HSPA4 regulated glioma progression via activation of AKT signaling pathway.

Glioma is still an incurable disease with high invasiveness. Heat shock 70 kDa protein 4 (HSPA4) is a member of the HSP110 family, and is associated with the development and progression of various cancers. In the current study, we assessed the expression of HSPA4 in clinical samples, and found that HSPA4 was up-regulated in glioma tissues and correlated with tumor recurrence and grade. Survival analyses demonstrated that glioma patients with high HSPA4 expression had lower overall survival and disease-free survival times. In vitro knockdown of HSPA4 inhibited glioma cell proliferation, mediated cell cycle arrest at G2 phase and apoptosis, and reduced the migration ability. In vivo, the growth of HSPA4-knockdown xenografts was markedly suppressed compared to the tumors formed by HSPA4-positive control cells. Additionally, Gene set enrichment analyses disclosed that HSPA4 was associated with the PI3K/Akt signaling pathway. The regulatory effect of the AKT activator SC79 on cell proliferation and apoptosis was suppressed by HSPA4 knockdown, indicating that HSPA4 is capable of promoting glioma development. In summary, these data showed that HSPA4 is likely to play a pivotal role in the progression of glioma, and consequently may be a promising therapeutic target for glioma therapy.

Integrating Transcriptomics and Proteomics to Characterize the Intestinal Responses to Cadmium Exposure Using a Piglet Model.

Cadmium (Cd) is a heavy metal element with a wide range of hazards and severe biotoxicity. Since Cd can be easily accumulated in the edible parts of plants, the exposure of humans to Cd is mainly through the intake of Cd-contaminated food. However, the intestinal responses to Cd exposure are not completely characterized. Herein, we simulated laboratory and environmental Cd exposure by feeding the piglets with CdCl2-added rice and Cd-contaminated rice (Cdcr) contained diet, as piglets show anatomical and physiological similarities to humans. Subsequent analysis of the metal element concentrations showed that exposure to the two types of Cd significantly increased Cd levels in piglets. After verifying the expression of major Cd transporters by Western blots, multi-omics further expanded the possible transporters of Cd and found Cd exposure causes wide alterations in the metabolism of piglets. Of significance, CdCl2 and Cdcr exhibited different body distribution and metabolic rewiring, and Cdcr had stronger carcinogenic and diabetes-inducing potential. Together, our results indicate that CdCl2 had a significant difference compared with Cdcr, which has important implications for a more intense study of Cd toxicity.

Crystalline Structure and Thermal Stability of an Unknown ZIF-L300 Phase.

In recent years, the synthesis, crystalline structure, and applications of zeolite imidazole frameworks (ZIFs) have attracted extensive attention. Since the ZIF-L phase was synthesized, a new phase was observed during the heating process, but its crystal structure is unknown. The unknown new phase, which was named ZIF-L300 in this study, was confirmed again. In this study, the X-ray powder diffraction technique and Rietveld refinement were used to solve the crystalline structure of the unknown ZIF-L300 phase. The results demonstrate that ZIF-L300 has the same chemical formula (ZnC8N4H10) as in ZIF-8 and belongs to a hexagonal structure with a space group of P61. The lattice parameters have been determined as follows: a = b = 8.708(7) Å, c = 24.195(19) Å, α = ß = 90°, and γ = 120°. The X-ray absorption fine structure (XAFS) technique was also used to extract the local atomic structures. The in situ X-ray diffraction (XRD) technique was used to monitor the structural evolution of the as-prepared ZIF-L in a temperature range from room temperature to 600 °C. The results show that the sample experiences a change process from the initial ZIF-L orthorhombic phase (<210 °C), to the ZIF-L300 hexagonal phase (∼300 °C), then to an amorphous phase (∼390 °C), and finally to a zincite ZnO phase (>420 °C). These sorts of structural information are helpful to the application of ZIF materials and enrich the knowledge of the thermal stability of ZIF materials.

Convergent Evidence Supports TH2LCRR as a Novel Asthma Susceptibility Gene.

