The role of serum-glucocorticoid regulated kinase 1 in reproductive viability: implications from prenatal programming and senescence.

OBJECTIVE: Organisms and cellular viability are of paramount importance to living creatures. Disruption of the balance between cell survival and apoptosis results in compromised viability and even carcinogenesis. One molecule involved in keeping this homeostasis is serum-glucocorticoid regulated kinase (SGK) 1. Emerging evidence points to a significant role of SGK1 in cell growth and survival, cell metabolism, reproduction, and life span, particularly in prenatal programming and reproductive senescence by the same token. Whether the hormone inducible SGK1 kinase is a major driver in the pathophysiological processes of prenatal programming and reproductive senescence? METHOD: The PubMed/Medline, Web of Science, Embase/Ovid, and Elsevier Science Direct literature databases were searched for articles in English focusing on SGK1 published up to July 2023 RESULT: Emerging evidence is accumulating pointing to a pathophysiological role of the ubiquitously expressed SGK1 in the cellular and organismal viability. Under the regulation of specific hormones, extracellular stimuli, and various signals, SGK1 is involved in several biological processes relevant to viability, including cell proliferation and survival, cell migration and differentiation. In line, SGK1 contributes to the development of germ cells, embryos, and fetuses, whereas SGK1 inhibition leads to abnormal gametogenesis, embryo loss, and truncated reproductive lifespan. CONCLUTION: SGK1 integrates a broad spectrum of effects to maintain the homeostasis of cell survival and apoptosis, conferring viability to multiple cell types as well as both simple and complex organisms, and thus ensuring appropriate prenatal development and reproductive lifespan.

Natural-human driving factors of groundwater salinization in a long-term irrigation area.

Salinization of groundwater is a major challenge for groundwater management in long-term irrigation areas, decoupling its complex influencing factors can provide insights for the sustainable development of irrigation areas. In this study, the natural-human driving factors of groundwater salinization in the Yinchuan Plain, a typical irrigated area, were identified using isotope analysis, information entropy, and self-organizing map. Results show that groundwater in the study area is seriously salinized with obvious spatial heterogeneity. Multiple natural conditions and frequent human activities complicate the salinization characteristics of groundwater. On this basis, four typical natural influence units of groundwater were identified, namely, an evaporation and upward leakage zone, a runoff zone, an evaporation zone, and a runoff and upward leakage zone. Information entropy was proposed to quantify the complexity of groundwater resulting from human activities: The complexity difference between densely populated areas and natural dominant areas is mainly reflected in Na+, SO42-, and Cl-. Multiple human-made drivers of complex water environment were further separated into three patterns by the SOM model: blockage-evaporation type, leakage-evaporation type, and irrigation type. The blockage of drainage ditches and obstruction of salt discharge has the highest impact on the salinization of groundwater, followed by irrigation activities and transportation losses. Water excessive stagnation caused by blockage or irrigation is the root cause of groundwater salinization in the irrigated area, and its impact is greater than that of the traditional understanding of groundwater level rise. Based on the evaluation of irrigation water quality, management initiatives for irrigated areas should prioritize dredging and maintaining a healthy soil and groundwater environment in tandem.

The impacts of minimally invasive surgery on intermediate- or high-risk cervical cancer patients received adjuvant radiotherapy.

