Circular mRNA-based TCR-T offers a safe and effective therapeutic strategy for treatment of cytomegalovirus infection.

Circular mRNA (cmRNA) is particular useful due to its high resistance to degradation by exonucleases, resulting in greater stability and protein expression compared to linear mRNA. T cell receptor (TCR)-engineered T cells (TCR-T) represent a promising means of treating viral infections and cancer. This study aimed to evaluate the feasibility and efficacy of cmRNA in antigen-specific-TCR discovery and TCR-T therapy. Using human cytomegalovirus (CMV) pp65 antigen as a model, we found that the expansion of pp65-responsive T cells was induced more effectively by monocyte-derived dendritic cells transfected with pp65-encoding cmRNA compared with linear mRNA. Subsequently, we developed cmRNA-transduced pp65-TCR-T (cm-pp65-TCR-T) that specifically targets the CMV-pp65 epitope. Our results showed that pp65-TCR could be expressed on primary T cells for more than 7 days. Moreover, both in vitro killing and in vivo CDX models demonstrated that cm-pp65-TCR-T cells specifically and persistently kill pp65-and HLA-expressing tumor cells, significantly prolonging the survival of mice. Collectively, our results demonstrated that cmRNA can be used as a more effective technical approach for antigen-specific TCR isolation and identification, and cm-pp65-TCR-T may provide a safe, non-viral, non-integrated therapeutic approach for controlling CMV infection, particularly in patients who have undergone allogeneic hematopoietic stem cell transplantation.

Azacitidine combined with interferon-α for pre-emptive treatment of AML/MDS after allogeneic peripheral blood stem cell transplantation: A prospective phase II study.

This prospective clinical study aimed to evaluate the efficacy and safety of the pre-emptive treatment modality of azacitidine in combination with interferon-α (IFN-α) in AML/MDS patients post-transplantation. Forty-seven patients aged 17-62 were enrolled with 14 patients having completed the planned 12 cycles. Following initiation, 72.3% responded positively after the first cycle, peaking at 77.2% by the fifth cycle. Notably, 24 patients maintained sustained responses throughout a median follow-up of 1050 days (range, 866-1234). Overall survival, leukaemia-free survival and event-free survival probabilities at 3 years were 69.5%, 60.4% and 35.7% respectively. Cumulative incidences of relapse and non-relapse mortality were 36.5% and 4.3% respectively. Multivariate analysis identified that receiving pre-emptive treatment for fewer than six cycles and the absence of chronic graft-versus-host disease after intervention was significantly associated with poorer clinical outcomes. The combination of azacitidine with IFN-α was well-tolerated with no observed severe myelotoxicity, and the majority of adverse events were reversible and manageable. In conclusion, the use of azacitidine in conjunction with IFN-α as pre-emptive therapy is a safe and effective treatment to prevent disease progression in AML/MDS patients with MRD positivity post-allo-HSCT.

Low-dose anti-thymocyte globulin plus low-dose posttransplant cyclophosphamide-based regimen for prevention of graft-versus-host disease in haploidentical peripheral blood stem cell transplantation for pediatric patients with hematologic malignancies.

The low-dose anti-thymocyte globulin (ATG) plus low-dose post transplantation cyclophosphamide (PTCy) -based (low-dose ATG/PTCy-based) regimen had a promising activity in preventing of graft-versus-host disease (GVHD) in adult patients. However, its efficacy in pediatric patients remain to be defined. Here, we presented the findings from 35 pediatric patients undergoing haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with the new regimen for GVHD prophylaxis. The cumulative incidences (CIs) of grades II-III and III-IV acute GVHD (aGVHD) were 34% (95% CI, 17-48%) and 11% (95% CI, 0-21%) within 180 days post-transplantation, respectively. The CIs of chronic GVHD (cGVHD) and moderate-to-severe cGVHD within 2 years were 26% (95% CI, 7-41%) and 12% (95% CI, 0-25%), respectively. The 2-year probabilities of overall survival, relapse-free survival, and graft-versus-host disease and relapse-free survival were 89% (95% CI, 78-100%), 82% (95% CI, 68-98%) and 59% (95% CI, 43-80%), respectively. The CIs of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation by day 180 were 37% (95% CI, 19-51%) and 20% (95% CI, 6-32%) respectively. These results strongly advocate for the efficacy of the low-dose ATG/PTCy-based regimen as a robust strategy for GVHD prevention in haplo-PBSCT for pediatric patients.

