Medulloblastomas Initiated by Homologous Recombination Defects in Mice.

Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibit genomic signatures of HR defects. We queried whether ablation of Brca2 and Palb2, and their related Brca1 and Bccip genes, in the mouse brain can differentially initiate medulloblastomas. Conditional knockout mouse models of these HR genes and a conditional knockdown of Bccip (shBccip-KD) were established. Deletion of any of these genes led to microcephaly and neurologic defects, with Brca1- and Bccip- producing the worst. Trp53 co-deletion significantly rescued the microcephaly with Brca1, Palb2, and Brca2 deficiency but exhibited limited impact on Bccip- mice. For the first time, inactivation of either Brca1 or Palb2 with Trp53 was found to induce medulloblastomas. Despite shBccip-CKD being highly penetrative, Bccip/Trp53 deletions failed to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. Although there were widespread up-regulations of cell proliferative pathways, most of the tumors expressed biomarkers of the sonic hedgehog subgroup. The medulloblastomas developed from Brca1-, Palb2-, and Brca2- mice were highly sensitive to a poly (ADP-ribose) polymerase inhibitor but not the ones from shBccip-CKD mice. These models recapitulate the spontaneous medulloblastoma development with high penetrance and a narrow time window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR-defective and HR-proficient tumors.

Efficacy and safety of mesenchymal stem cell therapies for ischemic stroke: a systematic review and meta-analysis.

BACKGROUND: The efficacy and safety of mesenchymal stem cells (MSCs) in the treatment of ischemic stroke (IS) remains controversial. Therefore, this study aimed to evaluate the efficacy and safety of MSCs for IS. METHODS: A literature search until May 23, 2023, was conducted using PubMed, EMBASE, the Cochrane Library, and the Web of Science to identify studies on stem cell therapy for IS. Interventional and observational clinical studies of MSCs in patients with IS were included, and the safety and efficacy were assessed. Two reviewers extracted data and assessed the quality independently. The meta-analysis was performed using RevMan5.4. RESULTS: Fifteen randomized controlled trials (RCTs) and 15 non-randomized trials, including 1217 patients (624 and 593 in the intervention and control arms, respectively), were analyzed. MSCs significantly improved patients' activities of daily living according to the modified Rankin scale (mean difference [MD]: -0.26; 95% confidence interval [CI]: -0.50 to -0.01; P = .04) and National Institutes of Health Stroke Scale score (MD: -1.69; 95% CI: -2.66 to -0.73; P < .001) in RCTs. MSC treatment was associated with lower mortality rates in RCTs (risk ratio: 0.44; 95% CI: 0.28-0.69; P < .001). Fever and headache were among the most reported adverse effects. CONCLUSIONS: Based on our review, MSC transplantation improves neurological deficits and daily activities in patients with IS. In the future, prospective studies with large sample sizes are needed for stem cell studies in ischemic stroke. This meta-analysis has been registered at PROSPERO with CRD42022347156.

Inhibition of YIPF2 Improves the Vulnerability of Oligodendrocytes to Human Islet Amyloid Polypeptide.

Excessive secretion of human islet amyloid polypeptide (hIAPP) is an important pathological basis of diabetic encephalopathy (DE). In this study, we aimed to investigate the potential implications of hIAPP in DE pathogenesis. Brain magnetic resonance imaging and cognitive scales were applied to evaluate white matter damage and cognitive function. We found that the concentration of serum hIAPP was positively correlated with white matter damage but negatively correlated with cognitive scores in patients with type 2 diabetes mellitus. In vitro assays revealed that oligodendrocytes, compared with neurons, were more prone to acidosis under exogenous hIAPP stimulation. Moreover, western blotting and co-immunoprecipitation indicated that hIAPP interfered with the binding process of monocarboxylate transporter (MCT)1 to its accessory protein CD147 but had no effect on the binding of MCT2 to its accessory protein gp70. Proteomic differential analysis of proteins co-immunoprecipitated with CD147 in oligodendrocytes revealed Yeast Rab GTPase-Interacting protein 2 (YIPF2, which modulates the transfer of CD147 to the cell membrane) as a significant target. Furthermore, YIPF2 inhibition significantly improved hIAPP-induced acidosis in oligodendrocytes and alleviated cognitive dysfunction in DE model mice. These findings suggest that increased CD147 translocation by inhibition of YIPF2 optimizes MCT1 and CD147 binding, potentially ameliorating hIAPP-induced acidosis and the consequent DE-related demyelination.

