Disruption of the ERLIN-TM6SF2-APOB complex destabilizes APOB and contributes to non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excess lipid accumulation in the liver without significant consumption of alcohol. The transmembrane 6 superfamily member 2 (TM6SF2) E167K missense variant strongly associates with NAFLD in humans. The E167K mutation destabilizes TM6SF2, resulting in hepatic lipid accumulation and low serum lipid levels. However, the molecular mechanism by which TM6SF2 regulates lipid metabolism remains unclear. By using tandem affinity purification in combination with mass spectrometry, we found that apolipoprotein B (APOB), ER lipid raft protein (ERLIN) 1 and 2 were TM6SF2-interacting proteins. ERLINs and TM6SF2 mutually bound and stabilized each other. TM6SF2 bound and stabilized APOB via two luminal loops. ERLINs did not interact with APOB directly but still increased APOB stability through stabilizing TM6SF2. This APOB stabilization was hampered by the E167K mutation that reduced the protein expression of TM6SF2. In mice, knockout of Tm6sf2 and knockdown of Tm6sf2 or Erlins decreased hepatic APOB protein level, causing lipid accumulation in the liver and lowering lipid levels in the serum. We conclude that defective APOB stabilization, as a result of ERLINs or TM6SF2 deficiency or E167K mutation, is a key factor contributing to NAFLD.

Hard-disk pressure computations-a historic perspective.

We discuss pressure computations for the hard-disk model performed since 1953 and compare them to the results that we obtain with a powerful event-chain Monte Carlo and a massively parallel Metropolis algorithm. Like other simple models in the sciences, such as the Drosophila model of biology, the hard-disk model has needed monumental efforts to be understood. In particular, we argue that the difficulty of estimating the pressure has not been fully realized in the decades-long controversy over the hard-disk phase-transition scenario. We present the physics of the hard-disk model, the definition of the pressure and its unbiased estimators, several of which are new. We further treat different sampling algorithms and crucial criteria for bounding mixing times in the absence of analytical predictions. Our definite results for the pressure, for up to one million disks, may serve as benchmarks for future sampling algorithms. A synopsis of hard-disk pressure data as well as different versions of the sampling algorithms and pressure estimators are made available in an open-source repository.

Survival Cost and Diverse Molecular Mechanisms of Magnaporthe oryzae Isolate Resistance to Epoxiconazole.

Rice blast caused by Magnaporthe oryzae is one of the most destructive diseases on rice worldwide. Epoxiconazole is a 14α-demethylation inhibitor (DMI) with excellent control on rice blast; to date, no resistant isolates have been observed in the field. Four mutants resistant to epoxiconazole were generated from three parental isolates via fungicide adaptation. Resistance was stable after 10 weekly consecutive transfers on fungicide-free medium. Three parameters, including growth rate, sporulation in vitro, and aggressiveness, were significantly lower for mutants compared with their parental isolates, with the exception of the low-resistance isolate. Sporulation and aggressiveness were negatively correlated with effective concentration values for 50% inhibition of mycelial growth for parental isolates and mutants (P < 0.05). Cross-resistance was found between epoxiconazole and prochloraz (ρ = 0.863, P = 0.000) or difenoconazole (ρ = 0.861, P = 0.000). The resistance factor for mutants was positively correlated with the relative expression of MoCYP51A in epoxiconazole treatment (r = 0.977, P = 0.02). In addition, two putative amino acid substitutions in MoCYP51A were found in two resistant mutants: Y126F in the high-resistance mutant and I125L in the low-resistance mutant. Mutation Y126F reduced the affinity of MoCYP51A with epoxiconazole, whereas I125L was not in the binding pocket of epoxiconazole. No amino acid change or overexpression in MoCYP51B was found in any of the mutants studied. To our knowledge, this is the first study to report DMI resistance observed in M. oryzae. The survival cost of M. oryzae resistance to epoxiconazole might be the reason why DMI resistance has not yet emerged in field populations worldwide.

Quantitative Analysis of Thymus-Independent Donor-Derived T Cell Expansion in Transplant Patients.

