Gut microbiota and female health.

The gut microbiota is recognized as an endocrine organ with the capacity to influence distant organs and associated biological pathways. Recent advancements underscore the critical role of gut microbial homeostasis in female health; with dysbiosis potentially leading to diseases among women such as polycystic ovarian syndrome, endometriosis, breast cancer, cervical cancer, and ovarian cancer etc. Despite this, there has been limited discussion on the underlying mechanisms. This editorial explores the three potential mechanisms through which gut microbiota dysbiosis may impact the development of diseases among women, namely, the immune system, the gut microbiota-estrogen axis, and the metabolite pathway. We focused on approaches for treating diseases in women by addressing gut microbiota imbalances through probiotics, prebiotics supplementation, and fecal microbiota transplantation (FMT). Future studies should focus on determining the molecular mechanisms underlying associations between dysbiosis of gut microbiota and female diseases to realize precision medicine, with FMT emerging as a promising intervention.

Molecular mechanism of different flower color formation of Cymbidium ensifolium.

Cymbidium ensifolium is one of the national orchids in China, which has high ornamental value with changeable flower colors. To understand the formation mechanism of different flower colors of C. ensifolium, this research conducted transcriptome and metabolome analyses on four different colored sepals of C. ensifolium. Metabolome analysis detected 204 flavonoid metabolites, including 17 polyphenols, 27 anthocyanins, 75 flavones, 34 flavonols, 25 flavonoids, 18 flavanones, and 8 isoflavones. Among them, purple-red and red sepals contain a lot of anthocyanins, including cyanidin, pelargonin, and paeoniflorin, while yellow-green and white sepals have less anthocyanins detected, and their metabolites are mainly flavonols, flavanones and flavonoids. Transcriptome sequencing analysis showed that the expression levels of the anthocyanin biosynthetic enzyme genes in red and purple-red sepals were significantly higher than those in white and yellow-green sepals of C. ensifolium. The experimental results showed that CeF3'H2, CeDFR, CeANS, CeF3H and CeUFGT1 may be the key genes involved in anthocyanin production in C. ensifolium sepals, and CeMYB104 has been proved to play an important role in the flower color formation of C. ensifolium. The results of transformation showed that the CeMYB104 is involved in the synthesis of anthocyanins and can form a purple-red color in the white perianth of Phalaenopsis. These findings provide a theoretical reference to understand the formation mechanism of flower color in C. ensifolium.

Antitumor Activity of Berberine by Activating Autophagy and Apoptosis in CAL-62 and BHT-101 Anaplastic Thyroid Carcinoma Cell Lines.

Introduction: Anaplastic thyroid carcinoma (ATC) is the most lethal thyroid carcinoma. Doxorubicin (DOX) is the only drug approved for anaplastic thyroid cancer treatment, but its clinical use is restricted due to irreversible tissue toxicity. Berberine (BER), an isoquinoline alkaloid extracted from Coptidis Rhizoma, has been proposed to have antitumor activity in many cancers. However, the underlying mechanisms by which BER regulates apoptosis and autophagy in ATC remain unclear. Thus, the present study aimed to assess the therapeutic effect of BER in human ATC cell lines CAL-62 and BHT-101 as well as the underlying mechanisms. In addition, we assessed the antitumor effects of a combination of BER and DOX in ATC cells. Methods: The cell viability of CAL-62 and BTH-101 with treatment of BER for different hours was measured by CCK-8 assay, and cell apoptosis was assessed by clone formation assay and flow cytometric analysis. The protein levels of apoptosis protein, autophagy-related proteins and PI3K/AKT/mTORpathway were determined Using Western blot. Autophagy in cells was observed with GFP-LC3 plasmid using confocal fluorescent microscopy. Flow cytometry was used to detect intracellular ROS. Results: The present results showed that BER significantly inhibited cell growth and induced apoptosis in ATC cells. BER treatment also significantly upregulated the expression of LC3B-II and increased the number of GFP-LC3 puncta in ATC cells. Inhibition of autophagy by 3-methyladenine (3-MA) suppressed BER-induced autophagic cell death. Moreover, BER induced the generation of reactive oxygen species (ROS). Mechanistically, we demonstrated that BER regulated the autophagy and apoptosis of human ATC cells through the PI3K/AKT/mTOR pathways. Furthermore, BER and DOX cooperated to promote apoptosis and autophagy in ATC cells. Conclusion: Taken together, the present findings indicated that BER induces apoptosis and autophagic cell death by activating ROS and regulating the PI3K/AKT/mTOR signaling pathway.