Asthma is a common, complex disease with apparent genetic predispositions, and previous genome-wide association studies suggest that rs1295686 within the IL13 (IL-13) gene is significantly associated with asthma. Analysis of the data provided by the 1,000 Genomes Project indicated an additional four SNPs in nearly complete linkage disequilibrium with rs1295686 in White people. However, the causal SNPs and the associated mechanism remain unclear. To investigate this issue, functional genomics approaches were utilized to analyze the functions of these SNPs. Dual-luciferase assays indicated that the functional SNP is not rs1295686 but a haplotype consisting of three other SNPs: rs1295685, rs848, and rs847. Through chromosome conformation capture, it was found that the enhancer containing the three functional SNPs interacts with the promoter of TH2LCRR (T helper type 2 locus control region associated RNA), a recently identified long noncoding RNA. RNA-seq data analysis indicated that TH2LCRR expression is significantly increased in patients with asthma and is dependent on the genotype at this locus, indicating that TH2LCRR is a novel susceptibility gene for asthma and that these SNPs confer asthma risk by regulating TH2LCRR expression. By chromatin immunoprecipitation, the related transcription factors that bind in the region surrounding these three SNPs were identified, and their interactions were investigated by functional genomics approaches. Our effort identified a novel mechanism through which genetic variations at this locus could influence asthma susceptibility.

Evaluation of Serologic Cross-Reactivity Between Dengue Virus and SARS-CoV-2 in Patients with Acute Febrile Illness - United States and Puerto Rico, April 2020-March 2021.

The diagnosis of dengue disease, caused by the dengue virus (DENV) (a flavivirus), often requires serologic testing during acute and early convalescent phases of the disease. Some symptoms of DENV infection, such as nonspecific fever, are similar to those caused by infection with SARS-CoV-2, the virus that causes COVID-19. In studies with few COVID-19 cases, positive DENV immunoglobulin M (IgM) results were reported with various serologic tests, indicating possible cross-reactivity in these tests for DENV and SARS-CoV-2 infections (1,2). DENV antibodies can cross-react with other flaviviruses, including Zika virus. To assess the potential cross-reactivity of SARS-CoV-2, DENV, and Zika virus IgM antibodies, serum specimens from 97 patients from Puerto Rico and 12 U.S.-based patients with confirmed COVID-19 were tested using the DENV Detect IgM Capture enzyme-linked immunosorbent assay (ELISA) (InBios International).* In addition, 122 serum specimens from patients with confirmed dengue and 121 from patients with confirmed Zika virus disease (all from Puerto Rico) were tested using the SARS-CoV-2 pan-Ig Spike Protein ELISA (CDC).† Results obtained for DENV, Zika virus IgM, and SARS-CoV-2 antibodies indicated 98% test specificity and minimal levels of cross-reactivity between the two flaviviruses and SARS-CoV-2. These findings indicate that diagnoses of dengue or Zika virus diseases with the serological assays described in this report are not affected by COVID-19, nor do dengue or Zika virus diseases interfere with the diagnosis of COVID-19.

The correlation between vitamin D, glucose homeostasis and androgen level among polycystic ovary syndrome patients: a cross-sectional study.

MATERIAL AND METHODS: A total of 290 women with PCOS participated in this cross-sectional study. Glucose homeostasis was assessed by a 75-g oral glucose tolerance test and the concentration of serum 25-hydroxy vitamin D was determined among all subjects. The homeostasis model assessment of insulin resistance (HOMA-IR) was taken as the indicator of insulin resistance. Beta cell function was estimated using the insulinogenic index and the disposition index. Free androgen index (FAI) was used to represent the androgen level. RESULTS: In our study, 7.2% of the patients had Vit D severe deficiency, 75.2% had Vit D deficiency and 15.5% had vit D insufficiency. The level of serum 25(OH)D showed a significant positive association with insulinogenic index (r = 0.147, p < .05), disposition index (r = 0.280, p < .05), and SHBG (r = 0.178, p < .05) but exhibited a negative association with HOMA-IR (r = -0.198, p < .05), FAI (r = -0.178, p < .05). Adjusted age and BMI, 25(OH)D would be the dependent variable on disposition index [B = 0.259, 95%CI(0.041,0.477)] and FAI [B = -0.125, 95%CI(-0.232, -0.017)]. CONCLUSIONS: According to our results, the low levels of serum 25(OH)D were common in women with PCOS, which was speculated to be associated with glucose homeostasis and the androgen level.

Intensity of pyrethroid resistance in Anopheles gambiae before and after a mass distribution of insecticide-treated nets in Kinshasa and in 11 provinces of the Democratic Republic of Congo.

