Identification of genetic and immune signatures for the recurrence of HER2-positive breast cancer after trastuzumab-based treatment.

PURPOSE: To determine the genetic and immune features associated with the recurrence of human epidermal growth factor receptor2-positive (HER2 +) breast cancer (BC) after trastuzumab-based treatment. METHODS: A retrospective cohort study of 48 patients who received trastuzumab-based treatment was divided into recurrent and non-recurrent groups according to clinical follow-up. Baseline samples from all 48 patients were analyzed for genetic variation, HLA allele type, gene expression, and immune features, which were linked to HER2 + BC recurrence. Statistics included logistic regression models, Kaplan-Meier plots, and Univariate Cox proportional hazards models. RESULTS: Compared with the non-recurrent group, the extracellular matrix-related pathway and 3 Hallmark gene sets were enriched in the recurrent group. The infiltration levels of immature B cells and activated B cells were significantly increased in the non-recurrent group, which correlated remarkably with improved overall survival (OS) in two other published gene expression datasets, including TCGA and METABRIC. In the TCGA cohort (n = 275), activated B cells (HR 0.23, 95%CI 0.13-0.43, p < 0.0001), and immature B cells (HR 0.26, 95%CI 0.12-0.59, p < 0.0001). In the METABRIC cohort (n = 236), activated B cells (HR 0.60, 95%CI 0.43-0.83, p = 0.002), and immature B cells (HR 0.65, 95%CI 0.47-0.91, p = 0.011). Cox regression suggested that immature B cells and activated B cells were protective factors for outcome OS. CONCLUSIONS: Aberrant activation of multiple pathways and low baseline tumor-infiltrating B cells are related to HER2 + BC trastuzumab-based recurrence, which primarily affects the antitumor activity of trastuzumab.

PTCH1 mutation promotes antitumor immunity and the response to immune checkpoint inhibitors in colorectal cancer patients.

Immunotherapy has emerged as an effective therapeutic strategy for various cancers, including colorectal cancer (CRC), but only a subset of MSI-H patients can benefit from such therapy. Patched1 (PTCH1) is a frequently altered gene in CRCs and its mutations contribute to unregulated Hedgehog (Hh) signaling. In the study, we evaluated the association of PTCH1 mutations with CRC immunity based on our single-center cohort and multiple cancer genomic datasets. Among 21 enrolled patients, six (28.6%) harbored a PTCH1 mutation based on WES analyses. In CRC patients, the PTCH1 mutation subgroup experienced a higher durable clinical benefit rate than the PTCH1 wild-type subgroup (100% vs. 40%, P = 0.017). In addition, patients with the PTCH1 mutation experienced greater progression-free survival (PFS, P = 0.037; HR, 0.208) and overall survival (OS, P = 0.045; HR, 0.185). A validation cohort from the MSKCC also confirmed the correlation between PTCH1 mutation and better prognosis (P = 0.022; HR, 0.290). Mechanically, diverse antitumor immune signatures were more highly enriched in PTCH1-mutated tumors than in PTCH1 wild-type tumors. Furthermore, PTCH1-mutated tumors had higher proportions of CD8 + T cells, activated NK cells, and M1 type macrophage infiltration, as well as elevated gene signatures of several steps in the cancer-immunity cycle. Notably, the PTCH1 mutation was correlated with tumor mutational burden (TMB), loss of heterozygosity score, and copy number variation burden. Our results show that the mutation of PTCH1 is a potential biomarker for predicting the response of CRC patients to immunotherapy.

Effects of melatonin to arecoline-induced reactive oxygen species production and DNA damage in oral squamous cell carcinoma.

