Colorectal cancer-specific IFNß delivery overcomes dysfunctional dsRNA-mediated type I interferon signaling to increase the abscopal effect of radiotherapy.

BACKGROUND: Cancer-intrinsic type I interferon (IFN-I) production triggered by radiotherapy (RT) is mainly dependent on cytosolic double-stranded DNA (dsDNA)-mediated cGAS/STING signaling and increases cancer immunogenicity and enhances the antitumor immune response to increase therapeutic efficacy. However, cGAS/STING deficiency in colorectal cancer (CRC) may suppress the RT-induced antitumor immunity. Therefore, we aimed to evaluate the importance of the dsRNA-mediated antitumor immune response induced by RT in patients with CRC. METHODS: Cytosolic dsRNA level and its sensors were evaluated via cell-based assays (co-culture assay, confocal microscopy, pharmacological inhibition and immunofluorescent staining) and in vivo experiments. Biopsies and surgical tissues from patients with CRC who received preoperative chemoradiotherapy (neoCRT) were collected for multiplex cytokine assays, immunohistochemical analysis and SNP genotyping. We also generated a cancer-specific adenovirus-associated virus (AAV)-IFNß1 construct to evaluate its therapeutic efficacy in combination with RT, and the immune profiles were analyzed by flow cytometry and RNA-seq. RESULTS: Our studies revealed that RT stimulates the autonomous release of dsRNA from cancer cells to activate TLR3-mediated IFN-I signatures to facilitate antitumor immune responses. Patients harboring a dysfunctional TLR3 variant had reduced serum levels of IFN-I-related cytokines and intratumoral CD8+ immune cells and shorter disease-free survival following neoCRT treatment. The engineered cancer-targeted construct AAV-IFNß1 significantly improved the response to RT, leading to systematic eradication of distant tumors and prolonged survival in defective TLR3 preclinical models. CONCLUSION: Our results support that increasing cancer-intrinsic IFNß1 expression is an immunotherapeutic strategy that enhances the RT-induced antitumor immune response in locally patients with advanced CRC with dysfunctional TLR3.

Activation of STING by the novel liposomal TLC388 enhances the therapeutic response to anti-PD-1 antibodies in combination with radiotherapy.

Current immune checkpoint inhibiters (ICIs) have contrasting clinical results in poorly immunogenic cancers such as microsatellite-stable colorectal cancer (MSS-CRC). Therefore, understanding and developing the combinational therapeutics for ICI-unresponsive cancers is critical. Here, we demonstrated that the novel topoisomerase I inhibitor TLC388 can reshape the tumor immune landscape, corroborating their antitumor effects combined with radiotherapy as well as immunotherapy. We found that TLC388 significantly triggered cytosolic single-stranded DNA (ssDNA) accumulation for STING activation, leading to type I interferons (IFN-Is) production for increased cancer immunogenicity to enhance antitumor immunity. TLC388-treated tumors were infiltrated by a vast number of dendritic cells, immune cells, and costimulatory molecules, contributing to the favorable antitumor immune response within the tumor microenvironment. The infiltration of cytotoxic T and NK cells were more profoundly existed within tumors in combination with radiotherapy and ICIs, leading to superior therapeutic efficacy in poorly immunogenic MSS-CRC. Taken together, these results showed that the novel topoisomerase I inhibitor TLC388 increased cancer immunogenicity by ssDNA/STING-mediated IFN-I production, enhancing antitumor immunity for better therapeutic efficacy in combination with radiotherapy and ICIs for poorly immunogenic cancer.

Phyllanthus emblica Fruit Improves Obesity by Reducing Appetite and Enhancing Mucosal Homeostasis via the Gut Microbiota-Brain-Liver Axis in HFD-Induced Leptin-Resistant Rats.

