A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates.

We present a multiomic cell atlas of human lung development that combines single-cell RNA and ATAC sequencing, high-throughput spatial transcriptomics, and single-cell imaging. Coupling single-cell methods with spatial analysis has allowed a comprehensive cellular survey of the epithelial, mesenchymal, endothelial, and erythrocyte/leukocyte compartments from 5-22 post-conception weeks. We identify previously uncharacterized cell states in all compartments. These include developmental-specific secretory progenitors and a subtype of neuroendocrine cell related to human small cell lung cancer. Our datasets are available through our web interface (https://lungcellatlas.org). To illustrate its general utility, we use our cell atlas to generate predictions about cell-cell signaling and transcription factor hierarchies which we rigorously test using organoid models.

Peptidoglycan maturation controls outer membrane protein assembly.

Linkages between the outer membrane of Gram-negative bacteria and the peptidoglycan layer are crucial for the maintenance of cellular integrity and enable survival in challenging environments1-5. The function of the outer membrane is dependent on outer membrane proteins (OMPs), which are inserted into the membrane by the ß-barrel assembly machine6,7 (BAM). Growing Escherichia coli cells segregate old OMPs towards the poles by a process known as binary partitioning, the basis of which is unknown8. Here we demonstrate that peptidoglycan underpins the spatiotemporal organization of OMPs. Mature, tetrapeptide-rich peptidoglycan binds to BAM components and suppresses OMP foldase activity. Nascent peptidoglycan, which is enriched in pentapeptides and concentrated at septa9, associates with BAM poorly and has little effect on its activity, leading to preferential insertion of OMPs at division sites. The synchronization of OMP biogenesis with cell wall growth results in the binary partitioning of OMPs as cells divide. Our study reveals that Gram-negative bacteria coordinate the assembly of two major cell envelope layers by rendering OMP biogenesis responsive to peptidoglycan maturation, a potential vulnerability that could be exploited in future antibiotic design.

SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling.

The balance between self-renewal and differentiation in human foetal lung epithelial progenitors controls the size and function of the adult organ. Moreover, progenitor cell gene regulation networks are employed by both regenerating and malignant lung cells, where modulators of their effects could potentially be of therapeutic value. Details of the molecular networks controlling human lung progenitor self-renewal remain unknown. We performed the first CRISPRi screen in primary human lung organoids to identify transcription factors controlling progenitor self-renewal. We show that SOX9 promotes proliferation of lung progenitors and inhibits precocious airway differentiation. Moreover, by identifying direct transcriptional targets using Targeted DamID, we place SOX9 at the centre of a transcriptional network, which amplifies WNT and RTK signalling to stabilise the progenitor cell state. In addition, the proof-of-principle CRISPRi screen and Targeted DamID tools establish a new workflow for using primary human organoids to elucidate detailed functional mechanisms underlying normal development and disease.

RTK signalling promotes epithelial columnar cell shape and apical junction maintenance in human lung progenitor cells.

Multipotent epithelial progenitor cells can be expanded from human embryonic lungs as organoids and maintained in a self-renewing state using a defined medium. The organoid cells are columnar, resembling the cell morphology of the developing lung tip epithelium in vivo. Cell shape dynamics and fate are tightly coordinated during development. We therefore used the organoid system to identify signalling pathways that maintain the columnar shape of human lung tip progenitors. We found that EGF, FGF7 and FGF10 have distinct functions in lung tip progenitors. FGF7 activates MAPK/ERK and PI3K/AKT signalling, and is sufficient to promote columnar cell shape in primary tip progenitors. Inhibitor experiments show that MAPK/ERK and PI3K/AKT signalling are key downstream pathways, regulating cell proliferation, columnar cell shape and cell junctions. We identified integrin signalling as a key pathway downstream of MAPK/ERK in the tip progenitors; disrupting integrin alters polarity, cell adhesion and tight junction assembly. By contrast, stimulation with FGF10 or EGF alone is not sufficient to maintain organoid columnar cell shape. This study employs organoids to provide insight into the cellular mechanisms regulating human lung development.

Characterization and mitigation of artifacts derived from NGS library preparation due to structure-specific sequences in the human genome.

