The senescence-associated secretory phenotype and its physiological and pathological implications.

Cellular senescence is a state of terminal growth arrest associated with the upregulation of different cell cycle inhibitors, mainly p16 and p21, structural and metabolic alterations, chronic DNA damage responses, and a hypersecretory state known as the senescence-associated secretory phenotype (SASP). The SASP is the major mediator of the paracrine effects of senescent cells in their tissue microenvironment and of various local and systemic biological functions. In this Review, we discuss the composition, dynamics and heterogeneity of the SASP as well as the mechanisms underlying its induction and regulation. We describe the various biological properties of the SASP, its beneficial and detrimental effects in different physiological and pathological settings, and its impact on overall health span. Finally, we discuss the use of the SASP as a biomarker and of SASP inhibitors as senomorphic interventions to treat cancer and other age-related conditions.

Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression.

Cellular senescence is a state of stable proliferative arrest triggered by damaging signals. Senescent cells persist during aging and promote age-related pathologies via the pro-inflammatory senescence-associated secretory phenotype (SASP), whose regulation depends on environmental factors. In vivo, a major environmental variable is oxygenation, which varies among and within tissues. Here, we demonstrate that senescent cells express lower levels of detrimental pro-inflammatory SASP factors in physiologically hypoxic environments, as measured in culture and in tissues. Mechanistically, exposure of senescent cells to low-oxygen conditions leads to AMPK activation and AMPK-mediated suppression of the mTOR-NF-κB signaling loop. Finally, we demonstrate that treatment with hypoxia-mimetic compounds reduces SASP in cells and tissues and improves strength in chemotherapy-treated and aged mice. Our findings highlight the importance of oxygen as a determinant for pro-inflammatory SASP expression and offer a potential new strategy to reduce detrimental paracrine effects of senescent cells.

Pharmacological CDK4/6 inhibition reveals a p53-dependent senescent state with restricted toxicity.

Cellular senescence is a state of stable growth arrest and a desired outcome of tumor suppressive interventions. Treatment with many anti-cancer drugs can cause premature senescence of non-malignant cells. These therapy-induced senescent cells can have pro-tumorigenic and pro-disease functions via activation of an inflammatory secretory phenotype (SASP). Inhibitors of cyclin-dependent kinases 4/6 (CDK4/6i) have recently proven to restrain tumor growth by activating a senescence-like program in cancer cells. However, the physiological consequence of exposing the whole organism to pharmacological CDK4/6i remains poorly characterized. Here, we show that exposure to CDK4/6i induces non-malignant cells to enter a premature state of senescence dependent on p53. We observe in mice and breast cancer patients that the CDK4/6i-induced senescent program activates only a partial SASP enriched in p53 targets but lacking pro-inflammatory and NF-κB-driven components. We find that CDK4/6i-induced senescent cells do not acquire pro-tumorigenic and detrimental properties but retain the ability to promote paracrine senescence and undergo clearance. Our results demonstrate that SASP composition is exquisitely stress-dependent and a predictor for the biological functions of different senescence subsets.

Sufu- and Spop-mediated regulation of Gli2 is essential for the control of mammalian cochlear hair cell differentiation.

Development of mammalian auditory epithelium, the organ of Corti, requires precise control of both cell cycle withdrawal and differentiation. Sensory progenitors (prosensory cells) in the cochlear apex exit the cell cycle first but differentiate last. Sonic hedgehog (Shh) signaling is required for the spatiotemporal regulation of prosensory cell differentiation, but the underlying mechanisms remain unclear. Here, we show that suppressor of fused (Sufu), a negative regulator of Shh signaling, is essential for controlling the timing and progression of hair cell (HC) differentiation. Removal of Sufu leads to abnormal Atoh1 expression and a severe delay of HC differentiation due to elevated Gli2 mRNA expression. Later in development, HC differentiation defects are restored in the Sufu mutant by the action of speckle-type PDZ protein (Spop), which promotes Gli2 protein degradation. Deletion of both Sufu and Spop results in robust Gli2 activation, exacerbating HC differentiation defects. We further demonstrate that Gli2 inhibits HC differentiation through maintaining the progenitor state of Sox2+ prosensory cells. Along the basal-apical axis of the developing cochlea, the Sox2 expression level is higher in the progenitor cells than in differentiating cells and is down-regulated from base to apex as differentiation proceeds. The dynamic spatiotemporal change of Sox2 expression levels is controlled by Shh signaling through Gli2. Together, our results reveal key functions of Gli2 in sustaining the progenitor state, thereby preventing HC differentiation and in turn governing the basal-apical progression of HC differentiation in the cochlea.

