BACKGROUND: The molecular mechanisms driving tumorigenesis have continually been the focus of researchers. Cuproplasia is defined as copper-dependent cell growth and proliferation, including its primary and secondary roles in tumor formation and proliferation through signaling pathways. In this study, we analyzed the differences in the expression of cuproplasia-associated genes (CAGs) in pan-cancerous tissues and investigated their role in immune-regulation and tumor prognostication. METHODS: Raw data from 11,057 cancer samples were acquired from multiple databases. Pan-cancer analysis was conducted to analyze the CAG expression, single-nucleotide variants, copy number variants, methylation signatures, and genomic signatures of micro RNA (miRNA)-messenger RNA (mRNA) interactions. The Genomics of Drug Sensitivity in Cancer and the Cancer Therapeutics Response Portal databases were used to evaluate drug sensitivity and resistance against CAGs. Using single-sample Gene Set Enrichment Analysis (ssGSEA) and Immune Cell Abundance Identifier database, immune cell infiltration was analyzed with the ssGSEA score as the standard. RESULTS: Aberrantly expressed CAGs were found in multiple cancers. The frequency of single-nucleotide variations in CAGs ranged from 1% to 54% among different cancers. Furthermore, the correlation between CAG expression in the tumor microenvironment and immune cell infiltration varied among different cancers. ATP7A and ATP7B were negatively correlated with macrophages in 16 tumors including breast invasive carcinoma and esophageal carcinoma, while the converse was true for MT1A and MT2A . In addition, we established cuproplasia scores and demonstrated their strong correlation with patient prognosis, immunotherapy responsiveness, and disease progression ( P  <0.05). Finally, we identified potential candidate drugs by matching gene targets with existing drugs. CONCLUSIONS This study reports the genomic characterization and clinical features of CAGs in pan-cancers. It helps clarify the relationship between CAGs and tumorigenesis, and may be helpful in the development of biomarkers and new therapeutic agents.
Humans ; Female ; Genomics ; Carcinogenesis ; Carcinoma ; Breast Neoplasms ; Cell Transformation, Neoplastic ; Nucleotides ; Tumor Microenvironment

Objective:To investigate the incidence of delayed onset of lactogenesis Ⅱ (DOL Ⅱ) in mothers of preterm infants and its influencing factors.Methods:This retrospective cohort study involved women who delivered prematurely at the Department of Obstetrics of the First Affiliated Hospital of Zhengzhou University from September 2021 to March 2022. Demographic and perinatal data of the subjects were collected. According to lactation outcome on the third day after delivery, these women were divided into DOL Ⅱ and non-DOL Ⅱ groups. The two groups' differences in general conditions were compared, and the potential factors influencing DOL Ⅱ were also analyzed. Chi-square test, two independent samples t-test, Mann-Whitney U test, and logistic regression analysis were used for statistical analysis. Results:There were 286 mothers of premature infants enrolled in this study, and 73 (25.5%) of them experienced DOL Ⅱ. The other 213 cases without DOL Ⅱwere included as the non-DOL Ⅱ group. Univariate analysis showed significant differences between the DOL Ⅱ and non-DOL Ⅱ groups in the following aspects: the proportion of women with adverse pregnancy history [28.8% (21/73) vs 41.8% (89/213), χ2=3.89], the proportion of primiparas [60.3% (44/73) vs 38.0% (81/213), χ2=10.93], the incidence of hypertensive disorders of pregnancy [35.6% (26/73) vs 16.4% (35/213), χ2=11.92], the time to initiate breastfeeding after birth[5.0 h (3.0-7.0 h) vs 4.0 h (2.0-5.0 h), Z=－4.27], and the frequency of breastfeeding or pumping within 48 h after delivery [7.0 times (6.0-9.0 times) vs 9.0 times (7.0-11.0 times), Z=－3.62] (all P<0.05). Multivariate logistic regression showed that primipara ( OR=2.720, 95% CI: 1.485-4.982), hypertensive disorders of pregnancy ( OR=3.178, 95% CI: 1.609-6.274), the time to initiate breastfeeding ( OR=1.394, 95% CI: 1.211-1.604) and the frequency of breastfeeding/pumping within 48 h after delivery ( OR=0.861, 95% CI: 0.772-0.962) were independent influencing factors for DOL Ⅱ (all P<0.05). Conclusions:?The factors that influence the occurrence of DOL Ⅱ in preterm mothers are primipara hypertensive disorders of pregnancy, breastfeeding initiation time after delivery, and the frequency of breastfeeding or pumping within 48 h postpartum.

