Vaccination reduces central nervous system IL-1ß and memory deficits after COVID-19 in mice.

Up to 25% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit postacute cognitive sequelae. Although millions of cases of coronavirus disease 2019 (COVID-19)-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1 (IL-1), a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of individuals with COVID-19. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 Beta variant leads to central nervous system infiltration of Ly6Chi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1ß and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes postacute cognitive deficits. Vaccination with a low dose of adenoviral-vectored spike protein prevents hippocampal production of IL-1ß during breakthrough SARS-CoV-2 infection, loss of neurogenesis and subsequent memory deficits. Our study identifies IL-1ß as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new mouse model that is prevented by vaccination.

Vaccination prevents IL-1ß-mediated cognitive deficits after COVID-19.

Up to 25% of SARS-CoV-2 patients exhibit post-acute cognitive sequelae. Although millions of cases of COVID-19-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1, a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of COVID-19 patients. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 beta variant, leads to CNS infiltration of Ly6Chi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1ß and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes post-acute cognitive deficits. Breakthrough infection after vaccination with a low dose of adenoviral vectored Spike protein prevents hippocampal production of IL-1ß during breakthrough SARS-CoV-2 infection, loss of neurogenesis, and subsequent memory deficits. Our study identifies IL-1ß as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new murine model that is prevented by vaccination.

A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic ß-cells.

Glucose-induced insulin secretion depends on ß-cell electrical activity. Inhibition of ATP-regulated potassium (KATP) channels is a key event in this process. However, KATP channel closure alone is not sufficient to induce ß-cell electrical activity; activation of a depolarizing membrane current is also required. Here we examine the role of the mechanosensor ion channel PIEZO1 in this process. Yoda1, a specific PIEZO1 agonist, activates a small membrane current and thereby triggers ß-cell electrical activity with resultant stimulation of Ca2+-influx and insulin secretion. Conversely, the PIEZO1 antagonist GsMTx4 reduces glucose-induced Ca2+-signaling, electrical activity and insulin secretion. Yet, PIEZO1 expression is elevated in islets from human donors with type-2 diabetes (T2D) and a rodent T2D model (db/db mouse), in which insulin secretion is reduced. This paradox is resolved by our finding that PIEZO1 translocates from the plasmalemma into the nucleus (where it cannot influence the membrane potential of the ß-cell) under experimental conditions emulating T2D (high glucose culture). ß-cell-specific Piezo1-knockout mice show impaired glucose tolerance in vivo and reduced glucose-induced insulin secretion, ß-cell electrical activity and Ca2+ elevation in vitro. These results implicate mechanotransduction and activation of PIEZO1, via intracellular accumulation of glucose metabolites, as an important physiological regulator of insulin secretion.

Factors influencing the quality of life in children after biliary atresia treatment.

BACKGROUND: Despite surgical treatment, children with biliary atresia (BA) may face many problems which seriously affect their quality of life. However, there is a paucity of studies in China examining the quality of life of these children after BA treatment. This study investigated the current status of the quality of life of children after BA treatment and analyzed the influencing factors so as to provide a scientific basis for the development of targeted interventional measures. METHODS: From May 1 to May 31, 2021, the STAR questionnaire method was used to conduct cross-sectional surveys in children following BA surgery in the West China Hospital of Sichuan University, China. The basic information questionnaire was used to investigate the general characteristics of the children. The children were also given quality of life questionnaires during follow-up sessions after surgical treatment for BA. In addition, a 12-point health survey was used to assess the physical and mental health of the children's caregivers. Age- and gender-matched healthy children were recruited as controls. Correlation analysis and multiple linear regression equations were established to explore the influencing factors of the quality of life of children after surgery for BA. RESULTS: After surgery, children with BA experienced significantly lower physical health, emotional function, social function, cognitive function, and quality of life compared to healthy children (P<0.050). Co-existing diseases had a statistically significant impact on the quality of life of children with BA (b=-12.566; t=-2.343; P=0.021), and the caregiver's understanding level of liver transplantation also had a statistically significant impact on the quality of life of these children (b=6.481; t=2.376; P=0.021). CONCLUSIONS: The quality of life of children after BA surgery was significantly lower than that of age-matched healthy children. Co-existing diseases and the caregiver's understanding level of liver transplantation were the main factors affecting the quality of life of these children.

