Early versus delayed appendicectomy for appendiceal phlegmon or abscess.

BACKGROUND: This is an update of a Cochrane review first published in 2017. Acute appendicitis (inflammation of the appendix) can be simple or complicated. Appendiceal phlegmon and appendiceal abscess are examples of complicated appendicitis. Appendiceal phlegmon is a diffuse inflammation in the bottom right of the appendix, while appendiceal abscess is a discrete inflamed mass in the abdomen that contains pus. Appendiceal phlegmon and abscess account for 2% to 10% of acute appendicitis. People with appendiceal phlegmon or abscess usually need an appendicectomy to relieve their symptoms (e.g. abdominal pain, loss of appetite, nausea, and vomiting) and avoid complications (e.g. peritonitis (infection of abdominal lining)). Surgery for people with appendiceal phlegmon or abscess may be early (immediately after hospital admission or within a few days of admission), or delayed (several weeks later in a subsequent hospital admission). The optimal timing of appendicectomy for appendiceal phlegmon or abscess is debated. OBJECTIVES: To assess the effects of early appendicectomy compared to delayed appendicectomy on overall morbidity and mortality in people with appendiceal phlegmon or abscess. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, two other databases, and five trials registers on 11 June 2023, together with reference checking to identify additional studies. SELECTION CRITERIA: We included all individual and cluster-randomised controlled trials (RCTs), irrespective of language, publication status, or age of participants, comparing early versus delayed appendicectomy in people with appendiceal phlegmon or abscess. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included eight RCTs that randomised 828 participants to early or delayed appendicectomy for appendiceal phlegmon (7 trials) or appendiceal abscess (1 trial). The studies were conducted in the USA, India, Nepal, and Pakistan. All RCTs were at high risk of bias because of lack of blinding and lack of published protocols. They were also unclear about methods of randomisation and length of follow-up. 1. Early versus delayed open or laparoscopic appendicectomy for appendiceal phlegmon We included seven trials involving 788 paediatric and adult participants with appendiceal phlegmon: 394 of the participants were randomised to the early appendicectomy group (open or laparoscopic appendicectomy as soon as the appendiceal mass resolved within the same admission), and 394 were randomised to the delayed appendicectomy group (initial conservative treatment followed by delayed open or laparoscopic appendicectomy several weeks later). There was no mortality in either group. The evidence is very uncertain about the effect of early appendicectomy on overall morbidity (risk ratio (RR) 0.74, 95% confidence interval (CI) 0.19 to 2.86; 3 trials, 146 participants; very low-certainty evidence), the proportion of participants who developed wound infections (RR 0.99, 95% CI 0.48 to 2.02; 7 trials, 788 participants), and the proportion of participants who developed faecal fistulas (RR 1.75, 95% CI 0.36 to 8.49; 5 trials, 388 participants). Early appendicectomy may reduce the abdominal abscess rate (RR 0.26, 95% CI 0.08 to 0.80; 4 trials, 626 participants; very low-certainty evidence), reduce the total length of hospital stay by about two days (mean difference (MD) -2.02 days, 95% CI -3.13 to -0.91; 5 trials, 680 participants), and increase the time away from normal activities by about five days (MD 5.00 days; 95% CI 1.52 to 8.48; 1 trial, 40 participants), but the evidence is very uncertain. 2. Early versus delayed laparoscopic appendicectomy for appendiceal abscess We included one trial involving 40 paediatric participants with appendiceal abscess: 20 were randomised to the early appendicectomy group (emergent laparoscopic appendicectomy), and 20 were randomised to the delayed appendicectomy group (initial conservative treatment followed by delayed laparoscopic appendicectomy 10 weeks later). There was no mortality in either group. The trial did not report on overall morbidity, various complications, or time away from normal activities. The evidence is very uncertain about the effect of early appendicectomy on the total length of hospital stay (MD -0.20 days, 95% CI -3.54 to 3.14; very low-certainty evidence). AUTHORS' CONCLUSIONS: For the comparison of early versus delayed open or laparoscopic appendicectomy for paediatric and adult participants with appendiceal phlegmon, very low-certainty evidence suggests that early appendicectomy may reduce the abdominal abscess rate. The evidence is very uncertain whether early appendicectomy prevents overall morbidity or other complications. Early appendicectomy may reduce the total length of hospital stay and increase the time away from normal activities, but the evidence is very uncertain. For the comparison of early versus delayed laparoscopic appendicectomy for paediatric participants with appendiceal abscess, data are sparse, and we cannot rule out significant benefits or harms of early versus delayed appendicectomy. Further trials on this topic are urgently needed and should specify a set of criteria for use of antibiotics, percutaneous drainage of the appendiceal abscess prior to surgery, and resolution of the appendiceal phlegmon or abscess. Future trials should include outcomes such as time away from normal activities and length of hospital stay.

