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Abstract The prevalence of papillary thyroid cancer (PTC) has been rising in recent years. Despite its relatively low mortality, PTC frequently metastasizes to lymph nodes and often recurs, posing significant health and economic burdens. The role of iodine in the pathogenesis and advancement of thyroid cancer remains poorly understood. Circular RNAs (circRNAs) are recognized to function as competing endogenous RNAs (ceRNAs) that modulate gene expression and play a role in various cancer stages. Consequently, this research aimed to elucidate the mechanism by which circRNA influences the impact of iodine on PTC. Our research indicates that high iodine levels can exacerbate the malignancy of PTC via the circ_0004851/miR-296-3p/FGF11 axis. These insights into iodine’s biological role in PTC and the association of circRNA with the disease could pave the way for novel biomarkers and potentially effective therapeutic strategies to mitigate PTC progression.

BackgroundRefractory gastroesophageal reflux disease (refractory GERD) is a heterogeneous disease characterized by unresponsiveness or poor efficacy to proton-pump inhibitors (PPIs). This chronic disorder substantially weakens patients’ mental wellbeing and quality of life, increasing the financial burden on society. Multiple articles have been reported in this area. However, literature involving scientometric analysis of refractory GERD is absent. Therefore, it is necessary to understand the evolution of research themes and the main hotspots of refractory GERD through bibliometric methods.MethodsAll documents related to refractory GERD based on the WOS Core Collection from January 2000 to November 2023 were selected for analysis. Citespace V 6.1 R6, VOSviewer V 1.6.20, and Scimago Graphica V 1.0.38 were used to perform bibliometric analysis.ResultsWe collected a total of 241 research articles from 36 countries and 322 institutions, contributed by over 1,000 authors. Over the last 20 years, the number of articles in this field has increased year by year, and since 2011, the number of publications has increased dramatically, with 85.89% of the papers. These countries are led by the United States and Japan. GUT had the highest number of citations and DIGESTION had the highest number of publications. Research on standardized diagnosis and management, mechanisms, novel monitoring methods, and innovative drugs and procedures for refractory GERD are the main topics and hotspots in this field. This study also found that neuroimmune interaction is closely related to refractory GERD, which may be a new direction for future mechanism research.ConclusionOur study is the first bibliometric analysis of the global literature on refractory GERD. This research provides valuable insights for researchers, enabling them to quickly understand the research frontier and hot topics of this field.

Metabolic syndrome (MetS) represents a constellation of metabolic abnormalities, typified by obesity, hypertension, hyperglycemia, and hyperlipidemia. It stems from intricate dysregulations in metabolic pathways governing energy and substrate metabolism. While comprehending the precise etiological mechanisms of MetS remains challenging, evidence underscores the pivotal roles of aberrations in lipid metabolism and insulin resistance (IR) in its pathogenesis. Notably, nicotinamide N-methyltransferase (NNMT) has recently surfaced as a promising therapeutic target for addressing MetS. Single nucleotide variants in the NNMT gene are significantly correlated with disturbances in energy metabolism, obesity, type 2 diabetes (T2D), hyperlipidemia, and hypertension. Elevated NNMT gene expression is notably observed in the liver and white adipose tissue (WAT) of individuals with diabetic mice, obesity, and rats afflicted with MetS. Knockdown of NNMT elicits heightened energy expenditure in adipose and hepatic tissues, mitigates lipid accumulation, and enhances insulin sensitivity. NNMT catalyzes the methylation of nicotinamide (NAM) using S-adenosyl-methionine (SAM) as the donor methyl group, resulting in the formation of S-adenosyl-l-homocysteine (SAH) and methylnicotinamide (MNAM). This enzymatic process results in the depletion of NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and the generation of SAH, a precursor of homocysteine (Hcy). Consequently, this cascade leads to reduced NAD+ levels and elevated Hcy levels, implicating NNMT in the pathogenesis of MetS. Moreover, experimental studies employing RNA interference (RNAi) strategies and small molecule inhibitors targeting NNMT have underscored its potential as a therapeutic target for preventing or treating MetS-related diseases. Nonetheless, the precise mechanistic underpinnings remain elusive, and as of yet, clinical trials focusing on NNMT have not been documented. Therefore, further investigations are warranted to elucidate the intricate roles of NNMT in MetS and to develop targeted therapeutic interventions.

Abstract Bridge cable is an important force transmission component of bridge, but it is easy to be damaged during service, such as fatigue damage and corrosion damage, which seriously threatens the safety of bridge structure. Therefore, it is necessary to identify damage of cable force. Generally, the damage of cable force can be identified by the change of cable frequency. This paper establishes a cable force damage identification model based on Bayesian inference and uses Metropolis‐Hastings (MH) algorithm to solve the posterior probability function of unknown parameter. In the Bayesian inference model, the influence of the priori function of unknown parameters on the posterior probability distribution model is discussed. In the MH algorithm, the influence of different proposed distributions (Normal distribution, Gamma distribution and Weibull distribution) on the sampling results is discussed based on three numerical simulation studies, and the influence of burned sample proportion on the establishment of a posteriori distribution function is analyzed. Furthermore, the influence of monitoring noise data and missing data on cable force damage identification is considered, and the robustness of the proposed method is analyzed.

Abstract Background This study aimed to evaluate the effect of sacubitril valsartan (SV) on heart failure (HF) hospitalization and cardiovascular mortality in patients on hemodialysis with HF with preserved ejection fraction (EF; HFpEF). Methods This single-center, prospective study enrolled 155 stable hemodialysis patients with EF > 40% who were followed up for 12 months. Fifty-nine patients were treated with SV; the others were matched for EF (57.89 ± 9.35 vs. 58.00 ± 11.82, P = 0.9) at a ratio of 1:1 and included as controls. The target dosage of SV was 200 mg/day. Results Twenty-three (23/155; 14.84%) had HF with mid-range EF (HFmrEF), while 132 (85.16%) had HFpEF. After SV treatment, the peak early diastolic transmitral flow velocity/peak early diastolic mitral annular tissue velocity(E/e’) improved from 17.19 ± 8.74 to 12.80 ± 5.52 (P = 0.006), the left ventricular (LV) end-diastolic diameter decreased from 53.14 ± 7.67 mm to 51.56 ± 7.44 mm (P = 0.03), and the LV mass index decreased from 165.7 ± 44.6 g/m2 to 154.8 ± 24.0 g/m2 (P = 0.02). LVEF (P = 0.08) and LV global longitudinal strain (P = 0.7) did not change significantly. The composite outcome of first and recurrent HF hospitalization or cardiovascular death showed no difference between group. However, the Acute Dialysis Quality Initiative Workgroup (ADQI) HF class improved in 39 and 15 patients and worsened in 1 and 11 patients in the SV and control groups, respectively (P 40%.

