IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce. PATIENTS AND METHODS: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. RESULTS: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure. CONCLUSIONS: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.

Acromegaly presented with acne vulgaris: a retrospective study with 123 cases.

BACKGROUND: Acne vulgaris is a prevalent skin condition. We have found that some acromegaly patients have acne. However, no study has examined the relationship between acromegaly and acne. OBJECTIVE: To explore prevalence and correlation of adult acne in patients with acromegaly. METHODS: For this cross-sectional study, we collected questionnaires, clinical information, and laboratory test results of acromegaly patients from January 2022 to December 2022 at Huashan Hospital. Of the 133 questionnaires returned, 123 had valid responses. RESULTS: Of the 123 patients with acromegaly enrolled in this study, 54.5% had adult acne. No statistically significant difference was found in prevalence between male and female patients. 61.2% of adult acne patients reported late-onset acne. Late-onset acne patients first developed acne years before acromegaly diagnosis (mean of 5.6 years for male and 4.5 years for female patients). Some acne patients have received traditional anti-acne treatment. Moreover, 31% of the patients reported no improvement, and only 3.5% of patients claimed complete resolution of acne after treatment. Before acromegaly treatment, the prevalence of adult acne was 51.2%, with mild acne accounting for 73.0%, moderate acne accounting for 23.8%, and severe acne accounting for 3.2%. After acromegaly treatment, the prevalence of adult acne was significantly decreased to 37.4% (P = 0.007). An overall decrease in acne severity was noted, with 93.5%, 6.5%, and 0% having mild, moderate, and severe acne, respectively. A total of 83.6% of the patients had self-assessed acne remission, and 33.3% of the patients reported complete acne resolution. However, 9.0% of patients reported that their condition had worsened after acromegaly treatment. After treatment, GH, IGF-1, IGF-1 index, insulin levels, and HOMA-IR decreased significantly in all patients with acromegaly (P < 0.05). Acne remission correlated positively with IGF-1 levels, but not with GH levels. The relationship between acromegaly and acne remains to be elucidated. CONCLUSIONS: Our findings provide preliminary evidence of the high prevalence of adult acne in acromegaly patients, and a high rate of late-onset acne as well. Traditional anti-acne treatments are less effective. Acne could be considerably relieved by treating acromegaly. Acne remission positively correlated with IGF-1 decline as well, which revealed the correlation between acne and IGF-1.

[Effects of high-fat and low-carbohydrate diet combined with radiotherapy on tumor microenvironment of Lewis lung cancer bearing mice].