Improving post-acute stroke follow-up care by adopting telecare consultations in a nurse-led clinic: Study protocol of a hybrid implementation-effectiveness trial.

AIM: To evaluate the clinical effectiveness and implementation strategies of telecare consultations in post-stroke nurse-led clinics. BACKGROUND: Telecare consultations could be an alternative to conventional in-person consultations and improve continuity of care for stroke survivors following their discharge from hospital. Previous studies utilizing telecare consultations only focused on testing their clinical effectiveness on stroke survivors; the appropriateness and feasibility of adopting this new delivery modality in a real-world setting were not examined. DESIGN: A Type II hybrid effectiveness-implementation design will be adopted. METHODS: Eligible stroke survivor participants will be randomly assigned to the intervention group (telecare consultation) or control group (usual in-person clinic consultation). Both groups will receive the same nursing intervention but delivered through different channels. The Reach, Effectiveness, Adoption, Implementation, Maintenance framework will be used to evaluate the clinical effectiveness and implementation outcomes. The primary outcome is the non-inferiority of the degree of disability between the two groups at 3 months into the intervention and at 3 months post-intervention. The paper complies with the SPIRIT guidelines for study protocols adapted for designing and reporting parallel group randomized trials. CONCLUSION: The findings of this study will provide key insights into the processes for implementing and adopting telecare consultations into long-term services for post-stroke patients. IMPACT: This study contributes to the translation of telecare consultations for stroke survivors into real-life settings. If effective, this program may provide guidance for expanding telecare consultations to other post-stroke nurse-led clinics or to patients with other chronic diseases. TRIAL REGISTRATION: This study has been registered at clinicaltrials.gov (identifier: NCT05183672). Registered on 10 January 2022.

Fingerprinting of physical manufacturing properties of different acids for effervescent systems.

The study aimed to fingerprint the physical manufacturing properties of five commonly used acid sources in effervescent systems for designing the formulation and process of such systems. The hygroscopicity, texture properties, rheological torque, compressibility, tabletability, etc., were investigated to inspect 'powder direct compression (DC)' and 'wet granulation and compression' properties of citric (CA), tartaric (TA), malic (MA), fumaric (FA), and adipic acid (AA). The DC ability was evaluated by the SeDeM expert system. The results indicated that all acid powders failed to meet flowability requirements for DC, and plastic deformation dominated during compression. Furthermore, CA exhibited strong hygroscopicity and punch sticking, while MA demonstrated the best tabletability. TA had a large wet granulation space and was relatively the most suitable for DC. AA was extremely hygroscopic, and its flowability improved significantly as particle size increased. Finally, FA displayed the lowest hygroscopicity and ejection force as well as great compressibility and wet granulation space, and did not exhibit punch sticking, while the granule fragments dissolved slowly during disintegration. Generally speaking, the formulation or granulation affected the tabletability, indicating that pairing with other acids or suitable fillers could potentially improve its disadvantages. These multidimensional assessments effectively reduce the pre-exploration and enhance the efficiency of the development of effervescent systems.

WITHDRAWN: Gut Microbiota Alter Visceral Pain Sensation and Inflammation via Modulation of Synthesis of Resolvin D1 in Colonic Tuft Cells

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Boosting Output Performance of Sliding Mode Triboelectric Nanogenerator by Shielding Layer and Shrouded-Tribo-Area Optimized Ternary Electrification Layered Architecture.