Treatment of a case of primary alveolar soft part sarcoma of the lung: Case report and literature review.

Alveolar soft part sarcoma (ASPS) is an extremely rare type of soft tissue sarcoma. The primary sites of ASPS are mostly located in the extremities and trunk. Primary pulmonary ASPS is extremely rare. A search of the PubMed® database identified only five cases of primary pulmonary ASPS. This current case report describes the sixth case of ASPS in a 15-year-old male that presented with recurrent headaches. Head computed tomography showed space-occupying lesions in the left parietal lobe. Positron emission tomography-computed tomography confirmed the space-occupying lesions in the left parietal lobe and showed multiple nodules and masses in the two lungs and pleura, which were considered to be low-grade malignant mesenchymal tumours. The case report presents the clinical characteristics, diagnosis and treatment process. Programmed cell death protein 1 monoclonal antibody (sintilimab) combined with a tyrosine kinase inhibitor (anlotinib hydrochloride) achieved a good therapeutic effect, indicating that this combination therapy is worth exploring further. Large-scale prospective studies are needed to explore and develop standardized treatments for ASPS.

Gender heterogeneity in the influencing factors for cerebral microbleeds in acute ischemic stroke patients.

BACKGROUND: Cerebral microbleeds (CMBs) are common in acute ischemic stroke (AIS) patients. The presence of CMBs increases the risk of hemorrhagic transformation in AIS patients, and it is also closely associated with cognitive decline and even dementia. At present, there exist different opinions on the independent risk factors for CMBs, and there is no consensus on whether there are gender differences in -post-stroke CMB. Therefore, this study sought to investigate gender heterogeneity in the influencing factors for CMBs by studying male and female AIS patients. METHODS: This was a China-based, Single-center, retrospective review of data from 482 AIS inpatients at the Neurology Department of Hebei General Hospital (NCT05882123). Both demographic and clinical data were collected from the study subjects. Different head magnetic resonance imaging sequences were used to assess the subjects' CMBs, white matter lesions, and old lacunar infarcts (LI). Various statistical methods, including the t-test, χ2 test, and logistic regression, were used to analyze the gender heterogeneity of the influencing factors for CMBs in AIS patients. RESULTS: When compared with the male AIS patients, the female AIS patients were older and had higher total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, ApoA, ApoB, and fibrinogen levels. The female AIS patients also had higher National Institute of Health Stroke Scale scores and hypertension disease composition ratios. By contrast, the proportions of female AIS patients with a history of smoking and a history of alcohol consumption were both lower than the corresponding proportions of male AIS patients. These differences were all statistically significant (p < .05). There were no statistically significant differences in the incidence and severity of CMBs between the male and female AIS patients (χ2 ＝ 0.851, 3.092, p > .05). The univariate and multivariate stepwise logistic regression analyses confirmed that age (OR = 1.074, 95% CI: 1.013-1.139, p = .016) and old LI (OR = 4.295, 95% CI: 1.062-17.375, p = .041) were independent risk factors for comorbid CMBs in the female AIS patients, while blood glucose (OR = 0.692, 95% CI: 0.494-0.968, p = .031) was an independent protective factor for comorbid CMBs in the female AIS patients. However, these factors were not found to be independent risk or protective factors for comorbid CMBs in male AIS patients. CONCLUSION: There are gender differences in the influencing factors for CMBs in AIS patients. Age, old LIs, and blood glucose are independent risk or protective factors for comorbid CMBs in female AIS patients, although they are not associated with the risk of developing CMBs in male AIS patients.

