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PURPOSE: To explore the application possibility of macrocephalic sperm from a patient with 100% macrocephalic sperm and AURKC gene variations. METHODS: We diagnosed a case of macrozoospermia with 100% macrocephalic sperm and 39.5% multi-tailed spermatozoa by morphological analysis. Whole-exome sequencing (WES) was used for the patient and his wife. Sanger sequencing technique was used to verify the AURKC mutations in the patient's parents and his offspring. Sperm's ploidy was tested by flow cytometry. The couple asked for intra-couple ART therapy. RESULTS: The patient presented novel compound heterozygous AURKC mutations (c.434C > T, c.497A > T) by WES. Sanger sequencing validation showed that variant of c.434C > T was observed in his father and c.497A > T was observed in his mother. Flow cytometry revealed that there existed a certain proportion of haploid sperm. Macrocephalic spermatozoa whose heads were smaller than the diameter of injection needle were selected for microinjection. A singleton pregnancy was achieved after embryo transfer. Prenatal diagnosis revealed that the fetus had normal chromosomal karyotype. Sanger sequencing technique showed that the fetus carried a c.434C > T mutation in one AURKC allele. A 3730 g healthy male fetus was delivered at term. CONCLUSION: Our study reported a successful live birth from a patient with definite AURKC gene variants and may provide insights for such patients to choose donor sperm or their own sperm.
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PURPOSE: Proper management of subcentimeter thyroid nodules remains challenging for both clinicians and patients. Conducting extensive sonographic research using a safe and inexpensive tool for identifying thyroid nodules is necessary. The aim of this study was to identify whether having the highest-risk ultrasound (US) characteristic suggests that US-guided fine-needle aspiration (FNA) biopsy of subcentimeter nodules is more appropriate for the identification of malignancy than active surveillance (AS) or surgery. METHODS: The data of patients with highly suspicious subcentimeter thyroid nodules and US characteristic data who underwent surgery were retrospectively examined. RESULTS: Among a total of 556 subcentimeter nodules, 223 (40.1%) were benign, and 333 (59.9%) were malignant, with a mean maximal nodule size of 8.1 mm. In addition to age younger than 45 years, several US features were significantly associated with malignancy: irregular margins, the presence of microcalcifications, and taller-than-wide shapes (P < 0.001). Multivariate analysis also revealed that a taller-than-wide shape (OR = 8.988, P = 0.0015) was an independent factor associated with malignancy in subcentimeter thyroid nodules. The diagnostic performance of preoperative FNA was classified as a malignancy, with a sensitivity of 98.4%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 76.9%. CONCLUSIONS: This is one of the few reports based on actual data of the most suspicious US features in subcentimeter thyroid nodules. A taller-than-wide shape US feature is most significantly associated with malignancy. FNA is a simple, accurate, and reliable preoperative method for diagnosing malignant subcentimeter thyroid nodules with highly suspicious US characteristics. AS was less appropriate than FNA for subcentimeter nodules with a taller-than-wide shape, especially in patients ≤ 45 years of age.