Sliding mode triboelectric nanogenerator (S-TENG) is effective for low-frequency mechanical energy harvesting owing to their more efficient mechanical energy extraction capability and easy packaging. Ternary electrification layered (TEL) architecture is proven useful for improving the output performance of S-TENG. However, the bottleneck of electric output is the air breakdown on the interface of tribo-layers, which seriously restricts its further improvement. Herein, a strategy is adopted by designing a shielding layer to prevent air breakdown on the central surface of tribo-layers. And the negative effects of air breakdown on the edge of sliding layer are averted by increasing the shrouded area of tribo-layers on slider. Output charge of this shielding-layer and shrouded-tribo-area optimized ternary electrification layered triboelectric nanogenerator (SS-TEL-TENG) achieves 3.59-fold enhancement of traditional S-TENG and 1.76-fold enhancement of TEL-TENG. Furthermore, even at a very low speed of 30 rpm, output charge, current, and average power of the rotation-type SS-TEL-TENG reach 4.15 µC, 74.9 µA, and 25.4 mW (2.05 W m-2 Hz-1 ), respectively. With such high-power output, 4248 LEDs can be lighted brightly by SS-TEL-TENG directly. The high-performance SS-TEL-TENG demonstrated in this work will have great applications for powering ubiquitous sensor network in the Internet of Things (IoT).

Fibrin sealants for the prevention of postoperative pancreatic fistula following pancreatic surgery.

BACKGROUND: Postoperative pancreatic fistula (POPF) is one of the most frequent and potentially life-threatening complications following pancreatic surgery. Fibrin sealants have been used in some centres to reduce POPF rate. However, the use of fibrin sealant during pancreatic surgery is controversial. This is an update of a Cochrane Review last published in 2020. OBJECTIVES: To evaluate the benefits and harms of fibrin sealant use for the prevention of POPF (grade B or C) in people undergoing pancreatic surgery compared to no fibrin sealant use. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, two other databases, and five trials registers on 09 March 2023, together with reference checking, citation searching, and contacting study authors to identify additional studies. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared fibrin sealant (fibrin glue or fibrin sealant patch) versus control (no fibrin sealant or placebo) in people undergoing pancreatic surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 14 RCTs, randomising 1989 participants, comparing fibrin sealant use versus no fibrin sealant use for different locations: stump closure reinforcement (eight trials), pancreatic anastomosis reinforcement (five trials), or main pancreatic duct occlusion (two trials). Six RCTs were carried out in single centres; two in dual centres; and six in multiple centres. One RCT was conducted in Australia; one in Austria; two in France; three in Italy; one in Japan; two in the Netherlands; two in South Korea; and two in the USA. The mean age of the participants ranged from 50.0 years to 66.5 years. All RCTs were at high risk of bias. Application of fibrin sealants to pancreatic stump closure reinforcement after distal pancreatectomy We included eight RCTs involving 1119 participants: 559 were randomised to the fibrin sealant group and 560 to the control group after distal pancreatectomy. Fibrin sealant use may result in little to no difference in the rate of POPF (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.73 to 1.21; 5 studies, 1002 participants; low-certainty evidence) and overall postoperative morbidity (RR 1.20, 95% CI 0.98 to 1.48; 4 studies, 893 participants; low-certainty evidence). After fibrin sealant use, approximately 199 people (155 to 256 people) out of 1000 developed POPF compared with 212 people out of 1000 when no fibrin sealant was used. The evidence is very uncertain about the effect of fibrin sealant use on postoperative mortality (Peto odds ratio (OR) 0.39, 95% CI 0.12 to 1.29; 7 studies, 1051 participants; very low-certainty evidence) and total length of hospital stay (mean difference (MD) 0.99 days, 95% CI -1.83 to 3.82; 2 studies, 371 participants; very low-certainty evidence). Fibrin sealant use may reduce the reoperation rate slightly (RR 0.40, 95% CI 0.18 to 0.90; 3 studies, 623 participants; low-certainty evidence). Serious adverse events were reported in five studies (732 participants), and there were no serious adverse events related to fibrin sealant use (low-certainty evidence). The studies did not report quality of life or cost-effectiveness. Application of fibrin sealants to pancreatic anastomosis reinforcement after pancreaticoduodenectomy We included five RCTs involving 519 participants: 248 were randomised to the fibrin sealant group and 271 to the control group after pancreaticoduodenectomy. The evidence is very uncertain about the effect of fibrin sealant use on the rate of POPF (RR 1.34, 95% CI 0.72 to 2.48; 3 studies, 323 participants; very low-certainty evidence), postoperative mortality (Peto OR 0.24, 95% CI 0.05 to 1.06; 5 studies, 517 participants; very low-certainty evidence), reoperation rate (RR 0.74, 95% CI 0.33 to 1.66; 3 studies, 323 participants; very low-certainty evidence), and total hospital cost (MD -1489.00 US dollars, 95% CI -3256.08 to 278.08; 1 study, 124 participants; very low-certainty evidence). After fibrin sealant use, approximately 130 people (70 to 240 people) out of 1000 developed POPF compared with 97 people out of 1000 when no fibrin sealant was used. Fibrin sealant use may result in little to no difference both in overall postoperative morbidity (RR 1.02, 95% CI 0.87 to 1.19; 4 studies, 447 participants; low-certainty evidence) and in total length of hospital stay (MD -0.33 days, 95% CI -2.30 to 1.63; 4 studies, 447 participants; low-certainty evidence). Serious adverse events were reported in two studies (194 participants), and there were no serious adverse events related to fibrin sealant use (very low-certainty evidence). The studies did not report quality of life. Application of fibrin sealants to pancreatic duct occlusion after pancreaticoduodenectomy We included two RCTs involving 351 participants: 188 were randomised to the fibrin sealant group and 163 to the control group after pancreaticoduodenectomy. The evidence is very uncertain about the effect of fibrin sealant use on postoperative mortality (Peto OR 1.41, 95% CI 0.63 to 3.13; 2 studies, 351 participants; very low-certainty evidence), overall postoperative morbidity (RR 1.16, 95% CI 0.67 to 2.02; 2 studies, 351 participants; very low-certainty evidence), and reoperation rate (RR 0.85, 95% CI 0.52 to 1.41; 2 studies, 351 participants; very low-certainty evidence). Fibrin sealant use may result in little to no difference in the total length of hospital stay (median 16 to 17 days versus 17 days; 2 studies, 351 participants; low-certainty evidence). Serious adverse events were reported in one study (169 participants; low-certainty evidence): more participants developed diabetes mellitus when fibrin sealants were applied to pancreatic duct occlusion, both at three months' follow-up (33.7% fibrin sealant group versus 10.8% control group; 29 participants versus 9 participants) and 12 months' follow-up (33.7% fibrin sealant group versus 14.5% control group; 29 participants versus 12 participants). The studies did not report POPF, quality of life, or cost-effectiveness. AUTHORS' CONCLUSIONS: Based on the current available evidence, fibrin sealant use may result in little to no difference in the rate of POPF in people undergoing distal pancreatectomy. The evidence is very uncertain about the effect of fibrin sealant use on the rate of POPF in people undergoing pancreaticoduodenectomy. The effect of fibrin sealant use on postoperative mortality is uncertain in people undergoing either distal pancreatectomy or pancreaticoduodenectomy.

