Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma.

Multiple myeloma is a hematological malignancy arising from immunoglobulin-secreting plasma cells. It remains poorly understood how chromatin rewiring of regulatory elements contributes to tumorigenesis and therapy resistance in myeloma. Here we generate a high-resolution contact map of myeloma-associated super-enhancers by integrating H3K27ac ChIP-seq and HiChIP from myeloma cell lines, patient-derived myeloma cells and normal plasma cells. Our comprehensive transcriptomic and phenomic analyses prioritize candidate genes with biological and clinical implications in myeloma. We show that myeloma cells frequently acquire SE that transcriptionally activate an oncogene PPP1R15B, which encodes a regulatory subunit of the holophosphatase complex that dephosphorylates translation initiation factor eIF2α. Epigenetic silencing or knockdown of PPP1R15B activates pro-apoptotic eIF2α-ATF4-CHOP pathway, while inhibiting protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B using Raphin1 potentiates the anti-myeloma effect of bortezomib. Our study reveals that myeloma cells are vulnerable to perturbation of PPP1R15B-dependent protein homeostasis, highlighting a promising therapeutic strategy.

Care preparedness of family caregivers of maintenance hemodialysis patients: a cross-sectional study.

With the increasing number of maintenance hemodialysis (MHD) patients, growing attention has been paid to the quality of care. Strengthening care preparedness of family caregivers is essential to improving the nursing quality. The purpose of this study is to explore the care preparedness level of family caregivers of MHD patients and its influencing factors, so as to provide guidance for the development of targeted care interventions. A total of 237 family caregivers of MHD patients were recruited from the hemodialysis room of two tertiary hospitals in Wuhan using the Convenience sampling method. They were surveyed by the general data questionnaire, Care Preparedness Scale and Positive Aspects of Caregiving. Statistical analysis was conducted using IBM SPSS software, version 21.0. The statistical tests conducted in this study were two-tailed, and a significance level of P < 0.05 was deemed as statistically significant. The care preparedness and positive aspects of caregiving scores of family caregivers of MHD patients were 19.05 ± 5.64 and 31.28 ± 7.28 points, respectively. The care preparedness level of family caregivers was significantly positively correlated with positive aspects of caregiving (P < 0.01). The results of multiple linear regression analysis showed that the total nursing time and whether family caregivers had chronic diseases and positive aspects of caregiving were the main factors influencing their care preparedness (all P < 0.05). These three factors accounted for 49.6% of the variance. The care preparedness of family caregivers of MHD patients remains to be continuously improved. Medical staff should emphasize the important role of total nursing time, whether the caregiver has a chronic disease, and positive aspects of caregiving in improving care preparedness in this population. To achieve this end, medical staff can provide targeted support and guidance for caregivers according to the influencing factors, such as implementing group psychological education, strengthening the training, offering social support, remote intervention (including family caregivers' education through the media), and so on. Meanwhile, caregivers should be evaluated dynamically, and information and emotional support should be provided for them.

Three-dimensional visualization technology for guiding one-step percutaneous transhepatic cholangioscopic lithotripsy for the treatment of complex hepatolithiasis.

BACKGROUND: Biliary stone disease is a highly prevalent condition and a leading cause of hospitalization worldwide. Hepatolithiasis with associated strictures has high residual and recurrence rates after traditional multisession percutaneous transhepatic cholangioscopic lithotripsy (PTCSL). AIM: To study one-step PTCSL using the percutaneous transhepatic one-step biliary fistulation (PTOBF) technique guided by three-dimensional (3D) visualization. METHODS: This was a retrospective, single-center study analyzing, 140 patients who, between October 2016 and October 2023, underwent one-step PTCSL for hepatolithiasis. The patients were divided into two groups: The 3D-PTOBF group and the PTOBF group. Stone clearance on choledochoscopy, complications, and long-term clearance and recurrence rates were assessed. RESULTS: Age, total bilirubin, direct bilirubin, Child-Pugh class, and stone location were similar between the 2 groups, but there was a significant difference in bile duct strictures, with biliary strictures more common in the 3D-PTOBF group (P = 0.001). The median follow-up time was 55.0 (55.0, 512.0) days. The immediate stone clearance ratio (88.6% vs 27.1%, P = 0.000) and stricture resolution ratio (97.1% vs 78.6%, P = 0.001) in the 3D-PTOBF group were significantly greater than those in the PTOBF group. Postoperative complication (8.6% vs 41.4%, P = 0.000) and stone recurrence rates (7.1% vs 38.6%, P = 0.000) were significantly lower in the 3D-PTOBF group. CONCLUSION: Three-dimensional visualization helps make one-step PTCSL a safe, effective, and promising treatment for patients with complicated primary hepatolithiasis. The perioperative and long-term outcomes are satisfactory for patients with complicated primary hepatolithiasis. This minimally invasive method has the potential to be used as a substitute for hepatobiliary surgery.

