Genome Sequencing and Characterization of Bacillus velezensis N23 as Biocontrol Agent against Plant Pathogens.

The overuse of chemical fungicides against fungal pathogens adversely affects soil and plant health, resulting in environmental problems and food safety. Therefore, biocontrol is considered as an environmentally friendly and cost-effective green technique in environmental protection and agricultural production. We obtained a bacterial strain N23 from a contaminated plate which showed significant inhibition to anthracnose. The strain N23 was identified as Bacillus velezensis based on 16S rRNA gene, gyrA gene, and whole-genome sequence. The bacterium N23 was able to suppress the mycelial growth of numerous plant pathogenic fungi on solid media. Tomato seeds treated with strain N23 showed significantly higher germination levels than untreated ones. Moreover, strain N23 effectively reduced the lesion area of pepper anthracnose disease in planta. The gene clusters responsible for antifungal metabolites (fengycin, surfactin, and iturin) were identified in the genome sequence of N23 based on genome mining and PCR. Furthermore, methanol extracts of the bacterial culture caused significant inhibition in growth of the fungal Colletotrichum sp. and Botrytis cinerea. These findings suggested that B. velezensis N23 could be a potential biocontrol agent in agricultural production and a source of antimicrobial compounds for further exploitation.

Mohawk protects against tendon damage via suppressing Wnt/ß-catenin pathway.

Degenerative tendon injuries are common clinical problems associated with overuse or aging, and understanding the mechanisms of tendon injury and regeneration can contribute to the study of tendon healing and repair. As a transcription factor, Mohawk (Mkx) is responsible for tendons development, yet, the roles of which in tendon damage remain mostly elusive. In this study, using Mkx overexpressed mice on long treadmill as an in vivo model and MkxOE Achilles tenocytes stimulated by equiaxial stretch as an in vitro model, we anaylsed the effects of Mkx overexpression on the tendon. Mkx and tendon tension strength were decreased after the expose to excessive mechanical forces, and Mkx overexpression protected the tendon from damage. Moreover, we revealed that the Wnt/ß-catenin activation, inflammation, and Runx2 expression were increased at the injured Achilles tendon, upregulated Mkx significantly reversed the increased Wnt/ß-catenin pathway, Tnf-α, Il-1ß, and Il-6 levels, and reduced tendon cell damage. However, Wnt3a, IWR and BIO had not significantly affected the Mkx expression in achilles tenocytes. In conclusion, Mkx is involved in tendon healing and protects the tendon from damage through suppressing Wnt/ß-catenin pathway, suggesting Mkx/Wnt/ß-catenin pathway may be potential therapeutic targets for tendon damage.

TRAIL-driven targeting and reversing cervical cancer radioresistance by seleno-nanotherapeutics through regulating cell metabolism.

Recently, radioresistance has become a major obstacle in the radiotherapy of cervical cancer. To demonstrate enhanced radiosensitization against radioresistant cervical cancer, radioresistant cervical cancer cell line was developed and the mechanism of radioresistance was explored. Due to the overexpression of (death receptor 5, DR5) in cervical cancer, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-overexpressed cervical cancer cell membrane-camouflaged Cu2-xSe nanomedicine (CCMT) was designed. Since the CCMT was encapsulated with TRAIL-modified cell membrane, it represented high target to cervical cancer cell and immune evasion. Furthermore, Cu2-xSe had the ability to scavenge glutathione (GSH) and produce ·OH with excess H2O2 in the tumor microenvironment. The presence of CCMT combined with radiation therapy could effectively increase the 1O2 produced by X-rays. In vitro and in vivo studies elaborated that CCMT exhibited excellent radiosensitization properties to reverse radiotolerance by scavenging GSH and promoting DNA damage, apoptosis, mitochondrial membrane potential damage and metabolic disruption. Collectively, this study suggested that the development of TRAIL-overexpressed cell membrane-camouflaged Cu2-xSe nanomedicine could advance future cervical cancer treatment and minimize the disadvantages associated with radiation treatment.

