Comparison of 16S rRNA gene sequencing microbiota among children with serological IgE-mediated food hypersensitivity.

BACKGROUND: We hypothesized that specific food hypersensitivity (FH) in children is linked to specific gut microbiota. The aim of our study was to quantify and evaluate differences in gut microbial composition among children with different IgE-mediated FH. METHODS: Children (n = 81) aged 18 to 36 months were enrolled, fecal samples of 57 children with FH and 24 healthy children were evaluated using next-generation sequencing. Individual microbial diversity and composition were analyzed via targeting the 16 S rRNA gene hypervariable V3-V5 regions. RESULTS: Children with IgE-mediated FH (in milk, egg white, soy) had significantly lower gut microbiota diversity and richness than healthy children. Children with IgE-mediated FH exhibited relatively high abundances of Firmicutes and relative underrepresentation of the phylum Bacteroidetes. We observed significant increases in relative abundances of Ruminococcaceae, Clostridiaceae, and Erysipelotrichaceae (p < 0.01, compared to control) in children with milk hypersensitivity and of Clostridiaceae and Erysipelotrichaceae (p < 0.01) in children with peanut hypersensitivity. We also found significant increases in the numbers of Clostridiaceae, Lachnospiraceae and Pasteurellaceae (p < 0.01) in children with egg white hypersensitivity. CONCLUSIONS: These findings identify early evidence of different gut microbiota development/ differentiation in children with food hypersensitivity. Specific food hypersensitivities may be associated with compositional changes in intestinal microbiota. IMPACT: These findings identify early evidence of different gut microbiota development/differentiation in children with food hypersensitivity. We built a gut microbial profile that could identify toddlers at risk for food hypersensitivity. Children with enriched Firmicutes (phylum) with partial different families may be associated with food hypersensitivity. Enriched family Clostridiaceae, Ruminococcaceae, Lachnospiraceae, or Erysipelotrichaceae in gut microbiota may be associated with specific food hypersensitivities (such as milk, egg white, peanut) in children.

Handgrip strength assessment at baseline in addition to bone parameters could potentially predict the risk of curve progression in adolescent idiopathic scoliosis.

Introduction: Adolescent idiopathic scoliosis (AIS) is characterized by deranged bone and muscle qualities, which are important prognostic factors for curve progression. This retrospective case-control study aims to investigate whether the baseline muscle parameters, in addition to the bone parameters, could predict curve progression in AIS. Methods: The study included a cohort of 126 female patients diagnosed with AIS who were between the ages of 12 and 14 years old at their initial clinical visit. These patients were longitudinally followed up every 6 months (average 4.08 years) until they reached skeletal maturity. The records of these patients were thoroughly reviewed as part of the study. The participants were categorized into two sub-groups: the progressive AIS group (increase in Cobb angle of ≥6°) and the stable AIS group (increase in Cobb angle <6°). Clinical and radiological assessments were conducted on each group. Results: Cobb angle increase of ≥6° was observed in 44 AIS patients (34.9%) prior to skeletal maturity. A progressive AIS was associated with decreased skeletal maturity and weight, lower trunk lean mass (5.7%, p = 0.027) and arm lean mass (8.9%, p < 0.050), weaker dominant handgrip strength (8.8%, p = 0.027), deranged cortical compartment [lower volumetric bone mineral density (vBMD) by 6.5%, p = 0.002], and lower bone mechanical properties [stiffness and estimated failure load lowered by 13.2% (p = 0.005) and 12.5% (p = 0.004)]. The best cut-off threshold of maximum dominant handgrip strength is 19.75 kg for distinguishing progressive AIS from stable AIS (75% sensitivity and 52.4% specificity, p = 0.011). Discussion: Patients with progressive AIS had poorer muscle and bone parameters than patients with stable AIS. The implementation of a cut-off threshold in the baseline dominant handgrip strength could potentially be used as an additional predictor, in addition to bone parameters, for identifying individuals with AIS who are at higher risk of experiencing curve progression.

Bazi Bushen maintains intestinal homeostasis through inhibiting TLR4/NFκB signaling pathway and regulating gut microbiota in SAMP6 mice.