Subject(s)
Predictive Value of Tests , Thyroid Nodule , Ultrasonography , Humans , Thyroid Nodule/diagnostic imaging , Thyroid Nodule/pathology , Thyroid Nodule/surgery , Retrospective Studies , Female , Middle Aged , Male , Adult , Ultrasonography/methods , Biopsy, Fine-Needle/methods , Aged , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/pathology , Thyroid Neoplasms/surgery , Young AdultABSTRACT
Background: Several prospective studies have found that local surgical resection did not improve the survival of patients with de novo metastatic breast cancer (dnMBC). However, a significant portion of dnMBC patients still undergo local surgery, and the role of axillary lymph node dissection (ALND) in dnMBC patients remains unclear. This study aimed to investigate the effect of ALND in patients with dnMBC. Methods: We included patients diagnosed with dnMBC between 2010 and 2020 using the data from the Surveillance, Epidemiology, and End Results program. The Chi-square test, binomial logistic regression, propensity score matching (PSM), Kaplan-Meier method, and multivariate Cox proportional models were employed for statistical analysis. Results: A total of 6,838 patients were identified, with 5,562 (81.3%) in the ALND group and 1,276 (18.7%) in the non-ALND group. Being diagnosed in later years emerged as an independent predictive factor related to the receipt of ALND (P=0.003). Before PSM, the 5-year breast cancer-specific survival (BCSS) was 51.1% and 38.2% in those with and without ALND, respectively (P<0.001). The 5-year overall survival (OS) was 45.9% and 32.3% in those with and without ALND, respectively (P<0.001). ALND was identified as an independent prognostic factor related to better BCSS (P<0.001) and OS (P<0.001) compared to the non-ALND group. Similar findings were observed after PSM. The outcomes were significantly better in the ALND group than in the non-ALND group in most subgroups. However, the number of removed lymph nodes did not show a significant association with BCSS (P=0.27) and OS (P=0.29). Conclusions: Our study suggests that ALND is associated with improved survival outcomes in dnMBC patients. These findings advocate for a re-evaluation of the role of surgical interventions in dnMBC, emphasizing the need for personalized treatment strategies that consider the potential benefits of ALND.
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BACKGROUND: In those with one to three positive lymph nodes (N1) breast cancer (BC), the 21-gene recurrence score (RS) classification can be referred for decision-making on adjuvant chemotherapy. This study aimed to investigate the effect of RS in predicting the survival benefit of postoperative radiotherapy (PORT) in T1-2N1 BC with estrogen receptor-positive and human epidermal growth factor receptor 2-negative disease after breast-conserving surgery (BCS). METHODS: We included patients with BC and available RS data from the Surveillance, Epidemiology, and End Results Oncotype DX database. The chi-square test, Kaplan-Meier method, propensity score matching (PSM) as well as multivariable Cox proportional hazard analyses were used for statistical analyses. RESULTS: We included 6509 patients in the analysis. Of these patients, 5302 (85.5%) were treated with BCS + PORT, and 207 (15.5%) had BCS alone. There were 1419 (21.8%), 4319 (66.4%), and 771 (11.8%) patients being low-, intermediate-, and high-risk RS, respectively. After PSM, PORT was significantly associated with a 5-year overall survival (OS) advantage (95.1% vs. 90.5%, P < 0.001) compared to those without PORT, which similar breast cancer-specific survival (BCSS) was found between the treatment arms (P = 0.126). The sensitivity analyses showed that PORT was not associated with a better BCSS (P = 0.472) and OS (P = 0.650) than those without PORT in the low-risk RS cohort. However, PORT was associated with a better BCSS (P = 0.031) and OS (P < 0.001) compared to those without PORT in the intermediate/high-risk RS cohorts. CONCLUSIONS: Our study highlights the possible role of the RS in predicting the outcome of PORT in T1-2N1 luminal BC patients undergoing BCS.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/radiotherapy , Breast Neoplasms/surgery , Mastectomy, Segmental , Neoplasm Staging , Chemotherapy, AdjuvantABSTRACT
The nuclear receptor superfamily RAR is generally considered to play a crucial role in the development of tumors by regulating the transcription of target genes. Nevertheless, whether RARγ performs tumor-promoting or tumor-suppressing functions and its specific mechanism in thyroid carcinoma (TC) remain unknown. Here, our study demonstrated that RARγ was abnormally overexpressed in TC tissues compared with normal thyroid tissues. Moreover, RARγ expression was remarkably correlated with cell phenotypes such as cell proliferation, migration and invasion. Mechanistically, RARγ knockdown effectively decreased the phosphorylation levels of JAK1 and STAT3, leading to decreased expression of the membrane protein CD24. In a coculture system, TC cells with high levels of CD24 in the membrane were more likely to escape phagocytosis by macrophages via the combination of CD24 with the inhibitory receptor Siglec-10 in the membrane of macrophages. In contrast, the ability of macrophages to engulf TC cells was notably elevated through exogenous addition of CD24 antibody. Collectively, our study revealed a previously undiscovered molecular mechanism of RARγ in promoting the development of TC, shedding light on RARγ as a promising therapeutic target for TC.
