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Male infertility is a worldwide health issue, affecting 8%–12% of the global population. Oligoasthenoteratozoospermia (OAT) represents a severe type of male infertility, characterized by reduced sperm count and motility and an increased frequency of sperm with aberrant morphology. Using whole-exome sequencing, this study identified a novel missense mutation (c.848C>A, p.A283E) in the coiled-coil domain-containing 34 gene (CCDC34) in a consanguineous Pakistani family. This rare mutation was predicted to be deleterious and to affect the protein stability. Hematoxylin and eosin staining of spermatozoa from the patient with OAT revealed multiple morphological abnormalities of the flagella and transmission electron microscopy indicated axonemal ultrastructural defects with a lack of outer dynein arms. These findings indicated that CCDC34 plays a role in maintaining the axonemal ultrastructure and the assembly or stability of the outer dynein arms, thus expanding the phenotypic spectrum of CCDC34 missense mutations.

Abstract In eukaryotes, topologically associating domains (TADs) organize the genome into functional compartments. While TAD-like structures are common in mammals and many plants, they are challenging to detect in Arabidopsis thaliana. Here, we demonstrate that Arabidopsis PDS5 proteins play a negative role in TAD-like domain formation. Through Hi-C analysis, we show that mutations in PDS5 genes lead to the widespread emergence of enhanced TAD-like domains throughout the Arabidopsis genome, excluding pericentromeric regions. These domains exhibit increased chromatin insulation and enhanced chromatin interactions, without significant changes in gene expression or histone modifications. Our results suggest that PDS5 proteins are key regulators of genome architecture, influencing 3D chromatin organization independently of transcriptional activity. This study provides insights into the unique chromatin structure of Arabidopsis and the broader mechanisms governing plant genome folding.

Abstract Dynamic axion insulators feature a time-dependent axion field that can be induced by antiferromagnetic resonance. Here, we show that a Josephson junction incorporating this dynamic axion insulator between two superconductors exhibits striking doubled Shapiro steps wherein all odd steps are completely suppressed in the joint presence of a DC bias and a static magnetic field. The resistively shunted junction simulation confirms that these doubled Shapiro steps originate from the distinctive axion electrodynamics driven by the antiferromagnetic resonance, which thus not only furnishes a hallmark to identify the dynamic axion insulator but also provides a method to evaluate its mass term. Furthermore, the experimentally feasible differential conductance is also determined. Our work holds significant importance in condensed matter physics and materials science for understanding the dynamic axion insulator, paving the way for its further exploration and applications.

Abstract Gastric cancer (GC) is a highly heterogeneous and aggressive malignant tumor that seriously affects the life safety of people all over the world. Its early manifestations are subtle. The present study aimed to investigate the clinical significance of serum lipid profiles, insulin resistance markers including the triglyceride-glucose (TyG) index and the atherosclerotic index (AI), in GC patients. A retrospective analysis encompassed 215 GC patients and 827 healthy individuals. The study results show that the total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein levels, and the TyG index of GC patients were significantly lower than those of the control group before and after propensity score matching analysis. In the GC group, the levels of CEA, CA199, CA125, and CA724 tumor markers were higher than those in the healthy control group. Patients in advanced stages exhibited lower serum levels of serum lipids and TyG index compared to those in early stages. ROC analysis revealed that the TyG index, CA125, and CA199 combination yielded the highest positive prediction rate for GC at 98.6%. TyG index is significantly associated with the risk of adverse reactions after chemotherapy (OR = 1.104, 95% CI 1.028–1.186, P

Through the analysis of natural gas composition, carbon and hydrogen isotopes of alkane gases, reservoir bitumen, source rock conditions, and source–reservoir combinations, this study clarifies the differences in gas sources and the origins of natural gas in the Permian Changxing Formation–Triassic Feixianguan Formation on both sides of the Kaijiang–Liangping Trough. Additionally, it identifies favorable exploration directions for coal-formed gas generated by the Longtan Formation in the Sichuan Basin. The following understanding was obtained: (1) The natural gas in the Changxing–Feixianguan formations mainly composed of alkane gas, typical of dry gas. (2) The carbon isotope values of methane and ethane in the Changxing–Feixianguan formations on the east side of the trough are lower than those on the west side. Specifically, the ethane carbon isotope value in the Longgang Gas Field on the west side is higher than that in the Yuanba Gas Field, while the methane hydrogen isotope value is lower in the Longgang Gas Field compared to the Yuanba Gas Field. (3) The natural gas in the Dongyuezhai, Puguang, and Yuanba gas fields predominantly originates from sapropelic organic matter of the Wujiaping Formation, with kerogen types II1–I; in contrast, the Longgang Gas Field contains a mixture of coal-formed gas and oil-type gas, with a slightly higher content of coal-formed gas, originating from mixed organic matter of the Wujiaping Formation, with kerogen type II1–II2. (4) Multiple types of gas, such as coal rock gas, tight sandstone gas, and shale gas, can be formed within the Longtan Formation. The Suining–Luzhou and Langzhong–Guang'an–Fuling areas are identified as favorable zones for the exploration of coal rock gas and marine–continental transitional shale gas, respectively. Additionally, the reef and shoal development areas of the Changxing Formation in the Suining–Hechuan and Guang'an–Nanchong regions are also favorable exploration areas for coal-formed gas.

Based on the “unidirectional break-up and convergence” geodynamic model, this study investigates the impact of the evolution of the Tethyan domain on the formation of petroleum systems in the Sichuan super basin and explores the enrichment pattern of natural gas. The results show that, firstly, the Sichuan Basin and its surrounding areas have experienced two unidirectional rifting-aggregation cycles triggered by the Proto-Tethys Ocean and the Paleo-Tethys Ocean during the Neoproterozoic to Triassic. During Jurassic–Cenozoic, the Sichuan Basin is incorporated in the circum-Tibetan plateau basin-mountain coupled tectonic domain system. The episodic tectonic movements within the plate control the sedimentary infill styles. Second, the evolution of the Tethyan domain, paleoclimatic environment and major geological events controlled the formation and distribution of high-quality source rocks within the basin. The rift valley and intracratonic rift, passive continental margin slope, and intracratonic sags are favorable areas for the development of source rocks. Third, the evolution of the Tethyan domain, supercontinent cycles, global sea level changes, and tectono-climatic events controlled the distribution of carbonate platform and reservoir-caprock combinations. The cratonic platform margins and sub-platform internal high terrains are key areas for finding carbonate high-energy facies belts. Syndepositional paleo-uplifts and surrounding slopes, regional unconformities, and later faults zone are areas where large-scale carbonate reservoirs are distributed. The regional evaporite or shale caprock are beneficial for the large-scale preservation of oil and gas in the basin. Fourth, the spatio-temporal matching relationship of reservoir forming factors influenced by the early tectonic-sedimentary evolution pattern and the degree of later tectonic modification is the key to oil and gas enrichment. Future oil and gas exploration should focus on potential gas systems during the Sinian rift period, Cambrian pre-salt gas systems in the eastern and southern Sichuan, as well as whole oil and gas systems of Permian and Triassic.

