Thermoregulatory pathway underlying the pyrogenic effects of prostaglandin E2 in the lateral parabrachial nucleus of male rats.

It has been shown that prostaglandin (PG) E2 synthesized in the lateral parabrachial nucleus (LPBN) is involved in lipopolysaccharide-induced fever. But the neural mechanisms of how intra-LPBN PGE2 induces fever remain unclear. In this study, we investigated whether the LPBN-preoptic area (POA) pathway, the thermoafferent pathway for feed-forward thermoregulatory responses, mediates fever induced by intra-LPBN PGE2 in male rats. The core temperature (Tcore) was monitored using a temperature radiotelemetry transponder implanted in rat abdomen. We showed that microinjection of PGE2 (0.28 nmol) into the LPBN significantly enhanced the density of c-Fos-positive neurons in the median preoptic area (MnPO). The chemical lesioning of MnPO with ibotenate or selective genetic lesioning or inhibition of the LPBN-MnPO pathway significantly attenuated fever induced by intra-LPBN injection of PGE2. We demonstrated that EP3 receptor was a pivotal receptor for PGE2-induced fever, since microinjection of EP3 receptor agonist sulprostone (0.2 nmol) or EP3 receptor antagonist L-798106 (2 nmol) into the LPBN mimicked or weakened the pyrogenic action of LPBN PGE2, respectively, but this was not the case for EP4 and EP1 receptors. Whole-cell recording from acute LPBN slices revealed that the majority of MnPO-projecting neurons originating from the external lateral (el) and dorsal (d) LPBN were excited and inhibited, respectively, by PGE2 perfusion, initiating heat-gain and heat-loss mechanisms. The amplitude but not the frequency of spontaneous and miniature glutamatergic excitatory postsynaptic currents (sEPSCs and mEPSCs) in MnPO-projecting LPBel neurons increased after perfusion with PGE2; whereas the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) and the A-type potassium (IA) current density did not change. In MnPO-projecting LPBd neurons, neither sEPSCs nor sIPSCs responded to PGE2; however, the IA current density was significantly increased by PGE2 perfusion. These electrophysiological responses and the thermoeffector reactions to intra-LPBN PGE2 injection, including increased brown adipose tissue thermogenesis, shivering, and decreased heat dissipation, were all abolished by L-798106, and mimicked by sulprostone. These results suggest that the pyrogenic effects of intra-LPBN PGE2 are mediated by both the inhibition of the LPBd-POA pathway through the EP3 receptor-mediated activation of IA currents and the activation of the LPBel-POA pathway through the selective enhancement of glutamatergic synaptic transmission via EP3 receptors.

Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin.

Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrence rate and is often diagnosed late. In ovarian cancer, multiple metabolic enzymes of lipid metabolism are abnormally expressed, resulting in metabolism disorder. As a characteristic pathway in polyunsaturated fatty acid (PUFA) metabolism, arachidonic acid (AA) metabolism is disturbed in ovarian cancer. Therefore, we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related genes. This 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms (TCGA, ICGC, and GSE17260). The high association between the risk subgroups and clinical characteristics indicated a good performance of the model. Our data further indicated that the high expression of LTA4H was positively correlated with poor prognosis in ovarian cancer. Deficiency of LTA4H enhanced sensitivity to Cisplatin and modified the characteristics of immune cell infiltration in ovarian cancer. Additionally, our results indicate that CCL5 was involved in the aberrant metabolism of the AA/LTA4H axis, which contributes to the reduction of tumor-infiltrating CD8+ T cells and immune escape in ovarian cancer. These findings provide new insights into the prognosis and potential target of LTA4H/CCL5 in treating ovarian cancer.

Clonal Hematopoiesis and Cardiovascular Disease in Patients With Multiple Myeloma Undergoing Hematopoietic Cell Transplant.

