Low-intensity ultrasound activates transmembrane chloride flow through CFTR.

Ultrasound has been demonstrated to activate mechanosensitive channels, which is considered the main mechanism of ultrasound neuromodulation. Currently, all channels that have been shown to be sensitive to ultrasound are cation channels. In addition to cation channels, anion channels also play indispensable roles in neural function. However, there have been no research on ultrasound regulation of anion channels until now. If anion channels can be activated by ultrasound as well, they will inevitably lead to more versatility in ultrasound neuromodulation. Cystic fibrosis transmembrane transduction regulator (CFTR) has been demonstrated to be a mechanically sensitive channel, mediating anionic transmembrane flow. To identify that CFTR is sensitive to ultrasound, CFTR was exogenously expressed in HEK293T cells and was stimulated by low intensity ultrasound. Outward currents in CFTR-expressed HEK293T cells were observed by using whole-cell patch clamp when ultrasound (0.8 MHz, 0.20 MPa) was delivered to these cells. These currents were abolished when the CFTR inhibitor (GlyH101) was applied to the solution or chloride ions was cleared from the solution. Meanwhile, the amplitude of these currents increased when the CFTR agonist (Forskolin) was applied. These results suggest that ultrasound stimuli can activate the CFTR to mediate transmembrane flowing of chloride ions at the single cell level. These findings may expand the application of ultrasound in the neuromodulation field.

A Novel Retrograde AAV Variant for Functional Manipulation of Cortical Projection Neurons in Mice and Monkeys.

Retrograde adeno-associated viruses (AAVs) are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks. However, few retrograde AAV capsids have been shown to offer access to cortical projection neurons across different species and enable the manipulation of neural function in non-human primates (NHPs). Here, we report the development of a novel retrograde AAV capsid, AAV-DJ8R, which efficiently labeled cortical projection neurons after local administration into the striatum of mice and macaques. In addition, intrastriatally injected AAV-DJ8R mediated opsin expression in the mouse motor cortex and induced robust behavioral alterations. Moreover, AAV-DJ8R markedly increased motor cortical neuron firing upon optogenetic light stimulation after viral delivery into the macaque putamen. These data demonstrate the usefulness of AAV-DJ8R as an efficient retrograde tracer for cortical projection neurons in rodents and NHPs and indicate its suitability for use in conducting functional interrogations.

Chinese expert consensus on the management of patients with hematologic malignancies infected with SARS-CoV-2.

In December 2022, the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became dominant in China due to its high infectivity and lower mortality rate. The risk of critical illness and mortality among patients with hematologic malignancies who contracted SARS-CoV-2 was particularly high. The aim of this study was to draft a consensus to facilitate effective treatments for these patients based on the type and severity of the disease. Following the outbreak of the novel coronavirus in China, a steering committee consisting of experienced hematologists was formed by the Specialized Committee of Oncology and Microecology of the Chinese Anti-Cancer Association. The expert group drafted a consensus on the management and intervention measures for different types of hematologic malignancies based on the clinical characteristics of the Omicron variant of the SARS-CoV-2 infection, along with relevant guidelines and literature. The expert group drafted independent recommendations on several important aspects based on the epidemiology of the Omicron variant in China and the unique vulnerability of patients with hematologic malignancies. These included prophylactic vaccinations for those with hematologic malignancies, the use of plasma from blood donors who recovered from the novel coronavirus infection, the establishment of negative pressure wards, the use of steady-state mobilization of peripheral blood hematopoietic stem cells, the provision of psychological support for patients and medical staff, and a focus on maintaining a healthy intestinal microecology.

Luminescent AgGaSe2/ZnSe nanocrystals: rapid synthesis, color tunability, aqueous phase transfer, and bio-labeling application.