BACKGROUND: Adjuvant chemoradiotherapy (CRT) has been shown to reduce the risk of recurrence for patients with risk factors after radical hysterectomy (RH). Early initiated CRT could result in superior oncological outcomes. Here, we aimed to compare the survival outcome of intermediate- or high-risk cervical cancer (CC) patients who, received adjuvant CRT between minimally invasive surgery (MIS) and open surgery. METHODS: Data on stage IB1-IIA2 patients who underwent RH and postoperative CRT in our institution, from 2014 to 2017, were retrospectively collected. Patients with high or intermediate-risk factors who met the Sedlis criteria received sequential chemoradiation (SCRT). According to the surgical approaches, the enrolled patients were divided into MIS and open surgery groups. Then, the disease-free survival (DFS), overall survival (OS), and prognostic factors were analyzed. RESULTS: Among 129 enrolled CC patients, 68 received open surgery and 61 received MIS. The median time interval from surgery to chemotherapy and to radiotherapy was shorter in the MIS group (7 days vs. 8 days, P=0.014; 28 days vs. 35, P<0.001). Three-year DFS and OS were similar in both groups (85.2% vs. 89.7%, P=0.274; 89.9% vs. 98.5%, P=0.499). Further, sub-analysis indicated that the DFS and OS in intermediate/high-risk groups had no significant difference. Cox-multivariate analyses found that tumor size >4 cm and time interval from surgery to radiotherapy beyond 7 weeks were adverse independent prognostic factors for DFS. CONCLUSION: Based on the population we studied, for early-stage (IB1-IIA2) CC patients with intermediate- or high-risk factors who received postoperative SCRT, although the difference was not significant, the DFS and OS in the MIS group were slightly lower than the ORH group, and tumor size >4 cm and delayed adjuvant radiotherapy beyond 7 weeks were risk factors for recurrence.

Groundwater quality assessment using a new integrated-weight water quality index (IWQI) and driver analysis in the Jiaokou Irrigation District, China.

Groundwater is an important water resource in arid and semi-arid regions. The impact of human activities on groundwater is increasing. After 60 years running, the groundwater quality and its formation mechanism are imperative questions needed to be answered in Jiaokou Irrigation District, Guanzhong Basin, China. In this study, the quality of groundwater in Jiaokou Irrigation District was assessed by a new integrated-weight water quality index (IWQI), and the groundwater chemistry is studied through integrated statistical, geostatistical and hydrogeochemical approaches. The patterns for the average anion and cation concentrations were HCO3- > SO42- > Cl- > NO3- > CO32- > NO2-, and Na+ > Mg2+ > Ca2+ > K+ > NH4+, respectively. Statistics showed that the major water chemistry types were HCO3-Na, SO4·Cl-Na, and Cl·SO4-Na. A new integrated-weight water quality index (IWQI) was proposed based on the entropy-weighted method and CRITIC method and showed excellent performance for explaining and evaluating the groundwater quality. The IWQI results show 65.33% of groundwater, mainly distributed in the central and western parts of this study area, was unsuitable for drinking. Furthermore, SO42－, HCO3－, Cl－, NO3－, and Na+ had more important effects on groundwater quality. The weathering process affecting groundwater quality in the study area is carbonate dissolution, followed by silicate weathering and evaporite dissolution, whereas the major geochemical processes include the dissolution and precipitation of calcite, as well as the dissolution of dolomite and gypsum (anhydrite). Cation exchange also plays an important role in the hydrogeochemical evolution of groundwater with a long residence time. Anthropogenic activities affecting groundwater quality included long-term irrigation infiltration and excessive use of fertilizers. The findings and the results of the study can improve understanding of the processes driving groundwater chemistry in Jiaokou Irrigation District, and can be used for reference to other similar regions in the world.

Er Miao San, a traditional Chinese herbal formula, attenuates complete Freund's adjuvant-induced arthritis in rats by regulating Th17/Treg cells.

Context: Er Miao San (EMS) is a traditional Chinese medicine composed of Atractylodis Rhizoma and Phellodendri Cortex in a 1:1 weight ratio. EMS has been used to treat rheumatism in China for many years.Objective: To evaluate the anti-arthritic activity of EMS extract on adjuvant-induced arthritis (AA) in Sprague-Dawley rats and to clarify its mechanisms of action.Materials and methods: EMS (0.75, 1.5 and 3 g/kg, once daily) was orally administered from day 18 after immunization to day 31. The effects of EMS on AA rats were evaluated by histopathological examination, paw swelling and polyarthritis index. The proliferation of fibroblast-like synoviocyte (FLS) and T cells was detected by CCK-8. The percentages of Th17 cells and Treg cells in splenocytes were determined by flow cytometry. Levels of cytokines in serum were detected by ELISA.Results: EMS treatment significantly decreased the paw volume (from 1.20 to 0.81), polyarthritis index (from 9.56 to 4.46) and alleviated ankle joint histopathology in AA rats. EMS inhibited the proliferation of FLS and T cells. Furthermore, EMS treatment decreased Th17 cells (from 4.62 to 2.08%) and increased Treg cells (from 2.77 to 4.75%) in splenocytes. The levels of IL-17A, TNF-α and IL-6 were remarkably decreased in the serum of EMS-treated rats, whereas the levels of IL-10 and TGF-ß1 were significantly increased.Conclusions: EMS exhibits anti-arthritic activity in the AA model by regulating the balance of cytokines and the ratio of Th17 and Treg cells. These insights may provide an experimental basis for the clinical treatment of RA.

