Pathological image profiling identifies onco-microbial, tumor immune microenvironment, and prognostic subtypes of colorectal cancer.

Histology slide, tissue microbes, and the host gene expression can be independent prognostic factors of colorectal cancer (CRC), but the underlying associations and biological significance of these multimodal omics remain unknown. Here, we comprehensively profiled the matched pathological images, intratumoral microbes, and host gene expression characteristics in 527 patients with CRC. By clustering these patients based on histology slide features, we classified the patients into two histology slide subtypes (HSS). Onco-microbial community and tumor immune microenvironment (TIME) were also significantly different between the two subtypes (HSS1 and HSS2) of patients. Furthermore, variation in intratumoral microbes-host interaction was associated with the prognostic heterogeneity between HSS1 and HSS2. This study proposes a new CRC classification based on pathological image features and elucidates the process by which tumor microbes-host interactions are reflected in pathological images through the TIME.

Predictable regulation of survival by intratumoral microbe-immune crosstalk in patients with lung adenocarcinoma.

Intratumoral microbiota can regulate the tumor immune microenvironment (TIME) and mediate tumor prognosis by promoting inflammatory response or inhibiting anti-tumor effects. Recent studies have elucidated the potential role of local tumor microbiota in the development and progression of lung adenocarcinoma (LUAD). However, whether intratumoral microbes are involved in the TIME that mediates the prognosis of LUAD remains unknown. Here, we obtained the matched tumor microbiome and host transcriptome and survival data of 478 patients with LUAD in The Cancer Genome Atlas (TCGA). Machine learning models based on immune cell marker genes can predict 1- to 5-year survival with relative accuracy. Patients were stratified into high- and low-survival-risk groups based on immune cell marker genes, with significant differences in intratumoral microbial communities. Specifically, patients in the high-risk group had significantly higher alpha diversity (p < 0.05) and were characterized by an enrichment of lung cancer-related genera such as Streptococcus. However, network analysis highlighted a more active pattern of dominant bacteria and immune cell crosstalk in TIME in the low-risk group compared to the high-risk group. Our study demonstrated that intratumoral microbiota-immune crosstalk was strongly associated with prognosis in LUAD patients, which would provide new targets for the development of precise therapeutic strategies.

A pilot randomised controlled trial of ride-on cars and postural combinations of standing and sitting for mobility and social function in toddlers with motor delays.

PURPOSE: Locomotor experiences in upright postures are essential for developing toddlers' mobility and social functions. This pilot randomised controlled trial aimed to examine the effectiveness of using a modified ride-on car (ROC) with postural combinations of standing and sitting on mobility and social function in toddlers with motor delays. MATERIALS AND METHODS: Nineteen participants aged 1-3 years with mild, moderate or severe motor delays were randomly assigned to four ROC groups. The ROC groups had different combinations of standing and sitting, namely standing for 70 min (ROC-Stand70, five participants), standing for 45 min (ROC-Stand45, four participants), standing for 25 min (ROC-Stand25, five participants) and sitting for 70 min (ROC-Sit70, five participants). All participants participated in 2-h sessions twice a week for 12 weeks. The Pediatric Evaluation of Disability Inventory, Goal Attainment Scaling and Bayley-III tests were administered before and after the intervention, and after 12 weeks of follow-up. A mixed-model analysis of variance was used to compare inter- and intra-group differences. This trial was registered at ClinicalTrials.gov (NCT03707405). RESULTS: All groups showed significantly improved mobility, social function and goal achievement at the post-test (p < .001). However, no significant changes were observed in Bayley scores. CONCLUSIONS: Combining physical and social environmental modifications with active exploration is crucial for early power mobility training in toddlers with motor delays. To enhance the robustness and generalisability of our findings, future studies should include larger sample sizes, consider variations in motor delays, and measure energy expenditure during the intervention.Implications for rehabilitationProviding active exploratory experience using ride-on cars (ROCs) with various postural combinations can improve a child's mobility.The ROC training with various postural combinations can improve social function, and the degree of improvement may depend on the severity of motor delays.Setting goals with caregivers and incorporating their roles in the training process can empower them to interact with children more frequently and actively.

