Effect of low-dose terazosin on arterial stiffness improvement: A pilot study.

Arterial stiffness, a prominent hallmark of ageing arteries, is a predictor of all-cause mortality. Strategies for promoting healthy vascular ageing are encouraged. Here we conducted a pilot study to evaluate the potential effects of low-dose Terazosin on arterial stiffness. We enrolled patients aged over 40 with elevated arterial stiffness, defined as a brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s, who were administered Terazosin (0.5 and 1.0 mg/day) from December 2020 to June 2023. Treatment responses were assessed every 3 months. Linear regression analysis was used to characterise the improvement. We matched cases who took Terazosin for 1 year with Terazosin-free controls using propensity score matching (PSM). Our findings demonstrate that Terazosin administration significantly affected arterial stiffness. (1) Arterial stiffness significantly improved (at least a 5% reduction in baPWV) in 50.0% of patients at 3 months, 48.6% at 6 months, 59.3% at 9 months, and 54.4% at 12 months, respectively. (2) Those with higher baseline baPWV and hypertension exhibited a significantly reduced risk of non-response. (3) Terazosin was associated with a reduction of baPWV at 1-year follow-up (linear regression: ß = -165.16, p < 0.001). This pilot study offers valuable insights into the potential significance of Terazosin in improving arterial stiffness and paves the way for future randomised clinical trials in combating vascular ageing.

Unidirectional guided-wave-driven metasurfaces for arbitrary wavefront control.

Metasurfaces are capable of fully reshaping the wavefronts of incident beams in desired manners. However, the requirement for external light excitation and the resonant nature of their meta-atoms, make challenging their on-chip integration. Here, we introduce the concept and design of a fresh class of metasurfaces, driven by unidirectional guided waves, capable of arbitrary wavefront control based on the unique dispersion properties of unidirectional guided waves rather than resonant meta-atoms. Upon experimentally demonstrating the feasibility of our designs in the microwave regime, we numerically validate the introduced principle through the design of several microwave meta-devices using metal-air-gyromagnetic unidirectional surface magneto-plasmons, agilely converting unidirectional guided modes into the wavefronts of 3D Bessel beams, focused waves, and controllable vortex beams. We, further, numerically demonstrate sub-diffraction focusing, which is beyond the capability of conventional metasurfaces. Our unfamiliar yet practical designs may enable full, broadband manipulation of electromagnetic waves on deep subwavelength scales.

Health-related quality of life in pregnant women with type 1 diabetes and associations with maternal and neonatal complications.

PURPOSE: Preexisting type 1 diabetes is a stressful situation for women in pregnancy. We aimed to evaluate health-related quality of life (HRQoL) during pregnancy in women with type 1 diabetes and examine the association between HRQoL and pregnancy outcomes. METHODS: This multicenter prospective cohort study involved 115 pregnant women with type 1 diabetes from 11 participating centers in China. HRQoL was investigated in three trimesters using European Quality-of-life 5-Dimension 5-Level questionnaire (EQ-5D-5 L). Chinese time trade-off value method was used to calculate the EQ-5D-5 L score. Multivariable logistic regression model was used to evaluate the effect of HRQoL on maternal and neonatal outcomes. Receiver operating characteristic curves and distribution-based methods were employed to estimate minimally important differences of clinically important decline in HRQoL. RESULTS: 50.43% of the studied women with type 1 diabetes reported impaired HRQoL in pregnancy. Estimated maternal HRQoL significantly decreased from early to mid-pregnancy (mean EQ-5D-5 L score 0.97 in the first trimester and 0.91 in the second trimester) and improved slightly in late pregnancy (mean EQ-5D-5 L score 0.95). Multivariable regression model showed that women who experienced impaired HRQoL in pregnancy had higher risk of hypertensive disorder, preterm birth, and composite pregnancy outcome. The estimated minimally important difference for composite pregnancy outcome was -0.045 to -0.043. CONCLUSIONS: Experiencing impaired HRQoL during pregnancy was associated with a higher risk of hypertensive disorder and preterm birth in women with type 1 diabetes. The estimated minimally important difference of EQ-5D-5 L might serve as a clinically important tool in prenatal care. TRIAL REGISTRATION: No.ChiCTR1900025955.

The association between pulse wave velocity and pregnancy-associated diseases: A systematic review and meta-analysis.