Anti-Inflammatory Effects of Different Elution Fractions of Er-Miao-San on Acute Inflammation Induced by Carrageenan in Rat Paw Tissue.

BACKGROUND Er-Miao-San (EMS) is used in traditional Chinese medicine. This study aimed to investigate the effect of different elution fractions of EMS on acute inflammation induced by carrageenan in the rat paw and the possible mechanisms of action. MATERIAL AND METHODS Different aqueous fractions of EMS added to an AB-8 macroporous resin column and eluted with 0, 30%, 60%, and 90% ethanol. The content of berberine was evaluated by ultra-performance liquid chromatography (UPLC). Following injection of carrageenan and elution fractions of EMS into the rat paw, the volume of edema, levels of prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1ß, and IL-10 in the rat tissue were quantified by enzyme-linked immunosorbent assay (ELISA). Myeloperoxidase (MPO) activity and nitric oxide (NO) levels were measured by spectrophotometry. RESULTS The 60% and 90% ethanol elution fractions of EMS contained berberine, and both inhibited edema after carrageenan injection, with inhibitory rates of 31.04-40.86% and 48.84-52.18%, respectively, and with a significant reduction in MPO activity and NO production. The 60% ethanol elution fraction of EMS significantly decreased IL-1ß levels and increased IL-10 levels, and the 30%, 60%, and 90% ethanol EMS elution fractions considerably reduced the levels of TNF-alpha. The 60% and 90% ethanol EMS elution fractions significantly reduced PGE2 levels in the rat paw. CONCLUSIONS The 60% and 90% ethanol elution fractions of EMS had an anti-inflammatory effect following injection of carrageenan in the rat paw.

Thermo-Sensitive PLGA-PEG-PLGA Tri-Block Copolymer Hydrogel as Three-Dimensional Cell Culture Matrix for Ovarian Cancer Cells.

Thermo-sensitive hydrogels which could encapsulate cells and provide a three dimensional (3D) microenvironment have great potential in building new cell culture models in vitro. In this study, a thermal responsive hydrogel based on PLGA-PEG-PLGA tri-block copolymers was developed as matrix for 3D ovarian cancer cell culturing. The gelation of PLGA-PEG-PLGA tri-block copolymer was concentration-dependent. SEM images showed the pores were suitable for the formation of 3D cell structures. Cell morphological results showed that large aggregates of ovarian cancer cells (HO8910) were formed after cultured for 10 days. Therefore, hydrogel based on PLGA-PEG-PLGA tri-block copolymers hold potential as in vitro cell culture matrix for ovarian cancer cells.

Redox tuning of a direct asymmetric aldol reaction.

Presented herein is a redox tuning strategy for asymmetric aminocatalysis with a designed chiral ferrocenophane. Under redox control, the ferrocenophane catalyst efficiently catalyzes the asymmetric aldol reaction at room temperature with excellent yield and good stereoselectivity. Moreover, the redox-active ferrocene moiety also served as phase-tag to facilitate catalyst recovery and reuse. The catalyst can be reused for five cycles without much loss of activity. Ferrocenium of the oxidized ferrocenophane was proposed to serve as Lewis acidic site, thus accounting for the stereo control.

Photodynamic therapy combined with CO2 laser for the treatment of seborrheic keratosis in the auricle: A case report.