Importance: There is a paucity of information on the association between clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular disease (CVD) in patients with cancer, including those with multiple myeloma (MM) undergoing hematopoietic cell transplant (HCT), a population at high risk of developing CVD after HCT. Objective: To examine the association between CHIP and CVD in patients with MM and to describe modifiers of CVD risk among those with CHIP. Design, Setting, and Participants: This was a retrospective cohort study of patients with MM who underwent HCT between 2010 and 2016 at City of Hope Comprehensive Cancer Center in Duarte, California, and had pre-HCT mobilized peripheral blood stem cell (PBSC) products cryopreserved and accessible for CHIP analyses. The study team performed targeted panel DNA sequencing to detect the presence of CHIP (variant allele frequency 2% or more). Main Outcomes and Measures: The primary end point was the 5-year cumulative incidence and risk for developing de novo CVD (heart failure, coronary artery disease, or stroke) after HCT. Results: Of 1036 consecutive patients with MM (580 male [56%]; median age, 60.0 years) who underwent a first autologous HCT, 201 patients had at least 1 CHIP variant (19.4%) and 35 patients had 2 or more variants (3.4%). The 5-year incidence of CVD was significantly higher in patients with CHIP (21.1% vs 8.4%; P < .001) compared with those without CHIP; the 5-year incidence among those with 2 or more variants was 25.6%. In the multivariable model, CHIP was associated with increased risk of CVD (hazard ratio [HR], 2.72; 95% CI, 1.70-4.39), as well as of individual outcomes of interest, including heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52). Patients who had both CHIP and preexisting hypertension or dyslipidemia were at nearly 7-fold and 4-fold increased risk of CVD, respectively (reference: no CHIP, no hypertension, or dyslipidemia). Conclusion and Relevance: CHIP was significantly and independently associated with risk of CVD in patients with MM undergoing HCT and may serve as a novel biologically plausible biomarker for CVD in this cohort. Patients with MM and both CHIP and cardiovascular risk factors had an exceptionally high risk of CVD. Additional studies are warranted to determine if cardiovascular preventive measures can reduce CHIP-associated CVD risk.

Bisbenzylisoquinoline alkaloid fangchinoline derivative HY-2 inhibits breast cancer cells by suppressing BLM DNA helicase.

The high expression of BLM (Bloom syndrome) DNA helicase in tumors involves its strong association with cell expansion. Bisbenzylisoquinoline alkaloids own an antitumor property and have developed as candidates for anticancer drugs. This paper aimed to study the antitumor effect of fangchinoline derivative HY-2 by targeting BLM642-1290 DNA helicase, and then explore its inhibitory mechanism on proliferation of MDA-MB-435 breast cancer cells. We confirmed that the mRNA and protein levels of BLM DNA helicase in breast cancer were higher than those in normal tissues. HY-2 could inhibit the DNA binding, ATPase and DNA unwinding of BLM642-1290 DNA helicase with enzymatic assay. HY-2 could also inhibit the DNA unwinding of DNA helicase in cells. In addition, HY-2 showed an inhibiting the MDA-MB-435, MDA-MB-231, MDA-MB-436 breast cancer cells expansion. The mRNA and protein levels of BLM DNA helicase in MDA-MB-435 cells increased after HY-2 treatment, which might contribute to HY-2 inhibiting the DNA binding, ATPase and DNA unwinding of BLM DNA helicase. The mechanism of HY-2 inhibition on BLM DNA helicase was further confirmed with the effect of HY-2 on the ultraviolet spectrogram of BLM642-1290 DNA helicase and Molecular dynamics simulation of the interacting between HY-2 and BLM640-1291 DNA helicase. Our study provided some valuable clues for the exploration of HY-2 in the living body and developing it as an anticancer drug.

Association Between Pretreatment Skeletal Muscle and Outcomes After CAR T-Cell Therapy.

BACKGROUND: The purpose of this study was to examine the association between baseline skeletal muscle measurements, acute toxicity (immune effector cell-associated neurotoxicity syndrome [ICANS], cytokine release syndrome), and treatment efficacy in patients undergoing CAR T-cell therapy for B-lineage lymphoma. PATIENTS AND METHODS: Skeletal muscle measurements were obtained from automated CT measurements in 226 consecutive patients who received CAR T-cell therapy between 2015 and 2021. The Kaplan-Meier method was used to examine progression-free survival (PFS) and overall survival (OS) at 1-year. Multivariable regression was used to calculate the hazard ratio (HR) with 95% confidence intervals, adjusted for covariates. RESULTS: The median age of the cohort was 63.1 years (range, 18.5-82.4 years), and most patients were male (66%) and had primary refractory disease (58%). Patients with abnormally low skeletal muscle at baseline were at greater risk of ICANS (HR, 1.74; 95% CI, 1.05-2.87) and had longer length of hospitalization (mean 27.7 vs 22.9 days; P<.05) compared with those with normal muscle mass. Abnormal skeletal muscle was independently associated with risk of disease progression (HR, 1.70; 95% CI, 1.11-2.57) and worse survival (HR, 2.44; 95% CI, 1.49-4.00) at 1 year compared with normal skeletal muscle. Individuals who had abnormal skeletal muscle and high lactate dehydrogenase (LDH) levels at baseline had poor 1-year PFS (17%) and OS (12%) compared with those with normal skeletal muscle and LDH levels (72% and 82%, respectively; P<.001). Patients who had abnormal skeletal muscle and LDH levels had a 5-fold risk (HR, 5.34; 95% CI, 2.97-9.62) of disease progression and a 10-fold risk (HR, 9.73; 95% CI, 4.81-19.70) of death (reference: normal skeletal muscle, normal LDH), independent of prior lines of therapy, extent of residual disease at time of CAR T-cell therapy, functional status, or product. CONCLUSIONS: This information can be used for risk stratification prior to CAR T-cell therapy or to implement prehabilitation and nutritional optimization before lymphodepletion as well as thereafter. These efforts will be complementary to ongoing efforts toward sustained efficacy after CAR T-cell therapy.