[Curative effect analysis of anterior cervical discectomy and fusion in patients with cervical spondylosis of vertebral artery type].

OBJECTIVE: To investigate the clinical effect of anterior cervical discectomy and fusion (ACDF) in the treatment of cervical spondylosis of vertebral artery type(CSA). METHODS: The clinical data of 42 patients with CSA from January 2020 to January 2022 were retrospectively analyzed. There were 25 males and 17 females, aged from 30 to 74 years old with an average of (53.9±11.0) years old. There were 18 cases with single-segment lesions, 17 cases with two-segment lesions, and 7 cases with three-segment lesions. The American Academy of Otolaryngology-Head and Neck Surgery's Hearing and Balance Committee score (CHE), the Neck Disability Index (NDI) and the cervical curvature Cobb angle were recorded before surgery and after surgery at 6 months. RESULTS: All 42 ACDF patients were followed up for 6 to 30 months with an average of (14.0±5.2) months. The operative time ranged from 95 to 220 min with an average of (160.38±36.77) min, the intraoperative blood loss ranged from 30 to 85 ml with an average of (53.60±18.98) ml. Tow patients had mild postoperative dysphagia, which improved with symptomatic treatment such as nebulized inhalation. CHE score decreased from (4.05±0.96) preoperatively to (2.40±0.70) at 6 months postoperatively (t=12.97, P<0.05). The number of improved vertigo at 6 months postoperatively was 38, with an improvement rate of 90.5%. NDI score was reduced from (34.43±8.04) preoperatively to (20.76±3.91) at 6 months postoperatively (t=11.83, P<0.05). The cervical curvature Cobb angle improved from (8.04±6.70)° preoperatively to (12.42±5.23)° at 6 months postoperatively (t=-15.96, P<0.05). CONCLUSION: The ACDF procedure has outstanding clinical efficacy in treating CSA. The operation can rapidly relieve patients' episodic vertigo symptoms by relieving bony compression and reconstructing cervical curvature. However, it is necessary to strictly grasp the indications for surgery and clarify the causes of vertigo in patients, and ACDF surgery is recommended for CSA patients for whom conservative treatment is ineffective.

Anxiety and sleep quality in patients receiving maintenance hemodialysis: multiple mediating roles of hope and family function.

The objective of this cross-sectional study was to examine the extent of sleep quality among individuals undergoing maintenance hemodialysis (MHD) and to scrutinize whether hope and family function serve as mediators in the association between anxiety and sleep quality in this cohort. A convenience sampling method was used to recruit 227 patients receiving maintenance hemodialysis from two tertiary hospitals in Wuhan. Participants completed several self-report questionnaires, including the Sociodemographic questionnaire, Hospital Anxiety and Depression Scale, Athens Insomnia Scale, Herth Hope Index, and Family APGAR Index. As per the findings of the chain mediation analysis, it was observed that the sleep quality scores were directly predicted by anxiety. Moreover, anxiety positively predicted sleep quality scores through hope and family function as mediators. The observed types of mediation were partial mediation. The total indirect effect value was 0.354, indicating the mediating effect of hope and family function, while the total effect value was 0.481, representing the overall effect of anxiety on sleep quality. The total effect size was 73.60% (0.354/0.481), indicating that the mediation accounted for a significant portion of the relationship. This study established the chain mediating effect of hope and family function between anxiety and sleep quality in patients receiving maintenance hemodialysis. The findings highlight the importance of addressing anxiety and promoting hope and family function to improve sleep quality in this population. The findings suggest that healthcare professionals should be attentive to the anxiety levels of these patients and implement targeted interventions to help alleviate anxiety, enhance hope, and improve family functioning, with the ultimate goal of improving sleep quality in this population.