Abstract IL-1β represents an important inflammatory factor involved in the host response against GBS infection. Prior research has suggested a potential involvement of IL-1β in the process of ferroptosis. However, the relationship between IL-1β and ferroptosis in the context of anti-GBS infection remains uncertain. This research demonstrates that the occurrence of ferroptosis is essential for the host’s defense against GBS infection in a mouse model of abdominal infection, with peritoneal macrophages identified as the primary cells undergoing ferroptosis. Further research indicates that IL-1β induces lipid oxidation in macrophages through the upregulation of pathways related to lipid oxidation. Concurrently, IL-1β is not only involved in the initiation of ferroptosis in macrophages, but its production is intricately linked to the onset of ferroptosis. Ultimately, we posit that ferroptosis acts as a crucial initiating factor in the host response to GBS infection, with IL-1β playing a significant role in the resistance to infection by serving as a key inducer of ferroptosis.

Abstract Cancer cells undergo significant metabolic reprogramming to support their rapid growth and survival. This study examines important metabolic pathways like glycolysis, oxidative phosphorylation, glutaminolysis, and lipid metabolism, focusing on how they are regulated and their contributions to the development of tumors. The interplay between oncogenes, tumor suppressors, epigenetic modifications, and the tumor microenvironment in modulating these pathways is examined. Furthermore, we discuss the therapeutic potential of targeting cancer metabolism, presenting inhibitors of glycolysis, glutaminolysis, the TCA cycle, fatty acid oxidation, LDH, and glucose transport, alongside emerging strategies targeting oxidative phosphorylation and lipid synthesis. Despite the promise, challenges such as metabolic plasticity and the need for combination therapies and robust biomarkers persist, underscoring the necessity for continued research in this dynamic field. Graphical Abstract

Probabilistic back-analysis is an important means to infer the statistics of uncertain soil parameters, making the slope reliability assessment closer to the engineering reality. However, multi-source information (including test data, monitored data, field observation and slope survival records) is rarely used in current probabilistic back-analysis. Conducting the probabilistic back-analysis of spatially varying soil parameters and slope reliability prediction under rainfalls by integrating multi-source information is a challenging task since thousands of random variables and high-dimensional likelihood function are usually involved. In this paper, a framework by integrating a modified Bayesian Updating with Subset simulation (mBUS) method with adaptive Conditional Sampling (aCS) algorithm is established for the probabilistic back-analysis of spatially varying soil parameters and slope reliability prediction. Within this framework, the high-dimensional probabilistic back-analysis problem can be easily tackled, and the multi-source information (e.g. monitored pressure heads and slope survival records) can be fully used in the back-analysis. A real Taoyuan landslide case in Taiwan, China is investigated to illustrate the effectiveness and performance of the established framework. The findings show that the posterior knowledge of soil parameters obtained from the established framework is in good agreement with the field observations. Furthermore, the updated knowledge of soil parameters can be utilized to reliably predict the occurrence probability of a landslide caused by the heavy rainfall event on September 12, 2004 or forecast the potential landslides under future rainfalls in the Fuhsing District of Taoyuan City, Taiwan, China.

Abstract Background Immune checkpoint inhibitor rechallenge has emerged as a prominent study area in non-small cell lung cancer (NSCLC). β-glucan was reported to reverse resistance to anti-PD-1/PD-L1 inhibitors by regulating the tumor microenvironment. In this self-initiated clinical trial (ChiCTR2100054796), NSCLC participants who have previously failed anti-PD-1 therapy received β-glucan (500 mg, bid, d1-21), Envafolimab (300 mg, d1) and Endostar (210 mg, civ72h) every 3 weeks until disease progression or unacceptable toxicity. The clinical efficacy and adverse events were observed, while serum samples were collected for proteomic analysis. Results Twenty Three patients were enrolled from January 2022 to March 2023 (median age, 65 years; male, n = 18 [78.3%]; squamous NSCLC, n = 9 [39.1%]; mutant type, n = 13 [56.5%]). The overall response rate (ORR) was 21.7% and disease control rate (DCR) was 73.9%. Median progression-free survival (mPFS) and median overall survival (mOS) was 4.3 months [95% CI: 2.0–6.6] and 9.8 months [95% CI: 7.2–12.4], respectively. The mPFS between PD-L1 positive and negative subgroup has significant difference (6.3 months vs. 2.3 months, p = 0.002). Treatment-related adverse events (TRAEs) occurred in 52.2% of patients. The most common TRAEs were hypothyroidism (26.1%) and fatigue (26.1%). 2 (8.7%) grade 3 adverse events were reported. No adverse reaction related deaths have been observed. Proteomic analysis revealed that the levels of CASP-8, ARG1, MMP12, CD28 and CXCL5 correlated with resistance to the treatment while the levels of CD40-L and EGF related to the favorable response. Conclusion β-glucan combined with Envafolimab and Endostar has considerable efficacy and safety for immune rechallenge in metastatic NSCLC patients who failed of anti-PD-1 treatment previously, especially for PD-L1 positive patients.

Abstract Background The development of acquired EGFR-TKI treatment resistance is still a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). This study aimed to investigate the role of HDAC1/FOXK1/miR-33a signaling in EGFR-TKI resistance. Methods The expression levels of miR‐33a, HDAC1, and FOXK1 were examined using quantitative polymerase chain reaction (PCR) and bioinformatics analysis. Cell proliferation, migration, and apoptosis were explored by cell number assay, Transwell, and flow cytometry assays, respectively. After overexpression or knockdown of HDAC1, miR-33a expression in the cells, cell functions were tested. Immunoprecipitation and correlation analyses were used to evaluate the interaction between HDAC1 and FOXK1 protein. The tumor-suppressive role of miR-33a was investigated by animal experiments. Results The suppression of miR-33a increased TKI resistance by affecting cell proliferation, migration, and apoptosis in gefitinib-resistant cells. HDAC1 is the key upstream molecule that inhibits miR-33 expression. HDAC1 upregulation increased gefitinib resistance by its binding to FOXK1 in cells to silence miR-33a expression. MiR-33a overexpression exerts tumor-suppressive effects by negatively regulating ABCB7 and p70S6K1 expression. Moreover, overexpression of miR-33a inhibited tumor growth in a xenograft nude mouse model. Conclusions HDAC1/FOXK1 upregulation and miR-33a silencing are new mechanisms of EGFR-TKI resistance in NSCLC.