Abstract To investigate the effects of neutrophil elastase inhibitor (sivelestat sodium) on gastrointestinal function in sepsis. A reanalysis of the data from previous clinical trials conducted at our center was performed. Septic patients were divided into either the sivelestat group or the non‐sivelestat group. The gastrointestinal dysfunction score (GIDS), feeding intolerance (FI) incidence, serum levels of intestinal barrier function and inflammatory biomarkers were recorded. The clinical severity and outcome variables were also documented. A total of 163 septic patients were included. The proportion of patients with GIDS ≥2 in the sivelestat group was reduced relative to that in the non‐sivelestat group (9.6% vs. 22.5%, p = 0.047) on the 7th day of intensive care unit (ICU) admission. The FI incidence was also remarkably reduced in the sivelestat group in contrast to that in the non‐sivelestat group (21.2% vs. 37.8%, p = 0.034). Furthermore, the sivelestat group had fewer days of FI [4 (3, 4) vs. 5 (4–6), p = 0.008]. The serum levels of d‐lactate (p = 0.033), intestinal fatty acid‐binding protein (p = 0.005), interleukin‐6 (p = 0.001), white blood cells (p = 0.007), C‐reactive protein (p = 0.001), and procalcitonin (p

Ocean currents play a role in both facilitating and impeding connectivity of marine organisms’ populations, serving as key drivers and potential barriers. The emergence of Taiwan around five million years ago (Mya) impacted the Kuroshio Current which later shaped the distribution of marine organisms. In this study, we examined how the Kuroshio Current influenced the distribution and population divergence of the marine red alga Dichotomaria elegans (Galaxauraceae, Nemaliales). Through phylogenetic analysis, species delimitation, and morphological comparison of Taiwanese species, we determined its phylogenetic position relative to other species within the D. marginata complex of the genus Dichotomaria. We uncovered the hidden cryptic diversity within the D. marginata complex in Taiwan and proposed the new combinations D. elegans and D. latifolia based on Galaxaura elegans and G. latifolia. Genetic analysis based on three loci (mitochondrial cox2-3 and cox1, and plastid rbcL) from 32 locations across the Philippines, Taiwan, and Japan revealed three allopatric lineages within D. elegans. The first lineage is restricted to the northern Philippines and southern Taiwan, while the second has a broader latitudinal range along the Kuroshio Current. The third lineage is found in southeast Luzon, Philippines, close to the bifurcation of the North Equatorial Current, near the start of the Kuroshio Current. The divergence of the first two lineages during the mid-Pliocene (~3.7 Mya) coincided with the emergence of Taiwan, with the current dynamics accentuating their separation. The Kuroshio Current exhibited a dual impact on the biogeography of D. elegans: promoting the dispersal of the second lineage towards higher latitudes and preventing the first lineage from moving northward. Principal component analysis showed that habitat conditions and morphologies differed between the two D. elegans lineages. This study provides insights into the cryptic diversity of Dichotomaria in Taiwan, as well as the genetic divergence, biogeographical patterns, and ecological associations of D. elegans, highlighting the interplay of island formation and currents shaping the diversification of seaweeds in the Northwest Pacific Ocean.

The complex process of aging leads to a gradual deterioration in the function of cells, tissues, and the entire organism, thereby increasing the risk of disease and death. Nicotinamide N-methyltransferase (NNMT) has attracted attention as a potential target for combating aging and its related pathologies. Studies have shown that NNMT activity increases over time, which is closely associated with the onset and progression of age-related diseases. NNMT uses S-adenosylmethionine (SAM) as a methyl donor to facilitate the methylation of nicotinamide (NAM), converting NAM into S-adenosyl-L-homocysteine (SAH) and methylnicotinamide (MNA). This enzymatic action depletes NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and generates SAH, a precursor of homocysteine (Hcy). The reduction in the NAD+ levels and the increase in the Hcy levels are considered important factors in the aging process and age-related diseases. The efficacy of RNA interference (RNAi) therapies and small-molecule inhibitors targeting NNMT demonstrates the potential of NNMT as a therapeutic target. Despite these advances, the exact mechanisms by which NNMT influences aging and age-related diseases remain unclear, and there is a lack of clinical trials involving NNMT inhibitors and RNAi drugs. Therefore, more in-depth research is needed to elucidate the precise functions of NNMT in aging and promote the development of targeted pharmaceutical interventions. This paper aims to explore the specific role of NNMT in aging, and to evaluate its potential as a therapeutic target.

Summary: Schlemm’s canal (SC) functions to maintain proper intraocular pressure (IOP) by draining aqueous humor and has emerged as a promising therapeutic target for glaucoma, the second-leading cause of irreversible blindness worldwide. However, our current understanding of the mechanisms governing SC development and functionality remains limited. Here, we show that vitronectin (VTN) produced by limbal macrophages promotes SC formation and prevents intraocular hypertension by activating integrin αvβ3 signaling. Genetic inactivation of this signaling system inhibited the phosphorylation of AKT and FOXO1 and reduced β-catenin activity and FOXC2 expression, thereby causing impaired Prox1 expression and deteriorated SC morphogenesis. This ultimately led to increased IOP and glaucomatous optic neuropathy. Intriguingly, we found that aged SC displayed downregulated integrin β3 in association with dampened Prox1 expression. Conversely, FOXO1 inhibition rejuvenated the aged SC by inducing Prox1 expression and SC regrowth, highlighting a possible strategy by targeting VTN/integrin αvβ3 signaling to improve SC functionality.

Aims: Endothelial dysfunction plays a pivotal role in atherosclerosis, but the detailed mechanism remains incomplete understood. Nogo-B is an endoplasmic reticulum (ER)-localized protein mediating ER-mitochondrial morphology. We previously showed endothelial Nogo-B as a key regulator of endothelial function in the setting of hypertension. Here, we aim to further assess the role of Nogo-B in coronary atherosclerosis in ApoE−/− mice with pressure overload. Methods and results: We generated double knockout (DKO) mouse models of systemically or endothelium-specifically excising Nogo-A/B gene on an ApoE−/− background. After 7 weeks of transverse aortic constriction (TAC) surgery, compared to ApoE−/− mice DKO mice were resistant to the development of coronary atherosclerotic lesions and plaque rapture. Sustained elevation of Nogo-B and adhesion molecules (VCAM-1/ICAM-1), early markers of atherosclerosis, was identified in heart tissues and endothelial cells (ECs) isolated from TAC ApoE−/− mice, changes that were significantly repressed by Nogo-B deficiency. In cultured human umbilical vein endothelial cells (HUVECs) exposure to inflammatory cytokines (TNF-α, IL-1β), Nogo-B was upregulated and activated reactive oxide species (ROS)-p38-p65 signaling axis. Mitofusin 2 (Mfn2) is a key protein tethering ER to mitochondria in ECs, and we showed that Nogo-B expression positively correlated with Mfn2 protein level. And Nogo-B deletion in ECs or in ApoE−/− mice reduced Mfn2 protein content and increased ER-mitochondria distance, reduced ER-mitochondrial Ca2+ transport and mitochondrial ROS generation, and prevented VCAM-1/ICAM-1 upregulation and EC dysfunction, eventually restrained atherosclerotic lesions development. Conclusion: Our study revealed that Nogo-B is a critical modulator in promoting endothelial dysfunction and consequent pathogenesis of coronary atherosclerosis in pressure overloaded hearts of ApoE−/− mice. Nogo-B may hold the promise to be a common therapeutic target in the setting of hypertension.

Absence seizures impair consciousness by an unknown neuronal mechanism. Here, the authors find that a rat absence seizure model’s behavior and hemodynamics recapitulate previously reported characteristics of human absence seizures, and uncover four distinct patterns of neuronal activity in cortex and thalamus during consciousness-impairing seizures.