BACKGROUND: Bazi Bushen is a Chinese patented medicine with multiple health benefits and geroprotective effects, yet, no research has explored its effects on intestinal homeostasis. In this study, we aimed to investigate the effect of Bazi Bushen on intestinal inflammation and the potential mechanism of gut microbiota dysbiosis and intestinal homeostasis in senescence-accelerated mouse prone 6 (SAMP6). The hematoxylin and eosin (H&E) staining and immunohistochemistry were performed to assess the function of the intestinal mucosal barrier. The enzyme-linked immunosorbent assay (ELISA) and Western blotting were used to determine the level of intestinal inflammation. The aging-related ß-galactosidase (SA-ß-gal) staining and Western blotting were used to measure the extent of intestinal aging. The 16S ribosomal RNA (16S rRNA) was performed to analyze the change in gut microbiota composition and distribution. RESULTS: Bazi Bushen exerted remarkable protective effects in SAMP6, showing a regulated mucosal barrier and increased barrier integrity. It also suppressed intestinal inflammation through down-regulating pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α) and inhibiting TLR4/NFκB signaling pathway (MYD88, p-p65, and TLR4). Bazi Bushen improved intestinal aging by reducing the area of SA-ß-gal-positive cells and the expression of senescence markers p16, p21, and p53. In addition, Bazi Bushen effectively rebuilt the gut microbiota ecosystem by decreasing the abundance of Bacteroides and Klebsiella, whiles increasing the ratio of Lactobacillus/Bacteroides and the abundance of Akkermansia. CONCLUSION: Our study shows that Bazi Bushen could serve as a potential therapy for maintaining intestinal homeostasis. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The Multiple Cooperative Mechanism and Globalization Path of Small Inland Cities in China: A Showcase Study of Dunhuang, China.

Currently, urbanization driven by global capital flows entails a main trend in many large cites in China, while global capital investment in small inland cities especially in western China is extremely scarce, where their globalization characters the powerful nationalization power and market activation. Dunhuang, a small inland city in western China, has transformed successfully from an agricultural county to an international tourist city, a platform for worldwide cultural communication, and a node city in the Belt and Road region because of its unique and brilliant resources: Mogao Grottoes and Dunhuangology. Therefore, this paper develops a conceptual framework of the multiple cooperative mechanisms and globalization path (MCMGP) of Dunhuang, elaborating the process of industrial transformation, urban globalization, and multiple cooperative mechanisms between government and market actors based on interviewing records and statistics. Findings show that the MCMGP features government-led intervention, resource orientation, and centralization that embodies the driver of state-owned enterprises (SOEs). Also, the MCM in Dunhuang's globalization contains the mechanism of enrolment, mobilization and action, governance and global marketing, distributed in the two phases. Equally important, in response to the Belt and Road Initiative (BRI) and Silk Road (Dunhuang) International Cultural Expo (SRDICE) from the state, the city government has significantly reinvested and refined cultural tourism via governance mechanisms, carving out a key node city in the Silk Road and elevating an international tourist city. Environmentally, Dunhuang's tourism internationalization enhances the process of the development of a sustainable shared mobility industry. Furthermore, its tourism development and social-ecology system maintain the synergistic relationships which international tourism promotes such as urban ecosystem and public welfare and in turn, social-ecological enhancement serve Dunhuang's international tourism well. Practical implications of how Dunhuang's experience may have lessons for others are discussed in China's peculiar socialist market economy discourse.

How Does Family Intergenerational Relationships Affect the Life Satisfaction of Middle-Aged and Elderly Parents in Urban Only-Child Families in Chengdu, China.

Over the past 40 years, the implementation of the family planning policy in China has led to the creation of many only-child families. In the process of modernization and urbanization, it is critical to focus on the intergenerational relationships in only-child families and their associational mechanism on the life satisfaction of middle-aged and elderly parents, which has crucial implications for them staying active and healthy aging. Using the survey data from Chengdu, China, this study analyzed the characteristics of only-child parents' life satisfaction and family intergenerational relationships, and explored the associational mechanism of family intergenerational relationships on only-child parents' life satisfaction in urban families, as well as the possible moderating role of gender. The results indicate that there are gender differences in the life satisfaction of only-child parents in urban families, and men are more satisfied than women. Moreover, parents of sons and daughters differ in life satisfaction from the dual-gender perspective. Parents of daughters are likely to have higher life satisfaction, especially mothers. The only-child families have not moved toward nucleation in urban families, and intergenerational members maintain close contact and provide frequent mutual support to achieve individual and family development. There are significant gender differences in structural, associational, affectual, and functional solidarity among only-child. This study confirms that there are differences in the associational mechanism of family intergenerational relationships on life satisfaction in different dimensions. Affectual solidarity is the most influential factor of life satisfaction. In terms of normative and consensual solidarity, gender plays a moderating role. For men, normative and consensual solidarity is beneficial for improving life satisfaction, but it has an insignificant effect on women. The effects of structural solidarity, association solidarity, and functional solidarity are not significant.

