Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting homologous recombination.

Oncogenic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2) produce 2-hydroxyglutarate (2HG), which inhibits dioxygenases that modulate chromatin dynamics. The effects of 2HG have been reported to sensitize IDH tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors. However, unlike PARP-inhibitor-sensitive BRCA1/2 tumors, which exhibit impaired homologous recombination, IDH-mutant tumors have a silent mutational profile and lack signatures associated with impaired homologous recombination. Instead, 2HG-producing IDH mutations lead to a heterochromatin-dependent slowing of DNA replication accompanied by increased replication stress and DNA double-strand breaks. This replicative stress manifests as replication fork slowing, but the breaks are repaired without a significant increase in mutation burden. Faithful resolution of replicative stress in IDH-mutant cells is dependent on poly-(ADP-ribosylation). Treatment with PARP inhibitors increases DNA replication but results in incomplete DNA repair. These findings demonstrate a role for PARP in the replication of heterochromatin and further validate PARP as a therapeutic target in IDH-mutant tumors.

Cytoreductive chemotherapy in induction therapy plays a key role in the prognosis of patients with low-risk acute promyelocytic leukaemia.

In order to explore the risk factors of relapse and potential optimized therapeutic regimen of low-risk acute promyelocytic leukaemia (APL), here we retrospectively analysed 282 patients who were diagnosed between February 2014 and September 2021. The median follow-up was 59 (9-102) months. The 5-year overall survival and cumulative relapse incidence were 97.9% and 5.9%, respectively. In terms of different cytoreductive therapies, 86 patients were administered with hydroxycarbamide (30.5%), 113 with anthracyclines or cytarabine (40.1%), 31 with etoposide (11.0%) and 52 with no cytoreductive therapy (18.4%) during the induction therapy. The hydroxycarbamide treatment group did not decrease the relapse rate compared to the no cytoreduction group (11.4% vs. 5.9%, p = 0.289). Compared with the hydroxycarbamide group, the anthracyclines/cytarabine treatment group showed improved 5-year RFS (88.145% vs. 98.113%, p = 0.008). Multivariate Cox regression analysis revealed that myeloblasts in bone marrow at diagnosis, and PML-RARA transcript level of 6.5% or more after induction therapy were associated with a subsequent risk of relapse. The only factor positively reducing the relapse rate was anthracyclines/cytarabine cytoreductive treatment. In conclusion, cytoreductive chemotherapy in induction therapy plays a potential key role in the prognosis of low-risk APL.

Clinical features and prognostic model for viral encephalitis after allogeneic haematopoietic stem cell transplantation.

The objective of this study was to identify independent prognostic factors of viral encephalitis (VE) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) and establish a prognostic model to identify post-transplant VE patients with a greater likelihood of mortality. Among 5380 patients in our centre from 2014 to 2022, 211 patients who developed VE after allo-HSCT were reviewed in this retrospective study. Prognostic factors were selected, and a prognostic model was constructed using Cox regression analysis. The model was subsequently validated and estimated using the area under the receiver operating characteristic curve (AUC), a calibration plot and decision curve analysis (DCA). Glasgow Coma Scale score <9, lesions >3 lobes on magnetic resonance imaging and severe thrombocytopenia were identified as independent prognostic risk factors for VE patients who underwent allo-HSCT. The prognostic model GTM (GTM is an abbreviation for a model composed of three risk factors: GCS score <9, severe thrombocytopenia [platelet count <20 000 per microliter], and lesions >3 lobes on MRI) was established according to the regression coefficients. The validated internal AUC was 0.862 (95% confidence interval [CI], 0.773-0.950), and the external AUC was 0.815 (95% CI, 0.708-0.922), indicating strong discriminatory ability. Furthermore, we constructed calibration plots that demonstrated good consistency between the predicted outcomes and the observed outcomes. DCA exhibited high accuracy in this system, leading to potential benefits for patients.

All-trans retinoic acid plus low-dose rituximab vs low-dose rituximab in corticosteroid-resistant or relapsed ITP.