Tertiary lymphoid structures in oral lichen planus and oral epithelial dysplasia with lichenoid features: A comparative study.

OBJECTIVE: Tertiary lymphoid structures (TLSs) provide sites for antigen presentation and activation of lymphocytes, promoting their infiltration; thus, enhancing specific immune responses. The aim of this comparative cross-sectional study was to reveal the characteristics and influence of TLSs in oral lichen planus (OLP) and oral epithelial dysplasia (OED) with lichenoid features. METHODS: Clinical information and samples of 51 OLP and 19 OED with lichenoid features were collected. Immunohistochemistry was performed, and the structures where CD20+ B cells and CD3+ T cells aggregated with peripheral lymph node addressin positive (PNAd+) vessels were defined as TLSs. The results and clinical information were analysed. RESULT: TLS were found in 44 (86.3%) patients with OLP and 19 (100%) patients with OED. The TLS score was higher in OED group (p = 0.023), accompanied by an increased number of PNAd+ vessels. The TLS was significantly correlated with PNAd+ vessels (p = 0.027), CD20+ B (p < 0.001) and CD208+ dendritic cells (p = 0.001). Foxp3+ Treg cells but not CD8+ T cells infiltrated more severely in OED (p = 0.003) and increased when TLS score was high (p = 0.002). CONCLUSIONS: This study revealed the widespread development of TLSs in the OLP and OED. The presence of TLSs showed a close relationship with dysplasia and may increase malignant potency by over-inducing Treg cells.

Influence of PD-1/PD-L1 on immune microenvironment in oral leukoplakia and oral squamous cell carcinoma.

OBJECTIVE: To evaluate the relation between the expression of PD-1, PD-L1, CD3, CD8, Foxp3 and clinicopathological features in patients with oral leukoplakia (OLK) and oral squamous cell carcinomas (OSCC) as well as the malignant outcome in OLK patients, and to study the effect of PD-1 and PD-L1 on immune microenvironment in the progression of oral carcinogenesis. METHODS: We evaluated the expression of PD-1/PD-L1 and composition of CD3+ , CD8+ and Foxp3+ T lymphocytes in OLK and OSCC samples by immunohistochemical (IHC) staining and analyzed their relation with clinical information and malignant transformation in OLK patients. RESULTS: IHC staining demonstrated that the expression of PD-1 was significantly increased in the high-grade OLK group than in the low-grade OLK group, while PD-L1 was detected mainly in OSCC. The expression of CD3, CD8, and Foxp3 was found higher in the high-grade OLK group than in the low-grade OLK group, and the Foxp3+ cells were found more in the OSCC group than in the high-grade OLK group. PD-1 was significantly correlated with CD3 (p < 0.05, R = 0.52), CD8 (p < 0.05, R = 0.46), and Foxp3 (p < 0.05, R = 0.46), and the low PD-1-expression group showed a better malignant-free survival than high PD-1 expression group in the OLK (p < 0.05). CONCLUSION: The PD-1/PD-L1 may induce immune suppression in OLK and accelerate the progress of malignant transformation.

[Zexie Decoction regulates Akt/TFEB signaling pathway to promote lipophagy in hepatocytes].