ASIC1 promotes migration and invasion of hepatocellular carcinoma via the PRKACA/AP-1 signaling pathway.

Hepatocellular carcinoma (HCC) exhibits a high mortality rate due to its high invasion and metastatic nature, and the acidic microenvironment plays a pivotal role. Acid-sensing ion channel 1 (ASIC1) is upregulated in HCC tissues and facilitates tumor progression in a pH-dependent manner, while the specific mechanisms therein remain currently unclear. Herein, we aimed to investigate the underlying mechanisms by which ASIC1 contributes to the development of HCC. Using bioinformatics analysis, we found a significant association between ASIC1 expression and malignant transformation of HCC, such as poor prognosis, metastasis and recurrence. Specifically, ASIC1 enhanced the migration and invasion capabilities of Li-7 cells in the in vivo experiment using an HCC lung metastasis mouse model, as well as in the in vitro experiments such as wound healing assay and Transwell assay. Furthermore, our comprehensive gene chip and molecular biology experiments revealed that ASIC1 promoted HCC migration and invasion by activating the PRKACA/AP-1 signaling pathway. Our findings indicate that targeting ASIC1 could have therapeutic potential for inhibiting HCC progression.

Simplified analysis and suppression of polarization aberration in planar symmetric optical systems.

Polarized remote sensing imaging has attracted more attention in recent years due to its wider detection information dimension compared to traditional imaging methods. However, the inherent instrument errors in optical systems can lead to errors in the polarization state of the incident and outgoing light, which is the polarization aberration of the optical system, resulting in a decrease in polarization detection accuracy. We propose a polarization aberration simplification calculation method for planar symmetric optical systems, by what only three ray samples are needed to obtain the distribution of polarization aberrations within the pupil. This method has a calculation accuracy close to traditional methods, and the sampling rate is 0.003 times that of traditional methods. Based on this, we designed a merit function that optimizes both wavefront and polarization aberrations simultaneously. It is found that diattenuation and retardance of the optical system are 62% and 58% of the original, and the polarization crosstalk term is reduced by 37% when the polarization weight factor takes an appropriate value. And at the same time, the wavefront aberration has also been well optimized.

Sarcopenia and gut microbiota alterations in patients with hematological diseases before and after hematopoietic stem cell transplantation.

Objective: The aim of this study was to investigate the prevalence of sarcopenia (SP) and its relationship with gut microbiota alterations in patients with hematological diseases before and after hematopoietic stem cell transplantation (HSCT). Methods: A total of 108 patients with various hematological disorders were selected from Peking University People's Hospital. SP was screened and diagnosed based on the 2019 Asian Sarcopenia Diagnosis Strategy. Physical measurements and fecal samples were collected, and 16S rRNA gene sequencing was conducted. Alpha and beta diversity analyses were performed to evaluate gut microbiota composition and diversity. Results: After HSCT, significant decreases in calf circumference and body mass index (BMI) were observed, accompanied by a decline in physical function. Gut microbiota analyses revealed significant differences in the relative abundance of Enterococcus, Bacteroides, Blautia and Dorea species before and after HSCT (P<0.05). Before HSCT, sarcopenic patients had lower Dorea levels and higher Phascolarctobacterium levels than non-sarcopenia patients (P<0.01). After HSCT, no significant differences in species abundance were observed. Alpha diversity analysis showed significant differences in species diversity among the groups, with the highest diversity in the post-HSCT 90-day group and the lowest in the post-HSCT 30-day group. Beta diversity analysis revealed significant differences in species composition between pre- and post-HSCT time points but not between SP groups. Linear discriminant analysis effect size (LEfSe) identified Alistipes, Rikenellaceae, Alistipes putredinis, Prevotellaceae defectiva and Blautia coccoides as biomarkers for the pre-HSCT sarcopenia group. Functional predictions showed significant differences in anaerobic, biofilm-forming and oxidative stress-tolerant functions among the groups (P<0.05). Conclusions: This study demonstrated a significant decline in physical function after HSCT and identified potential gut microbiota biomarkers and functional alterations associated with SP in patients with hematological disorders. Further research is needed to explore the underlying mechanisms and potential therapeutic targets.