AIM: To investigate the protective effect of Modified Taohong Siwu Decoction(MTSD)on hypoxia injury to retinal Müller cells rMC-1.METHODS: Retinal Müller cells rMC-1 were interfered with the MTSD drug-containing serum under hypoxia condition, and were randomly divided into control group(21%O2), hypoxia model group(1%O2), MTSD drug-containing serum low-dose(1%O2+5% medicated serum), medium-dose(1%O2+10% medicated serum)and high-dose(1%O2+15%medicated serum)groups. Cell viability was detected by CCK-8 method, and secretion of vascular endothelial growth factor(VEGF)and pigment epithelium derived factor(PEDF)was detected by ELISA. The protein expressions of p-STAT3, STAT3 and hypoxia-inducible factor-1α(HIF-1α)were detected by Western blot, and the gene expressions of VEGF, PEDF, STAT3 and HIF-1α were detected by real-time polymerase chain reaction(PCR).RESULTS: The viability of rMC-1 cells was significantly inhibited when cultured at 1%O2 for 48h compared with that of control group(P0.05). The low and medium doses of MTSD could reduce the protein expressions of VEGF in supernatant of rMC-1 cells under hypoxia condition(P0.05). The above two dose groups down-regulated the protein levels of both p-STAT3 and HIF-1α(P

Background: Erdheim-Chester disease is a form of histiocytosis. It is an extremely rare illness. Since its discovery, hundreds of cases of this disease have been identified across the globe. Pathologically, the condition is characterized by proliferation of lipid-rich foam-like tissue cells, which is especially prevalent in bones. Approximately 50% of patients develop infiltration into organs other than the bones. Case description: A patient with fever and bone pain is described in this case report. After visiting multiple hospitals and departments, undergoning battery of investigations, and ruling out other diseases, the patient was pathologically diagnosed with Erdheim-Chester disease after a biopsy of the associated bone destruction. The condition improved with symptomatic therapy. Conclusion: Numerous clinical symptoms make non-Langerhans cell histiocytosis challenging to diagnose and requires pathological diagnosis. Patients with unexplained multiple bone destruction must be alert against this disease from a clinical standpoint.

AIM: To investigate the prevalence and risk factors of dry eye(DE)among middle school students in Nantong.METHODS: A cross-sectional study was conducted among 1 939 middle school students in January 2021. The minimum sample size was calculated by cluster random sampling. A dry eye questionnaire was used to assess the prevalence and risk factors of DE in middle school students. DE was defined as often or all the time presence of one or more DE symptoms(i.e. “eye dryness” “grittiness” “burning sensation” “redness” “crusting of lashes” “eyelids getting stuck”). The risk factors associated with DE were evaluated by Logistics regression analysis.RESULTS: The prevalence of DE was 19.55%. The most reported dry eye symptom was “eyelids getting stuck”, accounting for 60.95%. Female(OR: 1.287, 95%CI: 1.018-1.626, P=0.035), the daily time of electrical appliances use at near distance >2h(OR: 1.927, 95%CI: 1.260-2.947, P=0.002), the daily time of reading and writing after class >3h(OR: 1.588, 95%CI: 1.214-2.079, P=0.001), frequent use of eye drops(OR: 1.908, 95%CI: 1.359-2.680, P6-8h, OR: 0.627, 95%CI: 0.477-0.823, P=0.001; >8h, OR: 0.511, 95%CI: 0.283-0.922, P=0.026)was an independent protective factor for the disease.CONCLUSION: The prevalence of DE among middle school students is high and should not be ignored. Preventive measures against risk factors may help to reduce the prevalence of DE and have a positive impact on the health of students.

Summary: Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we report that PPDPF is significantly downregulated in HCC and the decreased PPDPF expression indicates poor prognosis. In the dimethylnitrosamine (DEN)-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promotes hepatocarcinogenesis, and reintroduction of PPDPF into liver-specific Ppdpf knockout (LKO) mice inhibits the accelerated HCC development. Mechanistic study shows that PPDPF regulates nuclear factor κB (NF-κB) signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzes K63-linked ubiquitination of RIPK1 at K140. In addition, liver-specific overexpression of PPDPF activates NF-κB signaling and attenuates apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-κB signaling and provides a potential therapeutic candidate for HCC.

Type 2 diabetes mellitus (T2DM) is characterized by chronic low-grade systemic inflammation. Tissue infiltration by monocyte migration contributes to the pathogenesis of vascular complications in T2DM. We studied the role of intermediate-conductance Ca2+-activated K+ (KCa3.1) channels in the palmitic acid (PA)-induced migration of peripheral blood mononuclear cells (PBMCs) from T2DM patients and the influence of advanced glycation endproducts (AGEs). A total of 49 T2DM patients and 33 healthy subjects was recruited into this study. Using flow cytometry and Western blotting analysis as well as cell migration assay, we found that there was a significant decrease in frequency of T lymphocytes and monocytes in CD45+ leukocyte population. PA at 100 μM stimulated migration of PBMCs from T2DM individuals, which was inhibited by the specific KCa3.1 channel blocker TRAM-34 (1 μM). The PBMC migration was positively correlated with glycosylated hemoglobin A1 chain (HbA1c) level of T2DM patients, an indicator of AGEs, and PBMCs with higher level of HbA1c showed upregulated expression of toll-like receptor (TLR) 2/4 and KCa3.1 channels. In THP-1 cells, AGEs at 200 μg/ml increased protein expression of TLR 2/4 and KCa3.1 channels, and were synergistically involved in PA-induced migration through receptors of AGEs (RAGE)-mediated KCa3.1 upregulation. In conclusion, in PBMCs of T2DM patients, AGEs promotes PA-induced migration via upregulation of TLR2/4 and KCa3.1 channels.

AIM: To describe the clinical characteristics of 6 premature infants diagnosed as familial exudative vitreoretinopathy(FEVR).METHODS: From August 2018 to January 2019, the researchers collected six premature cases of FEVR from Xinhua Hospital Affiliated To Shanghai Jiao Tong University School of Medicine. All 6 infants born prematurely had examinations of fundus photography and fluorescein angiograms under anesthesia. Medical history and angiographic features were analyzed retrospectively.RESULTS: Six infants born prematurely were initially misdiagnosed as retinopathy of prematurity ROP. All underwent injection anti-vascular endothelial growth factor(anti-VEGF)drug into vitreous body cavity subsequently, two of whom were treated with injection anti-VEGF drug into vitreous body cavity twice. Six infants born prematurely had follow-up examinations of fundus photography and fluorescein angiograms with the machine of Retcam digital imaging system under anesthesia, they were eventually diagnosed as FEVR. Then 2 cases were treated with laser photocoagulation, 1 case was treated with injection anti-VEGF drug into vitreous body cavity combined laser photocoagulation, 1 case was treated with injection anti-VEGF drug into vitreous body cavity, 2 cases maintain the follow-up visit. CONCLUSION: Clinically, premature infants FEVR, tend to be misdiagnosed as ROP initially. If the demarcation line separating the avascular from the vascular retinal regions presents persistent or the condition turns to be worse, more examinations will be required to confirm the diagnosis such as fluorescein angiograms under anesthesia. FEVR is a lifelong disease, its symptoms, if present, typically take a progressive course during childhood and adolescence. Early diagnosis of FEVR is crucial due to its progressive nature and the genetic/familial underpinnings of the condition. The correct identification of those FEVR patients can help them receive timely treatment and genetic counseling for those of child-bearing age.