Subject(s)
Thyroid Neoplasms , Humans , CD24 Antigen , Cell Line, Tumor , Cell Proliferation , Janus Kinase 1 , STAT3 Transcription Factor , Thyroid Neoplasms/genetics , Retinoic Acid Receptor gammaABSTRACT
OBJECTIVE: This study aims to evaluate the prognostic value of m6A-associated long noncoding RNAs (lncRNAs) and their interaction with tumour microenvironment in thyroid cancer (THCA). METHODS: The clinical and gene expression data of tumours from 502 patients with THCA and 58 adjacent normal tissues were retrieved from The Cancer Genome Atlas (TCGA)-THCA dataset. The Pearson test was utilized to identify potential m6A-associated lncRNAs (p < 0.001 and Pearson correlation coefficient > 0.4). Quantitative real-time polymerase chain reaction was performed to verify the expression levels of lncRNAs in tissues. MTT, EdU, colony formation and wound-healing assays were performed to determine the functions of m6A-associated lncRNAs in THCA cell proliferation and metastasis. RESULTS: M6A-associated lncRNAs were identified in three cluster groups. A significant survival difference was found among them, with cluster 1 patients showing worse survival. Moreover, lower immune and estimate scores were correlated to poorer prognosis, and CD8+ T cell and memory CD4+ T cell levels were increased in cluster 1. Cluster 2, with better overall survival, had high expression of PD-L1 and CTLA-4. Eleven of the m6A-associated lncRNAs were screened to establish the risk model, including AC007365.1, AC008555.1, AC040160.1, AC064807.1, AC126773.4, AL023583.1, AL512306.2, EIF2AK3-DT, LINC00667, LYPLAL1-DT and MIR181A2HG. Based on the median risk score, THCA patients were stratified into low-risk and high-risk groups. Overall survival analysis showed a dramatic difference between the two groups. qRCR was performed to verify the expression levels of lncRNA (LYPLAL1-DT, EIF2AK3-DT and MIR181A2HG) in THCA and adjacent normal tissues. Furthermore, functional experiments showed that knockdown of MIR181A2HG obviously inhibited the proliferation and migration of papillary thyroid cancer (PTC) cells in vitro, whereas LYPLAL1-DT overexpression promoted PTC cell proliferation and migration. CONCLUSIONS: Eleven of the m6A-associated lncRNAs were identified as a risk model to predict clinical outcomes and provide a novel and efficient immunotherapeutic strategy for THCA patients.Key messagesm6A-associated lncRNAs can be used to predict the clinical outcomes of thyroid cancer patients.An m6A-associated lncRNAs risk model, which can accurately evaluate the immune status and risk stratification in individual thyroid cancer patients, was established.Knockdown/overexpression of representative lncRNAs in the risk model significantly affected the proliferation and migration of papillary thyroid cancer cells.
Subject(s)
RNA, Long Noncoding , Thyroid Neoplasms , Humans , RNA, Long Noncoding/genetics , Thyroid Cancer, Papillary , Thyroid Neoplasms/genetics , Prognosis , CD8-Positive T-Lymphocytes , Tumor Microenvironment/geneticsABSTRACT
Motions sickness (MS) occurs when the brain receives conflicting sensory signals from vestibular, visual and proprioceptive systems about a person's ongoing position and/or motion in relation to space. MS is typified by symptoms such as nausea and emesis and implicates complex physiological aspects of sensations and sensorimotor reflexes. Use of animal models has been integral to unraveling the physiological causality of MS. The commonly used rodents (rat and mouse), albeit lacking vomiting reflex, reliably display phenotypic behaviors of pica (eating of non-nutritive substance) and conditioned taste aversion (CTAver) or avoidance (CTAvoi) which utilize neural substrates with pathways that cause gastrointestinal malaise akin to nausea/emesis. As such, rodent pica and CTAver/CTAvoi have been widely used as proxies for nausea/emesis in studies dealing with neural mechanisms of nausea/emesis and MS, as well as for evaluating therapeutics. This review presents the rationale and experimental evidence that support the use of pica and CTAver/CTAvoi as indices for nausea and emesis. Key experimental steps and cautions required when using rodent MS models are also discussed. Finally, future directions are suggested for studying MS with rodent pica and CTAver/CTAvoi models.