Benefit-Risk Assessment of Dietary Patterns by Bioavailable Metals, Gut Microbes, and Their Interaction for Human Health.

The high-carbohydrate, low-fat, low-protein (HC-LFP) and low-carbohydrate, high-fat, high-protein (LC-HFP) diets are the main dietary patterns worldwide. The influence of dietary patterns on bioavailable metals, gut microbes, and their interaction is still unknown. A biomimetic digestive tract with full functions is constructed to transform the diets into chyme, and the gut microbes are cultured with the corresponding chyme. The diet species-specificity in bioavailable metal content and the positive and negative correlations between bioavailable metals and microbial reproductions are disclosed. The safe dosage and maximum consumption are 369.5 and 858.6 g/d and 268.6 and 3119.0 g/d for LC-HFP and HC-LFP, respectively. When replacing HC-LFP with LC-HFP for 21 days, the bioavailability of Fe and Cr is increased 83.2% and 268.4%, respectively; the reproductions of harmful and benefical microbes are significantly increased and decreased. The prevalences of obesity, inflammation, septicemia, and cancer are increased, and then the risk of dietary pattern shift is disclosed.

[PreS1 Antigen of HBV Down-Regulates MHC-â on the Surface of Hepatocytes and Promotes Hepatocarcinogenesis].

Objective: To explore the internal mechanism of hepatocellular carcinoma (HCC) induced by chronic hepatitis B virus (HBV) infection. Methods: L02, HepG2 and Huh7 cells stably overexpressing HBV preS1 antigen were analyzed by flow cytometry, qRT-PCR and tumorigenesis in nude mice to evaluate the effect of preS1 antigen in HBV-related hepatocarcinogenesis. Results: Our results showed that the expression of cancer stem cell (CSCs) related factors and cell surface markers in preS1 overexpressing cells were up-regulated, and the tumorigenicity of these cells was enhanced in nude mice. In addition, preS1 overexpression could down-regulate the expression of major histocompatibility complex Ⅰ (MHC-Ⅰ). The expression of MHC-Ⅰ on the cell surface could be restored by adding interferon gamma (IFN-γ) in the process of cell culturing and the tumorigenicity of cells in nude mice could thus be reduced. Conclusion: Based on the above results, we believe that preS1 is a carcinogen of HBV and that it promotes the formation of liver cancer through down regulating MHC-Ⅰ on the surface of hepatocytes.

Long-term stable, high accuracy, and visual detection platform for In-field analysis of nitrite in food based on colorimetric test paper and deep convolutional neural networks.

Nitrite is one of the most common carcinogens in daily food. Its simple, rapid, inexpensive, and in-field measurement is important for food safety, based on the requirements of the standard from Codex Alimentarius Commission and China. Using polyacrylonitrile (PAN) and thin layer silica gel (SG), p-aminophenylcyclic acid (SA) and naphthalene ethylenediamine hydrochloride (NEH), as carriers and chromogenic agents, respectively, PAN-NSS as nitrite color sensor is proposed. After fixing and protecting of SA and NEH with layer-upon-layer PAN, the validity period of the test paper can be prolonged from 7 days to more than 30 days. The reproducibility of PAN-NSS preparation is ensured by electrospinning. Combined with PAN-NSS, deep convolutional neural network (DCNN) and APP as a visual monitoring platform, which has the functions of rapid sampling, data processing and transmission, intuitive feedback, etc., and provides a fully integrated detection system for field detection.