Seborrheic keratosis(SK) is a very common skin tumor which is mostly frequently observed in the trunck, head, neck. SK in the auricle is rare and this condition should be excluded the possibility of malignancy by pathologic diagnosis. We report a case of 66-year-old man who presented with a brownish, papillomatous, verrucous mass in the auricle for the past seven years, which began to growing faster during the previous year. Dermoscopy and histopathological examination were performed and the patient was diagnosed with SK. He was treated with the carbon dioxide(CO2) laser and aminolevulinate photodynamic therapy (ALA-PDT). The CO2 laser was used for the removal of the thick hypertrophic lesions and to enhance the transdermal absorption efficiency of ALA. A 20% ALA cream(118 mg/cm2) was applied to his lesion and sealed for 3 h without light, followed by irradiation with 630-nm LED light (96 J/cm2, 80 mw/cm2). We use fluorescent diagnosis with aminolevulinic acid to define the tumor margins at the first session of ALA-PDT. After 4 sessions of ALA-PDT, the lesion was completely removed and did not recur. Therefore, we consider that ALA-PDT combined with CO2 laser is a safe and effective choice for the treatment of seborrheic keratosis in the auricle.

Progress in mitochondrial and omics studies in Alzheimer's disease research: from molecular mechanisms to therapeutic interventions.

Alzheimer's disease (Alzheimer's disease, AD) is a progressive neurological disorder characterized by memory loss and cognitive impairment. It is characterized by the formation of tau protein neurofibrillary tangles and ß-amyloid plaques. Recent studies have found that mitochondria in neuronal cells of AD patients exhibit various dysfunctions, including reduced numbers, ultrastructural changes, reduced enzyme activity, and abnormal kinetics. These abnormal mitochondria not only lead to the loss of normal neuronal cell function, but are also a major driver of AD progression. In this review, we will focus on the advances of mitochondria and their multi-omics in AD research, with particular emphasis on how mitochondrial dysfunction in AD drives disease progression. At the same time, we will focus on summarizing how mitochondrial genomics technologies have revealed specific details of these dysfunctions and how therapeutic strategies targeting mitochondria may provide new directions for future AD treatments. By delving into the key mechanisms of mitochondria in AD related to energy metabolism, altered kinetics, regulation of cell death, and dysregulation of calcium-ion homeostasis, and how mitochondrial multi-omics technologies can be utilized to provide us with a better understanding of these processes. In the future, mitochondria-centered therapeutic strategies will be a key idea in the treatment of AD.

Protective effect of quercetin on lipopolysaccharide­induced miscarriage based on animal experiments and network pharmacology.

Spontaneous abortion (SA) occurs in woman of child­bearing age, jeopardizing their physical and mental health. Quercetin is a natural flavonoid, which exhibits a variety of pharmacological activities. However, the role and mechanisms of quercetin in SA still need to be further explored. Animal experiments were performed to examine the effect of quercetin in treating SA. Institute of Cancer Research mice were injected with lipopolysaccharide into the tail vein on the 7th day of gestation to establish a SA model. Gavage was performed during days 3­8 of gestation with high­, medium­ and low­dose of quercetin. Then the effect of quercetin on embryos was evaluated. Animal experiment showed that quercetin could remarkably reduce the embryo loss rate and increase the mean weight of surviving embryos to some degree. Furthermore, network pharmacology was employed to explore the underlying mechanisms of quercetin in the treatment of SA. Several databases were used to collect the targets of SA and quercetin. Protein­protein interaction network, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to elucidate the interactions between SA and quercetin. The relative mRNA expressions of several targets in uterine were detected by quantitative reverse transcriptase polymerase chain reaction (RT­qPCR). Network pharmacology indicated that the effects of quercetin in treating SA were mainly related to hormone response and the modulation of defense response and inflammatory response, involving signaling pathways such as PI3K­Akt, VEGF, MAPK and core targets such as AKT1, albumin, caspase­3. RT­qPCR showed that quercetin could up­regulate AKT1, MAPK1, PGR, SGK1 and down­regulate ESR1, MAPK3. The results showed that quercetin may modulate multiple signaling pathways by targeting core targets to prevent and treat SA.