The impact of leptin resistance on intestinal mucosal barrier integrity, appetite regulation, and hepatic lipid metabolism through the microbiota-gut-brain-liver axis has yet to be determined. Water extract of Phyllanthus emblica L. fruit (WEPE) and its bioactive compound gallic acid (GA) effectively alleviated methylglyoxal (MG)-triggered leptin resistance in vitro. Therefore, this study investigated how WEPE and GA intervention relieve leptin resistance-associated dysfunction in the intestinal mucosa, appetite, and lipid accumulation through the microbiota-gut-brain-liver axis in high-fat diet (HFD)-fed rats. The results showed that WEPE and GA significantly reduced tissues (jejunum, brain, and liver) MG-evoked leptin resistance, malondialdehyde (MDA), proinflammatory cytokines, SOCS3, orexigenic neuropeptides, and lipid accumulation through increasing leptin receptor, tight junction proteins, antimicrobial peptides, anorexigenic neuropeptides, excretion of fecal triglyceride (TG), and short-chain fatty acids (SCFAs) via a positive correlation with the Allobaculum and Bifidobacterium microbiota. These novel findings suggest that WEPE holds the potential as a functional food ingredient for alleviating obesity and its complications.

Phyllanthus emblica L. polysaccharides ameliorate colitis via microbiota modulation and dual inhibition of the RAGE/NF-κB and MAPKs signaling pathways in rats.

Pharmacological treatments for colitis have limited efficacy and side effects. Plant polysaccharides improve colitis by modulating the gut microbiota. However, the specific benefits of Phyllanthus emblica L. polysaccharides (PEPs) in colitis remain unclear. Therefore, this study aimed to assess the physical characteristics and health advantages of PEP in rats subjected to 2,4,6-trinitrobenzene sulfonic acid (TNBS) treatment. The results showed that PEP (1.226 × 103 kDa) was an α-acidic pyran heteropolysaccharide rich in galactose and galacturonic acid. Prefeeding rats with PEP significantly decreased the levels of NO, MDA, proinflammatory cytokines (IL-6, IL-1ß, TNF-α), apoptosis, and the activities of mucinase and ß-glucuronidase. These changes were accompanied by increases in the levels of anti-inflammatory cytokines (IL-4, IL-10) and antioxidant enzymes (SOD, catalase, GPx) in colitis rats. Mechanistically, PEP suppressed the abundance of inflammatory-related bacteria (Bacteroides, Intestinimonas, and Parabacteroides) while promoting the growth of short-chain fatty acid (SCFA)-producing bacteria (Romboutsia, Clostridium_sensu_stricto_1, and Lactobacillus), along with an increase in SCFA secretion. SCFAs may engage with the GPR43 receptor and inhibit downstream HDAC3, consequently downregulating the activation of the RAGE/NF-κB and MAPK pathways. In conclusion, PEP demonstrated preventive effects through its antioxidant, anti-inflammatory, and microbiota modulation properties, thereby ameliorating TNBS-induced colitis in rats.

Analgesic Effect of Low-Level Laser Therapy before Heel Lance for Pain Management in Healthy Term Neonates: A Randomized Controlled Trial.

Currently, the prevention, assessment, and management of procedural pain in neonates continues to challenge clinicians and researchers. Objective. To investigate the analgesic effect of low-level laser therapy (LLLT) during heel lance compared to breast milk (BM) feeding in healthy term neonates. In this randomized controlled trial, healthy term neonates who underwent heel lance were randomly assigned to an LLLT or a BM group. The LLLT group received laser therapy to the heel lance site for 20 s before heel lance. The BM group received 5 mL expressed BM via a syringe before heel lance. The primary outcomes were behavioral responses. The secondary outcomes were physiological responses and levels of salivary cortisol and α-amylase. A total of 125 neonates were included, of whom 55 in the LLLT group and 59 in the BM group completed the study. There were no significant differences in latency to first cry and cry duration between the two groups. The squeeze time was significantly shorter in the LLLT group than in the BM group (p = 0.047). There were no significant differences in pain scores, heart rate, respiratory rate, oxygen saturation, and blood pressure before and after heel lance between the two groups. There were no significant differences in salivary cortisol and α-amylase levels in the LLLT group before and after heel lance; however, the differences were significant in the BM group. These findings suggest that the analgesic effect of LLLT is similar to that of BM during heel lance in healthy term neonates. LLLT has potential as an analgesic treatment.

Basophils Predict Mite Sensitization in Patients with Kawasaki Disease.