Background: Maintaining healthy vascular structure and function is important for a healthy pregnancy. Obesity is a well-known predictor for poor postoperative outcomes of vascular surgery. However, the association between pulse wave velocity (PWV), a well-recognized parameter for arterial stiffness assessment, and pregnancy-associated diseases is still unclear. Therefore, we conducted this systematic review, and a meta-analysis was performed to assess the relevant associations. Methods: We systematically searched the Web of Science and PubMed databases to obtain articles on PWV and pregnancy-associated diseases published before April 2023. The mean with standard deviation was used to assess the differences in PWV in pregnant women with or without relevant diseases. Subgroup analysis was conducted according to specific types of PWV. The Newcastle‒Ottawa Scale was used to evaluate the quality of the enrolled studies. Results: A total of 6488 individuals from 21 studies were included. All enrolled studies were high-quality. Overall, the PWV was elevated in pregnant women who suffered from preeclampsia (mean difference (MD) = 0.67, 95 % confidence interval (CI): 0.51,0.83, P < 0.00001), hypertension (MD = 1.04, 95 % CI: 1.00,1.08, P < 0.00001), gestational diabetes mellitus (MD = 0.34, 95%CI: 0.19,0.48, P < 0.00001), and diabetes (MD = 0.49, 95%CI: 0.27,0.70, P < 0.00001). Subgroup analysis based on specific types of PWV showed similar results. Conclusion: In our study, PWV is elevated in pregnancy-associated diseases, including preeclampsia, hypertension, and diabetes. The PWV assessment should be regarded as a clinical routine for pregnant women to prevent and manage cardiovascular diseases during pregnancy.

Microbial and metabolomic profiles of type 1 diabetes with depression: A case-control study.

BACKGROUND: Depression is the most common psychological disorder in patients with type 1 diabetes (T1D). However, the characteristics of microbiota and metabolites in these patients remain unclear. This study aimed to investigate microbial and metabolomic profiles and identify novel biomarkers for T1D with depression. METHODS: A case-control study was conducted in a total of 37 T1D patients with depression (TD+), 35 T1D patients without depression (TD-), and 29 healthy controls (HCs). 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis were conducted to investigate the characteristics of microbiota and metabolites. The association between altered microbiota and metabolites was explored by Spearman's rank correlation and visualized by a heatmap. The microbial signatures to discriminate TD+ from TD- were identified by a random forest (RF) classifying model. RESULTS: In microbiota, 15 genera enriched in TD- and 2 genera enriched in TD+, and in metabolites, 14 differential metabolites (11 upregulated and 3 downregulated) in TD+ versus TD- were identified. Additionally, 5 genera (including Phascolarctobacterium, Butyricimonas, and Alistipes from altered microbiota) demonstrated good diagnostic power (area under the curve [AUC] = 0.73; 95% CI, 0.58-0.87). In the correlation analysis, Butyricimonas was negatively correlated with glutaric acid (r = -0.28, p = 0.015) and malondialdehyde (r = -0.30, p = 0.012). Both Phascolarctobacterium (r = 0.27, p = 0.022) and Alistipes (r = 0.31, p = 0.009) were positively correlated with allopregnanolone. CONCLUSIONS: T1D patients with depression were characterized by unique profiles of gut microbiota and serum metabolites. Phascolarctobacterium, Butyricimonas, and Alistipes could predict the risk of T1D with depression. These findings provide further evidence that the microbiota-gut-brain axis is involved in T1D with depression.

Basal Hyperglycemia Contributes More Than Fifty Percent to Time in Range in Pregnant Women with Type 1 Diabetes.