Age and gender differences of normative values of spleen diffusion MRI parameters.

This study investigates age and gender differences of normative values of spleen diffusion MRI parameters.We recruited 124 volunteers with MRI conducted at 1.5T. Diffusion imaging had b-values of 0, 2, 4, 7, 10, 15, 20, 30, 46, 60, 72, 100, 150, 200, 400, 600 s/mm2. ADC, IVIM-Dslow, IVIM-PF, IVIM-Dfast, and DDVD (diffusion-derived vessel density) were computed. DDVD is the signal difference between the b=0 s/mm2 image and b=2, 4 s/mm2 image. Only images without apparent artifacts and with good curving fitting were included in the analysis. Finally, 34 females (age: 20-71 years) and 69 males (22-70 years) were measured with ADC; 20 females (20-71 years) and 48 males (22-67 years) were measured with IVIM; 32 females (20-71 years) and 65 males (22-70 years) were measured with DDVD parameter.An age-related decrease in ADC was noted for females, while such a trend was not noted for males. A very high level of heterogeneity was noted for the data for the males, with the highest ADC value being 1.710 × 10-3mm 2/s and the lowest ADC value being 0.705 × 10-3 mm2/s when b=0 and 600 s/mm 2 were used for ADC calculation. A male-female data comparison did not show a statistically significant difference between the ADC median value. However, ADCs > 1.3 × 10-3 mm2/s were only seen among males. A very high level of heterogeneity was also noted for males' Dslow, with the highest value being 1.468 × 10-3 mm2/s and the lowest value being 0.600 × 10-3 mm2/s. Both PF and Dfast demonstrated a trend of age-related increase for older subjects. PF values were higher among males than females. However, no difference was noted for Dfast between males and females. DDVD did not show an age-related trend both for females and males. No difference was noted in DDVD values between males and females.Interpreting normal spleen diffusion MRI parameters should consider age and gender factors. · An age-related decrease in spleen ADC and IVIM-Dslow was seen for healthy females.. · There is a high level of heterogeneity for spleen ADC and IVIM-Dslow data for healthy males.. · IVIM modelled perfusion fraction and Dfast demonstrate an artificial trend of age-related increase for older subjects.. · Vessel density measured on diffusion imaging does not show an age-related trend.. · Yu W, Ma FZ, Huang H et al. Age and gender differences of normative values of spleen diffusion MRI parameters. Fortschr Röntgenstr 2024; DOI 10.1055/a-2357-9741.

Research progresses of imaging studies on preoperative prediction of microvascular invasion of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, accounting for approximately 90% of liver cancer cases. It currently ranks as the fifth most prevalent cancer worldwide and represents the third leading cause of cancer-related mortality. As a malignant disease with surgical resection and ablative therapy being the sole curative options available, it is disheartening that most HCC patients who undergo liver resection experience relapse within five years. Microvascular invasion (MVI), defined as the presence of micrometastatic HCC emboli within liver vessels, serves as an important histopathological feature and indicative factor for both disease-free survival and overall survival in HCC patients. Therefore, achieving accurate preoperative noninvasive prediction of MVI holds vital significance in selecting appropriate clinical treatments and improving patient prognosis. Currently, there are no universally recognized criteria for preoperative diagnosis of MVI in clinical practice. Consequently, extensive research efforts have been directed towards preoperative imaging prediction of MVI to address this problem and the relative research progresses were reviewed in this article to summarize its current limitations and future research prospects.

Adherence to a planetary health diet, genetic susceptibility, and incident cardiovascular disease: a prospective cohort study from the UK Biobank.