The study aimed to compare the efficacy and safety of all-trans retinoic acid (ATRA) plus low-dose rituximab (LD-RTX) with LD-RTX monotherapy in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) patients. Recruited patients were randomized at a ratio of 2:1 into 2 groups: 112 patients received LD-RTX plus ATRA, and 56 patients received LD-RTX monotherapy. Overall response (OR), defined as achieving a platelet count of ≥30 × 109/L confirmed on ≥2 separate occasions (≥7 days apart), at least a doubling of the baseline platelet count without any other ITP-specific treatment, and the absence of bleeding within 1 year after enrollment, was observed in more patients in the LD-RTX plus ATRA group (80%) than in the LD-RTX monotherapy group (59%) (between-group difference, 0.22; 95% CI, 0.07-0.36). Sustained response (SR), defined as maintenance of a platelet count >30 × 109/L, an absence of bleeding, and no requirement for any other ITP-specific treatment for 6 consecutive months after achievement of OR during 1 year following enrollment, was achieved by 68 (61%) patients in the combination group and 23 (41%) patients in the monotherapy group (between-group difference, 0.20; 95% CI, 0.04-0.35). The 2 most common adverse events (AEs) for the combination group were dry skin and headache or dizziness. Our findings demonstrated that ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a promising treatment option for corticosteroid-resistant or relapsed adult ITP. This study is registered at www.clinicaltrials.gov as #NCT03304288.

Only FLT3-ITD co-mutation did not have a deleterious effect on acute myeloid leukemia patients with NPM1 mutation, but concomitant with DNMT3A co-mutation or a < 3log reduction of MRD2 predicted poor survival.

Co-occurring mutations are frequently observed in acute myeloid leukemia (AML) with NPM1 mutation, and NPM1 measurable residual disease (MRD) is an effective prognostic biomarker. This retrospective study investigated the impact of gene co-mutations and NPM1 MRD on outcomes in these patients. Among 234 patients, 11.5% carried the rare type NPM1 mutation (NPM1RT). The median age was 49 years (IQR 36-58), with a median follow-up of 30.4 months (IQR 12.1-55.7). Nine genes were mutated in > 10%, with DNMT3A (53.8%) and FLT3-ITD (44.4%) being most prevalent. Univariable analysis in 137 patients showed FLT3-ITD, DNMT3A co-mutations, and MRD2 < 3 log reduction predicted poorer survival. FLT3-ITD and DNMT3A co-mutations correlated with the lowest event-free (EFS) and overall survival (OS) (3-year EFS 30.0%; 3-year OS 34.4%; both p < 0.001). FLT3-ITD alone did not worsen survival compared to patients without FLT3-ITD. Multivariable analysis identified DNMT3A co-mutation [EFS, HR = 1.9, p = 0.021; OS, HR = 2.2, p = 0.023] and MRD2 ≥ 3 log reduction (EFS, HR = 0.2; OS, HR = 0.1, both p < 0.001) as independent survival predictors. Patients with FLT3-ITD and DNMT3A co-mutations or a MRD2 < 3 log reduction were identified as high risk, but allogeneic hematopoietic stem cell transplantation (allo-HSCT) improved survival significantly compared to chemotherapy only (3-year EFS, 57.9% vs. 30.0%, p = 0.012; 3-year OS, 72.9% vs. 34.4%, p = 0.001). In AML patients with NPM1 mutation, the detrimental impact of FLT3-ITD mutation was exacerbated by DNMT3A co-mutation. Poor-risk younger patients identified by FLT3-ITD and DNMT3A co-mutations or MRD2 < 3 log reduction benefit from allo-HSCT.

A predictive model of herpes zoster after allogeneic hematopoietic stem cell transplantation: VZV reactivation following antiviral prophylaxis discontinuation.