AIMS: To evaluate the relative contribution of basal hyperglycemia (BHG) and postprandial hyperglycemia (PHG) to the time in range (TIR) categories and adverse pregnancy outcomes in pregnant women with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This observational study included 112 pregnancies with T1DM from the CARNATION study who wore continuous glucose monitoring (CGM) devices during pregnancy. The data from CGM were analyzed for TIR (range, 3.5-7.8 mmol/L), areas under the curve (AUC) of PHG, AUC of BHG, basal and postprandial hyperglycemia contribution rates. The contribution rates of BHG and PHG to the different levels of TIR(＜60%, 60-78%, ≥78%) and adverse pregnancy outcomes were analyzed. RESULTS: The participants' average age was 28.8±3.9 years with a diabetes duration of 8.4±6.2 years. All women experienced a mean TIR of 75.6±19.0% and a mean HbA1c of 6.2±1.1% during pregnancy. The BHG contribution accounted for 74.9(36.8, 100)%, 69.2(13.4, 100)%, and 66.5(10.0, 100)% (P＜0.001) and PHG accounted for 25.1(0, 63.2)% and 30.8(0, 86.6)% and 33.5(0, 90.0)% (P＜0.001) when participants experienced the TIR＜60%, 60-78%, ≥78%, respectively. Participants with higher BHG contribution rates tended to have more adverse pregnancy outcomes. CONCLUSIONS: Basal hyperglycemia was the major contributor to TIR during pregnancy. Along with controlling the postprandial hyperglycemia, pregnant women with T1DM who did not reach the target of TIR may benefit more from the optimization of insulin regimens focusing on reducing basal glucose.

Continuous subcutaneous insulin infusion versus multiple daily injection therapy in pregnant women with type 1 diabetes.

INTRODUCTION: The study aimed to compare glycemic control and pregnancy outcomes in women with type 1 diabetes mellitus (T1DM) using multiple daily injection therapy (MDI) and continuous subcutaneous insulin infusion (CSII) and to compare outcomes of women treated with long-acting insulin or neutral protamine Hagedorn (NPH). METHODS: This multicenter prospective cohort study involved women with pregestational T1DM treated with MDI and CSII. Primary outcome was glycated hemoglobin (HbA1c) before and during pregnancy. Secondary outcomes included maternal and neonatal outcomes and quality of life. RESULTS: Of the 121 studied women, the average age was 28.48 years, and the average body mass index was 21.29 kg/m2 at conception and 26.32 kg/m2 at delivery. Of the studied women, 78.51% had planned pregnancy. Women treated with MDI and CSII had comparable HbA1c before pregnancy or in the first and second trimesters. In the third trimester, women on CSII therapy had significantly lower HbA1c (6.07 ± 0.62 vs 6.20 ± 0.88%, p = .017), higher HbA1c on-target rate (71.43% vs 64.62%, p = .030), and greater decline of HbA1c from preconception to the third trimester (-0.65 vs -0.30%, p = .047). Fewer daily insulin requirements were observed in those used CSII compared with MDI-treated women (0.60 ± 0.22 vs 0.73 ± 0.25 U/kg/day, p = .004). Newborns born of mothers treated with the CSII method were more likely to have neonatal jaundice (adjusted odds ratio [OR] 2.76, 95% confidence interval [CI] 1.16-6.57) and neonatal intensive care unit (adjusted OR 3.73, 95%CI 1.24-11.16), and women on CSII had lower scores in patient-reported quality of life (p = .045). In the MDI group, those receiving long-acting insulin had nonsignificant lower HbA1c and higher HbA1c on-target rate in the second and third trimesters, compared with those treated with NPH. CONCLUSIONS: Insulin pump users may achieve better glycemic control than multiple daily insulin injections, which did not substantially improve pregnancy outcome.

CD28null T cells in aging and diseases: From biology to assessment and intervention.

CD28null T cells, an atypical subset characterized by the loss of CD28 costimulatory molecule expression, exhibit functional variants and progressively expand with age. Moreover, T cells with these phenotypes are found in both typical and atypical humoral immune responses. Consequently, they accumulate during infectious diseases, autoimmune disorders, cardiovascular conditions, and neurodegenerative ailments. To provide an in-depth review of the current knowledge regarding CD28null T cells, we specifically focus on their phenotypic and functional characteristics as well as their physiological roles in aging and diseases. While uncertainties regarding the clinical utility remains, we will review the following two crucial research perspectives to explore clinical translational applications of the research on this specific T cell subset: 1) addressing the potential utility of CD28null T cells as immunological markers for prognosis and adverse outcomes in both aging and disease, and 2) speculating on the potential of targeting CD28null T cells as an interventional strategy for preventing or delaying immune aging processes and disease progression.

LncRNA AL645608.3 mediates malignant progression of acute myeloid leukemia.