BACKGROUND: Hybridization capture-based targeted next generation sequencing (NGS) is gaining importance in routine cancer clinical practice. DNA library preparation is a fundamental step to produce high-quality sequencing data. Numerous unexpected, low variant allele frequency calls were observed in libraries using sonication fragmentation and enzymatic fragmentation. In this study, we investigated the characteristics of the artifact reads induced by sonication and enzymatic fragmentation. We also developed a bioinformatic algorithm to filter these sequencing errors. RESULTS: We used pairwise comparisons of somatic single nucleotide variants (SNVs) and insertions and deletions (indels) of the same tumor DNA samples prepared using both ultrasonic and enzymatic fragmentation protocols. Our analysis revealed that the number of artifact variants was significantly greater in the samples generated using enzymatic fragmentation than using sonication. Most of the artifacts derived from the sonication-treated libraries were chimeric artifact reads containing both cis- and trans-inverted repeat sequences of the genomic DNA. In contrast, chimeric artifact reads of endonuclease-treated libraries contained palindromic sequences with mismatched bases. Based on these distinctive features, we proposed a mechanistic hypothesis model, PDSM (pairing of partial single strands derived from a similar molecule), by which these sequencing errors derive from ultrasonication and enzymatic fragmentation library preparation. We developed a bioinformatic algorithm to generate a custom mutation "blacklist" in the BED region to reduce errors in downstream analyses. CONCLUSIONS: We first proposed a mechanistic hypothesis model (PDSM) of sequencing errors caused by specific structures of inverted repeat sequences and palindromic sequences in the natural genome. This new hypothesis predicts the existence of chimeric reads that could not be explained by previous models, and provides a new direction for further improving NGS analysis accuracy. A bioinformatic algorithm, ArtifactsFinder, was developed and used to reduce the sequencing errors in libraries produced using sonication and enzymatic fragmentation.

Mixed-Mode Mindfulness-based cognitive therapy for psychological resilience, Self Esteem and Stigma of patients with schizophrenia: a randomized controlled trial.

BACKGROUND: People with schizophrenia often face challenges such as lower psychological resilience, reduced self-worth, and increased social stigma, hindering their recovery. Mindfulness-Based Cognitive Therapy (MBCT) has shown promise in boosting psychological resilience and self-esteem while diminishing stigma. However, MBCT demands professional involvement and substantial expenses, adding to the workload of professionals and the financial strain on patients. Mixed-mode Mindfulness-Based Cognitive Therapy (M-MBCT) integrates both "face-to-face" and "self-help" approaches to minimize staff effort and costs. This study aims to assess the impact of M-MBCT on the psychological resilience, self-esteem, and stigma in schizophrenia patients. METHODS: This randomized, controlled, parallel-group, assessor-blinded clinical trial enrolled 174 inpatients with schizophrenia. Participants were randomly assigned to either the experimental or control group. The experimental group underwent an 8-week M-MBCT intervention, while the control group received standard treatment. Data collection employed the Connor-Davidson Resilience Scale (CD-RISC), Internalized Stigma of Mental Illness Scale (ISMI), and Rosenberg Self-Esteem Scale (RSES) before and after the intervention. Post-intervention, significant differences in ISMI, CD-RISC, and RSES scores were observed between the experimental and control groups. RESULTS: In the experimental group, ISMI scores notably decreased, while CD-RISC and RSES scores significantly increased (P < 0.05). Multiple linear regression analysis identified age, education, and family history of mental illness as significant factors related to stigma (P < 0.05). Additionally, correlation analysis indicated a significant negative relationship between the reduction in CD-RISC scores and the reduction in ISMI scores (P < 0.05). CONCLUSION: M-MBCT effectively enhanced psychological resilience and self-esteem while diminishing stigma in individuals with schizophrenia. M-MBCT emerges as a promising treatment option for schizophrenia sufferers. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry on 03/06/2023 ( www.chictr.org.cn ; ChiCTR ID: ChiCTR2300069071).

miR-34a-5p facilitates osteogenic differentiation of bone marrow mesenchymal stem cells and modulates bone metabolism by targeting HDAC1 and promoting ER-α transcription.