SH3 domain-binding kinase 1 promotes proliferation and inhibits apoptosis of cervical cancer via activating the Wnt/ß-catenin and Raf/ERK1/2 signaling pathways.

SH3 domain-binding kinase 1 (SBK1), is a member of the serine/threonine protein kinases family, and was confirmed to be upregulated in cervical cancer in our previous study. Nonetheless, the role of SBK1 in regulating cancer occurrence and development is unclear. In this study, the stable SBK1-knockdown and -overexpressed cell models were constructed by plasmid transfection technology. Cell viability and growth were assessed through CCK-8, colony formation, and BrdU methods. Cell cycle and apoptosis were analyzed by flow cytometry. The JC-1 staining assay was used to explore mitochondrial membrane potential. The scratch and Transwell assays were used to evaluate the cell metastatic ability. The nude mice models were utilized to explore the SBK1 expression affecting tumor growth in vivo. Our research indicated a high expression of SBK1 both in tissues and cells of cervical cancer. The proliferative, migratory, as well as invasive capacities of cervical cancer cells, were suppressed, and apoptosis was enhanced after SBK1 silence, whereas SBK1 upregulation led to opposite results. In addition, Wnt/ß-catenin and Raf/ERK1/2 pathways were activated by SBK1 upregulation. Furthermore, downregulation of c-Raf or ß-catenin, reversed the proliferation promotion and apoptosis inhibition effects in SBK1-overexpressed cells. The same results were observed with the use of the specific Raf inhibitor. SBK1 overexpression also contributed to tumor growth in vivo. Overall, SBK1 played a vital role in cervical tumorigenesis via activating the Wnt/ß-catenin and Raf/ERK1/2 pathways.

Low temperature synthesis of carbon dots in microfluidic chip and their application for sensing cefquinome residues in milk.

In this study, the N-doped carbon dots were continuously synthesized by a facile microfluidic strategy at 90 °C, and their quantum yields reached 19.2%. The characteristics of the obtained carbon dots could be real-time monitored in order to synthesize carbon dots with specific properties. By incorporating the carbon dots into a well-established enzymatic cascade amplification system, an inner filter effect-based fluorescence immunoassay was set up for ultrasensitive detection of cefquinome residues in milk samples. The developed fluorescence immunoassay provided a low detection limit of 0.78 ng/mL, which satisfied the maximum residue limit set by authorities. The fluorescence immunoassay had an 50% inhibition concentration of 0.19 ng/mL against cefquinome and showed a good linear relationship from 0.013 ng/mL to 1.52 ng/mL. While, the average recovery values ranged from 77.8% to 107.8% in spiked milk samples, with relative standard deviations ranging from 6.8% to 10.9%. Compared with conventional methods, the microfluidic chip was more flexible on carbon dots synthesis and the developed fluorescence immunoassay was more sensitive and eco-friendlier for ultra-trace cefquinome residue analysis.

Aggregation-induced emission luminogens-encoded microspheres preparation and flow-through immunoaffinity chromatographic assay development for microcystin-LR analysis.

Despite decades of efforts, we are faced with the daunting task of on-site ultratrace environmental toxins detecting, especially the microcystins caused by water bloom. In this work, a novel fluorescent microsphere-based flow-through immunoaffinity chromatographic assay has been designed for detecting ultratrace microcystin-LR in water and aquatic products. The aggregation-induced emission luminogens were encapsulated into fluorescent microspheres to ensure microcystin-LR quantitation with a whole analytical time of less than 30 min. Furthermore, the colorimetric images were captured and quantitatively analyzed, which offered a limit of detection at 0.217 pg/mL and a limit of quantitation at 0.362 pg/mL in water and aquatic muscle samples. The developed immunoassays provide average recovery ranging from 79.1 % to 95.7 %, with relative standard deviations less than 13.4 %. Thus, the validated flow-through immunoaffinity chromatographic assay is an easy-to-use alternative for on-site screening of microcystin-LR in water and aquatic samples at picogram levels.