BACKGROUND: Between 2011 and 2018, an estimated 134.8 million pyrethroid-treated long-lasting insecticidal nets (LLINs) were distributed nationwide in the Democratic Republic of Congo (DRC) for malaria control. Pyrethroid resistance has developed in DRC in recent years, but the intensity of resistance and impact on LLIN efficacy was not known. Therefore, the intensity of resistance of Anopheles gambiae sensu lato (s.l.) to permethrin and deltamethrin was monitored before and after a mass distribution of LLINs in Kinshasa in December 2016, and in 6 other sites across the country in 2017 and 11 sites in 2018. METHODS: In Kinshasa, CDC bottle bioassays using 1, 2, 5, and 10 times the diagnostic dose of permethrin and deltamethrin were conducted using An. gambiae s.l. collected as larvae and reared to adults. Bioassays were conducted in four sites in Kinshasa province 6 months before a mass distribution of deltamethrin-treated LLINs and then two, six, and 10 months after the distribution. One site in neighbouring Kongo Central province was used as a control (no mass campaign of LLIN distribution during the study). Nationwide intensity assays were conducted in six sites in 2017 using CDC bottle bioassays and in 11 sites in 2018 using WHO intensity assays. A sub-sample of An. gambiae s.l. was tested by PCR to determine species composition and frequency of kdr-1014F and 1014S alleles. RESULTS: In June 2016, before LLIN distribution, permethrin resistance intensity was high in Kinshasa; the mean mortality rate was 43% at the 5× concentration and 73% at the 10× concentration. Bioassays at 3 time points after LLIN distribution showed considerable variation by site and time and there was no consistent evidence for an increase in pyrethroid resistance intensity compared to the neighbouring control site. Tests of An. gambiae s.l. in 6 sites across the country in 2017 and 11 sites in 2018 showed all populations were resistant to the diagnostic doses of 3 pyrethroids. In 2018, the intensity of resistance varied by site, but was generally moderate for all three pyrethroids, with survivors at ×5 the diagnostic dose. Anopheles gambiae sensu stricto (s.s.) was the most common species identified across 11 sites in DRC, but in Kinshasa, An. gambiae s.s. (91%) and Anopheles coluzzii (8%) were sympatric. CONCLUSIONS: Moderate or high intensity pyrethroid resistance was detected nationwide in DRC and is a serious threat to sustained malaria control with pyrethroid LLINs. Next generation nets (PBO nets or bi-treated nets) should be considered for mass distribution.

Ensuring high selectivity for preconcentration and detection of ultra-trace cadmium using a phage-functionalized metal-organic framework.

Metal-organic frameworks functionalized with Cd(ii) binding phages were for the first time fabricated for the isolation and preconcentration of ultra-trace cadmium. Highly specific Cd(ii) binding phages were screened through biological panning from a phage display peptide library. Thereafter, chloroauric acid (HAuCl4) was reduced by the phages to provide phage-stabilized gold nanoparticles (AuNPs). The phage-AuNP networks were then assembled onto the metal-organic framework UiO66-NH2 to serve as an affinity probe for the selective recognition and isolation of ultra-trace cadmium. 2.0 µg L-1 Cd2+ was selectively captured by the derived UiO66-NH2@phage composite with an adsorption efficiency of 100%. UiO66-NH2@phage exhibits favorable anti-interference capability against the coexisting species. It ensures highly selective and sensitive quantification of ultra-trace cadmium with detection by graphite furnace atomic absorption spectrometry (GFAAS). An enrichment factor of 17.4 was obtained along with a limit of detection (LOD) of 3.9 ng L-1 within a linear range of 0.01-0.35 µg L-1. The procedure was further validated by analyzing cadmium content in a certified reference material (CRM, simulated water, GBW08608) and a series of environmental water samples. In general, the present study provides a new protocol for the development of novel adsorbents toward the target by biopanning to regulate the selectivity.

Regulation of Iron Homeostasis and Related Diseases.