Targeting POH1 inhibits prostate cancer cell growth and enhances the suppressive efficacy of androgen deprivation and docetaxel.

BACKGROUND: POH1, a member of the JAMM domain containing deubiquitinases, functions in malignant progression of certain types of cancer. However, the role of POH1 in prostate cancer (PCa) remains unclear. METHODS: We performed RNA interference against the JAMM members in PC3 cells and analyzed cell proliferation. POH1 knockdown was established to evaluate the effects of POH1 on cell growth in vitro and in vivo. RNA-sequencing was utilized to explore the molecular details underlying the biological function of POH1 in PCa. The expression of POH1 in PCa tissues was detected by immunohistochemistry. The POH1 inhibitor capzimin was evaluated to explore whether pharmacologically inhibiting POH1 significantly affected PCa cell proliferation alone or enhanced the inhibitory efficacy of docetaxel and androgen deprivation. RESULTS: Functional analyses identified POH1 as a JAMM deubiquitinase that is required for PCa proliferation. Importantly, expression of POH1 was higher in human PCa tissues (PCas) than that in normal prostate tissues, and a positive correlation was detected between elevated POH1 expression and higher pathological grades in PCas. In vivo experiments further demonstrated that depleting POH1 significantly suppressed the growth of PCa cell xenografts. POH1 deficiency profoundly inhibited the expression of a set of genes involving the cell cycle and caused G0/G1 phase arrest. Furthermore, the POH1 inhibitor capzimin phenotypically recapitulated the effects of POH1 knockdown and improved the efficacy of docetaxel and androgen deprivation in PCa cells. CONCLUSIONS: POH1 was overexpressed in PCas and was correlated with pathological grades in human PCas. Inhibiting POH1 by gene silencing or pharmacological inhibition with capzimin suppressed PCa cell growth. Exploring the inhibition of POH1 in combination with other drugs may provide a strategy to benefit patients with PCa.

Endothelial progenitor cell-derived exosomes facilitate vascular endothelial cell repair through shuttling miR-21-5p to modulate Thrombospondin-1 expression.

Background: Our previous studies observed that administration of exosomes from endothelial progenitor cells (EPC) facilitated vascular repair in the rat model of balloon injury. However, the molecular events underlying this process remain elusive. Here, we aim to interrogate the key miRNAs within EPC-derived exosomes (EPC-exosomes) responsible for the activation of endothelial cell (EC) repair. Methods: The efficacy of EPC-exosomes in re-endothelialization was examined by Evans Blue dye and histological examination in the rat model of balloon-induced carotid artery injury. The effects of EPC-exosomes on human vascular EC (HUVEC) were also studied by evaluating the effects on growth, migratory and tube formation. To dissect the underlying mechanism, RNA-sequencing assays were performed to determine miRNA abundance in exosomes and mRNA profiles in exosome-treated HUVECs. Meanwhile, in vitro loss of function assays identified an exosomal miRNA and its target gene in EC, which engaged in EPC-exosomes-induced EC repair. Results: Administration of EPC-exosomes potentiated re-endothelialization in the early phase after endothelial damage in the rat carotid artery. The uptake of exogenous EPC-exosomes intensified HUVEC in proliferation rate, migration and tube-forming ability. Integrative analyses of miRNA-mRNA interactions revealed that miR-21-5p was highly enriched in EPC-exosomes and specifically suppressed the expression of an angiogenesis inhibitor Thrombospondin-1 (THBS1) in the recipient EC. The following functional studies demonstrated a fundamental role of miR-21-5p in the pro-angiogenic activities of EPC-exosomes. Conclusions: The present work highlights a critical event for the regulation of EC behavior by EPC-exosomes, which EPC-exosomes may deliver miR-21-5p and inhibit THBS1 expression to promote EC repair.