Herpes zoster (HZ) refers to the rash appearing on dermatomes due to varicella zoster virus (VZV) reactivation. The incidence of HZ is significantly higher in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients than in non-HSCT recipients. Although acyclovir prophylaxis is routinely administered to every allo-HSCT recipient for 1 year after transplantation, some individuals eventually develop late-onset HZ after completing prophylaxis. Little information is known about the clinical features of HZ after prophylactic antiviral treatment discontinuation, and an effective predictive model of late-onset HZ needs to be established. A total of 3366 patients who had received allo-HSCT from 2012 to 2017 were included in our study, among whom 201 developed HZ after 1 year (late-onset HZ). We designed a nested case-control study to identify potential predictors of late-onset HZ. Finally, we established a predictive model using binary logistic regression analysis. Age (p < .001), use of immunosuppressants at +1 year (p < .001), CD4-CD8 ratio at +1 year (p < .001), certain mental disorders (depression, anxiety, insomnia and adjustment disorder) (p < .001), engraftment time of neutrophils (p < .001), and CD8+ cell count at +30 days (p < .001) were independent predictors of late-onset HZ. A risk grading system was established based on regression coefficients. Discrimination and calibration analysis indicated that the model had good performance. We also identified several predictive factors of the incidence of HZ-related complications. This is the first scoring system for predicting the incidence of late-onset HZ after allo-HSCT. This model can be applied to identify individuals at high risk of late-onset HZ in the early period after receiving allo-HSCT.

Safety and efficacy of baricitinib in steroid-resistant or relapsed immune thrombocytopenia: An open-label pilot study.

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 109/L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 109/L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.

Prenatal Phenotypic Analysis of Branchio-Oto-Renal Spectrum Disorder Attributable to EYA1 Gene Pathogenic Variants and Systematic Literature Review.

BACKGROUND: Branchio-oto-renal (BOR) spectrum disorders are linked to pathogenic variants in the EYA1 gene, presenting significant challenges for prenatal ultrasound screening due to their phenotypic variability and complexity. Understanding these disorders' phenotypic expressions and genetic foundations is crucial. METHODS: Our study included pregnant women who underwent fetal whole-exome sequencing at the Department of Medical Genetics and Prenatal Diagnosis, The Third Affiliated Hospital of Zhengzhou University, Henan, China between January 2023 and March 2024. We identified a novel EYA1 gene pathogenic variant and conducted a systematic literature review of all reported prenatal cases associated with EYA1-related diseases, focusing on the detectability of these conditions in prenatal ultrasound. Additionally, we systematically reviewed case reports related to the EYA1 gene, emphasizing missense pathogenic variants for functional predictions and locus position analysis. RESULTS: Our research discovered a new pathogenic variant within the EYA1 gene, highlighting the difficulty of detecting BOR spectrum disorder phenotypes through prenatal ultrasound due to their subtle manifestations. We found that amniotic fluid anomalies and cardiac abnormalities are more prevalent in prenatal cases compared to postnatal cases. A critical region within the EYA Homologous Region (eyaHR) was identified, where missense pathogenic variants significantly affect protein stability, indicating a crucial area associated with the severity of phenotypic expression in EYA1 gene-associated disorders. CONCLUSION: This study enhances the understanding of the genetic landscape of BOR spectrum disorders and suggests that certain phenotypic markers and genetic regions may be pivotal in improving prenatal screening and diagnosis for EYA1-related diseases.

Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene.

Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genome-wide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element, which activated hTERT transcription in a cell in a chromatin-dependent manner. VNTR2-1, consisting of 42-bp repeats with an array of enhancer boxes, cooperated with the proximal promoter in the regulation of hTERT transcription by basic helix-loop-helix transcription factors and maintained hTERT expression during embryonic stem-cell differentiation. Genomic deletion of VNTR2-1 in MelJuSo melanoma cells markedly reduced hTERT transcription, leading to telomere shortening, cellular senescence, and impairment of xenograft tumor growth. Interestingly, VNTR2-1 lengths varied widely in human populations; hTERT alleles with shorter VNTR2-1 were underrepresented in African American centenarians, indicating its role in human aging. Therefore, this polymorphic element is likely a missing link in the telomerase regulatory network and a molecular basis for genetic diversities of telomere homeostasis and age-related disease susceptibilities.

