Computed Tomography-Based Intratumor Heterogeneity Predicts Response to Immunotherapy Plus Chemotherapy in Esophageal Squamous Cell Carcinoma.

RATIONALE AND OBJECTIVES: This study explored the intratumor heterogeneity (ITH) of esophageal squamous cell carcinoma (ESCC) using computed tomography (CT) and investigated the value of CT-based ITH in predicting the response to immune checkpoint inhibitor (ICI) plus chemotherapy in patients with ESCC. MATERIALS AND METHODS: This retrospective study included 416 patients with ESCC who received ICI plus chemotherapy at two independent hospitals between January 2019 and July 2022. Multiparametric CT features were extracted from ESCC lesions and screened using hierarchical clustering and dimensionality reduction algorithms. Logistic regression and machine learning models based on selected features were developed to predict treatment response and validated in separate datasets. ITH was quantified using the score calculated by the best-performing model and visualized through feature clustering and feature contribution heatmaps. A gene set enrichment analysis (GSEA) was performed to identify the biological pathways underlying the CT-based ITH. RESULTS: The extreme gradient boosting model based on CT-derived ITH had higher discriminative power, with areas under the receiver operating characteristic curve of 0.864 (95% confidence interval [CI]: 0.774-0.954) and 0.796 (95% CI: 0.698-0.893) in the internal and external validation sets. The CT-based ITH pattern differed significantly between responding and non-responding patients. The GSEA indicated that CT-based ITH was associated with immunity-, keratinization-, and epidermal cell differentiation-related pathways. CONCLUSION: CT-based ITH is an effective biomarker for identifying patients with ESCC who could benefit from ICI plus chemotherapy. Immunity-, keratinization-, and epidermal cell differentiation-related pathways may influence the patient's response to ICI plus chemotherapy.

Prognostic impact of deep learning-based quantification in clinical stage 0-I lung adenocarcinoma.

OBJECTIVES: To evaluate the performance of automatic deep learning (DL) algorithm for size, mass, and volume measurements in predicting prognosis of lung adenocarcinoma (LUAD) and compared with manual measurements. METHODS: A total of 542 patients with clinical stage 0-I peripheral LUAD and with preoperative CT data of 1-mm slice thickness were included. Maximal solid size on axial image (MSSA) was evaluated by two chest radiologists. MSSA, volume of solid component (SV), and mass of solid component (SM) were evaluated by DL. Consolidation-to-tumor ratios (CTRs) were calculated. For ground glass nodules (GGNs), solid parts were extracted with different density level thresholds. The prognosis prediction efficacy of DL was compared with that of manual measurements. Multivariate Cox proportional hazards model was used to find independent risk factors. RESULTS: The prognosis prediction efficacy of T-staging (TS) measured by radiologists was inferior to that of DL. For GGNs, MSSA-based CTR measured by radiologists (RMSSA%) could not stratify RFS and OS risk, whereas measured by DL using 0HU (2D-AIMSSA0HU%) could by using different cutoffs. SM and SV measured by DL using 0 HU (AISM0HU% and AISV0HU%) could effectively stratify the survival risk regardless of different cutoffs and were superior to 2D-AIMSSA0HU%. AISM0HU% and AISV0HU% were independent risk factors. CONCLUSION: DL algorithm can replace human for more accurate T-staging of LUAD. For GGNs, 2D-AIMSSA0HU% could predict prognosis rather than RMSSA%. The prediction efficacy of AISM0HU% and AISV0HU% was more accurate than of 2D-AIMSSA0HU% and both were independent risk factors. CLINICAL RELEVANCE STATEMENT: Deep learning algorithm could replace human for size measurements and could better stratify prognosis than manual measurements in patients with lung adenocarcinoma. KEY POINTS: • Deep learning (DL) algorithm could replace human for size measurements and could better stratify prognosis than manual measurements in patients with lung adenocarcinoma (LUAD). • For GGNs, maximal solid size on axial image (MSSA)-based consolidation-to-tumor ratio (CTR) measured by DL using 0 HU could stratify survival risk than that measured by radiologists. • The prediction efficacy of mass- and volume-based CTRs measured by DL using 0 HU was more accurate than of MSSA-based CTR and both were independent risk factors.