Objective: To investigate the effect of high-fat and low-carbohydrate diet combined with radiotherapy on the tumor microenvironment of mice with lung xenografts. Methods: C57BL/6J mice were selected to establish the Lewis lung cancer model, and they were divided into the normal diet group, the high-fat and low-carbohydrate diet group, the normal diet + radiotherapy group, and the high-fat and low-carbohydrate diet + radiotherapy group, with 18 mice in each group. The mice in the normal diet group and the normal diet + radiotherapy group were fed with the normal diet with 12.11% fat for energy supply, and the mice in the high-fat and low-carbohydrate diet group and the high-fat and low-carbohydrate diet + radiotherapy group were fed with high-fat and low-carbohydratediet with 45.00% fat for energy. On the 12th to 14th days, the tumor sites of the mice in the normal diet + radiotherapy group and the high-fat and low-carbohydrate diet + radiotherapy group were treated with radiotherapy, and the irradiation dose was 24 Gy/3f. The body weight, tumor volume, blood glucose and blood ketone level, liver and kidney function, and survival status of the mice were observed and monitored. Immunohistochemical staining was used to detect the tumor-associated microangiogenesis molecule (CD34) and lymphatic endothelial hyaluronan receptor 1 (LYVE-1), Sirius staining was used to detect collagen fibers, and multiplex immunofluorescence was used to detect CD8 and programmed death-1 (PD-1). Expression of immune cell phenotypes (CD3, CD4, CD8, and Treg) was detected by flow cytometry. Results: On the 27th day after inoculation, the body weigh of the common diet group was(24.78±2.22)g, which was significantly higher than that of the common diet + radiotherapy group [(22.15±0.48)g, P=0.030] and high-fat low-carbohydrate diet + radiotherapy group [(22.02±0.77)g, P=0.031)]. On the 15th day after inoculation, the tumor volume of the high-fat and low-carbohydrate diet + radiotherapy group was (220.88±130.05) mm3, which was significantly smaller than that of the normal diet group [(504.37±328.48) mm3, P=0.042)] and the high-fat, low-carbohydrate diet group [(534.26±230.42) mm3, P=0.016], but there was no statistically significant difference compared with the normal diet + radiotherapy group [(274.64±160.97) mm3]. In the 4th week, the blood glucose values of the mice in the high-fat and low-carbohydrate diet group were lower than those in the normal diet group, with the value being (8.00±0.36) mmol/L and (9.57±0.40) mmol/L, respectively, and the difference was statistically significant (P＜0.05). The blood ketone values of the mice in the high-fat and low-carbohydrate diet group were higher than those in the normal diet group, with the value being (1.00±0.20) mmol/L and (0.63±0.06) mmol/L, respectively, in the second week. In the third week, the blood ketone values of the two groups of mice were (0.90±0.17) mmol/L and (0.70±0.10) mmol/L, respectively, and the difference was statistically significant (P＜0.05). On the 30th day after inoculation, there were no significant differences in aspartate aminotransferase, alanine aminotransferase, creatinine, and urea between the normal diet group and the high-fat, low-carbohydrate diet group (all P＞0.05). The hearts, livers, spleens, lungs, and kidneys of the mice in each group had no obvious toxic changes and tumor metastasis. In the high-fat and low-carbohydrate diet + radiotherapy group, the expression of CD8 was up-regulated in the tumor tissues of mice, and the expressions of PD-1, CD34, LYVE-1, and collagen fibers were down-regulated. The proportion of CD8+ T cells in the paratumoral lymph nodes of the high-fat and low-carbohydrate diet + radiotherapy group was (25.13±0.97)%, higher than that of the normal diet group [(20.60±2.23)%, P＜0.050] and the normal diet + radiotherapy group [(19.26±3.07)%, P＜0.05], but there was no statistically significant difference with the high-fat and low-carbohydrate diet group [(22.03±1.75)%, P＞0.05]. The proportion, of CD4+ T cells in the lymph nodes adjacent to the tumor in the normal diet + radiotherapy group (31.33±5.16)% and the high-fat and low-carbohydrate diet + radiotherapy group (30.63±1.70)% were higher than that in the normal diet group [(20.27±2.15)%, P＜0.05] and the high-fat and low-carbohydrate diet group (23.70±2.62, P＜0.05). Treg cells accounted for the highest (16.58±5.10)% of T cells in the para-tumor lymph nodes of the normal diet + radiotherapy group, but compared with the normal diet group, the high-fat and low-carbohydrate diet group, and the high-fat and low-carbohydrate diet + radiotherapy group, there was no statistically significant difference (all P＞0.05). Conclusion: High-fat and low-carbohydrate diet plus radiotherapy can enhance the recruitment and function of immune effector cells in the tumor microenvironment, inhibit tumor microangiogenesis, and thus inhibit tumor growth.

[The relationship between rapid eye movement electromyogram activity and sleep stability in rapid eye movement sleep behavior disorder].

Objective: To investigate the relationship between the types of electromyogram (EMG) activity and sleep stability during rapid eye movement (REM) in patients with rapid eye movement sleep behavior disorder(RBD). Methods: One hundred and three patients with RBD who met the inclusion and exclusion criteria at the Second Affiliated Hospital of Air Force Military Medical University from January 2017 to December 2019 were retrospectively analyzed. The general situation, clinical symptoms, sleep and emotion questionnaires and nocturnal PSG data were collected. According to the different proportions of tonic and phasic EMG activity, the group with a higher proportion of tonic EMG than phasic EMG was defined as the tonic dominant group, and the group with a higher proportion of phasic EMG than tonic was defined as the phasic dominant group. The sleep instability index was calculated according to the ratio of the number of transitions from sleep to wakefulness to the total sleep time of each sleep stage. Multiple linear regression was used to explore the relationship between REM EMG activity and sleep instability index. Results: A total of 35 idiopathic RBD (iRBD) patients were included, aged(54.5±18.2)years, with 17 males and 18 females. There were 27 RBD with Parkinson's disease (PD), with an average age of (59.4±7.9)years, including 17 males and 10 females. Additionally, there were 41 RBD patients with narcolepsy, aged (21.2±13.2)years, consisting of 22 males and 19 females. Both iRBD and RBD patients with PD had lower objective total sleep time, sleep latency, sleep efficiency, wake time after sleep onset and the percentage of N3 sleep compared to RBD with episodic sleep disorder (all P<0.05). N1-W index[M(Q1, Q3),10.6 (6.5, 16.9)/h vs 7.3 (4.7, 10.5)/h], N2-W index [4.0 (2.2, 5.6)/h vs 2.3 (1.5, 3.9)/h], NREM-W index [ (5.8±2.9)/h vs (4.5±3.2)/h] and REM-W index[ 3.9 (1.9, 7.3)/h vs 2.7 (1.0, 4.0)/h] in the phasic dominant group were higher than those in the tonic dominant group. After adjusting for confounding factors, the effect of phasic EMG dominant group on REM-W was higher than that in the tonic dominant group (ß=2.05, 95%CI: 0.09-3.26, P=0.012). Conclusion: In RBD patients, the phasic EMG activity has a significant impact on sleep stability, especially on REM sleep stability.