BACKGROUND/PURPOSE: Arecoline, the major alkaloid of areca nut, is known to induce reactive oxygen species (ROS) and DNA damage during oral cancer progression. This study aim to evaluate whether melatonin, an antioxidant, supported or repressed the arecoline-induced carcinogenesis phenotypes in oral squamous cell carcinoma (OSCC). METHODS: The cytotoxicity of arecoline or melatonin treatment alone and their co-treatment in the OSCC cell line OEC-M1 were analyzed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell cycle, cell death, and total ROS production were analyzed using flow cytometer. The protein expression was determined using western blot analysis. The genotoxicity and mutation rate were determined using micronucleus assay and hypoxanthine phosphoribosyl transferase (HPRT) forward mutation assay, respectively, in CHO-K1 cells. The ataxia telangiectasia mutated (ATM) promoter activity and DNA repair ability were determined through reporter assay. RESULTS: The result showed that both the arecoline and melatonin induced ROS production and antioxidant enzymes expression. Melatonin treatment enhanced arecoline-induced ROS production, cytotoxicity, G2/M phase arrest, and cell apoptosis in OSCC cells. On the other hand, melatonin treatment activated DNA repair activity to reverse arecoline-induced DNA damage and mutation. CONCLUSION: These results indicated that melatonin is a potential chemopreventive agent for betel quid chewers to prevent OSCC initiation and progression.

RNAi-mediated silencing of Trichinella spiralis serpin-type serine protease inhibitors results in a reduction in larval infectivity.

Trichinella spiralis serpin-type serine protease inhibitors (TsSPIs) are expressed in adult worms (AW), newborn larvae (NBL) and muscle larvae (ML) of T. spiralis, with the ML stage demonstrating the highest expression level. This study aims to determine TsSPI functions in larval viability and invasion of intestinal epithelial cells in vitro, as well as their development, survival, and fecundity in vivo via RNAi. TsSPI-specific siRNAs and dsRNA were transfected into ML by incubation. The silencing effect of TsSPI transcription and expression was determined using qPCR and western blot, respectively. After incubation in 60 ng/µL dsRNA-TsSPI for 3 days, larval TsSPI mRNA and protein expression levels were reduced by 68.7% and 68.4% (P < 0.05), respectively. dsRNA-mediated silencing of TsSPI significantly impacted larval invasion into intestinal epithelial cells in vitro but did not affect the survival rate of larvae. After challenge with dsRNA-TsSPI-treated ML, mice exhibited a 56.0% reduction in intestinal AW burden and 56.9% reduction in ML burden (P < 0.05), but NBL production of female AW remained the same (P > 0.05). Our results revealed that RNAi-mediated silencing of TsSPI expression in T. spiralis significantly reduced larval infectivity and survival in the host but had no effect on the survival rate and fecundity. Furthermore, TsSPIs have no effect on the growth and reproduction of parasites but may be directly involved in regulating the interaction of T. spiralis and the host. Therefore, TsSPIs are crucial in the process of T. spiralis larval invasion and parasite survival in the host.

Proteomics and bioinformatics analysis of Fasciola hepatica somatic proteome in different growth phases.

Fasciola hepatica (F. hepatica) is a well-known zoonotic parasite that is crucial for economic and public health worldwide. Quantitative proteomics studies have been performed on proteins expressed by F. hepatica to investigate the differential expression of proteomes in different growth phases. And the screening of several marker proteins for use as early diagnostic antigens is essential. In this study, high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was conducted to analyze the differences in the expression of F. hepatica somatic proteins in different growth phases. Furthermore, gene ontology (GO) functional annotation, KEGG metabolic pathway, and clustering analyses were also performed. LC-MS/MS identified 629, 2286, 2254, and 2192 proteins in metacercariae, juvenile flukes 28dpi, immature flukes 59dpi, and adult phases, respectively. GO analysis revealed that differentially expressed proteins (DEPs) were mainly involved in transport, localization, metabolism, enzyme regulation, protein folding and binding, and nucleoside and nucleotide binding. The DEPs were enriched in cells, intracellular components, organelles, cytoplasm, vesicles, and membranes. KEGG pathway annotation results showed that the DEPs were involved in metabolism, genetic information processing, environmental information processing, cellular processes, organismal systems, and other processes. These findings provide a theoretical basis for vaccine development and establishing early diagnostic methods in the future.

[Relationship between unexplained palpitation in children and head-up tilt test].