Background and aimsThe efficacy and safety of systemic atezolizumab and bevacizumab (atezo/bev) in treatment of patients with unresectable hepatocellular carcinoma (HCC) have been demonstrated. However, the efficacy of this treatment in patients with HCC and extrahepatic portal vein tumor thrombus (ePVTT) is not satisfactory. This study aimed to study the efficacy and safety of combining intensity-modulated radiotherapy (IMRT) with systemic atezo/bev in treatment of these patients.MethodsThis multicenter prospective study included patients with ePVTT treated with IMRT combined with atezo/bev from March to September 2021 in three centers in China. The outcomes of this study included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and association between response and tumor mutational burden (TMB). Treatment-related adverse events (TRAEs) were analyzed to assess safety.ResultsOf 30 patients in this study, the median follow-up was 7.4 months. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the ORR was 76.6%, the median OS for the entire cohort was 9.8 months, the median PFS was 8.0 months, and the median TTP was not reached. This study failed to establish a significant correlation between TMB with any of the following outcomes, including ORR, OS, PFS or TTP. The most common TRAEs at all levels were neutropenia (46.7%), and the most common grade 3/4 TRAE was hypertension (16.7%). There was no treatment-related deaths.ConclusionsIMRT combined with atezo/bev showed encouraging treatment efficacy with an acceptable safety profile, making this treatment to be a promising option for HCC patients with ePVTT. Further studies are required to support the findings of this preliminary study.Clinical trial registrationhttp://www.chictr.org.cn, Identifier ChiCTR2200061793.

Background & Aims: Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor with high morbidity and mortality. AT-rich interaction domain 1A (ARID1A) accounts for up to 10% of mutations in liver cancer, however, its role in HCC remains controversial, and no targeted therapy has been established. Methods: The expression of ARID1A in clinical samples was examined by Western blot and immunohistochemical staining. ARID1A was knocked out by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) in HCC cell lines, and the effects of glucose deprivation on cell viability, proliferation, and apoptosis were measured. Mass spectrometry analysis was used to find ARID1A-interacting proteins, and the result was verified by co-immunoprecipitation and Glutathione S Transferase (GST) pull-down. The regulation of ARID1A target gene USP9X was investigated by chromatin immunoprecipitation, Glutathione S Transferase (GST) pull-down, luciferase reporter assay, and so forth. Finally, drug treatments were performed to explore the therapeutic potential of the agents targeting ARID1A-deficient HCC in vitro and in vivo. Results: Our study has shown that ARID1A loss protected cells from glucose deprivation–induced cell death. A mechanism study disclosed that AIRD1A recruited histone deacetylase 1 via its C-terminal region DUF3518 to the promoter of USP9X, resulting in down-regulation of USP9X and its target protein kinase AMP-activated catalytic subunit α2 (PRKAA2). ARID1A knockout and a 1989∗ truncation mutant in HCC abolished this effect, increased the levels of H3K9 and H3K27 acetylation at the USP9X promoter, and up-regulated the expression of USP9X and protein kinase AMP-activated catalytic subunit α2 (PRKAA2), which mediated the adaptation of tumor cells to glucose starvation. Compound C dramatically inhibited the growth of ARID1A-deficient tumors and prolongs the survival of tumor-bearing mice. Conclusions: HCC patients with ARID1A mutation may benefit from synthetic lethal therapy targeting the ubiquitin-specific peptidase 9 X-linked (USP9X)–adenosine 5‘-monophosphate–activated protein kinase (AMPK) axis.

Crystalline borates have received great attention due to their various structures and wide applications. For a long time, the corner-sharing B–O unit is considered a basic rule in borate structural chemistry. The Dy4B6O15 synthesized under high-pressure is the first oxoborate with edge-sharing [BO4] tetrahedra, while the KZnB3O6 is the first ambient pressure borate with the edge-sharing [BO4] tetrahedra. The edge-sharing connection modes greatly enrich the structural chemistry of borates and are expected to expand new applications in the future. In this review, we summarize the recent progress in crystalline borates with edge-sharing [BO4] tetrahedra. We discuss the synthesis, fundamental building blocks, structural features, and possible applications of these edge-sharing borates. Finally, we also discuss the future perspectives in this field.

Von Willebrand factor (VWF) is a glycoprotein synthesized and secreted by vascular endothelial cells and megakaryocytes, found on plasma surface, endothelial cells, and α-granule of platelets. VWF can be interacted with collagen and platelet membrane glycoproteins GPIb and GPIb-IIa and play an important role in platelet adhesion and aggregation. Growing research evidence suggests that VWF also mediates the prevention or protesting of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients from several clinical studies. While the mechanism of VWF in HCC protection or protest is still unclear, further study is required. This article aims to rationalize the role of VWF in the development of HCC, and the functional domain of VWF in cancer as well as cross-talking with platelets and miRNAs. This article also looks forward to the future development and challenges of VWF research.

Abstract Background To retrospectively analyze CT appearances and progression pattern of COVID-19 during hospitalization, and analyze imaging findings of follow-up on thin-section CT. Methods CT findings of 69 patients with COVID-19 were evaluated on initial CT, peak CT, and pre-discharge CT. CT pattern were divided into four types on CT progression. Lesion percentage of pulmonary lobe (lobe score) was graded. Correlation analysis was made between scores and intervals. 53 patients were followed up by CT. Results Among 69 patients, 33.3% exhibited improvement pattern, 65.2% peak pattern, 1.5% deterioration pattern, and 0% fluctuation pattern. The lobe scores were positively correlated with most of intervals. It was more common to observe consolidation, pleural thickening and pleural effusion on the peak CT, and irregular line and reticulation on pre-discharge CT. The peak-initial interval were shortened when the initial CT with consolidation and pleural thickening. The intervals were extended when the irregular lines appeared on peak CT and reticulation on pre-discharge CT. Among 53 follow-up patients, 37.7% showed normal chest CT, and 62.3% showed viral pneumonia remained that mainly included GGO (100.0%) and irregular lines (33.3%). Conclusions COVID-19 displayed different appearances on CT as progressing. The peak pattern was the most common progression pattern. The CT appearances showed closely related to the intervals. The COVID-19 pneumonia can be remained or completely absorbed on CT with follow-up.

BackgroundAs a recognized highly immunogenic tumor, immune checkpoint blockades (ICB) have been widely used as a systemic treatment option for melanoma. However, only about half of treated patients could benefit from it in Caucasians, and only about 15% in Chinese melanoma patients. Robust predictive biomarkers are needed. HHLA2, a new-found member of B7 family, is generally expressed in kinds of tumors, such as melanoma. This study focuses on illustrating the prognostic value of HHLA2 in melanoma immunotherapy and its association with tumor-infiltrating lymphocytes.MethodsHHLA2 expression in pan-cancer and the association with prognosis and immune microenvironment were identified by analyzing gene expression profiles from TCGA database with selected bioinformatics tools and methods. Tumor tissues from 81 cases with advanced and unresectable melanoma were collected for detecting HHLA2 and CD8 levels by immunohistochemistry.ResultsHHLA2 was found to be ubiquitously expressed in pan-cancer with high level and correlate with the prognosis of patients. Further comprehensive analysis from TCGA database demonstrated that the highly expressed HHLA2 was remarkably correlated with better prognosis, high infiltration status of various immune-active cells and immune activated pathways in skin cutaneous melanoma (SKCM). Moreover, immunohistochemistry (IHC) analyses of FFPE tissue from melanoma patients revealed that HHLA2 high expression was strongly related to improved response to ICB and indicated a longer progression-free survival (PFS) and overall survival (OS). Besides, HHLA2 expression was found to have a positive association with the density of CD8+ TILs.ConclusionOur findings revealed that high expression of HHLA2 has important values in predicting the response to ICB and indicating improved PFS and OS in patients with advanced and unresectable melanoma, suggesting that HHLA2 may serve as a costimulatory ligand in melanoma, which renders it as an ideal biomarker for immunotherapy.