Exploiting Broad-Spectrum Chimeric Lysin to Cooperate with Mupirocin against Staphylococcus aureus-Induced Skin Infections and Delay the Development of Mupirocin Resistance.

Staphylococcus aureus often leads to severe skin infections. However, S. aureus is facing a crisis of antibiotic resistance. The combination of phage and antibiotics is effective for drug-resistant S. aureus infections. Therefore, it is worth exploiting novel antibacterial agents to cooperate with antibiotics against S. aureus infections. Herein, a novel chimeric lysin ClyQ was constructed, which was composed of a cysteine- and histidine-dependent amidohydrolase/peptidase (CHAP) catalytic domain from S. aureus phage lysin LysGH15 and cell wall-binding domain (CBD) from Enterococcus faecalis phage lysin PlyV12. ClyQ had an exceptionally broad host range targeting streptococci, staphylococci, E. faecalis, and E. rhusiopathiae. ClyQ combined with mupirocin (2.64 log reduction) was more effective at treating S. aureus skin infections than ClyQ (0.46 log reduction) and mupirocin (2.23 log reduction) alone. Of equal importance, none of S. aureus ATCC 29213 or S3 exposed to ClyQ developed resistance, and the combination of ClyQ and mupirocin delayed the development of mupirocin resistance. Collectively, chimeric lysin ClyQ enriches the reservoirs for treating S. aureus infections. Our findings may provide a way to alleviate the current antibiotic resistance crisis. IMPORTANCE Staphylococcus aureus, as an Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) pathogen, can escape the elimination of existing antibiotics. At present, phages and phage lysins against S. aureus infections are considered alternative antibacterial agents. However, the development of broad-spectrum chimeric phage lysins to cooperate with antibiotics against S. aureus infections remains at its initial stage. In this study, we found that the broad-host-range chimeric lysin ClyQ can synergize with mupirocin to treat S. aureus skin infections. Furthermore, the development of S. aureus resistance to mupirocin is delayed by the combination of ClyQ and mupirocin in vitro. Our results bring research attention toward the development of chimeric lysin that cooperates with antibiotics to overcome bacterial infections.

Streptococcus suis prophage lysin as a new strategy for combating streptococci-induced mastitis and Streptococcus suis infection.

OBJECTIVES: The genus Streptococcus contains species of important zoonotic pathogens such as those that cause bovine mastitis. Unfortunately, many Streptococcus species have developed antibiotic resistance. Phage lysins are considered promising alternatives to antibiotics because it is difficult for bacteria to develop lysin resistance. However, there remains a lack of phage lysin resources for the treatment of streptococci-induced mastitis. METHODS: We identified the prophage lysin Lys0859 from the genome of the Streptococcus suis SS0859 strain. Lys0859 was subsequently characterized to determine its host range, MIC, bactericidal activity in milk, and ability to clear biofilms in vitro. Finally, to determine the effects of Lys0859 on the treatment of both bovine mastitis and S. suis infection in vivo, we established models of Streptococcus agalactiae ATCC 13813-induced mastitis and S. suis serotype 2 SC19 systemic infection. RESULTS: Our results demonstrate that Lys0859 possesses broad-spectrum lytic activity against Streptococcus and Staphylococcus species isolated from animals with bovine mastitis and 15 serotypes of S. suis isolated from swine. Intramammary and intramuscular injection of Lys0859 reduced the number of bacteria in mammary tissue by 3.75 and 1.45 logs compared with the PBS group, respectively. Furthermore, 100 µg/mouse of Lys0859 administered intraperitoneally at 1 h post-infection protected 83.3% (5/6) of mice from a lethal dose of S. suis infection. CONCLUSIONS: Overall, our results enhance the understanding and development of new strategies to combat both streptococci-induced mastitis and S. suis infection.

Surface-Roughness-Induced Plasticity in a Biodegradable Zn Alloy.