OBJECTIVE: Metabolism is essential for bone development. The expressions of catabolic markers in chondrocytes show association with miR-34a-5p. This study discussed the mechanism by which miR-34a-5p regulates osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) as well as bone metabolism. METHODS: Expressions of BMSC surface markers were determined via flow cytometry. Osteogenic differentiation of BMSCs was subsequently induced. miR-34a-5p mimic, oe-HDAC1, or ER-α activator Ferutinin was introduced in BMSCs. Alkaline phosphatase activity and calcification were detected. Expressions of miR-34a-5p, HDAC1, ER-α, and osteogenic markers were determined via RT-qPCR and Western blot. The binding relationship between miR-34a-5p and HDAC1 was verified by a dual-luciferase assay. Mice at the age of 6 months and 18 months were assigned to the young group and age group for in vivo experiments, and aged mice were treated with agomiR miR-34a-5p. Expressions of serum miR-34a-5p, HDAC1, ER-α, and bone metabolism markers in mice were determined. RESULTS: Osteogenic medium-induced BMSCs manifested increased expressions of miR-34a-5p and ER-α and decreased HDAC1 expression. miR-34a-5p overexpression promoted osteogenic differentiation of BMSCs. miR-34a-5p targeted HDAC1. HDAC1 overexpression partially counteracted the promotional action of miR-34a-5p overexpression on osteogenic differentiation of BMSCs. miR-34a-5p overexpression activated ER-α. ER-α activator Ferutinin partially nullified the regulatory function of miR-34a-5p/HDAC1 on osteogenic differentiation of BMSCs. In vivo experiments showed that miR-34a-5p overexpression enhanced the potential of bone metabolism in aged mice. CONCLUSION: miR-34a-5p overexpression promoted osteogenic differentiation of BMSCs and enhanced bone metabolism by promoting ER-α activation via targeting HDAC1.

The role of NFATc1/c-myc/PKM2/IL-10 axis in activating cervical cancer tumor-associated M2 macrophage polarization to promote cervical cancer progression.

Nuclear factor of activated T cells 1 (NFATc1) is mainly expressed in tumor microenvironment, especially in macrophages. However, whether NFATc1 is involved in the polarization of tumor associated macrophages (TAMs) and tumor progression in cervical cancer (CC) remains unclear. Immunofluorescence staining was used to detect the expression of CD68 and NFATc1 in CC tissues or adjacent normal tissues of patients. RT-qPCR, flow cytometry, ELISA, and inhibitors treatment were used to observe the effect of NFATc1 on TAMs polarization. Clonal formation, scratch, and transwell assays were used to examine the effects of NFATc1-transfected macrophages or NFATc1-transfected TAM on tumor proliferation, migration, and invasion. Further, a xenograft model was established to confirm the roles of NFATc1+ TAM in CC tumorigenesis. NFATc1+CD68+/CD68+ TAMs ratio was significantly increased in CC tissues compared with the normal tissue, and NFATc1+ TAM showed an M2-like TAM subtype. NFATc1 induced macrophages to secrete IL-10, which further induced M2 polarization of macrophages. Mechanically, the c-myc-PKM2 pathway mediated the expression of IL-10 in NFATc1-induced macrophages. Functionally, NFATc1 induced M2 macrophages promoted the proliferation, migration, and invasion of CC cells, and the knockout of NFATc1 in TAMs significantly inhibited the tumor-promoting function of TAMs. Further, the tumorigenesis test in nude mice confirmed that NFATc1+ TAM promoted the tumorigenicity of CC cells in vivo. In conclusion, NFATc1 mediated IL-10 secretion by regulating the c-myc/PKM2 pathway, thereby inducing M2 polarization of TAMs and promoting the progression of CC.