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Herein, we introduced a novel individual sperm freezing device named SpermCD, which consists of a right angular cryopiece (RA-Cryopiece, or "C") and a grooved petri dish ("D"). SpermCD allows embryologists to transfer sperm and perform ICSI on the same focal plane. Thirty-five patients underwent single sperm cryopreservation using SpermCD, including four patients with non-obstructive azoospermia (NOA), 14 patients with virtual azoospermia and 17 patients with cryptozoospermia. One hundred and twenty-five cryopreserved spermatozoa from nine patients were thawed on the day of the oocyte retrieval and 121 spermatozoa were found, with a sperm recovery rate of 97.1 ± 4.6%. Sixty-five MII oocytes from their spouse were injected with thawed sperm. Normal fertilization and high-quality embryo rates were 68.0% ± 33.2% and 24.4% ± 22.2%. Nineteen transplantable embryos were formed after fertilization with frozen sperm, eight of which were transplanted in five couples, resulting in four successful deliveries. SpermCD is a simple and practical individual sperm freezing device.
Subject(s)
Azoospermia , Humans , Male , Azoospermia/therapy , Sperm Injections, Intracytoplasmic/methods , Freezing , Embryo Transfer , Spermatozoa , Cryopreservation/methods , TestisABSTRACT
AIMS: This study was aimed to investigate the expression patterns and prognostic value of microRNA-517b-3p (miR-517b-3p) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). METHODS: The expression of miR-517b-3p in PVTT tissues and cells was estimated using qRT-PCR. Through Kaplan-Meier survival analysis, Cox regression assay and ROC analysis, the significance of miR-517b-3p was explored. In addition, cell experiments were performed to examine the functional role of miR-517b-3p during progression of PVTT. Moreover, the biological process and biological pathway analysis analyses were conducted through GSEA and FunRich. Besides, the protein-protein interaction (PPI) network of the DEGs was established through cBioPortal website. RESULTS: Compared with the controls, the miR-517b-3p was upregulated in both PVTT tissues and cells. The upregulated miR-517b-3p, which served as a potential diagnostic biomarker to distinguish PVTT from PT and controls, was associated with poor overall survival and acted as an independent prognostic factor. The cell proliferation, migration and invasion were proved to be enhanced by overexpression of miR-517b-3p. Furthermore, Wnt/ß-catenin signaling was suppressed by miR-517b-3p knockdown and might be involved in the progression of PVTT. CONCLUSION: miR-517b-3p may promote PVTT cell proliferation, migration and invasion via activation of Wnt/ß-catenin signaling pathway. Meanwhile, miR-517b-3p has overexpression in PVTT samples, and serves as a candidate diagnostic and prognostic biomarker in HCC patients with PVTT.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , MicroRNAs , Thrombosis , Biomarkers , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Liver Neoplasms/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasm Invasiveness/pathology , Portal Vein/metabolism , Portal Vein/pathology , Wnt Signaling Pathway/genetics , beta CateninABSTRACT
Motion sickness (MS) was frequently introduced for rodents in research work through passive motion that disturbed vestibular signals in the presence of visual and aleatory, proprioceptive inputs. Inducement of MS in this way causes conflicting signals that activate intermixed neural circuits representing multimodal stimulation. From reductionism, a lab setup to elicit rat MS via vestibular stimulation was configured in the present study for MS study in connection with dissection of the central vestibular component causally underlying MS. The individual animal was blinded to light with a custom-made restrainer, and positioned at an inclination of 30° for otolith organs to receive unusual actions by gravitoinertial vector. Following a 2-h double-axis (earth-vertical) rotation involving angular acceleration/deceleration, a suit of behaviors characterizing the MS was observed to be significantly changed including pica (eating non-nutritive substance like kaolin), conditioned taste avoidance and locomotion (p < 0.05). Notably, for the statistical hypothesis testing, the utility of net increased amount of kaolin consumption as independent variables in data processing was expounded. In addition, Fos-immunostained neurons in vestibular nucleus complex were significantly increased in number, suggesting the rotation-induced MS was closely related to the vestibular activation. In conclusion, our work indicated that the present setup could effectively elicit the MS by disturbing vestibular signals in rat in the context of well-controlled proprioceptive inputs and lack of visual afference.