[Diagnosis and differential diagnosis of large B-cell lymphoma with IRF4 rearrangement].

Objective: To analyze the clinicopathological features and differential diagnosis of large B-cell lymphoma with IRF4 rearrangement, aiming enhance its recognition and prevent misdiagnosis. Methods: The clinicopathological features, immunophenotype, and fluorescence in situ hybridization (FISH) results of six cases diagnosed with IRF4 rearrangement-positive B-cell lymphoma at the Affiliated Hospital of Xuzhou Medical University from 2015 to 2023 were retrospectively analyzed. Additionally, a comprehensive review of the literature was conducted. Results: Six patients with IRF4 rearrangement-positive large B-cell lymphoma were included. Patients 1 to 5 included three males and two females with a median age of 19 years ranging from 11 to 34 years. Four patients presented with head and neck lesions, while the other one had a breast nodule; all were in clinical Ann Arbor stages I to Ⅱ. Morphologically, entirely diffuse pattern was present in two cases, purely follicular pattern in one case, and diffuse and follicular patterns in other two cases. The tumor cells, predominantly centroblasts mixed with some irregular centrocytes, were of medium to large size, with a starry sky appearance observed in two cases. Immunophenotyping revealed all cases were positive for bcl-6 and MUM1, with a Ki-67 index ranging from 70% to 90%, and CD10 was positive in two cases. IRF4 rearrangement was confirmed in all cases by FISH analysis, with dual IRF4/bcl-6 rearrangements identified in two cases, leading to a diagnosis of LBCL-IRF4. Case 6, a 39-year-old female with a tonsillar mass and classified as clinical Ann Arbor stage Ⅳ, displayed predominantly diffuse large B-cell lymphoma (DLBCL) morphology with 20% high-grade follicular lymphoma characteristics. Immunohistochemistry showed negative CD10 and positive bcl-6/MUM1, with a Ki-67 index of approximately 80%. Triple rearrangements of IRF4/bcl-2/bcl-6 were identified by FISH, leading to a diagnosis of DLBCL with 20% follicular lymphoma (FL). All six patients achieved complete remission after treatment, with no progression or relapse during a follow-up period of 31-100 months. Conclusions: Large B-cell lymphoma with IRF4 rearrangement is a rare entity with pathological features that overlap with those of FL and DLBCL. While IRF4 rearrangement is necessary for diagnosing LBCL-IRF4, it is not specific and requires differentiation from other aggressive B-cell lymphomas with IRF4 rearrangement.

[Genotype-environment interaction on arterial stiffness: A pedigree-based study].

OBJECTIVE: To utilized the baseline data of the Beijing Fangshan Family Cohort Study, and to estimate whether the association between a healthy lifestyle and arterial stiffness might be modified by genetic effects. METHODS: Probands and their relatives from 9 rural areas in Fangshan district, Beijing were included in this study. We developed a healthy lifestyle score based on five lifestyle behaviors: smoking, alcohol consumption, body mass index (BMI), dietary pattern, and physical activity. The measurements of arterial stiffness were brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI). A variance component model was used to determine the heritability of arterial stiffness. Genotype-environment interaction effects were performed by the maximum likelihood methods. Subsequently, 45 candidate single nucleotide polymorphisms (SNPs) located in the glycolipid metabolism pathway were selected, and generalized estimated equations were used to assess the gene-environment interaction effects between particular genetic loci and healthy lifestyles. RESULTS: A total of 6 302 study subjects across 3 225 pedigrees were enrolled in this study, with a mean age of 56.9 years and 45.1% male. Heritability of baPWV and ABI was 0.360 (95%CI: 0.302-0.418) and 0.243 (95%CI: 0.175-0.311), respectively. Significant genotype-healthy diet interaction on baPWV and genotype-BMI interaction on ABI were observed. Following the findings of genotype-environment interaction analysis, we further identified two SNPs located in ADAMTS9-AS2 and CDH13 might modify the association between healthy dietary pattern and arterial stiffness, indicating that adherence to a healthy dietary pattern might attenuate the genetic risk on arterial stiffness. Three SNPs in CDKAL1, ATP8B2 and SLC30A8 were shown to interact with BMI, implying that maintaining BMI within a healthy range might decrease the genetic risk of arterial stiffness. CONCLUSION: The current study discovered that genotype-healthy dietary pattern and genotype-BMI interactions might affect the risk of arterial stiffness. Furthermore, we identified five genetic loci that might modify the relationship between healthy dietary pattern and BMI with arterial stiffness. Our findings suggested that a healthy lifestyle may reduce the genetic risk of arterial stiffness. This study has laid the groundwork for future research exploring mechanisms of arterial stiffness.