Effects of a Home-Based Exercise Intervention (E-Fit) on Bone Density, Muscle Function, and Quality of Life in Girls with Adolescent Idiopathic Scoliosis (AIS): A Pilot Randomized Controlled Trial.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) patients have lower physical activity levels than normal adolescents, and there is an association with poorer bone and muscle health. This study evaluated the effects of a home-based exercise intervention (E-Fit) on bone mineral density (BMD), muscle function, and quality of life (QoL) in AIS-affected girls. METHODS: A total of 40 AIS females aged 11 to 14 years were randomly assigned to the E-Fit or control group. The E-Fit group performed modified 7-min high-intensity interval training (HIIT) 5 days per week for 6 months. Outcome measures including BMD using dual-energy X-ray absorptiometry (DXA), muscle strength and endurance tests, physical activity levels, and QoL using self-reported questionnaires were assessed at baseline and at 6-month and 12-month follow-up. RESULTS: In total, 14 patients in the E-Fit and 16 in the control group completed the study. The E-Fit group showed a marginally significant interaction effect in the whole body areal BMD at the 6- (p = 0.096) and 12-month follow-ups (p = 0.085). The left arm lean mass in the E-Fit group showed a statistically significant interaction effect between the 6- and 12-month follow-ups (p = 0.046). The E-Fit group showed improvements in physical activity participation, as measured by the Modified Baecke Questionnaire (MBQ), with a significant interaction effect in work index (p = 0.043), sport index (p = 0.050), and total score (p = 0.016) from baseline to the 12-month follow-up. Improvement on self-image were noted in E-Fit group across time. CONCLUSIONS: The present results provided some evidence to support the positive benefits of E-Fit for bone health and muscle function in AIS girls.

Benefit-risk assessment of metal bioavailability in edible fungi by biomimetic whole digestive tracts with digestion, metabolism, and absorption functions.

As worldwide edible fungi, Lentinula edodes and Agaricus bisporus accumulate both essential and harmful metals. Metal bioavailability is important for metal benefit-risk assessment. A full functional model of digestive tracts (including digestion, metabolism, and absorption) is established. Under the digestive tract functions, the bioaccessible and bioavailable metals are released from edible fungi and absorbed by intestinal tract, respectively. Based on bioavailable metal contents in the intestine, safe dosage and maximum consumption are 43.52 g/d and 248.7 g/d for Agaricus bisporu, 20.59/328.9 g/d (for males/ female) and 132.9 g/d for Lentinus edodes; V, Co, Ni, Cu, Zn, Se, Cr, Cd and Pb in Agaricus bisporus and Lentinula edodes are absorbed mainly in the large intestine; Fe is mainly absorbed in small intestine; edible fungi species-specificity in metal bioavailability is observed for As and Mn, which are mainly absorbed by small and large intestine for Agaricus bisporus and Lentinus edodes, respectively; and then metal toxicity on small and large intestine is disclosed. Metal benefit-risk is assessed by the content of monolayer liposome-extracted metal in the chyme from small and large intestine, which is controlled by the gastrointestinal functions, metal and edible fungi species.

The applicability of the ACOSOG Z0011 Criteria to breast cancer patients in Hong Kong.

BACKGROUND: The ACOSOG Z0011 trial demonstrated safe omission of axillary lymph node dissection (ALND) in patients with one or two positive sentinel lymph nodes (SLNs) receiving breast conservative surgery, followed by whole breast irradiation and adjuvant systemic treatment. This study aims to evaluate the exportability of the ACOSOG Z0011 criteria in an Asian/Chinese cohort residing in Hong Kong. METHODS: Retrospective analysis of a prospectively maintained database in a University affiliated tertiary breast centre was performed from June 2014 to May 2019. All breast cancer patients with no palpable adenopathy before surgery, one or more positive sentinel lymph nodes on histological examination and no prior neoadjuvant systemic treatment were recruited. Patients were grouped as eligible or ineligible according to the ACOSOG Z0011 criteria. The eligible group was compared with the sentinel alone group in the ACOSOG Z0011 cohort. RESULTS: Two hundred and forty-eight patients were recruited into the study. Sixty patients (24%) met the ACOSOG Z0011 criteria and could potentially avoid ALND. A higher percentage of clinical T2 tumors were observed in our eligible group than in the ACOSOG Z0011 trial (P=0.002). The histological subtype, tumor grade, estrogen receptor (ER)/progestogen receptor (PR) status and lymphovascular invasion status did not differ. There was no statistically significant difference in the proportion of SLN micrometastasis and macrometastasis between the two groups. CONCLUSIONS: This study demonstrated clinical similarities between our eligible cohort and the ACOSOG Z0011 cohort, which confirms exportability of the ACOSOG Z0011 criteria to a subset of population in Hong Kong.

Magnet ingestion by children: A retrospective study in a medical center in Taiwan.