The establishment of B cell-deficient Igh-J KO mouse model by gene editing and efficacy evaluation.

Over the last few years, immunotherapy has made significant progress in treating various cancers with therapeutic antibodies. However, therapeutic antibodies have been validated for inducing an unintended immune response in human and animal models, which leads to the emergence of anti-drug antibodies (ADAs) and affects their effectiveness and safety. In preclinical research, ADAs production by B cells may accelerate antibody metabolism and result in missing potential candidate molecules. Thus, it is urgent to develop preclinical models that remove only B cells without affecting the function of T and NK cells. Rearrangement of immunoglobulin heavy chain J gene fragment (Igh-J) is the first link in B cell development, and immunotherapies are currently leaning toward combination treatments with PD-1/PD-L1 antibodies, here we created humanized PD-1, PD-L1 and Igh-J knockout (hPD-1/hPD-L1, Igh-J KO) mice and validated by using the reported high immunogenicity drug M7824 (a protein designed to simultaneously block PD-L1 and TGF-ß pathways, poorly anti-tumor efficacy in immunocompetent mice). Phenotypic analysis revealed that human PD-1 and PD-L1 were detectable in hPD-1/hPD-L1, Igh-J KO mice, but not mouse IgM and IgD. Igh-J KO depleted B cells while increased the percentage of other immune cell types. Meanwhile, the humanization of PD-1/PD-L1 and Igh-J KO had neither effect on the overall development, differentiation, or distribution of T cell subtypes, nor on the activation of NK and T cells, indicating that mice can be used for T and NK-related immunotherapies. Furthermore, M7824 treatment of these B cell-deficient mice inhibited tumor growth significantly, with higher M7824 analog concentrations and lower ADA-positive rates. These findings demonstrate that Igh-J KO mice are an effective and stable preclinical model for testing drugs based on T and NK cells with high immunogenicity in vivo.

Study on smoke blocking and thermal radiation attenuation by water curtain in tunnel fire.

A 1:10 scale model tunnel with a length, height and width of 9 m, 0.6 m and 0.8 m, respectively, was set up in this paper. A water curtain system was installed in the model to investigate the effect of water curtain systems on smoke flow and heat propagation. A reduced-scale experimental and theoretical study was carried out by varying the heat release rate of the fire source, the water curtain pressure, and the number of water curtain rows. A series of tests were carried out for various setups to quantify each mechanism of interaction between the water mist and hot smoke, to propose a method for qualitatively analysing water curtain systems blocking the propagation of heat radiation and the flow of smoke from combustion, and to propose a method for predicting heat fluxes. The study found that the pressure of the water curtain, the number of rows, and the heat release rate of the fire source all had an effect on the smoke blocking effect of the water curtain system. This effect decreased as the heat release rate of the fire source increased and increased significantly with the pressure of the water curtain and the number of rows. The smoke blocking effect was quantified using conservation of momentum by establishing a dimensionless parameter R to represent the ratio of water curtain momentum to smoke momentum, as well as the ratio of heat flux before and after the water curtain to represent the smoke blocking capacity [Formula: see text] of the water curtain. The smoke blockage rate [Formula: see text] ranges between 40 and 75%, and the smoke blockage rate increases as the momentum R increases. Finally, in tunnel fires, a predictive model for the attenuation of heat radiation by water curtains has been developed, providing theoretical support for the quantitative study of the smoke and thermal blockage effects of water curtains, which is beneficial to the protection of human life in confined spaces.

Disrupted BRCA1-PALB2 interaction induces tumor immunosuppression and T-lymphocyte infiltration in HCC through cGAS-STING pathway.