BACKGROUND: The influence of adherence to a planetary health diet (PHD) proposed by the EAT-Lancet Commission on cardiovascular disease (CVD) is inconclusive. Besides, whether genetic susceptibility to CVD can modify the association of PHD with CVD remains unknown. OBJECTIVE: We aimed to investigate the association between adherence to PHD and CVD, and to evaluate the interaction between PHD and genetic predisposition to CVD. METHODS: This study included 114,165 participants who completed at least two 24-h dietary recalls and were initially free of CVD from the UK Biobank. PHD score was calculated to assess adherence to PHD. Genetic risk was evaluated using the polygenic risk score. Incidence of total CVD, ischemic heart disease (IHD), atrial fibrillation (AF), heart failure (HF), and stroke were identified via electronic health records. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 9.9 y, 10,071 (8.8%) incident CVD cases were documented. Compared with participants with the lowest adherence to PHD, HRs (95% CIs) for total CVD, IHD, AF, HF, and stroke among those with the highest adherence were 0.79 (0.74, 0.84), 0.73 (0.67, 0.79), 0.90 (0.82, 0.99), 0.69 (0.59, 0.82), and 0.88 (0.75, 1.04), respectively. No significant interaction between the genetic risk of CVD and PHD was observed. Participants with high genetic risk and low PHD score, as compared with those with low genetic risk and high PHD score, had a 48% (95% CI: 40%, 56%) higher risk of CVD. The population-attributable risk (95% CI) of CVD for poor adherence to PHD ranged from 8.79% (5.36%, 12.51%) to 14.00% (9.00%, 18.88%). CONCLUSIONS: These findings suggest that higher adherence to PHD was associated with lower risk of total CVD, IHD, AF, and HF in populations across all genetic risk categories.

AANAT1 regulates insect midgut detoxification through the ROS/CncC pathway.

Insecticide resistance has been a problem in both the agricultural pests and vectors. Revealing the detoxification mechanisms may help to better manage insect pests. Here, we showed that arylalkylamine N-acetyltransferase 1 (AANAT1) regulates intestinal detoxification process through modulation of reactive oxygen species (ROS)-activated transcription factors cap"n"collar isoform-C (CncC): muscle aponeurosis fibromatosis (Maf) pathway in both the oriental fruit fly, Bactrocera dorsalis, and the arbovirus vector, Aedes aegypti. Knockout/knockdown of AANAT1 led to accumulation of biogenic amines, which induced a decreased in the gut ROS level. The reduced midgut ROS levels resulted in decreased expression of CncC and Maf, leading to lower expression level of detoxification genes. AANAT1 knockout/knockdown insects were more susceptible to insecticide treatments. Our study reveals that normal functionality of AANAT1 is important for the regulation of gut detoxification pathways, providing insights into the mechanism underlying the gut defense against xenobiotics in metazoans.

Mauritone A, a new polyketide from a fungal-bacterial symbiont Aspergillus spelaeus GXIMD 04541/Sphingomonas echinoides GXIMD 04532.

A new polyketide, mauritone A (1) with six known polyketides curvulone B (2), curvularin (3), 12-oxocurvularin (4), (10E,15S)-10,11-dehydrocurvularin (5), (11R,15S)-11-hydroxycurvularin (6), and (11S,15S)-11-hydroxycurvularin (7) were isolated from the fungal-bacterial symbiont Aspergillus spelaeus GXIMD 04541/Sphingomonas echinoides GXIMD 04532 derived from Mauritia arabica. Their structures were elucidated by extensive spectral analysis. All compounds (1-7) were evaluated for their anti-inflammatory effects. The inhibitory effects of 4, 5, and 7 on nitric oxide (NO) production were found to be significant, with IC50 values of 5.5 ± 0.26, 2.0 ± 0.31, and 8.3 ± 0.62 µM, respectively, surpassing that of the positive control quercetin (10.6 ± 0.64 µM). Compounds 3 and 6 exhibited moderate inhibition of NO, with IC50 values of 18.6 ± 0.53 and 12.7 ± 0.45 µM, respectively.

Impact and effect of imaging referral guidelines on patients and radiology services: a systematic review.

