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Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma
Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.
Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC. .
Journal Article
Bacillus tequilensis S40 inoculation alleviates salt stress by modifying bacterial community structure and regulating elemental cycling rhizosphere of Reaumuria soongorica
Plant growth‒promoting rhizobacteria (PGPRs) are pivotal in forest cultivation and saline‒alkaline soil improvement by altering the structure of rhizosphere bacterial communities and improving soil nutrient utilization efficiency. However, there are few reports on the exploration of PGPR bacterial resources and the mechanism by which PGPR enhance the salt tolerance of
Reaumuria soongorica
(
R. soongorica
) in desert shrubs. This study focused on
Bacillus tequilensis
(
B. tequilensis
) S40, which is a PGPR isolated from the rhizosphere of
R. soongorica
by our research group. We investigated the effects of the S40 strain on the rhizosphere microbial community and functional genes of
R. soongorica
through pot experiments. The results demonstrated that inoculation with the S40 strain could alleviate the negative effects of NaCl stress on the plant height, total root length, and rhizome leaf biomass.
Proteobacteria
,
Bacteroidetes
, and
Planctomycetota
were the dominant phyla. Notably, inoculation with S40 strain significantly increased the absolute abundances of functional genes involved in carbon (C), nitrogen (N), and phosphorus (P) cycling (
p
< 0.05). Furthermore, the genes related to C, N, and P cycling were significantly correlated with soil properties (available phosphorus, urease activity, sucrase activity), and the biomass of
R. soongorica
leaves, stems, and roots (
p
< 0.05). In conclusion, the PGPR strain S40 mediates the reorganization of bacterial community, drives the element cycle, and enhances soil nutrient availability, thus promoting plant growth and enhancing salt tolerance of plants and providing a method and scientific basis for cultivating shrub seedlings and alleviating the degree of soil salinization.
Journal Article
Elucidation of Interaction between Whey Proteins and Proanthocyanidins and Its Protective Effects on Proanthocyanidins during In-Vitro Digestion and Storage
Whey proteins and oligomeric proanthocyanidins have nutritional value and are widely used in combination as food supplements. However, the effect of the interactions between proanthocyanidins and whey proteins on their stability has not been studied in depth. In this work, we aimed to characterize the interactions between β-Lactoglobulin (β-LG) and α-lactalbumin (α-LA) and oligomeric proanthocyanidins, including A1, A2, B1, B2, B3, and C1, using multi-spectroscopic and molecular docking methods. Fluorescence spectroscopic data revealed that all of the oligomeric proanthocyanidins quenched the intrinsic fluorescence of β-LG or α-LA by binding-related fluorescence quenching. Among the six oligomeric proanthocyanidins, A1 showed the strongest affinity for β-LG (Ka = 2.951 (±0.447) × 104 L∙mol−1) and α-LA (Ka = 1.472 (±0.236) × 105 L∙mol−1) at 297 K. β-LG/α-LA and proanthocyanidins can spontaneously form complexes, which are mainly induced by hydrophobic interactions, hydrogen bonds, and van der Waals forces. Fourier-transform infrared spectroscopy (FTIR) and circular dichroism spectroscopy showed that the secondary structures of the proteins were rearranged after binding to oligomeric proanthocyanidins. During in vitro gastrointestinal digestion, the recovery rate of A1 and A2 increased with the addition of WPI by 11.90% and 38.43%, respectively. The addition of WPI (molar ratio of 1:1) increased the retention rate of proanthocyanidins A1, A2, B1, B2, B3, and C1 during storage at room temperature by 14.01%, 23.14%, 30.09%, 62.67%, 47.92%, and 60.56%, respectively. These results are helpful for the promotion of protein–proanthocyanidin complexes as functional food ingredients in the food industry.