Radium Ion Optical Clock.

We report the first operation of a Ra^{+} optical clock, a promising high-performance clock candidate. The clock uses a single trapped ^{226}Ra^{+} ion and operates on the 7s ^{2}S_{1/2}→6d ^{2}D_{5/2} electric quadrupole transition. By self-referencing three pairs of symmetric Zeeman transitions, we demonstrate a frequency instability of 1.1×10^{-13}/sqrt[τ], where τ is the averaging time in seconds. The total systematic uncertainty is evaluated to be Δν/ν=9×10^{-16}. Using the clock, we realize the first measurement of the ratio of the D_{5/2} state to the S_{1/2} state Landé g-factors: g_{D}/g_{S}=0.598 805 3(11). A Ra^{+} optical clock could improve limits on the time variation of the fine structure constant, α[over ˙]/α, in an optical frequency comparison. The ion also has several features that make it a suitable system for a transportable optical clock.

[Exploring the association between de novo mutations and non-syndromic cleft lip with or without palate based on whole exome sequencing of case-parent trios].

OBJECTIVE: To explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design. METHODS: Whole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database. RESULTS: A total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes. CONCLUSION: Our study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.

[Analysis of influencing factors on surgical outcome and exploration of technical principles during pancreaticojejunostomy].

Pancreaticojejunostomy is the most common anastomosis following pancreaticoduodenectomy and middle pancreatectomy. The detailed surgical technics of pancreaticojejunostomy vary dramatically, but none of them can achieve zero fistula rate. In recent years,with the development of new surgical concept,application of new surgical technology, high-tech materials and instruments,the incidence of pancreatic fistula has decreased. At the same time,researches on investigating the risk factors of pancreaticojejunostomy are gradually deepening. Based on years of surgical experience on pancreaticojejunostomy and current literatures, this paper analyzes the factors affecting the effect of pancreaticojejunostomy, such as the patient's basic physical state,pancreatic texture and diameter of the pancreatic duct,pathology and course of the disease,surgical technology and perioperative management,and summarizes six technical principles for pancreaticojejunostomy to be shared with surgical comrades:appropriate tension,protection of blood supply,hermetic closure of pancreatic section,accurate connection of pancreatic duct and intestinal mucosa,individualization,learning and accumulation of experience.

Optical Mass Spectrometry of Cold RaOH

We present an all-optical mass spectrometry technique to identify trapped ions. The new method uses laser-cooled ions to determine the mass of a cotrapped dark ion with a sub-dalton resolution within a few seconds. We apply the method to identify the first controlled synthesis of cold, trapped RaOH^{+} and RaOCH_{3}^{+}. These molecules are promising for their sensitivity to time and parity violations that could constrain sources of new physics beyond the standard model. The nondestructive nature of the mass spectrometry technique may help identify molecular ions or highly charged ions prior to optical spectroscopy. Unlike previous mass spectrometry techniques for small ion crystals that rely on scanning, the method uses a Fourier transform that is inherently broadband and comparatively fast. The technique's speed provides new opportunities for studying state-resolved chemical reactions in ion traps.

[Clinical characteristics and outcome of pregnant patients with myasthenia gravis].