Improving plasticity has been an eternal theme of developing metallic materials. It is difficult to increase room-temperature elongation of metallic materials over 100% without sacrificing strength using existing methods. Herein, surface-roughness-induced plasticity (SRIP) is discovered in biodegradable Zn-0.4Mn alloy. Surprisingly, in the good surface range that meets the international standard ISO 6892, reducing surface roughness results in significant increase in plasticity without loss of strength. From unground to 5000# sandpaper ground states, the surface roughness Ra of the alloy decreases from 0.63 to 0.05 µm, while its room temperature elongation increases from 74% to 143%. SRIP is the synergistic result of increased microstructure damage tolerance and decreased surface roughness. It provides a new method for improving plasticity.

Clinical Features of Aortic Dissection in the Emergency Department: A Single-center Experience from South China.

OBJECTIVES: Our goal in this study was to determine 1) whether there are any differences in clinical characteristics between Chinese and Western patients with aortic dissection (AD), and 2) the mortality rate of AD patients in the emergency department (ED) and identify the risk predictors for death. METHODS: We retrospectively analyzed patients who were diagnosed with AD and admitted to our ED between September 1, 2017-August 31, 2020. Data on age, gender, clinical manifestation, medical history, routine blood tests, liver and kidney function, coagulation, myocardial enzymology, and mortality were collected. RESULTS: We enrolled 535 AD patients (422 men and 113 women) with a mean age of 54.7±14.1 years. Type A AD constituted 40% of the total number of AD cases, while type B AD constituted 60%. The proportion of those who were females, 10-92 years, with type A AD, and hypertension in the Chinese population was lower than that in the Western population (P <0.05 for all). Type A AD patients had a higher proportion of acute AD clinical manifestations than did patients with type B AD (P = 0.0084, P <0.05). The mortality rate of type A AD patients (10.75%) was higher than that of type B AD patients (1.87%) (P <0.0001) in the ED. Higher values of white blood cells, neutrophils, high-density lipoprotein, activated partial thromboplastin time, and D-dimer level with worsened hepatic and renal function were found in the deceased group, and multivariate logistic regression revealed that blood urea nitrogen (BUN) levels (P = 0.0031, P <0.05) were significantly associated with death. CONCLUSION: In South China, patients with AD had a mean age of 54.7 years, with 78.88% prevalence in males and 66.92% hypertension rate. Type A AD accounted for 40% of all AD cases, and 10.70% of patients with type A AD died in the ED. Elevated BUN levels may be a risk predictor for death in patients with type A AD.

Caffeine alleviates acute liver injury by inducing the expression of NEDD4L and deceasing GRP78 level via ubiquitination.

BACKGROUND: Acute liver injury is liver cell injury that occurs rapidly in a short period of time. Caffeine has been shown to maintain hepatoprotective effect with an unclear mechanism. Endoplasmic reticulum stress (ERS) has significant effects in acute liver injury. Induction of GRP78 is a hallmark of ERS. Whether or not caffeine's function is related to GRP78 remains to be explored. METHODS: Acute liver injury model was established by LPS-treated L02 cells and in vivo administration of LPS/D-Gal in mice. Caffeine was pre-treated in L02 cells or mice. Gene levels was determined by real-time PCR and western blot. Cell viability was tested by CCK-8 assay and cell apoptosis was tested by flow cytometry. The interaction of GRP78 and NEDD4L was determined by Pull-down and co-immunoprecipitation (Co-IP) assay. The ubiquitination by NEDD4L on GRP78 was validated by in vitro ubiquitination assay. RESULTS: Caffeine protected liver cells against acute injury induced cell apoptosis and ERS both in vitro and in vivo. Suppression of GRP78 could block the LPS-induced cell apoptosis and ERS. NEDD4L was found to interact with GRP78 and ubiquitinate its lysine of 324 site directly. Caffeine treatment induced the expression of NEDD4L, resulting in the ubiquitination and inhibition of GRP78. CONCLUSION: Caffeine mitigated the acute liver injury by stimulating NEDD4L expression, which inhibited GRP78 expression via ubiquitination at its K324 site. Low dose of caffeine could be a promising therapeutic treatment for acute liver injury.