Complex Repair and Cruciate Ligament Reconstruction in KDs III and IV Multiligamentous Knee Injuries-Results of Mid-Term Follow-up.

The purpose of the present study was to describe the longitudinal outcomes of acute repair of extra-articular structure and anatomical reconstruction of cruciate ligament for knee dislocations (KDs) III and IV multiligamentous knee injuries. Forty-seven patients with an acute KD III or IV were treated with one-stage management within 9.2 days. Forty-five KDs III and IV with a follow-up at a mean of 53.2 months were evaluated. The mean International Knee Documentation Committee (IKDC) score, Lysholm score, and Tegner score were 81.5 ± 0.7, 89.6 ± 1.2, and 6.8 ± 0.5, respectively. Comparing preoperative data with those at the latest follow-up, significant improvements in IKDC score (p < 0.01), Lysholm score (p < 0.01), and Tegner score (p < 0.01) were noted in all groups. Comparing contralateral knee stability, no statistical differences were found including the varus/valgus (0 degree/30 degrees) and Telos stress radiography. So, acute repair of extra-articular structure and anatomical reconstruction of cruciate ligament resulted in satisfactory outcomes for KDs III and IV multiligamentous knee injuries.

Quantification and influencing factors of perioperative hidden blood loss in patients undergoing laparoscopic ovarian cystectomy for benign ovarian tumours.

This retrospective, monocentric study quantified hidden blood loss (HBL) and investigated its influencing factors in benign ovarian tumour patients undergoing laparoscopic ovarian cystectomy. Data from 153 patients who underwent laparoscopic ovarian cystectomy were retrospectively reviewed. HBL was calculated using the formula derived from 'Nadler' and 'Cross'. Pearson correlation was carried out to measure the association between HBL and potential risk factors. The average HBL was 280.22 ± 168.42 mL, accounting for 84.13 ± 19.20% of total blood loss (TBL) (347.48 ± 179.05 mL), which was a change of almost fourteen-fold relative to median visible blood loss [20.00 mL (10.00 mL, 57.5 mL)]. Surgical time, number of excisional tumours and preoperative albumin values were risk factors for HBL. HBL represents a large proportion more than 80% of TBL in patients undergoing laparoscopic ovarian cystectomy. Collectively, HBL is helpful for estimating intraoperative blood loss and better guidance of haemostatic agents, which reduces postoperative complications and expedites postoperative recovery. Additionally, the estimation of HBL also contributes to the summary, reflection and improvement of surgical technique.IMPACT STATEMENTWhat is already known on this subject? There has been a growing number of surgical patients with perioperative anaemia, which appears to be inconsistent with measured levels of visible intraoperative blood loss and postoperative drainage. This substantial but easily underestimated blood loss is known as hidden blood loss. To date, no published articles have evaluated HBL and its related risk factors in benign ovarian tumour patients undergoing laparoscopic ovarian cystectomy.What the results of this study add? HBL accounts for a large amount of TBL in laparoscopy for benign ovarian tumours. Surgical time, number of excisional tumours and preoperative albumin values are risk factors for HBL.What the implications are of these findings for clinical practice and/or further research? The management of HBL is important for the administration of perioperative blooding loss. In this context, HBL can be applied to estimate intraoperative blood loss and be better guidance of haemostatic agents to reduce postoperative complications and hasten postoperative rehabilitation. Additionally, the estimation of HBL also contributes to the summary, reflection and improvement of surgical technique.

Copper-based metal-organic framework impedes triple-negative breast cancer metastasis via local estrogen deprivation and platelets blockade.