Effects of different personalised sound therapies in tinnitus patients with hearing loss of various extents.

BACKGROUND: Limited by difficulties in choosing the appropriate sound, sound therapies could only effectively restrain the development of tinnitus in some patients. Thus, individualised sound therapies are of urgent needs. OBJECTIVE: The purpose of this study was to determine the therapeutic effect of different individualised sound therapies in tinnitus patients complicated with hearing loss of various extents. RESEARCH DESIGN: Participants were assigned to two different personalised sound therapies as counterbalanced by age and gender in this observational study. STUDY SAMPLE: Ninety-two tinnitus patients with hearing loss admitted to our hospital from January 2018 to January 2020 were enrolled and evenly grouped as the observation group and the control group in accordance with the random number table. DATA COLLECTION AND ANALYSES: Tinnitus characteristics of both the groups were determined before treatment. Patients from the observation group received pure tone sound therapy composed of 7 octaves (0.125, 0.25, 0.5, 1, 2, 4 and 8 kHz) based on frequencies determined from their tinnitus characteristics. The control group received pure tone sound therapy composed of 9 one-third octaves based on their tinnitus characteristics. RESULTS: The observation group had better therapeutic effects than that in the control group (91.30% vs 73.91%, P < .05). After 1 week, and 1- to 3-month treatment, patients in the observation group all presented with decreased tinnitus handicap, decreased tinnitus volume and improved sleep quality compared with the control group (P < .05). CONCLUSION: This study found that both personalised sound therapies were effective in tinnitus treatment while 7-octave pure tone adjusted from tinnitus frequencies were more promising in decreasing tinnitus handicap and tinnitus volume.

A single intranasal or intramuscular immunization with chimpanzee adenovirus-vectored SARS-CoV-2 vaccine protects against pneumonia in hamsters.

The development of an effective vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), is a global priority. Here, we compare the protective capacity of intranasal and intramuscular delivery of a chimpanzee adenovirus-vectored vaccine encoding a prefusion stabilized spike protein (chimpanzee adenovirus [ChAd]-SARS-CoV-2-S) in Golden Syrian hamsters. Although immunization with ChAd-SARS-CoV-2-S induces robust spike-protein-specific antibodies capable of neutralizing the virus, antibody levels in serum are higher in hamsters vaccinated by an intranasal compared to intramuscular route. Accordingly, against challenge with SARS-CoV-2, ChAd-SARS-CoV-2-S-immunized hamsters are protected against less weight loss and have reduced viral infection in nasal swabs and lungs, and reduced pathology and inflammatory gene expression in the lungs, compared to ChAd-control immunized hamsters. Intranasal immunization with ChAd-SARS-CoV-2-S provides superior protection against SARS-CoV-2 infection and inflammation in the upper respiratory tract. These findings support intranasal administration of the ChAd-SARS-CoV-2-S candidate vaccine to prevent SARS-CoV-2 infection, disease, and possibly transmission.

FDA Approval Summary: Atezolizumab Plus Bevacizumab for the Treatment of Patients with Advanced Unresectable or Metastatic Hepatocellular Carcinoma.

On May 29, 2020, the FDA approved atezolizumab for use in combination with bevacizumab, for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) with no prior systemic treatment. The approval was based on data from Study IMbrave150, which randomly allocated (2:1) patients to receive either atezolizumab plus bevacizumab (atezolizumab-bevacizumab) or sorafenib. Overall survival (OS) and independently assessed progression-free survival (PFS) in the intent-to-treat population were the primary endpoints. At the time of the primary analysis, the estimated median OS could not be estimated in the atezolizumab-bevacizumab arm and was 13.2 months in the sorafenib arm [HR, 0.58; 95% confidence interval (CI), 0.42-0.79]. The estimated median PFS was 6.8 months (95% CI, 5.8-8.3) and 4.3 months (95% CI, 4.0-5.6) in the atezolizumab-bevacizumab and sorafenib arms, respectively. Adverse reactions occurring in >20% of patients receiving atezolizumab-bevacizumab were hypertension, fatigue/asthenia, and proteinuria. Adverse reactions occurring in >20% of patients receiving sorafenib were palmar-plantar erythrodysesthesia, diarrhea, hypertension, and decreased appetite. Hemorrhage was reported more frequently in patients receiving atezolizumab-bevacizumab (25%) than in patients receiving sorafenib (17%). An evaluation for the presence of varices is recommended within 6 months of initiation of atezolizumab-bevacizumab in patients with HCC. Approval of atezolizumab-bevacizumab is likely to change the treatment paradigm for HCC, given that treatment with atezolizumab-bevacizumab resulted in improved OS and PFS compared with sorafenib, an accepted standard of care for first-line treatment of patients with unresectable HCC.See related commentary by Castet et al., p. 1827.