Although thymus-independent donor-derived T cell expansion may determine the occurrence of graft-versus-host disease (GVHD) and relapse after transplantation, the characteristics and dynamics of the expansion process remain unclear. To address this issue, we monitored T cell receptor ß repertoire at day 0, day 28, and day 61 after transplantation in 30 patients with hematologic malignancies by next-generation sequencing. The clonality index showed an increasing clonality over time (P = .001). The top 200 clonotypes accounted for more than half of the total clonotypes (median frequency, 63.55%) at day 61, and there was a remarkable overlapping between the top 200 clonotypes of each repertoire and its former repertoire (>50%). A normalized index, called the T Cell Response Index (TCRI), was designed on the basis of rank-shift analysis to quantify antigen-driven expansion. The TCRI during the first month was not related to relapse or GVHD (P> .05), whereas the TCRI during the second month was related to relapse (P = .006). Recipients with a TCRI below 1.0 during the second month had a higher cumulative relapse rate (31.25% versus 0%, P = .0323) and had a lower 1-year survival rate (56.25% versus 78.57%, P = .281). The clonotypes with strong competitiveness in the second month in the nonrelapse group preferentially used TRBV2, TRBV12-3, TRBJ1-1 and TRBJ1-5 segments (P< .01). In conclusion, homeostatic expansion predominates in the first month due to nonspecific T cell proliferation, whereas antigen-driven expansion predominates in the second month and results in a graft-versus-tumor (GvT) effect. Moreover, TCRI could serve as a quantitative indicator of GvT against relapse within the first year. The difference in V and J segment usage reveals that T cells responsible for potent GvT effect are similar among patients.

Comparison on Reduction of VOCs Emissions from Radiata Pine (Pinus Radiata D. Don) between Sodium Bicarbonate and Ozone Treatments.

Volatile organic compounds (VOCs) in wood furniture are an important factor that affects indoor air quality. In this study, radiata pine (Pinus radiata D. Don) was treated with sodium bicarbonate and ozone aqueous solution to reduce the VOC contents without sacrificing mechanical properties. The VOCs of radiata pine were identified by gas chromatography-mass spectrometry (GC-MS), and the functional group changes of wood samples were characterized by Fourier-transform infrared spectroscopy (FTIR). The results showed that the main VOCs of radiata pine include alkenes, aldehydes, and esters. The sodium bicarbonate and ozone treatments almost eliminated the VOC contents of radiata pine. The two treatments mentioned above had little effect on compressive strength and surface color of radiata pine.

A simplified system for generating recombinant E3-deleted canine adenovirus-2.

Canine adenovirus type 2 (CAV-2) has been used extensively as a vector for studying gene therapy and vaccine applications. We describe a simple strategy for generating a replication-competent recombinant CAV-2 using a backbone vector and a shuttle vector. The backbone plasmid containing the full-length CAV-2 genome was constructed by homologous recombination in Escherichia coli strain BJ5183. The shuttle plasmid, which has a deletion of 1478 bp in the nonessential E3 viral genome region, was generated by subcloning a fusion fragment containing the flanking sequences of the CAV-2 E3 region and expression cassette sequences from pcDNA3.1(+) into modified pUC18. To determine system effectiveness, a gene for enhanced green fluorescent protein (EGFP) was inserted into the shuttle plasmid and cloned into the backbone plasmid using two unique NruI and SalI sites. Transfection of Madin-Darby canine kidney (MDCK) cells with the recombinant adenovirus genome containing the EGFP expression cassette resulted in infectious viral particles. This strategy provides a solid foundation for developing candidate vaccines using CAV-2 as a delivery vector.

Production of a new type of cemented paste backfill with solid waste from carbide slag, soda residue, and red mud: mechanism, optimization, and its environmental effects.