The hyperthermic response to intra-preoptic area administration of agmatine in male rats.

Agmatine is an endogenous biogenic amine that exerts various effects on the central nervous system. The hypothalamic preoptic area (POA, thermoregulatory command center) has high agmatine immunoreactivity. In this study, in conscious and anesthetized male rats, agmatine microinjection into the POA induced hyperthermic responses associated with increased heat production and locomotor activity. Intra-POA administration of agmatine increased the locomotor activity, the brown adipose tissue temperature and rectum temperature, and induced shivering as demonstrated by increased neck muscle electromyographic activity. However, intra-POA administration of agmatine almost had no impact on the tail temperature of anesthetized rats. Furthermore, there were regional differences in the response to agmatine in the POA. The most effective sites for the microinjection of agmatine to elicit hyperthermic responses were localized in the medial preoptic area (MPA). Agmatine microinjection into the median preoptic nucleus (MnPO) and lateral preoptic nucleus (LPO) had a minimal effect on the mean core temperature. Analysis of the in vitro discharge activity of POA neurons in brain slices when perfused with agmatine showed that agmatine inhibited most warm-sensitive but not temperature-insensitive neurons in the MPA. However, regardless of thermosensitivity, the majority of MnPO and LPO neurons were not responsive to agmatine. The results demonstrated that agmatine injection into the POA of male rats, especially the MPA, induced hyperthermic responses, which may be associated with increased BAT thermogenesis, shivering and locomotor activity by inhibiting warm-sensitive neurons.

Fatal Motor Vehicle Crashes in Upstate and Long Island New York: The Impact of High Visibility Seat Belt Enforcement on Multiple Risky Driving Behaviors.

Despite an observed daytime front-seat seat belt use that exceeds 90%, nearly half of motor vehicle occupants who die in New York State (NYS) each year are not wearing a seat belt. Crash outcomes were examined by occupant, vehicle, environmental and traffic enforcement patterns related to the annual Click It or Ticket high visibility seat belt enforcement campaign. Three periods of enforcement were examined: pre-enforcement, peri-enforcement (during/immediately after), and post-enforcement. Of the 14.4 million traffic citations, 713,990 (5.0%) were seat belt violations. Relative risk with 95% CI was assessed using deaths from the Fatality Analysis Reporting System (FARS) and SAS Glimmix 9.4 software. Mortality was lower peri-enforcement (32.9%) compared to pre- (40.9%) or post-enforcement (37.1%) (p < 0.001) and tended to be elevated in low enforcement response areas (43.6%). Fatalities were 30% lower (0.7, 95% CI 0.6−0.9) during peri-enforcement in models adjusted for demographics, law coverage, enforcement response, rural, weekend, impairment, speeding, and vehicle type. Adjusted mortality was higher in rural (1.9, 1.6−2.6), alcohol-involved (1.8, 1.4−2.9), and speeding-involved (2.0, 1.7−2.5) crashes. Peri-enforcement alcohol- and speed-involved fatalities tended to be lower in restrained, unrestrained and occupants missing belt status. The finding of lower mortality in both belted and unbelted occupant's peri-enforcement­in the context of fewer fatal speed and alcohol-involved crashes­suggests that the mechanism(s) through which high visibility seat belt enforcement lowers mortality is through impacting multiple risky driving behaviors.

Sialylated IgG in epithelial cancers inhibits antitumor function of T cells via Siglec-7.

Although effective, immune checkpoint blockade induces response in only a subset of cancer patients. There is an urgent need to discover new immune checkpoint targets. Recently, it was found that a class of sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed on the surface of T cells in cancer patients inhibit T cell activation through their intracellular immunosuppressive motifs by recognizing sialic acid-carrying glycans, sialoglycans. However, ligands of Siglecs remain elusive. Here, we report sialylated IgG (SIA-IgG), a ligand to Siglec-7, that is highly expressed in epithelial cancer cells. SIA-IgG binds Siglec-7 directly and inhibits TCR signals. Blocking of either SIA-IgG or Siglec-7 elicited potent antitumor immunity in T cells. Our study suggests that blocking of Siglec-7/SIA-IgG offers an opportunity to enhance immune function while simultaneously sensitizing cancer cells to immune attack.

[Analysis of risk factors for prolonged mechanical ventilation in patients with sepsis after abdominal surgery].

