Novel GNAI3 mutation in a Chinese family with auriculocondylar syndrome and treatment of severe dentofacial deformities: a 5-year follow-up case report.

BACKGROUND: Auriculocondylar syndrome (ARCND) is an extremely rare autosomal dominant or recessive condition that typically manifests as question mark ears (QMEs), mandibular condyle hypoplasia, and micrognathia. Severe dental and maxillofacial malformations present considerable challenges in patients' lives and clinical treatment. Currently, only a few ARCND cases have been reported worldwide, but most of them are related to genetic mutations, clinical symptoms, and ear correction; there are few reports concerning the treatment of dentofacial deformities. CASE PRESENTATION: Here, we report a rare case of ARCND in a Chinese family. A novel insertional mutation in the guanine nucleotide-binding protein alpha-inhibiting activity polypeptide 3 (GNAI3) was identified in the patient and their brother using whole-exome sequencing. After a multidisciplinary consultation and examination, sequential orthodontic treatment and craniofacial surgery, including distraction osteogenesis and orthognathic surgery, were performed using three-dimensional (3D) digital technology to treat the patient's dentofacial deformity. A good prognosis was achieved at the 5-year follow-up, and the patient returned to normal life. CONCLUSIONS: ARCND is a monogenic and rare condition that can be diagnosed based on its clinical triad of core features. Molecular diagnosis plays a crucial role in the diagnosis of patients with inconspicuous clinical features. We present a novel insertion variation in GNAI3, which was identified in exon 2 of chromosome 110116384 in a Chinese family. Sequential therapy with preoperative orthodontic treatment combined with distraction osteogenesis and orthognathic surgery guided by 3D digital technology may be a practical and effective method for treating ARCND.

Subunit-specific analysis of cohesin-mutant myeloid malignancies reveals distinct ontogeny and outcomes.

Mutations in the cohesin complex components (STAG2, RAD21, SMC1A, SMC3, and PDS5B) are recurrent genetic drivers in myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Whether the different cohesin subunit mutations share clinical characteristics and prognostic significance is not known. We analyzed 790 cohesin-mutant patients from the Dana-Farber Cancer Institute (DFCI) and the Munich Leukemia Laboratory (MLL), 390 of which had available outcome data, and identified subunit-specific clinical, prognostic, and genetic characteristics suggestive of distinct ontogenies. We found that STAG2 mutations are acquired at MDS stage and are associated with secondary AML, adverse prognosis, and co-occurrence of secondary AML-type mutations. In contrast, mutations in RAD21, SMC1A and SMC3 share features with de novo AML with better prognosis, and co-occurrence with de novo AML-type lesions. The findings show the heterogeneous nature of cohesin complex mutations, and inform clinical and prognostic classification, as well as distinct biology of the cohesin complex.

Improved Immunotherapy Outcomes via Cuproptosis Upregulation of HLA-DRA Expression: Promoting the Aggregation of CD4+ and CD8+T Lymphocytes in Clear Cell Renal Cell Carcinoma.

Immunotherapy has shown promising clinical results in clear cell renal cell carcinoma (ccRCC), but low clinical target response rates due to dysfunction of the major histocompatibility complex (MHC) and an inhibitory tumor immune microenvironment (TIME) have largely limited the associated clinical benefits. In the present study, we explored the feasibility of enhancing tumor-specific-MHC-II-HLA-DRA expression, counteracting the TIME's suppressive effects, thereby improving the sensitivity of immune checkpoint inhibitor (ICI) therapy from the standpoint of cuproptosis. Immunohistochemical staining and in vitro experiments validated the expression of HLA-DRA in ccRCC and its positive impact on ICI therapy. Subsequently, we observed that cuproptosis upregulated HLA-DRA expression in a dose-dependent manner, further confirming the link between cuproptosis and HLA-DRA. In vivo experiments showed that cuproptosis increased the sensitivity to ICI treatment, and implementing cuproptosis alongside anti-PD-1 treatment curtailed tumor growth. Mechanistically, cuproptosis upregulates HLA-DRA expression at the transcriptional level in a dose-dependent manner by inducing the production of reactive oxygen species; high levels of HLA-DRA promote the expression of chemokines CCL5, CXCL9, and CXCL10 in the TIME, inhibiting the development of a pro-tumor microenvironment by promoting the infiltration of CD4+T and CD8+T cells, thereby synergizing ICI therapy and exerting anti-tumor effects. Taken together, this work highlights the role of cuproptosis in mediating TIME remodeling and synergistic immunotherapy, providing new evidence that cuproptosis can evoke effective anti-tumor immune responses.

Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.

While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).

Elevated Cancer-Associated Hyaluronan Correlates With Diagnosis and Lymph Node Metastasis of Papillary Thyroid Cancer.

The glycosaminoglycan hyaluronan (HA) plays an important role in tumor progression. However, its biological and clinical significance in papillary thyroid cancer (PTC) remains unknown. Immunohistochemistry was performed to examine HA expression in tissues from PTC patients. Two PTC cell lines were treated with HA synthesized inhibitor against HA production to assess its function. Serum HA levels from 107 PTC patients, 30 Hashimoto thyroiditis patients, and 45 normal controls (NC) were measured by chemiluminescence immunoassay. HA levels in fine needle aspiration (FNA) washouts obtained from thyroid nodules and lymph nodes (LNs) were measured by chemiluminescence immunoassay. Area under the curve (AUC) was computed to evaluate HA's clinical value. HA was highly expressed in PTC. Reducing HA production significantly inhibited PTC cell proliferation and invasion. Importantly, serum HA levels in PTC were significantly higher than those in NCs and Hashimoto thyroiditis and allowed distinguishing of thyroid cancers from NCs with high accuracy (AUC = 0.782). Moreover, elevated serum HA levels in PTC correlate with LN metastasis. HA levels in FNA washouts from PTC patients were significantly higher than those in benign controls, with a high AUC value (0.8644) for distinguishing PTC from benign controls. Furthermore, HA levels in FNA washouts from metastatic LN were significantly higher than those in nonmetastatic LN, with a high AUC value (0.8007) for distinguishing metastatic LNs from nonmetastatic LNs. HA levels in serum and FNA washout exhibited a potential significance for PTC diagnosis and an indicator for LN metastasis in patients with PTC.

Developing preclinical dog models for reconstructive severed spinal cord continuity via spinal cord fusion technique.

Background: Spinal cord injury (SCI) is a severe impairment of the central nervous system, leading to motor, sensory, and autonomic dysfunction. The present study investigates the efficacy of the polyethylene glycol (PEG)-mediated spinal cord fusion (SCF) techniques, demonstrating efficacious in various animal models with complete spinal cord transection at the T10 level. This research focuses on a comparative analysis of three SCF treatment models in beagles: spinal cord transection (SCT), vascular pedicle hemisected spinal cord transplantation (vSCT), and vascularized allograft spinal cord transplantation (vASCT) surgical model. Methods: Seven female beagles were included in the SCT surgical model, while four female dogs were enrolled in the vSCT surgical model. Additionally, twelve female dogs underwent vASCT in a paired donor-recipient setup. Three surgical model were evaluated and compared through electrophysiology, imaging and behavioral recovery. Results: The results showed a progressive recovery in the SCT, vSCT and vASCT surgical models, with no statistically significant differences observed in cBBB scores at both 2-month and 6-month post-operation (both P>0.05). Neuroimaging analysis across the SCT, vSCT and vASCT surgical models revealed spinal cord graft survival and fiber regrowth across transection sites at 6 months postoperatively. Also, positive MEP waveforms were recorded in all three surgical models at 6-month post-surgery. Conclusion: The study underscores the clinical relevance of PEG-mediated SCF techniques in promoting nerve fusion, repair, and motor functional recovery in SCI. SCT, vSCT, and vASCT, tailored to specific clinical characteristics, demonstrated similar effective therapeutic outcomes.

Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML.

Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

Recovery mechanism of bio-promoters on Cr(VI) suppressed denitrification: Toxicity remediation and enhanced electron transmission.