OBJECTIVES: The objective of this systematic review was to offer a comprehensive overview and explore the associated outcomes from imaging referral guidelines on various key stakeholders, such as patients and radiologists. MATERIALS AND METHODS: An electronic database search was conducted in Medline, Embase and Web of Science to retrieve citations published between 2013 and 2023. The search was constructed using medical subject headings and keywords. Only full-text articles and reviews written in English were included. The quality of the included papers was assessed using the mixed methods appraisal tool. A narrative synthesis was undertaken for the selected articles. RESULTS: The search yielded 4384 records. Following the abstract, full-text screening, and removal of duplication, 31 studies of varying levels of quality were included in the final analysis. Imaging referral guidelines from the American College of Radiology were most commonly used. Clinical decision support systems were the most evaluated mode of intervention, either integrated or standalone. Interventions showed reduced patient radiation doses and waiting times for imaging. There was a general reduction in radiology workload and utilisation of diagnostic imaging. Low-value imaging utilisation decreased with an increase in the appropriateness of imaging referrals and ratings and cost savings. Clinical effectiveness was maintained during the intervention period without notable adverse consequences. CONCLUSION: Using evidence-based imaging referral guidelines improves the quality of healthcare and outcomes while reducing healthcare costs. Imaging referral guidelines are one essential component of improving the value of radiology in the healthcare system. CLINICAL RELEVANCE STATEMENT: There is a need for broader dissemination of imaging referral guidelines to healthcare providers globally in tandem with the harmonisation of the application of these guidelines to improve the overall value of radiology within the healthcare system. KEY POINTS: The application of imaging referral guidelines has an impact and effect on patients, radiologists, and health policymakers. The adoption of imaging referral guidelines in clinical practice can impact healthcare costs and improve healthcare quality and outcomes. Implementing imaging referral guidelines contributes to the attainment of value-based radiology.

Association of trajectories and cumulative exposure of antenatal depression with high birth weight.

BACKGROUND: Inconsistent associations between antenatal depression and fetal birth weight were reported previously, and little is known about the dynamic changes and long-term cumulative effect of antenatal depression during pregnancy. METHODS: Participants were from the Tongji-Huaxi-Shuangliu Birth Cohort. Depressive symptoms were measured using the Edinburgh Postnatal Depression Scale in early, middle, and late pregnancy respectively. Trajectories of antenatal depression were assessed using the latent class mixed model. The percentage of days with depression (PDD) and frequency of antenatal depression were measured to assess the cumulative exposure. Multivariable logistic regression models were used to evaluate the associations of antenatal depression with macrosomia and large for gestational age (LGA). RESULTS: We identified four distinct trajectories, including the low stable group (n = 1,327, 27.99 %), the moderate stable group (n = 2,610, 55.05 %), the peak group (n = 407, 8.58 %), and the valley group (n = 397, 8.37 %). Compared with the low stable group, the valley group showed a higher risk of macrosomia (OR, 1.98; 95 % CI, 1.17, 3.38) and LGA (OR, 1.44; 95 % CI, 1.002, 2.09); the peak group showed a higher risk of LGA (OR, 1.52; 95 % CI, 1.07, 2.16), but the association was not significant for macrosomia (OR, 1.47; 95 % CI, 0.85, 2.55). Consistently, cumulative antenatal depression was also positively associated with the risks of macrosomia and LGA. LIMITATION: The antenatal depression was self-reported using a screening scale and information bias could not be ruled out. CONCLUSION: Certain trajectories and cumulative exposure of antenatal depression were associated with higher risks of high birth weight.

LECT2 mediates antibacterial immune response induced by Nocardia seriolae infection in the northern snakehead.