Background: Patients with Kawasaki disease (KD) are at a significantly increased risk of allergic diseases. Immunoglobulin E (IgE) is an immunoglobulin that mediates allergic sensitization to various allergens and is related to various allergic diseases. However, few studies have analyzed specific IgE on allergy biomarkers after KD is diagnosed. Objective: This study aimed to investigate the pattern of specific IgE levels against food and inhalant allergens. Methods: This retrospective study was conducted in Taiwan to identify patients admitted with KD. A subset of 453 admitted KD children younger than or equal to five years of age with intravenous immunoglobulin (IVIG) was followed up at our clinic with available specific IgE data. Results: The most common allergens were Dermatophagoides farina or pteronyssinus, house-dust, and cockroach mix. Positive specific IgE for Dermatophagoides farina or pteronyssinus was less common in children diagnosed with KD who were two years old or younger (p = 0.028). KD patients with higher basophils before IVIG (p = 0.010 and 0.018 for two different mites) and higher C-reactive protein (CRP, p = 0.030 and 0.028) after IVIG were at higher risk of mite sensitization. Integrated mite sensitization demonstrated higher basophils before IVIG, age at KD diagnosis, and the male sex to be clinically meaningful after logistic regression models. Conclusions: This study is the first to suggest that specific IgE in KD patients may be correlated with age at KD diagnosis, as well as basophils. Further longitudinal prospective studies are warranted to clarify the unique profile of specific IgE in KD patients.

Perinatal Characteristics and the Sensitization to Cow Milk, Egg Whites and Wheat in Children up to 3 Years of Age.

Food sensitization in early life identifies children at risk of developing allergic diseases. We investigated the sensitization to cow milk (CM), egg whites, and wheat. Newborns and infants under 3 years of age with available specific immunoglobulin E (sIgE) data were identified. A retrospective survey was conducted using data from the Chang Gung Research Database. Perinatal characteristics, such as singleton or multiples in a single pregnancy, parity, meconium staining, maternal age, spontaneous delivery or cesarean section, meconium passage, weeks of gestation, birth length, body weight, head and chest circumferences, and season, were obtained. The data on sIgE were collected, and a logistic regression model was used to determine the odds of sensitization. Positive sIgE for CM and egg whites was more likely to occur in boys than in girls. Early-life egg white and wheat sensitization was associated with increased birth body length and weight. A multivariate analysis indicated an association between egg white sIgE positivity and logarithmic total IgE. Higher total IgE levels and younger age were associated with egg white sensitization, and elevated weight and length at birth were linked to food sensitization, particularly to egg whites and wheat.

Evaluating the waste and CO2 reduction potential of packaging by reuse model in supermarkets in Taiwan.

Consumption of single-use packaging has been increasing globally and the waste produced causes negative impacts on both human and the environment. Retailers, such as supermarkets, developed quickly in recent years to provide for the modern lifestyle, using a lot of packaging in the process of distribution and sales. This research evaluates the packaging waste and CO2 reduction potential of 10 different products sold in supermarkets in Taiwan when adopting different reuse strategies of Reduce, Return and Refill. In the suggested reuse strategies, a total of 8 kilotons of packaging waste and 30 kilotons of packaging CO2 can be reduced, accounting for 50.8% and 59.8% reduction of the current situation, respectively. Retailers are suggested to provide different reuse strategies and experiential activities to increase consumers familiarity with new consumption methods. Significant impacts are made with a slight change in the small proportion investigated, which suggests considerable benefits if the scope is expanded.

A Novel Engineered AAV-Based Neoantigen Vaccine in Combination with Radiotherapy Eradicates Tumors.

