Maternal and neonatal outcomes for kidney transplant recipients.

OBJECTIVE: To report pregnancy outcomes for women with kidney transplantation and investigate whether different intervals after transplantation have different effects on pregnancy outcomes. METHODS: A single-center retrospective study was performed. Based on intervals after transplantation, pregnant women with kidney transplantation are divided into two groups: intervals <5 years and ≧5 years. The maternal and neonatal outcomes were compared between the two groups. RESULTS: No maternal and neonatal deaths occurred. The average age of mothers during pregnancy was 32.3 ± 4.1 years and they had a functioning transplant for 4 (interquartile ranges, 3, 6) years. Preeclampsia occurs in sixteen (16.5 %) pregnancies and gestational diabetes (GDM) occurs in twenty (20.6 %). Eighty-eight newborns (90.7 %) had a gestational age of <37 weeks. The average gestational age for live births was 33.8 ± 2.2 weeks and the average birth weight was 2285.6 ± 581.8 g. Neonatal respiratory distress syndrome (NRDS) occurs in fifty-one babies (52.6 %), intraventricular hemorrhage (ICH) occurs in twenty-nine (29.8 %), atrial septal defects (ASD) occurs in thirty-two (32.9 %) and bronchopulmonary dysplasia (BPD) occurs in seven (7.2 %). Further analysis, pregnancy results, including pre-eclampsia, hypertension or GDM, did not differentiate between the two groups (intervals <5 years vs. ≧5 years). Neonatal outcomes, including premature delivery, low birth weight, mode of birth, small for gestational age (SGA), RDS, ICH, ASD, BPD were not distinguishable between the two groups (intervals <5 years vs. ≧5 years). The level of neonatal blood creatinine after birth was linearly related to high maternal creatinine, and can drop to normal levels within a week. CONCLUSIONS: The incidence of maternal and neonatal complications in pregnancies following kidney transplantation is still high, despite the success of most pregnancies. Various posttransplant intervals had no significant impact on pregnancy outcomes.

Neonatal outcomes and related risk factors of 30 cases with aplastic anemia in pregnancy: A retrospective study.

OBJECTIVE: To analyze the neonatal outcomes of pregnancies complicated by aplastic anemia (AA) and to investigate the underlying risk factors. METHODS: A single-center retrospective study was performed. Thirty singleton gravidas with AA (AA group) and another thirty singleton gravidas (control group) without immune or blood system disorders who gave birth around the same time were selected. Neonatal outcomes were compared between the two groups. Meanwhile, multivariable analyses were utilized to investigate the association between underlying risk factors and adverse neonatal events. RESULTS: No neonatal deaths occurred. Compared to the control group, the offspring of women with AA had a smaller gestational age (36 ± 1.9 vs. 39.1 ± 0.9 weeks; P < 0.001) and birth weight (2683.7 ± 479.9 vs. 3324.3 ± 394.1 g; P < 0.001). Newborns of women with AA had a higher risk of premature delivery (53.3 % vs. 3.3 %; P < 0.001), low birth weight (23.3 % vs. 0 %; P < 0.001) and NICU admission (53.3 % vs. 16.7 %; P = 0.003). Multivariate analysis showed neutropenia, anemia and thrombocytopenia as risk factors for premature delivery and admission to NICU. Anemia was independently associated with low birth weight (OR 0.94, 95 % CI 0.9-0.98, P = 0.01). CONCLUSIONS: Neonatal complications such as premature delivery, low birth weight and NICU admission are more common in pregnant women with AA. Newborn babies' s hematopoietic system did not appear to have been affected. Maintaining a certain level of neutrophils, hemoglobin, and platelets in the mother can improve newborn outcomes.

Effect of prebiotics, probiotics, synbiotics on depression: results from a meta-analysis.