Although the biotoxicity of heavy metals has been widely studied, there are few reports on the recovery strategy of the inhibited bio-system. This study proposed a combined promoter-I (Primary promoter: l-cysteine, biotin, and cytokinin + Electron-shuttle: PMo12) to recover the denitrification suppressed by Cr(VI). Compared with self-recovery, combined promoter-I shortened the recovery time of 28 cycles, and the recovered reactor possessed more stable long-term operation performance with >95 % nitrogen removal. The biomass increased by 7.07 mg VSS/(cm3 carrier) than self-recovery due to the promoted bacterial reproduction, thereby reducing the toxicity load of chromium per unit biomass. The combined promoter-I strengthened the toxicity remediation by promoting 92.84 % of the intracellular chromium release and rapidly activating anti-oxidative stress response. During toxicity remediation, ROS content quickly decreased, and the PN/PS value was 2.27 times that of self-recovery. PMo12 relieved Cr(VI) inhibition on NO3--N reduction by increasing NAR activity. The enhanced intracellular and intercellular electron transmission benefited from the stimulated NADH, FMN, and Cyt.c secretion by the primary promoter and the improved transmembrane electron transmission by Mo. PMo12 and the primary promoter synergized in regulating community structure and improving microbial richness. This study provided practical approaches for microbial toxicity remediation and maintaining high-efficiency denitrification.

Anchoring of hyaluronan glycocalyx to CD44 reduces sensitivity of HER2-positive gastric cancer cells to trastuzumab.

Trastuzumab is widely used in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) therapy, but ubiquitous resistance limits its clinical application. In this study, we first showed that CD44 antigen is a significant predictor of overall survival for patients with HER2-positive GC. Next, we found that CD44 could be co-immunoprecipitated and co-localized with HER2 on the membrane of GC cells. By analyzing the interaction between CD44 and HER2, we identified that CD44 could upregulate HER2 protein by inhibiting its proteasome degradation. Notably, the overexpression of CD44 could decrease the sensitivity of HER2-positive GC cells to trastuzumab. Further mechanistic study showed that CD44 upregulation could induce its ligand, hyaluronan (HA), to deposit on the cancer cell surface, resulting in covering up the binding sites of trastuzumab to HER2. Removing the HA glycocalyx restored sensitivity of the cells to trastuzumab. Collectively, our findings suggested a role for CD44 in regulating trastuzumab sensitivity and provided novel insights into HER2-targeted therapy.

Diagnosis of Esophageal Squamous Cell Carcinoma by High-Performance Serum Metabolic Fingerprints: A Retrospective Study.

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive malignancy, and timely diagnosis of ESCC contributes to an increased cancer survival rate. However, current detection methods for ESCC mainly rely on endoscopic examination, limited by a relatively low participation rate. Herein, ferric-particle-enhanced laser desorption/ionization mass spectrometry (FPELDI MS) is utilized to record the serum metabolic fingerprints (SMFs) from a retrospective cohort (523 non-ESCC participants and 462 ESCC patients) to build diagnostic models toward ESCC. The PFELDI MS achieved high speed (≈30 s per sample), desirable reproducibility (coefficients of variation < 15%), and high throughput (985 samples with ≈124 200 data points for each spectrum). Desirable diagnostic performance with area-under-the-curves (AUCs) of 0.925-0.966 is obtained through machine learning of SMFs. Further, a metabolic biomarker panel is constructed, exhibiting superior diagnostic sensitivity (72.2-79.4%, p < 0.05) as compared with clinical protein biomarker tests (4.3-22.9%). Notably, the biomarker panel afforded an AUC of 0.844 (95% confidence interval [CI]: 0.806-0.880) toward early ESCC diagnosis. This work highlighted the potential of metabolic analysis for accurate screening and early detection of ESCC and offered insights into the metabolic characterization of diseases including but not limited to ESCC.

Mitigating greenhouse gas emissions from municipal wastewater treatment in China.