OBJECTIVE: To investigate the role of lncRNA AL645608.3 in the malignant progression of acute myeloid leukemia (AML) cells and explore relevant molecular mechanisms. METHODS: The expression level of AL645608.3 was measured in AML cell lines (THP-1, HL-60, KG-1, and AML-193) via real-time quantitative polymerase chain reaction (RT-qPCR). Small hairpin RNA (shRNA) and open reading frame of AL645608.3 were cloned into lentiviral vectors and were infected into THP-1 and AML-193 cells. The expression of casitas B-lineage lymphoma (CBL), interferon regulatory factor 6 (IRF6), and interferon beta 1 (IFNB1) was detected through RT-qPCR, and western blot. Co-immunoprecipitation (Co-IP) on IRF6 was conducted. Matrix metalloprotease-9 (MMP-9) activity was evaluated via gelatin zymography assay. RESULTS: LncRNA AL645608.3 was expressed in the four AML cell lines (THP-1, HL-60, KG-1, and AML-193). Silencing AL645608.3 mitigated the expression of IRF6 and IFNB1 but elevated the expression of CBL in THP-1 cells. Oppositely, AL645608.3 overexpression up-regulated the expression of IRF6 and IFNB1 but decreased the expression of CBL in AML-193 cells. Co-IP results proved that AL645608.3 could directly mediate IRF6 activity in THP-1 and AML-193 cells. MMP-9 activity was decreased by AL645608.3 knockdown and was improved by AL645608.3 overexpression in AML-193 cells. CONCLUSION: AL645608.3 is expressed in different AML cell lines, and mediates the expression of CBL, IRF6, IFNB1, and MMP-9. These findings might deepen our comprehension of the molecular mechanisms underlying AML.

DHCR24 Insufficiency Promotes Vascular Endothelial Cell Senescence and Endothelial Dysfunction via Inhibition of Caveolin-1/ERK Signaling.

Endothelial cells (ECs) senescence is critical for vascular dysfunction, which leads to age-related disease. DHCR24, a 3ß-hydroxysterol δ 24 reductase with multiple functions other than enzymatic activity, has been involved in age-related disease. However, little is known about the relationship between DHCR24 and vascular ECs senescence. We revealed that DHCR24 expression is chronologically decreased in senescent human umbilical vein endothelial cells (HUVECs) and the aortas of aged mice. ECs senescence in endothelium-specific DHCR24 knockout mice was characterized by increased P16 and senescence-associated secretory phenotype, decreased SIRT1 and cell proliferation, impaired endothelium-dependent relaxation, and elevated blood pressure. In vitro, DHCR24 knockdown in young HUVECs resulted in a similar senescence phenotype. DHCR24 deficiency impaired endothelial migration and tube formation and reduced nitric oxide (NO) levels. DHCR24 suppression also inhibited the caveolin-1/ERK signaling, probably responsible for increased reactive oxygen species production and decreased eNOS/NO. Conversely, DHCR24 overexpression enhanced this signaling pathway, blunted the senescence phenotype, and improved cellular function in senescent cells, effectively blocked by the ERK inhibitor U0126. Moreover, desmosterol accumulation induced by DHCR24 deficiency promoted HUVECs senescence and inhibited caveolin-1/ERK signaling. Our findings demonstrate that DHCR24 is essential in ECs senescence.

Terazosin attenuates abdominal aortic aneurysm formation by downregulating Peg3 expression to inhibit vascular smooth muscle cell apoptosis and senescence.

Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells (VSMCs), degradation of extracellular matrix (ECM), inflammation, and oxidative stress. Despite the severity of AAA, effective drugs for treatment are scarce. At low doses, terazosin (TZ) exerts antiapoptotic and anti-inflammatory effects in several diseases, but its potential to protect against AAA remains unexplored. Herein, we investigated the effects of TZ in two AAA animal models: Angiotensin II (Ang II) infusion in Apoe-/- mice and calcium chloride application in C57BL/6J mice. Mice were orally administered with TZ (100 or 1000 µg/kg/day). The in vivo results indicated that low-dose TZ alleviated AAA formation in both models. Low-dose TZ significantly reduced aortic pulse wave velocity without exerting an apparent antihypertensive effect in the Ang II-induced AAA model. Paternally expressed gene 3 (Peg3) was identified via RNA sequencing as a novel TZ target. PEG3 expression was significantly elevated in both mouse and human AAA tissues. TZ suppressed PEG3 expression and reduced the abundance of matrix metalloproteinases (MMP2/MMP9) in the tunica media. Functional experiments and molecular analyses revealed that TZ (10 nM) treatment and Peg3 knockdown effectively prevented Ang II-induced VSMC senescence and apoptosis in vitro. Thus, Peg3, a novel target of TZ, mediates inflammation-induced VSMC apoptosis and senescence. Low-dose TZ downregulates Peg3 expression to attenuate AAA formation and ECM degradation, suggesting a promising therapeutic strategy for AAA.