BACKGROUND: The ingestion of multiple magnets may lead to severe complications including bowel obstruction, perforation, fistula, peritonitis, short bowel syndrome, life-threatening injuries, and even death. The annual case number of high-powered neodymium magnets ingestion has been increasing in the western world and the dearth of available data demonstrates that this issue has been neglected in Taiwan. METHODS: We searched the electronic medical records of our institution for patients younger than 18 years old who were diagnosed with, who had ever visited our emergency department, or been hospitalized for magnetic foreign body ingestion between January 2009 and March 2018. Demographic data including the number, shape, and size of magnets ingested, the clinical presentation, type of intervention, and complications were reviewed. RESULTS: Thirteen patients who met the enrollment criteria were analyzed. One patient was documented between 2009 and 2013, and twelve were documented between January 2014 and March 2018. Five of the cases documented between 2014 and 2018 had ingested Buckyballs. The median age of the patients was 5 years. All of the patients with clinical symptoms had ingested more than one magnet and required endoscopic or surgical intervention. Bowel perforation or deep ulcer with impending perforation was found in three patients during surgery. CONCLUSION: The number of children who visited our emergency department or were hospitalized due to the ingestion of magnets has increased recently. The presence of high power of neodymium magnets in many products increases the risk of ingesting multiple magnets resulting in serious complications. Therefore, stricter policies are needed to prevent children from obtaining products that contain magnets.

Metronomic chemotherapy offsets HIFα induction upon maximum-tolerated dose in metastatic cancers.

Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia-inducible factor (HIF)-1α and (HIF)-2α (hereafter referred to as HIFα). Instead, frequent low-dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre-clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog-specific, MTD-dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11-gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα-targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra-metastatic tumor microenvironment.

Immunostimulatory and anti-tumor metronomic cyclophosphamide regimens assessed in primary orthotopic and metastatic murine breast cancer.

The impressive successes of immune checkpoint blockade antibodies to treat various types of cancer are limited to minor subsets of patients. Combination therapy strategies, including with chemotherapy, are being explored to possibly improve the efficacy of immunotherapies. Here we report results regarding the use of an immunostimulatory regimen of metronomic cyclophosphamide (CTX). We show that in orthotopic models of syngeneic murine triple-negative breast cancer (EMT6), CTX administered at 140 mg/kg every 6 days (CTX140 1q6d) is superior at inhibiting primary tumor growth when compared to maximum tolerated dose or daily oral (continuous) low-dose CTX. In SCID or SCID beige mice, anti-tumor effects of CTX140 1q6d are reduced, reinforcing the therapeutic contribution of the adaptive and innate immune systems. In a second breast cancer model (SP1-AC2M2), CTX140 1q6d again showed clear superiority in anti-tumor effects, causing complete tumor regressions; however, these mice were not protected from subsequent tumor re-challenge, suggesting absence of immune memory. We also show that in an aggressive and metastatic cisplatin-resistant variant (EMT6-CDDP), CTX140 1q6d is superior and invokes an influx of intra-tumoral CD4+ and CD8+ T cells. CTX increases expression of tumor cell PD-L1; however, when combined with concomitant PD-L1 antibody therapy none of the CTX regimens showed increased benefit. This work sheds light on the potential use of metronomic CTX for the treatment of breast cancer, in particular using the quasi-weekly regimen, but also underscores the complexity of the anti-tumor mechanisms and potential to improve immune checkpoint therapy efficacy.

[Anti-arthritic-related metal bioavailability for optimal compatibility ratio of Aconiti Radix Cocta and Paeoniae Radix Alba].

Trace metals deficiency or excess are associated with the etiology and pathogenesis of rheumatoid arthritis(RA). Aconiti Radix Cocta(A) and Paeoniae Radix Alba(B) are commonly used together for the treatment of RA. In this study, we aim to determine anti-arthritic-related metal bioavailability in the compatibility of herb A and B for avoiding metal deficiency or excess, and optimize the combination ratio of herb A and B, accordingly. Anti-arthritic-related metal bioaccessibility were evaluated by in vitro simulator of all gastrointestinal tract(including mouth, stomach, small and large intestines), and the roles of gastrointestinal digestive enzymes and intestinal microflora were investigated. Anti-arthritic-related metal bioavailability was assessed by the affinity adsorption with liposomes. The results indicated that compatibility proportion of corresponding herbal plants, gastrointestinal digestion and microbial metabolic, which could affect metal digestion and absorption. The optimal compatibility proportion of 1 A∶1 B is recommended, according to the dose of anti-arthritic-related metal bioavailability, which is often chosen for clinical practice of RA therapy. Thus, anti-arthritic-related metal bioavailability might be the key active substances for RA treatment.