Objective:To study the effects of plan-do-check-action (PDCA) cycle in quality improvement of neonatal resuscitation.Methods:From 2016 to 2020, the clinical data of neonates born in our hospital were analyzed. Neonates born during 2016 to 2017 were pre-PDCA group and neonates born during 2018 to 2020 were post-PDCA group. PDCA quality improvement included step-by-step, high-frequency and low-dose training, strengthening teamwork and adding equipment.Results:A total of 7 728 live-birth neonates were delivered before PDCA with 319 cases (4.1%) of asphyxia. 10 174 live-birth neonates were delivered after PDCA with 422 cases (4.1%) of asphyxia. The asphyxia rates showed no significant difference between the two groups ( P>0.05). The incidences of severe asphyxia before and after PDCA were both 0.8% without significant difference ( P>0.05). The success rates of resuscitation for severe asphyxia before and after PDCA was 27.9% and 44.9%, respectively, and the differences were statistically significant ( P<0.05). The mortality rates within 7 d before and after PDCA were 0.5‰ and 0.1‰ respectively, without significant differences ( P>0.05). Conclusions:The implementation of PDCA cycle and step-by-step, high-frequency, low-dose neonatal resuscitation training can effectively improve the success rate of resuscitation in newborns with severe asphyxia.

Epilepsy is a disorder of the brain charac-terized by abnormal neuron excitability.However,the underlying molecular mechanism of neuron excitability modulation remains elusive.With the help of bioinformatic methods,we have identified receptor-type tyrosine-pro-tein phosphatase-like N(PTPRN)as a critical gene dur-ing epileptogenesis.PTPRN recruits NEDD4L ubiquitin E3 ligase to NaV1.2 sodium channels,facilitating NEDD4L-mediated ubiquitination and endocytosis.Knockout of PTPRN endows hippocampal granule cells with augmented depolarization currents and higher intrinsic excitability,which is reflected by increased seizure susceptibility of transgenic mice.On the contrary,reduced neuron excit-ability and decreased seizure susceptibility are observed after PTPRN overexpression.Meanwhile,we find that a 133 aa fragment recaptures modulation effect of PTPRN full-length,and this fragment shows therapeutic potential towards epilepsy caused by NaV1.2 gain of function vari-ants.In brief,our results demonstrate PTPRN playsa criti-calroleinregulatingneuronexcitability,providing a poten-tial therapeutic approach for epilepsy.

Objective:To systematically review the correlation between caesarean section and delayed onset of lactogenesisⅡ (DOLⅡ) .Methods:We searched PubMed, Web of Science, China Biomedical Medline Disc, China National Knowledge Infrastructure, WanFang Data, and VIP through computers. The search period was from the establishment of the database to March 31, 2022. After two evaluators independently selected literature, extracted data, and evaluated the quality of the included studies, Meta-analysis was conducted using R 4.1.0 statistical software.Results:A total of 25 studies were included, involving 36 233 caesarean section women. Meta-analysis showed that the risk of DOLⅡ in caesarean section group was 1.74 times higher than that in natural childbirth group [ OR=1.74, 95% CI (1.46, 2.08), P<0.01]. Conclusions:Current evidence shows that caesarean section can increase the risk of DOLⅡ in delivery women. Due to the limitation of the number and quality of included studies, future studies need to further confirm the causality between caesarean section and DOL Ⅱ.

Objective:To analyze the factors influencing breast milk volume in mothers of preterm infants during the period of maternal separation.Methods:This study retrospectively analyzed the data from lactation diaries of mothers of preterm infants ( n=371) in neonatal intensive care unit from the first Affiliated Hospital of Zhengzhou University from January 2017 to August 2021. According to whether the milk production reached 800 ml/d or not within two weeks after delivery, these women were divided into the reached group ( n=289) or unreached group ( n=82). Two independent sample t-test and Chi-square test were used for univariate analysis, and logistic regression was used to analyze the influencing factors. Results:Mothers who achieved the target milk volume accounted for 77.9% (289/371). There were no statistically significant differences in the ratio of milk production ≥50 ml between breasts or between two adjacent breastfeeding sessions (both P>0.05), while there were statistically significant differences in the maternal education background[high school education or below:16.3% (47/289) vs 41.5% (34/82); junior college or above:83.7% (242/289) vs 58.5% (48/82); χ2=23.77], type of breast pump [diaphragm breast pump:34.9% (101/289) vs 51.2% (42/82); piston pump: 65.1% (188/289) vs 48.8% (40/82); χ2=7.14], pre-pregnancy body mass index [<18.5 kg/m 2: 3.5% (10/289) vs 4.9% (4/82);≥18.5～<24.0 kg/m 2: 90.7% (262/289) vs 61.0% (50/82); ≥24.0 kg/m 2: 5.9% (17/289) vs 34.1% (28/82); χ2=40.89], and the initiation of lactation instruction [within 7 d after delivery: 77.2% (223/289) vs 45.1% (37/82);at 7-14 d after delivery: 22.8%(66/289) vs 54.9%(45/82); χ2=31.28] between the reached and unreached group (all P<0.05). Logistic regression analysis showed that high school education or below ( OR=4.279, 95% CI: 2.253-8.126, P<0.001), diaphragm breast pump ( OR=2.352, 95% CI: 1.309-4.226, P=0.004), pre-pregnancy body mass index ≥24.0 kg/m 2 ( OR=9.352, 95% CI: 4.389-19.928, P<0.001), and seeking lactation consultation at 7-14 d after delivery ( OR=3.654, 95% CI: 2.043-6.535, P<0.001) were risk factors for not achieving the target milk volume. Conclusions:Instruction on breastfeeding for less-educated mothers of preterm infants should be strengthened. Using piston breast pump, maintaining pre-pregnancy body mass index within the normal range, and receiving lactation instruction as early as possible will contribute to achieving the target milk volume.