Immune reconstitution and survival of patients after allogeneic hematopoietic stem cell transplantation from older donors.

BACKGROUND: The impact of donor age on the immune reconstitution of patients with hematological malignancies who underwent hematopoietic cell transplantation (HCT) is unclear. METHOD: We retrospectively compared the outcomes of 381 patients who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from 308 donors under 50 years of age and 73 donors over 50 years of age. IVIG was regularly supplemented for patients in the first 3 months post-HCT. RESULTS: The counts of CD8+CD45RA+ naïve T cells were significantly lower in patients of the older donor group than in the younger donor group in the first year after PBSCT (190.6 cells/µl vs. 239.6 cells/µl, p = .018). Patients in the older donor group had significantly fewer CD19+ B cells on day +270 (123.4 cells/µl vs. 183.5 cells/µl, p = .021) and day +365 (169 cells/µl vs. 271.1 cells/µl, p = .01) after PBSCT. Serum IgA (.76 g/L vs. .97 g/L, p < .001) and IgM levels (.75 g/L vs. 1.04 g/L, p < .001) were significantly lower in patients in the older donor group from day +60 to +365 after PBSCT. The EBV reactivation rate within the first 3 months after PBSCT was significantly higher in patients in the older donor group (48.6% vs. 38.3%, p = .034). However, the incidences of CMV reactivation, II-IV acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), 3-year relapse rate, 3-year transplant-related mortality (TRM) and 3-year overall survival (OS) were not significantly different between the two groups. CONCLUSION: In conclusion, donors ≥50 years old were associated with inferior immune reconstitution and higher EBV reactivation in patients after PBSCT, but no change in OS.

Immune reconstitution and survival of patients with parvovirus B19 related pure red cell aplasia after haplo-PBSCT.

Parvovirus B19 (PvB19) infection and PvB19 related pure red cell aplasia (PRCA) in recipients with allogeneic hematopoietic stem cell transplantation have been reported sporadically. However, clinical studies with large sample sizes are lacking, especially in patients undergoing HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). In addition, clinical features, immune reconstitution, and outcomes of these patients are not clear. We conducted a retrospective analysis of 164 patients who received haplo-PBSCT with low-dose anti-thymocyte globulin (ATG) plus low-dose posttransplant cyclophosphamide (PTCy)-based regimen as graft-versus-host disease (GVHD) prophylaxis. We analyzed the incidence of PvB19 related PRCA and compared the clinical characteristics, immune reconstitution, incidence of GVHD, relapse rate, and survival between patients with and without PvB19 related PRCA. A total of 14 (8.5%) recipients developed PvB19 related PRCA after a median of 5.3 months after haplo-PBSCT. These patients with PvB19 related PRCA had slower immune reconstitution, but similar incidences of GVHD, relapse rate, and overall survival compared with recipients without PvB19 related PRCA. PvB19 related PRCA indicated relative delayed and poor immune reconstitution of the recipients early after haplo-PBSCT. PvB19 related PRCA had no effects on GVHD, relapse, and survival.

Comparison of microbial community structures between mesophilic and thermophilic anaerobic digestion of vegetable waste.