Leukocyte-derived chemotaxin-2 (LECT2) is a multifunctional immunoregulator that plays several pivotal roles in the host's defense against pathogens. This study aimed to elucidate the specific functions and mechanisms of LECT2 (CaLECT2) in the northern snakehead (Channa argus) during infections with pathogens such as Nocardia seriolae (N. seriolae). We identified CaLECT2 in the northern snakehead, demonstrating its participation in the immune response to N. seriolae infection. CaLECT2 contains an open reading frame (ORF) of 459 bp, encoding a peptide of 152 amino acids featuring a conserved peptidase M23 domain. The CaLECT2 protein shares 62%-84 % identities with proteins from various other fish species. Transcriptional expression analysis revealed that CaLECT2 was constitutively expressed in all examined tissues, with the highest expression observed in the liver. Following intraperitoneal infection with N. seriolae, CaLECT2 transcription increased in the spleen, trunk kidney, and liver. In vivo challenge experiments showed that injecting recombinant CaLECT2 (rCaLECT2) could protect the snakehead against N. seriolae infection by reducing bacterial load, enhancing serum antibacterial activity and antioxidant capacity, and minimizing tissue damage. Moreover, in vitro analysis indicated that rCaLECT2 significantly enhanced the migration, respiratory burst, and microbicidal activity of the head kidney-derived phagocytes. These findings provide new insights into the role of LECT2 in the antibacterial immunity of fish.

Trajectories of squamous cell carcinoma antigen and outcomes of patients with advanced penile cancer after chemotherapy based on paclitaxel, ifosfamid, and cisplatin regimen.

INTRODUCTION: Penile cancer (PC) is a lethal malignancy with no effective prognostic biomarker. We aim to investigate associations between trajectories of squamous cell carcinoma antigen (SCC-A) and patient outcomes after chemotherapy based on paclitaxel, ifosfamid, and cisplatin (TIP) regimen. METHODS: Consecutive AJCC staging III/IV PC patients who received TIP chemotherapy and repeated SCC-A measurements in 2014-2022 were analyzed. Latent class growth mixed (LCGM) models were employed to characterize patients' serum SCC-A trajectories. Patient survival, and clinical and pathological tumor responses were compared. Inverse probability treatment weighting was used to adjust confounding factors. RESULTS: Eighty patients were included. LCGM models identified two distinct trajectories of SCC-A: low-stable (40%; n = 32) and high-decline (60%; n = 48). Overall survival (HR [95% CI]: 3.60 [1.23-10.53], p = 0.019), progression-free survival (HR [95% CI]: 11.33 [3.19-40.3], p < 0.001), objective response rate (37.5% vs. 62.5% p = 0.028), disease control rate (60.4% vs. 96.9% p < 0.00), and pathological complete response rate (21.2% vs. 51.9%, p = 0.014) were significantly worse in the high-decline arm. CONCLUSION: PC patients' SCC-A change rate was associated with tumor response and patient survival after TIP chemotherapy. SCC-A might assist tumor monitoring after systemic therapies.

Quantitative CT lumbar spine BMD cutpoint value for classifying osteoporosis among older Chinese men can be the same as that of older Chinese women, both much lower than the value for Caucasians.

For older Caucasian women and men, the QCT (quantitative CT) lumbar spine (LS) bone mineral density (BMD) threshold for classifying osteoporosis is 80 mg/ml. It was recently proposed that, for older East Asian women, the QCT LS BMD value equivalent to the Caucasian women's threshold of 80 mg/mL is about 45∼50 mg/ml. For a data of 328 cases of Chinese men (age: 73.6 ± 4.4 years) who had QCT LS BMD and DXA LS BMD at the same time and with the DXA BMD value of ≤ 0.613 g/cm2 to classify osteoporosis, the corresponding QCT LS BMD threshold is 53 mg/ml. Osteoporotic-like vertebral fracture sum score (OLVFss) ≤ -2.5 has been proposed to diagnose osteoporosis. For 316 cases of Chinese men (age:73.7±4.5 years), OLVFss ≤ -2.5 defines an osteoporosis prevalence of 4.4%; to achieve this osteoporosis prevalence, the corresponding QCT LS BMD value is < 47.5 mg/ml. In the China Action on Spine and Hip Status study, a Genant grades 2/3 radiographic 'osteoporotic vertebral fracture' prevalence was 2.84% for Chinese men (total n = 1267, age: 62.77 ± 9.20 years); to achieve this osteoporosis prevalence, the corresponding BMD value was < 42.5 mg/ml. In a study of 357 Beijing older men, according to the clinical fragility fracture prevalence and femoral neck DXA T-score, the QCT LS BMD value to classify osteoporosis was between 39.45 mg/ml and 51.38 mg/ml. For older Chinese men (≥ 50 years), we recommend the cutpoint for the QCT LS BMD definition of osteoporosis to be 45∼50 mg/ml which is the same as the value for Chinese women.