In this study, cascade membrane technology was applied to classify polysaccharides from the peels of stem lettuce (PPSLs), and three graded polysaccharides (PPSL100, PPSL10, and PPSL1) were obtained using ultrafiltration membranes of 100, 10, and 1 kDa in sequence. The physicochemical properties and immune-modulatory activity of three PPSLs fractions were analyzed and compared. Results showed that all three fractions have characteristic absorption peak of polysaccharides determined by FT-IR, and their monosaccharide composition only consisted of glucose determined by HPLC. PPSL10 had the highest contents of total sugar (88.09 ± 3.52%), uronic acid (2.55 ± 0.10%), and sulfate group (4.15 ± 0.20%). Besides, all three fractions exhibited immune-enhancing activities using RAW264.7 macrophages model, and PPSL10 was the best able to promote phagocytosis of neutral red and nitric oxide generation, which might relate to the high contents of above compositions and medium molecular weight (32 kDa). The findings indicated that PPSL10 could be developed as immune-modulator in the field of functional foods.

Non-alcoholic fatty liver disease (NAFLD) has become a prevalent chronic liver disease, however, drugs to treat this disease are still lacking. Here, the authors show that PPDPF inhibits the development of hepatic steatosis by negatively regulating mTORC1-S6K-SREBP1 signaling, which provides a potential therapeutic candidate for NAFLD treatment.

The lacewing, Chrysoperla sinica, is a predaceous insect that is important in crop pest management. Chemical pesticides have adversely impacted predaceous insect species. Here we studied the effect of tolfenpyrad on C. sinica. The acute toxicity of tolfenpyrad to the second-instar larvae was determined and indicated that tolfenpyrad is a medium-risk insecticide. Sublethal concentrations (LC10, LC20, and LC30) of tolfenpyrad had effects on the development, reproduction, and predatory ability of C. sinica. When the second-instar larvae of C. sinica were exposed to sublethal concentrations of tolfenpyrad, the activities of protective enzymes, such as superoxide dismutase, peroxidase, and catalase, and detoxification enzymes, including carboxylesterase, glutathione-S-transferase, and P450 monooxygenases, were increased with exposure time. The second-instar larvae of C. sinica exposed to sublethal concentrations of tolfenpyrad exhibited an oxidative stress response that increased the levels of malondialdehyde and reactive oxygen species (ROS). Within 48–120 h after treatment, the contents of mitochondrial respiratory chain complex I and adenosine triphosphate in the second-instar larvae were decreased. This resulted in an imbalance between the production and clearance of ROS and caused cellular damage.

Considered the increased threaten of neurosyphilis in China, a review on cases reported in the literature to describe the clinical epidemiological characteristics of neurosyphilis cases, may be beneficial to the early detection and management strategies of neurosyphilis for clinicians. We searched the literature on Chinese neurosyphilis cases published from January 1, 2009 to December 31, 2021, described their clinical epidemiological characteristics and calculated the prevalence of neurosyphilis amongst other associated diseases, according to the individual study criteria. A total of 284 studies including 7,486 neurosyphilis cases were included. No meta-analysis was performed due to the heterogeneity of the data. Among 149 case reports and 93 retrospective case series studies, the main clinical manifestation of 3,507 neurosyphilis cases was cerebral parenchymal syphilis (57.3%), followed by asymptomatic neurosyphilis (16.7%), meningovascular syphilis (13.6%), meningitis syphilis (7.7%) and ocular syphilis (2.8%), etc. In addition, the initial diagnosis was incorrect in 53.2% patients, and the most frequent misdiagnoses were mental disorders (31.0%), stroke (15.9%), cognitive impairment (9.0%), etc. The positive or abnormal rates of cerebrospinal fluid non-treponemal and treponemal tests, white blood cell counts and protein concentrations were 74.2%, 96.2%, 61.5%, and 60.9%, respectively. Aqueous penicillin was the first choice for treatment in 88.3% cases, and 81.7% and 50.0% patients had response in the improvement of symptoms and serological effective in CSF, respectively. Among 26 studies on neurosyphilis patients amongst other associated diseases, the prevalence of neurosyphilis amongst central nervous system infectious diseases, syphilis-associated neurological symptoms, serofast status, coinfected with human immunodeficiency virus were 10.6%–30.1%, 23.2%–35.5%, 9.8%–56.1%, and 8.9%, respectively. In summary, the lack of early detection of neurosyphilis cases remains a clinical challenge. The high rate of misdiagnosis and high prevalence of neurosyphilis amongst associated diseases strongly remind clinicians to focus on the early detection among suspected cases. Besides, the standard treatment regimen and long-term follow-up, which complied with guideline should be provided. Further prospective studies are urgent to better delineate the clinical epidemiological characteristics of neurosyphilis in China.

BackgroundNursing is a high-stress occupation that can have an impact on mental health, particularly for neonatal nurses. Job-related stress factors and work-related behaviors have played a critical role in nurses' mental health. This study aimed to explore the prevalence of mood disorders and the impact of social factors, lifestyle on mood disorders among neonatal nurses.MethodsA total of 260 participants comprising neonatal nurses and nurses who work in neonatal intensive care units (NICU) were recruited. Data were collected using a validated generalized anxiety disorder questionnaire, patient health questionnaire-9, Pittsburgh sleep quality index, and social factors and lifestyle assessments.ResultsIn total, 49.23% of neonatal nurses exhibited mood disorders, particularly a combination of depression and anxiety. Female, poor interpersonal relationships and unhappy marital status, preference for smoking, alcohol, irregular diet, and poor sleep were common in neonatology nurses who exhibited mood disorders; preference for coffee and tea were lower in neonatology nurses without mood disorders (all P < 0.05). Interpersonal relationships, marital status, irregular diet, and poor sleep were independent factors associated with mood disorders among neonatal nurses (all P < 0.05). Mood disorders presented as functional dyspepsia (FD) among 50.78% of the participants (P < 0.05). Poor sleep and preference for smoking were common among neonatal nurses who had FD with mood disorders (all P < 0.05). Furthermore, the preference for sugary beverages was lower in participants with FD and mood disorders (P < 0.05). Poor sleep was independently associated with FD with mood disorders in neonatology nurses (P < 0.05).ConclusionPrevalence of anxiety and depression was higher among neonatal nurses. Furthermore, most cases of mood disorders presented as FD. Thus, social factors and lifestyle have an impact on mood disorders which can manifest through somatic symptoms.