Objective:To explore the risk factors of delayed onset of lactogenesis stage Ⅱ(DOL Ⅱ) after cesarean section, and to establish a risk prediction model.Methods:This study involved 330 women who underwent cesarean section in the First Affiliated Hospital of Zhengzhou University from September 2021 to January 2022 and were further divided into DOL Ⅱ group ( n=104) or non-DOL Ⅱ group ( n=226). All clinical data were compared. Univariate analysis and multivariate logistic regression were used to analyze the independent risk factors of DOL Ⅱ after cesarean section to establish the risk prediction model and draw nomogram. The predictive validity of the model was evaluated by the area under the receiver operating curve (AUC) and the goodness of fit was verified by Hosmer-Lemeshow test. Another 129 women who underwent cesarean section in our hospital from February to March 2022 were recruited for external validation. Results:The incidence of DOL Ⅱ in the model development and validation cohort were 31.5%(104/330) and 31.0%(40/129), respectively . In the model developing cohort, significant differences were shown in the constituent ratio of different groups of pre-pregnant body mass index {lean:[9.7%(22/226) vs 3.8%(4/104)]; fit: [66.8%(151/226) vs 62.5%(65/104)]; overweight or obsess:[23.5%(53/226) vs 33.7%(35/104)]}, the proportion of primiparas [50.4%(114/226) vs 61.5%(64/104)], breastfeeding education during pregnancy [64.2%(145/226) vs 40.4%(42/104)] and maternal separation [36.3%(82/226) vs 50.0%(52/104)], and the gestational age at delivery[38.0(36.0-39.0) vs 37.0(35.0-38.5) weeks] and frequency of breastfeeding within 48 h post-delivery [6.0(3.0-9.0) vs 2.0(0.5-5.0)] between the DOL Ⅱ and non-DOI Ⅱ group (all P<0.05). The predictors included in the model were pre-pregnancy overweight or obese ( OR=4.040, 95% CI:1.196-13.651), primipara ( OR=1.866, 95% CI:1.079-3.227), breastfeeding education during pregnancy ( OR=0.582, 95% CI:0.339-1.000), and frequency of breastfeeding within 48 h after delivery ( OR=0.791, 95% CI:0.720-0.857). The Hosmer-Lemeshow test showed that P=0.814 and the AUC was 0.784(95% CI:0.731-0.837). The Youden index was 1.504 with a sensitivity of 0.769 and a specificity of 0.735. While for the external validation, Hosmer-Lemeshow test showed that P=0.260 and the AUC was 0.751(95% CI:0.661-0.840). The Youden index was 1.460 with a sensitivity of 0.775 and a specificity of 0.685. Conclusion:The risk prediction model for DOL Ⅱ developed in this study has a good consistency and predictive performance, which can provide a reference for clinical screening of mothers at high risk of DOL Ⅱ following cesarean section.