FAP-Targeted Photodynamic Therapy Mediated by Ferritin Nanoparticles Elicits an Immune Response against Cancer Cells and Cancer Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) are present in many types of tumors and play a pivotal role in tumor progression and immunosuppression. Fibroblast-activation protein (FAP), which is overexpressed on CAFs, has been indicated as a universal tumor target. However, FAP expression is not restricted to tumors, and systemic treatment against FAP often causes severe side effects. To solve this problem, a photodynamic therapy (PDT) approach was developed based on ZnF16Pc (a photosensitizer)-loaded and FAP-specific single chain variable fragment (scFv)-conjugated apoferritin nanoparticles, or αFAP-Z@FRT. αFAP-Z@FRT PDT efficiently eradicates CAFs in tumors without inducing systemic toxicity. When tested in murine 4T1 models, the PDT treatment elicits anti-cancer immunity, causing suppression of both primary and distant tumors, i.e. abscopal effect. Treatment efficacy is enhanced when αFAP-Z@FRT PDT is used in combination with anti-PD1 antibodies. Interestingly, it is found that the PDT treatment not only elicits a cellular immunity against cancer cells, but also stimulates an anti-CAFs immunity. This is supported by an adoptive cell transfer study, where T cells taken from 4T1-tumor-bearing animals treated with αFAP PDT retard the growth of A549 tumors established on nude mice. Overall, our approach is unique for permitting site-specific eradication of CAFs and inducing a broad spectrum anti-cancer immunity.

Nanoconjugates to enhance PDT-mediated cancer immunotherapy by targeting the indoleamine-2,3-dioxygenase pathway.