The liver is the organ for iron storage and regulation; it senses circulating iron concentrations in the body through the BMP-SMAD pathway and regulates the iron intake from food and erythrocyte recovery into the bloodstream by secreting hepcidin. Under iron deficiency, hypoxia, and hemorrhage, the liver reduces the expression of hepcidin to ensure the erythropoiesis but increases the excretion of hepcidin during infection and inflammation to reduce the usage of iron by pathogens. Excessive iron causes system iron overload; it accumulates in never system and damages neurocyte leading to neurodegenerative diseases such as Parkinson's syndrome. When some gene mutations affect the perception of iron and iron regulation ability in the liver, then they decrease the expression of hepcidin, causing hereditary diseases such as hereditary hemochromatosis. This review summarizes the source and utilization of iron in the body, the liver regulates systemic iron homeostasis by sensing the circulating iron concentration, and the expression of hepcidin regulated by various signaling pathways, thereby understanding the pathogenesis of iron-related diseases.

Blocking lymphocyte trafficking with FTY720 prevents inflammation-sensitized hypoxic-ischemic brain injury in newborns.

Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic-ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood-brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking.

Prophylactic Edaravone Prevents Transient Hypoxic-Ischemic Brain Injury: Implications for Perioperative Neuroprotection.

BACKGROUND AND PURPOSE: Hypoperfusion-induced thrombosis is an important mechanism for postsurgery stroke and cognitive decline, but there are no perioperative neuroprotectants to date. This study investigated whether prophylactic application of Edaravone, a free radical scavenger already used in treating ischemic stroke in Japan, can prevent infarct and cognitive deficits in a murine model of transient cerebral hypoxia-ischemia. METHODS: Adult male C57BL/6 mice were subjected to transient hypoxic-ischemic (tHI) insult that consists of 30-minute occlusion of the unilateral common carotid artery and exposure to 7.5% oxygen. Edaravone or saline was prophylactically applied to compare their effects on cortical oxygen saturation, blood flow, coagulation, oxidative stress, metabolites, and learning-memory using methods that include photoacoustic imaging, laser speckle contrast imaging, solid-state NMR, and Morris water maze. The effects on infarct size by Edaravone application at different time points after tHI were also compared. RESULTS: Prophylactic administration of Edaravone (4.5 mg/kg×2, IP, 1 hour before and 1 hour after tHI) improved vascular reperfusion, oxygen saturation, and the maintenance of brain metabolites, reducing oxidative stress, thrombosis, white-matter injury, and learning impairment after tHI insult. Delayed Edaravone treatment after 3 h post-tHI became unable to reduce infarct size. CONCLUSIONS: Acute application of Edaravone may be a useful strategy to prevent postsurgery stroke and cognitive impairment, especially in patients with severe carotid stenosis.

Gas-phase Smiles rearrangement reactions of deprotonated N-phenylbenzamides studied by electrospray ionization tandem mass spectrometry.

RATIONALE: Electrospray ionization tandem mass spectrometry (ESI-MS(n)) is an invaluable tool for the study of gas-phase reactions. When N-phenylbenzamide is analyzed in negative ion mode, the nucleophilic deprotonated site of nitrogen or oxygen, together with the adjacent electrophilic phenyl carbon in the same molecule, provides a useful opportunity to study the intramolecular nucleophilic reaction in the gas phase. METHODS: All MS(n) experiments of deprotonated N-phenylbenzamides were conducted on an ion trap mass spectrometer using ESI in negative ion mode. The accurate masses of fragments were measured on an ESI quadrupole time-of-flight mass spectrometer in negative ion mode. Theoretical calculations were conducted at the B3LYP/6-31++G(d,p) level of density functional theory using the Gaussian 03 program. RESULTS: When the polarity of the substituent on the aniline ring was changed, gas-phase Smiles rearrangement reactions could be initiated by different atoms in the anionic center. Upon collisional activation, loss of CO from deprotonated N-phenylbenzamides could be observed, which can be interpreted as a nitrogen anion triggering the Smiles rearrangement reaction through a three-membered ring transition state. As the aniline ring was substituted by a strong electron-withdrawing group (e.g., NO(2), COCH(3), or CF(3)) at the para position, a characteristic phenolate anion was obtained, which was derived from the Smiles rearrangement reaction initiated by the oxygen anion through a four-membered ring transition state. CONCLUSIONS: In the fragmentation of deprotonated N-phenylbenzamides, the gas-phase Smiles rearrangement reaction initiated by either the nitrogen or the oxygen atom can proceed. The findings in this study have not only enriched knowledge on the gas-phase Smiles rearrangement reactions, but also provided valuable information for understanding the rearrangements of deprotonated aromatic amides in gas phase.