Accumulating studies have shown the effects of gut microbiota management tools in improving depression. We conducted a meta-analysis to evaluate the effects of prebiotics, probiotics, and synbiotics on patients with depression. We searched six databases up to July 2022. In total, 13 randomized controlled trials (RCTs) with 786 participants were included. The overall results demonstrated that patients who received prebiotics, probiotics or synbiotics had significantly improved symptoms of depression compared with those in the placebo group. However, subgroup analysis only confirmed the significant antidepressant effects of agents that contained probiotics. In addition, patients with mild or moderate depression could both benefit from the treatment. Studies with a lower proportion of females reported stronger effects for alleviating depressive symptoms. In conclusion, agents that manipulate gut microbiota might improve mild-to-moderate depression. It is necessary to further investigate the benefits of prebiotic, probiotic and synbiotic treatments relative to antidepressants and follow up with individuals over a longer time before these therapies are implemented in clinical practice.

Neonatal outcomes in pregnant women with pulmonary arterial hypertension associated with heart disease.

BACKGROUND: As an increasing number of women with pulmonary arterial hypertension (PAH) choose to become pregnant, outcomes in newborns have become a priority. The main purpose of this study was to compare the neonatal outcomes in pregnant women with PAH associated with heart disease. METHODS: A single-center retrospective study was performed. Pregnancy with heart disease is divided into three groups: no PAH, mild PAH and severe PAH. Neonatal outcomes of pregnant women were compared among groups. Meanwhile, multivariable analyses were used to investigate the association between maternal PAH and adverse neonatal events. RESULTS: A total of 127 pregnant women with heart disease were enrolled. Of these, 82 (64.6%) had no PAH, 19 (15%) had mild PAH and 26 (20.4%) had severe PAH. The offspring of women with severe PAH had a higher risk of preterm delivery, low birth weight, neonatal respiratory distress syndrome (NRDS), neonatal intensive care unit (NICU) admission and recurrence of congenital heart disease (CHD). Compared to the women without PAH, only the risk of preterm delivery (32-36 weeks) and NICU admission were slightly higher in mothers with mild PAH; other neonatal events were similar. Multivariate regression analyses showed that the risk of preterm delivery (<37 weeks) increased with the increasing severity of maternal PAH, with an OR of 3.1 (95% CI, 1.1-8.8) for mild and 21.9 (95%CI, 4.8-99.4) for severe PAH. The same pattern was observed for NICU admission. Mothers with severe PAH were independently associated with low birth weight (OR 13, 95%CI 4.3-39, P < 0.001), NRDS (OR 17.9, 95%CI 5.5-58.9, P < 0.001) and recurrence of CHD (OR 4.47, 95%CI 1.7-11.6, P = 0.002). CONCLUSION: Pregnancy in women with severe PAH can significantly increase the risks of neonatal events. While neonatal outcomes in pregnant women with mild PAH were considered optimistic in the present study, a multidisciplinary management of PAH in pregnancy would be necessary to have consistently good outcomes.

Neonatal Outcomes in Pregnant Women With Repaired and Unrepaired Congenital Heart Disease in Zhejiang, China.

OBJECTIVES: To compare the neonatal outcomes in pregnant women with repaired vs unrepaired congenital heart disease (CHD). METHODS: Data on pregnant women with CHD was retrieved from our hospital records for the duration April, 2014 to December, 2021. Pregnant women with CHD were divided into two groups: simple CHD and moderate-to-complex CHD. RESULTS: In simple CHD group, neonatal outcomes were similar in pregnant women with repaired and unrepaired CHD. By contrast, in moderate-to-complex CHD group, the offspring of women with unrepaired CHD had lower gestational age [mean (SD) 34.3 (2.7) vs 36.8 (2.1) week; P=0.016] and lower birth weight [mean (SD) 2126.8 (711.9) vs 2720 (645.7); P=0.037] than those with repaired CHD. Infants of women with unrepaired moderate-to-complex CHD had a higher risk of premature delivery (87.5% vs 45.5%, P=0.013), low birth weight (81.3% vs 36.4%, P=0.04) and neonatal intensive care unit (NICU) admission (68.8% vs 27.3%, P=0.034). CONCLUSION: Surgical repair before pregnancy in women with moderate-to-complex CHD significantly minimized the risks of neonatal complications.