Characterization of a germline variant TNS1 c.2999-1G > C in a hereditary cancer syndrome family.

Hereditary cancer syndromes result from the presence of inherited pathogenic variants within susceptibility genes. However, the susceptibility genes associated with hereditary cancer syndrome remain predominantly unidentified. Here, we reported a case of hereditary cancer syndrome observed in a Chinese family harboring a germline mutation in Tensin1 (TNS1). We described a 59-year-old female patient presented with Multiple myeloma and Thyroid carcinoma. The proband and her family members exhibited suspected tumor syndrome due to occurrences of other cancer cases. After oncogenetic counseling, whole-exome sequencing and Sanger sequencing were conducted and a primary driver mutation of TNS1 (NM_022648.7:c.2999-1G > C) was detected. Gene Expression Profiling Interactive Analysis revealed that TNS1 was expressed lower in different tumors when compared to normal, including Pancreatic adenocarcinoma, Breast invasive carcinoma, Thyroid carcinoma andColon adenocarcinoma cells. Despite the well-established role of TNS1 as a tumor suppressor in breast cancer and colorectal cancer, its potential utility as a marker gene for diagnosis and treatment of pancreatic cancer remains uncertain. Here, our data demonstrated that knockdown of TNS1 could promote cell proliferation and migration in Pancreatic adenocarcinoma (PDAC) cells. In addition, TNS1 regulated migration through EMT signaling pathway in PDAC cells. Our findings proposed that this variant was likely involved in cancer predisposition by disrupting the normal splicing process. In summary, we presented a genetic disease by linking an intronic mutation inTNS1. We aim to provide early detection of cancers by identifying germline variants in susceptibility genes.

Differential Expression of KIF18B in Gastric Cancer and Its Role in Chemotherapy Sensitivity.

Gastric cancer (GC) is a main cause of cancer death in the world, and improving the chemotherapy sensitivity can enhance the chemotherapy efficacy of GC. The study objective is to explore the differential KIF18B expression in GC and its effect on GC chemotherapy sensitivity. The KIF18B expression in GC tissues and adjacent normal tissues was analyzed by real-time quantitative polymerase chain reaction. The relationship between differential KIF18B expression and different clinicopathological features was detected. It was found that KIF18B was highly expressed in GC tissues, and KIF18B expression was differential in patients with different clinicopathological features. The upregulation of KIF18B has a positive correlation with the poor therapeutic effect and high KIF18 was associated with lower 3-year overall survival and disease-free survival. The KIF18B-downregulated NCI-N87 cells were constructed and tested by cell counting kit-8 assay and colony formation. Cell migration and invasion were detected by Transwell assay. The xenograft tumor model was established to observe the effect of KIF18B on the efficacy of chemotherapy. The upregulation of KIF18B reduced the chemotherapy sensitivity of GC cells and enhanced their proliferation, migration, and invasion. Silencing KIF18B inhibited tumor growth and promoted chemotherapy efficacy in vivo. In summary, KIF18B inhibitor may have a potential function for improving the efficacy of chemotherapy in GC.

TRIM56 protects against nonalcoholic fatty liver disease by promoting the degradation of fatty acid synthase.