OBJECTIVE: To explore the relationship between unexplained palpitation in children and head-up tilt test (HUTT).
 Methods: A total of 142 children with the main symptom of unexplained palpitation were admitted to the Specialist Out-Patient Clinic of Children's Cardiovascular Disease from Sept. 2008 to Feb. 2017 in the Second Xiangya Hospital, Central South University. Among them, 63 cases were male, 79 cases were female, with the mean age of (10.12±2.88) years old. The detailed history, physical examinations, conventional 12 electrocardiogram, chest X-ray, echocardiography, myocardial enzymes and thyroid function were all examined. The disorders of heart disease, systemic disease and drug effect were ruled out. The HUTT inspection was then given to them.
 Results: Among the 142 palpitation cases, 79 cases were HUTT positive (55.6%) and 63 cases were HUTT negative (44.4%). The age in HUTT positive patients was older than that in HUTT negative patients (P<0.05), with no significant difference in gender (P>0.05). There were three types of hemodynamic changes in HUTT positive patients. Among them, 38 cases were postural orthostatic tachycardia syndrome (48.1%), 36 cases were the vasovagal syncope vasodepressive type (45.6%) and 5 cases were the vasovagal syncope mixed type (6.3%). There were no hemodynamic types for vasovagal syncope cardioinhibitory type, orthostatic hypotension and orthostatic hypertension.
 Conclusion: Among the clinically unexplained palpitations children, more than half are caused by unbalanced autonomic nervous function. HUTT can help clear the cause of unexplained palpitations.

Calgary score and modified Calgary score in the differential diagnosis between neurally mediated syncope and epilepsy in children.

To evaluate the value of Calgary score and modified Calgary score in differential diagnosis between neurally mediated syncope and epilepsy in children. 201 children experienced one or more episodes of loss of consciousness and diagnosed as neurally mediated syncope or epilepsy were enrolled. Calgary score, modified Calgary score and receiver-operating characteristic curve were used to explore the predictive value in differential diagnosis. There were significant differences in median Calgary score between syncope [-4.00 (-6, 1)] and epilepsy [2 (-3, 5)] (z = -11.63, P < 0.01). When Calgary score ≥1, the sensitivity and specificity of differential diagnosis between syncope and epilepsy were 91.46 and 95.80 %, suggesting a diagnosis of epilepsy. There were significant differences in median modified Calgary score between syncope [-4.00 (-6, 1)] and epilepsy [3 (-3, 6)] (z = -11.71, P < 0.01). When modified Calgary score ≥1, the sensitivity and specificity were 92.68 and 96.64 %, suggesting a diagnosis of epilepsy. The sensitivity and specificity of modified Calgary score and Calgary score did not show significant differences (P > 0.05). Calgary score and modified Calgary score could be used to differential diagnosis between syncope and epilepsy in children.

[Changes in P-wave, T-wave, and ST segment amplitude in 12 lead electrocardiogram in children with breath holding spell].

OBJECTIVE: To explore the change of the amplitude of P wave, T wave and ST segment of 12 lead electrocardiogram (ECG) in children with breath holding spell.
 METHODS: A total of 29 children (24 males and 5 females) with breath holding spell in Second Xiangya Hospital, Central South University were enrolled for this study from October, 2009 to September, 2015. Their ages ranged from 3 months to 6 years, with an average of 1.82±1.27 years old. The control group consisted of 30 age-matched and gender-matched healthy children. All subjects were underwent electrocardiography by the SR-1000A comprehensive automatic electrocardiograph analyzer, and the changes of the ECG parameters were compared between the two groups.
 RESULTS: Compared with the control group, the amplitude of P-wave of V5 lead was decreased [(44.10±23.98) vs (58.30±21.19) µV, P<0.05], the amplitude of T-wave of V6 lead was increased [(423.80±122.6) vs (350.00±105.73) µV, P<0.05], the amplitude of ST segment of II lead was increased [(84.80±39.97) vs (57.30±38.77) µV, P<0.05], the amplitude of ST segment of aVR lead was increased [(-77.60±37.41) vs (-51.00±33.46) µV, P<0.05], the amplitude of ST segment of aVL lead was increased [(35.20±28.24) vs (17.70±33.90) µV, P<0.05], the amplitude of ST segment of V5 lead was increased [(111.00±59.36) vs (69.00±36.33) µV, P<0.05], the amplitude of ST segment of V6 lead was increased [(79.30±45.51) vs (51.30±33.19) µV, P<0.05]. 
 CONCLUSION: The children with breath holding spell have autonomic nerve dysfunction. The amplitude of ST segment changes is sensitive.