Efficacy and safety of blonanserin versus risperidone in the treatment of schizophrenia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of blonanserin and risperidone for the treatment of schizophrenia and to provide reliable pharmacotherapeutic evidence for in the clinical treatment of schizophrenia. METHODS: We systematically searched the PubMed, Cochrane Library, Embase, Chinese Biomedical Literature Database (CBM), and China National Knowledge Infrastructure (CNKI) databases for head-to-head randomized controlled trials that compared blonanserin with risperidone for the treatment of schizophrenia. We extracted the following data: author, year, country, diagnostic criteria, sample size, course of treatment, dosage and outcomes. Our main endpoint was the changes in the Positive and Negative Syndrome Scale (PANSS) total scores. Meta-analysis of the included data was conducted by RevMan 5.3 software. We used the GRADE criteria to evaluate the certainty of the evidence. RESULTS: A total of 411 studies were initially; 8 trials were eligible and were included in our analysis (N = 1386 participants). Regarding efficacy, there was no difference in changes in the PANSS total scores between the two groups (P > 0.05). In terms of safety, compared to risperidone, the incidence of serum prolactin increases and weight gain in the blonanserin group was lower (P<0.05), but the incidence of extrapyramidal symptoms (EPS) was higher (P<0.05). CONCLUSION: The efficacy of blonanserin is similar to that of risperidone, but it is unclear whether blonanserin is more effective than risperidone at improving cognitive and social function. More high-quality studies are needed to verify the efficacy and safety of blonanserin in the future.

Conversion therapy in liver transplantation for hepatocellular carcinoma: What's new in the era of molecular and immune therapy?

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, with limited therapies and unsatisfactory prognosis once in the advanced stages. With promising advances in locoregional and systematic treatments, fast development of targeted drugs, the success of immunotherapy, as well as the emergence of the therapeutic alliance, conversion therapy has recently become more well developed and an effective therapeutic strategy. This article aimed to review recent developments in conversion therapy in liver transplantation (LT) for HCC. DATA SOURCES: We searched for relevant publications on PubMed before September 2022, using the terms "HCC", "liver transplantation", "downstaging", "bridging treatment" and "conversion therapy." RESULTS: Conversion therapy was frequently represented as a combination of multiple treatment modalities to downstage HCC and make patients eligible for LT. Although combining various local and systematic treatments in conversion therapy is still controversial, growing evidence has suggested that multimodal combined treatment strategies downstage HCC in a shorter time, which ultimately increases the opportunities for LT. Moreover, the recent breakthrough of immunotherapy and targeted therapy for HCC also benefit patients with advanced-stage tumors. CONCLUSIONS: In the era of targeted therapy and immunotherapy, applying the thinking of transplant oncology to benefit HCC patients receiving LT is a new topic that has shed light on advanced-stage patients. With the expansion of conversion therapy concepts, further investigation and research is required to realize the full potential of conversion treatment strategies, including accurately selecting candidates, determining the timing of surgery, improving the conversion rate, and guaranteeing the safety and long-term efficacy of treatment.

Mineralize It or Not: Comparative Proteomics and Elemental Analysis Reveal Ancestral Compositions of Iron Mineralized Molluscan Radulae.

The radula is a unique foraging organ to Mollusca, which is important for their evolution and taxonomic classification. Many radulae are mineralized with metals. Although the remarkable mechanical properties of mineralized radulae are well-studied, the formation of mineralization from nonmineralized radulae is poorly understood. Taking advantage of the recently sequenced octopus and chiton genomes, we were able to identify more species-specific radular proteins by proteomics. Comparing these proteomes with the known limpet radula proteome enabled us to gain insight into the molecular components of nonmineralized and mineralized radula, highlighting that iron mineralization in the chiton radula is possibly due to the evolution of ferritins and peroxiredoxins. Through an in vitro binding assay, ferritin is shown to be important to iron accumulation into the nonmineralized radula. Moreover, radular proteomes reflect their adaption to dietary habits to some extent. The octopus radula has many scaffold modification proteins to suit flexibility while the chiton radula has abundant sugar metabolism proteins (e.g., glycosyl hydrolases) to adapt to algae feeding. This study provides a foundation for the understanding of molluscan radula formation and evolution and may inspire the synthesis of iron nanomaterials.

Classification and regression tree (CART) model to assist clinical prediction for tracheostomy in patients with traumatic cervical spinal cord injury: a 7-year study of 340 patients.