Spebrutinib (CC-292) Affects Markers of B Cell Activation, Chemotaxis, and Osteoclasts in Patients with Rheumatoid Arthritis: Results from a Mechanistic Study.

INTRODUCTION: Spebrutinib (CC-292) is an orally administered, covalent, small-molecule inhibitor of Bruton's tyrosine kinase (BTK), part of the B-cell and Fc receptor signaling pathways. This study evaluated spebrutinib pharmacology and mechanism of action over a 4-week treatment period in patients with active rheumatoid arthritis (RA). METHODS: Primary human B cells, T cells, natural killer cells, macrophages, dendritic cells, basophils, and osteoclasts were treated with spebrutinib in vitro. Clinical pharmacodynamics were studied in 47 patients with active RA on background methotrexate therapy randomized to oral spebrutinib 375 mg/day or placebo. RESULTS: In vitro, spebrutinib inhibited B-cell proliferation more potently than T-cell proliferation and reduced both lymphoid and myeloid cytokine production and degranulation, as well as osteoclastogenesis. Clinical efficacy trended higher in spebrutinib-treated RA patients, with 41.7% (10/24) achieving ≥ 20% improvement in ACR response criteria (ACR20) versus 21.7% (5/23) of placebo patients at week 4 (P = 0.25). Treatment-emergent adverse events were comparable between treatment groups. In spebrutinib-treated patients, median BTK occupancy in peripheral blood was 83%, and significant increases in total CD19+ and mature-naive CD27-CD38-IgD+ B cells and decreases in transitional CD27-CD38+ B cells were observed. Spebrutinib significantly reduced serum chemokines chemokine ligand 13 (CXCL13), macrophage inflammatory protein-1ß (MIP-1ß), and the bone resorption biomarker carboxy-terminal collagen cross-linking telopeptide (CTX-I) (P < 0.05). Clinical response to spebrutinib was associated with lower increases in CD19+ B cells and greater decreases in CXCL13 and MIP-1ß from baseline to week 4. High CD19+ B cells and low CTX-I at baseline were associated with better spebrutinib clinical response. CONCLUSIONS: Spebrutinib inhibited various leukocyte responses in vitro, including those of B cells and osteoclasts. In this small study in RA patients, spebrutinib was well tolerated, showed a downward trend for symptoms, significantly modulated B-cell populations, and reduced markers of chemotaxis and osteoclast activity. TRIAL REGISTRATION: NCT01975610.

NRF2 Induction Supporting Breast Cancer Cell Survival Is Enabled by Oxidative Stress-Induced DPP3-KEAP1 Interaction.

NRF2 is a transcription factor serving as a master regulator of the expression of many genes involved in cellular responses to oxidative and other stresses. In the absence of stress, NRF2 is constantly synthesized but maintained at low levels as it is targeted by KEAP1 for ubiquitination and proteasome-mediated degradation. NRF2 binds KEAP1 mainly through a conserved "ETGE" motif that has also been found in several other proteins, such as DPP3, which has been shown to bind KEAP1 and enhance NRF2 function upon overexpression. Here we demonstrate the interaction between endogenous DPP3 and endogenous KEAP1. We further show that the DPP3-KEAP1 interaction is strongly induced by hydrogen peroxide and that DPP3 is required for timely NRF2 induction and nuclear accumulation in the estrogen receptor (ER)-positive MCF7 breast cancer cells. Moreover, we present evidence that the binding of DPP3 to KEAP1 stabilizes the latter. Finally, we show that DPP3 is overexpressed in breast cancer and that elevated levels of DPP3 mRNA correlate with increased NRF2 downstream gene expression and poor prognosis, particularly for ER-positive breast cancer. Our studies reveal novel insights into the regulation of NRF2 and identify DPP3 and an NRF2 transcriptional signature as potential biomarkers for breast cancer prognosis and treatment. Cancer Res; 77(11); 2881-92. ©2017 AACR.