Abstract To evaluate the impact of neoadjuvant chemotherapy on perioperative immune function in breast cancer patients, focusing on CD3+, CD4+, CD8+, and natural killer (NK) cells, as well as the CD4+/CD8+ ratio. We retrospectively reviewed medical records of breast cancer patients who underwent surgery with or without neoadjuvant chemotherapy at our medical center from January 2020 to December 2022. Patients were matched 1:1 based on propensity scores. Immune cell proportions and the CD4+/CD8+ ratio were compared on preoperative day one and postoperative days one and seven. Among matched patients, immune cell proportions and the CD4+/CD8+ ratio did not significantly differ between those who received neoadjuvant chemotherapy and those who did not at any of the three time points. Similar results were observed in chemotherapy-sensitive patients compared to the entire group of patients who did not receive neoadjuvant chemotherapy. However, chemotherapy-insensitive patients had significantly lower proportions of CD4+ and NK cells, as well as a lower CD4+/CD8+ ratio, at all three time points compared to patients who did not receive neoadjuvant chemotherapy. Neoadjuvant chemotherapy may impair immune function in chemotherapy-insensitive patients, but not in those who are sensitive to the treatment.

Abstract Heterochromatin de-condensation in companion gametic cells is conserved in both plants and animals. In plants, microspore undergoes asymmetric pollen mitosis (PMI) to produce a vegetative cell (VC) and a generative cell (GC). Subsequently, the GC undergoes pollen mitosis (PMII) to produce two sperm cells (SC). Consistent with heterochromatin de-condensation in the VC, H3K9me2, a heterochromatin mark, is barely detected in VC. However, how H3K9me2 is differentially regulated during pollen mitosis remains unclear. Here, we show that H3K9me2 is gradually evicted from the VC since PMI but remain unchanged in the GC and SC. ARID1, a pollen-specific transcription factor that facilitates PMII, promotes H3K9me2 maintenance in the GC/SC but slows down its eviction in the VC. The genomic targets of ARID1 mostly overlaps with H3K9me2 loci, and ARID1 recruits H3K9 methyltransferase SUVH6. Our results uncover that differential pattern of H3K9me2 between two cell types is regulated by ARID1 during pollen mitosis.

Abstract Objective This study aims to investigate the anatomical structure of the C6 pedicle and lateral mass in children aged 0–14 years using CT imaging, providing detailed insights into their growth and development. Methods We conducted a comprehensive measurement of C6. Measurements included width, length, and height of the pedicles, as well as the length, width, and thickness of the lateral masses, and several angular metrics. Regression analysis was performed to understand the growth trends, and statistical analyses were carried out to identify differences between age groups, genders, and sides. Results In children younger than four years, the pedicle width exceeds its height, influencing the diameter of the pedicle screws. By age two to three, the pedicle height and lateral mass thickness reaches 3.0 mm, allowing for the use of 3.0 mm diameter screws. The pedicle transverse angle remains stable. Most parameters showed no significant differences between the left and right sides. Size parameters exhibited significant larger in males than females at ages 0–1, 3–7, and 10–12 years. Regression analysis revealed that the growth trends of size parameters follow cubic or polynomial curves. Most angular metrics follow cubic fitting curves without a clear trend of change with age. Conclusion This study provides a detailed analysis of the anatomical development of the C6 pedicle and lateral masses in children, offering valuable insights for pediatric cervical spine surgeries. The findings highlight the importance of considering age-specific anatomical variations when planning posterior surgical fixation, specifically at C6. It is necessary for us to perform thin-layer CT scans on children and carefully measure various indicators before surgery.

Abstract Non-Hermitian physics has emerged as a new paradigm that profoundly changes our understanding of non-equilibrium systems, introducing novel concepts such as exceptional points, spectral topology, and non-Hermitian skin effects (NHSEs). Most existing studies focus on non-Hermitian eigenstates, whereas dynamic properties have been discussed only recently, and the dynamic NHSEs are not yet confirmed in experiments. Here, we report the experimental observation of non-Hermitian skin dynamics using tunable one-dimensional nonreciprocal double-chain mechanical systems with glide-time symmetry. Remarkably, dynamic NHSEs are observed with various behaviors in different dynamic phases, which can be understood via the generalized Brillouin zone and the related concepts. Moreover, the observed dynamic NHSEs, amplifications, bulk unidirectional wave propagation, and boundary wave trapping provide promising ways to manipulate waves in a controllable and robust way. Our findings open a new pathway toward non-Hermitian dynamics, which will fertilize the study of non-equilibrium phases of matter.

Abstract Objective To evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis. Methods The literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens. Results A total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs. Conclusion In summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs.

Abstract Objective There were few reports in the literature regarding hidden blood loss following surgery for developmental dysplasia of the hip in children. This study aimed to evaluate the volume of hidden blood loss and its risk factors among children undergoing hip reconstruction for developmental dysplasia of the hip. Methods A retrospective analysis of clinical data from 42 patients (58 hips), who underwent Pemberton and femoral osteotomies between March 2020 and March 2023, was conducted. Serial complete blood count assays were conducted on the day of admission and four days post-surgery. Preoperative and postoperative hematocrit levels were documented to calculate hidden blood loss utilizing the Gross formula. Pearson and Spearman correlation analyses, along with multivariable linear regression, were employed to ascertain associations between patient characteristics and hidden blood loss. Results The mean hidden blood loss was recorded as 283.06 ± 271.05 mL, constituting 70.22% of the total blood loss. Multiple linear regression analysis identified weight and surgical duration as independent risk factors contributing to hidden blood loss. Conclusions A relevant amount of postoperative hidden blood loss occurs after Pemberton osteotomy and femoral osteotomy for developmental dysplasia of the hip. Surgeons should be aware that patients who require blood transfusions and have longer surgical durations are at a higher risk of developing more hidden blood loss. Therefore, attention should be given to hidden blood loss to ensure patient safety during the perioperative period for those undergoing Pemberton and femoral osteotomies. Level of evidence IV.

Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers. Here, we demonstrated that cyclin D1 is SUMOylated, and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1. We generated cyclin D1 mutant mice with mutations in the SUMOylation site, phosphorylation site, or both sites of cyclin D1, and found that double mutant mice developed a Mantle cell lymphoma (MCL)-like phenotype. We showed that arsenic trioxide (ATO) enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes, leading to MCL cell apoptosis. Treatment of severe combined immunodeficiency (SCID) mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth. In this study, we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.