The impact on Cd bioavailability and accumulation in rice (Oryza sativa L.) induced by dry direct-seeding cultivation method in field-scale experiments.

Dry direct-seeded rice cultivation has gained popularity and expanded its cultivated area due to reduced labor requirements and water consumption. However, the impact of this cultivation method on cadmium (Cd) bioavailability in soil and the accumulation levels in grains remains uncertain. Field experiments were conducted in acidic soils at two locations in southern China to compare rice varieties and evaluate the dry direct-seeding method alongside the wet direct-seeding and traditional transplanting methods. Dry direct-seeded rice reached significantly higher Cd concentrations in its tissues starting from the heading stage than transplanted rice. Cd accumulation levels by the maturation stage in the brown rice of dry direct-seeded rice were 18.33 %-150.69 % higher than those of wet direct-seeded and transplanted rice, with a considerable ability to translocate Cd into brown rice. Furthermore, dry direct seeding decreased iron plaque formation, particularly in the amorphous Fe form; it resulted in high soil temperature and low moisture content during tillering, elevating Cd availability in the soil. Additionally, the proportion of ions and more labile forms of Cd in the soil solution was high. Moreover, the soil under dry direct seeding had high urease and acid phosphatase enzyme activities. However, low richness and diversity in the bacterial community were characterized by a significant increase in the relative abundance of Actinobacteria and Gammaproteobacteria at the class level, while exhibiting decreased relative abundances of Alphaproteobacteria, Bacilli, and KD4-96, along with fewer biomarkers. Nonetheless, these differences are gradually reduced during the maturation stage. Overall, although dry direct seeding offers several advantages, it is crucial to implement additional measures to mitigate the increased health risks linked to rice cultivation through this approach in Cd-contaminated areas.

Efficacy and safety of intravitreal injection of conbercept for moderate to severe nonproliferative diabetic retinopathy.

Purpose: This study aimed to assess the effectiveness and safety of intravitreal injection of conbercept (IVC) in treating moderate to severe nonproliferative diabetic retinopathy (NPDR), with or without accompanying diabetic macular edema. Methods: In this longitudinal retrospective study, 35 patients (50 eyes) with moderate to severe NPDR and Diabetic Retinopathy Severity Scale (DRSS) scores between 43 and 53 were treated at the Department of Ophthalmology, First Affiliated Hospital of Kunming Medical University, from October 2018 to January 2023. Treatment protocol included three monthly IVC injections followed by a pro re nata (PRN) regimen over a two-year follow-up period. Outcome measures were best-corrected visual acuity (BCVA), intraocular pressure, central macular thickness (CMT), extent of hard exudate (HE), and changes in DRSS scores. DRSS scores before and after treatment were analyzed using the Wilcoxon rank-sum test. Both systemic and ocular adverse events were meticulously documented to ascertain safety. Results: From baseline to the final follow-up, the mean BCVA improved from 0.41 ± 0.39 to 0.23 ± 0.20 logMAR (p<0.05). The mean CMT decreased from 306.22 ± 77.40 to 297.97 ± 88.15 µm (p = 0.385). At 24 months, DRSS scores improved by ≥1 stage in 40 eyes (80%), ≥ 2 stages in 28 eyes (56%), ≥3 stages in 10 eyes (20%), and remained stable in 6 eyes (12%). The DRSS scores at each follow-up interval demonstrated statistically significant improvement from baseline (p<0.05). In 15 of 27 eyes (55.56%) with diabetic macular edema (DME), there was a significant reduction in the mean area of HE from baseline (p<0.05). No serious systemic adverse events were observed. Conclusion: IVC is an effective and safe treatment for moderate to severe NPDR, demonstrating significant improvements in DRSS scores.

Quantification of the provenance contribution and sedimentary mixing effect of sediments in the Yellow River Basin, China.