Objective: To study the clinical characteristics of pregnant patients with myasthenia gravis (MG) and the influence of MG to pregnancy. Methods: A retrospective study was conducted including 28 MG patients with 38 pregnancies admitted to the 8th Medical Center of PLA General Hospital between January 2013 and October 2018. Data were collected including clinical scores of MG, serum level of acetylcholine receptor (AChR) antibodies, abnormal repetitive nerve stimulation (RNS) and history of thymectomy before pregnancy. The course of pregnancy, delivery and neonatal outcome were also analyzed. According the outcome of MG, patients were divided into three groups, i.e. improvement group, stable group and deterioration group. Results: (1) The age of MG patients ranged from 21 to 36 (27±4) years. The previous course of MG was 0.5-17.2 (7.4±5.8)years. Based on Osserman clinical type, type ⅡA was the most common one [44.1% (15/34)], followed with type Ⅰ [29.4% (10/34)], type ⅡB [23.5% (8/34)] and type Ⅳ (2.9%).(2)There were 38 pregnancies in 28 women whose pregnancy outcomes resulted in one spontaneous abortion, three embryonic arrest and 34 live births. All abortions developed in the first trimester. Among the 34 pregnancies with live births, the symptoms of MG improved in 16 pregnancies (47.1%), whereas those deteriorated in 10 pregnancies (29.4%) during the first or third trimester and remained stable in 8 pregnancies (23.5%). (3) Compared with improvement group and stable group, the deterioration group had shorter duration of MG [(1.1±0.5) years vs. (7.1±5.1) years, (9.0±5.4) years respectively], higher clinical scores (20.9±6.0 vs. 14.8±6.6,13.3±5.0) and more frequent abnormal RNS(9/10 vs. 8/16, 4/8) and type ⅡB(6/10 vs. 1/16, 1/8) before pregnancy. Positive rate of serum AChR antibody and percentage of thymectomy before pregnancy were comparable between three groups. (4) Spinal anesthesia was performed in 23 pregnancies and 11 cases were vaginal delivery. No transient neonatal MG were found in live-born infants. Conclusions: Pregnancy in patients with under-controlled myasthenia gravis should not be discouraged. The outcome of MG is affected by the duration of MG, MG score and RNS before pregnancy. The first and third trimesters of pregnancy are considered high-risk periods for MG exacerbations. Neonatal transient myasthenia is uncommon, but the newborn should be carefully monitored by obstetricians and neurologists.

[Study on lung injury induced by rare earth samarium oxide particles in rats].

Objective: To study the effect of samarium trioxide (Sm(2)O(3)) particles on rat lung tissue and compare it with the same dose of silica (SiO(2)) particles, in order to find the reference index for early screening of pneumoconiosis. Methods: In October 2018, 72 SPF healthy male rats were randomly divided into control group, SiO(2) group and Sm(2)O(3) group. The lungs of rats in each group were perfused with 2.0 ml/kg normal saline and 280 mg/kg SiO(2) and Sm(2)O(3) particle suspension by one-time non exposed tracheal perfusion. The lungs of rats were stained with hematoxylin eosin (HE) staining, and the pathological changes of lung tissues were observed. The concentrations of SNAIL homologue 1 (SNAI1) , SNAIL homologue 2 (SNAI2) , and heat shock protein-27 (HSP-27) in rat serum were detected by enzyme-linked immunosorbent assay. 0.5 g of lung tissue from rats in Sm(2)O(3) group and control group exposed to dust for 56 days was screened for long-chain noncoding RNA (lncRNA) and circular RNA (circRNA) . Results: After 7 days of dust exposure, the alveoli in SiO(2) group and Sm(2)O(3) group were disordered, and lymphoid tissue aggregation and proliferation were observed around the bronchial wall. At 14 days, a large number of lymphocytes infiltrated in SiO(2) group, and a small number of macrophages containing Sm(2)O(3) and fibrotic nodules scattered in Sm(2)O(3) group. At 28 days, a small amount of lymphocyte infiltration appeared in SiO(2) group, and fibrotic nodules were seen in some areas of Sm(2)O(3) group. At 56 days, there was a small amount of fibroblast proliferation in SiO(2) group, and a large number of fibrotic nodules containing gray black matter were seen in Sm(2)O(3) group. There was no significant difference in lung organ coefficient among groups at different dust exposure time (P>0.05) . After 14 days of dust exposure, the contents of SNAI1 and SNAI2 in serum of rats in SiO(2) group were lower than those in control group, the content of SNAI2 in serum of Sm(2)O(3) group was lower than that in control group, and the contents of SNAI1 and SNAI2 in serum of Sm(2)O(3) group were higher than those in SiO(2) group (P<0.05) . The content of HSP-27 in SiO(2) group was lower than that in control group (P<0.05) . After 56 days of dust exposure, the content of HSP-27 in Sm(2)O(3) group was lower than that in control group (P<0.05) . At 56 days, lncRNA in Sm(2)O(3) group was up-regulated by 148 and down regulated by 725, circRNA was up-regulated by 16 and down regulated by 153. Conclusion: Sm(2)O(3) can cause lung injury in rats, and the change of SNAI2 content can be detected in the early stage, which can be used as a reference index for early screening of pneumoconiosis. There are differences in the expression of lncRNA and circRNA after 56 days of dust exposure in rats, which may be related to the pathogenesis of pneumoconiosis.

Three-field versus two-field lymphadenectomy in transthoracic oesophagectomy for oesophageal squamous cell carcinoma: short-term outcomes of a randomized clinical trial.