Genetic diversity and main functional composition of Lingzhi strains from main producing areas in China.

In this study, we used genotyping by sequencing (GBS) to examine the genetic diversity of 22 strains of Lingzhi and the quality differences in 15 fruit bodies of Lingzhi from different Chinese regions. The phylogenetic trees of 22 strains were constructed based on ITS (Internal transcribed spacer) and SNP (single nucleotide polymorphism). Moisture, ash, water-soluble extracts, alcohol-soluble extracts, polysaccharides, and triterpenoids from 15 fruit bodies of Lingzhi were detected and analyzed based on Chinese Pharmacopoeia and the US Pharmacopoeia references. Moreover, the monosaccharide composition of polysaccharides was studied using PMP-HPLC, and the effect of polysaccharides on the proliferation rate of splenocytes was investigated in vitro. The identification results of these strains by the phylogenetic trees which were constructed based on ITS sequences and SNPs showed that most of the strains applied in the main producing areas of Lingzhi in China were accurate except for a few inaccurate strains. The moisture, ash, water and alcohol soluble extractive, polysaccharide and triterpenoid content of all samples were meet the requirements of the Chinese Pharmacopoeia, while the polysaccharide and triterpenoid content of less than half of the samples meet the requirements of the U.S. Pharmacopoeia. The polysaccharide extracted from these samples have different effects on the proliferation rate of spleen cells. To sum up, this is the first study that reported on the differences in Lingzhi strains from the main producing areas in China. The quality of some fruit bodies did not meet the pharmacopeia requirements, and wrong strains were used in some production areas; thus, strains should be given special attention before legal processing.

Inhibitory effect of triterpenoids from the mushroom Inonotus obliquus against α-glucosidase and their interaction: Inhibition kinetics and molecular stimulations.

Bioassay-guided fractionation led to the isolation of a series of triterpenoids (1-46) including 12 new ones (1-12) from the mushroom Inonotus obliquus. The structures of all the compounds were elucidated by spectroscopic analysis as well as by comparison with literature data. Triterpenoids 1-3, 6, 7, 16, 24, 25, 27, 38, 43, 44 and 46 showed strong α-glucosidase inhibition, with IC50 values from 11.5 to 81.8 µM. Their structure-activity relationships were discussed. Inonotusol F (24) showed the strongest inhibitory activity and it presented noncompetitive inhibition against α-glucosidase. Molecular docking and molecular dynamics stimulation further demonstrated that GLU302 and PHE298 were key amino acids for the inhibition of inonotusol F (24) towards α-glucosidase. This study indicates the vital role of triterpenoids in explaining hypoglycemic effect of Inonotus obliquus and provides important evidence for further development and utilization of this mushroom.

Clinical Characteristics of Adult Hemophagocytic Lymphohistiocytosis in the Emergency Department.

PURPOSE: To determine the clinical manifestations and results of adult hemophagocytic lymphohistiocytosis (HLH) patients in our emergency department. METHODS: We retrospectively evaluated patients with HLH from 1 April 2018 to 31 December 2020. The clinical data of these patients (basic information, symptoms, vital signs, laboratory results, HLH diagnostic criteria, H Score, main treatments, outcomes) were collected. RESULTS: Thirty-three patients (23 males and 10 females; 40.55±18.78 years) with 34 clinical episodes (one male had two clinical episodes and died during the second episode) were enrolled. Twenty-five patients were placed in a "survivor" group, and nine patients were categorized into a "deceased" group. Fever, splenomegaly, hemoglobin <90 g/L and platelet count <100×109/L most commonly met the diagnostic standard for HLH. The H Score results in the survival group and deceased group was 212.4±37.18 and 252.1±40.95, respectively. Viral infection was the most common reason for HLH, followed by immune-system disease and cancer. Laboratory tests showed that deceased-group patients had multiple-organ dysfunction. Multivariate logistic regression showed that the lactate dehydrogenase (lactate dehydrogenase) level (P = 0.039; odds ratio, 0.999) was significantly related to death. CONCLUSION: In the emergency department, HLH should be considered for critically ill patients with fever, splenomegaly, low hemoglobin and low platelet count. The H Score might be useful to diagnose HLH quickly. In our study, 26.47% of HLH patients died in the emergency department, and patients with a significantly increased lactate dehydrogenase level had a markedly increased risk of death.