[Differences of age and gender in orthostatichypertension-a single-center study].

OBJECTIVE: To explore the differences of Chinese people's age and gender in orthostatic hypertension (OHT) by a single-center experience study.
 METHODS: A total of 2 994 patients with unexplained syncope and dizziness, who were outpatients or had been hospitalized in Second Xiangya Hospital, Central South University from January 2000 to August 2012, were chosen and subjected to the head-up tilt table test (HUTT). Their ages ranged from 2.00 to 78.00 years old, with an average at 19.07±14.78 years old. There were 1 406 and 1 588 cases for male and female, respectively. A total of 745 patients were OHT, who were divided into a adult group (≥18 years old, 247/904 cases) and a children group (<18 years old, 498/2 090 cases). The difference of the occurrence rate, classification, and 3 min quantity of blood pressure were analyzed.
 RESULTS: 1) The incidence of OHT in HUTT was 24.88% (745/2 994 cases). There was no statistical difference between the males and the females(25.75% vs 24.12%, χ2=1.058, P>0.05), but it was higher in the adult group compared with that in the children group (27.05% vs 23.83%, χ2=4.125, P=0.042). There were 52 cases (6.98%) of high systolic and high diastolic blood pressure (sOHT merge dOHT), 16 cases (2.15%) of simple high systolic blood pressure OHT (sOHT), and 677 cases (90.87%) of simple high diastolic blood pressure OHT (dOHT) in the 745 patients with OHT. The incidence of dOHT and sOHT merge sOHT in the adults group were significantly higher than those in the children group (1.11% vs 0.29%, χ2=7.965, P<0.01; 2.88% vs 1.24%, χ2=9.849, P<0.01, respectively); there was no statistical difference in simple dOHT between males and females (23.56% vs 22.20%, χ2=0.668, P>0.05); there was also no statistical difference in sOHT plus dOHT and dOHT between males and females (sOHT merge dOHT: 1.71% vs 1.76%, χ2=0.014, P>0.05; dOHT: 23.68% vs 21.66%, χ2=1.742, P>0.05; 1.71% vs 1.76%, χ2=0.014, P>0.05, respectively); but the dOHT was significantly higher in the males than that in the females in the children group (24.53% vs 19.74%, χ2=6.933, P>0.05). 2) There was no difference in the increment of systolic blood pressure in sOHT plus dOHT [(25.62±4.96) mmHg vs (23.54±5.83) mmHg, t=1.385, P>0.05] and the increment of diastolic blood pressure in dOHT [(13.46±3.49) mmHg vs (13.23±3.22) mmHg, t=0.840, P>0.05] between the adults group and the children group. There was no difference in the increment of systolic blood pressure in sOHT [(25.44±4.96) mmHg vs (23.68±5.35) mmHg, t=1.411, P>0.05] and the increment of diastolic blood pressure in dOHT [(14.09±4.28) mmHg vs (13.05±3.82) mmHg, t=1.887, P>0.05] between the adults group and the children group.
 CONCLUSION: The incidence of OHT is higher in the adults group than that in the children group. There is no difference in systolic and diastolic blood pressure increment within 3 minutes during HUTT between the adults and children.

[Incidence of long (short) PR interval in electrocardiogram among healthy people in Changsha and its clinical significance].

