Higher mortality and longer length of stay in hospitalized patients with newly diagnosed diabetes.

AIMS: We investigated the association between diabetes status at admission and in-hospital outcomes in all hospitalized patients, regardless of the reason for admission. METHODS: All individuals aged 20 years or older who were admitted to Yongin Severance Hospital between March 2020 and February 2022 were included in study. Subjects were categorized into three groups: non-DM, known DM, and newly diagnosed DM, based on medical history, anti-diabetic medications use, and laboratory test. Hospitalization-related outcomes, including in-hospital mortality and length of hospital stay, were compared between groups. RESULTS: 33,166 participants were enrolled. At hospitalization, 6,572 (19.8 %) subjects were classified as known DM, and another 2,634 (7.9 %) subjects were classified as newly diagnosed DM. In-hospital mortality was highest in newly diagnosed DM (HR 1.89, 95% CI 1.58-2.26, p < 0.001) followed by known DM (HR 1.41, 95% CI 1.18-1.69, p < 0.001) compared to non-DM. Length of hospital stay was significantly longer in newly diagnosed DM (median [IQR] 9.0 [5.0-18.0],days) than known DM (median [IQR] 5.0 [3.0-10.0],days)(p < 0.001) and non-DM (median [IQR] 4.0 [2.0-7.0],days). After adjusting for multiple covariates, newly diagnosed diabetes was independently associated with increased in-hospital mortality (p < 0.001). CONCLUSIONS: Diabetes status at admission was closely linked to hospitalization-related outcomes. Notably, individuals with newly diagnosed diabetes demonstrated a higher risk of in-hospital mortality and a prolonged length of hospital stay.

An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.

Analysis of the human hematopoietic progenitor compartment is being transformed by single-cell multimodal approaches. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) enables coupled surface protein and transcriptome profiling, thereby revealing genomic programs underlying progenitor states. To perform CITE-seq systematically on primary human bone marrow cells, we used titrations with 266 CITE-seq antibodies (antibody-derived tags) and machine learning to optimize a panel of 132 antibodies. Multimodal analysis resolved >80 stem, progenitor, immune, stromal and transitional cells defined by distinctive surface markers and transcriptomes. This dataset enables flow cytometry solutions for in silico-predicted cell states and identifies dozens of cell surface markers consistently detected across donors spanning race and sex. Finally, aligning annotations from this atlas, we nominate normal marrow equivalents for acute myeloid leukemia stem cell populations that differ in clinical response. This atlas serves as an advanced digital resource for hematopoietic progenitor analyses in human health and disease.

Robust Chemical Synthesis of "Difficult Peptides" via 2-Hydroxyphenol-pseudoproline (ψ2-hydroxyphenolpro) Modifications.

The challenging preparation of "difficult peptides" has always hindered the development of peptide-active pharmaceutical ingredients. Pseudoproline (ψpro) building blocks have been proven effective and powerful tools for the synthesis of "difficult peptides". In this paper, we efficiently prepared a set of novel 2-(oxazolidin-2-yl)phenol compounds as proline surrogates (2-hydroxyphenol-pseudoprolines, ψ2-hydroxyphenolpro) and applied it in the synthesis of many well-known "difficult peptides", including human thymosin α1, amylin, and ß-amyloid (1-42) (Aß42).

Synthesis and antimicrobial studies of cadasides analogues via on-resin esterification.

A series of cadasides analogues have been prepared via a combination of solid-phase peptide synthesis and solution-phase cyclization. Primary structure-activity relationship studies of cadasides have also been established and revealed the critical roles of unnatural amino acid residues, which will facilitate the further development of cadasides analogues with improved antimicrobial activities.

Objective Assessment of Visual Field Defects Caused by Optic Chiasm and Its Posterior Visual Pathway Injury.