Journal Article
circRNA 001306 enhances hepatocellular carcinoma growth by up‐regulating CDK16 expression via sponging miR‐584‐5p
Circular RNAs (circRNAs) have been demonstrated to play important roles in cancer progress. However, the roles in hepatocellular carcinoma (HCC) are still unclear. Here, we found has_circRNA_001306 (circ_1306) was up‐regulated in HCC tissues and cell lines. Knockdown the expression circ_1306 significantly suppressed HCC cell proliferation and induced the cell apoptosis in vitro and in vivo. Furthermore, we identified circ_1306 could up‐regulate the expression of CDK16 by sponging miR‐584‐5p. The expression of miR‐584‐5p was decreased, and the expression of CDK16 was increased in HCC tissues and cell lines. Meanwhile, either knockdown of miR‐584‐5p or overexpression of CDK16 could suppress the HCC cell proliferation. In vivo, overexpression of miR‐584‐5p or knockdown of circ_1306 could inhibit the expression of CDK16, and suppress tumour growth. Altogether, our findings suggested that circ_1306 could promoter HCC progress by miR‐584‐5p/CDK16 axis, which provided a novel marker for HCC diagnosis and treatment.
Journal Article
Efficacy of pulmonary surfactant with budesonide in premature infants: A systematic review and meta-analysis
Pulmonary surfactant (PS) is one of the main treatment for neonates with respiratory distress syndrome (RDS). Budesonide has recently been studied as an additional treatment in such cases, but there is limited evidence supporting this. This study was implemented to determine the efficacy of PS combined with budesonide in premature infants. To achieve this, we conducted a systematic review and meta-analysis of randomized controlled trials by searching PubMed, Scopus, Embase, and the Cochrane Library from inception until July 12, 2024. We utilized a random-effects model to calculate the risk ratio and mean differences (MDs) with 95% confidence intervals (CIs) for the clinical outcomes of PS with budesonide versus PS alone. We used the GRADE approach to assess the quality of the evidence. We included 26 randomized controlled trials with a total of 2701 patients in the analysis. Treatments of PS with budesonide and PS alone were compared in all trials. PS with budesonide reduced bronchopulmonary dysplasia (BPD) incidence (risk ratio, 0.61; 95% CI, 0.51, 0.73), duration of mechanical or invasive mechanical ventilation (MD, −2.21 days; 95% CI, −2.72, −1.71), duration requiring oxygen (MD, −5.86 days; 95% CI, −8.44, −3.29), and hospitalization time (MD, −5.61 days; 95% CI, −8.65, −2.56). These results were based on low to very low evidence certainty. Only moderate-to-severe BPD or severe BPD showed a significant reduction when PS was used in conjunction with budesonide, a finding supported by moderate evidence certainty. Our study showed that the administration of PS with budesonide significantly improved respiratory outcomes, including the incidence of BPD, duration of mechanical or invasive mechanical ventilation, duration requiring oxygen, and hospitalization time in preterm infants, without short-term adverse drug events. However, the evidence certainty was mostly low to very low.
Journal Article
Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response
Epilepsy, a common neurological disorder, is featured with recurrent seizures. Its underlying pathological mechanisms remain elusive. Here, we provide evidence for loss of neogenin (NEO1), a coreceptor for multiple ligands, including netrins and bone morphological proteins, in the development of epilepsy. NEO1 is reduced in hippocampi from patients with epilepsy based on transcriptome and proteomic analyses. Neo1 knocking out (KO) in mouse brains displays elevated epileptiform spikes and seizure susceptibility. These phenotypes were undetectable in mice, with selectively depleted NEO1 in excitatory (NeuroD6-Cre⁺) or inhibitory (parvalbumin⁺) neurons, but present in mice with specific hippocampal astrocytic Neo1 KO. Additionally, neurons in hippocampal dentate gyrus, a vulnerable region in epilepsy, in mice with astrocyte-specific Neo1 KO show reductions in inhibitory synaptic vesicles and the frequency of miniature inhibitory postsynaptic current(mIPSC), but increase of the duration of miniature excitatory postsynaptic current and tonic NMDA receptor currents, suggesting impairments in both GABAergic transmission and extracellular glutamate clearance. Further proteomic and cell biological analyses of cell-surface proteins identified GLAST, a glutamate–aspartate transporter that is marked reduced in Neo1 KO astrocytes and the hippocampus. NEO1 interacts with GLAST and promotes GLAST surface distribution in astrocytes. Expressing NEO1 or GLAST in Neo1 KO astrocytes in the hippocampus abolishes the epileptic phenotype. Taken together, these results uncover an unrecognized pathway of NEO1-GLAST in hippocampal GFAP⁺ astrocytes, which is critical for GLAST surface distribution and function, and GABAergic transmission, unveiling NEO1 as a valuable therapeutic target to protect the brain from epilepsy.