ABSTRACT: Whey protein isolate (WPI)-based nanodelivery systems have recently attracted an increasing amount of attention. Despite this, research focusing on milk protein concentrate (MPC) and micellar casein (MCC) as carriers loaded in hydrophobic compounds is lacking. This study investigated the mediated effect of docosahexaenoic acid (DHA) in 3 different milk proteins for the embedding of astaxanthin (ASTA) after ultrasound-assisted pH-shifting treatment. We then evaluated the application of milk protein carriers in cheese processing by comparing MPC, MCC, and WPI. The particle size, polydispersity index, and zeta potential results of the milk protein–DHA complex suggested that the addition of 0.36 μmol/mL DHA optimized the delivery of milk protein to ASTA. All 3 DHA-mediated milk proteins induced an improvement in encapsulation efficiency and antioxidant properties of ASTA. Furthermore, the DHA-mediated MPC and MCC played a stronger role in improving the bioaccessibility and thermal and storage stability of ASTA than those without DHA. Tests conducted to examine the application in cheese production indicated that MCC carrier had a positive effect on the texture of cheeses. However, the delivery effect was dependent on the milk protein variety, and MCC exhibited the best protection ability of ASTA, followed by MPC and WPI. The simulated digestion and storage stability results of cheese further confirmed that the protein encapsulation mediated by DHA was more conducive to ASTA absorption. These findings suggested that the DHA-mediated milk protein complexes studied here may be suitable hydrophilic delivery carriers for the hydrophobic nutrient ASTA, potentially playing different roles in improving its storage stability and bioaccessibility.

Abstract Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p. Results Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS. The DNA: RNA heteroduplexes vanished from the neutrophils when they were treated with a selective inhibitor of the L1 reverse transcriptase. We also report that ORF1p granules escape neutrophils during the extrusion of neutrophil extracellular traps (NETs) and, to a lesser degree, from neutrophils dying by pyroptosis, but not apoptosis. Conclusions These results bring new insights into the composition of ORF1p granules in SLE neutrophils and may explain, in part, why proteins in these granules become targeted by autoantibodies in this disease.

Abstract Objective Explore the feasibility of a mobile health(mHealth) and virtual reality (VR) based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. Methods We recruited cancer patients in the Oncology department of the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University from October 2022 to April 2023. The rehabilitation program was provided by a team of medical oncologists, dietitians, psychotherapists, and oncology specialist nurses. Participants received standard anti-cancer therapy and integrated intervention including hospitalized group-based exercise classes, at-home physical activity prescription, behavior change education, oral nutrition supplements, and psychological counseling. An effective intervention course includes two consecutive hospitalization and two periods of home-based rehabilitation (8 weeks). Access the feasibility as well as changes in aspects of physical, nutritional, and psychological status. Results At the cutoff date of April 2023, the recruitment rate was 75% (123/165). 11.4%patients were lost to follow-up, and 3.25% withdrew halfway. Respectively, the completion rate of nutrition, exercise, and psychology were 85%,55%, and 63%. Nutrition interventions show the highest compliance. The parameters in nutrition, psychology, muscle mass, and quality of life after the rehabilitation showed significant improvements (P .05) in handgrip strength and 6-minute walking speed. Conclusion It is feasible to conduct mHealth and VR-based nutrition-exercise-psychology integrated rehabilitation model in Chinese cancer patients. A larger multi-center trial is warranted in the future. Trial registration ChiCTR2200065748 Registered 14 November 2022.

Abstract Background Acute pancreatitis is one of the most common diseases requiring emergency surgery. Rapid and accurate recognition of acute pancreatitis can help improve clinical outcomes. This study aimed to develop a deep learning-powered diagnostic model for acute pancreatitis. Materials and methods In this investigation, we enrolled a cohort of 190 patients with acute pancreatitis who were admitted to Sichuan Provincial People’s Hospital between January 2020 and December 2021. Abdominal computed tomography (CT) scans were obtained from both patients with acute pancreatitis and healthy individuals. Our model was constructed using two modules: (1) the acute pancreatitis classifier module; (2) the pancreatitis lesion segmentation module. Each model’s performance was assessed based on precision, recall rate, F1-score, Area Under the Curve (AUC), loss rate, frequency-weighted accuracy (fwavacc), and Mean Intersection over Union (MIOU). Results Upon admission, significant variations were observed between patients with mild and severe acute pancreatitis in inflammatory indexes, liver, and kidney function indicators, as well as coagulation parameters. The acute pancreatitis classifier module exhibited commendable diagnostic efficacy, showing an impressive AUC of 0.993 (95%CI: 0.978–0.999) in the test set (comprising healthy examination patients vs. those with acute pancreatitis, P

Abstract Background Low immunity and sleep disorders are prevalent suboptimal health conditions in contemporary populations, which render them susceptible to the infiltration of pathogenic factors. LJC, which has a long history in traditional Chinese medicine for nourishing the Yin and blood and calming the mind, is obtained by modifying Qiyuan paste. Dendrobium officinale Kimura et Migo has been shown to improve the immune function in sleep-deprived mice. In this study, based on the traditional Chinese medicine theory, LJC was prepared by adding D. officinale Kimura et Migo to Qiyuan paste decoction. Methods Indicators of Yin deficiency syndrome, such as back temperature and grip strength, were measured in each group of mice; furthermore, behavioral tests and pentobarbital sodium-induced sleep tests were performed. An automatic biochemical analyzer, enzyme-linked immunosorbent assay kit, and other methods were used to determine routine blood parameters, serum immunoglobulin (IgG, IgA, and IgM), cont (C3, C4), acid phosphatase (ACP) and lactate dehydrogenase (LDH) levels in the spleen, serum hemolysin, and delayed-type hypersensitivity (DTH) levels. In addition, serum levels of γ-aminobutyric acid (GABA) and glutamate (Glu) were detected using high-performance liquid chromatography (HPLC). Hematoxylin–eosin staining and Nissl staining were used to assess the histological alterations in the hypothalamus tissue. Western blot and immunohistochemistry were used to detect the expressions of the GABA pathway proteins GABRA1, GAD, GAT1, and GABAT1 and those of CD4+ and CD8+ proteins in the thymus and spleen tissues. Results The findings indicated that LJC prolonged the sleep duration, improved the pathological changes in the hippocampus, effectively upregulated the GABA content in the serum of mice, downregulated the Glu content and Glu/GABA ratio, enhanced the expressions of GABRA1, GAT1, and GAD, and decreased the expression of GABAT1 to assuage sleep disorders. Importantly, LJC alleviated the damage to the thymus and spleen tissues in the model mice and enhanced the activities of ACP and LDH in the spleen of the immunocompromised mice. Moreover, serum hemolysin levels and serum IgG, IgA, and IgM levels increased after LJC administration, which manifested as increased CD4+ content, decreased CD8+ content, and enhanced DTH response. In addition, LJC significantly increased the levels of complement C3 and C4, increased the number of white blood cells and lymphocytes, and decreased the percentage of neutrophils in the blood. Conclusions LJC can lead to improvements in immunocompromised mice models with insufficient sleep. The underlying mechanism may involve regulation of the GABA/Glu content and the expression levels of GABA metabolism pathway-related proteins in the brain of mice, enhancing their specific and nonspecific immune functions. Graphical Abstract

Abstract During shield tunneling in highly abrasive formations such as sand–pebble strata, nonuniform wear of shield cutters is inevitable due to the different cutting distances. Frequent downtimes and cutter replacements have become major obstacles to long‐distance shield driving in sand–pebble strata. Based on the cutter wear characteristics in sand–pebble strata in Beijing, a design methodology for the cutterhead and cutters was established in this study to achieve uniform wear of all cutters by the principle of frictional wear. The applicability of the design method was verified through three‐dimensional simulations using the engineering discrete element method. The results show that uniform wear of all cutters on the cutterhead could be achieved by installing different numbers of cutters on each trajectory radius and designing a curved spoke with a certain arch height according to the shield diameter. Under the uniform wear scheme, the cutter wear coefficient is greatly reduced, and the largest shield driving distance is increased by approximately 47% over the engineering scheme. The research results indicate that the problem of nonuniform cutter wear in shield excavation could be overcome, thereby providing guiding significance for theoretical innovation and construction of long‐distance shield excavation in highly abrasive strata.