Taking lipophagy as the breakthrough point, we explored the mechanism of Zexie Decoction(ZXD) in improving lipid metabolism in the hepatocyte model induced by palmitic acid(PA) and in the animal model induced by high-fat diet(HFD) on the basis of protein kinase B(Akt)/transcription factor EB(TFEB) signaling pathway. Co-localization was carried out for the microtubule-associated protein light chain 3(LC3) plasmid labeled with green fluorescent protein(GFP) and lipid droplets(LDs), and immunofluorescence co-localization for liver LC3 of HFD mice and perilipin 2(PLIN2). The results showed that ZXD up-regulated the expression of LC3, reduced lipid accumulation in hepatocytes, and increased the co-localization of LC3 and LDs, thereby activating lipo-phagy. Western blot results confirmed that ZXD increased autophagy-related protein LC3Ⅱ/LC3Ⅰ transformation ratio and lysosome-associated membrane protein 2(LAMP2) in vivo and in vitro and promoted the degradation of sequestosome-1(SQSTM1/p62)(P<0.05). The results above jointly explained that ZXD regulated lipophagy. Furthermore, ZXD activated TFEB expression(P<0.05) and reversed the PA-and HFD-induced decrease of TFEB nuclear localization in hepatocytes(P<0.05). Meanwhile, ZXD activated liver TFEB to up-regulate the expression of the targets Lamp2, Lc3 B, Bcl2, and Atg5(P<0.05). Additionally, ZXD down-regulated the protein level of p-Akt upstream of TFEB in vivo and in vitro. In conclusion, ZXD may promote lipophagy by regulating the Akt/TFEB pathway.

Reproductive and oncological outcomes of fertility-sparing surgery in patients with stage I epithelial ovarian cancer: A systematic review and meta-analysis.

OBJECTIVE: We meta-analyzed available evidence on fertility, survival, and cancer recurrence in patients with stage I epithelial ovarian cancer (EOC) after fertility-sparing surgery (FSS). METHODS: We systematically reviewed PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials to identify studies reporting reproductive and oncological outcomes of patients with stage I EOC who underwent FSS. Random-effects models were used to calculate pooled rates of disease outcomes, along with 95% confidence intervals (CIs). Subgroup and sensitivity analyses were conducted to identify sources of heterogeneity in the data. RESULTS: We included 23 observational retrospective studies involving 1126 patients. The pooled pregnancy rate was 30% (95% CI, 0.26-0.34), while the pooled natural conception rate was 26% (95% CI, 0.20-0.33). The pooled live birth rate was 27% (95% CI, 0.22-0.32). The pooled rate of EOC recurrence was 12% (95% CI, 0.09-0.14), which did not differ significantly from the rate among patients who underwent radical surgery (odds ratio, 0.77; 95% CI, 0.45-1.33). CONCLUSIONS: FSS is associated with good oncological outcomes but less than satisfactory reproductive outcomes. All in all, the procedure appears to be a safe alternative to radical surgery for EOC patients who want to preserve fertility.

Therapeutic drug monitoring in inflammatory bowel disease treatments.

Recently, biological drugs have played a leading role in the treatment of inflammatory bowel disease, and therapeutic drug monitoring (TDM) may be useful in maximizing their effectiveness. TDM involves the measurement of serum drug and anti-drug antibodies concentrations as the basis for dosage adjustments or drug conversions to achieve a higher response rate. We believe that concentration thresholds should be individualized based on patients' disease severity, extent and phenotype, and therapeutic purposes should also be considered, with higher cut-offs mainly needed for endoscopic and fistula healing than for symptomatic remission. Proactive and reactive TDM can help optimize treatment, especially in patients receiving anti-tumour necrosis factor, and guide dose adjustment or drug conversion with lower cost. TDM is a promising approach to achieve precision medicine and targeted medicine in the future.

Cancer-associated fibroblasts promote oral squamous cell carcinoma progression through LOX-mediated matrix stiffness.