OBJECTIVE: To develop a classification and regression tree (CART) model to predict the need of tracheostomy in patients with traumatic cervical spinal cord injury (TCSCI) and to quantify scores of risk factors to make individualized clinical assessments. METHODS: The clinical characteristics of patients with TCSCI admitted to our hospital from January 2014 to December 2020 were retrospectively analyzed. The demographic characteristics (gender, age, smoking history), mechanism of injury, injury characteristics (ASIA impairment grades, neurological level of impairment, injury severity score), preexisting lung disease and preexisting medical conditions were statistically analyzed. The risk factors of tracheostomy were analyzed by univariate logistic regression analysis (ULRA) and multiple logistic regression analysis (MLRA). The CART model was established to predict tracheostomy. RESULTS: Three hundred and forty patients with TCSCI met the inclusion criteria, in which 41 patients underwent the tracheostomy. ULRA and MLRA showed that age > 50, ISS > 16, NLI > C5 and AIS A were significantly associated with tracheostomy. The CART model showed that AIS A and NLI > C5 were at the first and second decision node, which had a significant influence on the decision of tracheostomy. The final scores for tracheostomy from CART algorithm, composed of age, ISS, NLI and AIS A with a sensitivity of 0.78 and a specificity of 0.96, could also predict tracheostomy. CONCLUSION: The establishment of CART model provided a certain clinical guidance for the prediction of tracheostomy in TCSCI. Quantifications of risk factors enable accurate prediction of individual patient risk of need for tracheostomy.

The shoulder abductor strength is a novel predictor of tracheostomy in patients with traumatic cervical spinal cord injury.

BACKGROUND: Early prediction of tracheostomy in traumatic cervical spinal cord injury (TCSCI) patients is often difficult. This study aims to clarify the association between shoulder abductor strength (SAS) and tracheostomy in patients with TCSCI. METHODS: We retrospectively analyzed 513 TCSCI patients who were treated in our hospital. All patients were divided into a tracheostomy group and a non-tracheostomy group. The SAS was assessed using the Medical Research Council (MRC) Scale for Muscle Strength grading. Potential predictors were assessed for their association with tracheostomy in patients. A nomogram was developed based on multivariable logistic regression analysis (MLRA) to visualize the predictive ability of the SAS. Validation of the nomogram was performed to judge whether the nomogram was reliable for visual analysis of the SAS. Receiver operating characteristics curve, specificity, and sensitivity were also performed to assess the predictive ability of the SAS. RESULTS: The proportion of patients with the SAS grade 0-2 was significantly higher in the tracheostomy group than in the non-tracheostomy group (88.1% vs. 54.8%, p = 0.001). The SAS grade 0-2 was identified as a significant predictor of the tracheostomy (OR: 4.505; 95% CI: 2.080-9.758; p = 0.001). Points corresponding to both the SAS grade 0-2 and the neurological level of injury at C2-C4 were between 60 and 70 in the nomogram. The area under the curve for the SAS grade 0-2 was 0.692. The sensitivity of SAS grade 0-2 was 0.239. The specificity of SAS grade 0-2 was 0.951. CONCLUSIONS: SAS is a novel predictor of tracheostomy in patients after TCSCI. The SAS grade 0-2 had a good predictive ability of tracheostomy.

Depression, cognitive reserve markers, and dementia risk in the general population.

OBJECTIVES: We investigated depression, cognitive reserve, and their interaction as risk factors for incident dementia among community-dwelling older adults. METHODS: In total, 2099 participants, aged ≥65 years with no dementia during baseline assessment, who completed the follow-up two years later were included from the Cognitive Function and Ageing Study Wales. Baseline depression and dementia and dementia at follow-up were evaluated using the Geriatric Mental State Examination and the Automated Geriatric Examination for Computer Assisted Taxonomy. Cognitive reserve was measured by combining overall education, mid-life occupational complexity, and later-life social and cognitive activities. Risk of dementia in relation to depression and cognitive reserve was estimated using penalized maximum likelihood logistic regression. Interactions between cognitive reserve and depression were assessed using both multiplicative and additive scales. RESULTS: Baseline depression and low cognitive reserve significantly increased the risk of subsequent dementia at follow-up. No multiplicative interaction between cognitive reserve and depression existed. We observed an additive interaction between case-level depression and cognitive reserve. A significant association between depression and dementia was only found among people with low cognitive-reserve levels. CONCLUSIONS: Greater cognitive reserve attenuated the depression-associated risk of developing dementia. This suggests the need to emphasize prodromal dementia detection among older adults with lower cognitive reserve and depression.