Protein phosphatase 2A and DNA-dependent protein kinase are involved in mediating rapamycin-induced Akt phosphorylation.

BACKGROUND: The mechanisms underlying rapamycin-induced Akt phosphorylation have not been fully elucidated. RESULTS: Inhibition of PP2A or DNA-PK attenuates or abrogates rapamycin-induced Akt phosphorylation and co-inhibition of mTOR and DNA-PK enhances anticancer activity. CONCLUSION: PP2A-dependent and DNA-PK-mediated mechanism is involved in rapamycin-induced Akt phosphorylation. SIGNIFICANCE: A previously unknown mechanism underlying rapamycin-induced Akt phosphorylation and a novel strategy to enhance mTOR-targeted cancer therapy may be suggested. Inhibition of mammalian target of rapamycin complex 1 (mTORC1), for example with rapamycin, increases Akt phosphorylation while inhibiting mTORC1 signaling. However, the underlying mechanisms have not been fully elucidated. The current study has uncovered a previously unknown mechanism underlying rapamycin-induced Akt phosphorylation involving protein phosphatase 2A (PP2A)-dependent DNA protein kinase (DNA-PK) activation. In several cancer cell lines, inhibition of PP2A with okadaic acid, fostriecin, small T antigen, or PP2A knockdown abrogated rapamycin-induced Akt phosphorylation, and rapamycin increased PP2A activity. Chemical inhibition of DNA-PK, knockdown or deficiency of DNA-PK catalytic subunit (DNA-PKcs), or knock-out of the DNA-PK component Ku86 inhibited rapamycin-induced Akt phosphorylation. Exposure of cancer cells to rapamycin increased DNA-PK activity, and gene silencing-mediated PP2A inhibition attenuated rapamycin-induced DNA-PK activity. Collectively these results suggest that rapamycin induces PP2A-dependent and DNA-PK-mediated Akt phosphorylation. Accordingly, simultaneous inhibition of mTOR and DNA-PK did not stimulate Akt activity and synergistically inhibited the growth of cancer cells both in vitro and in vivo. Thus, our findings also suggest a novel strategy to enhance mTOR-targeted cancer therapy by co-targeting DNA-PK.

Using MRI radiomics to predict the efficacy of immunotherapy for brain metastasis in patients with small cell lung cancer.

BACKGROUND: Brain metastases (BMs) are common in small cell lung cancer (SCLC), and the efficacy of immune checkpoint inhibitors (ICIs) in these patients is uncertain. In this study we aimed to develop and validate a radiomics nomogram based on magnetic resonance imaging (MRI) for intracranial efficacy prediction of ICIs in patients with BMs from SCLC. METHODS: The training and validation cohorts consisted of 101 patients from two centers. The interclass correlation coefficient (ICC), logistic univariate regression analysis, and random forest were applied to select the radiomic features, generating the radiomics score (Rad-score) through the formula. Using multivariable logistic regression analysis, a nomogram was created by the combined model. The discrimination, calibration, and clinical utility were used to assess the performance of the nomogram. Kaplan-Meier curves were plotted based on the nomogram scores. RESULTS: Ten radiomic features were selected for calculating the Rad-score as they could differentiate the intracranial efficacy in the training (area under the curve [AUC], 0.759) and the validation cohort (AUC, 0.667). A nomogram was created by combining Rad-score, treatment lines, and neutrophil-to-lymphocyte ratio (NLR). The training cohort obtained an AUC of 0.878 for the combined model, verified in the validation cohort (AUC = 0.875). Kaplan-Meier analyses showed the nomogram was associated with progression-free survival (PFS) (p = 0.0152) and intracranial progression-free survival (iPFS) (p = 0.0052) but not overall survival (OS) (p = 0.4894). CONCLUSION: A radiomics nomogram model for predicting the intracranial efficacy of ICIs in SCLC patients with BMs can provide suggestions for exploring individual-based treatments for patients.

Progress of Research into Preformed Particle Gels for Profile Control and Water Shutoff Techniques.