The potency of tumor-specific antigen (TSA) vaccines, such as neoantigen (neoAg)-based cancer vaccines, can be compromised by host immune checkpoint inhibitory mechanisms, such as programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), that attenuate neoAg presentation on dendritic cells (DC) and hinder T cell-mediated cytotoxicity. To overcome PD-1/PD-L1 inhibition in DCs, we developed a novel adeno-associated virus (meAAV) neoAg vaccine, modified with TLR9 inhibitory fragments, PD-1 trap, and PD-L1 miRNA, which extend the persistence of meAAV and activate neoAg-specific T-cell responses in immune-competent colorectal and breast cancer murine models. Moreover, we found that in combination with radiotherapy, the meAAV-based neoAg cancer vaccine not only elicited higher antigen presentation ability, but also maintained neoAg-specific cytotoxic T lymphocyte (CTL) responses. These functional PD-1 traps and PD-L1 miRNAs overcome host PD-1/PD-L1 inhibitory mechanisms and boost the therapeutic efficacy of radiotherapy. More importantly, combined radiotherapy and meAAV neoAg cancer vaccines significantly enhanced neoAg-specific CTL responses, increased CTL infiltration in tumor microenvironment, and decreased tumor-associated immunosuppression. This process led to the complete elimination of colorectal cancer and delayed tumor growth of breast cancer in tumor-bearing mice. Taken together, our results demonstrated a novel strategy that combines neoAg cancer vaccine and radiotherapy to increase the therapeutic efficacy against colorectal and breast cancers.

Interrelationships among growth hormone, thyroid function, and endocrine-disrupting chemicals on the susceptibility to attention-deficit/hyperactivity disorder.

Abnormal growth hormones and thyroid function may be linked to pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Phthalates and bisphenol-A (BPA), two endocrine-disrupting chemicals (EDCs), may affect the human endocrine system. In this study, we aimed to perform a comprehensive investigation of whether growth hormone, thyroid function, and EDCs exhibited differential levels between ADHD patients and healthy controls. In total, 144 children with ADHD and 70 healthy control subjects were enrolled. Their endocrine systems were evaluated using the serum levels of insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and Free T4. The urinary levels of EDCs, including monoethyl phthalate (MEP), mono-methyl phthalate (MMP), monoethylhexyl phthalate (MEHP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), and BPA, were also examined. Patients with ADHD had lower IGF-1 levels than healthy controls (p = 0.003), but we observed no significant difference in IGFBP-3, TSH, T3, T4, or Free T4. Compared to the control group, patients with ADHD demonstrated higher MEHP levels (p = 0.043), MnBP (p = 0.033), and MBzP (p = 0.040). Furthermore, MEHP levels (p < 0.001) and BPA levels (p = 0.041) were negatively correlated with IGF-1 levels, while IGF-1 levels were negatively correlated with principal components consisting of ADHD clinical symptoms and neuropsychological performance variables. We suggest that MEHP exposure may be associated with decreased serum levels of IGF-1 and increased risk of ADHD. The mechanism underlying this association may be important for protecting children from environmental chemicals that adversely affect neurodevelopment.

Atypical vesicles and membranes with monolayer and multilayer structures formed by graft copolymers with diblock side-chains: nonlamellar structures and curvature-enhanced permeability.

Graft copolymers with diblock side-chains Am(-graft-B3Ay)n in a selective solvent have been reported to self-assemble into vesicles, but the structure is expected to differ distinctly from those of lipid bilayers. Surprisingly, the number of alternating hydrophobic A-block and hydrophilic B-block layers in the vesicle can vary from a monolayer to multilayers such as the hepta-layer, subject to the same copolymer concentration. The area density of the copolymer layer is not uniform across the membrane. This structural difference among different layers is attributed to the neighboring environment and the curvature of the layer. Because of the unusual polymer conformations, nonlamellar structures of polymersomes are formed, and they are much more intricate than those of liposomes. In fact, a copolymer can contribute to a single or two hydrophilic layers, and it can provide up to three hydrophobic layers. The influence of the backbone length (m) and side-chain length (y) and the permeation dynamics are also studied. The thickness of hydrophobic layers is found to increase with increasing side-chain length but is not sensitive to the backbone length. Although the permeation time increases with the layer number for planar membranes, the opposite behavior is observed for spherical vesicles owing to the curvature-enhanced permeability associated with Laplace pressure.

Engineered sTRAIL-armed MSCs overcome STING deficiency to enhance the therapeutic efficacy of radiotherapy for immune checkpoint blockade.