Municipal wastewater treatment plays an indispensable role in enhancing water quality by eliminating contaminants. While the process is vital, its environmental footprint, especially in terms of greenhouse gas (GHG) emissions, remains underexplored. Here we offer a comprehensive assessment of GHG emissions from wastewater treatment plants (WWTPs) across China. Our analyses reveal an estimated 1.54 (0.92-2.65) × 104 Gg release of GHGs (CO2-eq) in 2020, with a dominant contribution from N2O emissions and electricity consumption. We can foresee a 60-65% reduction potential in GHG emissions with promising advancements in wastewater treatment, such as cutting-edge biological techniques, intelligent wastewater strategies, and a shift towards renewable energy sources.

CD44s-activated tPA/LRP1-NFκB pathway drives lamellipodia outgrowth in luminal-type breast cancer cells.

Some cancer cells migration and metastasis are characterized by the outgrowth of lamellipodia protrusions in which the underlying mechanism remains unclear. Evidence has confirmed that lamellipodia formation could be regulated by various adhesion molecules, such as CD44, and we previously reported that lamellipodia at the leading edge of luminal type breast cancer (BrCa) were enriched with high expression of CD44. In this study, we found that the overexpression of CD44s could promote lamellipodia formation in BrCa cells through inducing tissue type plasminogen activator (tPA) upregulation, which was achieved by PI3K/Akt signaling pathway activation. Moreover, we revealed that tPA could interact with LDL receptor related protein 1 (LRP1) to activate the downstream NFκB signaling pathway, which in turn facilitate lamellipodia formation. Notably, inhibition of the tPA/LRP1-NFkB signaling cascade could attenuate the CD44s-induced lamellipodia formation. Thus, our findings uncover a novel role of CD44s in driving lamellipodia outgrowth through tPA/LRP1-NFkB axis in luminal BrCa cells that may be helpful for seeking potential therapeutic targets.

Absorption and Metabolism of Urolithin A and Ellagic Acid in Mice and Their Cytotoxicity in Human Colorectal Cancer Cells.

Background: Ellagic acid is a natural polyphenol compound found in pomegranates, walnuts, and many berries. It is not easily absorbed, but it could be metabolized to urolithins by the gut microbiota. Urolithin A, one of the ellagic acid metabolites, has been proved to prolong the lifespan of C. elegans and increases muscle function of mice. The purpose of this current study was to analyze the absorption and metabolites of urolithin A and ellagic acid in mice and the anticancer effects of urolithin A, urolithin B, and ellagic acid in colorectal cancer cells. Methods: Urolithin A and urolithin B were synthesized and analyzed by HPLC and NMR. A pharmacokinetic study of urolithin A was performed in mice by analyzing urolithin A and its metabolites in urines. Absorption and biotransformation of ellagic acid were also studied in mice by analyzing the plasma, liver, and feces. The cytotoxicity of urolithin A, urolithin B, and ellagic acid was assayed in SW480, SW620, HCT 116, and HT-29 cells. Results: Urolithin A and urolithin B were synthesized and purified to reach 98.1% and 99% purity, respectively, and the structures were identified by NMR. In urolithin A intake analysis, urolithin A was only detectable at 3 h, not at 6-24 h; it suggested that urolithin A was rapidly metabolized to some unknown metabolites. Using UPLC-MS/MS analysis, the metabolites might be urolithin A 3-O-glucuronide, urolithin A 3-sulfate, and urolithin A-sulfate glucuronide. After feeding mice with ellagic acid for consecutive 14 days, ellagic acid contents could be detected in the fecal samples, but not in plasma and liver, and urolithin A was not detected in all samples. It suggests that ellagic acid is not easily absorbed and that the biotransformation of ellagic acid to urolithin A by intestinal flora might be very low. From the cytotoxicity assay, it was found that there was anticancer effect in urolithin A and urolithin B but not in ellagic acid. In contrast, ellagic acid promoted the proliferation of SW480 and SW620 cells.

Clinical Significance of Porphyromonas gingivalis Enriching Cancer Stem Cells by Inhibiting Programmed Cell Death Factor 4 in Esophageal Squamous Cell Carcinoma.