Androgenic alopecia (AGA) is a highly prevalent form of non-scarring alopecia but lacks effective treatments. Stem cell exosomes have similar repair effects to stem cells, suffer from the drawbacks of high cost and low yield yet. Cell-derived nanovesicles acquired through mechanical extrusion exhibit favorable biomimetic properties similar to exosomes, enabling them to efficiently encapsulate substantial quantities of therapeutic proteins. In this study, we observed that JAM-A, an adhesion protein, resulted in a significantly increased the adhesion and resilience of dermal papilla cells to form snap structures against damage caused by dihydrotestosterone and macrophages, thereby facilitating the process of hair regrowth in cases of AGA. Consequently, adipose-derived stem cells were modified to overexpress JAM-A to produce engineered JAM-A overexpressing nanovesicles (JAM-AOE@NV). The incorporation of JAM-AOE@NV into a thermosensitive hydrogel matrix (JAM-AOE@NV Gel) to effectively addresses the limitations associated with the short half-life of JAM-AOE@NV, and resulted in the achievement of a sustained-release profile for JAM-AOE@NV. The physicochemical characteristics of the JAM-AOE@NV Gel were analyzed and assessed for its efficacy in promoting hair regrowth in vivo and vitro. The JAM-AOE@NV Gel, thus, presents a novel therapeutic approach and theoretical framework for promoting the treatment of low cell adhesion diseases similar to AGA.

Abstrcat: Basal cell carcinoma (BCC) of the prostate is a rare and enigmatic tumor with uncertain biological behavior and treatment modalities. Some studies suggest that BCC exhibits invasive characteristics and a high degree of malignancy, necessitating proactive management and vigilant monitoring. Notably, there is a lack of reported effective treatment utilizing programmed cell death protein-1 (PD-1) inhibitors for advanced BCC of the prostate. This study explores the efficacy of tislelizumab, as a single-agent therapy, in the successful treatment of advanced prostate BCC.

Objectives The use of awake extracorporeal membrane oxygenation (ECMO, without intubation or sedation under ECMO support in patients with cardiogenic shock is growing rapidly because emerging clinical investigations indicates it may reduce morbidity associated with sedation and intubation. We systematically reviewed the efficacy of awake ECMO and provided evidence for clinical practitioners and researchers.Design Systematic review and trial sequential meta-analysis based on observational studies.Data sources Data was retrieved from seven databases (PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang, Chinese Biomedical Literature Database and Cochrane Library) up to 1 March 2024.Eligibility criteria We included observational studies that compared the differences in clinical outcomes between awake ECMO and non-awake ECMO in patients with cardiogenic shock.Data extraction and synthesis Two reviewers rigorously conducted literature retrieval, screening and data extraction. The RevMan software was used for data synthesis.Results Five retrospective observational studies involving 1044 patients with cardiogenic shock were included. Compared with non-awake ECMO, awake ECMO was associated with a lower mortality rate of patients with cardiogenic shock (OR=0.28; 95% CI, (0.15, 0.49); p

Hexavalent chromium [Cr(VI)], one common environmental contaminant, has long been recognized as a carcinogen associated with lung cancer, but roles and mechanisms of Cr(VI)-induced epigenetic dysregulations in carcinogenesis remain to be investigated. In this study, we identified that RNA m5C methyltransferase NSUN2 was significantly upregulated in Cr(VI)-transformed cells and lung tissues of Cr(VI)-exposed mice. Inhibition of NSUN2 reduced cell proliferation, migration, colony formation and tube formation abilities. We found NSUN2-mediated m5C modification induced metabolic reprogramming and cell cycle by promoting the mRNA stabilities of ME1, GLUT3 and CDK2. In addition, knockdown of NSUN2 attenuated tumorigenesis and angiogenesis in vivo. RNA m5C reader ALYREF was identified to be involved in NSUN2-mediated m5C modification in Cr (VI)-induced carcinogenesis. Further study showed that EP300 induced NSUN2 upregulation through transcriptional activation by inducing histone modification at H3K27ac site for regulating Cr(VI) carcinogenesis. Our findings demonstrated novel role and mechanism of NSUN2 and epigenetic changes by increasing the RNA m5C modification that are important for Cr (VI)-induced carcinogenesis through NSUN2/ALYREF pathway. NSUN2, ALYREF, ME1, GLUT3 or/and CDK2 may be used as potential new biomarkers or/and therapeutic target(s) in the future.

Tandem duplications significantly influence the diversity of the human genome and the occurrence of many complex diseases. However, accurate detection of tandem duplications of low coverage remains a challenging task. Based on RD (read depth), the tandem duplication detection method assumes that there is a linear relationship between the RD value and the tandem duplication number in the region in the genome. However, at low coverage, the RD values of tandem duplication regions and normal regions in the sequencing sample are not significantly different, and it will affect the performance of tandem duplication detection. Therefore, relying on traditional statistical models based on RD strategy to detect tandem duplications often leads to relative low precision and recall. For solving this problem, we propose a new method for identifying tandem duplications in whole-genome sequencing data.TD-COF, a tandem duplication detection method, utilizes the COF (Connectivity-Based Outlier Factor) algorithm. Considering the relative connectivity between intervals in the genome, the algorithm applies a connectivity factor to each bin to calculate its outlier score Additionally, TD-COF introduces the Split Read strategy into RD-based methods, enabling precise identification of the start and end points of tandem duplications down to the level of individual bases. Furthermore, TD-COF incorporates mapping quality as a feature signal. The bins with lower mapping quality are assigned higher outlier values, effectively mitigating interference from mapping errors. Simulation experiments demonstrate that TD-COF outperforms other methods in terms of sensitivity, precision and F1 score. And, TD-COF exhibits high consistency with other methods when applied to real sequencing samples. This study indicates that TD-COF is an effective method for detecting tandem duplications even in regions of low or moderate coverage. In summary, we consider the TD-COF to be an effective method for detecting tandem duplications.