Quantifying the source contributions of sediments in large fluvial systems with active wind erosion problems has crucial implications for understanding morphological evolution and ecological progression in the Earth system. Much effort have been focused on characterizing sediments of the Yellow River, but quantitation of the sediment source proportions at the basin-wide scale is lacking. To this end, the research aims to quantitatively elucidate the potential source contributions of sediments in the Yellow River based on geochemical characteristics and sediment fingerprinting technique, in order to identify sedimentary mixing effect and propose sustainable development strategies. In total, samples of four source groups (n = 107) and target floodplain sediments (n = 61) were collected and tested for elemental composition, grain size, magnetic susceptibility, and quartz grain microtextures. The results indicated that the optimal tracer combination was determined as P, Zn, and Ca. The average contributions of the "Tibetan Plateau", "Sandy deserts-Loess Plateau", "Loess Plateau", and "Loess Plateau-Qinling Mountains" source groups to the target sediments were 23.0 %, 21.5 %, 31.6 %, and 23.9 %, respectively. The accuracy of source apportionments was supported by the goodness of fit (GOF) and virtual mixtures tests. Meanwhile, large amounts of debris from surrounding mountains was transported to the Loess Plateau through fluvial processes and ultimately mixed with aeolian deposits, leading to sedimentary mixing effect. To maintain water balance and minimize erosion risk, the drought-resistant perennial planting and moderate grazing were recommended. The findings are instrumental in promoting soil and water conservation and disclosing fluvial and aeolian interaction on a global scale.

Genome-Wide Identification, Expression and Evolution Analysis of m6A Writers, Readers and Erasers in Aegilops_tauschii.

N6-methyladenosine modifications (m6A) is one of the most abundant and prevalent post-transcriptional RNA modifications in plants, playing the crucial role in plant growth and development and stress adaptation. However, the m6A regulatory machinery in Aegilops_tauschii, the D genome progenitor of common wheat, is not well understood at present. Here, we systematically identified the m6A-related genes in Aegilops with a genome-wide search approach. In total, 25 putative m6A genes composed of 5 writers, 13 readers and 7 erasers were obtained. A phylogenetic analysis clearly grouped them into three subfamilies with the same subfamily showing similar gene structures and conserved domains. These m6A genes were found to contain a large number of cis-acting elements associating with plant hormones, regulation of growth and development as well as stress response, suggesting their widespread regulation function. Furthermore, the expression profiling of them was investigated using RNA-seq data to obtain stress-responsive candidates, of which 5 were further validated with a qPCR analysis. Finally, the genetic variation of m6A-related genes was investigated between Aegilops and D subgenome of wheat based on re-sequencing data, and an obvious genetic bottleneck occurred on them during the wheat domestication process. The promising haplotype association with domestication and agronomic traits was also detected. This study provided some insights on the genomic organization and evolutionary features of m6A-related genes in Aegilops, which will facilitate the further functional study and also contribute to broaden the genetic basis for genetic improvement in wheat and other crops.

Metformin regulates the LIN28B­mediated JNK/STAT3 signaling pathway through miR­140­3p in subretinal fibrosis.