BACKGROUND AND AIMS: BRCA1 (BRCA1 DNA repair associated) and PALB2 (partner and localizer of BRCA2) interact with each other to promote homologous recombination and DNA double-strand breaks repair. The disruption of this interaction has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood. APPROACH AND RESULTS: We demonstrated that mice with disrupted BRCA1-PALB2 interaction were more susceptible to HCC than wild-type mice. HCC tumors arising from these mice showed plenty of T-lymphocyte infiltration and a better response to programmed cell death 1 (PD-1) antibody treatment. Mechanistically, disruption of the BRCA1-PALB2 interaction causes persistent high level of DNA damage in HCC cells, leading to activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in both malignant hepatocytes and M1 macrophages in the tumor microenvironment. The activated cGAS-STING pathway induces programmed cell death 1 ligand 1 expression via the STING-interferon regulatory factor 3 (IRF3)-signal transducer and activator of transcription 1 pathway, causing immunosuppression to facilitate tumorigenesis and tumor progression. Meanwhile, M1 macrophages with an activated cGAS-STING pathway could recruit T lymphocytes through the STING-IRF3 pathway, leading to T-lymphocyte infiltration in tumors. After normalizing immune responses by PD-1 antibody treatment, the infiltrating T lymphocytes attack tumor cells rapidly and effectively. CONCLUSIONS: This study reveals that persistent DNA damage caused by a defective BRCA pathway induces tumor immunosuppression and T-lymphocyte infiltration in HCC through the cGAS-STING pathway, providing insight into tumor immune microenvironment remodeling that may help improve HCC response to PD-1 antibody treatment.

Label Noise Learning Method for Metallographic Image Recognition of Heat-Resistant Steel for Use in Pressure Equipment.

In metallographic examination, spherular pearlite gradation, an important step in a metallographic examination, is the main indicator used to assess the reliability of heat-resistant steel. Recognition of pearlite spheroidization via the manual way mainly depends on the subjective perceptions and experience of each inspector. Deep learning-based methods can eliminate the effects of the subjective factors that affect manual recognition. However, images with incorrect labels, known as noisy images, challenge successful application of image recognition of deep learning models to spherular pearlite gradation. A deep-learning-based label noise method for metallographic image recognition is thus proposed to solve this problem. We use a filtering process to pretreat the raw datasets and append a retraining process for deep learning models. The presented method was applied to image recognition for spherular pearlite gradation on a metallographic image dataset which contains 422 images. Meanwhile, three classic deep learning models were also used for image recognition, individually and coupled with the proposed method. Results showed that accuracy of image recognition by a deep learning model solely is lower than the one coupled with our method. Particularly, accuracy of ResNet18 was improved from 72.27% to 77.01%.

Unmasking the mammalian SET domain-containing protein 4.

SET domain-containing protein 4 (SETD4) is a member of a unique class of protein lysine methyltransferases. Here, we introduce the basic features of SETD4 and summarize the key findings from recent studies with emphases on its roles in tissue development and tumorigenesis, and its methylation substrates. SETD4 is expressed in stem/progenitor cells. Ablation of Setd4+ cells impedes the repopulation of acinar cells after pancreatic injury. Setd4 deletion in mice promotes the recovery of radiation-induced bone marrow (BM) failure by boosting the function of BM niche, facilitates the generation of endothelial cells and neovascularization of capillary vessels in the heart, enhances the proliferation of BM mesenchymal stem cells and disrupts the TLR4 signaling in BM-derived macrophages. SETD4 expression is also associated with the maintenance of quiescent breast cancer stem cells. While mouse Setd4 knockout delays radiation-induced T-lymphoma formation, elevated SETD4 expression has been observed in some proliferative cancer cells and is associated with a pro-survival potential. Oncogenic fusions of SETD4 have also been identified in cancer, albeit rare. In addition, SETD4 methylates lysine-570 in the C-terminal globular domain of KU70, which enables KU70 translocation to cytoplasm to suppress apoptosis.

Identification of an Inflammatory Response-Related Gene Signature to Predict Survival and Immune Status in Glioma Patients.