OBJECTIVE: To analyze the incidence of long (short) PR interval in electrocardiogram among healthy people in Changsha and the clinical significance.
 METHODS: Twelve-lead body surface electrocardiogram was taken to measure the heart rates and PR intervals from 4 025 healthy individuals (age range from 6 min after birth to 83 years old) who performed physical examination from Jan, 1993 to Dec, 2012 in the Second Xiangya Hospital, Central South University. Statistics were analyzed by SPSS 16.0.
 RESULTS: The total incidence of short PR interval was 19.65% (791/4 025). The age group from birth to 13 years old had a higher incidence than the other age groups (χ2=432, P<0.01). The age groups from 1 month after birth and from 1 month to younger than 1 year-old displayed the highest incidences (43.29% and 44.34%, respectively). The lowest incidences were obtained from the 14-17 year-old, 40-49 year-old and 50-59 year-old groups (0.20%, 0.41%, and 0.33%, respectively). The total incidence of long PR intervals was 3.58% (144/4 025). The 1 year-old group had the highest incidence (6.74%), which decreased with the increase of age. The lowest incidence of long PR intervals occurred in the age group from 14-17 years old, which gradually increased after 50 years old. There were no significant differences in long (short) PR intervals between the gender (P>0.05).
 CONCLUSION: The incidence of long (short) PR intervals varies in different age groups of healthy people. The incidences of long (short) PR intervals in children before 10 years old are higher than those in adults, especially the short PR intervals, as a result of the heart rate affected by childhood autonomic nervous function and the change in atrial volume with age. Adults have long (short) PR interval should be regularly followed-up to prevent cardiovascular events.

Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.

To explore whether oral rehydration salts (ORS) is effective in the treatment of children with vasovagal syncope (VVS). One hundred and sixty-six consecutive patients with recurrent syncope and positive head-up tilt testing (HUTT) were recruited, randomly divided to conventional therapy (health education and tilt training) plus ORS (with 500 ml of water) group (Group I, 87 patients) and conventional therapy group (Group II, 79 patients). Therapeutic effect was evaluated by changes of syncopal episode and reperformed HUTT response. At the end of 6-month follow-up, syncopal episode did not reoccur in 49 (56.3 %) patients, decreased in 34 (39.1 %) patients, and had no obvious change or increased in four (4.6 %) patients in Group I, and the results were 31 (39.2 %), 37 (46.8 %), and 11 (14 %) in Group II, respectively. The difference was significant (χ (2) = 7.074, P < 0.05). When HUTT was reperformed, 57 (65.5 %) and 28 (35.4 %) patients had negative response and 30 (34.5 %) and 51 (64.6 %) patients had positive response, respectively, in Group I and Group II. The difference was also significant (χ (2) = 13.808, P < 0.01). In Group I, the two aspects had no difference between vasodepressor type and mixed type; however, syncopal episode had a significant difference between children aged ≤12 and >12 years (χ (2) = 6.371, P < 0.05); there was no difference in reperformed HUTT response. ORS with 500 ml of water is an effective therapy for VVS. It can be recommended as one of non- pharmacological treatment measures in children with VVS.

[Time-dependent heart rate variability in the head-up tilt test in children with postural orthostatic tachycardia syndrome].

OBJECTIVE: To study the time-dependent heart rate (HR) variability in the head-up tilt test (HUTT) in children with postural orthostatic tachycardia syndrome (POTS) and to explore the HR diagnostic criteria for POTS in children. METHODS: A retrospective analysis was performed on the clinical data of 105 children diagnosed with POTS with HR≥120 beats per minute (bpm) within the first 10 minutes of HUTT between January 2007 and December 2014. Their HR variability within the first 10 minutes of HUTT was analyzed. RESULTS: The HR of children with POTS increased gradually from the supine position to a 60° head-up tilt position, and the increase in HR was 24±12 bpm at the beginning of HUTT, 30±14 bpm at 3 minutes of HUTT, 32±13 bpm at 5 minutes of HUTT, and 38±12 bpm at 10 minutes of HUTT. The average maximal HR increase within the first 10 minutes of HUTT was 43±10 bpm. CONCLUSIONS: In children with POTS, the HR variability gradually increases with time, and therefore, it is suggested that HR increase ≥40 bpm is more suitable for diagnosis of POTS in children.

Transient aphasia: a rare complication of head-up tilt test.