Subretinal fibrosis (SF) is an important cause of submacular neovascularization that leads to permanent vision loss, but has no effective clinical treatment. The present study examined the influence of metformin on SF, and investigated whether the mechanism involves the microRNA (miR)-140-3p/LIN28B/JNK/STAT3-mediated regulation of oxidative stress, angiogenesis and fibrosis-associated indicators. A mouse model of laser-induced SF was established. In addition, an ARPE-19 fibrotic cell model was established using TGF-ß1. A Cell Counting Kit-8 assay was used to examine cell viability. Flow cytometry was used to measure reactive oxygen species levels, and western blotting was used to detect the levels of proteins associated with epithelial-mesenchymal transition (EMT), signaling and fibrosis. The levels of superoxide dismutase, malondialdehyde, glutathione-peroxidase and catalase were measured using kits. Scratch assays and Transwell assays were used to assess cell migration and invasion, respectively, and reverse transcription-quantitative PCR was used to determine the levels of miR-140-3p and LIN28B. Dual-luciferase assays were used to verify the targeting relationship between miR-140-3p and LIN28B, and coimmunoprecipitation was used to confirm the interaction between LIN28B and JNK. Masson staining and hematoxylin and eosin staining were used to examine collagenous fibers and the histopathology of eye tissue. In ARPE-19 cells induced by TGF-ß1, metformin promoted miR-140-3p expression and inhibited LIN28B expression and JNK/STAT3 pathway activation, thereby inhibiting oxidative stress, EMT and fibrosis in ARPE-19 cells. The overexpression of LIN28B or treatment with the JNK/STAT3 agonist anisomycin partially reversed the inhibitory effect of metformin on oxidative stress and fibrosis in ARPE-19 cells. The dual-luciferase reporter assay and coimmunoprecipitation assay showed that miR-140-3p targeted the 3' untranslated region of LIN28B mRNA and inhibited LIN28B expression. LIN28B targeted and bound to JNK and regulated the JNK/STAT3 pathway. Therefore, it may be concluded that metformin can promote miR-140-3p expression, inhibit LIN28B and then inhibit the JNK/STAT3 pathway to alleviate SF.

Recombinant Human Adenovirus Type 5 (H101) Intra-Tumor Therapy in Patients with Persistent, Recurrent, or Metastatic Cervical Cancer: Genomic Profiling Relating to Clinical Efficacy.

Objective: Genomic profiles relating to H101 treatment-induced alterations are yet to be achieved. Here, we evaluated the impact of H101 via exome-sequencing approaches aiming to probe for potential biomarkers that are actionable in the treatment of persistent/recurrent/metastatic (P/R/M) cervical cancer. Methods: Whole exome sequencing (WES) was performd on paired pre- and post-H101 samples from 17 P/R/M cervical cancer patients who received serial intra-tumor injections of H101. Somatic mutations, including high-frequency mutations, microsatellite instability (MSI) status, tumor mutation burden (TMB), clonal evolution, and mutational signature were analyzed. Results: The median follow-up time after the H101 treatment was 14 months. Complete response was achieved in 9 patients, 3 patients achieved partial response, and 2 patients had stable disease, resulting in an objective response rate (ORR) of 70.6% (95% CI: 46.4%-96.7%). WES analysis showed no difference in treatment-related mutation characteristics, including non-synonymous-SNVs and TMB status. Patients with lower TMB were correlated with improved H101 response rates (P=0.044), whereas the same was not evident in high MSI (MSI-H) versus non-MSI-H patients (P=0.528). We observed a few high-frequency mutation genes (TTN, KMT2D, ALDOA, DNAH7, ADAP1, PTPN23, and THEMIS2) that probably carry functional importance in response to H101 treatment, among which KMT2D and ADAP1 mutations were associated with inferior progression-free survival (PFS) and/or overall survival (OS) (P<0.05). Notably, H101 treatment-induced accumulating subclones or clusters in primary tumors and some (Signature 2) were associated with shorter PFS. Conclusion: We conducted an unprecedented work via a WES-based approach and provided preliminary insights into H101 treatment-induced genetic aberrations in which some genes (TTN, KMT2D, ALDOA, DNAH7, ADAP1, PTPN23, and THEMIS2) could be considered potential therapeutic targets of H101-containing treatment in cervical carcinoma. Moreover, the therapy-associated characteristics such as clonal evolution and a mutational signature may warrant further evaluation of H101 in clinical settings for treating cervical carcinoma.

Insights into an NEk2 inhibitory profile of nitidine chloride by molecular docking and biological evaluation.

Deregulation of NEK2(NIMA-related serine/threonine 2) confers chemotherapeutic resistance to apoptosis and is closely correlated with poor prognosis in hepatocellular carcinoma (HCC). Here, we find that nanoparticles are prepared through hemisynthesis from natural nitidine chloride (NC) with enhanced antitumor activity. Nitidine chloride nanoparticle (TPGS-FA/NC) treatment show good therapy effect in Li-7 hepatocellular carcinoma cells. Additionally, molecular docking technologies are aimed at NEK2 protein (PDB ID: 6SGD) to analyze the detailed binding interactions with the potent target. NC participates in interactions with Asp159 residue. These studies advance the understanding of the modification of nitidine chloride substituent and provide useful drug design information for liver cancer treatment.