SORL1 stabilizes ABCB1 to promote cisplatin resistance in ovarian cancer.

Ovarian cancer (OC) has the worst prognosis among gynecological malignancies. Cisplatin (CDDP) is one of the most commonly used treatments for OC, but recurrence and metastasis are common due to endogenous or acquired resistance. High expression of ATP-binding cassette (ABC) transporters is an important mechanism of resistance to OC chemotherapy, but targeting ABC transporters in OC therapy remains a challenge. The expression of sortilin-related receptor 1 (SORL1; SorLA) in the response of OC to CDDP was determined by analysis of TCGA and GEO public datasets. Immunohistochemistry and western blotting were utilized to evaluate the expression levels of SORL1 in OC tissues and cells that were sensitive or resistant to CDDP treatment. The in vitro effect of SORL1 on OC cisplatin resistance was proven by CCK-8 and cell apoptosis assays. The subcutaneous xenotransplantation model verified the in vivo significance of SORL1 in OC. Finally, the molecular mechanism by which SORL1 regulates OC cisplatin resistance was revealed by coimmunoprecipitation, gene set enrichment analysis and immunofluorescence analysis. This study demonstrated that SORL1 is closely related to CDDP resistance and predicts a poor prognosis in OC. In vivo xenograft experiments showed that SORL1 knockdown significantly enhanced the effect of CDDP on CDDP-resistant OC cells. Mechanistically, silencing of SORL1 inhibits the early endosomal antigen 1 (EEA1) pathway, which impedes the stability of ATP-binding cassette B subfamily member 1 (ABCB1), sensitizing CDDP-resistant OC cells to CDDP. The findings of this study suggest that targeting SORL1 may represent a promising therapeutic approach for overcoming CDDP resistance in OC.

Tacrolimus prevents complement-mediated Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis of mesenchymal stem cells from immune thrombocytopenia.

The abnormal immunomodulatory functions of mesenchymal stem cells (MSCs) have been implicated in the development of immune thrombocytopenia (ITP). Recent studies have suggested important effects of complement on immune cell function. However, whether complement modulates bone marrow MSCs function in ITP is poorly defined. Tacrolimus has recently been applied to the treatment of autoimmune diseases. Here, we explored whether impaired ITP-MSCs could be targeted by tacrolimus. Our results showed that the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome was activated in ITP MSCs with complement deposition (MSCs-C+ ) and initiated caspase-1-dependent pyroptosis. Transcriptome sequencing results showed abnormal fatty acid metabolism in MSCs-C+ . Enhanced fatty acid ß-oxidation and reactive oxygen species production activated the NLRP3 inflammasome. Adipocytes derived from MSCs-C+ secreted less adiponectin. Adiponectin promoted the differentiation of megakaryocytes and inhibited the destruction of platelets. Tacrolimus inhibited NLRP3 inflammasome activation and MSCs-C+ pyroptosis in vitro and in vivo. Tacrolimus plus danazol elicited a higher sustained response than danazol monotherapy in corticosteroid-resistant patients with ITP. Our findings demonstrate that the activation of the NLRP3 inflammasome in ITP MSCs mediated by complement could be inhibited by tacrolimus, which might be a potential new therapy for ITP.

COVID-19 infection in patients with haematological malignancies: A single-centre survey in the latest Omicron wave in China.

As the COVID-19 variant Omicron surge in Beijing, China, a better understanding of risk factors for adverse outcomes may improve clinical management in patients with haematological malignancies (HM) diagnosed with COVID-19. The study sample includes 412 cases, mainly represented by acute leukaemia, chronic myeloid leukaemia (CML), plasma cell disorders and lymphoma and chronic lymphocytic leukaemia. COVID-19 pneumonia was observed in 10.4% (43/412) of patients, and severe/critical illness was observed in 5.3% (22/412). Among the 86 cases with advanced malignancies, 17.6% (12/86) of patients developed severe/critical COVID-19, which was significantly higher than reported in patients with stable malignancies (9/326, 2.70%, p < 0.001). Similarly, the advanced malignancy cohort had a higher mortality rate (9/86, 10.5% vs. 0/326, 0%, p < 0.001) and a poor 30-day overall survival (OS) compared with the stable malignancy cohort (74.2% vs. 100.0%, p < 0.0001). Overall, nine patients (2.2%) died. The primary cause of death was progressive HM in four patients and a combination of both COVID-19 and HM in five patients. In the multivariable analysis, over 65 years of age, comorbidities and advanced malignancy were correlated with severe/critical COVID-19 in HM patients. This study sheds light on the poor outcomes among COVID-19 HM patients with the leading cause of advanced malignancy.