Studies have confirmed that the colonization of Porphyromonas gingivalis (Pg) could promote the malignant evolution of esophageal squamous cell carcinoma (ESCC). Since pathogenic microorganisms can promote malignant tumor proliferation by inhibiting programmed cell death factor 4 (PDCD4) and the decrease of PDCD4 activity can enhance the stemness of cancer cells, we here investigated the functional mechanism by which Pg promoted ESCC chemoresistance and malignancy through inhibiting PDCD4 and enriching cancer stem cells (CSCs). The effects of Pg and PDCD4 on CSCs, chemoresistance and malignancy of ESCC cells were evaluated by in vitro studies. The expression of Pg, PDCD4, and ALDH1 in ESCC tissues were detected by IHC, and the correlations between each index and postoperative survival of ESCC patients were analyzed. The results showed that Pg could inhibit PDCD4 expression and lead to CSCs enrichment in ESCC cells. After eliminating Pg, the expression of PDCD4 was upregulated, the percentage of CSCs, chemoresistance and malignancy were decreased. ESCC patients with Pg-positive, PDCD4-negative, and ALDH1-positive have a significant shorter survival. This study proved that eliminating Pg and blocking CSCs enrichment caused by decreasing PDCD4 activity may provide a new strategy for ESCC treatment.

Impact of sertraline on biohydrogen production from alkaline anaerobic fermentation of waste activated sludge: Focusing on microbial community and metabolism.

Nowadays, antidepressants are massively consumed worldwide, inevitably bringing about the concern for their latent hazard to the natural environment. This research focused on exploring the effect of sertraline (SET, a typical antidepressant) on hydrogen yields from alkaline anaerobic fermentation of waste activated sludge (WAS). The hydrogen accumulation reached the peak of 14.73 mL/g VSS (volatile suspended solids) at a SET dosage of 50 mg/kg TSS (total suspended solids), i.e., 1.90 times of that in the control fermenter. The data of Illumina high-throughput sequencing demonstrated that SET promoted the expression of genes regulating the membrane transport. Microbial community analysis suggested that some species that could degrade refractory substances were enriched after SET exposure. Finally, metabolic pathways of hydrogen production and consumption were found to be significantly affected with SET addition. This study would deepen the concept of typical antidepressants influencing energy recovery from WAS.

The role of mononuclear phagocyte system in IgA nephropathy: pathogenesis and prognosis.

Although the "multiple hits" theory is a widely accepted pathogenesis in IgA nephropathy (IgAN), increasing evidence suggests that the mononuclear/macrophage system plays important roles in the progression of IgAN; however, the exact mechanism is unclear. In the present study, we explored 1,067 patients in 15 studies and found that the number of macrophages per glomerulus was positively related with the degree of hematuria, and the macrophages in the glomeruli were mainly related to mesangial proliferation (M) in renal biopsy. In the tubulointerstitium, macrophages were significantly paralleled to tubulointerstitial α-SMA and NF-kB expression, tubulointerstitial lesion, tubule atrophy/interstitial fibrosis (T), and segmental glomerulosclerosis (S). In the glomeruli and tubulointerstitium, M1 accounted for 85.41% in the M classification according to the Oxford MEST-C, while in the blood, M1 accounted for 100%, and the patients with low CD89+ monocyte mean fluorescence intensity displayed more severe pathological characteristics (S1 and T1-2) and clinical symptoms. M1 (CD80+) macrophages were associated with proinflammation in the acute phase; however, M2 (CD163+) macrophages participated in tissue repair and remodeling, which correlated with chronic inflammation. In the glomeruli, M2 macrophages activated glomerular matrix expansion by secreting cytokines such as IL-10 and tumor necrosis factor-ß (TGF-ß), and M0 (CD68+) macrophages stimulated glomerular hypercellularity. In the tubulointerstitium, M2 macrophages played pivotal roles in renal fibrosis and sclerosis. It is assumed that macrophages acted as antigen-presenting cells to activate T cells and released diverse cytokines to stimulate an inflammatory response. Macrophages infiltrating glomeruli destroy the integrity of podocytes through the mesangio-podocytic-tubular crosstalk as well as the injury of the tubule.