OBJECTIVE: To analyze the risk factors of prolonged mechanical ventilation (PMV) in patients with sepsis complicated by abdominal surgery, and to evaluate the predictive value of risk factors for PMV. METHODS: A retrospective case-control study was conducted. The clinical data of patients with postoperative abdominal sepsis complicated with invasive mechanical ventilation who were admitted to the intensive care unit (ICU) of the Affiliated Hospital of Guizhou Medical University from January 1, 2018 to December 31, 2020 were collected. The patients were divided into PMV group (duration of mechanical ventilation longer than 48 hours) and non-PMV group (duration of mechanical ventilation shorter than 48 hours) according to the duration of mechanical ventilation in ICU. The patient's gender, age, body mass index (BMI), underlying diseases, mean arterial pressure (MAP), complete blood count, blood biochemistry, arterial blood gas, cardiac function indicators, procalcitonin (PCT) at admission to the ICU, the acute physiology and chronic health evaluation II (APACHE II) and the sequential organ failure assessment (SOFA) scores in the first 24 hours of admission to the ICU, and other clinical information were recorded. Univariate and multivariate Logistic regression models were used to analyze the risk factors for PMV. Receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive value of related indicators for PMV. RESULTS: A total of 195 patients with sepsis after abdominal surgery who received invasive mechanical ventilation were enrolled, including 127 males (65.1%) and 68 females (34.9%), with the median age of 65 (21, 93) years old. There were 91 patients (46.7%) in the non-PMV group and 104 patients (53.3%) in the PMV group. Univariate analysis showed that the APACHE II score, SOFA score, cardiac troponin T (cTnT), N-terminal pro-B type natriuretic peptide (NT-proBNP) in the PMV group were significantly higher than those in the non-PMV group. Oxygenation index (PaO2/FiO2), total protein (TP) and prealbumin (PA) in the PMV group were all lower than those in the non-PMV group when admitted to ICU. In the PMV group, serum creatinine (SCr), blood urea nitrogen (BUN), cystatin C (Cys C) were significantly increased, prothrombin time (PT) was significantly prolonged, the proportion of patients with septic shock and hypertension were significantly increased as compared with those in the non-PMV group. Multivariate analysis showed that low PaO2/FiO2 at ICU admission [odds ratio (OR) = 0.995, 95% confidence interval (95%CI) was 0.992-0.999, P = 0.010], high ln PCT (OR = 1.301, 95%CI was 1.088-1.555, P = 0.004), high ln cTnT (OR = 1.562, 95%CI was 1.079-2.261, P = 0.018) and septic shock (OR = 4.967, 95%CI was 2.461-10.026, P = 0.000) were the independent risk factors for PMV in patients with sepsis after abdominal surgery. ROC curve analysis showed that the PaO2/FiO2, ln cTnT, ln PCT and septic shock had certain predictive value for PMV, the area under the ROC curve (AUC) of the four variables were 0.607, 0.638, 0.690 and 0.711, the sensitivity was 50.0%, 62.5%, 86.5% and 74.0%, and the specificity was 71.4%, 62.6%, 48.3% and 68.1%, respectively. The AUC for the joint prediction of the four variables was 0.803, with a sensitivity of 76.0% and a specificity of 78.0%. It suggested that the multivariate joint prediction of PMV was more accurate. CONCLUSIONS: Decreased PaO2/FiO2, increased PCT, increased cTnT and the occurrence of septic shock are independent risk factors for PMV in patients with sepsis complicated by abdominal surgery. The combination of above four indices was more accurate than one single variable in predicting PMV and had higher diagnostic value.

Risk of Subsequent Malignant Neoplasms Following Hematopoietic Stem Cell Transplantation with Total Body Irradiation or Total Marrow Irradiation: Insights from Early Follow-Up.

Total marrow irradiation (TMI) is an alternative to total body irradiation (TBI) as a component of the conditioning regimen for hematopoietic cell transplantation (HCT), offering the ability to deliver more targeted doses and facilitating organ-sparing. The organ-sparing effect of TMI is theorized to decrease the risk of complications associated with radiation, including subsequent malignant neoplasms (SMNs), while allowing for dosage escalation to improve oncologic outcomes. The purpose of this study was to compare SMNs rates among patients treated with TBI- or TMI-based conditioning regimens. We hypothesized that TMI would yield a rate of SMNs comparable to, if not lower than, TBI. A retrospective matched-pair analysis of patients who underwent allogeneic HCT and received either TBI- or TMI-based conditioning regimens to a total dose of 12 to 20 Gy was performed. A total of 171 patients received TMI-based conditioning and 171 received TBI-based conditioning, matched based on age, sex, diagnosis, and length of follow-up. SMNs were identified from an established long-term follow-up protocol, our institutional cancer registry, and the California Cancer Registry. There were no significant differences in patient and clinical characteristics between the TMI and TBI cohorts except for clinical response status at transplantation and radiation dose. As expected, patients in the TMI received higher radiation doses (median dose, 16.0 Gy for the TMI cohort versus 13.2 Gy for the TBI cohort; P < .001). The median follow-up for both cohorts was 2.0 years (range, .5 to 12.3 years). There was no significant difference in the risk of developing SMNs between the 2 cohorts (P = .81). A total of 9 patients (5.3%) conditioned with TBI and 10 patients (5.8%) conditioned with TMI developed SMNs, at a median of 3.3 years and 1.7 years following HCT, respectively. Excluding nonmelanoma skin cancers and noninvasive neoplasms, 2 patients in the TBI cohort developed SMNs (both melanomas), and 1 patient in the TMI cohort developed an SMN (colon cancer). No patients developed a subsequent hematologic malignancy. TMI-based conditioning is not associated with a significant difference in the risk of developing SMNs compared with TBI-based conditioning during early post-HCT follow-up. Future studies with longer follow-up may be needed to further characterize the risk of SMNs associated with TMI-based conditioning regimens compared with TBI-based regimens.