The unique optoelectronic properties of I-III-VI2 nanocrystals (NCs) have attracted extensive attention. Herein, element Se in oleylamine reduced by alkythiol, which has been demonstrated to generate highly reactive alkylammonium selenide, was selected as the Se precursor by us to successfully synthesize high-quality tetragonal AgGaSe2 NCs via a facile colloidal method in just 2 minutes. Further, the photoluminescence (PL) properties of the as-synthesized AgGaSe2 NCs were systematically optimized through utilizing one Zn precursor to integrate shell coating and anionic/cationic alloying strategies into our reactive system, resulting in not only the obvious improvement of PL intensity but also tunable PL color from blue to red. Furthermore, the ligand exchange approach was adopted for the aqueous phase transfer of the oleophilic AgGaSe2/ZnSe NCs. Our data suggest that either metalated mercaptopropionic acid (Zn-MPA) short- or 11-mercaptoundecanoic acid long-chain ligand exchanged NCs all could maintain the original high crystallinity, present good water solubility, and retain up to nearly 95% and 70% of the initial PL intensity, respectively. Benefiting from the low cytotoxicity, the water-soluble AgGaSe2/ZnSe NCs can be applied as a fluorescent probe in cell imaging and signal labels for the fluoroimmunoassay of prostate-specific antigen, implying their potential in biological application.

USP11 plays a critical role in the onset and progression of acute graft-versus-host disease：Novel target for precision therapeutics.

Acute graft-versus-host disease (aGvHD) is considered a result of "cytokine storm." Targeted therapeutic interventions on cytokines via ubiquitination regulatory pathways may provide a potential approach for aGvHD treatment. Ubiquitin-specific peptidase 11 (USP11) has been reported to play key roles in a variety of physiopathological processes by regulating the stability and function of several vital protein molecules. However, its role in aGvHD remains unclear. In this study, we identified USP11 was associated with aGvHD in patients. In the aGvHD mouse model, the colon and liver were more seriously affected in recipient mice who received USP11 wt bone marrow (BM) cells and eased after the donor was treated with a USP11 inhibitor or received USP11 ko BM cells. In mouse models, IL-6 was identified as a major effecter in accelerating aGvHD induced by USP11. In the cell model, IL-6 mRNA transcript was affected by USP11. In addition, USP11 also inhibited IL-6 degradation by affecting IL-6 ubiquitination. Furthermore, the positive correlation between USP11 and IL-6 was confirmed in the GvHD patients' samples. Collectively, all results indicated that USP11 played a critical role in the onset and progression of aGvHD. USP11 might be a potential target for aGvHD treatment.

Fecal microbiota transplantation combined with ruxolitinib as a salvage treatment for intestinal steroid-refractory acute GVHD.

Acute graft-versus-host disease (aGVHD), especially intestinal aGVHD, is one of the most severe complications after allogeneic hematopoietic stem cell transplantation (HSCT). Fecal microbiota transplantation (FMT) has been applied to the treatment of intestinal steroid-refractory aGVHD (SR-aGVHD). Ruxolitinib is the first drug recommended for SR-aGVHD. Here, we reported the outcome data from 21 patients who had received the combined treatment of FMT with ruxolitinib as a salvage treatment in intestinal SR-aGVHD after HSCT. The overall response rate on day 28 was 71.4% (95% CI 50.4-92.5%), including 10 patients with complete responses. The durable overall response at day 56 in responders was 80%. GVHD relapse rate was 33.3% in responders. The levels of inflammatory cytokines as well as T cells and NK cells activation declined. The diversity of the intestinal microbiota was improved in responders. Viral reactivations and severe cytopenia were the major adverse events (61.9% and 81% respectively). The estimated 6-month overall survival was 57.1% (95% CI: 35.9-78.3%), while event-free survival was 52.4% (95% CI: 21.7%-64.1%). Collectively, FMT with ruxolitinib could be an effective treatment for intestinal SR-aGVHD after HSCT.Trial registration: ClinicalTrials.gov identifier: NCT03148743.

Pilot Study of Effects of Intermittent Pneumatic Compression in the Immediate Peri-Operative Period on Hemodynamic Parameters in Patients After Laparoscopic Gynecologic Surgery.