The anaerobic digestion performance correlates with the functional microbial community. Mesophilic and thermophilic digestions of vegetable waste were conducted, and dynamics of the microbial community were investigated. The mesophilic and thermophilic collapsed stages occurred at organic loading rates of 1.5 and 2.0 g VS/(L d) due to the accumulation of volatile fatty acids with final concentrations of 2276 and 6476 mg/L, respectively. A high concentration of volatile fatty acids caused the severe inhibition of methanogens, which finally led to the imbalance between acetogenesis and methanogenesis. The mesophilic digestion exhibited a higher microbial diversity and richness than the thermophilic digestion. Syntrophic acetate-oxidizing coupled with hydrogenotrophic methanogenesis was the dominant pathway in the thermophilic stable system, and acetoclastic methanogenesis in the mesophilic stable system. The dominant acidogens, syntrophus, and methanogens were unclassified_f__Anaerolineaceae (8.68%), Candidatus_Cloacamonas (19.70%), Methanosaeta (6.10%), and Methanosarcina (4.08%) in the mesophilic stable stage, and Anaerobaculum (12.59%), Syntrophaceticus (4.84%), Methanosarcina (30.58%), and Methanothermobacter (3.17%) in thermophilic stable stage. Spirochaetae and Thermotogae phyla were the characteristic microorganisms in the mesophilic and thermophilic collapsed stages, respectively. These findings provided valuable information for the deep understanding of the difference of the microbial community and methane-producing mechanism between mesophilic and thermophilic digestion of vegetable waste.

Batch preparation of gold nanoparticles with highly uniform morphology and tunable plasmonic properties.

The plasmonic properties of individual metallic nanostructures are of great importance for application in surface science, materials science, and nanophotonics. Herein, being facilitated with a home-made flow device and pulsed laser irradiation, we proposed a batch preparation protocol towards spherical Au nanoparticles (Au NPs) and cage shell entrapped spherical core nanoparticles (Au@cAu NPs) with highly uniform morphology and a tunable size distribution. The Fano resonance behavior exhibited by the effective interaction between spherical Au NPs and the silicon surface has great potential for the design of ultrasensitive optical sensing devices. In comparison with the spherical Au NP, the individual Au@cAu NP displayed not only a red-shifted and broadened localized surface plasmon resonance (LSPR) scattering peak, but also a higher electromagnetic field enhancement. Therefore, the Au@cAu NPs offer a better choice for plasmonic enhancement-based applications in the red and near-infrared region. In general, the current work provides a new and easy method for the large-scale preparation of gold-based uniform nanostructures, and offers an avenue to understand the interference of different plasmon modes in plasmonic systems, which has potential applications in surface science.

High-dose etoposide could discriminate the benefit from autologous peripheral blood stem cell transplantation in the patients with refractory diffuse large B cell lymphoma.

To evaluate the strategy of using high-dose etoposide mobilization followed by autologous peripheral blood stem cell transplantation (APBSCT) in patients with diffuse large B cell lymphoma (DLBCL) refractory to rituximab-based chemotherapy. Forty patients with refractory DLBCL were treated with high-dose etoposide for stem cell mobilization. All patients were in progressive disease (PD) prior to mobilization and underwent high-dose chemotherapy followed by APBSCT. Successful PBSC mobilization was achieved in all patients. Twenty-three patients (57.5%) showed a clinical response to high-dose etoposide. After APBSCT, 17 patients (42.5%) achieved CR. The 2-year progression-free (PFS) and overall survival (OS) rate were higher in patients responding to high-dose etoposide (64.1% and 77.7%) compared to those without response (11.8% and 11.8%; P < 0.001 for both). The response to high-dose etoposide mobilization therapy was an independent prognostic factor for CR achievement, PFS and OS after APBSCT. High-dose etoposide mobilization chemotherapy followed by APBSCT could rescue a proportion of patients with refractory DLBCL who responded to etoposide mobilization regimen.

Bacterial Pathogens Differed Between Neutropenic and Non-neutropenic Patients in the Same Hematological Ward: An 8-Year Survey.

