Category: Nevin Manimala

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

BMJ Neurol Open. 2024 Jul 5;6(2):e000724. doi: 10.1136/bmjno-2024-000724. eCollection 2024.

ABSTRACT

OBJECTIVE: Interventional stroke therapy made thrombi available for histological analysis. Unfortunately, simple composition aspects such as erythrocyte versus fibrin/platelet rich did not allow a feasible allocation to thrombi’s cardiac or carotid origin. Since the mentioned criteria represent characteristics of thrombus age, we used established histological criteria for determining thrombus age in patients who had an atherosclerotic (TOAST (Trial of Org 10172 in Acute stroke Treatment) 1) stroke versus patients who had a cardioembolic (TOAST 2) stroke.

METHODS: We assessed prospectively data from stroke patients presenting with occlusion of the middle cerebral artery eligible for catheter-based intervention. Besides patient characteristics and stroke workup, extracted thrombi were classified into different age categories according to their cellular to fibrotic transition. Thrombi were collected in an erythrocyte lysing solution to reduce acute clotting effects. Statistics were done with a non-parametric Kolmogorov-Smirnov test.

RESULTS: 170 patients were included, of which 50 (38 men; 73±12 years) had a TOAST 1 and 99 (59 women; 75±10 years) had a TOAST 2 categorised stroke. Age, National Institutes of Health Stroke Score (13±7 vs 15±7), Alberta Stroke Program Early CT Score (9±3 vs 9±2), Thrombolysis in Cerebral Infarction Score (2.9±0.2 vs 2.9±0.3), modified Rankin Score on discharge (3.2±2 vs 3.2±2), number of vascular risk factors (0.9±1.4 vs 1.0±1.1) or time span between symptom onset to reperfusion (266±115 vs 260±128 min) remained non-significant. Also, thrombus age did not differ between the groups. The mean age of thrombi was 5-8 days. However, the male-female ratio differed significantly (p<0.0005) between groups, with more men in TOAST 1 group and more women in TOAST 2 group.

CONCLUSION: Age aspects of thrombi seem not feasible to allow reliable source allocation. However, the young age of thrombi points to a rapid detachment. The difference in sex relation is in line with previous reports.

PMID:38979394 | PMC:PMC11227751 | DOI:10.1136/bmjno-2024-000724

bioRxiv [Preprint]. 2024 Jun 24:2024.03.05.583616. doi: 10.1101/2024.03.05.583616.

ABSTRACT

A simple lateral dynamic walker, with swing leg dynamics and three adjustable input parameters, is used to study how motor regulation affects frontal plane stepping. Motivated by experimental observations and phenomenological models, we imposed task-level multiobjective regulation targeting the walker’s optimal lateral foot placement at each step. The regulator prioritizes achieving step width and lateral body position goals to varying degrees by choosing a mixture parameter. Our model thus integrates a lateral mechanical template , which captures fundamental mechanics of frontal-plane walking, with a lateral motor regulation template , an empirically verified model of how humans manipulate lateral foot placements in a goal-directed manner. The model captures experimentally observed stepping fluctuation statistics and demonstrates how linear empirical models of stepping dynamics can emerge from first-principles nonlinear mechanics. We find that task-level regulation gives rise to a goal equivalent manifold in the system’s extended state space of mechanical states and inputs, a subset of which contains a continuum of period-1 gaits forming a semistable set: perturbations off of any of its gaits result in transients that return to the set, though typically to different gaits.

PMID:38979349 | PMC:PMC11230222 | DOI:10.1101/2024.03.05.583616

bioRxiv [Preprint]. 2024 Jun 30:2024.06.26.600724. doi: 10.1101/2024.06.26.600724.

ABSTRACT

OBJECTIVES: To provide a level-adjusted correction to the current standard relating anatomical cochlear place to characteristic frequency in humans, and to re-evaluate anatomical frequency mismatch in cochlear implant (CI) recipients considering this correction. It is hypothesized that a level-adjusted place-frequency function may represent a more accurate tonotopic benchmark for CIs in comparison to the current standard.

DESIGN: The present analytical study compiled data from fifteen previous animal studies that reported iso-intensity responses from cochlear structures at different stimulation levels. Extracted outcome measures were characteristic frequencies and centroid-based best frequencies at 70 dB SPL input from 47 specimens spanning a broad range of cochlear locations. A simple relationship was used to transform these measures to human estimates of characteristic and best frequencies, and non-linear regression was applied to these estimates to determine how the standard human place-frequency function should be adjusted to reflect best frequency rather than characteristic frequency. The proposed level-adjusted correction was then compared to average place-frequency positions of commonly used CI devices when programmed with clinical settings.

RESULTS: The present study showed that the best frequency at 70 dB SPL (BF70) tends to shift away from characteristic frequency (CF). The amount of shift was statistically significant (signed-rank test z = 5.143, p < 0.001), but the amount and direction of shift depended on cochlear location. At cochlear locations up to 600° from the base, BF70 shifted downwards in frequency relative to CF by about 4 semitones on average. Beyond 600° from the base, BF70 shifted upwards in frequency relative to CF by about 6 semitones on average. In terms of spread (90% prediction interval), the amount of shift between CF and BF70 varied from relatively no shift to nearly an octave of shift. With the new level-adjusted frequency-place function, the amount of anatomical frequency mismatch for devices programmed with standard of care settings is less extreme than originally thought, and may be nonexistent for all but the most apical electrodes.