Radiotherapy (RT) mainly elicits antitumor immunity via the cGAS/STING axis for type I interferon (IFN) production. However, dysregulation of cGAS/STING constrains radiotherapy-induced antitumor immunity and type I IFN-dependent cell death and is associated with shorter survival of patients with colorectal cancer (CRC). Due to their tumor tropism, mesenchymal stem cells (MSCs) have shown the potential to deliver therapeutic genes for cancer therapy. Here, we showed that MSCs enhance the sensitivity to RT by inducing TRAIL-dependent cell death and remodel the tumor microenvironment by recruiting CD8+ immune cells to upregulate PD-L1 in the tumor. By engineering MSCs to express CRC-specific soluble TRAIL via adenovirus-associated virus 2 (AAV2), we found that the therapeutic activity of MSC-sTRAIL was superior to that of MSCs alone when combined with RT. Combined treatment with MSC-sTRAIL and RT significantly reduced cell viability and increased apoptosis by inducing TRAIL-dependent cell death in STING-deficient colorectal cancer cells. MSC-sTRAIL directly triggered TRAIL-dependent cell death to overcome the deficiency of the cGAS/STING axis. Moreover, these combination treatments of MSC-sTRAIL and RT significantly remodeled the tumor microenvironment, which was more suitable for anti-PD-L1 immunotherapy. Taken together, this therapeutic strategy represents a novel targeted treatment option for patients with colorectal cancer, especially cGAS/STING-deficient patients.

Allergen Tests of Fruit Sensitization Involving Children with Allergic Diseases.

Fruit is a kind of plant food which is rich in nutrients and immune-regulating ingredients. A meta-analysis has demonstrated that fruits have a protective effects against asthma. On the other hand, clinical syndromes of allergic reactions to fruits manifest as an oral allergy syndrome. We aimed to investigate the patterns and associated factors of fruit allergen-specific IgE (sIgE) sensitization among patients with suspected clinical symptoms. Data were extracted from the Chang Gung Research Database. Fruit sensitization in Taiwan was evaluated using the presence of IgE antibodies against specific fruits. The overall prevalence of positive sIgE responses to fruit allergens in Taiwan, in order of decreasing importance, was pineapple, kiwi, banana, and papaya. Children aged 0-18 had a higher positive rate of allergic responses to pineapple, kiwi, banana, and papaya than adults over the age of 18. Positive specific IgE for kiwi, banana, or papaya was more frequent in younger than in older children and children with a higher total IgE of both logarithmic (log) and arithmetic values. The analysis of log IgE for pineapple positive vs. negative children determined an optimal cutoff value, log IgE 2.2, with both sensitivity (0.9) and specificity (0.5). Dermatitis was significantly more prevalent in children with positive IgE for pineapple, kiwi, banana, and papaya than negative specific IgE. The highest positive rate of sIgE against fruits was pineapple among children. Even in older children, the positive rate of pineapple allergens was high. IgE discriminates with and without sIgE for pineapple, with an optimal cutoff of 158.5 U/mL.

A novel anti-tumor/anti-tumor-associated fibroblast/anti-mPEG tri-specific antibody to maximize the efficacy of mPEGylated nanomedicines against fibroblast-rich solid tumor.

The therapeutic efficacy of methoxypolyethylene glycol (mPEG)-coated nanomedicines in solid tumor treatment is hindered by tumor-associated fibroblasts (TAFs), which promote tumor progression and form physical barriers. We developed an anti-HER2/anti-FAP/anti-mPEG tri-specific antibody (TsAb) for one-step conversion of mPEG-coated liposomal doxorubicin (Lipo-Dox) to immunoliposomes, which simultaneously target HER2+ breast cancer cells and FAP+ TAFs. The non-covalent modification did not adversely alter the physical characteristics and stability of Lipo-Dox. The TsAb-Lipo-Dox exhibited specific targeting and enhanced cytotoxicity against mono- and co-cultured HER2+ breast cancer cells and FAP+ TAFs, compared to bi-specific antibody (BsAb) modified or unmodified Lipo-Dox. An in vivo model of human breast tumor containing TAFs also revealed the improved tumor accumulation and therapeutic efficacy of TsAb-modified mPEGylated liposomes without signs of toxicity. Our data indicate that arming clinical mPEGylated nanomedicines with the TsAb is a feasible and applicable approach for overcoming the difficulties caused by TAFs in solid tumor treatment.

Strengthening mechanism of the mechanical properties of graft copolymers with incompatible pendant groups: nano-clusters and weak cross-linking.