Deletion of endothelial IGFBP5 protects against ischaemic hindlimb injury by promoting angiogenesis.

BACKGROUND: Angiogenesis is critical for forming new blood vessels from antedating vascular vessels. The endothelium is essential for angiogenesis, vascular remodelling and minimisation of functional deficits following ischaemia. The insulin-like growth factor (IGF) family is crucial for angiogenesis. Insulin-like growth factor-binding protein 5 (IGFBP5), a binding protein of the IGF family, may have places in angiogenesis, but the mechanisms are not yet completely understood. We sought to probe whether IGFBP5 is involved in pathological angiogenesis and uncover the molecular mechanisms behind it. METHODS AND RESULTS: IGFBP5 expression was elevated in the vascular endothelium of gastrocnemius muscle from critical limb ischaemia patients and hindlimb ischaemic (HLI) mice and hypoxic human umbilical vein endothelial cells (HUVECs). In vivo, loss of endothelial IGFBP5 (IGFBP5EKO) facilitated the recovery of blood vessel function and limb necrosis in HLI mice. Moreover, skin damage healing and aortic ring sprouting were faster in IGFBP5EKO mice than in control mice. In vitro, the genetic inhibition of IGFBP5 in HUVECs significantly promoted tube formation, cell proliferation and migration by mediating the phosphorylation of IGF1R, Erk1/2 and Akt. Intriguingly, pharmacological treatment of HUVECs with recombinant human IGFBP5 ensued a contrasting effect on angiogenesis by inhibiting the IGF1 or IGF2 function. Genetic inhibition of IGFBP5 promoted cellular oxygen consumption and extracellular acidification rates via IGF1R-mediated glycolytic adenosine triphosphate (ATP) metabolism. Mechanistically, IGFBP5 exerted its role via E3 ubiquitin ligase Von Hippel-Lindau (VHL)-regulated HIF1α stability. Furthermore, the knockdown of the endothelial IGF1R partially abolished the reformative effect of IGFBP5EKO mice post-HLI. CONCLUSION: Our findings demonstrate that IGFBP5 ablation enhances angiogenesis by promoting ATP metabolism and stabilising HIF1α, implying IGFBP5 is a novel therapeutic target for treating abnormal angiogenesis-related conditions.

For older women, the majority of hip fragility fractures and radiographic vertebral fragility fractures occur among the densitometrically osteoporotic population: a literature analysis.

It has been frequently cited that 'the majority of fragility fractures (FF) occur at non-osteoporotic bone mineral density (BMD)'. For the reports with T-score measured around the time of a hip fracture, we conducted a systematic literature search in December 2022, and resulted in 10 studies with five for Caucasian women and five for East Asian women. Femoral neck (FN) T-score was reported in five Caucasian studies and three East Asian studies, three of five Caucasian studies had a mean T-score ≤-2.5, and one study had the majority of their patients measuring a mean T-score ≤-2.5. All three East Asian studies reported a mean FN T-score ≤-2.7. Total hip T-score was reported in two Caucasian studies and three East Asian studies, the two Caucasian studies both had a mean T-score ≤-2.5, and all three East Asian studies had a mean T-score ≤-2.6. A new literature search conducted in April 2024 results in additional three studies, with results being consistent with the data described above. A trend was noted that 'younger' patients suffer from hip fractures at a 'higher' T-score. For the highly cited articles where the notion the majority of FF occur at non-osteoporotic BMD was derived from, authors reported prospective epidemiological studies where BMD was not measured at the timepoint of hip fracture, instead, BMD was measured at the study baseline. These epidemiological studies suggest that >50% of hip fractures likely occur in women with an osteoporotic FN or hip T-score. However, a pattern was seen that older men suffer from hip fracture at a notably higher T-score than older women. For the cases of radiographic vertebral FF, despite varying criteria being used to classify these FFs, the majority of female patients had spine densitometric osteoporosis. Literature shows, compared with the cases of hip fracture, distal forearm fracture occurs at a 'younger' age and 'higher' BMD, suggesting distal forearm fracture is more likely associated with a 'higher' trauma energy level.