The randomized controlled study investigated the impacts of immediate peri-operative Intermittent pneumatic compression (IPC) on hemodynamic indicators in patients undergoing laparoscopic gynecologic surgery. Patients scheduled for elective laparoscopic gynecologic surgery were randomized to control (IPC not used), pre-operative IPC, post-operative IPC, and peri-operative IPC (performed both before and after surgery) groups. Systolic blood pressure (SBP), mean blood pressure (MBP) cardiac output (CO), heart rate (HR) and systemic vascular resistance (SVR) were measured at different time points. The results showed that SBP changes not obviously over time in the control and peri-operative IPC group. Compared with values before surgery, the pre-operative IPC group had a lower SBP (P < 0.01) at the end of PACU stay, whereas the post-operative IPC group had a higher SBP (P < 0.01) after surgery. All groups exhibited little or no variation in HR, CO and SVR. Conclusion is peri-operative IPC has no major adverse effects on hemodynamic parameters.

H22954, a long non-coding RNA, inhibits glucose uptake in leukemia cells in a GLUT10-dependent manner.

OBJECTIVES: To investigate the performance of H22954, a novel long non-coding RNA (lncRNA), in inhibiting glucose uptake in leukemia cells. METHODS: 18F-FDG uptake, RNA half-life quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase assays were performed to detect the glucose uptake in the condition of leukemia. Microarrays and qRT-PCR analyses were used to identify the related genes or proteins and elucidate the underlying these processes. RESULTS: H22954, a novel lncRNA, inhibited glucose uptake in leukemia cells. Using bioinformatics and microarray analyses, GLUT10 was identified as a possible target molecule of H22954. H22954 targeted the 3'untranslated region of GLUT10. In the luciferase assay, the luciferase activity of pGL3-GLUT10 was inhibited by H22954. Consistently, H22954 expression levels were inversely correlated with GLUT10 expression in cell lines and acute myeloid leukemia (AML) samples. Conversely, the degradation rate of GLUT10 mRNA was increased after H22954 overexpression. Moreover, glucose uptake was recovered when the GLUT10-interaction sites in H22954 were mutated. CONCLUSION: The lncRNA H22954 regulated GLUT10 expression to inhibit glucose uptake in leukemia cells. Our findings provide potentially valuable data for designing new targeted strategies based on H22954.

Risk factors associated with intraoperative shivering during caesarean section: a prospective nested case-control study.

BACKGROUND: To study the incidence and risk factors of shivering in pregnant women during cesarean section. METHODS: We performed a prospective nested case-control study involving parturients scheduled for cesarean sections between July 2018 and May 2021. The overall incidence of intraoperative shivering and its potential risk factors were investigated. The potential risk factors evaluated were pain, anxiety, emergency surgery, transfer from the delivery room, epidural labor analgesia, membrane rupture, labor, and the timing of the surgery. Shivering and body temperature at different time points during the cesarean section were also recorded. The selected seven time points were: entering the operating room, post-anesthesia, post-disinfection, post-delivery, post-oxytocin, post additional hysterotonics, and before leaving the operating room. RESULTS: We analyzed 212 cesarean section parturients. The overall incidence of shivering was 89 (42.0%). Multivariate logistic regression showed that anxiety, emergency delivery, and transfer from the delivery room to the operating room increased the overall shivering incidence (odds ratio = 1.77, 2.90, and 3.83, respectively). The peak shivering incidence occurred after skin disinfection (63, 29.7%), and the lowest body temperature occurred after oxytocin treatment (36.24 ± 0.30 °C). Stratified analysis of surgery origin showed that emergency delivery was a risk factor for shivering (odds ratio = 2.99) in women transferred from the obstetric ward to the operating room. CONCLUSION: Shivering occurred frequently during cesarean sections, with the peak incidence occurring after skin disinfection. Anxiety, emergency delivery, and transfer from the delivery room to the operating room increased the risk of shivering development during cesarean sections. TRIAL REGISTRATION: The study protocol was registered online at China Clinical Registration Center (registration number: ChiCTR-ROC-17010532, Registered on 29 January 2017).

lncRNA H22954 Inhibits Angiogenesis in Acute Myeloid Leukemia through a PDGFA-dependent Mechanism.