Background: Glioma is the most common primary brain tumor with high mortality and poor outcomes. As a hallmark of cancers, inflammatory responses are crucial for their progression. The present study is aimed at exploring the prognostic value of inflammatory response-related genes (IRRGs) and constructing a prognostic IRRG signature for gliomas. Materials and Methods: We investigated the relationship between IRRGs and gliomas by integrating the transcriptomic data for gliomas from public databases. Differentially expressed IRRGs (DE-IRRGs) were identified in the GSE4290 cohort. Further, univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses were conducted to construct an IRRG signature using The Cancer Genome Atlas (TCGA) cohort. Gliomas from the Chinese Glioma Genome Atlas (CGGA) cohort were employed for independent validation. The performance of gene signature was assessed by survival and receiver operating characteristic curve analyses. The differences in clinical correlations, immune infiltrate types, immunotherapeutic response predictions, and pathway enrichment among subgroups were investigated via bioinformatic algorithms. Results: In total, 37 DE-IRRGs were determined, of which 31 were found to be associated with survival. Ultimately, eight genes were retained to construct an IRRG signature that further classified glioma patients into two groups; the high-risk group suffered a poorer outcome as compared to the low-risk group. Furthermore, the high-risk group was significantly correlated with several risk factors, including older age, higher tumor grade, IDH wild type, 1p19q noncodel, and MGMT unmethylation. The nomogram was constructed by integrating the risk scores and other independent clinical characteristics. Moreover, the high-risk group had a greater immune infiltration and was most likely to benefit from immunotherapy. Gene set enrichment analysis suggested that immune and oncogenic pathways were enriched in high-risk glioma patients. Conclusion: We constructed a signature composed of eight IRRGs for gliomas, which could effectively predict survival and guide decision-making for treatment.

Experimental study on the desorption effect of penetrant on gas-containing coal.

Two non-ionic reagents, polyethylene glycol 4000 and Tween-80, two anionic reagents, sodium dodecyl benzenesulfonate and sodium lauryl sulfate, and a mixture of these non-ionic and anionic reagents were used as penetrants. The processes of replacement desorption and relief-pressure desorption of gas-containing coal were studied, the influence of the penetrant on the amount of gas replacement desorption and relief-pressure desorption was explored, and the change rule of the amounts of gas replacement desorption and relief-pressure desorption was analysed. The results show that the increase rate of the replacement desorption amount of the mixed penetrant is 11.81%-34.75%, and the decrease rate of the relief-pressure desorption amount is 51.68%-72.69%, which are higher values than those with a single penetrant. As the mass fraction of penetrant increases within the range of 0.5%~2%, the capacity of gas replacement desorption and hindering gas relief-pressure desorption will increase. At the same mass fraction, the effect of the mixed penetrant is better than that of the anionic penetrant, which in turn is better than that of the non-ionic penetrant.

BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage.

The BRCA2 tumor suppressor protects genome integrity by promoting homologous recombination-based repair of DNA breaks, stability of stalled DNA replication forks and DNA damage-induced cell cycle checkpoints. BRCA2 deficient cells display the radio-resistant DNA synthesis (RDS) phenotype, however the mechanism has remained elusive. Here we show that cells without BRCA2 are unable to sufficiently restrain DNA replication fork progression after DNA damage, and the underrestrained fork progression is due primarily to Primase-Polymerase (PRIMPOL)-mediated repriming of DNA synthesis downstream of lesions, leaving behind single-stranded DNA gaps. Moreover, we find that BRCA2 associates with the essential DNA replication factor MCM10 and this association suppresses PRIMPOL-mediated repriming and ssDNA gap formation, while having no impact on the stability of stalled replication forks. Our findings establish an important function for BRCA2, provide insights into replication fork control during the DNA damage response, and may have implications in tumor suppression and therapy response.

Predictors and Prognosis of Symptomatic Intracranial Hemorrhage in Acute Ischemic Stroke Patients Without Thrombolysis: Analysis of Data From the Chinese Acute Ischemic Stroke Treatment Outcome Registry.