The short-term outcome of modified laparoscopic Kasai portoenterostomy for biliary atresia.

OBJECTIVES: Laparoscopic Kasai portoenterostomy (LKPE) has been shown to be a safe and feasible procedure in patients with biliary atresia (BA). The purpose of this study was to investigate the efficacy of modified LKPE (MLKPE) in the treatment of BA. METHODS: Data of 58 BA patients undertaken MLPKE from July 2014 to December 2015 were retrospectively analyzed (group B), and compared with that of 43 BA patients received open Kasai portoenterostomy (OKPE) during the same period (group C). In addition, 195 BA patients who had undergone LKPE during May 2009 to June 2014 were also included (group A). RESULTS: All 296 patients enrolled in this study were non-syndromic type III BA. Compared with group A, group B had shorter operative time (ORT) (P < 0.01) and fewer intraoperative blood transfusion (IOBT) (P < 0.05). The conversion rate and cholangitis rate were also significantly lower in group B than that in group A (P < 0.05). The postoperative oral intake resumed (POOR), any postoperative complications (APOC), clearance of jaundice (CJ), 1-year and 3-year survival rate with native liver (SNL) were not significantly different between group A and group B (P > 0.05). The ORT, IOBT, POOR, APOC, CJ, 1-year and 3-year SNL in group B were much better than that of group C (P < 0.05). CONCLUSION: The MLKPE was associated with good perioperative with ORT, IOBT, POOR, and APOC. The short-term outcomes in MLKPE were no worse than that of OKPE and LKPE. MLKPE can be regarded as a treatment option for BA.

A single intranasal or intramuscular immunization with chimpanzee adenovirus vectored SARS-CoV-2 vaccine protects against pneumonia in hamsters.

The development of an effective vaccine against SARS-CoV-2, the etiologic agent of COVID-19, is a global priority. Here, we compared the protective capacity of intranasal and intramuscular delivery of a chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike protein (ChAd-SARS-CoV-2-S) in Golden Syrian hamsters. While immunization with ChAd-SARS-CoV-2-S induced robust spike protein specific antibodies capable or neutralizing the virus, antibody levels in serum were higher in hamsters immunized by an intranasal compared to intramuscular route. Accordingly, ChAd-SARS-CoV-2-S immunized hamsters were protected against a challenge with a high dose of SARS-CoV-2. After challenge, ChAd-SARS-CoV-2-S-immunized hamsters had less weight loss and showed reductions in viral RNA and infectious virus titer in both nasal swabs and lungs, and reduced pathology and inflammatory gene expression in the lungs, compared to ChAd-Control immunized hamsters. Intranasal immunization with ChAd-SARS-CoV-2-S provided superior protection against SARS-CoV-2 infection and inflammation in the upper respiratory tract. These findings support intranasal administration of the ChAd-SARS-CoV-2-S candidate vaccine to prevent SARS-CoV-2 infection, disease, and possibly transmission.

Hydroxyapatite Nanowire-Reinforced Poly(ethylene oxide)-Based Polymer Solid Electrolyte for Application in High-Temperature Lithium Batteries.