BACKGROUND: Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment, have prominent roles in the development of solid tumors as stromal targets. However, the underlying mechanism of CAFs' function in oral squamous cell carcinoma (OSCC) development remains unclear. Here, we investigated the role of lysyl oxidase (LOX) expression in CAFs in tumor stromal remodeling and the mechanism of its effect on OSCC progression. METHODS: Multiple immunohistochemistry (IHC) staining was performed to detect the correlation of CAFs and LOX in the stroma of OSCC specimens, as well as the correlation with clinicopathological parameters and prognosis. The expression of LOX in CAFs were detected by RT-qPCR and western blot. The effects of LOX in CAFs on the biological characteristics of OSCC cell line were investigated using CCK-8, wound-healing and transwell assay. CAFs were co-cultured with type I collagen in vitro, and collagen contraction test, microstructure observation and rheometer were used to detect the effect of CAFs on remodeling collagen matrix. Then, collagen with different stiffness were established to investigate the effect of matrix stiffness on the progression of OSCC. Moreover, we used focal adhesion kinase (FAK) phosphorylation inhibitors to explored whether the increase in matrix stiffness promote the progression of OSCC through activating FAK phosphorylation pathway. RESULTS: LOX was colocalized with CAFs in the stroma of OSCC tissues, and its expression was significantly related to the degree of malignant differentiation and poor prognosis in OSCC. LOX was highly expressed in CAFs, and its knockdown impaired the proliferation, migration, invasion and EMT process of OSCC cells. The expression of LOX in CAFs can catalyze collagen crosslinking and increase matrix stiffness. Furthermore, CAFs-derived LOX-mediated increase in collagen stiffness induced morphological changes and promoted invasion and EMT process in OSCC cells by activating FAK phosphorylation pathway. CONCLUSIONS: Our findings suggest that CAFs highly express LOX in the stroma of OSCC and can remodel the matrix collagen microenvironment, and the increase in matrix stiffness mediated by CAFs-derived LOX promotes OSCC development through FAK phosphorylation pathway. Thus, LOX may be a potential target for the early diagnosis and therapeutic treatment of OSCC.

Subphrenic Lymph Node Metastasis Predicts Poorer Prognosis for Nasopharyngeal Carcinoma Patients With Metachronous Metastasis.

AIM: We retrospectively analyzed the distribution of distant lymph node metastasis and its impact on prognosis in patients with metastatic NPC after treatment. METHODS: From 2010 to 2016, 219 NPC patients out of 1,601 (182 from the Affiliated Cancer Hospital and Institute of Guangzhou Medical University, and 37 from the Affiliated Dongguan Hospital, Southern Medical University) developed distant metastasis after primary radiation therapy. Metastatic lesions were divided into groups according to location: bones above the diaphragm (supraphrenic bone, SUP-B); bones below the diaphragm (subphrenic bone, SUB-B); distant lymph nodes above the diaphragm (supraphrenic distant lymph nodes, SUP-DLN); distant lymph nodes below the diaphragm (subphrenic distant lymph nodes, SUB-DLN), liver, lung, and other lesions beyond bone/lung/distant lymph node above the diaphragm (supraphrenic other lesions, SUP-OL); other lesions beyond bone/liver/distant lymph node below the diaphragm (subphrenic other lesions, SUB-OL); the subtotal above the diaphragm (supraphrenic total lesions, SUP-TL); and the subtotal below the diaphragm (subphrenic total lesions, SUB-TL). Kaplan-Meier methods were used to estimate the probability of patients' overall survival (OS). Univariate and multivariate analyses were applied using the Cox proportional hazard model to explore prediction factors of OS. RESULTS: The most frequent metastatic locations were bone (45.2%), lung (40.6%), liver (32.0%), and distant lymph nodes (20.1%). The total number of distant lymph node metastasis was 44, of which 22 (10.0%) were above the diaphragm, 18 (8.2%) were below the diaphragm, and 4 (1.8%) were both above and below the diaphragm. Age (HR: 1.02, 95% CI: 1.00, 1.03, p = 0.012), N stage (HR: 1.26, 95% CI: 1.04, 1.54, p = 0.019), number of metastatic locations (HR: 1.39, 95% CI: 1.12, 1.73, p = 0.003), bone (HR: 1.65, 95% CI: 1.20, 2.25, p = 0.002), SUB-B (HR: 1.51, 95% CI: 1.07, 2.12, p = 0.019), SUB-DLN (HR: 1.72, 95% CI: 1.03, 2.86, p = 0.038), and SUB-O L(HR: 4.46, 95% CI: 1.39, 14.3, p = 0.012) were associated with OS. Multivariate analyses revealed that a higher N stage (HR: 1.23, 95% CI: 1.00, 1.50, p = 0.048), SUB-DLN (HR: 1.72, 95% CI: 1.02, 2.90, p = 0.043), and SUB-OL (HR: 3.72, 95% CI: 1.14, 12.16, p = 0.029) were associated with worse OS. CONCLUSION: Subphrenic lymph node metastasis predicts poorer prognosis for NPC patients with metachronous metastasis; however, this needs validation by large prospective studies.