Background and Purpose: There is limited information on symptomatic intracranial hemorrhage (sICH) in stroke patients without thrombolysis. This study aimed to evaluate the risk factors of sICH and the association between sICH and the prognosis at 3 and 12 months in acute ischemic stroke patients without thrombolysis. Methods: Data originated from the Chinese Acute Ischemic Stroke Treatment Outcome Registry. Univariate analysis and multivariate logistic regression were used to screen the risk factors of sICH. Multivariable logistic regression models were used to assess the association of sICH with poor outcome and all-cause mortality. Results: Totally, 9,484 patients were included, of which 69 (0.73%) had sICH. Atrial fibrillation (odds ratio [OR], 3.682; 95% confidence interval [CI], 1.945-6.971; p < 0.001), history of tumors (OR, 2.956; 95% CI, 1.115-7.593; p = 0.024), and the National Institutes of Health Stroke Scale (NIHSS) score on admission ([6-15: OR, 2.344; 95% CI, 1.365-4.024; p = 0.002] [>15: OR, 4.731; 95% CI, 1.648-13.583; p = 0.004]) were independently associated with sICH. After adjustment of the confounders, patients with sICH had a higher risk of poor outcome (OR, 1.983; 95% CI, 1.117-3.521; p = 0.018) at 3 months and that of all-cause mortality at 3 (OR, 6.135; 95% CI, 2.328-16.169; p < 0.001) and 12 months (OR, 3.720; 95% CI, 1.513-9.148; p = 0.004). Conclusion: sICH occurred in 0.73% of acute ischemic stroke patients without thrombolysis and was associated with a worse prognosis at 3 and 12 months. Atrial fibrillation, history of tumors, and NIHSS score at admission were independent risk factors of sICH.

Structure of human BCCIP and implications for binding and modification of partner proteins.

BCCIP was isolated based on its interactions with tumor suppressors BRCA2 and p21. Knockdown or knockout of BCCIP causes embryonic lethality in mice. BCCIP deficient cells exhibit impaired cell proliferation and chromosome instability. BCCIP also plays a key role in biogenesis of ribosome 60S subunits. BCCIP is conserved from yeast to humans, but it has no discernible sequence similarity to proteins of known structures. Here we report two crystal structures of an N-terminal truncated human BCCIPß, consisting of residues 61-314. Structurally BCCIP is similar to GCN5-related acetyltransferases (GNATs) but contains different sequence motifs. Moreover, both acetyl-CoA and substrate-binding grooves are altered in BCCIP. A large 19-residue flap over the putative CoA binding site adopts either an open or closed conformation in BCCIP. The substrate binding groove is significantly reduced in size and is positively charged despite the acidic isoelectric point of BCCIP. BCCIP has potential binding sites for partner proteins and may have enzymatic activity.

Requirement of Bccip for the Regeneration of Intestinal Progenitors.

BCCIP was originally identified as a BRCA2 and CDKN1A/p21 interaction protein. Although a partial loss of BCCIP function is sufficient to trigger genomic instability and tumorigenesis, complete deletion of BCCIP is lethal to cells. Using Rosa26-CreERT2 mouse models, we found that induced Bccip deletion in adult mice caused an acute intestinal epithelial denudation that cannot be relieved by co-deletion of Trp53. The critical role of Bccip in intestine epithelial renewal was verified with a Villin-CreERT2 mouse model. The epithelium degeneration was associated with a rapid loss of the proliferative capability of the crypt progenitor cells in vivo, lack of crypt base columnar stem cell markers, and a failure of in vitro crypt organoid growth. RNA-Seq analysis of freshly isolated intestinal crypt cells showed that Bccip deletion caused an overwhelming down-regulation of genes involved in mitotic cell division but an up-regulation of genes involved in apoptosis and stress response to microbiomes. Our data not only indicate that intestinal epithelium is the most sensitive tissue to whole-body deletion of Bccip but also point to Bccip as a novel and critical factor for the proliferation of the intestinal progenitors. These findings have significant implications for understanding why a hypomorphic loss of BCCIP functions is more relevant to tumorigenesis.

BCCIP is required for nucleolar recruitment of eIF6 and 12S pre-rRNA production during 60S ribosome biogenesis.