Abnormal Osteoblastic Response to Leptin in Patients with Adolescent Idiopathic Scoliosis.

Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional structural deformity of the spine with unknown etiology. Although leptin has been postulated as one of the etiologic factors in AIS, its effects on osteoblastic activity remain unknown. Herein, we conducted this study to investigate whether there are abnormal functional responses to leptin and abnormal expression of leptin receptor in AIS osteoblasts. In vitro assays were performed with osteoblasts isolated from 12 severe AIS girls and 6 non-AIS controls. The osteoblasts were exposed to different concentrations of leptin (0, 10, 100, 1000 ng/mL). The effects of leptin on cell proliferation, differentiation and mineralization were determined. Protein expressions of leptin receptor (LEP-R) under basal and osteogenic conditions were also evaluated by Western blot. Our results showed that leptin significantly stimulated osteoblasts from non-AIS subjects to proliferate, differentiate and mineralized. However, in the AIS group, the stimulatory effects of leptin on cell proliferation, differentiation, and mineralization were not observed. In addition, no statistically significant difference in the expression of leptin receptor under both basal and osteogenic conditions was found between AIS and control group. In conclusion, these findings might help to explain the low bone mass and deranged bone quality that is clinically associated with AIS girls.

Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion.

Metronomic chemotherapy using the 5-FU prodrug uracil-tegafur (UFT) and cyclophosphamide (CTX) was previously shown to only modestly delay primary tumor growth, but nevertheless markedly suppressed the development of micro-metastasis in an orthotopic breast cancer xenograft model, using the metastatic variant of the MDA-MB-231 cell line, 231/LM2-4. Furthermore, a remarkable prolongation of survival, with no toxicity, was observed in a model of postsurgical advanced metastatic disease. A question that has remained unanswered is the seemingly selective anti-metastatic mechanisms of action responsible for this treatment. We assessed the in vivo effect of metronomic UFT, CTX or their combination, on vascular density, collagen deposition and c-Met (cell mediators or modulators of tumor cell invasion or dissemination) via histochemistry/immunohistochemistry of primary tumor sections. We also assessed the effect of continuous exposure to low and non-toxic doses of active drug metabolites 5-fluorouracil (5-FU), 4-hydroperoxycyclophosphamide (4-HC) or their combination, on 231/LM2-4 cell invasiveness in vitro. In the in vivo studies, a significant reduction in vascular density and p-Met[Y1003] levels was associated with UFT+CTX treatment. All treatments reduced intratumoral collagen deposition. In the in vitro studies, a significant reduction of collagen IV invasion by all treatments was observed. The 3D structures formed by 231/LM2-4 on Matrigel showed a predominantly Mass phenotype under treated conditions and Stellate phenotype in untreated cultures. Taken together, the results suggest the low-dose metronomic chemotherapy regimens tested can suppress several mediators of tumor invasiveness highlighting a new perspective for the anti-metastatic efficacy of metronomic chemotherapy.

Variable impact of three different antiangiogenic drugs alone or in combination with chemotherapy on multiple bone marrow-derived cell populations involved in angiogenesis and immunity.

In contrast to VEGF pathway-targeting antibodies, antiangiogenic tyrosine kinase inhibitors (TKIs) have failed to meet primary endpoints in almost all phase III clinical trials when combined with conventional chemotherapy. One exception is the combination of nintedanib and docetaxel as a second-line therapy for rapidly progressing advanced NSCLC. In addition to increased toxicity caused by this type of combination, thus necessitating drug dose reductions or treatment breaks, such phase III trial failures may also be related to the differential impact of host-mediated responses involving mobilization and tumor infiltration of bone marrow-derived cell populations (BMDCs), comprising both pro-angiogenic as well as immune effector cells. Herein, we evaluated two different antiangiogenic TKIs (sunitinib or nintedanib) and a VEGFR-2 antibody (DC101) either alone or combined with maximum tolerated dose paclitaxel for their differential impact on the BMDC host response, evaluating four different cell types. TKIs (in particular sunitinib) induced myelosuppression similar to paclitaxel, whereas DC101 had no such effect. Sunitinib also significantly decreased the number of tumor-infiltrating CD8 + T and B cells, MDSCs, and macrophages. In contrast, the effect of nintedanib on these BMDC populations was less marked, behaving closer to the VEGFR-2 antibody effects than sunitinib. The results raise the possibility that differences observed between antiangiogenic antibodies and TKIs in increasing chemotherapy efficacy could be related, at least in part, to differential effects on cells associated with local immunity within the tumor microenvironment.