To solve the disposal problems of carbide slag (CS), soda residue (SR), and red mud (RM) solid wastes, a new type of cemented paste backfill (CPB) was prepared with CS, SR, and RM solid wastes. The mixing proportion for the CPB was optimized by combining the Box‒Behnken design (BBD) response surface method and the satisfaction function method. The strength formation mechanism for the CPB was analyzed with physical and mechanical property tests, X-ray diffraction (XRD), Fourier transform infrared (FTIR), scanning electron microscopy (SEM), etc. The safety of the CPB was evaluated with heavy metal leaching testing. The results showed that the 28-day unconfined compressive strength (UCS) of CPB first increased and then decreased with increasing CS/RM (0.2 ~ 0.6) and SR/RM (0.2 ~ 0.6); the optimum mixing ratios were CS/RM = 0.45 and SR/RM = 0.37, and the solid mass concentration was 64.75%; dense calcium silicate (aluminum) hydrate (C-S-H/C-A-S-H) bound to the solid particles of red mud and filled pores to provide early strength for the CPB, laminar interwoven Friedel's salt (Fs), ettringite and portlandite hydration products provided late strength for the CPB; and the leaching concentrations of five heavy metals (Fe, Mn, Cu, Zn, and Cr) in the solidified CPB were greatly reduced and far below the leaching limits specified in China's Quality Standard for Groundwater (GB/T 14848-2017).

Numerical Simulation Research on Partial Discharge of Particle Defects at Epoxy Interface Excited by High-Frequency Sinusoidal Voltage.

In order to improve the effectiveness of partial discharge detection in attached metal particle insulators, this paper proposes a partial discharge detection method for particle defects in insulators under high-frequency sinusoidal voltage excitation. In order to study the development process of partial discharge under high-frequency electrical stress, a two-dimensional plasma simulation model of partial discharge with particle defects at the epoxy interface is established under plate-plate electrode structure, which realizes the dynamic simulation of particulate defect partial discharge. By studying the microscopic mechanism of partial discharge, the spatial and temporal distribution characteristics of microscopic parameters such as electron density, electron temperature, and surface charge density are obtained. Based on this simulation model, this paper further studies the partial discharge characteristics of epoxy interface particle defects at different frequencies, and verifies the accuracy of the model from two aspects of discharge intensity and surface damages through experimental means. The results show that with the increase in the frequency of applied voltage, the amplitude of electron temperature shows an increasing trend. However, the surface charge density gradually decreases with the increase in frequency. These two factors make partial discharge severest when the frequency of the applied voltage is 15 kHz.

Relationship between ferroptosis and mitophagy in cardiac ischemia reperfusion injury: a mini-review.

Cardiovascular diseases (CVD), with high morbidity and mortality, seriously affect people's life and social development. Clinically, reperfusion therapy is typically used to treat ischemic cardiomyopathy, such as severe coronary heart disease and acute myocardial infarction. However, reperfusion therapy can lead to myocardial ischemia reperfusion injury (MIRI), which can affect the prognosis of patients. Studying the mechanisms of MIRI can help us improve the treatment of MIRI. The pathological process of MIRI involves many mechanisms such as ferroptosis and mitophagy. Ferroptosis can exacerbate MIRI, and regulation of mitophagy can alleviate MIRI. Both ferroptosis and mitophagy are closely related to ROS, but there is no clear understanding of the relationship between ferroptosis and mitophagy. In this review, we analyzed the relationship between ferroptosis and mitophagy according to the role of mTOR, NLPR3 and HIF. In addition, simultaneous regulation of mitophagy and ferroptosis may be superior to single therapy for MIRI. We summarized potential drugs that can regulate mitophagy and/or ferroptosis, hoping to provide reference for the development of drugs and methods for MIRI treatment.

Screening of potential chemical marker with interspecific differences in Pterocarpus wood and a spatially-resolved approach to visualize the distribution of the characteristic markers.