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We aimed to investigate the difference in the time to pregnancy (TTP) between women with previous ectopic pregnancy (EP) and control women following in vitro fertilization (IVF) treatment and the association between TTP and the number of oocytes retrieved and embryos available. A retrospective study involving 1097 women, 547 of which had previous EP and 550 were control women whose previous pregnancy were abortion, was conducted. Women in the EP group had significantly longer median TTP than those in the control group (36; range, 12-252 vs 28; range, 12-220; P = 0.019). For women with previous EP, > 48 months TTP was most likely associated with low numbers of oocytes retrieved and embryos available compared to TTP of ≤ 24 months or 25-48 months, and women with younger age had a shorter TTP, higher numbers of oocytes retrieved and embryos available. A Cox proportional hazards model showed that maternal age was significantly related to the pregnancy over the TTP (adjusted hazard ratio, 0.934; P < 0.001). In conclusion, women with previous EP have a significantly increased TTP than control women with previous abortion. For women with previous EP, TTP is negatively associated with the numbers of oocytes retrieved and embryos available.
Subject(s)
Pregnancy, Ectopic , Time-to-Pregnancy , Female , Fertilization in Vitro , Humans , Pregnancy , Pregnancy Rate , Retrospective StudiesABSTRACT
X-box binding protein 1 (XBP1) is mainly expressed in breast cancer (BC) in human cancers. Its tumorigenesis and favourable prognosis are contradictory, and its essential role in chemotherapeutic response and immunosuppression is unknown in BC. The study firstly identified XBP1 who received neoadjuvant chemotherapy (NAC) from GSE25055 and GSE24460. Associations between XBP1 expression and clinicopathological characteristics was investigated using Oncomine, TCGA, UALCAN and bc-GenExMiner. The prognostic value of XBP1 was assessed using the Kaplan-Meier Plotter, bc-GenExMiner, GSE25055, and GSE25056. Furthermore, we systematically correlated XBP1 and immunological characteristics in the BC tumour microenvironment (TME) using TISIDB, TIMER, GSE25055, GSE25056 and TCGA dataset. Finally, an essential role of XBP1 in chemotherapy response was evaluated based on GSE25055, GSE25065, GSE24460, GSE5846, ROC Plotter and CELL databases. Furthermore, XBP1 mRNA expression levels were obviously highest in BC among human cancers and were significantly related to a good prognosis. In addition, XBP1 mRNA and protein levels were higher in the luminal subtype than in normal tissues and basal-like subtype, which might be attributed to membrane transport-related processes. Apart from BC, negative immunological correlations of XBP1 were not observed in other malignancies. XBP1 might shape the non-inflamed TME in BC. Finally, XBP1 expression was higher in chemo-resistive than chemo-sensitive cases, it had a predictive value and could independently predict chemotherapy response in BC patients receiving NAC. Our study suggests that the essential role of XBP1 in clinical pathologic features, non-inflamed TME, chemotherapy response in BC.