Predicting short-term and long-term mortalities from sepsis in patients who receive allogeneic haematopoietic stem cell transplantation.

Patients who receive allogeneic haematopoietic stem cell transplantation (allo-HSCT) may develop sepsis, which result in a highly intensive care unit admission rate and mortality. Therefore, short-term and long-term prognostic models for sepsis after allo-HSCT are urgently needed. We enrolled patients receiving allo-HSCT who developed sepsis after allo-HSCT at Peking University People's Hospital between 2012 and 2021, including 287 patients who received allo-HSCT in 2018-2021 in the derivation cohort, and 337 patients in 2012-2017 in the validation cohort. Multivariate logistic regression analysis was used to identify prognostic factors, and these identified factors were incorporated into two scoring models. Seven independent factors (acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD), total bilirubin, lactate dehydrogenase (LDH) and organ dysfunction [renal, lung and heart]) were included in the 6-month prognostic model, and six factors (cGVHD, C-reactive protein, LDH, organ dysfunction [lung, neurologic and coagulation]) were included in the 14-day prognostic model. The area under the receiver operating characteristic curves, calibration plots and decision curve analysis demonstrated the robust predictive performance of the models, better than the Sequential Organ Failure Assessment score. Early identification of patients with high risk of 6-month and 14-day death may allow clinicians to provide timely treatments and improve the therapeutic effects.

Piezoelectric micropump with integrated elastomeric check valves: design, performance characterization and primary application for 3D cell culture.

This paper reports on the study of a piezoelectric actuated micropump with integrated elastomeric check valves that can transport small amounts of fluid in a highly controllable manner. The proposed micropump consists of a piezoelectric actuated fluid chamber with two integrated elastomeric check valves for regulating input and output flow direction, while restricting backflows. The actuation, fluid dynamic response and fluid-structure interactions at various working cycles are studied through a fully coupled multiphysics simulation (solid mechanics, electrostatic and fluid flow). The pump bodies are manufactured by micromachining of PMMA sheets, while the middle elastomeric membrane and diaphragm are fabricated by spin-coating PDMS. The experimental results confirm that the micropump can provide sufficiently low-velocity outflow for biomedical applications between 3.4 - 41.8 µl/min. The performance of the micropump is improved significantly through a convenient geometric modification of an off-the-shelf piezoelectric brass disc. Furthermore, the combination of this micropump with the 3D cell-culture microfluidic chip realizes the dynamic culture of cells encapsulated in 3D hydrogels with a continuous flowing medium, which offers the potential for changing the traditional mode of 3D cell culture with a static supply of nutrition and factors.

Efficiency enhancement mechanism of piezoelectric effect in long wavelength InGaN-based LED.

Improving the luminescence efficiency of InGaN-based long wavelength LEDs for use in micro-LED full-colour displays remains a huge challenge. The strain-induced piezoelectric effect is an effective measure for modulating the carrier redistribution at the InGaN/GaN heterointerfaces. Our theoretical results reveal that the hole injection is significantly improved by the diminution of the valence band offset (VBO) of the InGaN/GaN heterointerfaces along the [0001] direction, and inversely, the VBO increases along the [0001] direction. The energy band structures showed that the tensile strain of the GaN film grown on a silicon (Si) substrate could weaken the internal electric field of the InGaN well layer leading to a flattening of the energy band, which increases the overlap of electron and hole wave functions. In addition, the strain-induced piezoelectric polarisation of the InGaN layer on the Si substrate generates opposite sheet-bound charges at the heterointerfaces, which causes a reduction in the depletion region of the InGaN/GaN quantum wells (QWs). A systematic analysis illustrates that the control of the piezoelectric polarisation of the InGaN QW layer is available improve the internal quantum efficiency of the InGaN-based LEDs.