Rare mutations of ADAM17 from TOFs induce hypertrophy in human embryonic stem cell-derived cardiomyocytes via HB-EGF signaling.

Tetralogy of Fallot (TOF) is the most common cyanotic form of congenital heart defects (CHDs). The right ventricular hypertrophy is associated with the survival rate of patients with repaired TOF. However, very little is known concerning its genetic etiology. Based on mouse model studies, a disintergrin and metalloprotease 10/17 (ADAM10 and ADAM17) are the key enzymes for the NOTCH and ErbB pathways, which are critical pathways for heart development. Mutations in these two genes have not been previously reported in human TOF patients. In this study, we sequenced ADAM10 and ADAM17 in a Han Chinese CHD cohort comprised of 80 TOF patients, 286 other CHD patients, and 480 matched healthy controls. Three missense variants of ADAM17 were only identified in 80 TOF patients, two of which (Y42D and L659P) are novel and not found in the Exome Aggregation Consortium (ExAC) database. Point mutation knock-in (KI) and ADAM17 knock-out (KO) human embryonic stem cells (hESCs) were generated by CRISPR/Cas9 and programmed to differentiate into cardiomyocytes (CMs). Y42D or L659P KI cells or complete KO cells all developed hypertrophy with disorganized sarcomeres. RNA-seq results showed that phosphatidylinositide 3-kinases/protein kinase B (PI3K/Akt), which is downstream of epidermal growth factor receptor (EGFR) signaling, was affected in both ADAM17 KO and KI hESC-CMs. In vitro experiments showed that these two mutations are loss-of-function mutations in shedding heparin-binding EGF-like growth factor (HB-EGF) but not NOTCH signaling. Our results revealed that CM hypertrophy in TOF could be the result of mutations in ADAM17 which affects HB-EGF/ErbB signaling.

Population Genomics Reveals Low Genetic Diversity and Adaptation to Hypoxia in Snub-Nosed Monkeys.

Snub-nosed monkeys (genus Rhinopithecus) are a group of endangered colobines endemic to South Asia. Here, we re-sequenced the whole genomes of 38 snub-nosed monkeys representing four species within this genus. By conducting population genomic analyses, we observed a similar load of deleterious variation in snub-nosed monkeys living in both smaller and larger populations and found that genomic diversity was lower than that reported in other primates. Reconstruction of Rhinopithecus evolutionary history suggested that episodes of climatic variation over the past 2 million years, associated with glacial advances and retreats and population isolation, have shaped snub-nosed monkey demography and evolution. We further identified several hypoxia-related genes under selection in R. bieti (black snub-nosed monkey), a species that exploits habitats higher than any other nonhuman primate. These results provide the first detailed and comprehensive genomic insights into genetic diversity, demography, genetic burden, and adaptation in this radiation of endangered primates.

Comprehensive evaluation of nutritional status before and after hematopoietic stem cell transplantation in 170 patients with hematological diseases.