BACKGROUND: Photodynamic therapy (PDT) may elicit antitumor immune response in addition to killing cancer cells. However, PDT as a monotherapy often fails to induce a strong immunity. Immune checkpoint inhibitors, which selectively block regulatory axes, may be used in combination with PDT to improve treatment outcomes. Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme and an important meditator of tumor immune escape. Combination therapy with PDT and IDO-targeted immune checkpoint blockage is promising but has been seldom been explored. METHODS: Herein we report a composite nanoparticle that allows for simultaneous delivery of photosensitizer and IDO inhibitor. Briefly, we separately load ZnF16Pc, a photosensitizer, and NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor, into ferritin and poly(lactide-co-glycolic)-block-poly(ethylene glycol) (PEG-PLGA) nanoparticles; we then conjugate these two compartments to form a composite nanoparticle referred to as PPF NPs. We tested combination treatment with PPF NPs first in vitro and then in vivo in B16F10-tumor bearing C57/BL6 mice. RESULTS: Our results showed that PPF NPs can efficiently encapsulate both ZnF16Pc and NLG919. In vivo studies found that the combination treatment led to significantly improved tumor suppression and animal survival. Moreover, the treatment increased tumor infiltration of CD8+ T cells, while reducing frequencies of MDSCs and Tregs. 30% of the animals showed complete tumor eradication, and they successfully rejected a second tumor inoculation. Overall, our studies introduce a unique composite nanoplatform that allows for co-delivery of photosensitizer and IDO inhibitor with minimal inter-species interference, which is ideal for combination therapy.

Transcriptome analysis of adult Caenorhabditis elegans cells reveals tissue-specific gene and isoform expression.

The biology and behavior of adults differ substantially from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific isolation to identify the transcriptomes of C. elegans' four major tissues (or "tissue-ome"), identifying ubiquitously expressed and tissue-specific "enriched" genes. These data newly reveal the hypodermis' metabolic character, suggest potential worm-human tissue orthologies, and identify tissue-specific changes in the Insulin/IGF-1 signaling pathway. Tissue-specific alternative splicing analysis identified a large set of collagen isoforms. Finally, we developed a machine learning-based prediction tool for 76 sub-tissue cell types, which we used to predict cellular expression differences in IIS/FOXO signaling, stage-specific TGF-ß activity, and basal vs. memory-induced CREB transcription. Together, these data provide a rich resource for understanding the biology governing multicellular adult animals.

[Roles of highly expressed bone-specific genes in bone metastatic prostate cancer PC3 cells: Advances in studies].

Prostate cancer (PCa) is a maligmancy with high morbidity and mortality. Bone metastasis is the main cause of short survival time and difficulties in the treatment and prevention of PCa. Previous findings of our team showed 155 bone-specific genes highly expressed in bone metastatic PC3 cells, which is considered to be the key to their adaptation to the bone micro-environment, proliferation and formation of metastatic tumor, and extensively exists in cancer metastasis in multiple systems. This review summarizes the published literature on the highly expressed bone-specific genes, focusing on the roles and values of these genes in the metastasis, progression, clinical diagnosis, treatment and prognosis of PCa, offering a prospect of the direction and targets in the studies of PCa bone metastasis so as to enrich the bone metastatic theories and clinical treatment principles of this disease in the future.

Evidence of Duodenal Epithelial Barrier Impairment and Increased Pyroptosis in Patients With Functional Dyspepsia on Confocal Laser Endomicroscopy and "Ex Vivo" Mucosa Analysis.