Prognostic value of hypertension in patients with nasopharyngeal carcinoma treated with intensity-modulated radiation therapy.

BACKGROUND: The prognostic value of hypertension remains unknown in nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). In this study, we aimed to develop hypertension as a prognostic signature for improving the clinical outcome of non-metastatic NPC patients treated with IMRT. METHODS: A clinical cohort, comprising 1,057 patients with non-metastatic, histologically proven, NPC who were treated with IMRT were retrospectively reviewed. Associations between hypertension and overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) were estimated by Cox regression. A subgroup analysis of the relationship between hypertension grade and NPC prognosis was also conducted. RESULTS: Among the 1057 patients, 94 (8.9%) had hypertension. Significant differences were observed between patients with hypertension and patients without hypertension in relation to OS (66.6% vs. 85.4%; P<0.0001), PFS (60.8% vs. 76.3%; P=0.001), LRRFS (85.3% vs. 90.5%; P=0.024), and DMFS (77.4% vs. 85.1%; P=0.048), and patients without hypertension had greater treatment success rates. The Cox analysis showed that hypertension was an independent unfavorable prognostic factor for OS [hazards ratio (HR), 2.056; P=0.001], PFS (HR, 1.716; P=0.005), and DMFS (HR, 1.658; P=0.049). The patients with more severe levels of hypertension had worse OS and LRRFS. Specifically, the 5-year OS and LRRFS for grades 1, 2, and 3 were 70.6%, 64.3%, and 62.4% (P=0.712), and 89.5%, 86.4%, and 76.1% (P=0.376), respectively. CONCLUSIONS: Hypertension is an independent adverse prognostic factor in NPC patients treated with IMRT. The question of whether the severity of hypertension affects prognosis needs to be further verified by large sample data.

FSCN1 Promotes Radiation Resistance in Patients With PIK3CA Gene Alteration.

Radiotherapy is one of the standard treatments for cervical cancer and head and neck cancer. However, the clinical efficacy of this treatment is limited by radioresistance. The discovery of effective prognostic biomarkers and the identification of new therapeutic targets have helped to overcome the problem of radioresistance. In this study, we show that in the context of PIK3CA mutation or amplification, high expression of fascin actin-bundling protein 1 (FSCN1) (using the median as the cut-off value) is associated with poor prognosis and radiotherapy response in cancer patients. Silencing FSCN1 enhances radiosensitivity and promotes apoptosis in cancer cells with PIK3CA alterations, and this process may be associated with the downregulation of YWHAZ. These results reveal that FSCN1 may be a key regulator of radioresistance and could be a potential target for improving radiotherapy efficacy in cervical cancer and head and neck cancer patients with PIK3CA alterations.

Influence of lymph node involvement or lymphadenectomy on prognosis of patients with borderline ovarian tumors: A systematic review and meta-analysis.