Clinical application of dual-layer spectral CT multi-parameter feature to predict microvascular invasion in hepatocellular carcinoma.

OBJECTIVE: This study aimed to investigate the feasibility of using dual-layer spectral CT multi-parameter feature to predict microvascular invasion of hepatocellular carcinoma. METHODS: This retrospective study enrolled 50 HCC patients who underwent multiphase contrast-enhanced spectral CT studies preoperatively. Combined clinical data, radiological features with spectral CT quantitative parameter were constructed to predict MVI. ROC was applied to identify potential predictors of MVI. The CT values obtained by simulating the conventional CT scans with 70 keV images were compared with those obtained with 40 keV images. RESULTS: 50 hepatocellular carcinomas were detected with 30 lesions (Group A) with microvascular invasion and 20 (Group B) without. There were significant differences in AFP,tumer size, IC, NIC,slope and effective atomic number in AP and ICrr in VP between Group A ((1000(10.875,1000),4.360±0.3105, 1.7750 (1.5350,1.8825) mg/ml, 0.1785 (0.1621,0.2124), 2.0362±0.2108,8.0960±0.1043,0.2830±0.0777) and Group B (4.750(3.325,20.425),3.190±0.2979,1.4700 (1.4500,1.5775) mg/ml, 0.1441 (0.1373,0.1490),1.8601±0.1595, 7.8105±0.7830 and 0.2228±0.0612) (all p < 0.05). Using 0.1586 as the threshold for NIC, one could obtain an area-under-curve (AUC) of 0.875 in ROC to differentiate between tumours with and without microvascular invasion. AUC was 0.625 with CT value at 70 keV and improved to 0.843 at 40 keV. CONCLUSION: Dual-layer spectral CT provides additional quantitative parameters than conventional CT to enhance the differentiation between hepatocellular carcinoma with and without microvascular invasion. Especially, the normalized iodine concentration (NIC) in arterial phase has the greatest potential application value in determining whether microvascular invasion exists, and can offer an important reference for clinical treatment plan and prognosis assessment.

Circulating metabolic biomarkers and risk of new-onset hypertension: findings from the UK Biobank.

OBJECTIVE: The evidence regarding the associations of circulating metabolic biomarkers with hypertension risk is scarce. We aimed to examine the associations between circulating metabolites and risk of hypertension. METHODS: We included 49 422 individuals free of hypertension at baseline with a mean (SD) age of 53.5 (8.0) years from the UK Biobank. Nuclear magnetic resonance spectroscopy was used to quantify 143 individual metabolites. Multivariable-adjusted Cox regression models were used to estimate hazard ratios and 95% confidence intervals (CIs). RESULTS: During a mean (SD) follow-up of 11.2 (1.8) years, 2686 incident hypertension cases occurred. Out of 143 metabolites, 76 were associated with incident hypertension, among which phenylalanine (hazard ratio: 1.40; 95% CI: 1.24-1.58) and apolipoprotein A1 (hazard ratio: 0.76; 95% CI: 0.66-0.87) had the strongest association when comparing the highest to the lowest quintile. In general, very-low-density lipoprotein (VLDL) particles were positively, whereas high-density lipoprotein (HDL) particles were inversely associated with risk of hypertension. Similar patterns of cholesterol, phospholipids, and total lipids within VLDL and HDL particles were observed. Triglycerides within all lipoproteins were positively associated with hypertension risk. Other metabolites showed significant associations with risk of hypertension included amino acids, fatty acids, ketone bodies, fluid balance and inflammation markers. Adding 10 selected metabolic biomarkers to the traditional hypertension risk model modestly improved discrimination (C-statistic from 0.745 to 0.752, P < 0.001) for prediction of 10-year hypertension incidence. CONCLUSION: Among UK adults, disturbances in metabolic biomarkers are associated with incident hypertension. Comprehensive metabolomic profiling may provide potential novel biomarkers to identify high-risk individuals.