Head-up tilt test (HUT) is widely used as a diagnostic tool. It reproduces vasovagal attacks in many susceptible patients. Although it is known to be safe and well tolerated, it is a procedure with potential neurologic complications. We observed that it could cause transient aphasia in some patients. To explore clinical characteristics and possible pathogenesis of aphasia induced by HUT, we reviewed the data of patients undergoing HUT in our hospital. 13 patients experienced transient aphasia in 3,488 cases. According to the hemodynamic changes, the incidence in vasodepressor, mixed, cardioinhibition and the negative response were 6.67, 5.52, 0 and 1.14 ‰ orderly, and not significantly different among the groups. It had significant difference between the positive response and the negative response and between vasodepressor and the negative response (both p < 0.05). The incidence in adults was significantly higher than that in children (<18 years) (p < 0.01), but not different between female and male. The average onset time was 11.33 ± 6.66 min (range 4-17 min) during baseline HUT or 4.90 ± 2.69 min (range 2-10 min) during sublingual nitroglycerin-provocated HUT. The duration was 3-60 min, except for one who was completely relieved of the disorder 4 h later. In conclusions, there is a risk of provoking transient aphasia during HUT. It reminds that performer should alert the possibility of transient aphasia during the test, especially when the patient is an adult and has a positive response.

[Evaluation of psychological fear in children undergoing head-up tilt test].

OBJECTIVE: To investigate the effects of different tilt angles of head-up tilt test (HUTT) and different responses to HUTT on the psychological fear in children undergoing the test. METHODS: HUTT was performed on children with unexplained syncope or pre-syncope (107 cases: 52 males and 55 females), aged 5.5-17.8 years (mean 12.0±2.8 years). All subjects were randomly assigned to undergo HUTT at an angle of 60°, 70° or 80°; the negative cases underwent sublingual nitroglycerin-provocation HUTT at the same tilt angle. The Wong-Baker Faces Pain Rating Scale was used for self-assessment of psychological fear in subjects during HUTT at the end point of the test. RESULTS: The positive rate, hemodynamic changes and distribution of response types showed no significant differences between children at tilt angles of 60°, 70° and 80° (P>0.05). The greater the tilt angle, the higher the degree of psychological fear in children undergoing the test, but there were no significant differences between them (P>0.05). The degree of psychological fear in children who showed a positive response to HUTT (n=76) was significantly higher than that in children who showed a negative response (n=31) (P<0.01). CONCLUSIONS: HUTT can cause psychological fear in children undergoing the test, and the degree of psychological fear increases in children tested at tilt angles from 60° to 80°, but the differences have no statistical significance. A positive response to HUTT can significantly increase the psychological fear in children.

[Clinical characteristics and treatment of 89 patients with head-up tilt table test induced syncope with convulsion].

OBJECTIVE: To study the clinical features and intervention strategies of head-up tilt table test (HUTT) induced syncope triggering convulsion. METHODS: HUTT was performed in 2377 cases (male 1116 cases and female 1261 cases) with syncope, dizziness, headache, chest tightness at Second Xiangya Hospital of Central South University from September 2000 to August 2011. They were 2.00-78.00 (18.57±14.36) years old, 1719 cases were younger than 18 years (the children group) [(2.00-17.92 (10.88±3.02) years] and 658 were older than 18 years (the adult group) [(18.00-78.00 (38.66±12.87) years]. We analyzed the related factors for inducing syncope triggering convulsion symptom and other serious side effects in HUTT. RESULTS: 1) Eighty-nine patients (3.74%) induced syncope with convulsion symptoms during HUTT, with more adults (62.92%) than children (37.08%) (χ(2)=87.842, P<0.01). 2) Sinus cardiac arrest and heart rate recovery time: 25 (28.09%) out of the 89 patients had sinus cardiac arrest. The sinus cardiac arrest time was 3.00-14.60 (7.90±3.44) s. After the HUTT, the heart rate recovery time was 0.50-37.00 (3.05±4.11) min, 70 of which (78.65%) resumed 3 min. 3) INTERVENTIONS: when all patients completed the HUTT, they would take oxygen and drink milk and other measures to relieve convulsions and recover heart rate and blood pressure. No one died, and the vital signs of 2 patients returned to normal after intravenous administration. CONCLUSION: Induced syncope triggering convulsion symptom in HUTT is more common in adult patients. Convulsions disappear and heart rate and blood pressure return to normal after taking oxygen and milk and other measures. HUTT in clinical practice is safe, and can be used in patients of all ages.