Gel treatment is an economical and efficient method of controlling excessive water production. The gelation of in situ gels is prone to being affected by the dilution of formation water, chromatographic during the transportation process, and thus controlling the gelation time and penetration depth is a challenging task. Therefore, a novel gel system termed preformed particle gels (PPGs) has been developed to overcome the drawbacks of in situ gels. PPGs are superabsorbent polymer gels which can swell but not dissolve in brines. Typically, PPGs are a granular gels formed based on the crosslinking of polyacrylamide, characterized by controllable particle size and strength. This work summarizes the application scenarios of PPGs and elucidates their plugging mechanisms. Additionally, several newly developed PPG systems such as high-temperature-resistant PPGs, re-crosslinkable PPGs, and delayed-swelling PPGs are also covered. This research indicates that PPGs can selectively block the formation of fractures or high-permeability channels. The performance of the novel modified PPGs was superior to in situ gels in harsh environments. Lastly, we outlined recommended improvements for the novel PPGs and suggested future research directions.

Noninvasive radiomic biomarkers for predicting pseudoprogression and hyperprogression in patients with non-small cell lung cancer treated with immune checkpoint inhibition.

This study aimed to develop a computed tomography (CT)-based radiomics model capable of precisely predicting hyperprogression and pseudoprogression (PP) in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. We retrospectively analyzed 105 patients with NSCLC, from three institutions, treated with immune checkpoint inhibitors (ICIs) and categorized them into training and independent testing set. Subsequently, we processed CT scans with a series of image-preprocessing techniques, and 6008 radiomic features capturing intra- and peritumoral texture patterns were extracted. We used the least absolute shrinkage and selection operator logistic regression model to select radiomic features and construct machine learning models. To further differentiate between progressive disease (PD) and hyperprogressive disease (HPD), we developed a new radiomics model. The logistic regression (LR) model showed optimal performance in distinguishing PP from HPD, with areas under the receiver operating characteristic curve (AUC) of 0.95 (95% confidence interval [CI]: 0.91-0.99) and 0.88 (95% CI: 0.66-1) in the training and testing sets, respectively. Additionally, the support vector machine model showed optimal performance in distinguishing PD from HPD, with AUC of 0.97 (95% CI: 0.93-1) and 0.87 (95% CI: 0.72-1) in the training and testing sets, respectively. Kaplan‒Meier survival curves showed clear stratification between PP predicted by the radiomics model and true progression (HPD and PD) (hazard ratio = 0.337, 95% CI: 0.200-0.568, p < 0.01) in overall survival. Our study demonstrates that radiomic features extracted from baseline CT scans are effective in predicting PP and HPD in patients with NSCLC treated with ICIs.

Development and validation of an MRI-Based nomogram to predict the effectiveness of immunotherapy for brain metastasis in patients with non-small cell lung cancer.

Introduction: The variability and unpredictability of immune checkpoint inhibitors (ICIs) in treating brain metastases (BMs) in patients with advanced non-small cell lung cancer (NSCLC) is the main concern. We assessed the utility of novel imaging biomarkers (radiomics) for discerning patients with NSCLC and BMs who would derive advantages from ICIs treatment. Methods: Data clinical outcomes and pretreatment magnetic resonance images (MRI) were collected on patients with NSCLC with BMs treated with ICIs between June 2019 and June 2022 and divided into training and test sets. Metastatic brain lesions were contoured using ITK-SNAP software, and 3748 radiomic features capturing both intra- and peritumoral texture patterns were extracted. A clinical radiomic nomogram (CRN) was built to evaluate intracranial progression-free survival, progression-free survival, and overall survival. The prognostic value of the CRN was assessed by Kaplan-Meier survival analysis and log-rank tests. Results: In the study, a total of 174 patients were included, and 122 and 52 were allocated to the training and validation sets correspondingly. The intratumoral radiomic signature, peritumoral radiomic signature, clinical signature, and CRN predicted intracranial objective response rate. Kaplan-Meier analyses showed a significantly longer intracranial progression-free survival in the low-CRN group than in the high-CRN group (p < 0.001). The CRN was also significantly associated with progression-free survival (p < 0.001) but not overall survival. Discussion: Radiomics biomarkers from pretreatment MRI images were predictive of intracranial response. Pretreatment radiomics may allow the early prediction of benefits.

Metabolic reprogramming and interventions in angiogenesis.