OBJECTIVES: To investigate the characteristics and objective assessment method of visual field defects caused by optic chiasm and its posterior visual pathway injury. METHODS: Typical cases of visual field defects caused by injuries to the optic chiasm, optic tracts, optic radiations, and visual cortex were selected. Visual field examinations, visual evoked potential (VEP) and multifocal visual evolved potential (mfVEP) measurements, craniocerebral CT/MRI, and retinal optical coherence tomography (OCT) were performed, respectively, and the aforementioned visual electrophysiological and neuroimaging indicators were analyzed comprehensively. RESULTS: The electrophysiological manifestations of visual field defects caused by optic chiasm injuries were bitemporal hemianopsia mfVEP abnormalities. The visual field defects caused by optic tract, optic radiation, and visual cortex injuries were all manifested homonymous hemianopsia mfVEP abnormalities contralateral to the lesion. Mild relative afferent pupil disorder (RAPD) and characteristic optic nerve atrophy were observed in hemianopsia patients with optic tract injuries, but not in patients with optic radiation or visual cortex injuries. Neuroimaging could provide morphological evidence of damages to the optic chiasm and its posterior visual pathway. CONCLUSIONS: Visual field defects caused by optic chiasm, optic tract, optic radiation, and visual cortex injuries have their respective characteristics. The combined application of mfVEP and static visual field measurements, in combination with neuroimaging, can maximize the assessment of the location and degree of visual pathway damage, providing an effective scheme for the identification of such injuries.

Bering: joint cell segmentation and annotation for spatial transcriptomics with transferred graph embeddings.

Single-cell spatial transcriptomics such as in-situ hybridization or sequencing technologies can provide subcellular resolution that enables the identification of individual cell identities, locations, and a deep understanding of subcellular mechanisms. However, accurate segmentation and annotation that allows individual cell boundaries to be determined remains a major challenge that limits all the above and downstream insights. Current machine learning methods heavily rely on nuclei or cell body staining, resulting in the significant loss of both transcriptome depth and the limited ability to learn latent representations of spatial colocalization relationships. Here, we propose Bering, a graph deep learning model that leverages transcript colocalization relationships for joint noise-aware cell segmentation and molecular annotation in 2D and 3D spatial transcriptomics data. Graph embeddings for the cell annotation are transferred as a component of multi-modal input for cell segmentation, which is employed to enrich gene relationships throughout the process. To evaluate performance, we benchmarked Bering with state-of-the-art methods and observed significant improvement in cell segmentation accuracies and numbers of detected transcripts across various spatial technologies and tissues. To streamline segmentation processes, we constructed expansive pre-trained models, which yield high segmentation accuracy in new data through transfer learning and self-distillation, demonstrating the generalizability of Bering.

Spatiotemporal variability and environmental effects of greenhouse gases, nutrients, and dissolved carbons in an ice-covered reservoir.

Ice cover restructures the distribution of substances in ice and underlying water and poses non-negligible environmental effects. This study aimed to clarify the spatiotemporal variability and environmental effects of methane (CH4), nitrous oxide (N2O), total nitrogen (TN), total phosphorus (TP), dissolved organic carbon (DOC), and dissolved inorganic carbon (DIC) in ice and water columns during different ice-covered periods. We surveyed the ice-growth, ice-stability, and ice-melt periods in an ice-covered reservoir located in Northeast China. The results showed that underlying water (CH4: 1218.9 ± 2678.9 nmol L-1 and N2O: 19.3 ± 7.3 nmol L-1) and ice (CH4: 535.2 ± 2373.1 nmol L-1 and N2O: 9.9 ± 1.5 nmol L-1) were sources of atmospheric greenhouse gases. N2O concentrations were the highest in the bottom water of the reservoir while CH4 accumulated the most below the ice in the riverine zone. These can be attributed to differences in the solubilities and relative molecular masses of the two gases. Higher concentrations of N2O, TN, TP, DOC, and DIC were recorded in the underlying water than those in the ice due to the preferential redistribution of these substances in the aqueous phase during ice formation. Additionally, we distinguished between bubble and no-bubble areas in the riverine zone and found that the higher CH4 concentrations in the underlying water than those in the ice were due to CH4 bubbles. In addition, we reviewed various substances in ice-water systems and found that the substances in ice-water systems can be divided into solute exclusion and particle entrapment, which are attributed to differences between dissolved and particulate states. These findings are important for a comprehensive understanding of substances dynamics during ice-covered periods.