Ribosome biogenesis is a fundamental process required for cell proliferation. Although evolutionally conserved, the mammalian ribosome assembly system is more complex than in yeasts. BCCIP was originally identified as a BRCA2 and p21 interacting protein. A partial loss of BCCIP function was sufficient to trigger genomic instability and tumorigenesis. However, a complete deletion of BCCIP arrested cell growth and was lethal in mice. Here, we report that a fraction of mammalian BCCIP localizes in the nucleolus and regulates 60S ribosome biogenesis. Both abrogation of BCCIP nucleolar localization and impaired BCCIP-eIF6 interaction can compromise eIF6 recruitment to the nucleolus and 60S ribosome biogenesis. BCCIP is vital for a pre-rRNA processing step that produces 12S pre-rRNA, a precursor to the 5.8S rRNA. However, a heterozygous Bccip loss was insufficient to impair 60S biogenesis in mouse embryo fibroblasts, but a profound reduction of BCCIP was required to abrogate its function in 60S biogenesis. These results suggest that BCCIP is a critical factor for mammalian pre-rRNA processing and 60S generation and offer an explanation as to why a subtle dysfunction of BCCIP can be tumorigenic but a complete depletion of BCCIP is lethal.

Parkin ubiquitinates phosphoglycerate dehydrogenase to suppress serine synthesis and tumor progression.

Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson's disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer.

Deletion of Mouse Setd4 Promotes the Recovery of Hematopoietic Failure.

PURPOSE: Acquired hematopoietic failure is commonly caused by therapeutic and accidental exposure of the bone marrow (BM) to toxic agents. Efficient recovery from BM failure is dictated not only by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells but also by the BM environment niche. Identification of genetic factors that improve recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized and putatively nonhistone methyltransferase. This study aims to identify the roles of SETD4 in BM recovery. METHODS AND MATERIALS: An inducible SETD4 knockout mouse model (Setd4flox/flox;Rosa26-CreERT2+) was used. Adult sex-matched littermates were treated with tamoxifen to induce Setd4 deletion or oil as the control. Tamoxifen-treated Setd4wt/wt;Rosa26-CreERT2+ mice were included as another control. Those mice were irradiated to induce hematopoietic syndrome and analyzed to identify the roles and mechanisms of Setd4 in of BM recovery. RESULTS: Loss of Setd4 in adult mice improved the survival of whole-body irradiation-induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSCs) and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to radiation resistance of the Setd4-deficient HSCs but that Setd4-deficient HSCs were actually more sensitive to radiation. However, the Setd4-deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was enhanced splenic erythropoiesis in Setd4-deficient mice. CONCLUSION: These findings not only revealed a previously unrecognized role of Setd4 as a unique modulator of hematopoiesis but also underscored the critical role of the BM niche in recovery from hematopoietic failure. Our study also implicated Setd4 as a potential target for therapeutic inhibition to improve the conditioning of the BM niche before allogeneic transplantation.

Spontaneous Development of Hepatocellular Carcinoma and B-Cell Lymphoma in Mosaic and Heterozygous Brca2 and Cdkn1a Interacting Protein Knockout Mice.

Hepatocellular carcinoma (HCC) is the most common form of liver tumors. Although HCC is associated with chronic viral infections, alcoholic cirrhosis, and nonalcoholic fatty liver disease, genetic factors that contribute to the HCC risk remain unknown. The BRCA2 DNA repair associated (BRCA2) and cyclin-dependent kinase inhibitor 1A (CDKN1A) interacting protein, known as BCCIP, are essential for cell viability and maintenance of genomic stability. In this study, we established a new genetically engineered mouse model with Bccip deficiency. Mosaic or heterozygous Bccip deletion conferred an increased risk of spontaneous liver tumorigenesis and B-cell lymphoma development at old age. These abnormalities are accompanied with chronic inflammation, histologic features of nonalcoholic steatohepatitis, keratin and ubiquitin aggregates within cytoplasmic Mallory-Denk bodies, and changes of the intracellular distribution of high-mobility group box 1 protein. Our study suggests BCCIP dysregulation as a risk factor for HCC and offers a novel mouse model for future investigations of nonviral or nonalcoholic causes of HCC development.