High-mobility group box-1 and receptor for advanced glycation end products in preterm infants with brain injury.

BACKGROUND: High-mobility group box-1 (HMGB1) protein acts as an important pro-infl ammatory mediator, which is capable of activating inflammation and tissue repair. HMGB1 can bind to its receptor such as advanced glycation end products (RAGE). RAGE, in turn, can promote the production of pro-inflammatory cytokines. Soluble RAGE (sRAGE) is a truncated form of the receptor comprising the extracellular domain of RAGE and can inhibit RAGE-activation. The objective of this study was to investigate whether HMGB1 and RAGE are involved in the development of brain injury in preterm infants. METHODS: In total, 108 infants ≤34 weeks gestation at birth were divided into 3 groups according to cranial altrasound scan: mild brain damage (n=33), severe brain damage (n=8) and no brain damage (n=67). All the placentas were submitted for pathologic evaluation. Histological chorioamnionitis (HCA) was defined as neutrophil infi ltration of amniotic membranes, umbilical cord or chorionic plate. Expressions of HMGB1 and RAGE proteins were assessed by immunohistochemical analysis. The concentration of HMGB1 and sRAGE in umbilical cord blood were measured by enzyme-linked immunosorbent assay. RESULTS: The frequency of HCA was 30.12%. HCA was associated with elevated concentrations of HMGB1 and decreased sRAGE in umbilical cord blood. The severe brain injury group demonstrated higher cord blood HMGB1 concentrations (P<0.001) and lower sRAGE concentrations (P<0.001) than both other groups. Brain injury in the premature infants was linked to intense staining for HMGB1/RAGE, particularly in infl ammatory cells. CONCLUSIONS: Changes of cord blood HMGB1 and sRAGE of premature infants had direct relationship with the degree of infl ammation and severity of brain damage. Monitoring sRAGE and HMGB1 levels may be helpful to predict intrauterine infection and brain injury in premature infants.

Effects of permissive hypercapnia on pulmonary and neurodevelopmental sequelae in extremely low birth weight infants: a meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis of the efficacy and safety of permissive hypercapnia in extremely low birth weight infants. METHODS: A systematic search of MEDLINE, EMBASE, the Cochrane Database of randomized trials. Eligibility and quality of trials were assessed, and data on study design, patient characteristics, and relevant outcomes were extracted. RESULTS: Four studies that enrolled a total of 693 participants were selected. Meta-analysis revealed no effect of permissive hypercapnia on decreasing rates of bronchopulmonary dysplasia (BPD). Permissive hypercapnia also had no significant effect on mortality, intraventricular haemorrhage (IVH), IVH (grade 3-4), periventricular leukomalacia (PVL), necrotising enterocolitis (NEC), retinopathy of prematurity (ROP) or air leaks in extremely low birth weight infants. Neurodevelopmental outcomes were comparable at 18-22 months' corrected age in two studies. permissive hypercapnia did not increase the risk of cerebral palsy, Mental Developmental Index <70, Psychomotor Developmental Index <70, visual deficit, or hearing deficit. CONCLUSIONS: Permissive hypercapnia did not reduce the rate of BPD in extremely low birth weight infants. The rates of mortality, IVH, PVL, NEC, ROP and neurodevelopmental outcomes did not differ between these two groups. These results suggest that permissive hypercapnia does not bring extra benefits in extremely low birth weight infants.

High Mobility Group Box 1 in Preterm Infants with Intraventricular Hemorrhage.

We studied the level of high mobility group box 1(HMGB1) in preterm infants with intraventricular hemorrhage (IVH). Using enzyme-linked immunosorbent assay (ELISA), the concentration of HMGB1 in cord blood obtained from 41 infants with IVH and 67 infants without IVH were measured. The cord blood concentration of HMGB1 in infants with IVH were significantly higher than those without IVH (P=0.041). Increased levels of HMGB1 might be associated with IVH in preterm infants.