Metastasis is one of the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Abnormally estrogen level and activated platelets are the key driving forces for TNBC metastasis. Herein, an "ion/gas" bioactive nanogenerator (termed as IGBN), comprising a copper-based MOF and loaded cisplatin-arginine (Pt-Arg) prodrug is developed for metastasis-promoting tumor microenvironment reprogramming and TNBC therapy. The copper-based MOF not only serves as a drug carrier, but also specifically produces Cu2+ in tumors, which catalytic oxidizing estrogen to reduce estrogen levels in situ. Meanwhile, the rationally designed Pt-Arg prodrug reduced into cisplatin to significantly promote the generation of H2O2 in the tumor, then permitting self-augmented cascade NO gas generation by oxidizing Arg through a H2O2 self-supplied way, thus blocking platelet activation in tumor. We clarified that IGBN inhibited TNBC metastasis through local estrogen deprivation and platelets blockade, affording 88.4% inhibition of pulmonary metastasis in a 4T1 mammary adenocarcinoma model. Notably, the locally copper ion interference, NO gas therapy and cisplatin chemotherapy together resulted in an enhanced therapeutic efficacy in primary tumor ablation without significant toxicity. This "ion/gas" bioactive nanogenerator offers a robust and safe strategy for TNBC therapy.

Herpesvirus-Mimicking DNAzyme-Loaded Nanoparticles as a Mitochondrial DNA Stress Inducer to Activate Innate Immunity for Tumor Therapy.

Virus-based immunotherapy is a promising approach to treat tumor. Closely mimicking the structure and sequential infection processes of natural viruses is highly desirable for effective tumor immunotherapy but remains challenging. Here, inspired by the robust innate immunity induced by herpesvirus, a herpesvirus-mimicking nanoparticle (named Vir-ZM@TD) is engineered for tumor therapy by mimicking the structure and infection processes of herpesvirus. In this biomimetic system, DNAzyme-loaded manganese-doped zeolitic imidazolate framework-90 (ZIF-90) nanoparticles (ZM@TD) mimic the virus nucleocapsid containing the genome; the erythrocyte membrane mimics the viral envelope; and two functional peptides, RGD and HA2 peptides, resemble the surface glycoprotein spikes of herpesvirus. Vir-ZM@TD can both effectively evade rapid clearance in the blood circulation and closely mimic the serial infection processes of herpesvirus, including specific tumor targeting, membrane fusion-mediated endosomal escape, and TFAM (transcription factor A, mitochondrial) deficiency-triggered mitochondrial DNA stress, as well as the release of manganese ions (Mn2+ ) from organelles into the cytosol, ultimately effectively priming cGAS-STING pathway-mediated innate immunity with 68% complete regression of primary tumors and extending by 32 days the median survival time of 4T1-tumor-bearing mice.

Effects of Different Nonsteroidal Anti-Inflammatory Drugs Combined with Platelet-Rich Plasma on Inflammatory Factor Levels in Patients with Osteoarthritis.

Objective: To investigate the effects of different nonsteroidal anti-inflammatory drugs combined with platelet-rich plasma on inflammatory factor levels in patients with osteoarthritis. Methods: The clinic data of 120 patients with osteoarthritis who were treated in our hospital (June 2019-June 2021) were retrospectively reviewed. All the patients were given platelet-rich plasma. According to the different nonsteroidal anti-inflammatory drugs the patients received, they were equalized into diclofenac sodium group, celecoxib group, and iguratimod group, with 40 cases in each group. After treatment, the patients' clinical efficacy was compared and analyzed. Results: After treatment, the pain degrees of the patients in the three groups were gradually reduced. After 4 weeks and 8 weeks of treatment, the statistical differences in the scores of Visual Analogue Scale (VAS) were found among the three groups. Specifically, compared with the other two groups, the iguratimod group had remarkably lower VAS scores (P < 0.05) and the celecoxib group had signally lower VAS scores compared with the diclofenac sodium group (P < 0.05). After treatment, the inflammatory factor levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) in the diclofenac sodium group were observably higher compared with the celecoxib group (P < 0.05), and the inflammatory factor levels in the celecoxib group were remarkably higher compared with the iguratimod group (P < 0.05). Before treatment, no notable difference in the Lysholm scores was found among the three groups, and the patients' knee joint function was gradually improved after treatment. To be specific, after 4 and 8 weeks of treatment, the iguratimod group had observably higher Lysholm scores compared with the other two groups (P < 0.05), and the celecoxib group had signally higher Lysholm scores compared with the diclofenac sodium group (P < 0.05). The iguratimod group got markedly lower Western Ontario and McMaster Universities (WOMAC) score compared with the celecoxib group (P < 0.05); Compared with the diclofenac sodium group, the celecoxib group got remarkably lower WOMAC score (P < 0.05). During treatment, few patients suffered from mild gastrointestinal discomfort and hepatic dysfunction in the three groups, and no other severe adverse reactions were found. No statistical difference in the total incidence of adverse reactions among the three groups was observed (P > 0.05). Conclusion: The combination of nonsteroidal anti-inflammatory drugs with platelet-rich plasma can further reduce the inflammatory reactions of the patients with osteoarthritis and improve their knee joint function. Significantly, the iguratimod, with high safety, has observably better effects on inhibiting inflammatory factors and improving knee joint function compared with diclofenac sodium and celecoxib.