Social Vulnerability and Risk of Nonrelapse Mortality After Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: Risk of nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT) is high. Patient-level clinical prediction models such as the HCT-comorbidity index (HCT-CI) help identify those at increased risk for NRM, but the independent contribution of social determinants of health on HCT outcomes is not well characterized. METHODS: This study included 1602 patients who underwent allogeneic HCT between 2013 and 2019 at City of Hope. Census tract-level social vulnerability was measured using the social vulnerability index (SVI). Fine-Gray multivariable regression evaluated the association between SVI and 1-year NRM. Subgroup analysis examined risk of NRM across combined SVI and HCT-CI categories and by race and ethnicity. RESULTS: Cumulative incidence of 1-year NRM after HCT was 15.3% (95% confidence interval [CI] = 13.6% to 17.1%). In multivariable analysis, patients in the highest SVI tertile (highest social vulnerability) had a 1.4-fold risk (subdistribution hazard ratio [sHR] = 1.36, 95% CI = 1.04 to 1.78) of NRM compared with individuals in the lower tertiles; patients in the highest SVI tertile who also had elevated (≥3) HCT-CI scores had the highest risk (sHR = 1.81, 95% CI = 1.26 to 2.58) of 1-year NRM (reference: lower SVI tertiles and HCT-CI < 3). High social vulnerability was associated with risk of 1-year NRM in Asian (sHR = 2.03, 95% CI = 1.09 to 3.78) and Hispanic (sHR = 1.63, 95% CI = 1.04 to 2.55) but not non-Hispanic White patients. CONCLUSIONS: High social vulnerability independently associated with 1-year NRM after HCT, specifically among minority populations and those with a high comorbidity burden at HCT. These findings may inform targeted approaches for needs assessment during and after HCT, allowing for timely interventions to improve health outcomes in at-risk patients.

Ascitic Senescent T Cells Are Linked to Chemoresistance in Patients With Advanced High-Grade Serous Ovarian Cancer.

Senescent T cells are reported to be increased in patients with cancer and are poor prognostic indicators. However, the distribution of senescent T cells and their correlation with clinical features in high-grade serous ovarian cancer (HGSOC) is unknown. We detected the percentage of senescent T cells in the peripheral blood and ascites of patients with advanced HGSOC (n = 86) at diagnosis by flow cytometry. Compared with healthy donors, patients with HGSOC exhibited an accumulation of CD28-CD57+ (Tsen) CD8+ T cells in the peripheral blood and ascites. The frequency of Tsen CD8+ T cells in the peripheral blood was positively correlated with age and pretreatment serum CA125 and increased in patients with large volume ascites, whereas the frequency of Tsen CD8+ T cells in ascites was elevated in patients with lymph node metastasis. Patients with Tsen-high in ascites (>19.92%), but not in the peripheral blood, were more likely to be resistant to chemotherapy and had shorter progression-free survival. Tsen CD8+ T cells exhibited common senescence features including increased SA-ß-gal activity, declines in proliferation, loss of CD27 and gain of KLRG-1, and the production of cytokines. In ascites, the percentage of Tsen CD8+ T cells was positively correlated with levels of interleukin-10 and granzyme B. This study suggests the potential of ascitic Tsen CD8+ T cells at diagnosis as a prognostic biomarker in HGSOC.