Nonalcoholic fatty liver disease (NAFLD) encompasses a disease continuum from simple steatosis to nonalcoholic steatohepatitis (NASH). However, there are currently no approved pharmacotherapies for NAFLD, although several drugs are in advanced stages of clinical development. Because of the complex pathophysiology and heterogeneity of NAFLD, the identification of potential therapeutic targets is clinically important. Here, we demonstrated that tripartite motif 56 (TRIM56) protein abundance was markedly downregulated in the livers of individuals with NAFLD and of mice fed a high-fat diet. Hepatocyte-specific ablation of TRIM56 exacerbated the progression of NAFLD, while hepatic TRIM56 overexpression suppressed it. Integrative analyses of interactome and transcriptome profiling revealed a pivotal role of TRIM56 in lipid metabolism and identified the lipogenesis factor fatty acid synthase (FASN) as a direct binding partner of TRIM56. TRIM56 directly interacted with FASN and triggered its K48-linked ubiquitination-dependent degradation. Finally, using artificial intelligence-based virtual screening, we discovered an orally bioavailable small-molecule inhibitor of FASN (named FASstatin) that potentiates TRIM56-mediated FASN ubiquitination. Therapeutic administration of FASstatin improved NAFLD and NASH pathologies in mice with an optimal safety, tolerability, and pharmacokinetics profile. Our findings provide proof of concept that targeting the TRIM56/FASN axis in hepatocytes may offer potential therapeutic avenues to treat NAFLD.

Therapeutic potential of anti-PIK3CG treatment for multiple myeloma via inhibiting c-Myc pathway.

Multiple myeloma (MM) is a malignant plasma cell disease. The activity of PIK3CG (PI3K catalytic subunit γ) is regulated directly by G-protein-coupled receptor and has been confirmed to be highly expressed in MM cells. This study aimed to determine the effect of pharmacological inhibition of PIK3CG on MM. We found that different concentrations of the PIK3CG inhibitor AS-605240 could suppress the growth of MM cell lines and the expression of c-Myc. The combination of PIK3CG inhibitor and the chemotherapy Melphalan could effectively inhibit the proliferation and migration of MM cells, promote the cell apoptosis, and decrease the ratio of Bcl-2/Bax and the expression of vimentin. The expression of proto-oncogene c-Myc was decreased and the sensitivity of cells to chemotherapeutic drugs was enhanced. Collectively, PIK3CG regulates growth of MM via c-Myc pathway, thus emerging as a promising molecular targeted therapy.

Preconception episodes of severe hypoglycemia and risk of adverse pregnancy outcomes in pregnant women with type 1 diabetes mellitus.

AIMS: To explore the relationship between preconception severe hypoglycemia (PSH) and pregnancy outcomes in pregnancies complicated with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: In this multicenter prospective cohort study, women with pregestational T1DM were stratified by episodes of severe hypoglycemia within 1 year before conception: No PSH, sporadic PSH (1-6 times/year), and recurrent PSH (>6 times/year). We analysed the predictive ability of PSH for maternal and neonatal outcomes using log-binomial regression models and receiver operating characteristic (ROC) curve. RESULTS: Of the 124 women studied, 37.1% experienced at least one episode of severe hypoglycemia preconception. In the multiple adjusted regression models, recurrent PSH was significantly associated with increased incidence of preeclampsia (RR 17.59, 95% CI: 2.89-150.62, p for trend = 0.007), preterm birth (RR 6.34, 95% CI: 1.22-40.63, p for trend = 0.027), neonatal hypoglycemia (RR 4.52, 95% CI: 1.14-17.16, p for trend = 0.017), neonatal hyperbilirubinemia (RR 4.12, 95% CI: 1.11-15.56, p for trend = 0.004), and composite neonatal outcome (RR 3.85, 95% CI: 1.01-19.61, p for trend = 0.003). In the ROC analysis, PSH predicted preeclampsia, preterm birth, neonatal hypoglycemia, neonatal hyperbilirubinemia, and composite neonatal outcome with areas under the ROC curve all ≥0.6. CONCLUSIONS: Recurrent preconception severe hypoglycemia is associated with increased risks of adverse outcomes in pregnant women with T1DM.

Effect of artificial pancreas system use on glycaemic control among pregnant women with type 1 diabetes mellitus: A meta-analysis of randomized controlled trials.