Association of RDM1 with osteosarcoma progression via cell cycle and MEK/ERK signalling pathway regulation.

RAD52 motif-containing 1 (RDM1), a key regulator of DNA double-strand break repair and recombination, has been reported to play an important role in the development of various human cancers, such as papillary thyroid carcinoma, neuroblastoma and lung cancer. However, the effect of RDM1 on osteosarcoma (OS) progression remains unclear. Here, this study mainly explored the connection between RDM1 and OS progression, as well as the underlying mechanism. It was found that RDM1 was highly expressed in OS cells compared with human osteoblast cells. Knockdown of RDM1 caused OS cell proliferation inhibition, cell apoptosis promotion and cell cycle arrest at G1 stage, whereas RDM1 overexpression resulted in the opposite phenotypes. Furthermore, RDM1 silencing leads to a significant decrease in tumour growth in xenograft mouse model. RDM1 also increased the protein levels of MEK 1/2 and ERK 1/2. All these findings suggest that RDM1 plays an oncogenic role in OS via stimulating cell cycle transition from G1 to S stage, and regulating MEK/ERK signalling pathway, providing a promising therapeutic factor for the treatment of OS.

Human lung development: recent progress and new challenges.

Recent studies have revealed biologically significant differences between human and mouse lung development, and have reported new in vitro systems that allow experimental manipulation of human lung models. At the same time, emerging clinical data suggest that the origins of some adult lung diseases are found in embryonic development and childhood. The convergence of these research themes has fuelled a resurgence of interest in human lung developmental biology. In this Review, we discuss our current understanding of human lung development, which has been profoundly influenced by studies in mice and, more recently, by experiments using in vitro human lung developmental models and RNA sequencing of human foetal lung tissue. Together, these approaches are helping to shed light on the mechanisms underlying human lung development and disease, and may help pave the way for new therapies.

White matter injury in the neonatal hypoxic-ischemic brain and potential therapies targeting microglia.

Neonatal hypoxic-ischemic (H-I) injury, which mainly causes neuronal damage and white matter injury (WMI), is among the predominant causes of infant morbidity (cerebral palsy, cognitive and persistent motor disabilities) and mortality. Disruptions to the oxygen and blood supply in the perinatal brain affect the cerebral microenvironment and may affect microglial activation, excitotoxicity, and oxidative stress. Microglia are significantly associated with axonal damage and myelinating oligodendrocytes, which are major pathological components of WMI. However, the effects of H-I injury on microglial functions and underlying transformation mechanisms remain poorly understood. The historical perception that these cells are major risk factors for ischemic stroke has been questioned due to our improved understanding of the diversity of microglial phenotypes and their alterable functions, which exacerbate or attenuate injuries in different regions in response to environmental instability. Unfortunately, although therapeutic hypothermia is an efficient treatment, death and disability remain the prognosis for a large proportion of neonates with H-I injury. Hence, novel neuroprotective therapies to treat WMI following H-I injury are urgently needed. Here, we review microglial mechanisms that might occur in the developing brain due to neonatal H-I injury and discuss whether microglia function as a double-edged sword in WMI. Then, we emphasize microglial heterogeneity, notably at the single-cell level, and sex-specific effects on the etiology of neurological diseases. Finally, we discuss current knowledge of strategies aiming to improve microglia modulation and remyelination following neonatal H-I injury. Overall, microglia-targeted therapy might provide novel and valuable insights into the treatment of neonatal H-I insult.

Neuronal deficiency of hypoxia-inducible factor 2α increases hypoxic-ischemic brain injury in neonatal mice.