Hybrid polymer electrolytes with excellent performance at high temperatures are very promising for developing solid-state lithium batteries for high-temperature applications. Herein, we use a self-supporting hydroxyapatite (HAP) nanowire membrane as a filler to improve the performance of a poly(ethylene oxide) (PEO)-based solid-state electrolyte. The HAP membrane could comprehensively improve the properties of the hybrid polymer electrolyte, including the higher room-temperature ionic conductivity of 1.05 × 10-5 S cm-1, broad electrochemical windows of up to 5.9 V at 60 °C and 4.9 V at 160 °C, and a high lithium-ion migration of 0.69. In addition, the LiFePO4//Li full battery with a solid electrolyte possesses good rate capability, cycling, and Coulomb efficiency at extreme high temperatures, that is, after 300 continuous charge and discharge cycles at 4 C rate, the discharge capacity retention rate is 77% and the Coulomb efficiency is 99%. The use of the flexible self-supporting HAP nanowire membrane to improve the PEO-based solid composite electrolyte provides new strategies and opportunities for developing rechargeable lithium batteries in extreme high-temperature applications.

Incidence, risk factors, and outcomes of acute kidney injury in neonates after surgical procedures.

BACKGROUND: Acute kidney injury (AKI) is common and associated with poor outcomes in critically ill neonates. The objective of this study was to study the incidence, risk factors, and clinical outcomes of AKI in neonates receiving non-cardiac surgery. METHODS: We performed a single-center retrospective study between January 2017 and December 2018 of neonates who had received abdominal and thoracic surgical procedures. AKI was defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Patient information, clinical data, and outcomes were collected and analyzed. Logistic regression was used to analyze risk factors of AKI and association between AKI and mortality. RESULTS: Fifty-four (33.8%) of 160 patients developed AKI after surgical procedures. Compared with neonates without AKI, neonates with AKI had higher mortality rate (18.5% VS 5.7%, p = 0.022), lower gestational age (30.5 weeks, interquartile range [IQR] 28-33.5, VS 34.5 weeks, IQR 33-37.5, p = 0.035), higher rates of very low birth weight (33.3% VS 17.0%, p = 0.019), longer duration of mechanical ventilation (0.5 days, IQR 0-1.5, VS 0 days, IQR 0-1, p = 0.043) and higher rates of sepsis (35.2% VS 19.8%, p = 0.034). Risk factors of AKI included gestational age under 32 weeks (OR 4.8, 95% CI 1.8-12.6; p = 0.001), sepsis (OR 4.3, 95% CI 1.7-11.3; p = 0.003), operation time longer than 120 min (OR 2.7, 95% CI 1.1-6.6; p = 0.024), and diagnosis of necrotizing enterocolitis (OR 3.5, 95% CI 1.3-9.1; p = 0.011). AKI after surgery was significantly associated with mortality (OR 4.3, 95% CI 1.1-16.9; p = 0.036). CONCLUSIONS: AKI is common and associated with poor outcomes in surgical neonates. Early recognition and intervention of AKI in these patients are important.

Drp1 mediates high glucose-induced mitochondrial dysfunction and epithelial-mesenchymal transition in endometrial cancer cells.

This study aims to clarify the role and molecular mechanism of dynamin-related protein 1 (Drp1)-mediated mitochondrial homeostasis in high glucose (HG)-induced endometrial cancer (EC). Normal endometrium and tumor tissues of EC patients with normal and HG levels were collected, and Drp1 and p-Drp1 expression levels were detected by immunohistochemistry. Human EC cells were cultured with different glucose concentrations, and Drp1 and p-Drp1 expression levels were evaluated by Western blotting. Cell models of control and siDrp1 groups under normal and HG conditions were established, and subsequent functional experiments were conducted. Histology and in vitro experiments showed that the HG environment increased Drp1 activation, which could lead to mitochondrial dysfunction. Moreover, the imbalance of mitochondrial homeostasis mediated by Drp1 resulted in cell dysfunction, including altered glucose metabolism and increased epithelial-mesenchymal transition (EMT), migration and invasion. All these changes caused by HG could be partially alleviated by Drp1 knockdown. This study revealed that Drp1 was involved in the progression of EC associated with HG, and Drp1 might be a new potential therapeutic target for EC patients with diabetes.

Prognostic significance of artemin in gastric cancer and its role in tumorigenesis.