Cyclic di-GMP regulates bacterial colonization and further biocontrol efficacy of Bacillus velezensis against apple ring rot disease via its potential receptor YdaK.

Bacillus species are among the most investigated beneficial bacteria and widely used in agricultural systems as biological control agents. Its biocontrol efficacy is controlled by diverse regulators. Cyclic diguanylate (c-di-GMP) is a nearly universal second messenger in bacteria and modulates various important physiological processes, including motility, biofilm formation, antifungal antibiotic production and host colonization. However, the impact of c-di-GMP on biocontrol efficacy of beneficial bacteria is unknown. Bacillus velezensis PG12 is an effective biocontrol strain against apple ring rot disease caused by Botryosphaeria dothidea. In this study, the contribution of c-di-GMP to biocontrol efficacy of B. velezensis PG12 was investigated. Deletion of single gene encoding diguanylate cyclase or phosphodiesterase did not affect its biocontrol efficacy against apple ring rot. However, artificial modulation of c-di-GMP level in the cells leads to a significant change of biocontrol efficacy, suggesting that c-di-GMP positively regulates biocontrol efficacy of B. velezensis PG12 against apple ring rot disease. More evidences indicate that c-di-GMP does not affect the antagonistic activity of B. velezensis PG12 against B. dothidea in vitro and in vivo, but positively regulates biofilm formation of B. velezensis PG12 and its colonization on apple fruits. Importantly, deletion of ydaK could rescue the inhibition of biofilm formation, bacterial colonization and biocontrol efficacy caused by low c-di-GMP level, indicating that YdaK is the potential c-di-GMP receptor to regulate biofilm formation, colonization and effective biological control. However, YdaK did not affect the antagonistic activity of B. velezensis PG12 against B. dothidea. Based on these findings, we propose that c-di-GMP regulates biofilm formation, subsequently the bacterial colonization on apple fruits and thus biocontrol efficacy of B. velezensis through its receptor YdaK. This is the first report showing that c-di-GMP plays a role in biocontrol efficacy of beneficial bacteria.

Personalized medicine of non-gene-specific chemotherapies for non-small cell lung cancer.

Non-small cell lung cancer is recognized as the deadliest cancer across the globe. In some areas, it is more common in women than even breast and cervical cancer. Its rise, vaulted by smoking habits and increasing air pollution, has garnered much attention and resource in the medical field. The first lung cancer treatments were developed more than half a century ago. Unfortunately, many of the earlier chemotherapies often did more harm than good, especially when they were used to treat genetically unsuitable patients. With the introduction of personalized medicine, physicians are increasingly aware of when, how, and in whom, to use certain anti-cancer agents. Drugs such as tyrosine kinase inhibitors, anaplastic lymphoma kinase inhibitors, and monoclonal antibodies possess limited utility because they target specific oncogenic mutations, but other drugs that target mechanisms universal to all cancers do not. In this review, we discuss many of these non-oncogene-targeting anti-cancer agents including DNA replication inhibitors (i.e., alkylating agents and topoisomerase inhibitors) and cytoskeletal function inhibitors to highlight their application in the setting of personalized medicine as well as their limitations and resistance factors.