Huoxue Tongluo decoction combined with acupuncture in the treatment of lumbar disc herniation and its effect on JOA and VAS scores.

BACKGROUND: Lumbar disc herniation (LDH) is a common clinical disease of the skeletal system, and its prevalence has been on a rise. OBJECTIVE: To evaluate the efficacy of Huoxue Tongluo decoction plus acupuncture in the treatment of lumbar disc herniation and its effectiveness in improving the functional recovery of the patients' affected joints and mitigating their pain. METHODS: In this prospective study, 110 patients with lumbar disc herniation enrolled in our Hospital from June 2019 to June 2021 were collected and randomized to receive either conventional treatment (control group) or Huoxue Tongluo Decoction plus acupuncture (study group). RESULTS: Huoxue Tongluo Decoction plus acupuncture resulted in more rapid mitigation of lower extremity symptoms and lumbar symptoms versus conventional treatment (P< 0.05). Patients receiving traditional Chinese medicine (TCM) showed milder inflammatory responses than those with conventional medication, as evidenced by the lower serum concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and high-sensitivity C-reactive protein (hs-CRP) (P< 0.05). After treatment, the study group had higher Japanese Orthopedic Association (JOA) scores and lower visual analogue scale (VAS) scores than the control group (P< 0.05), suggesting that the combination of the herbal decoction and acupuncture provided better functional recovery of the affected joints and pain mitigation for the patients. Furthermore, the lower Pittsburgh sleep quality index (PSQI) scores in patients in the study group indicated better sleep quality of patients after TCM intervention than after conventional treatment (P< 0.05). Huoxue Tongluo Decoction plus acupuncture was associated with a significantly higher efficacy (94.55%) versus conventional treatment (80%) (P< 0.05). CONCLUSIONS: Huoxue Tongluo Decoction combined with acupuncture significantly offers a viable treatment alternative for lumbar disc herniation with promising treatment outcomes, mitigates patients' limb pain, and improves their lumbar function and sleep quality. Further trials are, however, required prior to general application in clinical practice.

Guided construction of single cell reference for human and mouse lung.

Accurate cell type identification is a key and rate-limiting step in single-cell data analysis. Single-cell references with comprehensive cell types, reproducible and functionally validated cell identities, and common nomenclatures are much needed by the research community for automated cell type annotation, data integration, and data sharing. Here, we develop a computational pipeline utilizing the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples to construct LungMAP single-cell reference (CellRef) for both normal human and mouse lungs. CellRefs define 48 human and 40 mouse lung cell types catalogued from diverse anatomic locations and developmental time points. We demonstrate the accuracy and stability of LungMAP CellRefs and their utility for automated cell type annotation of both normal and diseased lungs using multiple independent methods and testing data. We develop user-friendly web interfaces for easy access and maximal utilization of the LungMAP CellRefs.

Single-cell m6A mapping in vivo using picoMeRIP-seq.

Current N6-methyladenosine (m6A) mapping methods need large amounts of RNA or are limited to cultured cells. Through optimized sample recovery and signal-to-noise ratio, we developed picogram-scale m6A RNA immunoprecipitation and sequencing (picoMeRIP-seq) for studying m6A in vivo in single cells and scarce cell types using standard laboratory equipment. We benchmark m6A mapping on titrations of poly(A) RNA and embryonic stem cells and in single zebrafish zygotes, mouse oocytes and embryos.

Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids.