Therapeutical plasma exchange for thrombotic thrombocytopenic purpura in the emergency department: A single center experience.

INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening and easily misdiagnosed thrombotic microangiopathy disease. Few studies have reported the use of therapeutic plasma exchange (TPE) for TTP in emergency departments in China. The present study was a retrospective analysis of patients with TTP who were treated with TPE in our emergency intensive care unit (EICU). METHODS: This study retrospectively analyzed patients with TTP who received TPE management from July 1, 2014 to February 1, 2020. The following clinical data of these patients were collected: laboratory results, first symptoms, ADAMTS13 levels, glucocorticoid levels, TPE times and outcomes. RESULTS: The study included 19 patients (9 male and 10 female) with 20 clinical episodes, and 1 female patient had two episodes. TPE was used in 17 patients, and TPE was performed once every 2-3 days in patients. The volume for each TPE treatment was 2000 ml. In total, 4 male patients died, and 15 patients survived. One female experienced a relapse. No significant differences in age, RBC, HGB, PLT, ALT, AST, BUN, Cr, LDH, or bilirubin were noted between the survival and death groups. The mortality rate of male patients was significantly higher than that of female patients(p = 0.0325, p < 0.05), and the mean age of deceased patients was 64.25 ± 4.78 years, which was older than the mean age of survivors (47.38 ± 4.30). However, no significant difference was noted (p = 0.0787). CONCLUSION: TPE had satisfactory results for TTP patients although it was not performed every day. Older male TTP patients exhibited a relatively increased risk of death.

WITHDRAWN: Clinical and CT imaging features of 2019 novel coronavirus disease (COVID-19).

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Effect of ulinastatin combined with mild therapeutic hypothermia on intestinal barrier dysfunction following cardiopulmonary resuscitation in rats.

The aim of the present study was to investigate the effect of ulinastatin (UTI) alone or combined with mild therapeutic hypothermia (MTH) on intestinal barrier dysfunction following cardiopulmonary resuscitation (CPR) in rats. A total of 25 adult male Sprague-Dawley rats were randomly organized into five groups: Sham; control; UTI; MTH; and the combined group. The latter four groups were induced with the asphyxiated cardiac arrest rat model and treated with different interventions. After 6 h of treatment, the intestinal tissues of the rats were examined by electron microscopy, and the levels of intestinal malondialdehyde (MDA) and superoxide dismutase (SOD) were determined. The results of the present study indicated that the target temperature had successfully been attained in MTH and the combined group, and the other three groups of rats all survived at a normal temperature. In the rats treated with UTI or MTH, the epithelial cells exhibited pathological changes in their tight junctions and epithelial cell surface microvilli compared with the sham group. In the rats treated with a combination of UTI and MTH, whilst the epithelial cells exhibited a few slight changes, including mitochondrial edema, they were largely similar to the normal epithelial cells. However, there were significant differences in the levels of MDA and SOD between the different treatment groups. UTI combined with MTH may serve a protective role by suppressing oxidative stress in the small intestinal mucosa following CPR in rats compared with either UTI or MTH treatment alone.

Ultrabright fluorescent microsphere and its novel application for improving the sensitivity of immunochromatographic assay.