Profiling the spatial distributions and tissue changes of characteristic compounds with interspecific differences is critical to elucidate the complex species identification during tree species traceability, wood anti-counterfeiting verification and timber trade control. In this research, in order to visualize the spatial position of characteristic compounds in two species with similar morphology (Pterocarpus santalinus and Pterocarpus tinctorius), a high coverage MALDI-TOF-MS imaging method was used to found the mass spectra fingerprints of different wood species. 2-Mercaptobenzothiazole matrix was used to spray wood tissue section to enhance the detection effect of metabolic molecules, and the mass spectrometry imaging data were obtained. Based on this technology, the spatial location of fifteen potential chemical markers with remarkable interspecific differences in 2 Pterocarpus timber species were successfully obtained. Distinct chemical signatures obtained from this method can promote rapid identification at the wood species level. Thus, matrix-assisted laser desorption/time-of-flight/ionization mass spectrometry imaging (MALDI-TOF-MSI) provides a spatial-resolved way for traditional wood morphological classification and breaking through the limitations of traditional wood identification technology.

Durability and life prediction of fly ash geopolymer concrete in corrosion environments caused by dry and wet circulation.

The use of tailings, waste rock, fly ash, and slag to prepare geopolymer concrete can effectively solve the problems of land resources occupied by tailings and waste rock, low utilization rate, and environmental pollution. Using a dry-wet circulation method, fly ash for a different corrosion solution to geopolymer concrete (referred to as TWGPC) was analyzed. Through an appearance change, the corrosion resistance coefficient of the compressive strength, relative dynamic elastic modulus, tensile splitting strength, relative mass, and durability were investigated, using scanning electron microscopy (SEM) analysis of the microstructure, The life of TWGPC was predicted based on the GM(1,1) prediction model of grey system theory. The test results show that with an increase in the number of dry-wet cycles, the surface of the specimen crystallizes, cracks, spalls, and exhibits other phenomena. The compressive strength corrosion coefficient, relative dynamic elastic modulus, crack tensile strength, and relative mass show a trend of increasing first and then decreasing, finally reaching the peak value after 40 cycles. The erosion products generated by the early reaction fill the slurry aggregate pores and improve the strength of TWGPC. In a later stage, a large number of erosion products absorb water and expand; the internal pores of TWGPC are connected, leading to a decrease in strength. Cl- inhibits the corrosion of SO42- in concrete and improves the durability of concrete.

The Efficacy of Rosuvastatin, Amlodipine, and Aspirin in the Treatment of Hypertension with Coronary Heart Disease and Its Effect on Platelet Aggregation.

Objective: This study was to study the efficacy of rosuvastatin, amlodipine, and aspirin in the treatment of hypertension with coronary heart disease and its effect on platelet aggregation. Methods: The participants included 60 patients with hypertension and coronary heart disease who were treated at our hospital between January 2020 and May 2021 and were randomly assigned to receive either rosuvastatin, amlodipine, and Ziyin Huoxue Recipe (observation group) or rosuvastatin, amlodipine, Ziyin Huoxue Recipe, and aspirin (experimental group), with 30 patients in each. Outcome measures included clinical effectiveness, blood pressure indicators, blood lipid indices, plasma viscosity, platelet aggregation, cardiac function, and adverse responses. Results: The clinical efficacy in the experimental group was significantly higher than that in the observation group (P < 0.05). The differences were found in blood pressure indices and blood lipid indices between the two groups before treatment (P > 0.05). However, after treatment, the blood pressure indices in the experimental group were significantly lower than those in the observation group (P < 0.05). After treatment, the blood lipid indices, plasma viscosity, and platelet aggregation in the experimental group were significantly lower than those in the observation group (P < 0.05). The left ventricular ejection fraction (LVEF) of patients in the experimental group after treatment was significantly higher than that of patients in the observation group (P < 0.05). There was no significant difference in the incidence of adverse reactions among patients in the two groups (P > 0.05). Conclusion: The clinical efficacy of rosuvastatin, amlodipine, and aspirin markedly reduces the blood pressure indices, blood lipid indices, plasma viscosity, and platelet aggregation of patients with hypertension and coronary heart disease, improves LVEF, and has a good safety profile.

Model Embraced Electromechanical Coupling Time for Estimation of Heart Failure in Patients With Hypertrophic Cardiomyopathy.