Recombinant antibodies are rapidly developing therapeutic agents; approximately 40 novel antibody molecules enter clinical trials each year, most of which are produced from Chinese hamster ovary (CHO) cells. However, one of the major bottlenecks restricting the development of antibody drugs is how to perform high-level expression and production of recombinant antibodies. The high-efficiency expression and quality of recombinant antibodies in CHO cells is determined by multiple factors. This review provides a comprehensive overview of several state-of-the-art approaches, such as optimization of gene sequence of antibody, construction and optimization of high-efficiency expression vector, using antibody expression system, transformation of host cell lines, and glycosylation modification. Finally, the authors discuss the potential of large-scale production of recombinant antibodies and development of culture processes for biopharmaceutical manufacturing in the future.

Li Zhang et al. characterize ckrw2, cytokinin-induced root waving 2, as a mutant form of HUB1 in Arabidopsis, the gene required for histone H2B monoubiquitination. This study implicates the involvement of H2Bub1 in regulating auxin biosynthesis.

Background Blood pressure (BP) variability is highly correlated with cardiovascular and kidney outcomes in patients with chronic kidney disease (CKD). However, appropriate BP targets in patients with CKD remain uncertain. Methods We searched PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) of CKD patients who underwent intensive BP management. Kappa score was used to assess inter-rater agreement. A good agreement between the authors was observed to inter-rater reliability of RCTs selection (kappa = 0.77; P = 0.005). Results Ten relevant studies involving 20 059 patients were included in the meta-analysis. Overall, intensive BP management may reduce the incidence of cardiovascular disease mortality (RR: 0.69, 95% CI: 0.53 to 0.90, P: 0.01), all-cause mortality (RR: 0.77, 95% CI: 0.67 to 0.88, P

Background: As a potent mediator of hypothermic neuroprotection, the cold-inducible protein RBM3 is characterized with one RNA-recognition motifs (RRM) and one arginine-glycine-rich (RGG) domain. It is known that these conserved domains are required for nuclear localization in some RNA-binding proteins. However, little is known about the actual role of RRM and RGG domains in subcellular localization of RBM3. Methods: To clarify it, various mutants of human Rbm3 gene were constructed. Plasmids were transfected into cells and the localization of RBM3 protein and its varias mutants in cells and role in neuroprotection. Results: In human neuroblastoma SH-SY5Y cells, either a truncation of RRM domain (aa 1–86) or RGG domain (aa 87–157) led to an obvious cytoplasmic distribution, compared to a predominant nuclear localization of whole RBM3 protein (aa 1–157). In contrast, mutants in several potential phosphorylated sites of RBM3, including Ser102, Tyr129, Ser147, and Tyr155, did not alter the nuclear localization of RBM3. Similarly, mutants in two Di-RGG motif sites also did not affect the subcellular distribution of RBM3. Lastly, the role of Di-RGG motif in RGG domains was further investigated. The mutant of double arginines in either Di-RGG motif-1 (Arg87/90) or -2 (Arg99/105) exhibited a higher cytoplasmic localization, indicating that both Di-RGG motifs are required for nucleic localization of RBM3. Conclusions: Our data suggest that RRM and RGG domains are both required for the nuclear localization of RBM3, with two Di-RGG domain being crucial for nucleocytoplasmic shuttling of RBM3.

Ulcerative colitis (UC) is a chronic, relapsing, and nonspecific inflammatory bowel disease (IBD). Phillygenin (PHI), a natural bioactive ingredient, isolated from Forsythiae Fructus, exhibits anti-inflammatory, anti-oxidative, and hepatoprotective activities. However, few reports provide direct evidence on the efficacy of PHI in improving colitis mice. The present study elucidated that the symptoms of DSS-induced colitis mice were alleviated after PHI administration, including body weight loss, the disease activity index, colon length shortening, colonic pathological damage, splenomegaly, and hepatomegaly. PHI treatment improved the intestinal mucosal barrier by protecting goblet cells, promoting gene expressions of Clca1, Slc26a3, and Aqp8, increasing tight junction proteins (TJs), and reducing epithelial cell apoptosis. In addition, the levels of oxidative stress (MPO, SOD, and MDA) and inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-10) were reversed by PHI in colitis mice. According to transcriptome and network pharmacology analysis, inflammatory pathway might be an important mechanism for PHI to improve colitis. Western blotting displayed that the PHI inhibited the activation of tyrosine kinase Src mediated by TLR4, and then reduced the phosphorylation of downstream proteins p38, JNK, and NF-κB in colitis mice. In summary, our results suggested that PHI might be an appropriate and effective drug candidate to protect colitis.

Room-temperature phosphorescence has attracted attention for bioimaging, but quenching in aqueous systems is an issue. Here, the authors report on the synthesis of a water soluble organic phosphorescent polymer and demonstrate application is cancer cell targeting and imaging.

Sjögren's syndrome (SS) is a chronic, systemic, inflammatory autoimmune disease characterized by lymphocyte proliferation and progressive damage to exocrine glands. The diagnosis of SS is challenging due to its complicated clinical manifestations and non-specific signs. Salivary gland biopsy plays an important role in the diagnosis of SS, especially with anti-Sjögren's syndrome antigen A (SSA) and anti-SSB antibody negativity. Histopathology based on biopsy has clinical significance for disease stratification and prognosis evaluation, such as risk assessment for the development of non-Hodgkin's lymphoma. Furthermore, histopathological changes of salivary gland may be implicated in evaluating the efficacy of biological agents in SS. In this review, we summarize the histopathological features of salivary gland, the mechanism of histopathological changes and their clinical significance, as well as non-invasive imaging techniques of salivary glands as a potential alternative to salivary gland biopsy in SS.

BackgroundThe incineration and burying of the soiled bedding of laboratory animals, as well as using detergents to treat their feces, is hazardous to the environment. This highlights the need for an alternative, environmentally friendly solution for the treatment of the waste of laboratory animal facilities. This study aims to evaluate the efficacy of ozone disinfection of the soiled bedding and feces of laboratory animals.MethodsTwo grams of soiled beddings were randomly sampled from the cages of mice and rats. These samples were mixed in a beaker with 40ml saline. Ozone was piped into the beaker at a concentration of 500mg/h. Samples were taken from the beaker at time 0min, 30min, 45min and 60min after ozone treatment for microbiological culturing in an incubator for 48h. Colony form unit of each plate (CFU/plate) at each time point were counted, the mean CFU/plate at each time point after ozone treatment were compared with that present at time zero. Feces of rabbits and dogs were treated and pathogens were counted the similar way as that of bedding of the mice and rats; samples being taken at 0min, 15min, 30min, 45min and 60min.ResultsPathogens were observed in beddings of both mice and rats as well as in feces of rabbits and dogs. Ozone treatment for 30min killed more than 93% of pathogens in the bedding of the two rodent species and 60min of treatment killed over 99% of pathogens. Treatment of rabbit and dog feces for 30min killed over 96% pathogens present, and 60min's treatment killed nearly all the pathogens. Both Gram positive and Gram negative pathogens were sensitive to ozone treatment.ConclusionOzone treatment of bedding and feces is an effective and environment friendly way to deal with the waste of animal facilities, saving energy and potentially enabling their reuse as fertilizer.