BACKGROUND: Abundant evidence suggests that a neurotrophic factor, artemin (ARTN), is involved in the tumorigenesis and progression in several malignancies. However, the biological functions of ARTN in gastric cancer (GC) remain poorly elucidated. METHODS: ARTN expression was evaluated by immunohistochemistry in GC tissue, and its clinical and prognosis significance was analyzed. Cell counting kit-8 (CCK-8), transwell chamber assay, and western blot were used to detect the effects of ARTN knockdown on GC cell behavior in vitro. RESULTS: ARTN was highly expressed in GC tissue, and its positive expression predicted poor prognosis of GC. In vitro studies showed that ARTN knockdown inhibited the STAT3 phosphorylation, thus impeding cell proliferation and DNA synthesis in GC. Furthermore, the promotion of ARTN on the migration and invasion of GC cells was achieved by regulating the expression of MMP9 and E-cadherin. CONCLUSIONS: ARTN might be a promising prognostic marker and a potential therapeutic target for GC.

Thoracoscopic Treatment of Late-Presenting Congenital Diaphragmatic Hernia in Infants and Children.

PURPOSE: Given that the application of thoracoscopic surgery to late-presenting congenital diaphragmatic hernia (CDH) in infants and children is controversial, we summarized our experiences with patients at two medical centers and aimed to discuss the safety and feasibility of thoracoscopic repair. MATERIALS AND METHODS: A retrospective review of late-presenting CDH cases involving patients who underwent thoracoscopic repair from October 2010 to June 2017 was performed. Data, including patients' demographic characteristics, manipulative details, and postoperative complications, were extracted and analyzed. RESULTS: A total of 59 cases were included in this study. Patients ranged in age from 2 months to 8 years (mean: 18 months). Twenty-five patients presented with shortness of breath and dyspnea. Furthermore, 34 cases were found occasionally. Forty-six left-sided hernias and 13 right-sided hernias were found. Operating time ranged from 30 to 100 minutes (mean: 55 minutes), and the amount of blood loss was 3-5 mL (mean: 3.8 mL). The size of the diaphragmatic defect ranged from 2 × 2 cm to 5 × 8 cm. The chest tubes were taken out within 24 hours. The average length of postoperative hospital stay was 5.2 ± 0.4 days (range: 4-6 days). The length of the follow-up period ranged from 3 months to 3 years (mean: 18 months), with no recurrences. CONCLUSION: Thoracoscopic repair of late-presenting CDH is a safe and efficacious technique. It can facilitate the procedure and decrease the recurrence rate by shifting the focus to operative details. The prognosis is excellent once the correct operative details are achieved.

Infant progressive colonic stenosis caused by antibiotic-related Clostridium difficile colitis - a case report and literature review.

BACKGROUND: Colonic stenosis is a rare cause of pediatric intestinal obstruction. The root cause underlying colonic stenosis is unclear and there is no fixed operation. CASE PRESENTATION: We reported on a male infant with progressive colonic stenosis caused by antibiotic-related colitis. The infant was admitted to our hospital with pneumonia but developed progressive abdominal distension and diarrhea following antibiotic treatment with meropenem. Initial testing of stool culture showed a Clostridium difficile infection. Additional testing with barium enema imaging showed stenosis at the junction of the sigmoid and descending colon at first and another stenosis occurred at the right half of the transverse colon 3 weeks later. Staged surgical treatment was performed with primary resections of the two parts suffering stenosis, ileostomy, and secondary intestinal anastomosis. A pathological exam then confirmed the diagnosis of colonic stenosis and the patient had an uneventful recovery and has been recovering well as evidenced by the 1-year follow-up. CONCLUSIONS: Based on a review of the literature and our case report, we found that progressive colonic stenosis caused by colitis due to antibiotic-related Clostridium difficile infection is rare in infants. Infants with colitis and repeated abdominal distention, vomiting, and constipation should be treated with the utmost caution and screened. Despite this, clinical manifestations depended on the severity of the stenosis. Barium enema, colonoscopy, laprascopy or laparotomy and colonic biopsy are helpful for diagnosis and differential diagnosis. While both one-stage and multiple-stage operations are feasible, a staged operation should be used for multiple colonic stenoses.