Abstract The risk for suffering immune checkpoint inhibitors (ICIs)‐associated myocarditis increases in patients with pre‐existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single‐cell RNA sequencing, and flow cytometry are used to decipher how anti‐cytotoxic T lymphocyte antigen‐4 m2a antibody (anti‐CTLA‐4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti‐CTLA‐4 m2a antibody increases cardiac fibroblast‐derived C‐X‐C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1‐Cxcr2 chemotaxis. It is identified that the C–C motif chemokine ligand 5 (Ccl5)‐neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF‐κB signaling, and cellular response to interferon‐gamma and that the Ccl5‐neutrophil subpopulation and its‐associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti‐CTLA‐4 m2a antibody‐induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti‐CTLA‐4 m2a antibody‐induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5‐neutrophil subpopulation plays a critical role in aggravating anti‐CTLA‐4 m2a antibody‐induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs‐associated myocarditis.

In the realm of renewable energy, the integration of wind power and hydrogen energy systems represents a promising avenue towards environmental sustainability. However, the development of cost-effective hydrogen energy storage solutions is crucial to fully realize the potential of hydrogen as a renewable energy source. By combining wind power generation with hydrogen storage, a comprehensive hydrogen energy system can be established. This study aims to devise a physiologically inspired optimization approach for designing a standalone wind power producer that incorporates a hydrogen energy system on a global scale. The optimization process considers both total cost and capacity loss to determine the optimal configuration for the system. The optimal setup for an off-grid solution involves the utilization of eight distinct types of compact horizontal-axis wind turbines. Additionally, a sensitivity analysis is conducted by varying component capital costs to assess their impact on overall cost and load loss. Simulation results indicate that at a 15 % loss, the cost of energy (COE) is $1.3772, while at 0 % loss, it stands at $1.6908. Capital expenses associated with wind turbines and hydrogen storage systems significantly contribute to the overall cost. Consequently, the wind turbine-hydrogen storage system emerges as the most cost-effective and reliable option due to its low cost of energy.

BackgroundWhile sarcopenia has been found to be associated with increased risks of cardiovascular diseases (CVDs), evidence exploring sex-related differences remains insufficient. This study aimed to investigate the differences in how often sarcopenia occurs in each sex, as determined by skeletal muscle area (SMA) in chest CT images, and its association with CVD common risk factors.MethodsThis cross-sectional study involved 1,340 inpatients from the Department of Geriatrics of Renji Hospital, affiliated to Shanghai Jiaotong University School of Medicine. Data on age, sex, body mass index (BMI), smoking status, disease history, and clinical parameters were collected. Sarcopenia was defined using chest CT images with a cut-off value of T12-SMA/height2

The characteristics of elements, isotopes, and small shelly fossils were investigated for Late Ediacaran to Early Cambrian stratigraphy division and to discuss their geological implications in the northwestern Sichuan Basin. The results reveal that small shelly fossils can be detected in the high-phosphorous section, with the concentration of phosphorus mainly ranging from 2% to 8%, suggesting that this interval belongs to the Early Cambrian, which is also consistent with the carbon isotopic composition results. In addition, the Early Cambrian is denudated in the Sichuan Basin due to tectonic movement, and the characteristics of some isotopes and small shell fossils are different from those in other basins. It can be proposed that P content can support the recognition of lithological boundaries, and the high phosphorus content can be used as a reference to identify the top and bottom boundaries of the Maidiping Formation in the study area. According to the elemental compositions in the Ediacaran Dengying Formation, the variations in Si, Al, Fe, and K contents are similar in the platform area and rift area, suggesting that the third and fourth member of the Dengying Formation are also developed in the Deyang–Anyue Rift. The results suggest that both the Deng-4 member and Maidiping Formation feature contemporaneous deposition of different facies in the northwestern Sichuan Basin. The strata consist of shale intercalated with thin carbonate rock deposits in the Deyang–Anyue Rift, while carbonate rock deposits in the platform. The Deyang–Anyue Rift expanded gradually in the Late Ediacaran and eventually filled in the Early Cambrian. The data in this study illustrate that elemental compositions, isotopes, and small shelly fossils can be combined to correlate the Late Ediacaran to Early Cambrian strata and provide new evidence for Deyang–Anyue Rift evolution. The results offer some new insights for deep oil and gas exploration in the Sichuan Basin and for the tectonic–depositional–environmental–biological synergistic evolution in the Late Ediacaran to Early Cambrian transition.

Abstract Mesenchymal stem cells (MSCs) have demonstrated promising advantages in the therapies of many diseases, while its multi-directional differentiation potential and immunotoxicity are the major concerns hindered their clinical translation. In this study, human umbilical Mesenchymal stem cell (hUC-MSCs) were labeled with a near-infrared fluorescent dye DiR before infused into cynomolgus monkeys, and the amount of hUC-MSCs in the peripheral blood were dynamically estimated from 5 min to 28 days post a single administration at 3 × 106 cells/kg and 2 × 107 cells/kg intravenously. As results, some hUC-MSCs distributed to the whole body within 5 min, while most of the cells accumulate in the lungs along with the systemic blood circulation, and subsequently released into the blood. The toxicity potentials of hUC-MSCs were investigated in another 30 cynomolgus monkeys, and the cells were repeatedly administrated at doses of 3 × 106 cells/kg and 2 × 107 cells/kg for 5 times on a weekly basis, with a recovery period of 1 months. hUC-MSCs showed no obvious toxic effects in cynomolgus monkeys, except xenogeneic immune rejection to human stem cells. Low levels of the hUC-MSC gene were detected in the peripheral blood of a few animals administered 2 × 107 cells/kg at 30 min subsequent to the first and last administration, and there was no significant difference in the copy number of the hUC-MSC gene in the blood samples compared with the first and last administration, indicating that the hUC-MSC was not significantly amplified in vivo, and it its safe in non-human primates. Our study for the first time verified the safety of long-term use of hUC-MSCs in primates. We have pioneered a technology for the real-time detection of hUC-MSCs in peripheral blood and provide dynamicand rapid monitoring of the distribution characteristics of hUC-MSCs in vivo. Here, we provide data supporting the application of such products for clinical treatment and the application of stem cells in major refractory diseases and regenerative medicine.