INTRODUCTION: Duodenal epithelial barrier impairment and immune activation may play a role in the pathogenesis of functional dyspepsia (FD). This study was aimed to evaluate the duodenal epithelium of patients with FD and healthy individuals for detectable microscopic structural abnormalities. METHODS: This is a prospective study using esophagogastroduodenoscopy enhanced with duodenal confocal laser endomicroscopy (CLE) and mucosal biopsies in patients with FD (n = 16) and healthy controls (n = 18). Blinded CLE images analysis evaluated the density of epithelial gaps (cell extrusion zones), a validated endoscopic measure of the intestinal barrier status. Analyses of the biopsied duodenal mucosa included standard histology, quantification of mucosal immune cells/cytokines, and immunohistochemistry for inflammatory epithelial cell death called pyroptosis. Transepithelial electrical resistance (TEER) was measured using Ussing chambers. Epithelial cell-to-cell adhesion proteins expression was assessed by real-time polymerase chain reaction. RESULTS: Patients with FD had significantly higher epithelial gap density on CLE in the distal duodenum than that of controls (P = 0.002). These mucosal abnormalities corresponded to significant changes in the duodenal biopsy samples of patients with FD, compared with controls, including impaired mucosal integrity by TEER (P = 0.009) and increased number of epithelial cells undergoing pyroptosis (P = 0.04). Reduced TEER inversely correlated with the severity of certain dyspeptic symptoms. Furthermore, patients with FD demonstrated altered duodenal expression of claudin-1 and interleukin-6. No differences in standard histology were found between the groups. DISCUSSION: This is the first report of duodenal CLE abnormalities in patients with FD, corroborated by biopsy findings of epithelial barrier impairment and increased cell death, implicating that duodenal barrier disruption is a pathogenesis factor in FD and introducing CLE a potential diagnostic biomarker in FD.

A correlation analysis of HHV infection and its predictive factors in an HIV-seropositive population in Yunnan, China.

Human herpesviruses (HHVs) have a particularly high prevalence in certain high-risk populations and cause increased morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). Screening and treating subclinical HHV infections reduce human immunodeficiency virus (HIV) infection incidence, disease progression, and transmission. However, there are few studies on HHVs, HIV coinfection rates, and their related risk factors. We aimed to clarify the prevalence of all eight HHVs in peripheral blood samples collected from HIV-positive patients, and explore the association of HHV infection in HIV-positive patients in an HIV-seropositive population in Yunnan. We recruited 121 HIV-positive patients with highly active antiretroviral therapy (HAART) and 45 healthy individuals. All the eight HHVs were detected using polymerase chain reaction and their epidemiological information and clinical data were collected and statistically analyzed. A high prevalence of HHVs (89.3%) was observed in individuals with HIV infections and with herpes simplex virus (HSV)-2 (65.3%), and HSV-1 (59.5%) being the most common. Coinfection with more than two different HHVs was more common in patients with HIV infections receiving HAART (72.7%) than in healthy controls. Older age, being married, higher HIV-1 plasma viral loads, and use of antiviral protease inhibitors were independently correlated with an increased frequency of HHVs, but we found no association with CD4 count, WHO HIV clinical stage, and HIV infection duration. Our findings are of great significance for the prevention of HHV opportunistic infection in patients with AIDS and their clinical treatment.

Barium tungstate nanoparticles to enhance radiation therapy against cancer.

High-Z nanoparticles have emerged as a novel type of radiosensitizers due to their relatively large X-ray cross-section and ability to enhance radical production under irradiation. Recently, CaWO4 nanoparticles have been prepared and their potential as a radiosensitizer has been demonstrated. Herein, we investigated BaWO4 nanoparticles as a novel type of alkaline-earth metal tungstate radiosensitizer for radiotherapy (RT). We synthesized BaWO4 nanoparticles using hydrothermal reaction and coated them with polyvinylpyrrolidone (PVP). We found that BaWO4 nanoparticles could more efficiently enhance hydroxyl radical production under irradiation than CaWO4 nanoparticles. When tested in vitro, BaWO4 nanoparticles showed lower toxicity than CaWO4 nanoparticles in the absence of irradiation, but induced more significant oxidative stress under irradiation. When tested in vivo, BaWO4 nanoparticles led to more efficient tumor inhibition without causing systemic toxicity. Overall, our results suggest that BaWO4 nanoparticles can efficiently enhance RT and hold great potential as a novel type of radiosensitizing agent.

Altered R-spondin 1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes.