OBJECTIVE: Borderline ovarian tumors (BOTs) account for about 15% of all epithelial tumors of the ovary, and around 75% of patients are diagnosed in early stages. Although many of these patients have lymph node involvement (LNI), whether LNI decreases their survival is controversial, raising the question of whether lymphadenectomy should be performed. We conducted a systematic review and meta-analysis of these questions. METHODS: We searched articles related to LNI and lymphadenectomy in patients with BOTs in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Data on rate of LNI, recurrence and survival were pooled and meta-analyzed using a random-effects model. Heterogeneity was evaluated using the I2 test. RESULTS: A total of 25 studies with 12,503 patients were meta-analyzed. The overall pooled rate of LNI was 10% [95% confidence interval (CI) 0.07-0.13]. LNI was associated with a higher risk of recurrence [odds ratio (OR) 2.23, 95% CI 1.13-4.40]. However, LNI did not significantly affect cause-specific survival [hazard ratio (HR) 1.73, 95% CI 0.99-3.02] or disease-free survival (HR 1.48, 95% CI 0.56-3.92). Similarly, lymphadenectomy did not significantly affect risk of recurrence (OR 0.91, 95% CI 0.57-1.46), overall survival (HR 0.90, 95% CI 0.58-1.40), disease-free survival (HR 0.95, 95% CI 0.61-1.50) or progression-free survival (HR 0.60, 95% CI 0.24-1.49). CONCLUSIONS: LNI appears to increase risk of recurrence in BOT patients, but neither it nor lymphadenectomy appears to influence prognosis. Therefore, lymphadenectomy should be considered only for certain BOT patients, such as those with suspected LNI based on imaging or surgical exploration.

PBK phosphorylates MSL1 to elicit epigenetic modulation of CD276 in nasopharyngeal carcinoma.

CD276 (also known as B7-H3, an immune checkpoint molecule) is aberrantly overexpressed in many cancers. However, the upregulation mechanism and in particular, whether oncogenic signaling has a role, is unclear. Here we demonstrate that a pro-oncogenic kinase PBK, the expression of which is associated with immune infiltration in nasopharyngeal carcinoma (NPC), stimulates the expression of CD276 epigenetically. Mechanistically, PBK phosphorylates MSL1 and enhances the interaction between MSL1 and MSL2, MSL3, and KAT8, the components of the MSL complex. As a consequence, PBK promotes the enrichment of MSL complex on CD276 promoter, leading to the increased histone H4 K16 acetylation and the activation of CD276 transcription. In addition, we show that CD276 is highly upregulated and associated with immune infiltrating levels in NPC. Collectively, our findings describe a novel PBK/MSL1/CD276 signaling axis, which may play an important role in immune evasion of NPC and may be targeted for cancer immunotherapy.

Ovarian metastasis in women with cervical carcinoma in stages IA to IIB: A systematic review and meta-analysis.

BACKGROUND: Cervical cancer is one of the common malignancies that afflict women worldwide. In rare cases, cervical cancer leads to ovarian metastasis (OM), resulting in poor outcomes. We conducted a systematic review and meta-analysis to evaluate the incidence and risk factors of OM in patients with adenocarcinoma (ADC) or squamous cell carcinoma (SCC) of the cervix. METHODS: We searched articles focused on OM in cervical carcinoma in PubMed, Embase, and the Cochrane Central Register of Controlled Trials. A meta-analysis was performed including selected publications. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated using random-effects models. The heterogeneity was evaluated by the I test. I > 50% was considered high heterogeneity. RESULTS: A total of 12 studies with 18,389 patients with cervical cancer in International Federation of Gynecology and Obstetrics stages IA to IIB were included in the meta-analysis. The overall incidence of OM was 3.61% among patients with ADC and 1.46% among patients with SCC (ADC vs SCC: OR 3.89, 95% CI 2.62-5.78; P < .001). Risk factors for OM were age >40 years (OR 1.79, 95% CI 1.02-3.13), bulky tumor (OR 2.65, 95% CI 1.77-3.95), pelvic lymph node involvement (PLNI; OR 9.33, 95% CI 6.34-13.73), lymphovascular space involvement (LVSI; OR 4.38, 95% CI 1.86-10.31), parametrial invasion (PMI; OR 7.87, 95% CI 5.01-12.36), and corpus uteri invasion (CUI; OR 7.64, 95% CI 2.51-23.24). PLNI, LVSI, and PMI were the leading risk factors, contributing to OM with respective population attributable fractions of 64.8%, 58.8%, and 51.5%. CONCLUSION: The incidence of OM is relatively low in ADC and SCC patients. Risk factors for OM include PLNI, LVSI, PMI, bulky tumor, CUI, or age over 40 years, with the first 3 contributing more to risk of OM.