Subject(s)
Breast Neoplasms , Biomarkers, Tumor/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Humans , Neoadjuvant Therapy , RNA, Messenger/metabolism , Tumor Microenvironment/genetics , X-Box Binding Protein 1/geneticsABSTRACT
Objective: The aim was to clarify whether using testicular sperm reduces embryo fragmentation and improves cycle outcomes. Methods: Fragmented embryo was defined as an embryo in which fragments account for more than one third of the embryonic surface area. High rate of fragmented embryos was defined by a proportion of fragmented embryos higher than 50%. We recruited infertile couples who had undergone at least one ovarian stimulation cycle using ejaculated sperm but failed to conceive due to high rate of fragmented embryos in each previous cycle. After fully informed consent, the couples agreed to obtain testicular sperm by testicular puncture and use testicular sperm for intracytoplasmic sperm injection (ICSI). The normal fertilization rate, transferable embryo rate, fragmented embryo rate and cycle outcomes were compared between ejaculated sperm group (EJA-sperm group) and testicular sperm group (TESTI-sperm group). Results: Twenty-two couples who agreed to participate in our study underwent 32 ICSI cycles with ejaculated spermatozoa and 23 ICSI cycles with testicular spermatozoa. Embryo transfers were cancelled in 8 ejaculated cycles and 4 testicular cycles because of no transferable embryos. There were no significant differences in age, normal fertilization rate and high-quality embryo rate between ejaculated and testicular groups. The transferable embryo rate and implantation rate in TESTI-sperm group were significantly higher than those in EJA-sperm group (36.9% vs. 22.0%, p < 0.01; 34.2% vs. 0%, p < 0.001). The fragmented embryo rate in TESTI-sperm group was significantly lower than that in EJA-sperm group (61.2% vs. 75.7%, p < 0.05). Conclusion: Our small retrospective cohort study suggests that using testicular sperm may be a recommended option for couples with previous ART failure because of high rate of fragmented embryos. Large samples, multicenter studies or randomized controlled trial (RCT) are needed to further confirm the superiority of testicular sperm.
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Acephalic spermatozoa syndrome is a rare type of teratozoospermia that severely impairs the reproductive ability of male patients, and genetic defects have been recognized as the main cause of acephalic spermatozoa syndrome. Spermatogenesis and centriole-associated 1 like (SPATC1L) is indispensable for maintaining the integrity of sperm head-to-tail connections in mice, but its roles in human sperm and early embryonic development remain largely unknown. Herein, we conducted whole-exome sequencing (WES) of 22 infertile men with acephalic spermatozoa syndrome. An in silico analysis of the candidate variants was conducted, and WES data analysis was performed using another cohort consisting of 34 patients with acephalic spermatozoa syndrome and 25 control subjects with proven fertility. We identified biallelic mutations in SPATC1L (c.910C>T:p.Arg304Cys and c.994G>T:p.Glu332X) from a patient whose sperm displayed complete acephalia. Both SPATC1L variants are rare and deleterious. SPATC1L is mainly expressed at the head-tail junction of elongating spermatids. Plasmids containing pathogenic variants decreased the level of SPATC1L in vitro. Moreover, none of the patient's four attempts at intracytoplasmic sperm injection (ICSI) resulted in a transplantable embryo, which suggests that SPATC1L defects might affect early embryonic development. In conclusion, this study provides the first identification of SPATC1L as a novel gene for human acephalic spermatozoa syndrome. Furthermore, WES might be applied for patients with acephalic spermatozoa syndrome who exhibit reiterative ICSI failures.