Hyperphagia is common in diabetes and may worsen hyperglycemia and diabetic complications. The responsible mechanisms are not well understood. The hypothalamus is a key center for the control of appetite and energy homeostasis. The ventromedial nucleus (VMH) and arcuate nucleus (ARC) are two critical nuclei involved in these processes. We have reported that R-spondin 1 (Rspo1) and its receptor leucin-rich repeat and G protein-coupled receptor 4 (LGR4) in the VMH and ARC suppressed appetite, but the downstream neuronal pathways are unclear. Here we show that neurons containing cocaine and amphetamine-regulated transcript (CART) in ARC express both LGR4 and insulin receptor; intracerebroventricular injection of Rspo1 induced c-Fos expression in CART neurons of ARC; and silencing CART in ARC attenuated the anorexigenic actions of Rspo1. In diabetic and obese fa/fa rats, Rspo1 mRNA in VMH and CART mRNA in ARC were reduced; this was accompanied by increased food consumption. Insulin treatment restored Rspo1 and CART gene expressions and normalized eating behavior. Chronic intracerebroventricular injection of Rspo1 inhibited food intake and normalized diabetic hyperphagia; intracerebroventricular injection of Rspo1 or insulin increased CART mRNA in ARC. In the CART neuron cell line, Rspo1 and insulin potentiated each other on pERK and ß-catenin, and in rats, they acted synergistically to inhibit food intake. Silencing Rspo1 in VMH reduced CART expression in ARC and attenuated the inhibitory effect of insulin on food intake. In conclusion, our data indicated that CART works downstream of Rspo1 and Rspo1 mediated the action of insulin centrally. The altered Rspo1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes. NEW & NOTEWORTHY This study reports that cocaine and amphetamine-regulated transcript (CART) neurons in the arcuate nucleus (ARC) of hypothalamus acted downstream of R-spondin 1 (Rspo1) to inhibit food intake. The Rspo1 mRNA level in ventromedial nucleus (VMH) and CART mRNA level in ARC were reduced in type 1 diabetic rat and obese fa/fa rat. Rspo1 and insulin acted synergistically on phospho-ERK and ß-catenin signal pathways and in suppressing food intake. The current results proposed that altered Rspo1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes.

Macrophage-Restricted Shp2 Tyrosine Phosphatase Acts as a Rheostat for MMP12 through TGF-ß Activation in the Prevention of Age-Related Emphysema in Mice.

Persistent activation of macrophages in lungs plays a critical role in the production of matrix metalloproteinases (MMPs) that contributes to the destruction of alveolar walls, a hallmark for pulmonary emphysema. Dysregulated TGF-ß1 signaling has been an essential determinant in the elevation of MMPs during the development of emphysema. Nevertheless, the mechanism for this MMP-dependent pathogenesis has yet to be clearly investigated. Recently, we identified an important role for tyrosine phosphatase Src homology domain-containing protein tyrosine phosphatase 2 (Shp2) in regulating the activation of alveolar macrophages. Over a long-term observation period, mice with Shp2 deletion in macrophages (LysMCre:Shp2fl/fl ) develop spontaneous, progressive emphysema-like injury in the lungs, characterized by massive destruction of alveolar morphology, interstitial extracellular matrix degradation, and elevated levels of MMPs, particularly, significant increases of macrophage elastase (MMP12) in aged mice. Further analysis demonstrated that MMP12 suppression by TGF-ß1 activation was apparently abrogated in LysMCre:Shp2fl/fl mice, whereas the TGF-ß1 concentration in the lungs was relatively the same. Mechanistically, we found that loss of Shp2 resulted in attenuated SMAD2/3 phosphorylation and nuclear translocation in response to TGF-ß activation, thereby upregulating MMP12 expression in macrophages. Together, our findings define a novel physiological function of Shp2 in TGF-ß1/MMP12-dependent emphysema, adding insights into potential etiologies for this chronic lung disorder.

Expression of TaGF14b, a 14-3-3 adaptor protein gene from wheat, enhances drought and salt tolerance in transgenic tobacco.

MAIN CONCLUSION: TaGF14b enhances tolerance to multiple stresses through ABA signaling pathway by altering physiological and biochemical processes, including ROS-scavenging system, stomatal closure, compatible osmolytes, and stress-related gene expressions in tobaccos. The 14-3-3 proteins are involved in plant growth, development, and in responding to abiotic stresses. However, the precise functions of 14-3-3s in responding to drought and salt stresses remained unclear, especially in wheat. In this study, a 14-3-3 gene from wheat, designated TaGF14b, was cloned and characterized. TaGF14b was upregulated by polyethylene glycol 6000, sodium chloride, hydrogen peroxide, and abscisic acid (ABA) treatments. Ectopic expression of TaGF14b in tobacco conferred enhanced tolerance to drought and salt stresses. Transgenic tobaccos had longer root, better growth status, and higher relative water content, survival rate, photosynthetic rate, and water use efficiency than control plants under drought and salt stresses. The contribution of TaGF14b to drought and salt tolerance relies on the regulations of ABA biosynthesis and ABA signaling, as well as stomatal closure and stress-related gene expressions. Moreover, TaGF14b expression could significantly enhance the reactive oxygen species (ROS) scavenging system to ameliorate oxidative damage to cells. In addition, TaGF14b increased tolerance to osmotic stress evoked by drought and salinity through modifying water conservation and compatible osmolytes in plants. In conclusion, TaGF14b enhances tolerance to multiple abiotic stresses through the ABA signaling pathway in transgenic tobaccos by altering physiological and biochemical processes.