Objective:To identify 3 the disease-causing genes and mutations of Leber congenital amaurosis (LCA), and to study the correlation of phenotype and genotype.Methods:A retrospective study. Four LCA patients and seven family members who were diagnosed by eye examination in Ning Xia Eye Hospital of People's Hospital of Ningxia Hui Autonomous Region from January to December 2021 were included in the study. Four patients were from 3 unrelated families. Detailed collection of medical history and family history were received. Related ophthalmologic examination were collected and genomic DNA was extracted from peripheral blood. Whole-exome sequencing method was used for genetic diagnosis. The identified variant was confirmed with Sanger sequencing. Potential pathogenic mutation was analyzed using software and conserved domain analysis and performed co-separated analysis between the family member and the proband.Results:Of the 4 patients, 1 patient was males and 3 patients were females; the age was from 4 to 18 years. Nystagmus were seen in 3 cases, finger pressing eyes and night blindness was seen in 1 cases; electroretinogram showed 4 cases of extinction or near extinction. The foveal reflection was visible in all eyes, and there was no obvious abnormality in the peripheral retina. One eye had strong reflection signal with raised ellipsoid in macular area; two eyes had weak reflection signal faintly visible between retinal layers; 1 eye had increased blood vessel branches, peripheral retinal non-perfusion area with capillary leakage; annular strong autofluorescence in macular area 4 eyes. No obvious abnormality was found in the phenotypes of family members. Genetic testing showed that the proband of pedigree 1 (Ⅱ-1) was found a homozygous missense mutation in c.640A>T (p.C214S) (M1) of PRPH2 gene. The proband of pedigree 2 (Ⅱ-2) was found compound heterozygous mutation in c.1256G>A(p.R419Q) (M2) and c.1A>C (p.M1L) (M3) of TULP1 gene. The proband 3 (Ⅱ-1) and her sister (Ⅱ-2) were both found compound heterozygous mutation in c.1943T>C (p.L648P) (M4) and c.380C>T (p.P127L) (M5) of GUCY2D gene. The parents and sister (Ⅱ-1) of the proband in family 2 and the parents of the proband in family 3 were all carriers of the corresponding heterozygous variant. M1, M3, M4, M5 were novel mutations and unreported. The genotype and disease phenotype were co-segregated within the family. According to the analysis of pedigree and genetic testing results, all 3 families were autosomal recessive inheritance. The amino acid conservation analysis found that M1, M2, M3, M4, and M5 were highly conserved among species. The results of bioinformatics analysis were all pathogenic variants. Conclusions:PRPH2 gene M1, TULP1 gene M3, and GUCY2D gene M4, M5 were novel mutations and not been reported in the literature and database. This research expanded the gene mutation spectrum of LCA. The patients with LCA have available characterristics, including onset age, varying ocular fundus and severe visual impairment.

Objective To analyze the relationship between genotype and phenotype in 3 pedigrees with Stargardt disease.Methods Three pedigrees with Stargardt disease were included in Ningxia Eye Hospital from January 2017 to September 2017.The clinical features of patients and other family members were evaluated by ophthalmic examinations,including visual acuity,best corrected visual acuity (BCVA),fundus examination,optical coherence tomography (OCT),fundus fluorescein angiography (FFA) and electroretinogram (ERG).The periphery blood sample of 5 ml from patients and 1 family member with normal phonotye in each family were collected.The next generation sequencing,PCR and direct sequencing were used to confirm the disease-causing mutation.The relationship between genotype and phenotype was analyzed.This study was approved by Ethic Committee of Ningxia Eye Hospital and informed consent was obtained from each subject.Results In 3 Stargardt pedigrees,2 pedigrees showed autosomal recessive inheritance,and 1 pedigree was pseudodominant inheritance.Five mutations on ABCA4 gene were detected and p.F2188S and p.Y345C were novel muations.All pedigrees carried two heterozygous mutation.The onset age of the patients were adolescence except just one patient who suffered at the age of 50 years old.The visual acuity was severely affected and the OCT indicated different degrees of macular atrophy.The results of the ocular fundus photography and the FFA were variable.Conclusions The patients with stargardt disease often carry heterozygous mutation on ABCA4 gene and available characteristics,including early onset age,varying ocular fundus and severe visual impairment.Next generation sequencing technique shows the advantages of rapid and high efficiency in the diagnosis of Stargardt disease.

Objective To evaluate the efficacy and safety of frequently nebulized hypertonic saline(HS) in different concentration with Terbutaline in infants with moderate to severe bronchiolitis.Methods A total of 195 infants were randomly enrolled to either Group A(5% HS 4ml+Terbutaline 2.5mg,n=65),Group B(3% HS 4ml + Terbutaline 2.5mg,n=65) or Group C[0.9% normal saline(NS) 4ml + Terbutaline 2.5mg,n=65].All the infants were given inhalation treatment q6h after admission for 4 times,and then q8h till the remission of wheezing.The primary outcome was the hospital length of stay(LOS),and the secondary outcomes were the clinical severity score(CSS),remission time of wheezing,cost and side effects.