BACKGROUND: Angiogenesis is a hallmark of cancer, which is regulated by diverse factors, including long non-coding RNAs (lncRNAS). Our previous study showed that the long non-coding RNA H22954 inhibits tumor growth, albeit whether it is involved in the angiogenesis of cancer re-mains unknown. OBJECTIVES: This study aimed to investigate the role of lncRNA H22954 in angiogenesis of acute myeloid leukemia (AML) and the underlying molecular mechanism. METHODS: Bioinformatics analysis was conducted to screen the targeted molecule of H22954. Western blot and ELISA analysis detected PDGFA protein expression, and RT-qPCR detected H22954 and PDGFA expression in cell lines and AML samples. Dual-luciferase reporter gene assay and half-life assay were applied to validate the relationship between H22954 and PDGFA. The functional experi-ment was conducted to investigate the role of H22954 in tube formation. RESULTS: Overexpression of H22954 inhibited angiogenesis in mouse xenograft tumors and cultured acute myeloid leukemia (AML) cells. Bioinformatics analysis and luciferase assay revealed that H22954 targeted the 3' untranslated region (UTR) of the platelet-derived growth factor subunit A (PDGFA) gene. In transfected cells, H22954 overexpression reduced PDGFA expression and protein levels. Tube formation was rescued following the addition of exogenous human PDGFA to the con-ditioned medium from cells overexpressing H22954. The expression of H22954 in K562 cells re-duced the half-life of PDGFA mRNA. Furthermore, H22954 expression was inversely correlated with PDGFA expression in patient samples. CONCLUSION: These findings indicate that H22954 inhibits angiogenesis in AML through the down-regulation of PDGFA expression. Administering recombinant lncRNA H22954 may be a therapeutic approach for patients with AML.

CALCRL Gene is a Suitable Prognostic Factor in AML/ETO+ AML Patients.

Introduction: The t(8 ; 21) translocation is the most common chromosomal abnormality in human acute myeloid leukemia (AML) subtype 2 (M2), which forms the AML/ETO fusion gene. However, AML/ETO alone does not necessarily cause leukemia. Other factors are thought to contribute to the disease. Calcitonin receptor-like (CALCRL), a G-protein-coupled neuropeptide receptor, is involved in various biological processes, such as colony formation and drug resistance. Methods: First, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to determine any differences in CALCRL expression in AML patients with and without AML/ETO and the prognostic significance of CALCRL expression in AML patients was further evaluated. Next, we detected the CALCRL expression level in 67 AML/ETO+ AML patients and 16 patients with nonmalignant hematological diseases using qRT-PCR and identified its prognostic relevance. Results: Individuals in the group expressing low levels of CALCRL had a longer median survival time. In AML/ETO+ AML patients, higher mRNA levels of CALCRL were observed before treatment, which decreased after the complete remission that followed multiple chemotherapy sessions. Clinical features indicated that more patients in the CALCRLhigh group also had c-kit mutations compared with patients in other groups. Overall survival (OS) was longer in patients with lower levels of CALCRL expression, especially in patients with c-kit mutations or with more blast cells in bone marrow (BM). In addition, a longer OS was observed in the CALCRLlow group after hematopoietic stem cell transplantation (HSCT). Conclusions: This preliminary study indicates that CALCRL could serve as a suitable prognostic factor in AML/ETO+ AML patients.

Chinese expert consensus on intestinal microecology and management of digestive tract complications related to tumor treatment (version 2022).

The human gut microbiota represents a complex ecosystem that is composed of bacteria, fungi, viruses, and archaea. It affects many physiological functions including metabolism, inflammation, and the immune response. The gut microbiota also plays a role in preventing infection. Chemotherapy disrupts an organism's microbiome, increasing the risk of microbial invasive infection; therefore, restoring the gut microbiota composition is one potential strategy to reduce this risk. The gut microbiome can develop colonization resistance, in which pathogenic bacteria and other competing microorganisms are destroyed through attacks on bacterial cell walls by bacteriocins, antimicrobial peptides, and other proteins produced by symbiotic bacteria. There is also a direct way. For example, Escherichia coli colonized in the human body competes with pathogenic Escherichia coli 0157 for proline, which shows that symbiotic bacteria compete with pathogens for resources and niches, thus improving the host's ability to resist pathogenic bacteria. Increased attention has been given to the impact of microecological changes in the digestive tract on tumor treatment. After 2019, the global pandemic of novel coronavirus disease 2019 (COVID-19), the development of novel tumor-targeting drugs, immune checkpoint inhibitors, and the increased prevalence of antimicrobial resistance have posed serious challenges and threats to public health. Currently, it is becoming increasingly important to manage the adverse effects and complications after chemotherapy. Gastrointestinal reactions are a common clinical presentation in patients with solid and hematologic tumors after chemotherapy, which increases the treatment risks of patients and affects treatment efficacy and prognosis. Gastrointestinal symptoms after chemotherapy range from nausea, vomiting, and anorexia to severe oral and intestinal mucositis, abdominal pain, diarrhea, and constipation, which are often closely associated with the dose and toxicity of chemotherapeutic drugs. It is particularly important to profile the gastrointestinal microecological flora and monitor the impact of antibiotics in older patients, low immune function, neutropenia, and bone marrow suppression, especially in complex clinical situations involving special pathogenic microbial infections (such as clostridioides difficile, multidrug-resistant Escherichia coli, carbapenem-resistant bacteria, and norovirus).