Comparing the efficacy of thyroglobulin and thyroglobulin/ thyroid-stimulating hormone ratio models in predicting a successful response to radioactive iodine therapy.

BACKGROUND: The thyroglobulin (Tg)/ thyroid-stimulating hormone (TSH) ratio has manifested to be a reliable marker for predicting prognosis in patients with differentiated thyroid carcinoma (DTC). The objective of this study was to compare the efficacy of Tg and Tg/TSH ratio models in predicting a successful response to radioactive iodine therapy. METHODS: One thousand six hundred forty-two DTC patients receiving 131I radiotherapy were finally enrolled in this retrospective study. The patients were divided into a training set (n = 973) and a validation set (n = 669) by the patient consultation time (July 2019). A receiver-operating characteristic curve was constructed for Tg and the Tg/TSH ratio to establish their cutoffs. Then, the variables were screened by univariate logistic regression and incorporated into logistic prediction models by stepwise regression, where Tg/TSH was excluded from model 1 and Tg was excluded from model 2. RESULTS: In 1642 enrolled DTC patients, the first 131I radiotherapy had an excellent response in 855 patients. The cut-offs for Tg level and Tg/TSH ratio were 3.40 ng/ mL [area under the curve (AUC): 0.789] and 36.03 ng/mIU (AUC: 0.788), respectively. In addition, the AUC of the model including Tg was higher than that of the model including Tg/TSH in both the training set (0.837 vs 0.833) and the testing set (0.854 vs 0.836). CONCLUSIONS: Both Tg and Tg/TSH ratios could be considered predictors of the effects of the first 131I ablative therapy. However, the prediction model including Tg performed better than the model including Tg/TSH.

Nicotinamide mononucleotides alleviated neurological impairment via anti-neuroinflammation in traumatic brain injury.

Traumatic brain injury (TBI) is one of the main factors of death and disability in adults with a high incidence worldwide. Nervous system injury, as the most common and serious secondary injury after TBI, determines the prognosis of TBI patients. NAD+ has been confirmed to have neuroprotective effects in neurodegenerative diseases, but its role in TBI remains to be explored. In our study, nicotinamide mononucleotides (NMN), a direct precursor of NAD+, was used to explore the specific role of NAD+ in rats with TBI. Our results showed that NMN administration markedly attenuated histological damages, neuronal death, brain edema, and improved neurological and cognitive deficits in TBI rats. Moreover, NMN treatment significantly suppressed activated astrocytes and microglia after TBI, and further inhibited the expressions of inflammatory factor. Besides, RNA sequencing was used to access the differently expressed genes (DEGs) and their enriched (Kyoto Encyclopedia of Genes and Genomes) KEGG pathways between Sham, TBI, and TBI+NMN. We found that 1589 genes were significantly changed in TBI and 792 genes were reversed by NMN administration. For example, inflammatory factor CCL2, toll like receptors TLR2 and TLR4, proinflammatory cytokines IL-6, IL-11 and IL1rn which were activated after TBI and were decreased by NMN treatment. GO analysis also demonstrated that inflammatory response was the most significant biological process reversed by NMN treatment. Moreover, the reversed DEGs were typically enriched in NF-Kappa B signaling pathway, Jak-STAT signaling pathway and TNF signaling pathway. Taken together, our data showed that NMN alleviated neurological impairment via anti-neuroinflammation in traumatic brain injury and the mechanisms may involve TLR2/4-NF-κB signaling.

Recombinant human thrombopoietin increases platelet count in severe thrombocytopenic patients with hepatitis B-related cirrhosis: Multicentre real-world observational study.