Background: Bacterial infections are very common among patients with hematological diseases. Scant data are available regarding differences in the epidemiology and biological features of bacterial infections in neutropenic and non-neutropenic patients. Methods: The aim of this survey was to compare the bacterial pathogens in neutropenic and non-neutropenic patients in the same ward during an 8-year period. Results: A total of 1139 bacterial strains were isolated from 1071 patients with hematological diseases. The percentage of Gram-negative bacteria was significantly higher in neutropenic patients than in non-neutropenic patients (70.4% vs. 55.0%, respectively, P < .01). In neutropenic patients, the most commonly-isolated bacterium was Pseudomonas aeruginosa, followed by Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In respiratory exudates, Gram-negative bacteria were also more frequently isolated from neutropenic patients than from non-neutropenic patients (79.1% vs. 56.1%, respectively, P < .01). The proportion of non-fermentative Gram-negative bacilli was significantly higher in neutropenic patients than in non-neutropenic patients (52.9% vs. 30.5%, respectively, P < .01). In blood culture samples from neutropenic patients, the most frequently identified pathogens, apart from coagulase negative staphylococcus, were Gram-negative bacilli (58.2%). In addition, the proportion of Escherichia coli in neutropenic patients was significantly higher than that in non-neutropenic patients (P < .01). Escherichia coli and Klebsiella pneumoniae strains from neutropenic patients also produced extended-spectrum ß-lactamases at a higher rate of than those strains from non-neutropenic patients (Escherichia coli, 57.6% vs. 30.3%, respectively, P < .01; Klebsiella pneumonia, 31.9% vs. 13.0%, respectively, P < .01). Conclusions: This study showed that there are significant differences in the epidemiology and biological features of bacteria isolated from neutropenic and non-neutropenic patients.

Electrochemical Impedance Spectroscopy for Real-Time Detection of Lipid Membrane Damage Based on a Porous Self-Assembly Monolayer Support.

Layer-by-layer dissolution and permeable pore formation are two typical membrane damage pathways, which induce membrane function disorder and result in serious disease, such as Alzheimer's disease, Keshan disease, Sickle-cell disease, and so on. To effectively distinguish and sensitively monitor these two typical membrane damage pathways, a facile electrochemical impedance strategy was developed on a porous self-assembly monolayer (pSAM) supported bilayer lipid membrane (BLM). The pSAM was prepared by selectively electrochemical reductive desorption of the mercaptopropionic acid in a mixed mercaptopropionic acid/11-mercaptoundecanoic acid self-assembled monolayer, which created plenty of nanopores with tens of nanometers in diameter and several nanometers in height (defined as inner-pores). The ultralow aspect ratio of the inner-pores was advantageous to the mass transfer of electrochemical probe [Fe(CN)6]3-/4-, simplifying the equivalent electric circuit for electrochemical impedance spectroscopy analysis at the electrode/membrane interface. [Fe(CN)6]3-/4- transferring from the bulk solution into the inner-pore induce significant changes of the interfacial impedance properties, improving the detection sensitivity. Based on these, the different membrane damage pathways were effectively distinguished and sensitively monitored with the normalized resistance-capacitance changes of inner-pore-related parameters including the electrolyte resistance within the pore length ( Rpore) and the metal/inner-pore interfacial capacitance ( Cpore) and the charge-transfer resistance ( Rct-in) at the metal/inner-pore interface.

Early tapering of immunosuppressive agents after HLA-matched donor transplantation can improve the survival of patients with advanced acute myeloid leukemia.