De novo mutations and copy number deletions in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how NRXN1 deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cell-derived forebrain organoid models carrying NRXN1 heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single-cell transcriptomic analysis over the course of brain organoid development from 3 weeks to 3.5 months. Intriguingly, while both deletions similarly impacted molecular pathways associated with ubiquitin-proteasome system, alternative splicing, and synaptic signaling in maturing glutamatergic and GABAergic neurons, SCZ-NRXN1 deletions specifically perturbed developmental trajectories of early neural progenitors and accumulated disease-specific transcriptomic signatures. Using calcium imaging, we found that both deletions led to long-lasting changes in spontaneous and synchronous neuronal networks, implicating synaptic dysfunction. Our study reveals developmental-timing- and cell-type-dependent actions of NRXN1 deletions in unique genetic contexts.

Chemical Strategies towards the Development of Effective Anticancer Peptides.

Cancer is increasingly recognized as one of the primary causes of death and has become a multifaceted global health issue. Modern medical science has made significant advancements in the diagnosis and therapy of cancer over the past decade. The detrimental side effects, lack of efficacy, and multidrug resistance of conventional cancer therapies have created an urgent need for novel anticancer therapeutics or treatments with low cytotoxicity and drug resistance. The pharmaceutical groups have recognized the crucial role that peptide therapeutic agents can play in addressing unsatisfied healthcare demands and how these become great supplements or even preferable alternatives to biological therapies and small molecules. Anticancer peptides, as a vibrant therapeutic strategy against various cancer cells, have demonstrated incredible anticancer potential due to high specificity and selectivity, low toxicity, and the ability to target the surface of traditional "undruggable" proteins. This review will provide the research progression of anticancer peptides, mainly focusing on the discovery and modifications along with the optimization and application of these peptides in clinical practice.

Association between motoric cognitive risk syndrome and future falls among Chinese community-dwelling elderly: A nationwide cohort study.

BACKGROUND: Motoric Cognitive Risk syndrome (MCR), known as the predementia stage, is characterized by both subjective cognitive complaint (SCC) and slow gait. This study aimed to investigate the causal relationship between MCR, its components, and falls. METHODS: Participants aged ≥ 60 years were selected from China Health and Retirement Longitudinal Study. SCC was determined by participants' responses to the question "How would you rate your memory at present?" with "poor" being the indicative answer. Slow gait was defined as one standard deviation or more below age- and gender-appropriate mean values of gait speed. MCR was identified when both SCC and slow gait were presented. Future falls were investigated by the question "have you fallen down during follow-up until wave 4 in 2018?" Logistic regression analysis was performed to test the longitudinal association of MCR, its components and future falls during the following 3 years. RESULTS: Of 3748 samples in this study, the prevalence of MCR, SCC, and slow gait was 5.92%, 33.06%, and 15.21%, respectively. MCR increased the risk of falls during the following 3 years by 66.7% compared to non-MCR after controlling for covariates. In the fully adjusted models, with the healthy group as reference, MCR (OR = 1.519, 95%CI = 1.086-2.126) and SCC (OR = 1.241, 95%CI = 1.018-1.513), but not slow gait, increased the risk of future falls. CONCLUSIONS: MCR independently predicts future falls risk in the following 3 years. Measuring MCR can be a pragmatic tool for early identification of falls risk.

Ethacrynic acid suppresses B7-H4 expression involved in epithelial-mesenchymal transition of lung adenocarcinoma cells via inhibiting STAT3 pathway.

Lung cancer is characterized by high incidence and mortality. 90% of cancer deaths are caused by metastases. The epithelial-mesenchymal transition (EMT) process in cancer cells is a prerequisite for the metastatic process. Ethacrynic acid (ECA) is a loop diuretic that inhibits the EMT process in lung cancer cells. EMT has been related to the tumour immunemicroenvironment. However, the effect of ECA on immune checkpoint molecules in the context of cancer has not been fully identified. In the present study, we found that sphingosylphosphorylcholine (SPC) and TGF-ß1, awell-known EMT inducer, induced the expression of B7-H4 in lung cancer cells. We also investigated the involvement of B7-H4 in the SPC-induced EMT process. Knockdown of B7-H4 suppressed SPC-induced EMT, while B7-H4 overexpression enhanced EMT of lung cancer cells. ECA inhibited SPC/TGF-ß1-induced B7-H4 expression via suppression of STAT3 activation. Moreover, ECA inhibits the colonization of mice lung by tail vein-injected LLC1 cells. ECA-treated mice increased the CD4-positive T cells in lung tumour tissues. In summary, these results suggested that ECA inhibits B7-H4 expression via STAT3 inhibition, leading to SPC/TGF-ß1-induced EMT. Therefore, ECA might be an immune oncological drug for B7-H4-positive cancer, especially lung cancer.