Anxiety is frequently observed in patients with systemic lupus erythematosus (SLE) and the immune system could act as a trigger for anxiety. To recognize abnormal T-cell and B-cell subsets for SLE patients with anxiety, in this study, patient disease phenotypes data from electronic lupus symptom records were extracted by using natural language processing. The Hospital Anxiety and Depression Scale (HADS) was used to distinguish patients, and 107 patients were selected to meet research requirements. Then, peripheral blood was collected from two patient groups for multicolor flow cytometry experiments. The characteristics of 75 T-cell and 15 B-cell subsets were investigated between SLE patients with- (n = 23) and without-anxiety (n = 84) groups by four machine learning methods. The findings showed 13 T-cell subsets were significantly different between the two groups. Furthermore, BMI, fatigue, depression, unstable emotions, CD27+CD28+ Th/Treg, CD27−CD28− Th/Treg, CD45RA−CD27− Th, and CD45RA+HLADR+ Th cells may be important characteristics between SLE patients with- and without-anxiety groups. The findings not only point out the difference of T-cell subsets in SLE patients with or without anxiety, but also imply that T cells might play the important role in patients with anxiety disorder.

Abstract. CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy is effective in refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL). This review focuses on achievements, current obstacles, and future directions in CAR-T research. A high complete remission rate of 68% to 93% could be achieved after anti-CD19 CAR-T treatment for B-ALL. Cytokine release syndrome and CAR-T-related neurotoxicity could be managed. In view of difficulties collecting autologous lymphocytes, universal CAR-T is a direction to explore. Regarding the high relapse rate after anti-CD19 CAR-T therapy, the main solutions have been developing new targets including CD22 CAR-T, or CD19/CD22 dual CAR-T. Additionally, some studies showed that bridging into transplant post-CAR-T could improve leukemia-free survival. Some patients who did not respond to CAR-T therapy were found to have an abnormal conformation of the CD19 exon or trogocytosis. Anti-CD19 CAR-T therapy for R/R B-ALL is effective. From individual to universal CAR-T, from one target to multi-targets, CAR-T-cell has a chance to be off the shelf in the future.

Abstract Background Modern breeding in the poultry industry mainly aims to produce high-performance poultry lines and breeds in two main directions of productivity, meat and eggs. To understand more about the productive potential of lowly selected Chinese native chicken populations, we selected 14 representative SNP markers strongly associated with growth traits or carcass traits and 14 SNP markers strongly associated with egg laying traits through previous reports. By using the MassArray technology, we detected the genotype frequency distributions of these 28 SNP markers in seven populations including four lowly selected as well as one moderately selected Sichuan native chicken populations, one commercial broiler line and one commercial layer line. Results Based on the genotype frequency distributions of these 28 SNP markers in 5 native chicken populations and 2 commercial lines, the results suggested that these Chinese indigenous chicken populations have a relatively close relationship with the commercial broiler line but a marked distinction from the commercial layer line. Two native chicken breeds, Shimian Caoke Chicken and Daheng Broilers, share similar genetic structure with the broiler line. Conclusions Our observations may help us to better select and breed superior domestic chickens and provide new clues for further study of breeding programs in local chicken populations.

The histone deacetylase inhibitor, trichostatin A, is used to treat Alzheimer’s disease and can improve learning and memory but its underlying mechanism of action is unknown. To determine whether the therapeutic effect of trichostatin A on Alzheimer’s disease is associated with the nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like epichlorohydrin-related protein-1 (Keap1) signaling pathway, amyloid β-peptide 25–35 (Aβ25–35) was used to induce Alzheimer’s disease-like pathological changes in SH-SY5Y neuroblastoma cells. Cells were then treated with trichostatin A. The effects of trichostatin A on the expression of Keap1 and Nrf2 were detected by real-time quantitative polymerase chain reaction, western blot assays and immunofluorescence. Total antioxidant capacity and autophagy activity were evaluated by total antioxidant capacity assay kit and light chain 3-I/II levels, respectively. We found that trichostatin A increased cell viability and Nrf2 expression, and decreased Keap1 expression in SH-SY5Y cells. Furthermore, trichostatin A increased the expression of Nrf2-related target genes, such as superoxide dismutase, NAD(P)H quinone dehydrogenase 1 and glutathione S-transferase, thereby increasing the total antioxidant capacity of SH-SY5Y cells and inhibiting amyloid β-peptide-induced autophagy. Knockdown of Keap1 in SH-SY5Y cells further increased trichostatin A-induced Nrf2 expression. These results indicate that the therapeutic effect of trichostatin A on Alzheimer’s disease is associated with the Keap1-Nrf2 pathway. The mechanism for this action may be that trichostatin A increases cell viability and the antioxidant capacity of SH-SY5Y cells by alleviating Keap1-mediated inhibition Nrf2 signaling, thereby alleviating amyloid β-peptide-induced cell damage.

Background: Augmented renal clearance (ARC) risk factors and effects on vancomycin (VCM) of obstetric patients were possibly different from other populations based on pathophysiological characteristics. Our study was to establish a regression model for prediction of ARC and analyze the effects of ARC on VCM treatment in critically ill obstetric patients.Methods: We retrospectively included 427 patients, grouped into ARC and non-ARC patients. Logistic regression analysis was used to analyze the factors related to ARC. Receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of the model for ARC. Patients who received VCM therapy were collected. The published VCM population pharmacokinetic (PPK) model was used to calculate pharmacokinetic parameters. A linear regression analysis was made between the predicted and measured concentrations.Results: Of the 427 patients, ARC was present in 201 patients (47.1%). The independent risk factors of ARC were heavier, greater gestational age, higher albumin level, fewer caesarean section, severe preeclampsia and vasoactive drug; more infection, hypertriglyceridemia and acute pancreatitis. We established the above nine-variable prediction regression model and calculated the predicted probability. ROC curve showed that the predicted probability of combined weight, albumin and gestational age had better sensitivity (70.0%) and specificity (89.8%) as well as the maximal area under the curve (AUC, AUC = 0.863). 41 cases received VCM; 21 cases (51.2%) had ARC. The initial trough concentration in ARC patients was lower than in non-ARC patients (7.9 ± 3.2 mg/L vs 9.5 ± 3.3 mg/L; p = 0.033). Comparing the predicted trough concentration of two published VCM PPK models with the measured trough concentration, correlation coefficients (r) were all more than 0.8 in the ARC group and non-ARC group. AUC was significantly decreased in the ARC group (p = 0.003; p = 0.013), and clearance (CL) increased in the ARC group (p < 0.001; p = 0.008) when compared with the non-ARC group.Conclusion: ARC is a common state in critically ill obstetric patients. The regression model of nine variables had high predictive value for predicting ARC. The published VCM PPK models had good predictive performance for predicting trough concentrations of obstetric patients. Pharmacokinetic parameters of VCM are different in ARC obstetric patients, which results in enhanced VCM clearance and decreased trough concentration.