Hepatitis E virus infection in HIV-infected patients: A large cohort study in Yunnan province, China.

Hepatitis E virus (HEV) infection in immunocompromised patients often results in distinct outcome, compared to the infection in general population. This study aimed to investigate the prevalence, potential risk factors, and clinical features of HEV infection among HIV patients treated with antiretroviral therapy (ART) in Yunnan province, China. A total of 770 HIV-infected patients between May 2015 and February 2016 were enrolled in Yunnan, China. All patients received ART. All plasma samples were tested for anti-HEV IgG, anti-HEV IgM antibodies using ELISA kits, and HEV RNA by real-time qRT-PCR. Association between anti-HEV antibody positivity and demographic, clinical and laboratory measures was assessed in univariate and multivariate logistic regression models. Of the 770 HIV-infected patients, 342 patients (44.42%) were anti-HEV IgG antibody positive, and six patients (0.78%) were anti-HEV IgM antibody positive. None of the patients was HEV RNA positive, as tested in our assays. We found that age, gender, CD4 cell count, WHO stage, marital status, and total cholesterol levels were associated with HEV infection. We report a high seroprevalence rate and several potential risk factors of HEV infection in a large HIV cohort from Yunnan province in China. Further research on identification of the circulating HEV strains and the clinical outcome of this patient population is required.

Self-Organized Kilotesla Magnetic-Tube Array in an Expanding Spherical Plasma Irradiated by kHz Femtosecond Laser Pulses.

By using a millijoule kHz femtosecond laser pulse to irradiate a preformed expanding spherical plasma, which is driven by a prepulse with intensity of 1×10^{14} W/cm^{2}, we observe fast-electron-mediated filamentary structures and an accompanying self-organized magnetic-tube array with 2000 T via time-resolved magneto-optical polarization rotation measurements. We reveal that these periodical filamentary structures predominantly originate from ejected energetic electron flows from the inner denser region of the spherical plasma, which will induce the electron Weibel instability and magnetic field organization and amplification in the expanding plasma in 2 ps. These results open new paths to investigate amplification of intense magnetic fields and the radiation signature from gamma-ray bursts just by means of a much smaller and robust experimental platform.

Photosensitizer-Encapsulated Ferritins Mediate Photodynamic Therapy against Cancer-Associated Fibroblasts and Improve Tumor Accumulation of Nanoparticles.

Nanoparticles have been widely tested as drug delivery carriers or imaging agents, largely because of their ability to selectively accumulate in tumors through the enhanced permeability and retention (EPR) effect. However, studies show that many tumors afford a less efficient EPR effect and that many nanoparticles are trapped in the perivascular region after extravasation and barely migrate into tumor centers. This is to a large degree attributed to the dense tumor extracellular matrix (ECM), which functions as a physical barrier to prevent efficient nanoparticle extravasation and diffusion. In this study, we report a photodynamic therapy (PDT) approach to enhance tumor uptake of nanoparticles. Briefly, we encapsulate ZnF16Pc, a photosensitizer, into ferritin nanocages, and then conjugate to the surface of the ferritin a single chain viable fragment (scFv) sequence specific to fibroblast activation protein (FAP). FAP is a plasma surface protein widely upregulated in cancer-associated fibroblasts (CAFs), which is a major source of the ECM fiber components. We found that the scFv-conjugated and ZnF16Pc-loaded ferritin nanoparticles (scFv-Z@FRT) can mediate efficient and selective PDT, leading to eradication of CAFs in tumors. When tested in bilateral 4T1 tumor models, we found that the tumor accumulation of serum albumin (BSA), 10 nm quantum dots (QDs), and 50 nm QDs was increased by 2-, 3.5-, and 18-fold after scFv-Z@FRT mediated PDT. Our studies suggest a novel and safe method to enhance the delivery of nanoparticles to tumors.