BACKGROUND: Endothelial cell (EC) metabolism plays a crucial role in the process of angiogenesis. Intrinsic metabolic events such as glycolysis, fatty acid oxidation, and glutamine metabolism, support secure vascular migration and proliferation, energy and biomass production, as well as redox homeostasis maintenance during vessel formation. Nevertheless, perturbation of EC metabolism instigates vascular dysregulation-associated diseases, especially cancer. AIM OF REVIEW: In this review, we aim to discuss the metabolic regulation of angiogenesis by EC metabolites and metabolic enzymes, as well as prospect the possible therapeutic opportunities and strategies targeting EC metabolism. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this work, we discuss various aspects of EC metabolism considering normal and diseased vasculature. Of relevance, we highlight that the implications of EC metabolism-targeted intervention (chiefly by metabolic enzymes or metabolites) could be harnessed in orchestrating a spectrum of pathological angiogenesis-associated diseases.

Intra-Abdominal Hypertension Contributes to the Development of Ventilator-Associated Pneumonia from Intestinal Bacteria.

Introduction: Ventilator-associated pneumonia (VAP) is an ICU (intensive care unit)-acquired pulmonary parenchymal infection that is complicated by mechanical ventilation and is associated with high morbidity and mortality. Klebsiella pneumoniae (KPN) is known to asymptomatically colonize the gastrointestinal tract and may increase the incidence of corresponding VAP. Our study aims were to investigate the exact origin of the carbapenem-resistant Klebsiella pneumoniae (CRKP) causing VAP in our patient. Methods: Various environmental samples, including the patient's anal swab, were collected in order to find the source of the bacteria. Minimum inhibitory concentrations (MICs) for antimicrobial agents were determined according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI); resistant genes were detected by using PCR and sequencing; clone relationships were analyzed by using multilocus-sequence typing (MLST) and pulsed field gel electrophoresis (PFGE). The IAP values were obtained via urinary catheter. Results: One CRKP strain was detected in the patient's anal swab; this strain was confirmed with the same gene type as the strain isolated from the sputum. We found that the patient's intra-abdominal pressure (IAP) was 29.41, 27.06, 24.12, and 22.66 mmHg; the IAP was either equal to or above 12 mmHg, on the operation day and the following three days. Intra-abdominal hypertension (IAH) occurred during the patient's hospitalization and was considered to be caused by the surgical procedure. Meanwhile, we found that there was a correlation between IAH and the detection of CRKP in the sputum. The findings suggested that his VAP was caused by intestinal colonial KPN, and not from the environment. Discussion: Our research illustrated that the ST11 KPC-2-producing strain colonized the intestinal tract and caused the development of VAP when the IAP was elevated. Routine screening for the intestinal carriage of CRKP, among patients in ICUs, can limit and prevent current and future outbreaks.

Single­nucleotide polymorphism rs6592645 confers asthma risk through regulating LRRC32 expression.

Asthma is a complex disease, often with evident genetic predisposition; for example, the single-nucleotide polymorphism (SNP) rs7130588 was significantly associated with asthma by genome-wide association study (GWAS). Analysis of 1000 Genomes Project data suggests that there is another SNP, rs6592645, in complete linkage disequilibrium with rs7130588 and should present the same signal in GWAS. However, the causal SNP and the mechanism for the association between rs7130588 and asthma remain to be elucidated. In the presents study, results from dual-luciferase assays indicated that the A/G alleles of rs7130588 failed to present significantly different reporter gene expression. By contrast, A allele of rs6592645 presented a significant increase in relative luciferase activity than G allele, thus suggesting that rs6592645 may be a causal SNP. Using chromosome conformation capture, the enhancer region containing rs6592645 was observed to interact with promoter region of leucine-rich repeat-containing 32 (LRRC32). Gene expression quantification suggested that LRRC32 expression is significantly increased in lung tissue of patients with asthma and is dependent on the genotype of this locus, thus verifying that LRRC32 may be involved in asthma onset and that rs6592645 can regulate LRRC32 expression. Through chromatin immunoprecipitation, transcription factor 3 (TCF3) was identified to bind to rs6592645 surrounding region and the interaction between TCF3 and rs6592645 surrounding region was investigated. Results from the present study may improve our understanding of the mechanism by which the genetic variation in this locus might influence asthma susceptibility.