Association Between Body Composition and Development of Glucose Intolerance after Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) recipients have increased risk of developing glucose intolerance and diabetes mellitus (DM). The strongest risk factor for glucose intolerance is being overweight/obese, as determined by body mass index (BMI), which does not account for differences in body composition. We examined the association between body composition measures from pre-HCT CT and early-onset (≤30 days) de novo glucose intolerance after HCT, and determined its impact on nonrelapse mortality (NRM). METHODS: This study included 749 patients without pre-HCT DM. Skeletal muscle loss [abnormal skeletal muscle gauge (SMG)] and abnormal visceral adiposity (VA) were defined by sex-specific tertiles. Fine-Gray proportional subdistribution HR estimates and 95% confidence intervals (CI) were obtained to determine the association between muscle loss and VA and development of glucose intolerance. 1 year NRM was calculated for patients alive at day 30. RESULTS: Median age at HCT was 50.2 years. By day 30, 8.1% of patients developed glucose intolerance and 731 remained alive. In multivariable analysis, abnormal SMG was associated with increased risk of glucose intolerance in nonoverweight (BMI < 25 kg/m2) patients (HR = 3.00; 95% CI, 1.15-7.81; P = 0.024); abnormal VA was associated with increased risk of glucose intolerance in overweight/obese patients (HR = 2.26; 95% CI, 1.24-4.12; P = 0.008). Glucose intolerance was independently associated with NRM (HR = 1.88; 95% CI, 1.05-3.39; P = 0.035). CONCLUSIONS: Abnormal SMG and VA were associated with glucose intolerance in nonoverweight and overweight/obese patients, respectively, which contributed to increased risk of 1 year NRM. IMPACT: This information may guide personalized interventions to decrease the risk of adverse outcomes after HCT. See related commentary by Giri and Williams, p. 2002.

The prognostic miR-532-5p-correlated ceRNA-mediated lipid droplet accumulation drives nodal metastasis of cervical cancer.

Introduction: The prognosis for cervical cancer (CC) patients with lymph node metastasis (LNM) is extremely poor. Lipid droplets (LDs) have a pivotal role in promoting tumor metastasis. The crosstalk mechanism between LDs and LNM modulated in CC remains largely unknown. Objectives: This study aimed to construct a miRNA-dependent progonostic model for CC patients and investigate whether miR-532-5p has a biological impact on LNM by regualting LDs accumulation. Methods: LASSO-Cox regression was applied to establish a prognostic prediction model. miR-532-5p had the lowest P-value in RNA expression (P < 0.001) and prognostic prediction (P < 0.0001) and was selected for further study. The functional role of the prognostic miR-532-5p-correlated competing endogenous RNA (ceRNA) network was investigated to clarify the crosstalk between LDs and LNM. The underlying mechanism was determined using site-directed mutagenesis, dual luciferase reporter assays, RNA immunoprecipitation assays, and rescue experiments. A xenograft LNM model was established to evaluate the effect of miR-532-5p and orlistat combination therapy on tumor growth and LNM. Results: A novel 5-miRNAs prognostic signature was constructed to better predict the prognosis of CC patient. Further study demonstrated that miR-532-5p inhibited epithelial-mesenchymal transition and lymphangiogenesis by regulating LDs accumulation. Interestingly, we also found that LDs accumulation promoted cell metastasis in vitro. Mechanistically, we demonstrated a miR-532-5p-correlated ceRNA network in which LINC01410 was bound directly to miR-532-5p and effectively functioned as miR-532-5p sponge to disinhibit its target gene-fatty acid synthase (FASN). Combined therapy with miR-532-5p and FASN inhibitor-orlistat further inhibited tumor growth and LNM in vivo. Conclusion: Our findings highlight a LD accumulation-dependent mechanism of miR-532-5p-modulated LNM and support treatment with miR-532-5p/orlistat as novel strategy for treating patients with LNM in CC.

Association between basal platelet count and all-cause mortality in critically ill patients with acute respiratory failure: a secondary analysis from the eICU collaborative research database.

BACKGROUND: Evidence regarding the correlation between platelet count and all-cause mortality in critically ill patients with acute respiratory failure (ARF) is limited. Therefore, the aim of the study was to evaluate whether platelet count was associated with all-cause mortality in critical patients with ARF by using the electronic intensive care unit (eICU) Collaborative Research Database (eICU-CRD). METHODS: In this retrospective multicenter cohort study, the data of 26961 patients with ARF hospitalized in ICUs between 2014 and 2015 were collected. The independent variable was log2 basal platelet count, and the dependent variables were all-cause in-hospital and ICU mortality. Covariates including demographic data, Acute Physiology and Chronic Health Evaluation (APACHE) IV score, supportive treatment, and comorbidities were collected. RESULTS: In the fully adjusted model, log2 basal platelet count was negatively associated with all-cause mortality both in hospital [RR: 0.87, 95% CI: 0.84-0.91] and in ICU [RR: 0.87, 95% CI: 0.83-0.92]. A non-linear relationship between log2 basal platelet count and all-cause in-hospital and ICU mortality was identified by the nonlinearity test. The inflection points we got were 6.83 and 6.86 respectively (after inverse log2 logarithmic conversion, the platelet counts were 114×109/L and 116×109/L, respectively). On the right side of the inflection point, however, no association was observed between blood platelets and all-cause in-hospital (RR: 0.96, 95% CI: 0.88-1.03) and ICU mortality (RR: 0.97, 95% CI: 0.91-1.04). CONCLUSIONS: For patients with ARF in ICU, platelet count was negatively associated with all-cause in-hospital and ICU mortality when the platelet count was less than 114×109/L and 116×109/L respectively, but when the platelet count was higher, we failed to observe a correlation between them. The safe ranges of platelet count for hospital stay and ICU stay were 78×109/L-145×109/L and 89×109/L-147×109/L respectively.