OBJECTIVE: To investigate the nutritional status of patients before and after hematopoietic stem cell transplantation (HSCT), and explore optimal methods for assessing nutritional status in patients with hematological diseases. METHODS: This cohort study enrolled 170 patients who were diagnosed with hematological diseases and underwent allogeneic HSCT in the Department of Hematology, Peking University People's Hospital between May 2011 and April 2013. We used fixed-point continuous sampling and four nutritional screening tools, Nutritional Risk Screening 2002 (NRS-2002), Mini Nutritional Assessment (MNA), Subjective Global Assessment (SGA) and Malnutrition Universal Screening Tools (MUST), in combination with body measurements, to extensively screen and evaluate nutritional risks and status in patients receiving HSCT before entering and after leaving laminar air flow rooms. RESULTS: After HSCT, patients had significant reduction in weight, hip circumference, waist-hip ratio, calf circumference, mid-upper arm circumference, and suprailiac skinfold thickness compared with pre-HSCT measurements. Before HSCT, NRS-2002 identified that 21.2% of patients were at nutritional risks, compared with 100% after HSCT. MUST indicated that before HSCT, 11.77% of patients were at high nutritional risk, compared with 59.63% after HSCT. MNA assessed that 0.06% of patients were malnourished before HSCT, compared with 19.27% after HSCT. SGA identified that before HSCT, 1.76% of patients had mild to severe malnutrition, which increased to 83.3% after HSCT. There is a significant increase in the nutritional risk and malnutrition in patients who received HSCT. CONCLUSIONS: Before HSCT, some patients already had nutritional risk or nutritional deficiencies, and prompt and close nutritional screening or assessment should be performed. The nutritional status of patients after HSCT was generally deteriorated compared with that before transplantation. Body measurements should be taken more frequently during the subsequent treatment window in the laminar air flow rooms. After HSCT, it is recommended to combine MNA and SGA to fully evaluate the nutritional status, and thus provide timely and reasonable nutritional support.

Implications of genetics and current protected areas for conservation of 5 endangered primates in China.

Most of China's 24-28 primate species are threatened with extinction. Habitat reduction and fragmentation are perhaps the greatest threats. We used published data from a conservation genetics study of 5 endangered primates in China (Rhinopithecus roxellana, R. bieti, R. brelichi, Trachypithecus francoisi, and T. leucocephalus); distribution data on these species; and the distribution, area, and location of protected areas to inform conservation strategies for these primates. All 5 species were separated into subpopulations with unique genetic components. Gene flow appeared to be strongly impeded by agricultural land, meadows used for grazing, highways, and humans dwellings. Most species declined severely or diverged concurrently as human population and crop land cover increased. Nature reserves were not evenly distributed across subpopulations with unique genetic backgrounds. Certain small subpopulations were severely fragmented and had higher extinction risk than others. Primate mobility is limited and their genetic structure is strong and susceptible to substantial loss of diversity due to local extinction. Thus, to maximize preservation of genetic diversity in all these primate species, our results suggest protection is required for all sub-populations. Key priorities for their conservation include maintaining R. roxellana in Shennongjia national reserve, subpopulations S4 and S5 of R. bieti and of R. brelichi in Fanjingshan national reserve, subpopulation CGX of T. francoisi in central Guangxi Province, and all 3 T. leucocephalus sub-populations in central Guangxi Province.

Full-length Numt analysis provides evidence for hybridization between the Asian colobine genera Trachypithecus and Semnopithecus.

The phylogenetic position of the genus Semnopithecusis unresolved because of topological incongruence when inferred using different molecular markers. Although some studies proposed hybridization between the genera Semnopithecus and Trachypithecus to explain the discordance, no conclusive evidence for hybridization has been identified. To address this issue, we used DNA walking and long-range PCR to describe a nuclear mitochondrial DNA (Numt) segment present in Trachypithecus pileatus which extends over more than 15 kb, and represents approximately 92% of the entire mitochondrial genome. We assessed the presence of this Numt in 16 other colobine species, including four species of the genus Trachypithecus, six species of the genus Semnopithecus, and representative species of six other genera belonging to the subfamily Colobinae. We failed to detect a Numt sequence in any of the other colobine species except for T. shortridgei, which is closely related to T. pileatus. The sister relationship of this Numt within the genus Semnopithecus suggests that it was derived from the mt genome of the genus Semnopithecus and invaded the nuclear genome of T. pileatus by unidirectional introgression hybridization. These results offer the most conclusive evidence for the existence of hybridization between Semnopithecus and Trachypithecus.