Objective: This study aimed to establish a model embraced electromechanical coupling time (EMC-T) and assess the value of the model for the prediction of heart failure (HF) in patients with hypertrophic cardiomyopathy (HCM). Materials and Methods: Data on 82 patients with HCM at Shaanxi Provincial People's Hospital between February 2019 and November 2021 were collected and then formed the training dataset (n = 82). Data were used to screen predictors of HF using univariate and multivariate analyses. Predictors were implemented to discover the optimal cut-off value, were incorporated into a model, and shown as a nomogram. The cumulative HF curve was calculated using the Kaplan-Meier method. Additionally, patients with HCM at other hospitals collected from March 2019 to March 2021 formed the validation dataset. The model's performance was confirmed both in training and validation sets. Results: During a median of 22.91 months, 19 (13.38%) patients experienced HF. Cox analysis showed that EMC-T courses in the lateral wall, myoglobin, PR interval, and left atrial volume index were independent predictors of HF in patients with HCM. Five factors were incorporated into the model and shown as a nomogram. Stratification of patients into two risk subgroups by applying risk score (<230.65, ≥230.65) allowed significant distinction between Kaplan-Meier curves for cumulative incidence of HF events. In training dataset, the model had an AUC of 0.948 (95% CI: 0.885-1.000, p < 0.001) and achieved a good C-index of 0.918 (95% CI: 0.867-0.969). In validation dataset, the model had an AUC of 0.991 (95% CI: 0.848-1.000, p < 0.001) and achieved a strong C-index of 0.941 (95% CI: 0.923-1.000). Calibration plots showed high agreement between predicted and observed outcomes in both two datasets. Conclusion: We established and validated a novel model incorporating electromechanical coupling time courses for predicting HF in patients with HCM.

Lignin Distribution on Cell Wall Micro-Morphological Regions of Fibre in Developmental Phyllostachys pubescens Culms.

Bamboo is a natural fibre reinforced composite with excellent performance which is, to a certain extent, an alternative to the shortage of wood resources. The heterogeneous distribution and molecular structure of lignin is one of the factors that determines its performance, and it is the key and most difficult component in the basic research into the chemistry of bamboo and in bamboo processing and utilization. In this study, the distribution of lignin components and lignin content in micro-morphological regions were measured in semi-quantitative level by age and radial location by means of visible-light microspectrophotometry (VLMS) coupled with the Wiesner and Maule reaction. There as guaiacyl lignin and syringyl lignin in the cell wall of the fibre. Lignin content of the secondary cell wall and cell corner increased at about 10 days, reached a maximum at 1 year, and then decreased gradually. From 17 days to 4 years, the lignin content of the secondary cell wall in the outer part of bamboo is higher than that in the middle part (which is, in turn, higher than that in the inner part of the bamboo). VLSM results of the micro-morphological regions showed that bamboo lignification developed by aging. Guaiacyl and syringl lignin units can be found in the cell wall of the fibre, parenchyma, and vessel. There was a difference in lignin content among different ages, different radial location, and different micro-morphological regions of the cell wall. The fibre walls were rich in guaiacyl lignin in the early stage of lignification and rich in syringyl units in the later stage of lignification. The guaiacyl and syringyl lignin deposition of bamboo green was earlier than that of the middle part of bamboo culm, and that of the middle part of bamboo culm was earlier than that of bamboo yellow. The single molecule lignin content of the thin layer is higher than that of thick layers, while the primary wall is higher than the secondary cell wall, showing that lignin deposition is consistent with the rules of cell wall formation. The obtained cytological information is helpful to understand the origin of the anisotropic, physical, mechanical, chemical, and machining properties of bamboo.

Allogeneic haematopoietic stem cell transplantation with decitabine-containing preconditioning regimen in TP53-mutant myelodysplastic syndromes: A case study.