BACKGROUND: The benefit and harm of three-field lymphadenectomy for oesophageal cancer are still unknown. The aim of this study was to compare overall survival and morbidity and mortality between three- and two-field lymphadenectomy in patients with oesophageal squamous cell carcinoma. METHODS: Between March 2013 and November 2016, patients with squamous cell carcinoma of the middle or distal oesophagus were assigned randomly to open oesophagectomy with three-field (cervical-thoracic-abdominal) or two-field (thoracic-abdominal) lymphadenectomy. No chemo(radio) therapy was given before surgery. This paper reports on the secondary outcomes of the study: pathology and surgical complications. RESULTS: Some 400 patients were randomized, 200 in each group. A median of 37 (i.q.r. 30-49) lymph nodes were dissected in the three-field group, compared with 24 (18-30) in the two-field group (P < 0·001). Some 43 of 200 patients (21·5 per cent) in the three-field group had cervical lymph node metastasis. More patients in the three-field group had pN3 disease: 21 of 200 (10·5 per cent) versus 10 of 200 (5·0 per cent) (P = 0·040). The rate and severity of postoperative complications were comparable between the two groups, except that six patients in the three-field arm needed reintubation compared with none in the two-field group (3·0 versus 0 per cent; P = 0·030). The 90-day mortality rate was 0 per cent in the three-field group and 0·5 per cent (1 patient) in the two-field group (P = 1·000). CONCLUSION: Oesophagectomy with three-field lymphadenectomy increased the number of lymph nodes dissected and led to stage migration owing to a 21·5 per cent rate of cervical lymph node metastasis. Postoperative complications were largely comparable between two- and three-field lymphadenectomy. Registration number: NCT01807936 ( https://www.clinicaltrials.gov).

ANTECEDENTES: El beneficio y los daños potenciales de la linfadenectomía en tres campos (three-field, 3-FLD) en el cáncer de esófago aún se desconoce. El objetivo de este estudio fue comparar la supervivencia global y la morbilidad y mortalidad entre la linfadenectomía en tres campos (3-FLD) y la linfadenectomía en dos campos (two-field lymphadenectomy, 2-FLD) en pacientes con carcinoma escamoso de esófago. MÉTODOS: Entre marzo de 2013 y noviembre de 2016, pacientes con carcinoma escamoso del tercio medio y distal del esófago fueron asignados de forma aleatoria a esofaguectomía abierta con linfadenectomía 3-FLD (cervical-torácica-abdominal) o 2-FLD (torácica-abdominal). No se administró quimioterapia o quimiorradioterapia antes de la cirugía. Este estudio describe los resultados secundarios: datos de la anatomía patología y complicaciones quirúrgicas. RESULTADOS: Se aleatorizaron un total de 400 pacientes a linfadenectomía 3-FLD y 2-FLD (200 pacientes en cada grupo). En el grupo de 3-FLD se disecaron una mediana (rango) de 37 (30-49) ganglios linfáticos en comparación con 24 (18-30) en el grupo de 2-FLD (P < 0,001). Un total de 43 de 200 (21,5%) pacientes en el grupo 3-FLD presentaron metástasis en los ganglios linfáticos (lymph node metastasis, LNM) cervicales. Más pacientes en el grupo 3-FLD presentaron un estadio de la enfermedad pN3 en comparación con el grupo 2-FLD: 21 de 200 (10,5%) versus 10 de 200 (5,0%), P = 0,040). La tasa y gravedad de las complicaciones postoperatorias fue comparable en ambos grupos, aparte de 6 pacientes en la rama 3-FLD que necesitaron reintubación (3,0%) en comparación con ninguno en el grupo 2-FLD (P = 0,030). La mortalidad a los 90 días fue del 0% en 3-FLD y del 0,5% (1 paciente en el grupo 2-FLD (P = 1,000). CONCLUSIÓN: La esofaguectomía con 3-FLD aumenta el número de ganglios linfáticos y conduce a una migración del estadio debido a la tasa de LNM cervicales del 21,5%. Las complicaciones postoperatorias fueron similares entre las linfadenectomías 3-FLD y 2-FLD.

Temperature and humidity associated with increases in tuberculosis notifications: a time-series study in Hong Kong.

Previous studies have revealed associations of meteorological factors with tuberculosis (TB) cases. However, few studies have examined their lag effects on TB cases. This study was aimed to analyse nonlinear lag effects of meteorological factors on the number of TB notifications in Hong Kong. Using a 22-year consecutive surveillance data in Hong Kong, we examined the association of monthly average temperature and relative humidity with temporal dynamics of the monthly number of TB notifications using a distributed lag nonlinear models combined with a Poisson regression. The relative risks (RRs) of TB notifications were >1.15 as monthly average temperatures were between 16.3 and 17.3 °C at lagged 13-15 months, reaching the peak risk of 1.18 (95% confidence interval (CI) 1.02-1.35) when it was 16.8 °C at lagged 14 months. The RRs of TB notifications were >1.05 as relative humidities of 60.0-63.6% at lagged 9-11 months expanded to 68.0-71.0% at lagged 12-17 months, reaching the highest risk of 1.06 (95% CI 1.01-1.11) when it was 69.0% at lagged 13 months. The nonlinear and delayed effects of average temperature and relative humidity on TB epidemic were identified, which may provide a practical reference for improving the TB warning system.