MicroRNA-146a overexpression alleviates intestinal ischemia/reperfusion-induced acute lung injury in mice.

Previous studies have shown that microRNAs (miRs), such as miR-146a play an important role in the pathogenesis of intestinal ischemia/reperfusion (I/R)-induced injury; however, the role of miR-146a in intestinal I/R-induced acute lung injury has not been elucidated. An intestinal I/R-induced injury mouse model was established in the present study by clamping the superior mesenteric artery and expression levels of miR-146a in intestinal and lung tissue samples were evaluated using reverse transcription-quantitative PCR (RT-qPCR). Intestinal and lung histopathological characteristics in mice with intestinal I/R-induced injury were assessed by hematoxylin and eosin staining, and mRNA and protein expression levels in intestinal and lung tissue samples were evaluated using RT-qPCR and western blotting, respectively. miR-146a expression was significantly downregulated in the intestinal and lung tissue samples of mice with intestinal I/R-induced injury. Intestinal I/R injury-induced histopathological changes in the lung and intestines, and pulmonary edema in mice transduced with an adenoviral miR-146a-overexpression vector (the miR-146a overexpression group) were alleviated. mRNA expression levels of TNF-α, IL-1ß, IFN-γ and TGF-ß1, and protein expression levels of TNF receptor-associated factor 6, phosphorylated-p65 NF-κB, cleaved caspase-3 and cleaved caspase-9 in lung and intestinal tissue samples were downregulated in I/R-miR-146a-overexpressing mice, compared with those from the I/R-negative control group. Thus, the present study identified that pre-treatment with the miR-146a overexpression vector alleviated intestinal I/R-induced acute lung injury in mice.

Safety and Efficacy of Fecal Microbiota Transplantation for Grade IV Steroid Refractory GI-GvHD Patients: Interim Results From FMT2017002 Trial.

Gastrointestinal (GI) tract graft-versus-host disease (GvHD) is a major cause of post-allo-HSCT (hematopoietic stem cell transplantation) morbidity and mortality. Patients with steroid-refractory GI-GvHD have a poor prognosis and limited therapeutic options. FMT2017002 trial (#NCT03148743) was a non-randomized, open-label, phase I/II clinical study of FMT for treating patients with grade IV steroid-refractory GI-GvHD. A total of 55 patients with steroid-refractory GI-GvHD were enrolled in this study. Forty-one patients with grade IV steroid-refractory GI-GvHD were included in the final statistical analysis. Of them, 23 patients and 18 patients were assigned to the FMT group and the control group, respectively. On days 14 and 21 after FMT, clinical remission was significantly greater in the FMT group than in the control group. Within a follow-up period of 90 days, the FMT group showed a better overall survival (OS). At the end of the study, the median survival time was >539 days in the FMT group and 107 days in the control group (HR=3.51; 95% CI, 1.21-10.17; p=0.021). Both the event-free survival time (EFS) (HR=2.3, 95% CI, 0.99-5.4; p=0.08) and OS (HR=4.4, 95% CI, 1.5-13.04; p=0.008) were higher in the FMT group during the follow-up period. Overall, the mortality rate was lower in the FMT group (HR=3.97; 95% CI, 1.34-11.75; p=0.013). No differences in the occurrence of any other side effects were observed. Our data suggest that the diversity of the intestinal microbiota could be affected by allo-HSCT. Although its effectiveness and safety need further evaluation, FMT may serve as a therapeutic option for grade IV steroid-refractory GI-GvHD. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT03148743].