Subject(s)
Centrioles , Infertility, Male , Centrioles/genetics , Homozygote , Humans , Infertility, Male/genetics , Male , Mutation , Spermatogenesis/genetics , SpermatozoaABSTRACT
This study combined with bioinformatics analysis and investigated the expression pattern of miR-181b-5p, as well as explored its role and mechanism in cholangiocarcinoma (CCA or CHOL). Several bioinformatics databases were used to analyze the expression of miR-181b and the enrichment of miR-181b in biological activities and biological pathways in CCA. The RT-qPCR analysis was used to examine the expression levels of miR-181b-5p. A receiver operation characteristics (ROC) curve analysis and the Kaplan-Meier survival assay were conducted to validate the diagnostic and prognostic implication of miR-181b-5p. Cell experiments were used to explore the possible functional role of miR-181b-5p in CCA progression. The bioinformatics assay was used to predict the target gene of miR-181b-5p and Western blot was used to confirm the related signaling pathway. The bioinformatics analysis results suggest that miR-181b-5p was highly expressed in cholangiocarcinoma and its expression was negatively related to PARK2 expression in CCA tissues. miR-181b-5p expression in the serum and tissues was upregulated and associated with lymph node metastasis and TNM stage. Increased expression of miR-181b-5p had relatively high diagnostic accuracy and showed poor prognosis in CCA patients. In addition, miR-181b-5p overexpression enhanced cell proliferation, migration, and invasion by targeting PARK2. Overexpression of miR-181b-5p activated the PI3K/AKT signaling pathway, while knockdown of miR-181b-5p suppressed the signaling pathway. Increased expression of miR-181b-5p in CCA may be a potential diagnostic or/and prognostic indicator for CCA patients. The present data indicated miR-181b-5p acted as an oncogene in CCA through promoting tumor cell proliferation, migration, and invasion of CCA via the PTEN/PI3K/AKT signaling pathway by targeting PARK2, which might be a promising therapeutic target or biomarker for CCA.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , MicroRNAs , Ubiquitin-Protein Ligases/genetics , Bile Duct Neoplasms/genetics , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cholangiocarcinoma/genetics , Humans , MicroRNAs/genetics , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Signal TransductionABSTRACT
BACKGROUND: The zona pellucida (ZP) of human oocytes plays essential protective roles in sperm-egg interactions during fertilisation and embryo development. ZP4-null female rabbits exhibit a thin and irregular ZP, which severely impairs embryo development and fertility. However, the effects of ZP4 defect on human female reproduction remain unknown. METHODS AND RESULTS: We performed whole-exome sequencing in 26 female patients with abnormal (thin and irregular) ZP and identified heterozygous variants in ZP4 (OMIM: 613514) from 3 patients (approximately 11%). No ZP4 variant was found in the 30 control women with proven fertility. We constructed ZP4-mutated plasmids and found that the variants reduced the secretion of ZP4 in vitro. Lower suction pressure facilitated egg retrieval, and intracytoplasmic sperm injection (ICSI) was a desirable treatment for ZP4-mutated patients with abnormal ZP. CONCLUSIONS: We identified ZP4 as a novel gene for human abnormal ZP and found that lower suction pressure and ICSI are efficient treatment strategies.
Subject(s)
Infertility, Female/genetics , Zona Pellucida Glycoproteins/genetics , Embryonic Development , Female , Fertility , Gene Expression , Humans , Infertility, Female/pathology , Mutation , Exome Sequencing , Zona Pellucida/pathology , Zona Pellucida Glycoproteins/metabolismABSTRACT
MicroRNAs play a vital role in the regulatory mechanisms of tumorigenesis. Current research indicates that microRNA-423 (miR-423) is abnormally expressed in various human tumors and participates in multiple signaling pathways of cancer progression. In most studies, miR-423 was confirmed as oncomiR, while a few contradictory reports considered miR-423 as an anticancer miRNA. The paradoxical role in cancer may hinder the application of miR-423 as a diagnostic and therapeutic target. Simultaneously, the interaction mechanism between miR-423 and lncRNA also needs attention. In this review, we have summarized the dual role of aberrant miR-423 expression and its mechanisms in tumorigenesis, and the therapeutic potential of miR-423 in human tumors.