[Relationship between placental inflammation and fetal inflammatory response syndrome and brain injury in preterm infants].

OBJECTIVE: To explore the relationship between histological chorioamnionitis (HCA) and fetal inflammatory response syndrome (FIRS) and brain injury in preterm infants. METHODS: One hundred and three singleton infants with premature rupture of membranes (PROM) (gestation ages of less than 34 weeks) were enrolled. All the placentas were submitted for pathological evaluation. Umbilical cord blood interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor alpha (TNF-α) and granulocyte-colony stimulating factor (G-CSF) levels were measured with liquid chip. All preterm infants accepted brain imaging examinations. Based on the placental pathological examination and umbilical cord blood level of IL-6, the 103 infants were classified into HCA⁻ FIRS⁻, HCA⁺ FIRS⁻, and HCA⁺ FIRS⁺ groups. RESULTS: The incidences of HCA, FIRS, and brain injury were 53.4%, 20.4% and 38.8% respectively. The prevalence of brain injury in HCA⁻ FIRS⁻, HCA⁺ FIRS⁻, and HCA⁺ FIRS⁺ cases was 21%, 41%, and 76% respectively (P<0.01). The grade 2 and grade 3 of placental inflammation and the inflammation at stage 2 and stage 3 increased the risk of brain injury. The cord blood levels of IL-8, TNF-α, and G-CSF in the HCA⁺ FIRS⁺ group were significantly higher than in the other two groups, and the levels of the above parameters in the HCA⁺ FIRS⁻ were higher than in the HCA⁻ FIRS⁻ group (P<0.05). CONCLUSIONS: Placental inflammation and FIRS are associated with brain injury in preterm infants. Preterm infants exposed to severe placental inflammation have an increased risk of brain injury. Cord blood IL-8, TNF-α and G-CSF may be involved in the process of brain injury in preterm infants with placental inflammation and FIRS.

Requirement of heterogeneous nuclear ribonucleoprotein C for BRCA gene expression and homologous recombination.

BACKGROUND: Heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNP C) is a core component of 40S ribonucleoprotein particles that bind pre-mRNAs and influence their processing, stability and export. Breast cancer tumor suppressors BRCA1, BRCA2 and PALB2 form a complex and play key roles in homologous recombination (HR), DNA double strand break (DSB) repair and cell cycle regulation following DNA damage. METHODS: PALB2 nucleoprotein complexes were isolated using tandem affinity purification from nuclease-solubilized nuclear fraction. Immunofluorescence was used for localization studies of proteins. siRNA-mediated gene silencing and flow cytometry were used for studying DNA repair efficiency and cell cycle distribution/checkpoints. The effect of hnRNP C on mRNA abundance was assayed using quantitative reverse transcriptase PCR. RESULTS AND SIGNIFICANCE: We identified hnRNP C as a component of a nucleoprotein complex containing breast cancer suppressor proteins PALB2, BRCA2 and BRCA1. Notably, other components of the 40S ribonucleoprotein particle were not present in the complex. hnRNP C was found to undergo significant changes of sub-nuclear localization after ionizing radiation (IR) and to partially localize to DNA damage sites. Depletion of hnRNP C substantially altered the normal balance of repair mechanisms following DSB induction, reducing HR usage in particular, and impaired S phase progression after IR. Moreover, loss of hnRNP C strongly reduced the abundance of key HR proteins BRCA1, BRCA2, RAD51 and BRIP1, which can be attributed, at least in part, to the downregulation of their mRNAs due to aberrant splicing. Our results establish hnRNP C as a key regulator of BRCA gene expression and HR-based DNA repair. They also suggest the existence of an RNA regulatory program at sites of DNA damage, which involves a unique function of hnRNP C that is independent of the 40S ribonucleoprotein particles and most other hnRNP proteins.

PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function.

PALB2/FANCN is mutated in breast and pancreatic cancers and Fanconi anemia (FA). It controls the intranuclear localization, stability, and DNA repair function of BRCA2 and links BRCA1 and BRCA2 in DNA homologous recombination repair and breast cancer suppression. Here, we show that PALB2 directly interacts with KEAP1, an oxidative stress sensor that binds and represses the master antioxidant transcription factor NRF2. PALB2 shares with NRF2 a highly conserved ETGE-type KEAP1 binding motif and can effectively compete with NRF2 for KEAP1 binding. PALB2 promotes NRF2 accumulation and function in the nucleus and lowers the cellular reactive oxygen species (ROS) level. In addition, PALB2 also regulates the rate of NRF2 export from the nucleus following induction. Our findings identify PALB2 as a regulator of cellular redox homeostasis and provide a new link between oxidative stress and the development of cancer and FA.

PALB2 links BRCA1 and BRCA2 in the DNA-damage response.

BRCA1 and BRCA2 are often mutated in familial breast and ovarian cancer. Both tumor suppressors play key roles in the DNA-damage response. However, it remains unclear whether these two tumor suppressor function together in the same DNA-damage response pathway. Here, we show that BRCA1 associates with BRCA2 through PALB2/FANCN, a major binding partner of BRCA2. The interaction between BRCA1 and BRCA2 is abrogated in PALB2-deficient Fanconi anemia cells and in the cells depleted of PALB2 by small interfering RNA. Moreover, we show that BRCA1 promotes the concentration of PALB2 and BRCA2 at DNA-damage sites and the interaction between BRCA1 and PALB2 is important for the homologous recombination repair. Taken together, our results indicate that BRCA1 is an upstream regulator of BRCA2 in the DNA-damage response, and PALB2 is the linker between BRCA1 and BRCA2.

Non-snRNP U1A levels decrease during mammalian B-cell differentiation and release the IgM secretory poly(A) site from repression.

A regulated shift from the production of membrane to secretory forms of Immunoglobulin M (IgM) mRNA occurs during B cell differentiation due to the activation of an upstream secretory poly(A) site. U1A plays a key role in inhibiting the expression of the secretory poly(A) site by inhibiting both cleavage at the poly(A) site and subsequent poly(A) tail addition. However, how the inhibitory effect of U1A is alleviated in differentiated cells, which express the secretory poly(A) site, is not known. Using B cell lines representing different stages of B cell differentiation, we show that the amount of U1A available to inhibit the secretory poly(A) site is reduced in differentiated cells. Undifferentiated B cells have more total U1A than differentiated cells and a greater proportion of this is not associated with the U1snRNP. We show that this is available to inhibit poly(A) addition at the secretory poly(A) site using cold competitor RNA oligos to de-repress poly(A) addition in nuclear extracts from the respective cell lines. In addition, endogenous non-snRNP associated U1A-immunopurified from the different cell lines-inhibits poly(A) polymerase activity proportional to U1A recovered, suggesting that available U1A level alone is responsible for changes in its inhibitory effect at the secretory IgM poly (A) site.

A hydrogel prepared by in situ cross-linking of a thiol-containing poly(ethylene glycol)-based copolymer: a new biomaterial for protein drug delivery.

A new poly(ethylene glycol)-based copolymer containing multiple thiol (-SH) groups was cross-linked in situ to form a polymer hydrogel under mild conditions. No organic solvent, elevated temperature, or harsh pH is required in the formulation or patient administration processes, making it particularly useful for delivery of fragile therapeutics, such as proteins. The in vitro release of fluorescein-labeled bovine serum albumin and the in vivo release of the model proteins, erythropoietin, RANTES and three PEG-conjugated RANTES derivatives showed sustained release for 2-4 weeks and demonstrated prolonged biological activity of the released proteins in animals.