Clinicopathological Features and Survival of Adolescent and Young Adults with Cervical Cancer.

PURPOSE: To explore clinicopathological characteristics and their prognostic value among young patients with cervical cancer (who are aged ≤25 years old). METHODS: The Surveillance, Epidemiology, and End Results Program (SEER) database was used to extract data on cervical cancer patients. They were then stratified by age as young women (≤25 years old) and old women (26-35 years old) and analyzed for clinicopathology characteristics and treatment modalities. Prognosis was analyzed using Kaplan-Meier survival curve, as well as hazard ratios using Cox regression modeling. The nomogram was developed based on Cox hazards regression model. RESULTS: Compared to 26-35 years old women, patients aged ≤25 years tended to be white ethnicity, unmarried, had earlier stage of disease. There was also a better prognosis among younger cohort. Grade, FIGO stage, histologic subtypes, and surgical modalities influenced the survival outcomes of young patients. Among young cohorts, surgery prolonged the survival time of IA-IIA stage patients while surgical and non-surgical management presented no statistically prognostic difference among patients at IIB-IVB stage. Besides, the nomogram which constructed according to Cox hazards regression model which contained independent prognosis factors including FIGO stage, surgery type, and histologic type of tumor can robustly predict survival of young patients. CONCLUSION: Cervical cancer patients ≤25 years old were uncommon and lived longer than the older patients. Among these young patients at IA-IIA stage, surgical treatment could be more effective at preventing death than non-surgery. The nomogram could perfectly predict the prognosis of young adults and adolescents with cervical cancer.

The role of lncRNAs and circRNAs in the PD-1/PD-L1 pathway in cancer immunotherapy.

Cancer immunotherapy has recently shown promising antitumor effects in various types of tumors. Among all immune checkpoints, the PD-1/PD-L1 pathway plays an important role in the immune evasion of tumor cells, making it a potent target in antitumor immunity. Accordingly, antibodies targeting the PD-1/PD-L1 pathway have been developed to attack tumor cells; however, resistance to immune therapy remains to be solved. Hence, identification of the underlying modulators of the PD-1/PD-L1 pathway is of significant importance to understand the mechanisms of antitumor immunotherapy. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been identified to regulate the PD-1/PD-L1 pathway, leading to participation in the immune response and immunotherapy. Therefore, this review focuses on the functions of lncRNAs and circRNAs in regulation of the PD-1/PD-L1 axis in tumorigenesis and tumor progression. We hope this review will stimulate research to supply more precise and effective cancer immune checkpoint therapies for a large number of tumors.

E26 transformation-specific variant 4 as a tumor promotor in human cancers through specific molecular mechanisms.

E26 transformation-specific (ETS) variant 4 (ETV4) is an important transcription factor that belongs to the ETS transcription factor family and is essential for much cellular physiology. Recent evidence has revealed that ETV4 is aberrantly expressed in many types of tumors, and its overexpression is related to poor prognosis of cancer patients. Additionally, increasing studies have identified that ETV4 promotes cancer growth, invasion, metastasis, and drug resistance. Mechanistically, the level of ETV4 is regulated by some post-translation modulations in a broad spectrum of cancers. However, little progress has been made to comprehensively summarize the critical roles of ETV4 in different human cancers. Hence, this review mainly focuses on the physiological functions of ETV4 in various human tumors. In addition, the molecular mechanisms of ETV4-mediated cancer progression were elucidated, including how ETV4 modulates its downstream signaling pathways and how ETV4 is regulated by some factors. On this basis, the present review may provide a valuable therapeutics strategy for future cancer treatment by targeting ETV4-related pathways.