Incidence and predictors of anthracycline-related left ventricular dysfunction in acute myeloid leukemia.

INTRODUCTION: Anthracycline-related left ventricular dysfunction (ARLVD) is a concern in patients with acute myeloid leukemia (AML) undergoing anthracyclinecontaining induction chemotherapy. However, the incidence of ARLVD in the modern era of routine pretreatment left ventricular ejection fraction (LVEF) echocardiographic assessment, as well as the clinical and genetic predictors of ARLVD are not well understood. METHODS: Consecutive adult patients with AML receiving anthracycline-containing induction chemotherapy at the Dana-Farber Cancer Institute from 2014 to 2022 were studied. Inclusion criteria included availability of a pre and post chemotherapy echocardiogram to assess the LVEF, pre-treatment LVEF > 50 %, as well as comprehensive diagnostic next generation sequencing assessing for the presence of myeloid mutations. The primary endpoint was the incidence of ARLVD defined as LVEF < 50 % post-induction. RESULTS: Out of 419 patients meeting inclusion criteria, 34 (8%) patients developed ARLVD. Among the 122/419 patients who did not undergo planned allogeneic stem cell transplantation (allo-SCT), ARLVD was the deciding factor for ineligibility in 4 patients (1%). Baseline cardiovascular comorbidities (hypertension, diabetes mellitus, hyperlipidemia, smoking and coronary artery disease) and cumulative anthracycline dose were not predictive of post-induction ARLVD. However, the presence of a JAK2 mutation (but not other myeloid mutations) was associated with an increased risk of ARLVD in multivariable analysis (OR 8.34, 95 % CI 1.55-39.3, p = 0.007). DISCUSSION: In a group of AML patients with normal LVEF prior to anthracycline-containing induction chemotherapy, ARLVD was infrequent and did not commonly preclude post-remission allo-SCT consolidation. Genetic predictors of ARLVD require further investigation in a larger patient cohort.

Mesenchymal stromal cell-derived magnetic nanovesicles for enhanced skin retention and hair follicle growth.

BACKGROUND AIMS: Extracellular vesicles and exosome-mimetic nanovesicles (NVs) derived from mesenchymal stromal cells (MSCs) have emerged as promising to promote hair growth. However, short local skin retention after subcutaneous administration hinders their clinical applications. METHODS: In this study, we prepared magnetic nanovesicles (MNVs) from iron oxide nanoparticle-incorporated MSCs. MNVs contained more therapeutic growth factors than NVs derived from naive MSCs, and their localization and internalization were manipulated by external magnetic field. RESULTS: Following the subcutaneous injection of MNVs into a mouse model of depilation-induced hair regeneration, the magnetic attraction increased their skin retention. Then, the cellular proliferation and ß-catenin signaling in hair follicles (HF) were markedly enhanced by MNV injection and magnetic field application. Furthermore, an acceleration of HF growth was revealed by histological analysis. CONCLUSIONS: The proposed strategy can enhance the therapeutic potential of MSC-derived NVs for hair regeneration and other dermatological diseases.

A Model-free Variable Screening Method Based on Leverage Score.

With rapid advances in information technology, massive datasets are collected in all fields of science, such as biology, chemistry, and social science. Useful or meaningful information is extracted from these data often through statistical learning or model fitting. In massive datasets, both sample size and number of predictors can be large, in which case conventional methods face computational challenges. Recently, an innovative and effective sampling scheme based on leverage scores via singular value decompositions has been proposed to select rows of a design matrix as a surrogate of the full data in linear regression. Analogously, variable screening can be viewed as selecting rows of the design matrix. However, effective variable selection along this line of thinking remains elusive. In this article, we bridge this gap to propose a weighted leverage variable screening method by utilizing both the left and right singular vectors of the design matrix. We show theoretically and empirically that the predictors selected using our method can consistently include true predictors not only for linear models but also for complicated general index models. Extensive simulation studies show that the weighted leverage screening method is highly computationally efficient and effective. We also demonstrate its success in identifying carcinoma related genes using spatial transcriptome data.