The Efficacy and Safety of Early Renal Replacement Therapy in Critically Ill Patients With Acute Kidney Injury: A Meta-Analysis With Trial Sequential Analysis of Randomized Controlled Trials.

The efficacy and safety of early renal replacement therapy (eRRT) for critically ill patients with acute kidney injury (AKI) remain controversial. Therefore, the purpose of our study was to perform an up-to-date meta-analysis with the trial sequential analysis (TSA) of randomized controlled trials (RCTs) to evaluate the therapeutic effect of eRRT on patients in an intensive care unit (ICU). We extensively searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov, Gray Literature Report, and Bielefeld Academic Search Engine (BASE), and conducted an updated search on December 27, 2021. The included studies were RCTs, which compared the efficacy and safety of eRRT and delayed renal replacement therapy (dRRT) on critically ill patients with AKI. We adopted TSA and sensitivity analysis to strengthen the robustness of the results. About 12 RCTs with a total of 5,423 participants were included. Patients receiving eRRT and dRRT had the similar rate of all-cause mortality at day 28 (38.7% vs. 38.9%) [risk ratio (RR), 1.00; 95%CI, 0.93-1.07, p = 0.93, I 2 = 0%, p = 0.93]. A sensitivity and subgroup analysis produced similar results for the primary outcome. TSA showed that the required information size was 5,034, and the cumulative Z-curve crossed trial sequential monitoring boundaries for futility. Patients receiving eRRT had a higher rate of renal replacement therapy (RRT) (RR, 1.50, 95% CI: 1.28-1.76, p < 0.00001, I 2 = 96%), and experienced more adverse events comparing to those receiving dRRT (RR: 1.41, 95% CI: 1.22-1.63, p < 0.0001, heterogeneity not applied). The most remarkable and important experimental finding is that, to our knowledge, the current meta-analysis included the largest sample size from the RCTs, which were published in the past 10 years to date, show that eRRT had no significant survival benefit for ill patients with AKI compared with dRRT and TSA indicating that no more studies were needed to confirm it. Trial Registration: INPLASY, INPLASY2020120030. Registered 04 December 2020.

High-energy high-dose microfocus X-ray computed tomography driven by high-average-current photo-injector.

High-energy, high-dose, microfocus X-ray computed tomography (HHM CT) is one of the most effective methods for high-resolution X-ray radiography inspection of high-density samples with fine structures. Minimizing the effective focal spot size of the X-ray source can significantly improve the spatial resolution and the quality of the sample images, which is critical and important for the performance of HHM CT. The objective of this study is to present a 9 MeV HHM CT prototype based on a high-average-current photo-injector in which X-rays with about 70µm focal spot size are produced via using tightly focused electron beams with 65/66µm beam size to hit an optimized tungsten target. In digital radiography (DR) experiment using this HHM CT, clear imaging of a standard 0.1 mm lead DR resolution phantom reveals a resolution of 6 lp/mm (line pairs per mm), while a 5 lp/mm resolution is obtained in CT mode using another resolution phantom made of 10 mm ferrum. Moreover, comparing with the common CT systems, a better turbine blade prototype image was obtained with this HHM CT system, which also indicates the promising application potentials of HHM CT in non-destructive inspection or testing for high-density fine-structure samples.

[Comparative study of dexmedetomidine vs. midazolam on plasma catecholamine levels and hemodynamics in patients with septic shock].