It is known that the adhesive property and mechanical strength of an apolar polymer can be improved by grafting with polar side chains, whereas the underlying mechanism is still elusive. In this work, the equilibrium structure and mechanical moduli of the melt of graft copolymers have been explored by dissipative particle dynamics. Due to the strong immiscibility of the non-polar backbone and polar side chains, nano-clusters of side chains formed and acted as physical crosslinkers. Moreover, non-affinity adsorption of polar side chains in the melt to the wall was observed, revealing an improvement in the adhesion property. Subjecting graft copolymers to cyclic deformation, the storage and loss moduli were acquired, and they grew with increasing grafting density. The melt strength in terms of the crossover frequency ascended with more side chains on the backbone. Our findings reveal that the strengthening of the mechanical properties of graft copolymers can be attributed to the formation of weakly cross-linked structures, thus offering an insight into the molecular design to aid the development of stronger graft copolymers.

Immunogenic Cell Death by the Novel Topoisomerase I Inhibitor TLC388 Enhances the Therapeutic Efficacy of Radiotherapy.

Rectal cancer accounts for 30-40% of colorectal cancer (CRC) and is the most common cancer-related death worldwide. The preoperative neoadjuvant chemoradiotherapy (neoCRT) regimen is the main therapeutic strategy for patients with locally advanced rectal cancer (LARC) to control tumor growth and reduce distant metastasis. However, 30-40% of patients achieve a partial response to neoCRT and suffer from unnecessary drug toxicity side effects and a risk of distant metastasis. In our study, we found that the novel topoisomerase I inhibitor lipotecan (TLC388) can elicit immunogenic cell death (ICD) to release damage-associated molecular patterns (DAMPs), including HMGB1, ANXA1, and CRT exposure. Lipotecan thereby increases cancer immunogenicity and triggers an antitumor immune response to attract immune cell infiltration within the tumor microenvironment (TME) in vitro and in vivo. Taken together, these results show that lipotecan can remodel the tumor microenvironment to provoke anticancer immune responses, which can provide potential clinical benefits to the therapeutic efficacy of neoCRT in LARC patients.

The appropriate frequency of dressing for percutaneous central venous catheters in preventing catheter-related blood stream infection in NICU - A randomized controlled trial.

BACKGROUND: Complications of percutaneous central venous catheters (PCVCs) include catheter-related blood stream infection (CRBSI), occlusion, leakage, and phlebitis, which may lead to sepsis or prolonged hospitalization. The primary objective of this randomized controlled trial was to determine the appropriate frequency of dressing for percutaneous central venous catheters in preventing CRBSI, every week regularly vs. non-regularly, in premature neonates in NICU. METHODS: Patients in NICU requiring PCVCs from March 2019-May 2020 were enrolled. Enrolled patients were randomly assigned into 2 groups: regular dressing group (RD), for which dressings were changed every week regularly, or additionally when oozing was noticed; and non-regular dressing group (ND), for which dressings were changed only when oozing was visible. The incidence of CRBSI, occlusion, leakage, and phlebitis were compared between the two groups using the Chi-squared test. The incidence of catheter-related complications was defined as numbers of episodes per 1000 catheter-days. RESULTS: A total of 197 PCVCs were enrolled. The ND and RD groups had 99 and 98 PCVCs, respectively. The average CD interval was 9.3 days in ND group and 5.8 days in RD group. The incidence of CRBSI in RD group was 0‰, which was significantly lower than that of ND group, which was 2.0‰ (p = 0.048), but no significant differences were found between groups in the incidence of occlusion, leakage, and phlebitis of PCVCs. CONCLUSION: Regular dressing changes every week and when oozing occurs while maintaining the protocol of maximum sterile barrier precautions is the best method and frequency of dressings of PCVCs.

The role of ultrasonography for detecting tip location of percutaneous central venous catheters in neonates-a single-center, prospective cohort study.