Resolution of recurrent pediatric acute liver failure with liver transplantation in a patient with NBAS mutation.

BACKGROUND: Pediatric acute liver failure (PALF) remains an enigmatic process of rapid end-organ dysfunction associated with a variety of pathologic conditions though the predominant cause is indeterminate. A growing body of research has identified mutations in the NBAS gene to be associated with recurrent acute liver failure and multi-systemic disease including short stature, skeletal dysplasia, facial dysmorphism, immunologic abnormalities, and Pelger-Huët anomaly. METHODS AND RESULTS: Here, we describe a 4-year-old girl who presented with dehydration in the setting of acute gastroenteritis and fever but went on to develop PALF on day 2 of hospitalization. She clinically recovered with supportive measures, but after discharge, had at least 2 additional episodes of PALF. Ultimately, she underwent liver transplant and her recurrent episodes of PALF did not recur throughout a 6-year follow-up period. Whole-exome sequencing post-liver transplant initially revealed two variants of uncertain significance in the NBAS gene. Parental studies confirmed the c.1549C > T(p.R517C; now likely pathogenic) variant from her mother and a novel c.4646T > C(p.L1549P) variant from her father. In silico analyses predicted these variants to have a deleterious effect on protein function. Consistent with previously characterized NBAS mutation-associated disease (NMAD), our patient demonstrated the following features: progeroid facial features, hypoplasia of the 12th ribs, Pelger-Huët anomaly on peripheral blood smear, and abnormal B and NK cell function. CONCLUSION: Altogether, we describe a novel pathogenic variant in the NBAS gene of a patient with NMAD and report the resolution of recurrent PALF secondary to NMAD following liver transplantation.

Discovery of key genes as novel biomarkers specifically associated with HPV-negative cervical cancer.

Cervical cancer is a common female malignancy that is mainly caused by human papillomavirus (HPV) infection. However, the incidence of HPV-negative cervical cancer has shown an increasing trend in recent years. Because the mechanism of HPV-negative cervical cancer development is unclear, this study aims to find the pattern of differential gene expression in HPV-negative cervical cancer and verify the underlying potential mechanism. Differentially expressed genes were compared among HPV-positive cervical cancer, HPV-negative cervical cancer, and normal cervical tissues retrieved from TCGA. Subsequently, dysregulated differentially expressed genes specifically existed in HPV-negative cervical cancer tissues and HPV-negative cell lines were validated by qRT-PCR, western blotting, and immunohistochemical staining. We found seventeen highly expressed genes that were particularly associated with HPV-negative cervical cancer from analysis of TCGA database. Among the 17 novel genes, 7 genes (preferentially expressed antigen in melanoma [PRAME], HMGA2, ETS variant 4 [ETV4], MEX3A, TM7SF2, SLC19A1, and tweety-homologs 3 [TTYH3]) displayed significantly elevated expression in HPV-negative cervical cancer cells and HPV-negative cervical cancer tissues. Additionally, higher expression of MEX3A and TTYH3 was associated with a shorter overall survival of patients with HPV-negative cervical cancer. Our study implies that these seven genes are more likely to provide novel insights into the occurrence and progression of HPV-negative cervical cancer.

The roles of PD-1/PD-L1 in the prognosis and immunotherapy of prostate cancer.

Multiple studies have confirmed that programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) and immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 play pivotal roles in the treatment of numerous tumors. Patients suffering from cancer are provided hope in the form of immunotherapy. In this review, we discuss the finding that high PD-L1 expression is associated with poor clinical outcomes in prostate cancer patients. Some molecules exert their antitumor effects by downregulating PD-L1 expression in prostate cancer. Additionally, we discuss and summarize the important roles played by anti-PD-1/PD-L1 immunotherapy and its combination with other drugs, including chemotherapy and vaccines, in the treatment of prostate cancer.