The cellular responses to hypoxia or hypoxia-ischemia (HI) are governed largely by the hypoxia-inducible factor (HIF) family of transcription factors. Our previous studies show that HIF-1α induction is an important factor that mediates protective effects in the brain after neonatal HI. In the present study, we investigated the contribution of another closely related HIF α isoform, HIF-2α, specifically the neuronal HIF-2α, to brain HI injury. Homozygous transgenic mice with a floxed exon 2 of HIF-2α were bred with CaMKIIα-Cre mice to generate a mouse line with selective deletion of HIF-2α in forebrain neurons. These mice, along with their wildtype littermates, were subjected to HI at postnatal day 9. Brain injury at different ages was evaluated by the levels of cleaved caspase-3 and spectrin breakdown products at 24 hr; and histologically at 6 days or 3 months after HI. Multiple behavioral tests were performed at 3 months, prior to sacrifice. Loss of neuronal HIF-2α exacerbated brain injury during the acute (24 hr) and subacute phases (6 days), with a trend toward more severe volume loss in the adult brain. The long-term brain function for coordinated movement and recognition memory, however, were not impacted in the neuronal HIF-2α deficient mice. Our data suggest that, similar to HIF-1α, neuronal HIF-2α promotes cell survival in the immature mouse brain. The two HIF alpha isoforms may act through partially overlapping or distinct transcriptional targets to mediate their intrinsic protective responses against neonatal HI brain injury.

The role of long non-coding RNAs in drug resistance of cancer.

Long non-coding RNAs (lncRNAs), a class of long RNAs, are longer than 200 nucleotides in length but lack protein-coding capacity. LncRNAs, as critical genomic regulators, are involved in genomic imprinting regulation, histone modification and gene expression regulation as well as tumor initiation and progression. However, it is also found that lncRNAs are associated with drug resistance in several types of cancer. Drug resistance is an important reason for clinical chemotherapy failure, and the molecular mechanism of tumor resistance is complex, which is a process of multi-cause, multi-gene and multi-signal transduction pathway interaction. Then comprehending the mechanisms of chemoresistance will help find ways to control the tumor progression effectively. Therefore, in this review, we will construct lncRNAs /drug resistance interaction network and shed light on the role of lncRNAs in drug resistance.

Albumin-to-alkaline phosphatase ratio as a promising indicator of prognosis in human cancers: is it possible?

BACKGROUND: The impact of albumin-to-alkaline phosphatase ratio (AAPR) on prognosis in cancer patients remains uncertain, despite having multiple relevant studies in publication. METHODS: We systemically compiled literatures from 3 databases (Cochrane Library, PubMed, and Web of Science) updated to May 24th, 2020. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed and synthesized using STATA 14, values were then pooled and utilized in order to assess the overall impact of AAPR on patient's prognosis. RESULTS: In total, 18 studies involving 25 cohorts with 7019 cases were incorporated. Pooled results originated from both univariate and multivariate analyses (HR = 2.14, 95%CI:1.83-2.51, random-effects model; HR = 1.93, 95%CI:1.75-2.12, fixed-effects model; respectively) suggested that decreased AAPR had adverse effect on overall survival (OS). Similarly, pooled results from both univariate and multivariate analysis of fixed-effects model, evinced that decreased AAPR also had adverse effect on disease-free survival (DFS) (HR = 1.81, 95%CI:1.60-2.04, I2 = 29.5%, P = 0.174; HR = 1.69, 95%CI:1.45-1.97, I2 = 13.0%, P = 0.330; respectively), progression-free survival (PFS) (HR = 1.71, 95%CI:1.31-2.22, I2 = 0.0%, P = 0.754; HR = 1.90, 95%CI:1.16-3.12, I2 = 0.0%, P = 0.339; respectively), and cancer-specific survival (CSS) (HR = 2.22, 95%CI:1.67-2.95, I2 = 5.6%, P = 0.347; HR = 1.88, 95%CI:1.38-2.57, I2 = 26.4%, P = 0.244; respectively). Admittedly, heterogeneity and publication bias existed, but stratification of univariate meta-analytic results, as well as adjusted meta-analytic results via trim and fill method, all showed that AAPR still significantly correlated with poor OS despite of confounding factors. CONCLUSIONS: In summary, decreased AAPR had adverse effect on prognosis in cancer patients. As an inexpensive and convenient ratio derived from liver function test, AAPR might become a promising indicator of prognosis in human cancers.