Myelodysplastic syndrome (MDS) with TP53 mutations has a poor prognosis after transplantation, and novel therapeutic means are urgently needed. Decitabine (Dec) monotherapy has demonstrated improved overall response rates in MDS and acute myeloid leukaemia, although these responses were not durable. This study aimed to preliminary evaluate the efficacy of a Dec-containing allogeneic haematopoietic stem cell transplantation (allo-HSCT) preconditioning regimen in TP53-mutant MDS. Nine patients with TP53-mutant myelodysplastic syndromes received the decitabine-containing preconditioning regimen and subsequent myeloablative allo-HCT between April 2013 and September 2021 in different centres. At a median follow-up of 42 months (range, 5 to 61 months), the overall survival (OS) was 89% (8/9), progression-free survival (PFS) was 89% (8/9), and relapse incidence was 11.1%. The incidence of severe acute (grade III-IV) graft-versus-host disease (GVHD) was 22.2% (2/9) and that of chronic moderate-to-severe GVHD was 11.1% (1/9). The 1-year GVHD-free/relapse-free survival (GRFS) was 56% (5/9). In conclusion, we found real-world clinical data that supports the use of a Dec-containing preconditioning regimen before allo-HSCT for possible improved outcomes in TP53-mutant MDS patients; there is therefore an urgent call for an in-depth exploration of the involved mechanism to confirm these preliminary findings.

Puffed Rice Inspired Porous Carbon Co-MOFs Derived Composite Electrode for Lithium Ion Batteries.

Carbon matrix metal organic frameworks (MOFs) hybrid is often used as electrode materials for lithium ion batteries (LIBs). Herein, we report three dimensional (3D) puffed rice inspired porous carbon (3DPRC) supported Co-MOFs derived composite by facile method. Co/C nanoparticles are uniformly dispersed on porous carbon sheets surface, forming unique 3D structures. As anode of LIBs, the prepared Co/C-3DPRC electrode shows excellent electrochemical properties when compared with the pristine Co/C electrode. With capacity of 430 mAh g-1 at 1C and 300 mAh g-1 at 10C is obtained in the composite electrode, respectively. The excellent properties can attribute to the Co/C-3DPRC interconnected porous framework with a high electrical conductivity and large surface area. Our developed design strategies can be extended for fabrication of other heteroatom doped carbon matrix hybrid for environmental energy fields.

Retrospective analysis on the efficacy of sunitinib/sorafenib in combination with dendritic cells-cytokine-induced killer in metastasis renal cell carcinoma after radical nephrectomy.

OBJECTIVE: Sunitinib/sorafenib (SU/SO), dendritic cells (DCs), or DC-cytokine-induced killer (CIK) could significantly prolong progression-free survival (PFS), 3-year overall survival (OS), or 5-year OS for patients with metastatic renal cell carcinoma (mRCC). We retrospectively analyzed the clinical efficacy between SU/SO combined with DC-CIK and SU/SO monotherapy in treating renal cell carcinoma (RCC) patients with metastasis after radical nephrectomy. MATERIALS AND METHODS: All patients (n = 34) with postoperative mRCC in our hospital from January 2009 to January 2014 were received either SU/SO monotherapy (Group 1, n = 15) or in combination with DC-CIK (Group 2, n = 19). A retrospective study was based on the primary endpoint (PFS) and secondary endpoint (OS). RESULTS: At a median follow-up of 19.5 months, in Group 2, as compared with in Group 1, the median PFS was significantly longer (28.0 vs. 11.0 months, P = 0.03). Moreover, the 3-year OS was higher (57.1% vs. 28.6%). The cases of progressive diseases (PDs) and deaths were less in Group 2 than that in Group 1 (PD: 8 vs. 9, deaths: 3 vs. 5); however, the cases of stable diseases were more (11 vs. 6). In addition, the 3-year OS was higher in SU + DC-CIK group than that in SO + DC-CIK group (63.36% vs. 50%). There was no significant difference for PFS between SO + DC-CIK group and SU single agent group. CONCLUSIONS: SU/SO with DC-CIK could significantly prolong the median PFS, improve the 3-year OS rate, prolong the 3-year OS. It is likely to be a new approach for mRCC after radical nephrectomy.

Recombinant canine adenovirus type 2 expressing rabbit hemorrhagic disease virus VP60 protein provided protection against RHD in rabbits.