BACKGROUND: Percutaneous central venous catheters (PCVCs) are used commonly and widely in the neonatal intensive care unit (NICU). Malposition of PCVCs may cause life-threatening complications and prolong hospitalization. In Taiwan, conventional chest-abdomen radiography (CXR) has been used widely and routinely for assessing tip location of PCVCs. Compared to ultrasonography (US), CXR cannot provide real-time assessment, and patients are exposed to radiation. Therefore, this study aimed to analyze the role of US in detecting PCVC tip location in the lower extremities. METHODS: Neonates who received PCVC insertion in the lower extremities in NICU from March 2019 to April 2020 were enrolled in this prospective cohort study. PCVC tip location was confirmed finally by conventional CXR after US examination and patients were included in the sono group; those not assessed by US formed the non-sono group. In addition, PCVCs inserted in 2018 for which tip location was evaluated only by CXR, were reviewed retrospectively and these cases were included in the non-sono group. Withdrawal rates between the two groups were analyzed using Chi-square test. RESULTS: The sono group included 166 neonates with PCVCs and 141 were in the non-sono group. Median gestational age at date of PCVC insertion was 33.21 and 32.71 weeks in sono and non-sono groups, respectively (p = 0.37). Withdrawal rates were 10.84% and 65.95% (p < 0.001) and duration for catheter location confirmation were 2-4.75 min and 75-247.25 min (p < 0.001), respectively. CONCLUSION: US provides more reliable images than conventional radiography alone for identifying PCVC tip locations in the lower extremities. It can effectively reduce catheter insertion duration, and was associated with fewer manipulations.

ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer.

AAA domain containing 3A (ATAD3A) is a nucleus-encoded mitochondrial protein with vital function in communication between endoplasmic reticulum (ER) and mitochondria which is participated in cancer metastasis. Here we show that elevated ATAD3A expression is clinically associated with poor 5-year disease-free survival in patients with colorectal cancer (CRC), especially high-risk CRC patients who received adjuvant chemotherapy. Our results indicated ATAD3A is significantly upregulated to reduce chemotherapy-induced cancer cell death. We found that knockdown of ATAD3A leads to dysregulation in protein processing for inducing ER stress by RNA sequencing (RNA-seq). In response to chemotherapy-induced ER stress, ATAD3A interacts with elevated GRP78 protein to assist protein folding and alleviate ER stress for cancer cell survival. This reduction of ER stress leads to reduce the surface exposure of calreticulin, which is the initiator of immunogenic cell death and antitumor immunity. However, silencing of ATAD3A enhances cell death, triggers the feasibility of chemotherapy-induced ER stress for antitumor immunity, increases infiltration of T lymphocytes and delays tumor regrowth in vitro and in vivo. Clinically, CRC patients with less ATAD3A have high density of CD45+ intratumoral infiltrating lymphocytes (TILs) and memory CD45RO+ TILs. Taken together, our results suggest that pharmacologic targeting to ATAD3A might be a potential therapeutic strategy to enhance antitumor immunity for CRC patients who received adjuvant chemotherapy.

Floating and Diving Loops of ABA Triblock Copolymers in Lipid Bilayers and Stability Enhancement for Asymmetric Membranes.

Hybrid membranes of lipids and AxByAz triblock copolymers can possess better biocompatibility and mechanical stability. In this work, triblock copolymer conformations and stability of asymmetric membranes are explored by dissipative particle dynamics. The triblock copolymers in the membranes exhibit either the bridge or loop conformation. As hydrophobic B-blocks interact attractively with lipid heads, bridge-shaped copolymers are significantly inhibited and loop-shaped copolymers prefer to stay at the interface between hydrophilic and hydrophobic layers. This floating loop has a flattened conformation, consistent with the experimental findings. In contrast, for repulsive interactions between B-blocks and lipid heads, bridge-shaped copolymers are abundant and loop-shaped copolymers tend to plunge into the hydrophobic layer. This diving loop displays a random coil conformation. The asymmetric membrane in which the fractions of loop-shaped copolymers in the upper and lower leaflets are different is thermodynamically unstable. Two approaches are proposed to acquire kinetically stable asymmetric membranes. First, membrane symmetrization is arrested by eliminating bridge-shaped copolymers, which is achieved by B-block/lipid head attraction and B-block/lipid tail repulsion. Second, asymmetric triblock copolymers (x ≠ z) are used to prevent the passage of the long A-block through the hydrophobic layer.