Disease recurrence is the most important obstacle to achieve long-term survival for patients with advanced acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to reduce the relapse risk and improve the survival, the strategy of early tapering of immunosuppressive agents was prospectively evaluated. Thirty-one patients with advanced AML received early tapering of immunosuppressive drugs, while 32 patients with AML in complete remission (CR) were given the routine tapering of immunosuppressive agents after HLA-matched donor transplantation. All advanced AML patients achieved CR after allo-HSCT. At 24 months after transplantation, relapse incidences were 22% in advanced group and 16% in CR group (P = 0.553); disease-free survival (DFS) and overall survival (OS) were 57.7 and 57.8% in advanced group, while in CR group were 66.6% (P = 0.388) and 66.2% (P = 0.423); immunosuppressive agent-free DFS (IDFS) were similar between two groups (P = 0.407). Acute graft-versus-host disease (aGvHD) incidences were similar between two groups (P = 0.311). Chronic GvHD (cGvHD) incidence was much higher in advanced group than in CR group (70.4 vs 38.7%, P = 0.02), but severe cGvHD had no difference. In multivariate analysis, cGvHD was an independent prognostic factor for lower risk of relapse and better DFS and OS; early tapering of immunosuppressive agents was an independent prognostic factor for cGvHD. The study suggested that advanced AML patients could be directly treated with allo-HSCT and its survival could be improved through the strategy of early tapering of immunosuppressive agents without significant adverse effects ( Clinicaltrials.org NCT03150134).

Diagnostic value of trait antinuclear antibodies and multiple immunoglobulin production in autoimmune diseases.

BACKGROUND: Our article aims to evaluate the proportion of monospecific antinuclear antibodies (ANA) and polyclonal ANAs in patients with autoimmune diseases based on the results of an ANA panel and to evaluate the efficiency of trait ANAs as a novel diagnostic tool. This study also aims to investigate immunoglobulin production in autoimmune diseases by detecting different antibodies. METHODS: The serum ANA profile of 634 patients with autoimmune diseases was analyzed using the immunoblot method. A specific formula was developed in an effort to calculate the theoretical proportion of monospecific ANA (TPM) in different disease groups. Different IgM, IgG, and IgE variants for several pathologies were detected. RESULTS: The observed proportions of monospecific ANAs (OPM) were all lower than the predicted TPM in autoimmune diseases. Polyclonal ANAs were predominant in patients with systemic lupus erythematosus (SLE). There were statistical differences in OPM and TPM in all disease groups (P < .001). Receiver operating characteristic curve (ROC curve) analysis of trait ANAs between the SLE group and the control groups indicated an area under the curve of 0.916. Differences were found in IgM of Toxoplasma gondii (TOXO) and IgG of hepatitis C virus (HCV) and Treponema pallidum (TP) when comparing the various disease groups to the control group. CONCLUSION: The higher TPM suggests that polyclonal differentiation is the major mechanism of ANA in autoimmune diseases. Trait ANA is potentially a valuable new index for diagnosis in SLE. Further investigation is needed to understand the link between B-cell differentiation and autoimmune diseases.

Role of norepinephrine in Aß-related neurotoxicity: dual interactions with Tyr10 and SNK(26-28) of Aß.

With their capability to inhibit the formation of amyloid-ß peptide (Aß) fibril, norepinephrine (NE), and other catechol derivatives have been considered for the potential treatment of Alzheimer's disease (AD). Such treatment, however, remains debatable because of the diverse functions of Aß and NE in AD pathology. Moreover, the complicated oxidation accompanying NE has caused the majority of the previous research to focus on the binding of NE oxides onto Aß. The molecular mechanism by which Aß interacts with the reduction state of NE, which is correlated with the brain function, should be urgently explored. In this work, by controlling rigorous anaerobic experimental conditions, the molecular mechanism of the Aß/NE interaction was investigated, and two binding sites were revealed. Tyr10 was identified as the strong binding site of NE, and SNK(26-28) segment was the weak binding segment. Furthermore, thioflavin T fluorescence confirmed NE's positive function of inhibiting Aß aggregation through its weak binding with SNK(26-28) segment. Meanwhile, 7-OHCCA fluorescence exhibited NE's negative function of enhancing ·OH generation through inhibiting the Aß/Cu2+ coordination. The viability tests of the neuroblastoma SH-SY5Y cells displayed that the coexistence of NE, Cu2+, and Aß induced lower cell viability than free Cu2+, indicating the significant negative effect of excessive NE on AD progression. These data revealed the possible pathway of NE-induced damage in AD brain, which is significant for understanding the function of NE in Aß-involved AD neuropathology and for designing an NE-related therapeutic strategy for AD.