A quality-of-life system to evaluate children with leukemia in China.

The scale for assessing the quality of life (QOL) of children with leukemia of different ages is vacant in China.Items for developing a QOL scale were selected through a literature review, interviews with 58 parents and children with leukemia by Delphi method, which involved pediatric oncologists, psychologists, and pediatricians. The initial items were formulated through 2 rounds of the Delphi method and statistical analyses. The formulated scale was pre-tested for reliability and validity. A method was adopted to weight the importance of items within the evaluation index system.The final scale includes 5 dimensions. There are 10 secondary items for age 2 to 4 years, 12 secondary items for all other age groups, and 29, 46, 52, and 50 tertiary items for the age groups 2 to 4 years, 5 to 7 years, 8 to 12 years, and 13 to 18 years, respectively. The authority coefficient for experts was 0.75, with Kendall's W coefficient P < .01, for both rounds. The entire Cronbach alpha was >0.9, and the content validity >0.75. The weights of the first-grade items are: 0.201, 0.203, 0.198, 0.201, and 0.198.This quality-of-life scale for children with leukemia in China has demonstrated reliability and validity, while a further validity assessment is required.

FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring BRAF V600E Mutations.

On June 22, 2017, the Food and Drug Administration expanded indications for dabrafenib and trametinib to include treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations. Approval was based on results from an international, multicenter, multicohort, noncomparative, open-label trial, study BRF113928, which sequentially enrolled 93 patients who had received previous systemic treatment for advanced NSCLC (Cohort B, n = 57) or were treatment-naïve (Cohort C, n = 36). All patients received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily. In Cohort B, overall response rate (ORR) was 63% (95% confidence interval [CI] 49%-76%) with response durations ≥6 months in 64% of responders. In Cohort C, ORR was 61% (95% CI 44%-77%) with response durations ≥6 months in 59% of responders. Results were evaluated in the context of the Intergroupe Francophone de Cancérologie Thoracique registry and a chart review of U.S. electronic health records at two academic sites, characterizing treatment outcomes data for patients with metastatic NSCLC with or without BRAF V600E mutations. The treatment effect of dabrafenib 150 mg twice daily was evaluated in 78 patients with previously treated BRAF mutant NSCLC, yielding an ORR of 27% (95% CI 18%-38%), establishing that dabrafenib alone is active, but that the addition of trametinib is necessary to achieve an ORR of >40%. The most common adverse reactions (≥20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. IMPLICATIONS FOR PRACTICE: The approvals of dabrafenib and trametinib, administered concurrently, provide a new regimen for the treatment of a rare subset of non-small cell lung cancer (NSCLC) and demonstrate how drugs active for treatment of BRAF-mutant tumors in one setting predict efficacy and can provide supportive evidence for approval in another setting. The FDA also approved the first next-generation sequencing oncology panel test for simultaneous assessment of multiple actionable mutations, which will facilitate selection of optimal, personalized therapy. The test was shown to accurately and reliably select patients with NSCLC with the BRAF V600E mutation for whom treatment with dabrafenib and trametinib is the optimal treatment.

Benefit-Risk Summary of Regorafenib for the Treatment of Patients with Advanced Hepatocellular Carcinoma That Has Progressed on Sorafenib.

On April 27, 2017, the U.S. Food and Drug Administration approved regorafenib for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with sorafenib. Approval was based on the results of a single, randomized, placebo-controlled trial (RESORCE) that demonstrated an improvement in overall survival (OS). Patients were randomly allocated to receive regorafenib160 mg orally once daily or matching placebo for the first 21 days of each 28-day cycle. The trial demonstrated a significant improvement in OS (hazard ratio [HR] = 0.63; 95% confidence interval [CI], 0.50-0.79, p < .0001) with an estimated median OS of 10.6 months in the regorafenib arm and 7.8 months in the placebo arm. A statistically significant improvement in progression-free survival (PFS) based on modified RECIST for HCC [Semin Liver Dis 2010;30:52-60] (HR = 0.46; 95% CI, 0.37-0.56, p < .0001) was also demonstrated; the estimated median PFS was 3.1 and 1.5 months in the regorafenib and placebo arms, respectively. The overall response rate, based on modified RECIST for HCC, was 11% in the regorafenib arm and 4% in the placebo arm. The toxicity profile was consistent with that observed in other indications; the most clinically significant adverse reactions were palmar-plantar erythrodysesthesia, diarrhea, and hypertension. Based on the improvement in survival and acceptable toxicity, a favorable benefit-to-risk evaluation led to approval for treatment of patients with advanced HCC. IMPLICATIONS FOR PRACTICE: Regorafenib is the first drug approved by the U.S. Food and Drug Administration for the treatment of hepatocellular carcinoma that has progressed on sorafenib and is expected to become a standard of care for these patients.