Abstract Background The use of gene therapy to deliver microRNAs (miRNAs) has gradually translated to preclinical application for the treatment of intervertebral disc degeneration (IDD). However, the effects of miRNAs are hindered by the short half-life time and the poor cellular uptake, owing to the lack of efficient delivery systems. Here, we investigated nucleus pulposus cell (NPC) specific aptamer-decorated polymeric nanoparticles that can load miR-150-5p for IDD treatment. Methods The role of miR-150-5p during disc development and degeneration was examined by miR-150-5p knockout (KO) mice. Histological analysis was undertaken in disc specimens. The functional mechanism of miR-150-5p in IDD development was investigated by qRT-PCR assay, Western blot, coimmunoprecipitation and immunofluorescence. NPC specific aptamer-decorated nanoparticles was designed, and its penetration, stability and safety were evaluated. IDD progression was assessed by radiological analysis including X-ray and MRI, after the annulus fibrosus needle puncture surgery with miR-150-5p manipulation by intradiscal injection of nanoparticles. The investigations into the interaction between aptamer and receptor were conducted using mass spectrometry, molecular docking and molecular dynamics simulations. Results We investigated NPC-specific aptamer-decorated polymeric nanoparticles that can bind to miR-150-5p for IDD treatment. Furthermore, we detected that nanoparticle-loaded miR-150-5p inhibitors alleviated NPC senescence in vitro, and the effects of the nanoparticles were sustained for more than 3 months in vivo. The microenvironment of NPCs improves the endo/lysosomal escape of miRNAs, greatly inhibiting the secretion of senescence-associated factors and the subsequent degeneration of NPCs. Importantly, nanoparticles delivering miR-150-5p inhibitors attenuated needle puncture-induced IDD in mouse models by targeting FBXW11 and inhibiting TAK1 ubiquitination, resulting in the downregulation of NF-kB signaling pathway activity. Conclusions NPC-targeting nanoparticles delivering miR-150-5p show favorable therapeutic efficacy and safety and may constitute a promising treatment for IDD. Graphical Abstract

Abstract Axion insulators possess a quantized axion field θ = π protected by combined lattice and time-reversal symmetry, holding great potential for device applications in layertronics and quantum computing. Here, we propose a high-spin axion insulator (HSAI) defined in large spin-s representation, which maintains the same inherent symmetry but possesses a notable axion field θ = (s + 1/2)2 π. Such distinct axion field is confirmed independently by the direct calculation of the axion term using hybrid Wannier functions, layer-resolved Chern numbers, as well as the topological magneto-electric effect. We show that the guaranteed gapless quasi-particle excitation is absent at the boundary of the HSAI despite its integer surface Chern number, hinting an unusual quantum anomaly violating the conventional bulk-boundary correspondence. Furthermore, we ascertain that the axion field θ can be precisely tuned through an external magnetic field, enabling the manipulation of bonded transport properties. The HSAI proposed here can be experimentally verified in ultra-cold atoms by the quantized non-reciprocal conductance or topological magnetoelectric response. Our work enriches the understanding of axion insulators in condensed matter physics, paving the way for future device applications.

Immunoprecipitation (IP) coupled with mass spectrometry effectively maps protein–protein interactions when genome-wide, affinity-tagged cell collections are used. Such studies have recorded significant portions of the compositions of physiological protein complexes, providing draft ’interactomes’; yet many constituents of protein complexes still remain uncharted. This gap exists partly because high-throughput approaches cannot optimize each IP. A key challenge for IP optimization is stabilizing in vivo interactions during the transfer from cells to test tubes; failure to do so leads to the loss of genuine interactions during the IP and subsequent failure to detect. Our high-content screening method explores the relationship between in vitro chemical conditions and IP outcomes, enabling rapid empirical optimization of conditions for capturing target macromolecular assemblies.

Abstract Background Mesenchymal stem cells (MSCs) hold a great promise for cell-based therapy in the field of regenerative medicine. In this study, we aimed to evaluate the safety and efficacy of intravenous infusion of human umbilical cord-derived MSCs (HUC-MSCs) in patients with aging frailty. Methods In this randomized, double-blind, placebo-controlled trial, participants diagnosed with aging frailty were randomly assigned to receive intravenous administrations of HUC-MSCs or placebo. All of serious adverse events and AEs were monitored to evaluate the safety of treatment during the 6-month follow-up. The primary efficacy endpoint was alteration of physical component scores (PCS) of SF-36 qualities of life at 6 months. The secondary outcomes including physical performance tests and pro-inflammatory cytokines, were also observed and compared at each follow-up visits. All evaluations were performed at 1 week, 1, 2, 3 and 6 months following the first intravenous infusion of HUC-MSCs. Results In the MSCs group, significant improvements in PCS of SF-36 were observed from first post-treatment visit and sustained throughout the follow-up period, with greater changes compared to the placebo group (p = 0.042). EQ-VAS scores of MSCs group improved significantly at 2 month (p = 0.023) and continued until the end of the 6-month visit (p = 0.002) in comparison to the placebo group. The timed up and go (TUG) physical performance test revealed significant group difference and showed continual enhancements over 6 months (p

Abstract Aims MNDA (myeloid nuclear differentiation antigen) has been considered as a potential diagnostic marker for marginal zone lymphoma (MZL), but its utility in distinguishing MZL from other B-cell non-Hodgkin lymphomas (B-NHLs) and its clinicopathologic relevance in diffuse large B-cell lymphoma (DLBCL) are ambiguous. We comprehensively investigated MNDA expression in a large series of B-NHLs and evaluated its diagnostic value. Methods MNDA expression in a cohort of 1293 cases of B-NHLs and 338 cases of reactive lymphoid hyperplasia (RLH) was determined using immunohistochemistry and compared among different types of B-NHL. The clinicopathologic relevance of MNDA in DLBCL was investigated. Results MNDA was highly expressed in MZLs (437/663, 65.9%), compared with the confined staining in marginal zone B-cells in RLH; whereas neoplastic cells with plasmacytic differentiation lost MNDA expression. MNDA expression was significantly higher in mantle cell lymphoma (MCL, 79.6%, p = 0.006), whereas lower in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, 44.8%, p = 0.001) and lymphoplasmacytic lymphoma (LPL, 25%, p = 0.016), and dramatically lower in follicular lymphoma (FL, 5.2%, p

Lung cancer is the leading factor of cancer-related death in the worldwide. Hexavalent chromium [Cr(VI)] is a potential carcinogen for inducing lung cancers. To understand new mechanism of Cr(VI)-induced tumorigenesis and cancer development, we identified that PDK1 expression levels were greatly increased in chromium-transformed cells (Cr-T) compared to the parental BEAS-2B (B2B) cells by proteomic profiling and Western blotting; PDK1 levels were also induced in lung cancer cell lines and in lung samples of mice exposed to Cr(VI). Cr(VI) increased Warburg effect, cell migration, proliferation and colony formation through PDK1 upregulation. To identify the mechanism of PDK1 induction, we performed miRNA-seq analysis of Cr-T and B2B cells, and found miR-493 levels was significantly suppressed by Cr(VI). PDK1 was induced by miR-493 suppression, and was a direct target of miR-493. Interestingly, we also found HIF-1α was directly targeting by miR-493 and was induced by miR-493 downregulation. HIF-1α expression levels were upregulated in lung samples of mice with Cr(VI)-exposure. PDK1 was induced by HIF-1α, showing miR-493 suppression can directly induce PDK1 as well as through HIF-1α induction. MiR-493 overexpression was sufficient to suppress tumor growth, PDK1 and HIF-1α expression in vivo. We also showed that levels of miR-493 suppression, HIF-1α and PDK1 elevations were strongly correlated with poor prognosis of lung cancer subjects. These results demonstrate both HIF-1α and PDK1 expression are induced by Cr(VI)-mediated miR-493 suppression, and MiR-493/HIF-1α/PDK1 axis is a new pathway in Cr(VI)-inducing carcinogenesis and tumor growth.