PR1-specific cytotoxic T lymphocytes are relatively frequent in umbilical cord blood and can be effectively expanded to target myeloid leukemia.

BACKGROUND AIMS: PR1 is an HLA-A2 restricted leukemia-associated antigen derived from neutrophil elastase and proteinase 3, both of which are normally stored in the azurophil granules of myeloid cells but overexpressed in myeloid leukemic cells. PR1-specific cytotoxic lymphocytes (PR1-CTLs) have activity against primary myeloid leukemia in vitro and in vivo and thus could have great potential in the setting of adoptive cellular therapy (ACT). Adult peripheral blood-derived PR1-CTLs are infrequent but preferentially lyse myeloid leukemia cells. We sought to examine PR1-CTLs in umbilical cord blood (UCB) because UCB units provide a rapidly available cell source and a lower risk of graft-versus-host disease, even in the setting of mismatched human leukocyte antigen (HLA) loci. METHODS: We first determined the frequency of PR1-CTLs in HLA-A2(+) UCB units and then successfully expanded them ex vivo using repeated stimulation with PR1 peptide-pulsed antigen-presenting cells (APCs). After expansion, we assessed the PR1-CTL phenotype (naive, effector, memory) and function against PR1-expressing target cells. RESULTS: PR1-CTLs are detected at an average frequency of 0.14% within the CD8(+) population of fresh UCB units, which is 45 times higher than in healthy adult peripheral blood. UCB PR1-CTLs are phenotypically naive, consistent with the UCB CD8(+) population as a whole. In addition, the cells can be expanded by stimulation with PR1 peptide-pulsed APCs. Expansion results in an increased frequency of PR1-CTLs, up to 4.56%, with an average 20-fold increase in total number. After expansion, UCB PR1-CTLs express markers consistent with effector memory T cells. Expanded UCB PR1-CTLs are functional in vitro as they are able to produce cytokines and lyse PR1-expressing leukemia cell lines. CONCLUSIONS: This study is the first report to show that T cells specific for a leukemia-associated antigen are found at a significantly higher frequency in UCB than adult blood. Our results also demonstrate specific cytotoxicity of expanded UCB-derived PR1-CTLs against PR1-expressing targets. Together, our data suggest that UCB PR1-CTLs could be useful to prevent or treat leukemia relapse in myeloid leukemia patients.

Case report: Autoimmune encephalomyelitis following cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

Introduction: Cytomegalovirus (CMV) can cause various end-organ diseases in immunocompromised hosts, including allogeneic hematopoietic cell transplant (allo-HSCT) recipients. Interestingly, CMV viremia has been associated with various complications and poor prognosis in allo-HSCT recipients. Complications involving the central nervous system (CNS) occur in 9-14% of patients following allo-HSCT. However, autoimmune encephalitis (AE) secondary to CMV infection after allo-HSCT has rarely been reported. Here we report a case of possible AE following CMV viremia after allo-HSCT, which was successfully treated with high-dose pulsed methylprednisolone and intravenous immunoglobulins (IVIg). Case description: A 53-year-old female underwent allo-HSCT for T-lymphoblastic lymphoma/leukemia. The patient developed CMV viremia on day 36 after transplantation, and serum CMV-DNA remained positive after initiating ganciclovir antiviral therapy, turning negative one month later. Four months later, she started experiencing memory impairment, weakness in the left limbs, cognitive dysfunction, and hallucinations. A magnetic resonance imaging brain scan showed scattered ischemic lesions under the bilateral frontal cortex. Viral detection in cerebral spinal fluid (CSF) by next-generation gene sequencing technology showed no obvious abnormality. Antibodies specific to AE and paraneoplastic diseases in serum and CSF were absent. The oligoclonal bands in the CSF were detected using isoelectric focusing and immunofixation, and the results were negative. However, after extensive investigation regarding infections, autoimmune disorders, and recurrence of the malignancy, possible AE could not be excluded. The patient was treated with high-dose steroids combined with IVIg therapy; the patient's symptoms were significantly improved. Conclusion: The mechanisms of AE after allo-HSCT and the relationship with CMV infection should be further studied. Therefore, reporting this and similar cases will improve our awareness and understanding of the underlying disease mechanisms.