Rabbit hemorrhagic disease virus (RHDV) is responsible for rabbit hemorrhagic disease (RHD), which is an acute, lethal and highly contagious disease in both wild and domestic rabbits. Although current vaccines are highly effective for controlling RHD, they are derived from infected rabbit livers and their use is thus associated with safety and animal-welfare concerns. In this study, we generated a recombinant lentogenic canine adenovirus type 2 (CAV2) vector expressing the RHDV vp60 gene, named rCAV2-VP60. rCAV2-VP60 expressed VP60 protein in Madin-Darby canine kidney cells as demonstrated by western blot and immunofluorescence assay. Polymerase chain reaction confirmed that the vp60 gene was successfully inserted into rCAV2-VP60 and was still detectable after 20 passages, indicating its stable genetic character. We evaluated the feasibility of rCAV2-VP60 as a live-virus-vectored RHD vaccine in rabbits. rCAV2-VP60 significantly induced specific antibodies to RHDV and provided effective protection against RHDV lethal challenge. These results suggest that rCAV2 expressing RHDV VP60 could be a safe and efficient candidate vaccine against RHDV in rabbits.

Efficacy of intracellular immune checkpoint-silenced DC vaccine.

BACKGROUND: DC-based tumor vaccines have had limited clinical success thus far. SOCS1, a key inhibitor of inflammatory cytokine signaling, is an immune checkpoint regulator that limits DC immunopotency. METHODS: We generated a genetically modified DC (gmDC) vaccine to perform immunotherapy. The adenovirus (Ad-siSSF) delivers two tumor-associated antigens (TAAs), survivin and MUC1; secretory bacterial flagellin for DC maturation; and an RNA interference moiety to suppress SOCS1. A 2-stage phase I trial was performed for patients with relapsed acute leukemia after allogenic hematopoietic stem cell transplantation: in stage 1, we compared the safety and efficacy between gmDC treatment (23 patients) and standard donor lymphocyte infusion (25 patients); in stage 2, we tested the efficacy of the gmDC vaccine for 12 acute myeloid leukemia (AML) patients with early molecular relapse. RESULTS: gmDCs elicited potent TAA-specific CTL responses in vitro, and the immunostimulatory activity of gmDC vaccination was demonstrated in rhesus monkeys. A stage 1 study established that this combinatory gmDC vaccine is safe in acute leukemia patients and yielded improved survival rate. In stage 2, we observed a complete remission rate of 83% in 12 relapsed AML patients. Overall, no grade 3 or grade 4 graft-versus-host disease incidence was detected in any of the 35 patients enrolled. CONCLUSIONS: This study, with combinatory modifications in DCs, demonstrates the safety and efficacy of SOCS1-silenced DCs in treating relapsed acute leukemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT01956630. FUNDING: National Institute of Health (R01CA90427); the Key New Drug Development and Manufacturing Program of the "Twelfth Five-Year Plan" of China (2011ZX09102-001-29); and Clinical Application Research of Beijing (Z131107002213148).

Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia.

The survival rate of childhood acute lymphoblastic leukemia (ALL) is approaching 90%, while the prognosis of adults remains poor due to the limited therapeutic approaches. In order to identify new targets for ALL, we performed whole-exome sequencing on four adults with B-ALL and discovered a somatic JAK1 S646P mutation. Sanger sequencing of JAK1 was conducted on 53 ALL patients, and two cases exhibited A639G and P960S mutations separately. Functional studies demonstrated that only JAK1 S646P mutation could activate multiple signaling pathways, drive cytokine-independent cell growth, and promote proliferation of malignant cells in nude mice. Moreover, a high sensitivity to the JAK1/2 inhibitor ruxolitinib was observed in S646P mutant model. Exploration in a total of 209 ALL cases showed that JAK1 mutations occur at a frequency of 10.5% in T-ALL (2/19) and 1.6% in B-ALL (3/190). Collectively, our results suggested that JAK1 S646P is an activating mutation in vitro and in vivo. JAK-STAT pathway might represent a promising therapeutic target for ALL.