimplantation time. The correlation between laboratory parameters and surgery success was evaluated and defined as infection absence/resolution at the last follow-up.
RESULTS: A total of 57 patients with PJI were evaluated (62% males; average age 70 years, SD 12.14). Fifty-three patients with chronic PJI were included. Nine patients underwent DAIR revision surgery and chronic suppressive therapy; two patients died. Nineteen patients completed the two-stage revision process (prosthetic removal, spacer placement, and subsequent replanting). Among them, none showed signs of reinfection or persistence of infection at the last available follow-up. The other twenty-three patients did not replant due to persistent infection: among them, some (the most) underwent spacer retention; others (fewer in number) were submitted to resection arthroplasty and arthrodesis (Girdlestone technique) or chronic suppressive antibiotic therapy; the remaining were, over time, lost to follow-up. Of the patients who concluded the two-stage revision, the ones with high SIRI values (mean 3.08 SD 1.7 and p-value 0.04) and MLR values (mean 0.4 SD 0.2 and p-value 0.02) at the explantation time were associated with a higher probability of infection resolution. Moreover, higher variation in the SIRI and PCR, also defined, respectively, as delta-SIRI (mean -2.3 SD 1.8 and p-value 0.03) and delta-PCR (mean -46 SD 35.7 and p-value 0.03), were associated with favorable outcomes.
CONCLUSIONS: The results of our study suggest that, in patients with PJI undergoing EP, the SIRI and MLR values and delta-SIRI and delta-PCR values could be predictive of a favorable outcome. The evaluation of these laboratory indices, especially their determination at 4 weeks after removal, could therefore help to determine which patients could be successfully replanted and to identify the best time to replant. More studies analyzing a wider cohort of patients with chronic PJI are needed to validate the promising results of this study.

UNASSIGNED: Hierarchical management is advocated in China to effectively manage chronic obstructive pulmonary disease (COPD) patients and reduce the incidence and mortality of acute exacerbation of COPD (AE-COPD). However, primary and community hospitals often have limited access to advanced equipment and technology. Complete blood count (CBC), which is commonly used in these hospitals, offers the advantages of being cost-effective and easily accessible. This study aims to evaluate the significance of routine blood indicators in aiding of diagnosing AE-COPD.
UNASSIGNED: In this research, we enrolled a total of 112 patients diagnosed with AE-COPD, 92 patients with stable COPD, and a control group comprising 60 healthy individuals. Clinical characteristics, CBC parameters, and serum CRP levels were collected within two hours. To assess the associations between NLR/PLR/MLR and CRP by Spearman correlation test. The diagnostic accuracy of NLR, PLR and MLR in AE-COPD was assessed using Receiver Operating Characteristic Curve (ROC) and the area under the curve (AUC). Binary Logistic Regression analysis was conducted for the indicators of NLR, PLR and MLR.
UNASSIGNED: We found that patients with AE-COPD had significantly higher levels of NLR, PLR and MLR in contrast to patients with stable COPD. Additionally, the study revealed a noteworthy correlation between CRP and NLR (rs=0.5319, P<0.001), PLR (rs=0.4424, P<0.001), and MLR (rs=0.4628, P<0.001). By utilizing specific cut-off values, the amalgamation of NLR, PLR and MLR augmented diagnostic sensitivity. Binary logistic regression analysis demonstrated that heightened NLR and MLR act as risk factors for the progression of AE-COPD.
UNASSIGNED: The increasing levels of NLR, PLR and MLR could function as biomarkers, akin to CRP, for diagnosis and assessment of acute exacerbations among COPD patients. Further research is required to validate this concept.

Aim: This study aims to investigate the passive diffusion of protein kinase inhibitors through the blood-brain barrier (BBB) and to develop a model for their permeability prediction. Materials & methods: We used the parallel artificial membrane permeability assay to obtain logPe values of each of 34 compounds and calculated descriptors for these structures to perform quantitative structure-property relationship modeling, creating different regression models. Results: The logPe values have been calculated for all 34 compounds. Support vector machine regression was considered the most reliable, and CATS2D_09_DA, CATS2D_04_AA, B04[N-S] and F07[C-N] descriptors were identified as the most influential to passive BBB permeability. Conclusion: The quantitative structure-property relationship-support vector machine regression model that has been generated can serve as an efficient method for preliminary screening of BBB permeability of new analogs.
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