Patients with hepatitis B-related cirrhosis complicated with thrombocytopenia have a higher risk of bleeding, which may lead to higher mortality. We aimed to explore the efficacy and safety of recombinant human thrombopoietin (rhTPO) in the treatment of hepatitis B-related cirrhosis complicated with severe thrombocytopenia. Patients with hepatitis B-related compensated liver cirrhosis complicated with severe thrombocytopenia were divided into four groups according to the treatment method for thrombocytopenia. Platelet counts, the appearance of bleeding symptoms and adverse events were evaluated during the observation period. Also during the observational period, the platelet counts in the prednisone group, rhTPO group and prednisone plus rhTPO group were higher than those in the no treatment group. Patients without splenomegaly reacted better to rhTPO. Fewer bleeding events of grade 2 or worse were observed in the three treatment groups compared to the no treatment group. The platelet counts at baseline and treatment with rhTPO and/or prednisone were factors associated with bleeding events of grade 2 or worse in multivariate analysis. There could be a potential advantage for the use of rhTPO plus prednisone based on higher platelet counts and fewer bleeding events. Treatment with rhTPO was more effective in patients without splenomegaly.

The genetic duet of BRAF V600E and TERT promoter mutations predicts the poor curative effect of radioiodine therapy in papillary thyroid cancer.

OBJECTIVE: The BRAF V600E and TERT promoter mutations are well known to be associated with poor clinical outcomes of papillary thyroid cancer (PTC). Radioactive iodide (RAI)-refractory can be evaluated in advance of treatment, for which predictive biomarkers may be helpful. The present study is to analyze the correlation of both mutations with the curative effect of radioiodine therapy. METHODS: A total of 126 patients who underwent RAI therapy from October 2016 to August 2019 were recruited. Treatment and follow-up were defined according to criteria used in the 2015 ATA guidelines. The RAI response of patients was assessed as excellent response (ER) and RAI-refractory at the end of follow-up. RESULTS: When dividing the 126 patients into 4 groups, the no mutation, only BRAF V600E mutation, only TERT promoter mutation, and coexistence of two mutation groups were found in 15.8%, 68.3%, 2.4%, and 13.5% patients. RAI-refractory was found in 52.9% (9/17) patients with the coexisting BRAF and TERT mutations. In logistic regression analysis, M1, BRAF, and TERT mutation were confirmed to be independent factors predicting the RAI-refractory. Moreover, 35.3%, 41.2%, and 23.5% of patients in the BRAF and TERT mutation group were assessed as ER, SIR, and BIR respectively. Kaplan-Meier analyses revealed that the genetic duet of BRAF V600E and TERT promoter mutations was associated with a lower ER reached time. CONCLUSIONS: We found that BRAF V600E and TERT promoter mutation is significantly correlated with the poor curative effect of RAI therapy in PTC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ChiCTR1800018760.

Significantly suppressed thermal transport by doping In and Al atoms in gallium nitride.

Thermal transport plays a key role in the working stability of gallium nitride (GaN) based optoelectronic devices, where doping has been widely employed for practical applications. However, it remains unclear how doping affects thermal transport. In this study, based on first-principles calculations, we studied the doping effect on the thermal transport properties of GaN by substituting Ga with In/Al atoms. The thermal conductivities at 300 K along the in-plane(out-of-plane) directions of In- and Al-doped GaN are calculated to be 7.3(8.62) and 12.45(11.80) W m-1 K-1, respectively, which are more than one order of magnitude lower compared to that of GaN [242(239) W m-1 K-1]. From the analysis of phonon transport properties, we find that the low phonon group velocity and small phonon relaxation time dominate the degenerated thermal conductivity, which originated from the strong phonon anharmonicity of In/Al-doped GaN. Furthermore, by examining the crystal structure and electronic properties, the lowered thermal conductivity is revealed lying in the strong polarization of In-N and Al-N bonds, which is due to the large difference in electronegativity of In/Al and N atoms. The results achieved in this study have guiding significance to the thermal transport design of GaN-based optoelectronic devices.