AIM: To assess the efficacy of artificial pancreas systems (APS) use among pregnant women with type 1 diabetes mellitus (T1DM) by conducting a meta-analysis. METHODS: We searched five databases, including EMBASE, Web of Science, PubMed, Cochrane Library and SCOPUS, for literature on APS use among pregnant women with T1DM before October 9, 2023. The primary endpoint was 24-hour time in range (TIR; 3.5-7.8 mmol/L). Secondary endpoints included glycaemic metrics for 24-hour (mean blood glucose [MBG], time above range [TAR], time below range [TBR]), and overnight TIR and TBR. RESULTS: We identified four randomized controlled trials involving 164 participants; one study with 16 participants focused on overnight APS use, and the other three focused on 24-hour APS use. Compared with standard care, APS exhibited a favourable effect on 24-hour TIR (standard mean difference [SMD] = 0.53, 95% confidence interval [CI] 0.25, 0.80, P < 0.001), overnight TIR (SMD = 0.67, 95% CI 0.39, 0.95, P < 0.001), and overnight TBR (<3.5 mmol/L; SMD = -0.49, 95% CI -0.77, -0.21 P < 0.001), while there was no significant difference in 24-hour TAR, 24-hour TBR, or MBG between the two groups. We further conducted subgroup analyses after removing the trial focused on overnight APS use and showed that 24-hour APS use reduced not only the 24-hour TIR (SMD = 0.41, 95% CI 0.12, 0.71; P = 0.007) but also the 24-hour TBR (<2.8 mmol/L; SMD = -0.77, 95% CI -1.32, -0.23, P = 0.006). CONCLUSION: Our findings suggest that APS might improve 24-hour TIR and overnight glycaemic control, and 24-hour APS use also significantly reduced 24-hour TBR (2.8 mmol/L) among pregnant women with T1DM.

Counteracting Age-Related Netrin-1 Signaling Insufficiency Ameliorates Endothelial Cell Senescence and Angiogenesis Impairment.

Senescent cells that accumulate are regarded as promising therapeutic targets. However, senolytic therapy failed to achieve satisfactory results. We previously discovered that young human plasma improved vascular endothelial cell senescence, and UNC5B might be a novel intervention target. Netrin-1, as a natural ligand of UNC5B, plays roles in multiple age-related vascular disorders, but its involvement in aging is still unclear. Here, we observed a significant decrease in plasma Netrin-1 levels in old healthy subjects compared to the young. In vivo, adeno-associated-virus-mediated delivery of Netrin-1 into aged mice significantly improved functional recovery in a model of hindlimb ischemia, promoted angiogenesis in ischemic tissues, and activated the endothelial nitric oxide synthase. Furthermore, we revealed that low-dose Netrin-1 recombinant protein significantly reduced senescence-associated-ß-galactosidase-positive cells, inhibited the P53 pathway, promoted cell migration, increased tubule formation, and elevated nitric oxide production in senescent endothelial cells. However, UNC5B inhibition blocked the pro-angiogenesis effect of low-dose Netrin-1 on senescent cells or aortic rings. In summary, this study depicts that modulating Netrin-1 signaling can result in improved vascular health and Netrin-1 may have therapeutic potential for age-related ischemic diseases.

STAT5a and SH2B3 novel mutations display malignancy roles in a triple-negative primary myelofibrosis patient.

Primary myelofibrosis (PMF) patients frequently have JAK2 (V617F), CALR (exon 9), or MPL (W515 or exon 10) strong driver gene mutation, which triggers abnormal activation of the JAK2-STATs signaling pathway that plays a complex role in the occurrence of PMF. However, about 10-15% of PMF patients have no above typical mutations in these strong driver genes, known as being "triple-negative", which are associated with poor prognosis. In this paper, we reported a unique secondary acute myeloid leukemia (sAML) case transformed from triple-negative PMF combined with lung cancer and erythroderma occurrence at the same time, which has not been reported so far. Through whole blood exome sequencing, four novel noncanonical mutations were detected in key regulatory genes SH2B3 (Q748 and S710) and STAT5a (C350 and K354). Meanwhile, STAT5a-S710 and SH2B3-K354 noncanonical mutations gained strong malignant biofunction on promoting cell growth and tumorigenesis by accelerating the G1/S transition. In the mechanistic study, these pernicious phenotypes driven by noncanonical mutations might be initial PMF by activating p-STAT5a/c-Myc/CyclinD1 and p-STAT3/p-AKT/p-ERK1/2 signaling axes. Therefore, our study explored the deleterious roles of novel noncanonical mutations in STAT5a and SH2B3, which may serve as susceptibility genes and display the oncogenic biofunction in the progression of PMF to acute myeloid leukemia-M2a (AML-M2a).