A telomere-related gene risk model for predicting prognosis and treatment response in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a prevalent hematological malignancy among adults. Recent studies suggest that the length of telomeres could significantly affect both the risk of developing AML and the overall survival (OS). Despite the limited focus on the prognostic value of telomere-related genes (TRGs) in AML, our study aims at addressing this gap by compiling a list of TRGs from TelNet, as well as collecting clinical information and TRGs expression data through the Gene Expression Omnibus (GEO) database. The GSE37642 dataset, sourced from GEO and based on the GPL96 platform, was divided into training and validation sets at a 6:4 ratio. Additionally, the GSE71014 dataset (based on the GPL10558 platform), GSE12417 dataset (based on the GPL96 and GPL570 platforms), and another portion of the GSE37642 dataset (based on the GPL570 platform) were designated as external testing sets. Univariate Cox regression analysis identified 96 TRGs significantly associated with OS. Subsequent Lasso-Cox stepwise regression analysis pinpointed eight TRGs (MCPH1, SLC25A6, STK19, PSAT1, KCTD15, DNMT3B, PSMD5, and TAF2) exhibiting robust predictive potential for patient survival. Both univariate and multivariate survival analyses unveiled TRG risk scores and age as independent prognostic variables. To refine the accuracy of survival prognosis, we developed both a nomogram integrating clinical parameters and a predictive risk score model based on TRGs. In subsequent investigations, associations were emphasized not solely regarding the TRG risk score and immune infiltration patterns but also concerning the response to immune-checkpoint inhibitor (ICI) therapy. In summary, the establishment of a telomere-associated genetic risk model offers a valuable tool for prognosticating AML outcomes, thereby facilitating informed treatment decisions.

T-Cell Posttransplant Lymphoproliferative Disorders After Allogeneic Hematopoietic Stem Cell Transplantation: Case Series and Systemic Review.

Posttransplant lymphoproliferative disorder (PTLD) is a rare lymphoid and/or plasmocytic proliferation that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to identify the pathologic features and clinical outcomes of T-cell PTLD, an extremely rare subtype of PTLD, after allo-HSCT. In this study, six allo-HSCT recipients with T-cell PTLD from five transplant centers in China were enrolled. All the T-cell PTLD were donor-derived, and three patients were with monomorphic and three with polymorphic types, respectively. All patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. Five patients achieved complete response (CR), and one experienced progressive disease (PD). The median time from HSCT to onset was 4 (range: 0.6-72) months, analyzed in combination with the other 16 patients with T-cell PTLD identified from previous reports. About 56.3% of the T-cell samples (9/16) were positive for in situ hybridization with an Epstein-Barr virus (EBV)-encoded small nuclear early region (EBER ISH). CHOP-based chemotherapy might be the optimal strategy for patients who showed no response to empiric therapy with a CR rate of 87.5%. In conclusion, our study observed that T-cell PTLD has distinct clinical manifestations and morphological features, which characterized by less relation to EBV, later occurrence, and poorer prognosis when compared with B-cell PTLD.

A Novel JAK1 Inhibitor SHR0302 Combined With Prednisone for First-Line Treatment of Chronic Graft-Versus-Host Disease: A Phase I Clinical Trial.

Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation. Standard steroid first-line treatment could not satisfy therapeutic needs due to limited efficacy. As a highly selective Janus kinase (JAK) 1 inhibitor, SHR0302 exhibits a reduced inhibition effect on JAK2 and might have less effect on hematopoiesis. This phase I clinical trial investigated the tolerability and safety of SHR0302 in combination with prednisone, and its early efficacy evidence as a potential first-line treatment to moderate/severe cGVHD. The standard 3 + 3 dose escalation was implemented to find the optimal dose of SHR0302. And prednisone was concurrently administrated with a dose of 1 mg/kg/d and then gradually tapered after 2 weeks. Eighteen patients were enrolled into the study. Grade ≥ 3 treatment-related adverse events were observed in 38.9% of patients. Only one patient developed DLT (grade ≥ 3 hypercholesterolemia) in the highest dose-level group who had pre-existing hypercholesterolemia. The maximum tolerated dose was not reached. No patient discontinued treatment due to AEs. Sixteen out of 18 patients were evaluable for responses, the ORR at week 4 and week 24 were 94.4 and 87.5%, respectively. Overall, the treatment of SHR0302 combined with prednisone was safe and well-tolerated, preliminary clinical results presented a high response for previously untreated cGVHD and a significant reduction in prednisone use in this study. A phase II trial will be conducted to further investigate its therapeutic effects clinically.

The association between the respiratory tract microbiome and clinical outcomes in patients with COPD.

Though it has been widely accepted that infections of the respiratory tract is associated with aetiology of acute exacerbation of chronic obstructive pulmonary disease (AECOPD), more recent techniques have shown emerging evidence on the importance of alterations of diversity and composition of microbiota itself in the disease process. Specifically, these alterations is widely present in COPD patients from a variety of populations, and is associated with severity of disease, frequency of acute exacerbation, as well as prediction of exacerbation. In addition, the microbiota from respiratory tract contributes to disease mechanisms, and more recently have been shown to interact with gut microbiota in a bidirectional way. Therefore, updating progress in the field is crucial as it not only reveals potential underlying mechanisms of the disease, but also highlights the potential utilisation of microbiota as a biomarker for disease prediction and as a target for treatment. In this narrative review, we summarize current updates on microbiota dysbiosis in COPD, including techniques for sampling and analysis of microbiota, recent findings on the presence of microbiota dysbiosis and its correlation with clinical prediction and prognosis of the disease, as well as its potential roles in disease mechanisms. In addition, how gut-lung axis contributes to COPD progression is also discussed. Finally, we addressed the utilisation of prebiotic and probiotic treatment for COPD. Together, we hope to provide useful information to advocate the use of microbial parameters as important tools for diagnosis, treatment and long-term follow-up for COPD patients.

Alleviating acid inhibition via bentonite supplementation during acidulated swine manure anaerobic digestion: Performance enhancement and microbial mechanism analysis.

Swine manure is usually transmitted by the "collection-storage-transport" mode of the biogas project. However, this particular application pattern results in high volatile fatty acids (VFAs) concentration due to the long transition time in the "collection-storage-transport" process. In this work, acidulated swine manure anaerobic digestion (AD) with bentonite supplementation was firstly investigated with an expectation of acid alleviation, performance enhancement and microbial mechanism. Results indicated that the methane production rate in the 20 g/L bentonite-added digester was 2.87 fold higher than that of the control digester. Chemical oxygen demand (COD) removal rate was elevated by 140.1% via bentonite supplementation. Besides, the rapid decrease of VFAs and ammonia indicated that bentonite supplementation could offer buffering capacity and alleviate acid inhibition. Microbial community analysis revealed that acetoclastic methanogenesis (Methanosaeta and Methanosarcina) was the predominant methanogenesis pathway in this AD system. Syntrophic acetate oxidation (SAO) bacteria were discovered in the bentonite-added digester, and they converted acetate into H2/CO2 to support hydrogenotrophic methanogenesis. This study could offer guidance for acidulated swine manure AD in the practical biogas project.