Diversity of endophytic fungi from the leaves of Vaccinium dunalianum.

This study was focus on investigating the community composition of endophytic fungi in the leaves of Vaccinium dunalianum Wight. Based on a combination of morphological features and molecular evidence, 239 endophytic fungal isolates belonging to 33 genera including 62 species were obtained and identified. By comparing the relative abundance (RA) values, the most frequent species belonged to Phyllosticta and Guignardia with RA of 26·78 and 14·22% respectively. Of which, the strains P. capitalensis and G. mangiferae with potential antimicrobial activity were the dominant endophytes to the sampling of leaves. A high diversity of endophytic fungi from V. dunalianum leaves was observed with high species richness S (62), Margalef index D' (11·1386), Shannon-Wiener index H' (3·2588), Simpson's diversity index Ds (0·9179), probability of interspecific encounter index (0·9218), and evenness Pielou index J (0·7896) but a low dominant index λ (0·0821). SIGNIFICANCE AND IMPACT OF THE STUDY: The isolated 239 endophytic fungal strains belong to 33 genera, 62 species, in which a high diversity of endophytic fungi was observed in Vaccinium dunalianum leaves. In this study, two taxa Phyllosticta capitalensis and Guignardia mangiferae with potential antimicrobial activity were the dominant endophytes. This is a promising source of natural bioactive compounds for future agro-industry application.

Laser Cooling of Radium Ions.

The unstable radium nucleus is appealing for probing new physics due to its high mass, octupole deformation, and energy level structure. Ion traps, with long hold times and low particle numbers, are excellent for work with radioactive species, such as radium and radium-based molecular ions, where low activity, and hence low total numbers, is desirable. We address the challenges associated with the lack of stable isotopes in a tabletop experiment with a low-activity (∼10 µCi) source where we laser-cool trapped radium ions. With a laser-cooled radium ion we measured the 7p^{2}P_{1/2}^{o} state's branching fractions to the ground state, 7s^{2}S_{1/2}, and a metastable excited state, 6d^{2}D_{3/2}, to be p=0.9104(7) and 0.0896(7), respectively. With a nearby tellurium reference line we measured the 7s^{2}S_{1/2}→7p^{2}P_{1/2}^{o} transition frequency, 640.096 63(6) THz.

Antimicrobial effects of the ginsenoside Rh2 on monospecies and multispecies cariogenic biofilms.

AIMS: To investigate the effects of the ginsenoside Rh2 on monospecies and multispecies cariogenic biofilms and explore the mechanism of the antibiofilm effect of Rh2 in vitro. METHODS AND RESULTS: Streptococcus mutans, Streptococcus sobrinus and Streptococcus sanguinis were chosen to form the monospecies or multispecies biofilms. Crystal violet staining and laser scanning confocal microscopy were used to observe the effect of Rh2 on biofilms in vitro. Cytotoxicity was examined by the Cell Counting Kit-8. The effects of Rh2 on bacterial membranes were observed via transmission electron microscopy (TEM). The isobaric tags for relative and absolute quantification (iTRAQ) method were used to profile the common differentially expressed proteins. Gene expression was analysed by reverse transcription quantitative polymerase chain reaction. In general, the treatment of cariogenic biofilms with Rh2 significantly decreased biomass accumulation by inhibiting bacterial growth and extracellular polysaccharide synthesis without any cytotoxic effects. TEM imaging showed that Rh2 could disrupt the cell membranes of these bacteria. The iTRAQ results indicated that the levels of mannose-specific IIC/D and acetaldehyde/alcohol dehydrogenase were substantially down-regulated, while the mRNA expression of the corresponding genes were significantly changed. CONCLUSIONS: Our data revealed a potential application for Rh2 in the protection against dental caries via the inhibition of cariogenic biofilms. SIGNIFICANCE AND IMPACT OF THE STUDY: This study describes the first application of a ginsenoside against multispecies cariogenic biofilms. Rh2 may serve as an alternative agent to prevent dental caries by effectively modulating the pathogenic potentials of oral biofilms.

Effect of milk protein composition and amount of ß-casein on growth performance, gut hormones, and inflammatory cytokines in an in vivo piglet model.