Liquid Crystalline Systems from Nature and Interaction of Living Organisms with Liquid Crystals.

Biomaterials, which are substances interacting with biological systems, have been extensively explored to understand living organisms and obtain scientific inspiration (such as biomimetics). However, many aspects of biomaterials have yet to be fully understood. Because liquid crystalline phases are ubiquitously found in biomaterials (e.g., cholesterol, amphiphile, DNA, cellulose, bacteria), therefore, a wide range of research has made attempts to approach unresolved issues with the concept of liquid crystals (LCs). This review presents these studies that address the interactive correlation between biomaterials and LCs. Specifically, intrinsic LC behavior of various biomaterials such as DNA, cellulose nanocrystals, and bacteriaare first introduced. Second, the dynamics of bacteria in LC media are addressed, with focus on how bacteria interact with LCs, and how dynamics of bacteria can be controlled by exploiting the characteristics of LCs. Lastly, how the strong correlation between LCs and biomaterials has been leveraged to design a new class of biosensors with additional functionalities (e.g., self-regulated drug release) that are not available in previous systems is reviewed. Examples addressed in this review convey the message that the intersection between biomaterials and LCs offers deep insights into fundamental understanding of biomaterials, and provides resources for development of transformative technologies.

Function and structure of bradykinin receptor 2 for drug discovery.

Type 2 bradykinin receptor (B2R) is an essential G protein-coupled receptor (GPCR) that regulates the cardiovascular system as a vasodepressor. Dysfunction of B2R is also closely related to cancers and hereditary angioedema (HAE). Although several B2R agonists and antagonists have been developed, icatibant is the only B2R antagonist clinically used for treating HAE. The recently determined structures of B2R have provided molecular insights into the functions and regulation of B2R, which shed light on structure-based drug design for the treatment of B2R-related diseases. In this review, we summarize the structure and function of B2R in relation to drug discovery and discuss future research directions to elucidate the remaining unknown functions of B2R dimerization.

Busulfan, Melphalan, and Etoposide (BuME) Showed an Equivalent Effect to Busulfan, Cyclophosphamide, and Etoposide (BuCE) as Conditioning Therapy for Autologous Stem Cell Transplantation in Patients with Relapsed or High-Risk Non-Hodgkin’s Lymphoma: A Multicenter Randomized Phase II Study bythe Consortium for Improving Survival of Lymphoma (CISL) / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard management for relapsed or high-risk non-Hodgkin’s lymphoma (NHL). We reported the busulfan, melphalan, and etoposide (BuME) conditioning regimen was effective in patients with relapsed or high-risk NHL. Moreover, the busulfan, cyclophosphamide, and etoposide (BuCE) conditioning regimen has been used widely in ASCT for NHL. Therefore, based on these encouraging results, this randomized phase II multicenter trial compared the outcomes of BuME and BuCE as conditioning therapies for ASCT in patients with NHL. @*Materials and Methods@#Patients were randomly assigned to receive either BuME (n=36) or BuCE (n=39). The BuME regimen was comprised of busulfan (3.2 mg/kg/day, intravenously) administered on days –7, –6, and –5, etoposide (400 mg/m2 intravenously) on days –5 and –4, and melphalan (50 mg/m2/day intravenously) on days –3 and –2. The BuCE regimen was comprised of busulfan (3.2 mg/kg/day intravenously) on days –7, –6, and –5, etoposide (400 mg/m2/day intravenously) on days –5 and –4, and cyclophosphamide (50 mg/kg/day intravenously) on days –3 and –2. The primary endpoint was 2-year progression-free survival (PFS). @*Results@#Seventy-five patients were enrolled. Eleven patients (30.5%) in the BuME group and 13 patients (33.3%) in the BuCE group had disease progression or died. The 2-year PFS rate was 65.4% in the BuME group and 60.6% in the BuCE group (p=0.746). There were no non-relapse mortalities within 100 days after transplantation. @*Conclusion@#There were no significant differences in PFS between the two groups. Therefore, busulfan-based conditioning regimens, BuME and BuCE, may be important treatment substitutes for the BCNU-containing regimens.