A novel nitidine chloride nanoparticle overcomes the stemness of CD133+EPCAM+ Huh7 hepatocellular carcinoma cells for liver cancer therapy.

BACKGROUND: Stemness of CD133+EPCAM+ hepatocellular carcinoma cells ensures cancer resistance to apoptosis,which is a challenge to current liver cancer treatments. In this study, we evaluated the tumorcidal activity of a novel nanoparticle of nitidine chloride (TPGS-FA/NC, TPGS-FA: folic acid modified D-α-tocopheryl polyethylene glycol 1000 succinate, NC: nitidine chloride), against human hepatocellular carcinoma (HCC) cell line Huh7 growth in vitro and in vivo. METHODS: Huh7 cells were treated with TPGS-FA/NC. Cell proliferation was assessed using MTT and colony assays. The expression of cell markers and signaling proteins was detected using western blot analyses. A sphere culture technique was used to enrich cancer stem cells (CSC) in Huh7 cells. TPGS-FA/NC (7.5, 15, 30, 60, 120 µg/mL) dose-dependently inhibited the proliferation of HCC cells, which associated with a reduction in AQP3 and STAT3 expression. Importantly,TPGS-FA/NC (10, 20, and 40 µg/mL) significantly reduced the EpCAM+/CD133+cell numbers, suppressed the sphere formation. The in vivo antitumor efficacy of TPGS-FA/NC was proved in Huh7 cell xenograft model in BALB/c nude mice, which were administered TPGS-FA/NC(4 mg· kg - 1· d - 1, ig) for 2 weeks. RESULTS: TPGS-FA/NC dose-dependently suppressed the AQP3/STAT3/CD133 axis in Huh7 cells. In Huh7 xenograft bearing nude mice, TPGS-FA/NC administration markedly inhibited Huh7 xenograft tumor growth . CONCLUSIONS: TPGS-FA/NC inhibit HCC tumor growth through multiple mechanisms, and it may be a promising candidate drug for the clinical therapy of hepatocellular carcinoma.

Efficacy and Safety of Recombinant Human Adenovirus Type 5 (H101) in Persistent, Recurrent, or Metastatic Gynecologic Malignancies: A Retrospective Study.

Background: To assess the efficacy and safety of recombinant human adenovirus type 5 (H101) in patients with persistent, recurrent, or metastatic gynecologic malignancies. Methods: The study retrospectively enrolled patients with persistent/recurrent/metastatic gynecologic malignancies who received H101-containing treatment at The First Affiliated Hospital of Xi'an Jiaotong University from September 1, 2019 to September 30, 2021. H101 was injected intratumorally into target lesions and dosage was calculated based on tumor diameter once a day for five consecutive days. The primary endpoint was local control (LC) rate. Secondary endpoints included objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS). Safety was the exploratory endpoint. Depending on prior treatment, patients received H101 either as monotherapy or as a combination therapy. Results: Totally, 29 patients were enrolled in the study. Median follow-up was 6.3 months (range: 3.2-27.9) from data analysis cut-off on December 31, 2021. The LC rate at 3 months was 44.8%, while ORR was 72.4%. Median DOR and PFS rates were not determined. The DOR rate, PFS rate at 6 and 12 months were 88.1%, 74.6% and 70.5%, 62.2%, respectively. Responses were observed in all four cancer types. Most treatment-related adverse events (90.5%) were grade 1 or 2, with the most common being fever (70%). Clinically significant adverse events were uncommon (7.9% in grade 3 and 1.6% in grade 4). No treatment-related deaths occurred. Conclusion: Our study showed that H101 (either monotherapy or combination therapy) has promising efficacy and favorable safety in patients with persistent, recurrent, metastatic gynecologic malignancies.