Fluorescent microsphere (FM) is widely used as probe in immunochromatographic assay (ICA). However, the performance of conventional FM is limited because of the aggregation-caused quenching effect. Herein, we compared a kind of conventional FM (DMFFM, loading DMF) with novel aggregation-induced emission FM (AIEFM, loading TCBPE). The fluorescence intensity of DMFFM initially increased and then decreased as the concentrations of the loading DMF increased. The fluorescence intensity of AIEFM increased as the concentrations of the loading TCBPE increased and retained a high value. AIEFM was compared with two commercial FMs purchased from Ocean (OFM) and Merk (MFM). The maximum fluorescence intensity and relative quantum yield of AIEFM was approximately 5 and 4.5 times higher than those of two commercial FMs. We used the novel AIEFM as a probe to improve the sensitivity of ICA. When Escherichia coli O157:H7 was detected as the target, the limit of detection of ICA based on AIEFM, OFM and MFM were 3.98 × 103 CFU/mL, 4.48 × 104 and 2.78 × 104 CFU/mL, respectively. The ICA of AIEFM had 11 and 7 times improvement in sensitivity compared with that of OFM and MFM. Our results could be used as a basis for novel probes in practical ICA applications.

SCN1B and SCN2B gene variants analysis in dravet syndrome patients: Analysis of 22 cases.

Previous research identified SCN1B variants in some cases of Dravet syndrome (DS). We investigated whether SCN1B and SCN2B variants are commonly happened in DS patients without SCN1A variants. A total of 22 DS patients without SCN1A variants and 100 healthy controls were enrolled in this genetic study. DNA from DS patients was sequenced by Sanger method in whole exons of SCN1B and SCN2B genes. We identified two exon variants (c.351C>T, p.G117G and c.467C>T, p.T156M), which were present both in 1000 egenomes database and in healthy controls with a frequency of 0.54% and 4%, 0.06% and 0%, respectively. Additionally, eight intron or 3 prime UTR variants showing benign clinical significance have also been identified. Our results suggest that variants of SCN1B and SCN2B may not be common causes of DS according to our data. Further large sample-size cohort studies are needed to confirm our conclusion.

Intestinal pseudo-obstruction as the initial manifestation of systemic lupus erythematosus.

Small bowel obstruction is common in emergency departments. However, the exact cause of intestinal pseudo-obstruction (IPO) is often misdiagnosed. IPO is considered a severe manifestation of systemic lupus erythematosus (SLE). However, IPO is rare as the initial manifestation of SLE. This paper reports a female patient who presented with IPO as the initial manifestation and was ultimately diagnosed with SLE. The 31-year-old female was definitively diagnosed with SLE after IPO symptoms for 1 month. She then presented multiple organ dysfunction syndrome (MODS) leading to a poor prognosis. Patients with unexplained SBO symptoms should be aware of systemic diseases. Early diagnosis and prompt medical treatment are crucial to avoid unnecessary surgery and obtain satisfactory outcomes.

Hydrogen-rich saline protects rat from oxygen glucose deprivation and reperusion-induced apoptosis through VDAC1 via Bcl-2.

BACKGROUND: Hydrogen is received as an inert gas that thought to be non-functional in vivo previously. Recently, emerging evidences showed that in ischemia/reperfusion (IR) condition, hydrogen reduced cellular reactive oxygen species (ROS) production and ameliorated cell apoptosis. However, the underlying mechanism of hydrogen on IR-induced apoptosis remains elusive. Here we tried to unravel the mode of action of hydrogen with rat adrenal medulla cell line PC-12 in vitro. METHODS: The mitochondrial functions before and after oxygen glucose deprivation and reperfusion (OGD/RP) were determined with corresponding dyes. The expression of Bcl-2, Bax, VDAC1, cytochrome c and caspase 9 was detected using qRT-PCR and Western Blotting method. Then Bcl-2 inhibitor, AB-199, was applied to investigate the role of Bcl-2 in OGD/RP-induced cell apoptosis. Finally, we manipulated the expression of VDAC1 with plasmids transfection to understand the effects of VDAC1 on Bcl-2-mediated anti-apoptosis in OGD/RP. RESULTS: In this study, we demonstrated that hydrogen-rich saline (HRS) reduced OGD/RP-mediated neuronal loss by stimulating the expression of Bcl-2, which suppressed the activity of VDAC1. Consequently, HRS maintained the mitochondrial functions, restrained the release of cytochrome c and caspase 9 activation, resulting in ameliorated cell viability. CONCLUSIONS: HRS ameliorated OGD/RP-induced PC-12 cell apoptosis and provided a novel treatment option for ischemia.