Low-Intensity Ultrasound Causes Direct Excitation of Auditory Cortical Neurons.

Cochlear implantation is the first-line treatment for severe and profound hearing loss in children and adults. However, deaf patients with cochlear malformations or with cochlear nerve deficiencies are ineligible for cochlear implants. Meanwhile, the limited spatial selectivity and high risk of invasive craniotomy restrict the wide application of auditory brainstem implants. A noninvasive alternative strategy for safe and effective neuronal stimulation is urgently needed to address this issue. Because of its advantage in neural modulation over electrical stimulation, low-intensity ultrasound (US) is considered a safe modality for eliciting neural activity in the central auditory system. Although the neural modulation ability of low-intensity US has been demonstrated in the human primary somatosensory cortex and primary visual cortex, whether low-intensity US can directly activate auditory cortical neurons is still a topic of debate. To clarify the direct effects on auditory neurons, in the present study, we employed low-intensity US to stimulate auditory cortical neurons in vitro. Our data show that both low-frequency (0.8 MHz) and high-frequency (>27 MHz) US stimulation can elicit the inward current and action potentials in cultured neurons. c-Fos staining results indicate that low-intensity US is efficient for stimulating most neurons. Our study suggests that low-intensity US can excite auditory cortical neurons directly, implying that US-induced neural modulation can be a potential approach for activating the auditory cortex of deaf patients.

CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity.

CFTR, a chloride channel and ion channel regulator studied mostly in epithelial cells, has been reported to participate in immune regulation and likely affect the risk of cancer development. However, little is known about the effects of CFTR on the differentiation and function of γδ T cells. In this study, we observed that CFTR was functionally expressed on the cell surface of γδ T cells. Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γ release by peripheral γδ T cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo. Interestingly, the molecular mechanisms underlying the regulation of γδ T cell IFN-γ production by CFTR were either TCR dependent or related to Ca2+ influx. CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling. In addition, CFTR was found to modulate TCR-induced Ca2+ influx and membrane potential (Vm)-induced Ca2+ influx and subsequently regulate the calcineurin-NFATc1 signaling pathway in γδ T cells. Thus, CFTR serves as a negative regulator of IFN-γ production in γδ T cells and the function of these cells in antitumor immunity. Our investigation suggests that modification of the CFTR activity of γδ T cells may be a potential immunotherapeutic strategy for cancer.

Pulsatilla saponin A Induces Apoptosis and Differentiation of Myeloma Cells.

OBJECTIVES: To investigate the performance of Pulsatilla saponin A (PsA) in Multiple Myeloma (MM) cells. METHODS: Proliferation, cell cycle analysis, apoptosis and TUNEL assays were conducted to detect the growth and apoptosis in MM cells. Western blotting was used to identify the change in the protein. RESULTS: In cell assays, PsA significantly inhibited the growth and apoptosis in MM cells. Cyclin B1, caspase-3, cleaved-caspase-3, PARP, cleaved-PARP, p-ERK increased, while Bcl-2 decreased after PSA treatment. The CD49e positive rate of U266 cells was increased after 96h PsA treatment. At the same time, immunoglobulin and the Free Light Chain (FLC) ratio in the culture supernatant obviously increased. Also, the differentiation induced by PsA was confirmed in the primary myeloma cells. CONCLUSION: Our findings reveal that PsA may exert its antitumor effect by causing G2 arrest and apoptosis in myeloma cells. And low-dose PsA can induce the differentiation of myeloma cell lines and primary myeloma cells, probably through the MEK/ERK signaling pathway in vitro.

[Analysis of Factors Influencing Overall Survival of MDS Patients Transplanted with HSCs].