The toxicity spectrum between Chinese and Caucasian patients with melanoma who were treated with BRAF inhibitors (BRAFi) may differ. The purpose of the present study was to assess the safety and tolerability of BRAFi and BRAFi-based combination therapies [MEK inhibitors (MEKi) or anti-programmed death-1 (PD-1) antibody] in Chinese patients with BRAF V600E/K mutation-positive metastatic melanoma. We also investigated whether treatment-related adverse events (AEs) correlated with the prognosis. This retrospective study collected data from 43 patients with BRAF V600E/K mutation-positive metastatic melanoma from a single Chinese cancer center. Of the 43 patients, 12 patients received BRAFi monotherapy, 12 patients received BRAFi+MEKi, and 19 patients received BRAFi combined with the anti-PD-1 antibody. The median follow-up time was 19 months. In the BRAFi group, the most common AEs were rashes, palmoplantar erythrodysesthesia, and arthralgia. Four out of 12 (30%) patients experienced grade 3–4 treatment-related AEs. All grades of AEs in the BRAFi+MEKi group were similar to the BRAFi group, except for higher pyrexia (58.3%) and fewer cutaneous AEs. Three out of 12 (25%) patients experienced grade 3–4 AEs, especially pyrexia (16.7%). In the BRAFi+anti-PD-1 antibody group, AEs were similar to the BRAFi group, except for an increased aminotransferase level (36.8%), increased bilirubin (31.6%), and hypothyroidism (15.8%). Eleven out of 19 (57.9%) patients experienced grade 3–4 AEs and four out of 19 (21%) patients discontinued the therapy due to AEs. Treatment-related hepatotoxicity (trHE), defined as an increase in either alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin levels, was the only AE identified as a significant poor-prognosis indicator in this study. The median progression-free survival of patients with trHE (41.9%) was 8 months, whereas it was 18 months for those without trHE [p = 0.046, hazard ratio (HR) = 2.116]. Moreover, this association was independent of medication regimens (p = 0.014, HR = 2.971). The overall response rate of patients with trHE was significantly lower than those without trHE (44.4 vs. 60.0%, p = 0.024), and we observed a similar trend in patients treated with BRAFi, BRAFi+MEKi, and BRAFi+anti-PD-1 antibody. In conclusion, BRAFi and BRAFi-based combination therapies were tolerable with reversible AEs in Chinese patients with melanoma. The trHE in patients receiving BRAFi and BRAFi-based regimens might indicate a poor therapy-related prognosis.

Background: Numerous vancomycin population pharmacokinetic models in neonates have been published; however, their predictive performances remain unknown. This study aims to evaluate their external predictability and explore the factors that might affect model performance.Methods: Published population pharmacokinetic models in neonates were identified from the literature and evaluated using datasets from two clinical centers, including 171 neonates with a total of 319 measurements of vancomycin levels. Predictive performance was assessed by prediction- and simulation-based diagnostics and Bayesian forecasting. Furthermore, the effect of model structure and a number of identified covariates was also investigated.Results: Eighteen published pharmacokinetic models of vancomycin were identified after a systematic literature search. Using prediction-based diagnostics, no model had a median prediction error of ≤ ± 15%, a median absolute prediction error of ≤30%, and a percentage of prediction error that fell within ±30% of >50%. A simulation-based visual predictive check of most models showed there were large deviations between observations and simulations. After Bayesian forecasting with one or two prior observations, the predicted performance improved significantly. Weight, age, and serum creatinine were identified as the most important covariates. Moreover, employing a maturation model based on weight and age as well as nonlinear model to incorporate serum creatinine level significantly improved predictive performance.Conclusion: The predictability of the pharmacokinetic models for vancomycin is closely related to the approach used for modeling covariates. Bayesian forecasting can significantly improve the predictive performance of models.

Metastasis-associated recurrence is a major cause of poor prognosis in hepatocellular carcinoma. Here, the authors show that expression of choroideremia-like (CHML) is elevated and associates with poor prognosis in hepatocellular carcinoma, and mechanistically CHML promotes metastasis in a Rab14-dependent manner.

BackgroundClinical studies have shown that electroacupuncture (EA) alleviates chronic itch. Gastrin-releasing peptide receptor (GRPR) and dynorphin (DYN) in the spinal dorsal horn positively or negatively regulate itch, respectively. However, which frequency of EA is effective on relieving chronic itch and reducing the expression of GRPR, whether DYN-A in the spinal cord is involved in the underlying mechanism of the antipruritus effect of EA remains unknown.MethodsThe mixture of acetone and diethyl ether (1:1) [designated as AEW (acetone/diethyl ether and water) treatment] was used to induce the dry skin model of chronic itch. EA was applied to Quchi (LI11) and Hegu (LI4). Western blot was used to detect the expression of GRPR and DYN-A. Immunofluorescence was used to detect the expression of DYN-A.ResultsThe AEW administration induced remarkable spontaneous scratching, enhanced the expression of GRPR, and reduced the expression of DYN-A. Compared with the sham EA, 2 Hz EA, or 15 Hz EA group, 100 Hz EA was the most effective frequency for relieving chronic itch, reducing the expression of GRPR, and increasing the expression of DYN-A in the cervical dorsal horn. Furthermore, intraperitoneal injection of kappa opioid receptors (KORs) antagonist nor-Binaltorphimine dihydrochloride (nor-BNI) significantly reversed the effect of 100 Hz EA on the inhibition of both itching behavior and GRPR expression.ConclusionEA at 100 Hz is the most effective frequency that inhibits chronic itch and GRPR expression through activation of KORs in the spinal dorsal horn, which can effectively guide the clinical treatment and improve the antipruritic effect of acupuncture.

Organic room‐temperature phosphorescence (RTP) has attracted tremendous attention in recent years due to its potential utility in combination with artificial soft materials. Herein, a room‐temperature‐phosphorescent hybrid xerogel held together by electrostatic and host–guest interactions is reported. The xerogel is constructed by noncovalent complexation of 7‐[6‐deoxy‐6‐(2‐sulfonic)]‐β‐cyclodextrin (SCD) with the phosphor bromophenyl‐methyl‐pyridinium chloride (PYCl) and in situ incorporation of the anionic SCD⊃PYCl complex into a cationic amino clay (AC) via electrostatic interactions. The resulting xerogel, designated AC/SCD⊃PYCl, has a network structure that can suppress vibrational and nonradiative relaxation of the phosphor, leading to green RTP emission as well as good fluorescence–phosphorescence dual emission. Notably, the intensity of the xerogel RTP varies with humidity and can be switched on and off repeatedly, which indicates that the xerogel has potential utility as an organic light‐emitting humidity‐sensing material.

Climate-driven shifts of coastal species’ ranges constitute a key factor shaping both the vegetation composition and biodiversity of coastal ecosystems. Although phylogeographic studies relying on genetic data have shed light on the evolutionary history of macroalgae along the Northwest Pacific (NW-Pacific) coast, their distribution dynamics are less understood and require interdisciplinary examination. Here, we used a combination of species distribution models (SDMs) and genetic data to explain the causes of population persistence and genetic differentiation and their consequences for the brown seaweed Sargassum horneri in the NW-Pacific. In this region, the phylogeographic structure of S. horneri was analyzed by screening 72 populations spawning across the entire coastal distribution and obtaining their mtDNA cox3 data. Population genetic structure and SDMs based on paleoclimatic data consistently revealed that southern coasts of the Sea of Japan, North-Pacific-Japan, and the northern part of Okinawa Trough might have served as potential refugia for S. horneri during the Last Glacial Maximum (LGM). Furthermore, we projected the distribution dynamics of S. horneri under future climate scenarios. The range of S. horneri was predicted to move northward, with a significant loss of suitable habitat, under the high emissions scenario (RCP 8.5). By contrast, projected range shifts were minimal under the low emissions scenario (RCP 2.6). Furthermore, North-Pacific-Japan was projected to be long-term persistence habitat for S. horneri under future climatic conditions, thus including this area in conservation planning could help mitigate for climate change implications. Our results enable a better understanding of the impacts of climate change on the spatio-temporal distribution of macroalgae and how this can inform coastal management and marine conservation planning.