Outcomes in Refractory Diffuse Large B-Cell Lymphoma: Results from Two Prospective Korean Cohorts / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy worldwide. Although substantial improvement has been achieved by the frontline rituximab-based chemoimmunotherapy, up to 40%-50% of patients will eventually have relapsed or refractory disease, whose prognosis is extremely dismal. @*Materials and Methods@#We have carried out two prospective cohort studies that include over 1,500 DLBCL patients treated with rituximab plus CHOP (#NCT01202448 and #NCT02474550). In the current report, we describe the outcomes of refractory DLBCL patients. Patients were defined to have refractory DLBCL if they met one of the followings, not achieving at least partial response after 4 or more cycles of R-CHOP; not achieving at least partial response after 2 or more cycles of salvage therapy; progressive disease within 12 months after autologous stem cell transplantation. @*Results@#Among 1,581 patients, a total of 260 patients met the criteria for the refractory disease after a median time to progression of 9.1 months. The objective response rate of salvage treatment was 26.4%, and the complete response rate was 9.6%. The median overall survival (OS) was 7.5 months (95% confidence interval, 6.4 to 8.6), and the 2-year survival rate was 22.1%±2.8%. The median OS for each refractory category was not significantly different (p=0.529). @*Conclusion@#In line with the previous studies, the outcomes of refractory DLBCL patients were extremely poor, which necessitates novel approaches for this population.

Epidemiologic and Clinical Outcomes of Pediatric Renal Tumors in Korea: A Retrospective Analysis of The Korean Pediatric Hematology and Oncology Group (KPHOG) Data / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Renal tumors account for approximately 7% of all childhood cancers. These include Wilms tumor (WT), clear cell sarcoma of the kidney (CCSK), malignant rhabdoid tumor of the kidney (MRTK), renal cell carcinoma (RCC), congenital mesoblastic nephroma (CMN) and other rare tumors. We investigated the epidemiology of pediatric renal tumors in Korea. @*Materials and Methods@#From January 2001 to December 2015, data of pediatric patients (0–18 years) newly-diagnosed with renal tumors at 26 hospitals were retrospectively analyzed. @*Results@#Among 439 patients (male, 240), the most common tumor was WT (n=342, 77.9%), followed by RCC (n=36, 8.2%), CCSK (n=24, 5.5%), MRTK (n=16, 3.6%), CMN (n=12, 2.7%), and others (n=9, 2.1%). Median age at diagnosis was 27.1 months (range 0-225.5) and median follow-up duration was 88.5 months (range 0-211.6). Overall, 32 patients died, of whom 17, 11, 1, and 3 died of relapse, progressive disease, second malignant neoplasm, and treatment-related mortality. Five-year overall survival and event free survival were 97.2% and 84.8% in WT, 90.6% and 82.1% in RCC, 81.1% and 63.6% in CCSK, 60.3% and 56.2% in MRTK, and 100% and 91.7% in CMN, respectively (p < 0.001). @*Conclusion@#The pediatric renal tumor types in Korea are similar to those previously reported in other countries. WT accounted for a large proportion and survival was excellent. Non-Wilms renal tumors included a variety of tumors and showed inferior outcome, especially MRTK. Further efforts are necessary to optimize the treatment and analyze the genetic characteristics of pediatric renal tumors in Korea.