Journal Article
Influence of thermal-cycling or staining medium on the surface properties and color stability of conventional, milled, and 3D-printed base materials
The study of denture base resin fabricated by digital technology with surface properties or color stability remains limited. In this study, thermal cycling and staining media (distilled water, artificial saliva, green tea, and Coca-Cola) immersion were used to simulate the intraoral environment to assess the surface properties and color stability of CAD/CAM (milled) and 3D-printed base resin materials, the conventionally polymerized base served as the control group. After thermal cycling, all groups showed increased surface roughness, contact angle (i.e. hydrophilicity) and color difference (∆E), the 3D-printed group had the most significant increase among the 3 groups (
P<
0.001). While there were no significant difference (or the difference is very small) between the conventional and milled groups. After 7 and 30 days of immersion in four staining media, the ∆E values remained highest in the 3D-printed group (∆E ≥ 3.34) (
P<
0.001), exceeding the clinically acceptable threshold (∆E = 2.7) at 30 days. Additionally, all groups showed significantly higher ∆E values after 30 days compared to 7 days (
P<
0.05). The 3D-printed group exhibited a rougher surface, poorer hydrophilicity, and reduced color stability compared to the conventional or milled groups, indicating that further improvements are needed before clinical application.
Journal Article
Survival outcome and prognostic factors of patients with nasopharyngeal cancer in Yogyakarta, Indonesia: A hospital-based retrospective study
This study aimed to determine the survival outcome and prognostic factors of patients with nasopharyngeal cancer accessing treatment in Yogyakarta, Indonesia.
Data on 759 patients with NPC diagnosed from 2007 to 2016 at Dr Sardjito General Hospital were included. Potential prognostic variables included sociodemographic, clinicopathology and treatment parameters. Multivariable analyses were implemented using semi-parametric Cox proportional hazards modelling and fully parametric survival analysis.
The median time of observation was 14.39 months. In the whole cohort the median observed survival was 31.08 months. In the univariable analysis, age, education status, insurance type, BMI, ECOG index, stage and treatment strategy had an impact on overall survival (OS) (p values <0.01). Semi-parametric multivariable analyses with stage stratification showed that education status, ECOG index, and treatment modality were independent prognostic factors for OS (p values <0.05). In the fully parametric models age, education status, ECOG index, stage, and treatment modality were independent prognostic factors for OS (p values <0.05). For both multivariable analyses, all treatment strategies were associated with a reduced hazard (semi-parametric models, p values <0.05) and a better OS (parametric models, p values <0.05) compared with no treatment. Furthermore, compared with radiation alone or chemotherapy alone, a combination of chemotherapy and radiation either in a form of concurrent chemoradiotherapy (CCRT), sequential chemotherapy and radiation, or induction chemotherapy followed by CCRT demonstrated a reduced hazard (hazard ratio/HR 0.226, 95% confidence interval/CI 0.089-0.363, and HR 0.390, 95%CI 0.260-0.519) and a better OS (time ratio/TR 3.108, 95%CI 1.274-4.942 and TR 2.531, 95%CI 1.829-3.233) (p values < 0.01).
Median OS for the cohort was low compared to those reported in both endemic and non-endemic regions. By combining the findings of multivariable analyses, we showed that age, education status, ECOG index, stage and first treatment modality were independent predictors for the OS.
Journal Article
Self adaptive viscosity-type inertial extragradient algorithms for solving variational inequalities with applications
In this paper, we introduce two new inertial extragradient algorithms with non-monotonic stepsizes for solving monotone and Lipschitz continuous variational inequality problems in real Hilbert spaces. Strong convergence theorems of the suggested iterative schemes are established without the prior knowledge of the Lipschitz constant of the mapping. Finally, some numerical examples are provided to illustrate the efficiency and advantages of the proposed algorithms and compare them with some related ones.
Journal Article