Inhibition of atypical protein kinase Cι induces apoptosis through autophagic degradation of ß-catenin in esophageal cancer cells.

Atypical protein kinase Cι (PKCι) has been identified as an oncoprotein in esophageal squamous cell carcinomas. However, the mechanisms underlying the role of PKCι in this disease remain unclear. In the present work, we found that inhibition of PKCι expression by RNAi induced apoptosis via the down-regulation of ß-catenin in esophageal cancer cells. Furthermore, we found that PKCι regulated ß-catenin in an autophagy dependent way. Since down-regulation of ß-catenin induced by knockdown of PKCι could be rescued by autophagy inhibition; knockdown of PKCι activated autophagy and promoted the recruitment of ß-catenin into autophagosome. These results suggested that PKCι positively regulated ß-catenin through negatively regulated autophagy and depletion of PKCι promoted apoptosis via autophagic degradation of ß-catenin in esophageal cancer cells. These data provide new insights into PKCι signaling in human cancer.

Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma.

Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates liver cancer cell proliferation. Mechanistically, liver-TEs are predominantly occupied by the histone demethylase, KDM1A. KDM1A negatively influences the methylation of histone H3 Lys4 (H3K4) of liver-TEs, resulting in the epigenetic silencing of HNF4A expression. The suppression of HNF4A mediated by KDM1A promotes liver cancer cell proliferation. In conclusion, this study uncovers a liver-TE/KDM1A/HNF4A regulatory axis that promotes liver cancer growth and highlights KDM1A as a promising therapeutic target. Our findings provide insight into the transposable element-related molecular mechanisms underlying liver cancer progression.

Myeloid TGF-ß signaling contributes to colitis-associated tumorigenesis in mice.

Myeloid cells have a critical role in maintaining intestinal homeostasis and regulating the development of inflammatory bowel disease and colitis-associated cancer (CAC). However, the signaling pathways that control the function of colonic myeloid cells in these pathological processes are still poorly defined. In this study, we demonstrate that transforming growth factor-ß (TGF-ß) signaling in colonic myeloid cells is significantly involved in the development of CAC. Myeloid TGF-ß receptor II (Tgfbr2)-deficient mice showed reduced susceptibility to chemically induced colitis-associated tumorigenesis, as evidenced by decreases in number and size of tumors. Myeloid Tgfbr2 deficiency markedly decreased the production of interleukin-6 and tumor necrosis factor-α, two proinflammatory cytokines that are essential for colonic tumorigenesis; in addition, a marked increase in the proportions of Foxp3+CD4+ regulatory T cells was observed in the colonic lamina propria in the initial stage of CAC. Loss of myeloid Tgfbr2 was associated with a decrease in the presence of F4/80 positive macrophages and a downregulation of phosphorylated STAT3, proliferative cell nuclear antigen and cyclin D1 expression in colonic adenoma tissues. TGF-ß enhanced macrophage recruitment, at least in part, through modulating the expression of the chemokine (C-C motif) receptor 2 (CCR2) ligands in tumor environment and the CCR2 signaling in macrophages. Collectively, these results suggest that myeloid TGF-ß signaling modulates intestinal inflammation and significantly promotes tumorigenesis in the development of colitis-associated colon cancer.

Autophagy negatively regulates cancer cell proliferation via selectively targeting VPRBP.