Effects of the long-term consumption of hydrogen-rich water on the antioxidant activity and the gut flora in female juvenile soccer players from Suzhou, China.

Expending a considerable amount of physical energy inevitably leads to fatigue during both training and competition in football. An increasing number of experimental findings have confirmed the relationship between the generation and clearance of free radicals, fatigue, and exercise injury. Recently, hydrogen was identified as a new selective antioxidant with potential beneficial applications in sports. The present study evaluated the effect of 2-month consumption of hydrogen-rich water on the gut flora in juvenile female soccer players from Suzhou. As demonstrated by enzyme linked immunosorbent assay and 16S rDNA sequence analysis of stool samples, the consumption of hydrogen-rich water for two months significantly reduced serum malondialdehyde, interleukin-1, interleukin-6, tumour necrosis factor-α levels; then significantly increased serum superoxide dismutase, total antioxidant capacity levels and haemoglobin levels of whole blood. Furthermore, the consumption of hydrogen-rich water improved the diversity and abundance of the gut flora in athletes. All examined indices, including the shannon, sobs, ace, and chao indices, were higher in the control group than those proposed to result from hydrogen-rich water consumption prior to the trial, but these indices were all reversed and were higher than those in the controls after the 2-month intervention. Nevertheless, there were some differences in the gut flora components of these two groups before the trial, whereas there were no significant changes in the gut flora composition during the trial period. Thus, the consumption of hydrogen-rich water for two months might play a role modulating in the gut flora of athletes based on its selective antioxidant and anti-inflammatory activities. The study protocol was approved by the ethics committee of the Suzhou Sports School (approved number: SSS-EC150903).

Neuron-derived CCL2 contributes to microglia activation and neurological decline in hepatic encephalopathy.

BACKGROUND: CCL2 was up-regulated in neurons and involved in microglia activation and neurological decline in mice suffering from hepatic encephalopathy (HE). However, no data exist concerning the effect of neuron-derived CCL2 on microglia activation in vitro. METHODS: The rats were pretreated with CCL2 receptor inhibitors (INCB or C021, 1 mg/kg/day i.p.) for 3 days prior to thioacetamide (TAA) administration (300 mg/kg/day i.p.) for inducing HE model. At 8 h following the last injection (and every 4 h after), the grade of encephalopathy was assessed. Blood and whole brains were collected at coma for measuring CCL2 and Iba1 expression. In vitro, primary neurons were stimulated with TNF-α, and then the medium were collected for addition to microglia cultures with or without INCB or C021 pretreatment. The effect of the medium on microglia proliferation and activation was evaluated after 24 h. RESULTS: CCL2 expression and microglia activation were elevated in the cerebral cortex of rats received TAA alone. CCL2 receptors inhibition improved neurological score and reduced cortical microglia activation. In vitro, TNF-α treatment induced CCL2 release by neurons. Medium from TNF-α stimulated neurons caused microglia proliferation and M1 markers expression, including iNOS, COX2, IL-6 and IL-1ß, which could be suppressed by INCB or C021 pretreatment. The medium could also facilitate p65 nuclear translocation and IκBα phosphorylation, and NF-κB inhibition reduced the increased IL-6 and IL-1ß expression induced by the medium. CONCLUSION: Neuron-derived CCL2 contributed to microglia activation and neurological decline in HE. Blocking CCL2 or inhibiting microglia excessive activation may be potential strategies for HE.