CONCLUSIONS: The present study validates the current standard for relating cochlear place to characteristic frequency, and introduces a level-adjusted correction for how best frequency shifts away from characteristic frequency at moderately loud stimulation levels. This correction may represent a more accurate tonotopic reference for CIs. To the extent that it does, its implementation may potentially enhance perceptual accommodation and speech understanding in CI users, thereby improving CI outcomes and contributing to advancements in the programming and clinical management of CIs.

PMID:38979194 | PMC:PMC11230407 | DOI:10.1101/2024.06.26.600724

bioRxiv [Preprint]. 2024 Jun 25:2024.02.20.581048. doi: 10.1101/2024.02.20.581048.

ABSTRACT

BACKGROUND: MHC class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression.

METHODS: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single cell neighborhoods from mIF images followed by multivariate discriminant analysis.

RESULTS: Spatial quantitation of tumor cell MHC-I expression revealed intra- and inter-tumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56 ⁺ cell numbers in patient tumors were positively associated with disease-free survival (DFS) (HR=0.58, p =0.064) and over-all survival (OS) (HR=0.496, p =0.041). The OS association strengthened with high counts of both CD56 ⁺ and CD8 ⁺ cells (HR=0.199, p <1×10 ^-3 ). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3 ⁺ CD8 ⁺ T cells and CD3 ^– CD56 ⁺ NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single cell neighborhood profiles to delineate the cellular environments of IFNγ ^+/- NK cells and T cells. We discovered that both IFNγ ⁺ NK and CD8 T cells were more frequently associated with other IFNγ ⁺ lymphocytes in comparison to IFNγ ^– NK cells and CD8 T cells (p<1×10 ^-30 ). Moreover, IFNγ ⁺ lymphocytes were most often found clustered near MHC-I ⁺ tumor cells.

CONCLUSIONS: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Co-association of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent co-localization of IFNγ ⁺ NK cells with other IFNγ ⁺ lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.

WHAT IS ALREADY KNOWN ON THIS TOPIC: MHC-I loss occurs frequently in NSCLC and corresponds with waning immunity in the tumor microenvironment (TME). NK cells recognize “missing-self” targets and could be leveraged to target NSCLC tumors with MHC-I loss. While NK cell presence at tumor margins has been documented in NSCLC, they were shown to lose function in this environment.

WHAT THIS STUDY ADDS: We developed spatial analysis pipelines leveraging the local heterogeneity of the TME at single cell resolution to test whether NK cells and T cells together contribute antitumoral immunity in NSCLC. We discovered that a high density of tumor-infiltrating NK cells corresponded with DFS, and this association was increased in patients with high coincident CD8 T cells, especially those in central tumor. Intriguingly, both cell types were found clustered together in MHC-I-bearing tumors, especially when both expressed IFNγ, suggesting coordinated lymphocyte activities may enhance immune control of NSCLC.

HOW THIS STUDY MIGHT AFFECT RESEARCH PRACTICE OR POLICY: This study provides a rationale for developing novel immunotherapies that simultaneously increase NK and T cell anti-tumoral immunity. Associations linking NK cells with patient survival and increased immune effector activity in NSCLC, even in MHC-I-deficient tumors, further highlights the need to devise and deploy NK cell activating strategies which may be highly efficacious in CD8 T cell refractory NSCLC.

PMID:38979183 | PMC:PMC11230195 | DOI:10.1101/2024.02.20.581048

bioRxiv [Preprint]. 2024 Jun 24:2024.06.19.599719. doi: 10.1101/2024.06.19.599719.

ABSTRACT

PURPOSE: Relaxation correction is crucial for accurately estimating metabolite concentrations measured using in vivo magnetic resonance spectroscopy (MRS). However, the majority of MRS quantification routines assume that relaxation values remain constant across the lifespan, despite prior evidence of T ₂ changes with aging for multiple of the major metabolites. Here, we comprehensively investigate correlations between T ₂ and age in a large, multi-site cohort.

METHODS: We recruited approximately 10 male and 10 female participants from each decade of life: 18-29, 30-39, 40-49, 50-59, and 60+ years old ( n =101 total). We collected PRESS data at 8 TEs (30, 50, 74, 101, 135, 179, 241, and 350 ms) from voxels placed in white-matter-rich centrum semiovale (CSO) and gray-matter-rich posterior cingulate cortex (PCC). We quantified metabolite amplitudes using Osprey and fit exponential decay curves to estimate T ₂ .

RESULTS: Older age was correlated with shorter T ₂ for tNAA, tCr _3.0 , tCr _3.9 , tCho, Glx, and tissue water in CSO and PCC; r _s = -0.21 to -0.65, all p <0.05, FDR-corrected for multiple comparisons. These associations remained statistically significant when controlling for cortical atrophy. T ₂ values did not differ across the adult lifespan for mI. By region, T ₂ values were longer in the CSO for tNAA, tCr _3.0 , tCr _3.9 , Glx, and tissue water and longer in the PCC for tCho and mI.

CONCLUSION: These findings underscore the importance of considering metabolite T ₂ changes with aging in MRS quantification. We suggest that future 3T work utilize the equations presented here to estimate age-specific T ₂ values instead of relying on uniform default values.

PMID:38979133 | PMC:PMC11230243 | DOI:10.1101/2024.06.19.599719