OBJECTIVE: To compare the effects of dexmedetomidine (DEX) and midazolam on the endogenous plasma catecholamine levels and the dosage of exogenous norepinephrine (NE) to maintain blood pressure in patients with septic shock. METHODS: From January 2018 to December 2019, patients admitted to the department of critical care medicine of the Affiliated Hospital of Guizhou Medical University who needed invasive mechanical ventilation and had a stay of more than 48 hours in the intensive care unit (ICU) for septic shock and received DEX or midazolam for sedation were enrolled in this study. The hemodynamic data, arterial blood lactic acid (Lac) level, arterial blood gas analysis and vasoactive drug dose at 0, 12, 24, 48, 72 hours after entering the ICU were dynamically recorded, and the plasma catecholamine levels at 0, 24, 48 hours after entering the ICU were recorded. The acute physiology and chronic health evaluation II (APACHE II) score and sequential organ failure assessment (SOFA) score on ICU-admission were calculated. The parameters of prognosis were collected. RESULTS: A total of 24 patients were enrolled, 12 in the DEX group and 12 in the midazolam group. There were similar dynamic trends in heart rate (HR), central venous pressure (CVP), venous-arterial carbon dioxide pressure difference (Pv-aCO2), oxygenation index (PaO2/FiO2), and Lac level of patients between the two groups. Only the 12-hour CVP and 72-hour Pv-aCO2 in the DEX group were significantly higher than those in the midazolam group [CVP (mmHg, 1 mmHg = 0.133 kPa): 13±3 vs. 10±3, Pv-aCO2 (mmHg): 9.4±5.2 vs. 4.8±2.2, both P < 0.05], and the mean arterial pressure (MAP) of patients in the DEX group at 48 hours and 72 hours was significantly higher than that in the midazolam group (mmHg: 95±10 vs. 86±10, 96±9 vs. 88±7, both P < 0.05). There was no statistically significant difference in the duration of mechanical ventilation, ICU mortality or in-hospital mortality between the DEX group and the midazolam group [duration of mechanical ventilation (days): 5.6 (3.8, 9.5) vs. 10.5 (5.9, 15.0), ICU mortality: 16.7% vs. 33.3%, in-hospital mortality: 25.0% vs. 41.7%, all P > 0.05]. There was no significant difference in the dosage of propofol or sufentanil between the DEX group and the midazolam group [propofol (mg/kg): 0 (0, 9.35) vs. 4.07 (0, 13.75), sufentanil (µg/kg): 6.26 (4.90, 9.80) vs. 8.32 (3.52, 9.34), both P > 0.05]. The levels of plasma NE, dopamine and dobutamine in the DEX group at 48 hours were significantly lower than those in the midazolam group [NE (ng/L): 1 850.12 (342.16, 2 938.05) vs. 4 596.60 (3 310.56, 5 546.84), dopamine (ng/L): 119.10 (60.47, 200.71) vs. 275.40 (214.61, 418.88), dobutamine (ng/L): 51.20 (36.85, 75.59) vs. 98.97 (85.65, 107.10), all P < 0.05], but the amount of NE required to maintain MAP between 65 mmHg and 75 mmHg in the DEX group and the midazolam group was similar [µg/kg: 1 922 (1 170, 4 887) vs. 2 466 (2 043, 3 438), P > 0.05]. CONCLUSIONS: DEX can reduce plasma catecholamine levels in patients with septic shock more than midazolam, and does not increase the dose of exogenous NE, and has a smaller effect on hemodynamics in patients with septic shock than midazolam.

Andrographolide sulfonate attenuates alveolar hypercoagulation and fibrinolytic inhibition partly via NF-κB pathway in LPS-induced acute respiratory distress syndrome in mice.

BACKGROUND: Alveolar hypercoagulation and fibrinolytic inhibition are important characteristics during acute respiratory distress syndrome (ARDS), and NF-κB p65 signaling pathway is involved to regulate these pathophysiologies. We hypothesize that targeting NF-κB signal pathway could ameliorate alveolar hypercoagulation and fibrinolyitc inhibition, thus attenuating lung injury in ARDS. PURPOSE: We explore the efficacy and the potential mechanism of andrographolide sulfonate (Andro-S) on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS in mice. METHODS: ARDS was made by lipopolysaccharide (LPS) inhalation in C57BLmice. Andrographolide sulfonate (2.5, 5 and 10 mg/kg) was intraperitoneally given to the mice (once a day for three consecutive days) before LPS administration. NEMO binding domain peptide (NBD), an inhibitor of NF-κB, was used as the positive control and it replaced Andro-S in mice of NBD group. Mice in normal control received saline instead of LPS. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis of alveolar coagulation, fibrinolytic inhibition as well as of pulmonary inflammatory response after 8 h of LPS inhalation. NF-κB signal pathway in lung tissue was simultaneously determined. RESULTS: Andro-S dose-dependently inhibited tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 expressions either in mRNA or in protein in lung tissue of ARDS mice, and it also decreased the concentrations of TF, PAI-1, thrombin-antithrombin complex (TAT), procollagen peptide type Ⅲ (PⅢP) while promoting the production of activated protein C (APC) in BALF. Meanwhile, Andro-S effectively inhibited inflammatory response (interleukin 1ß and myeloperoxidase) induced by LPS. LPS stimulation dramatically activated NF-κB signal pathway, indicated by increased expressions of phosphorylation of p65 (p-p65), p-IKKα/ß and p-IκBα and the higher p65-DNA binding activity, which were all dose-dependently reversed by Andro-S. Andro-S and NBD presented similar efficacies. CONCLUSIONS: Andro-S treatment improves alveolar hypercoagulation and fibrinolytic inhibition and attenuates pulmonary inflammation in LPS-induced ARDS in mice partly through NF-κB pathway inactivation. The drug is expected to be an effective choice for ARDS.