Background Renal insufficiency (RI) is a key factor affecting the prognosis of multiple myeloma (MM) patients. Because the benefit of daratumumab for treating MM patients with RI remains unclear, our objective was to evaluate the efficacy of daratumumab on MM patients with RI.Methods We conducted a systematic search of the PubMed, EMBASE, and Cochrane Library databases as of October 24, 2023. Two independent reviewers screened the article titles, abstracts, and full text to identify the randomized controlled trials (RCTs) meeting the inclusion and exclusion criteria. Meta-analyses were performed using RevMan version 5.4. Outcomes of interest were progression-free survival (PFS), overall survival (OS), complete response or better (≥CR), and minimal residual disease (MRD) negativity, all calculated as hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs).Results A total of 10 RCTs with 5003 patients were included. Add-on daratumumab improved PFS and OS among newly diagnosed MM (NDMM) patients with RI (HR 0.48 [95% CI: 0.36, 0.64, I2 = 65%] and HR 0.63 [95% CI: 0.48, 0.82, I2 = 0%]) as well as relapsed/refractory MM (RRMM)-RI patients, compared with the control group (HR 0.46 [95% CI: 0.37, 0.58, I2 = 0%] and HR 0.68 [95% CI: 0.51, 0.92, I2 = 0%]). In terms of the renal status, the efficacy of add-on daratumumab for MMRI patients was similar to that for MM patients with normal renal function. A prolonged PFS benefit for add-on daratumumab treatment versus the control was evident across all RRMM-RI subgroups, and the benefits tended to increase with the follow-up time.Conclusions Our results indicate that MM patients with RI could benefit from a daratumumab-added regimen regardless of MM status. Additional high-quality RCTs are still warranted to confirm our findings.

Abstract Background Mecapegfilgrastim, a long‐acting granulocyte‐colony stimulating factor has been approved for reducing the incidence of infection, particularly febrile neutropenia (FN), in China. Objective We conducted a multicenter prospective observational study to examine the safety and effectiveness of mecapegfilgrastim in preventing neutropenia in gastrointestinal patients receiving the chemotherapy, including S‐1/capecitabine‐based regimens or the fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) regimens. Method Five hundred and sixty‐one gastrointestinal patients from 40 sites across China, between May 2019 and November 2021, were included. The administration of mecapegfilgrastim was prescribed at the discretion of local physicians. Results The most common adverse drug reactions (ADRs) of any grade for all patients was increased white blood cells (2.9%). Grade 3/4 ADRs were observed for anemia (0.2%), decreased white blood cells (0.2%), and decreased neutrophil count (0.2%). Among the 116 patients who received S‐1/capecitabine‐based chemotherapy throughout all cycles, ADRs of any grade included anemia (1.7%), myalgia (0.9%), and increased alanine aminotransferase (0.9%). No grade 3/4 ADRs were observed. In 414 cycles of patients who underwent S‐1/capecitabine‐based regimens, only one (0.2%) cycle experienced grade 4 neutropenia. In the FOLFIRINOX, FOLFOXIRI, and FOLFOX chemotherapy regimens, grade 4 neutropenia occurred in one (2.7%) of 37 cycles, four (4.7%) of 85 cycles, and two (1.2%) of 167 cycles, respectively. Conclusion In a real‐world setting, mecapegfilgrastim has proven effective in preventing severe neutropenia in gastrointestinal patients following chemotherapy. This includes commonly used moderate or high‐risk FN regimens or regimens containing S1/capecitabine, all of which have demonstrated favorable efficacy and safety profiles.

IntroductionOdontoid incidence (OI) is an important parameter that has recently been developed. However, there are currently no studies on OI in adolescent idiopathic scoliosis (AIS) patients. We aimed to examine the significance of OI in describing cervical sagittal alignment in AIS patients, explore the differences in cervical sagittal parameters among these patients with different curve types, and investigate the correlations between coronal deformity and cervical sagittal parameters in AIS patients.MethodsThe whole-spine anteroposterior and lateral plain radiographs of AIS patients were retrospectively analyzed. The parameters, including OI, odontoid tilt (OT), C2 slope, cervical lordosis (CL), T1 slope (T1S), and others, were measured. The AIS patients were grouped based on different curve types. Measurement parameters were compared between different groups. Pearson correlation analysis was performed for cervical sagittal parameters and Cobb angle.ResultsNinety AIS patients were included, consisting of 14 males and 76 females. The main thoracic curve group exhibited a smaller OI compared to the main thoracolumbar/lumbar curve group (P

Backgroundβ-glucan has been reported to be a potential natural immune modulator for tumor growth inhibition. We aimed to evaluate the efficacy and safety of β-glucan plus immunotherapy and chemotherapy in the first-line treatment of advanced gastric adenocarcinoma.MethodsThis is a phase IB, prospective, single-arm, investigator-initiated trail. Advanced gastric adenocarcinoma patients received β-glucan, camrelizumab, oxaliplatin, oral S-1 every 3 weeks. The curative effect was evaluated every 2 cycles. The primary endpoints were objective response rate (ORR) and safety, with secondary endpoints were median progression-free survival (mPFS) and median overall survival (mOS). The exploratory endpoint explored biomarkers of response to treatment efficacy.ResultsA total of 30 patients had been enrolled, including 20 (66.7%) males and all patients with an ECOG PS score of ≥1. The ORR was 60%, the mPFS was 10.4 months (95% confidence interval [CI], 9.52-11.27), the mOS was 14.0 months (95% CI, 11.09-16.91). A total of 19 patients (63.3%) had TRAEs, with 9 patients (30%) with grade ≥ 3. The most common TRAEs were nausea (53.3%). After 2 cycles of treatment, the levels of IL-2, IFN-γ and CD4+ T cells significantly increased (P < 0.05). Furthermore, biomarker analysis indicated that patient with better response and longer OS exhibited lower GZMA expression at baseline serum.ConclusionsThis preliminary study demonstrates that β-glucan plus camrelizumab and SOX chemotherapy offers favorable efficacy and a manageable safety profile in patients with advanced gastric adenocarcinoma, and further studies are needed to verify its efficacy and safety.Clinical Trial RegistrationChinese Clinical Trials Registry, identifier ChiCTR2100044088