Subject(s)
Biomarkers, Tumor/metabolism , MicroRNAs/metabolism , Neoplasms/metabolism , Antineoplastic Agents/therapeutic use , Apoptosis , Autophagy , Biomarkers, Tumor/genetics , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs/genetics , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Polymorphism, Single Nucleotide , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Signal TransductionABSTRACT
Nerve injury in somatosensory pathways may lead to neuropathic pain, which affects the life quality of â¼8% of people. Long-term enhancement of excitatory synaptic transmission along somatosensory pathways contributes to neuropathic pain. Caspase 3 (Casp3) plays a non-apoptotic role in the hippocampus and regulates internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. Whether Casp3-AMPAR interaction is involved in the maintenance of peripheral hypersensitivity after nerve injury remained unknown. Here, we show that nerve injury suppresses long-term depression (LTD) and downregulates Casp3 in the anterior cingulate cortex (ACC). Interfering with interactions between Casp3 and AMPAR subunits or reducing Casp3 activity in the ACC suppresses LTD induction and causes peripheral hypersensitivity. Overexpression of Casp3 restores LTD and reduces peripheral hypersensitivity after nerve injury. We reveal how Casp3 is involved in the maintenance of peripheral hypersensitivity. Our findings suggest that restoration of LTD via Casp3 provides a therapeutic strategy for neuropathic pain management.
Subject(s)
Caspase 3/metabolism , Depression/genetics , Gyrus Cinguli/physiopathology , Neuralgia/physiopathology , HumansABSTRACT
BACKGROUND: Integrin subunit α 8 (ITGA8) methylation has been associated with the development of several cancers, but its contribution to breast cancer remains unclear. The present study aimed to investigate the methylation status of ITGA8, and the underlying regulatory mechanisms of ITGA8 methylation in breast cancer. METHODS: ITGA8 expression was investigated using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database and the Breast Cancer Gene-Expression Miner v.4.4 (bc-GenExMiner v4.4). The association between ITGA8 expression levels and the survival rate of breast cancer patients was evaluated using The Cancer Genome Atlas (TCGA) database and Gene Expression-based Outcome for Breast Cancer Online (GOBO): Gene Set Analysis. Methylation-specific PCR (MSP) was used to detect the methylation of ITGA8. Protein level of ITGA8 was determined by Western blot analysis. RESULTS: ITGA8 was expressed at low levels in human breast cancer cells compared to non-tumorigenic breast cells and breast tissue, and was upregulated in estrogen receptor (ER)-positive tissue compared with ER-negative tissue (P<0.01). ITGA8 gene expression was negatively associated with breast tumor stage and survival rate in all breast cancer patients. However, ER-positive patients with low ITGA8 expression showed poorer distant metastasis-free survival (DMFS) and recurrence-free survival (RFS) rates than patients with high ITGA8 expression. This was not observed in the ER-negative population. Mechanistically speaking, hypermethylation of ITGA8 was discovered in ER-positive breast cancer cells. Administration of the methylation inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC), significantly elevated protein expression of ITGA8 in ER-positive breast cancer cells compared to ER-negative cells. The positive association between ITGA8 status and methylation was also observed in clinical tissue specimens. When treated with 17-beta-estradiol, an antagonist of ERα, 5-aza-dC-induced upregulation of ITGA8 in ER-positive breast cancer cells was no longer observed. CONCLUSIONS: Low ITGA8 expression in ER-positive breast cancer might be caused by the hypermethylation of ITGA8, a process dependent on ERα. Our findings provide an important foundation for investigations into ITGA8-targeted treatment strategies for ER-positive breast cancer.
ABSTRACT
A class of 2-aminopyridine 1-oxides are discovered to be effective ligands for the Cu-catalyzed amination of less reactive (hetero)aryl chlorides. A wide range of functionalized (hetero)aryl chlorides reacted with various aliphatic amines to afford the desired products in good to excellent yields under the catalyst of CuI/2-aminopyridine 1-oxides. Furthermore, the catalyst system worked well for the coupling of cyclic secondary amines and N-methyl benzylamine with (hetero)aryl chlorides.