The objective of this work was to better understand the effect of differences in milk protein composition, and specifically, a change in ß-casein to total casein in a milk-based matrix, on growth performance and metabolic and inflammatory responses using a piglet model. Three formulas were optimized for piglets, with similar metabolizable energy, total protein content, and other essential nutrients. Only the protein type and ratio varied between the treatments: the protein fraction of the control diet contained only whey proteins, whereas 2 other matrices contained a whey protein to casein ratio of 60:40, and differed in the amount of ß-casein (12.5 and 17.1% of total protein). Piglets fed formula containing whey proteins and caseins, regardless of the concentration of ß-casein, showed a significantly higher average daily gain, average daily feed intake, and feed efficiency compared with piglets consuming the formula with only whey protein. Consumption of the formula containing only whey protein showed higher levels of plasma glucagon-like peptide-1 and ghrelin compared with the consumption of formula containing casein and whey protein. A positive correlation was observed between postprandial time and glucagon-like peptide-1 response. The intestinal pro-inflammatory cytokine tumor necrosis factor α increased significantly in piglets fed the whey protein/casein diet compared with those fed whey protein formula. All formula-fed piglets showed a lower level of IL-6 cytokine compared with the ad libitum sow-fed piglets, regardless of composition. No significant differences in the anti-inflammatory IL-10 concentration were observed between treatment groups. Milk protein composition contributed to the regulation of piglets' metabolic and physiological responses, with whey protein/casein formula promoting growth performance and a different immune regulatory balance compared with a formula containing only whey protein. Results indicated no differences between treatments containing different levels of ß-casein.

Identified OAS3 gene variants associated with coexistence of HBsAg and anti-HBs in chronic HBV infection.

The underlying mechanism of coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antigen antibody (anti-HBs) is still controversial. To identify the host genetic factors related to this unusual clinical phenomenon, a two-stage study was conducted in the Chinese Han population. In the first stage, we performed a case-control (1:1) age- and gender-matched study of 101 cases with concurrent HBsAg and anti-HBs and 102 controls with negative HBsAg and positive anti-HBs using whole exome sequencing. In the second validation stage, we directly sequence the 16 exons on the OAS3 gene in two dependent cohorts of 48 cases and 200 controls. Although, in the first stage, a genome-wide association study of 58,563 polymorphism variants in 101 cases and 102 controls found no significant loci (P-value ≤ .05/58563), and neither locus achieved a conservative genome-wide significance threshold (P-value ≤ 5e-08), gene-based burden analysis showed that OAS3 gene rare variants were associated with the coexistence of HBsAg and anti-HBs. (P-value = 4.127e-06 ≤ 0.05/6994). A total of 16 rare variants were screened out from 21 cases and 3 controls. In the second validation stage, one case with a stop-gained rare variant was identified. Fisher's exact test of all 149 cases and 302 controls showed that the rare coding sequence mutations were more frequent in cases vs controls (P-value = 7.299e-09, OR = 17.27, 95% CI [5.01-58.72]). Protein-coding rare variations on the OAS3 gene are associated with the coexistence of HBsAg and anti-HBs in patients with chronic HBV infection in Chinese Han population.

Effect of milk protein composition of a model infant formula on the physicochemical properties of in vivo gastric digestates.

We investigated the effect of protein composition and, in particular, the presence of whey proteins or ß-casein on the digestion behavior of a model infant formula using an in vivo piglet model. Three isocaloric diets optimized for piglets were prepared with the same concentrations of protein. For protein source, 1 diet contained only whey proteins and 2 contained a casein:whey protein ratio of 40:60 but differed in the amount of ß-casein. To obtain the desired protein compositions, skim milk was microfiltered at 7 or 22°C, and retentates and permeates were combined with whey protein isolate. The diets were optimized to the nutritional needs of the piglets and fed to 24 newborn piglets for 18 d. Eight piglets were also fed ad libitum with sow milk and considered only as reference (not included in the statistical analysis). The study was carried out in 2 blocks, killing the animals 60 and 120 min after the last meal. All gastric contents, regardless of diet, showed a wide range of pH. Postprandial time did not affect the pH or physical properties of the gastric digesta. The digesta from whey protein-casein formulas showed significantly higher viscosity, a higher storage modulus, and a denser microstructure than digesta obtained from piglets fed whey protein formula. The ß-casein:total casein ratio at the level used in this study did not significantly affect the physical and chemical properties of the stomach digestate. Although caseins showed extensive gastric hydrolysis, whey proteins remained largely intact at both postprandial times. The results indicate that the presence of different concentrations of milk proteins can be critical to the digestion properties of the food matrix and may affect the nutritional properties of the components.