[Clinical significance of changes in T wave and ST segment amplitudes on electrocardiogram from supine to standing position among children with unexplained chest tightness or pain in resting stage].

OBJECTIVE: To investigate the clinical significance of changes in T wave and ST segment amplitudes on electrocardiogram (ECG) from supine to standing position in children with unexplained chest tightness or pain in resting stage. METHODS: A total of 122 6-14-year-old children with a chief complaint of unexplained chest tightness or pain (resting stage) underwent head-up tilt test (HUTT). According to HUTT results, these children were divided into HUTT-positive (n=61) and HUTT-negative groups (n=61). They underwent 12-lead ECG in the supine and standing positions, and heart rate and T wave and ST segment amplitudes in II, III, aVF and V5 leads were measured. RESULTS: In the HUTT-negative group, heart rates were significantly higher in the standing position than in the supine position (P<0.05), T wave amplitudes in II, III, aVF, and V5 leads were significantly lower in the standing position than in the supine position (P<0.05), and ST segment amplitudes in II, aVF and V5 leads were significantly higher in the standing position than in the supine position (P<0.05). In the HUTT-positive group, heart rates were significantly higher in the standing position than in the supine position (P<0.05), T wave amplitudes in II, III, aVF and V5 leads were significantly lower in the standing position than in the supine position (P<0.05), and ST segment amplitude in V5 lead was significantly higher in the standing position than in the supine position (P<0.05). There were no significant differences between the two groups with respect to ST segment amplitude and T wave amplitude in II, III and aVF leads of the supine or standing position (P>0.05). Compared with the HUTT-negative group, the HUTT-positive group had significantly greater T wave amplitude differences in II, III, aVF and V5 leads, and heart rate difference from supine to standing position (P<0.05). CONCLUSIONS: Among the children with unexplained chest tightness or pain in resting stage, T wave amplitude differences in II, III, aVF and V5 leads and heart rate difference from supine to standing position are greater in the HUTT-positive group than in the HUTT-negative group. This suggests that the changes in T wave amplitude on ECG from supine to standing position can indicate autonomic nervous system dysfunction.

[Investigation of 24-hour blood pressure monitoring for evaluating treatment outcome of nerve-mediated syncope in children].

OBJECTIVE: To investigate the clinical significance of 24-hour blood pressure monitoring (ABPM) for evaluating the treatment outcome of nerve-mediated syncope (NMS) in children. METHODS: Twenty-eight children with NMS confirmed by a head-up tilt table test (HUTT) (12 males and 16 females, aged 6-13 years) and with a chief complaint of unexplained syncope or pre-syncope between February 2010 and August 2012, were included in the study. These children received health education combined with therapy using oral rehydration salts solution and were then reexamined for clinical symptoms as well as HUTT and ABPM results. RESULTS: Of 28 NMS cases, 22 were vasodepressive type, 5 were mixed type, and 1 was cardioinhibitory type. The follow-up showed that 27 (96%) of all cases had improved clinical symptoms, and 18 (64%) had improved HUTT results. The ABPM follow-up revealed no significant changes in 24-hour mean systolic pressure, 24-hour mean diastolic pressure, daytime mean systolic pressure, daytime mean diastolic pressure, nighttime mean systolic pressure, nighttime mean diastolic pressure, day-night difference of systolic pressure, and day-night difference of diastolic pressure after treatment (P>0.05). The percentage of children with a dipper blood pressure pattern increased from 29% (8/28) before treatment to 50% (14/28) after treatment; the percentage of children with a non-dipper blood pressure pattern decreased from 71% (20/28) before treatment to 50% (14/28) after treatment. CONCLUSIONS: As an effective, objective and non-invasive monitoring means, ABPM is of some clinical significance for evaluating the treatment outcome of NMS in children.

The characteristics and clinical relevance of tumor fusion burden in head and neck squamous cell carcinoma.