Probiotic Lactobacillus casei: Effective for Managing Childhood Diarrhea by Altering Gut Microbiota and Attenuating Fecal Inflammatory Markers.

BACKGROUND: Acute diarrhea is a major cause of childhood morbidity and an economic burden for families. The aim of this study is to explore the effect of probiotics on clinical symptoms, intestinal microbiota, and inflammatory markers during childhood diarrhea. METHODS: Children (n = 81) aged six months to six years (mean age 2.31 years) hospitalized for acute diarrhea were randomized to receive probiotics (Lactobacillus casei variety rhamnosus; n = 42) or no probiotics (n = 39) orally twice daily for seven days. Feces samples were also collected to evaluate microbial content using a traditional agar plate and next-generation sequencing. Immunoglobulin A (IgA), lactoferrin, and calprotectin were determined by enzyme-linked immunosorbent assay (ELISA) and compared in different groups. Other clinical symptoms or signs, including fever, vomiting, diarrhea, abdominal pain, bloated abdomen, daily intake, appetite, and body weight were also assessed. RESULTS: Data were collected from 81 individuals across three different time points. Total fecal IgA levels in fecal extracts of the probiotics group were higher than those in the control group, reaching statistical significance (p < 0.05). Concentrations of fecal lactoferrin and calprotectin were significantly downregulated in patients with probiotic Lactobacillus casei variety rhamnosus (Lc) consumption compared to those of the control (p < 0.05). Probiotic Lc administration may be beneficial for gut-microbiota modulation, as shown by the data collected at one week after enrollment. Counts of Bifidobacteria and Lactobacillus species were elevated in stool culture of the probiotic group. Appetite and oral intake, body-weight gain, abdominal pain, bloating, as well as bowel habits (diarrhea) were much better in children receiving probiotics compared with those in the control group. CONCLUSION: Fecal IgA increased during acute diarrhea under Lc treatment; in contrast, fecal lactoferrin and calprotectin were downregulated during acute diarrhea under Lc treatment. Probiotic Lc may be a useful supplement for application in children during acute diarrhea to reduce clinical severity and intestinal inflammatory reaction.

Changes in the neurotransmitter profile in the central nervous system of marine medaka (Oryzias melastigma) after exposure to brevetoxin PbTx-1 - A multivariate approach to establish exposure biomarkers.

A strategy to construct multivariate biomarkers for exposure to algal neurotoxins via correlating changes to the profiles of a series of neurotransmitters and their metabolites in the central nervous system (CNS) of exposed test organism is reported. 3-Month-old marine medaka (Oryzais melastigma) were exposed to waterborne brevetoxin PbTx-1 at two sub-lethal dose levels (0.5 and 2.5 µg-PbTx-1 L-1) for a duration of 12 h before quantification of 43 selected neurotransmitters and metabolites in their CNS were measured via dansyl chloride derivatization and LC-MS/MS determination. The profiling data were analyzed by multivariate statistical analyses, including principle component analysis (PCA), projection on latent structure-discriminate analysis (PLS-DA) and orthogonal projection on latent structure-discriminate analysis (OPLS-DA). Neurotransmitters and metabolites related to activation of voltage-gated sodium channels (VGSCs), N-methyl-D-aspartic acid receptors (NMDARs) and cholinergic neurotransmission were found to contribute significantly to class separation in the corresponding OPLS-DA models. Those models obtained from different exposure dosages were correlated by the Shared and Unique Structures Plot (SUS-plot) to identify appropriate variables for the construction of exposure biomarkers in the form of multivariate predictive scores. The established biomarkers for male and female medaka fish were able to predict acute sub-lethal exposure to PbTx-1 with good sensitivity and specificity (male fish: sensitivity 94.7%, specificity 80.0%; female fish: sensitivity 91.4%, specificity 83.3%). Neurotransmitter profiles in the CNS of medaka fish that should have recovered from exposure to PbTx-1 have also been determined to reveal long-term impacts to the CNS of the affected organism even after the exposure has been interrupted.