There have been multiple lines of evidence suggesting that autophagy selectively targets signalling proteins and regulates cancer cell signalling in addition to bulk clearance of long-lived proteins and organelles. Protein degradation through autophagy requires receptor protein LC3B to sequester the substrates into the autophagosome. In the present study, we screened LC3B (light-chain 3B)-binding partners and identified autophagic substrates in cancer cells. With lung cancer NCI-H1975 and oesophageal cancer KYSE30 cell lines as models, we found that VPRBP (viral protein R-binding protein) was a novel LC3B-binding protein through GST (glutathione transferase)-LC3B pull-down combined with LC-MS/MS (liquid chromatography-tandem MS) methods. Co-immunoprecipitation assay showed that VPRBP-LC3/p62 were in the same protein complex as the two cell lines. Induction of autophagy led to a down-regulation of VPRPB, which could be rescued by the inhibition of autophagy degradation by BFA1 (bafilomycin A1) and by the disruption of autophagy through ATG5-knockdown. We also found that induction of autophagy promotes VPRBP-LC3/p62 interaction. Immunohistochemical examination of human NSCLC (non-small cell lung cancer) tissues showed that VPRBP was positively correlated with p62 and negatively correlated with LC3B. Moreover, p62 and VPRBP were associated with poor prognosis in lung ADC (adenocarcinoma) (p62, P=0.019; VPRBP, P=0.005). Patients with low expression of both p62 and VPRBP showed the best prognosis.

Nutritional assessment with different tools in leukemia patients after hematopoietic stem cell transplantation.

OBJECTIVE: Correct nutritional assessment is essential for leukemia patients after hematopoietic stem cell transplantation (HSCT). This study aimed to investigate the best nutritional assessment method for leukemia patients after HSCT, and find the possible nutritional risk of the patients during the transplantation process in order to intervene in the patients with nutritional risks and undernourished patients timely, so that the entire transplantation process could be successfully completed. METHODS: A prospective study was performed in 108 leukemia patients after HSCT, and different nutritional assessment methods, including nutritional risk screening 2002 (NRS2002), mini nutritional assessment (MNA), subjective globe assessment (SGA) and malnutritional universal screening tools (MUST), were used. The associations between nutritional status of these patients and nutritional assessment methods were analyzed. RESULTS: A total of 108 patients completed SGA, and 99 patients completed NRS2002, MNA and MUST. During the treatment process, 85.2% of the patients lost weight, wherein, 50% lost weight greater than 5%, and 42.6% had significantly reduced food intake. For nutritional risk assessment, the positive rates of NRS2002, MNA and MUST were 100%, 74.7% and 63.6%, respectively. There was a significant difference (P<0.05) among the positive rates of NRS2002, MNA and MUST. In undernutrition assessment, the positive rate of SGA (83.3%) was significantly higher than that of MNA (17.2%) (P<0.05), and the incidence rate of nutritional risk among leukemia patients ≤30 years old was greater than that of patients >30 years old (P<0.05). CONCLUSIONS: Patients with leukemia were in poor nutritional status during and after HSCT. The leukemia patients ≤30 years old had a greater incidence rate of nutritional risk. As nutritional risk screening tool, the specificity of NRS2002 is not high, but it can be used for evaluating nutritional deficiencies. MNA is a good nutritional risk screening tool, but not an adequate tool for nutritional assessment. If assessment of undernutrition is necessary, the combination of all these screening tools and clinical laboratory indicators should be applied to improve accuracy.

POH1 facilitates pancreatic carcinogenesis through MYC-driven acinar-to-ductal metaplasia and is a potential therapeutic target.

Pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), a necessary process for pancreatic ductal adenocarcinoma (PDAC) initiation. However, the regulatory role of POH1, a deubiquitinase linked to several types of cancer, in ADM and PDAC is unclear. In this study, we investigated the role of POH1 in ADM and PDAC using murine models. Our findings suggest that pancreatic-specific deletion of Poh1 alleles attenuates ADM and impairs pancreatic carcinogenesis, improving murine survival. Mechanistically, POH1 deubiquitinates and stabilizes the MYC protein, which potentiates ADM and PDAC. Furthermore, POH1 is highly expressed in PDAC samples, and clinical evidence establishes a positive correlation between aberrantly expressed POH1 and poor prognosis in PDAC patients. Targeting POH1 with a specific small-molecule inhibitor significantly reduces pancreatic tumor formation, highlighting POH1 as a promising therapeutic target for PDAC treatment. Overall, POH1-mediated MYC deubiquitination is crucial for ADM and PDAC onset, and targeting POH1 could be an effective strategy for PDAC treatment, offering new avenues for PDAC targeted therapy.