BACKGROUND: Recent studies suggest that tumor fusion burden (TFB) is a hallmark of immune infiltration in prostate cancer, the correlation of TFB with immune microenvironment, and genomic patterns in head and neck squamous cell carcinomas (HNSC) remain largely unclear. METHODS: Gene fusion, genomic, transcriptomic, and clinical data of HNSC patients from the cancer genome atlas (TCGA) database were collected to analyze the correlation of TFB with mutation patterns, tumor immune microenvironment, and survival time in HNSC patients. RESULTS: Human papillomavirus (HPV) (-) patients with low TFB exhibited significantly enhanced CD8+ T cells infiltration and cytolysis activity and increased level of interferon-gamma (IL-γ), human leukocyte antigen (HLA) class I, and chemokines. Moreover, TFB was positively correlated with TP53 mutation, score of gene copy number, and loss of heterozygosity (LOH), as well as the biological progress of epithelial-mesenchymal transition (EMT), metastasis, and stem cell characteristics. Further analysis revealed that HPV (-) HNSC patients with low TFB have a better prognosis. CONCLUSIONS: Our data revealed the correlation of TFB with tumor immune microenvironment and predictive features for immunotherapy, implying tumors with low TFB may be potential candidates for immunotherapeutic agents. Moreover, the TFB low group had prolonged overall survival (OS) in the HPV (-) HNSC cohort.

[Causes of unexplained syncope in children].

OBJECTIVE: To investigate the common causes of unexplained syncope in children. METHODS: A total of 434 children with unexplained syncope who were aged from 3.0 to 17.9 years (192 males and 242 females) and who saw the doctor between January 2006 and October 2011. were examined in order to explore the detailed histories and causes of syncope and to analyze variance in causes among different ages, genders, syncope frequencies and head-up tilt test (HUTT) results. RESULTS: (1) The causes of occasional syncope included persistent standing (30%), movement (13%), change in body position(9%), sitting(7%), and playing(6%). Persistent standing was more common as a cause in females than in males (P<0.01). Micturition syncope was mainly seen in males. Sultry weather was the main cause of syncope in females. Change in body position was a more common cause in the ≥12 years group than in the <12 years group (P<0.05), while other causes showed no significant differences among different age groups. Change in body position was a more common cause of syncope in children with negative HUTT results than in those with positive HUTT results (P<0.05). (2) All causes of occasional syncope can induce repeated syncope, and most repeated syncope (56%) had the same cause. CONCLUSIONS: The common causes of unexplained syncope include persistent standing, movement and changes of body position in children. Avoiding these causes is helpful for prevention of childhood syncope.

The genomic mutational landscape and its correlation with TMB, PD-L1 expression and CD8+ T cell infiltration in Chinese lung large cell neuroendocrine carcinoma.

OBJECTIVES: The aim of this study was to illustrate the genomic mutational landscape, tumor mutation burden (TMB), PD-L1 expression, CD8+ T cell infiltration and their prognostic value in resectable Lung large cell neuroendocrine carcinoma (LCNEC). MATERIALS AND METHODS: The tumor tissues and corresponding normal tissues of 37 LCNEC patients undergoing surgical resection were collected and determined by whole exome sequencing (WES). Subsequently, the tumor samples were stained with the antibodies of PD-L1 and CD8 via multiplex immunohistochemistry (Multi IHC) to evaluate PD-L1 expression and CD8+ T cells infiltration in stroma and tumor regions. Univariate and multivariate analysis were applied to assess the association among genomic features, immune profiles, clinical data and prognosis of LCNEC patients. RESULTS: The median TMB was 5.42 mutations per megabase. Mutations in Wnt (p = 0.049) and Hippo (p = 0.005) pathways were markedly associated with higher TMB value, mutations in p53 pathway were related with higher stromal PD-L1 expression (p = 0.041). LCNEC patients with KEAP1 mutation (p = 0.044) or without adjuvant radiochemotherapy (p = 0.023) had significantly shorter OS. Multivariate analysis showed that high stromal CD8 + T cells infiltration was an independent favorable factor for disease free survival (p = 0.030). The patient stratification of KEAP1 mutation status and stroma PD-L1 expression was independent prognostic factors for overall survival (p = 0.049). CONCLUSION: The investigation of prognostic factor in resectable LCNEC may provide guidance for timely intervention and new therapy strategy for LCENC patients.