OBJECTIVE: To analyze the effect of clinical features, routine laboratory examination and related gene mutation on the OS of patients with myelodysplastic syndrome (MDS) after hematopoietic stem cell transplantation (HSCT). METHODS: 121 patients diagnosed as MDS and underwent hematopoietic stem cell transplantation in the First Affiliated Hospital of Soochow University from October 2013 to August 2018 were selected. Basic information of the patients was collected, and blood cells, bone marrow blasts at initial diagnosis, chromosomal karyotypes and gene mutations of the patients were detected.The effect of different factors on overall survival (OS) was analyzed by statistical method. RESULTS: Kaplan-Meier univariate analysis shows that OS was significanly different among different age groups. The 3-year OS rate of patients aged 0-29 years was (83.3±7.7) %, the 3-year OS rate in patients aged 30-49 years was (58.1±7.7 %), and the 3-year OS rate of patients aged 50-69 years was (31.0±22.6) %, which was statistically different (P＜0.05) between different groups. There were also significant differences in OS among patients with different transplantation types. 3-year OS rate: HLA-matched sibling HSCT＞unrelated HLA-matched HSCT＞haploidentical HSCT＞micro HSCT. The OS rate of patients with bone marrow blasts≥10% seems lower than blasts＜10%, but there was no statistical difference.The 3-year OS rate of patients with chromosomal karyotype complex abnormality was (47.7±11.5) %, and that of patients without complex abnormality was (80±4.2) % which was statistical difference (P＜0.05). Patients with DNMT3A, NRAS, TP53 and GATA2 mutations had shorter OS time compared with patients without mutation of these genes, which shows statistically significant (P＜0.05). COX multivariate analysis showed that age, chromosome karyotype, DNMT3A, TET2, GATA2 and NRAS were the independent factors influencing OS of patients after HSCT, with statistically significant difference. CONCLUSION: age of patients, donor selection of HSCT, chromosome karyotype, DNMT3A, NRAS, TP53, GATA2 and TET2 gene mutations are all independent factors affecting the OS of patients after HSCT. Therefore, the assessment of the OS of MDS patients with transplantation requires comprehensive consideration.

H22954, a novel long non-coding RNA down-regulated in AML, inhibits cancer growth in a BCL-2-dependent mechanism.

Long non-coding RNAs (lncRNAs) are important in cancer biology. In this study, we analyzed differentially expressed genes in CD34 + hematopoietic cells and identified a novel lncRNA, H22954, which was down-regulated in acute myeloid leukemia (AML) patients. In cultured AML cells and mouse xenograft models, H22954 expression inhibited cell proliferation and tumor growth, respectively. Bioinformatic analysis and RNA antisense purification assay indicated that H22954 targeted the 3' untranslated region of the BCL2 gene. In luciferase assays, H22954 expression inhibited BCL2 expression. In transfected K562 cells and mouse xenograft tumors, H22954 overexpression reduced BCL-2 protein levels and promoted cell death. In AML patients, H22954 expression inversely correlated with BCL-2 protein levels in bone marrow cells, blast cell numbers and disease prognosis. These results indicate that H22954 is a novel regulator of BCL-2 and that reduced H22954 expression may play an important role in the pathogenesis of AML.

Ectopic expression of human airway trypsin-like protease 4 in acute myeloid leukemia promotes cancer cell invasion and tumor growth.

Transmembrane serine proteases have been implicated in the development and progression of solid and hematological cancers. Human airway trypsin-like protease 4 (HAT-L4) is a transmembrane serine protease expressed in epithelial cells and exocrine glands. In the skin, HAT-L4 is important for normal epidermal barrier function. Here, we report an unexpected finding of ectopic HAT-L4 expression in neutrophils and monocytes from acute myeloid leukemia (AML) patients. Such expression was not detected in bone marrow cells from normal individuals or patients with chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia. In AML patients who underwent chemotherapy, persistent HAT-L4 expression in bone marrow cells was associated with minimal residual disease and poor prognostic outcomes. In culture, silencing HAT-L4 expression in AML-derived THP-1 cells by short hairpin RNAs inhibited matrix metalloproteinase-2 activation and Matrigel invasion. In mouse xenograft models, inhibition of HAT-L4 expression reduced the proliferation and growth of THP-1 cell-derived tumors. Our results indicate that ectopic HAT-L4 expression is a pathological mechanism in AML and that HAT-L4 may be used as a cell surface marker for AML blast detection and targeting.