Pan-cancer analyses reveal the stratification of patient prognosis by viral composition in tumor tissues.

The associations between cancer and bacteria/fungi have been extensively studied, but the implications of cancer-associated viruses have not been thoroughly examined. In this study, we comprehensively characterized the cancer virome of tissue samples across 31 cancer types, as well as blood samples from 23 cancer types. Our findings demonstrated the presence of viral DNA at low abundances in both tissue and blood across major human cancers, with significant differences in viral community composition observed among various cancer types. Furthermore, Cox regression analyses conducted on four cancers, including Head and Neck squamous cell carcinoma (HNSC), Kidney renal clear cell carcinoma (KIRC), Stomach adenocarcinoma (STAD), and Uterine Corpus Endometrial Carcinoma (UCEC), revealed strong correlation between viral composition/abundance in tissues and patient survival. Additionally, we identified virus-associated prognostic signatures (VAPS) for these four cancers, and discerned differences in the interplay between VAPS and dominant bacteria in tissues among patients with varying survival risks. Notably, clinically relevant analyses revealed prognostic capacities of the VAPS in these four cancers. Taken together, our study provides novel insights into the role of viruses in tissue in the prognosis of multiple cancers and offers guidance on the use of tissue viruses to stratify prognosis for patients with cancer.

The specific viral composition in triple-negative breast cancer tissue shapes the specific tumor microenvironment characterized on pathological images.

Numerous studies have shown that different subtypes of breast cancer (BC) have significant differences in terms of the tumor microbiome, host gene expression, and histopathological image, whereas the biological links between these cancer-associated indicators are still unknown. Here, we performed a comprehensive analysis with 610 patients of the four subtypes of BC with matched tissue microbiota, host transcriptome, and histopathological image samples. Correlation analysis showed that the composition of intratumoral viruses shaped the tumor microenvironment (TME) of patients with BC, and the TME was further reflected in the histopathological images. Of the four subtypes, patients with triple-negative breast cancer (TNBC) had unique intratumoral viral community composition, non-cancer cell infiltration in the TME, and histopathological image characteristics. Furthermore, we detected multiple virus-cell-image association axes in TNBC, in which tumor-associated macrophages (TAMs) have clinical prognostic implication. This study provides a comprehensive map of the associations between the intratumoral virome, TME, and histopathological image of TNBC, as well as insights into disease prognosis that can be crucial for precise therapeutic intervention strategies.

An atopic dermatitis-like murine model by skin-brushed cockroach Per a 2 and oral tolerance induction by Lactococcus lactis-derived Per a 2.

Atopic dermatitis (AD) is a complex, chronic inflammatory skin disease. An estimated 57.5% of asthmatic patients and 50.7% of rhinitis patients are allergic to cockroaches in Taiwan. However, the role of cockroaches in the pathogenesis of AD is undetermined. Oral tolerance might be another strategy for protecting against AD and allergic inflammation by regulating T helper 2 (Th2) immune responses. Aim to examine the underlying immunologic mechanism, we developed an AD-like murine model by skin-brushing with cockroach Per a 2. We also investigated whether the systemic inflammation of AD in this murine model could be improved by specific tolerance to Lactococcus lactis-expressing Per a 2, which was administered orally. Repeated painting of Per a 2 without adjuvant to the skin of mice resulted in increased total IgE, Per a 2-specific IgE, and IgG1, but not IgG2a. In addition, epidermal thickening was significantly increased, there were more scratch episodes, and there were increases in total white blood cells (eosinophil, neutrophil, and lymphocyte) and Th2 cytokines (Interleukin (IL)-4, IL-5, IL-9, and IL-13) in a dose-dependent manner. The results revealed that oral administration of L. lactis-Per a 2 ameliorated Per a 2-induced scratch behavior and decreased the production of total IgE, Per a 2-specific IgE, and IgG1. Furthermore, L. lactis-Per a 2 treatment also suppressed inflammatory infiltration, expressions of thymic stromal lymphopoietin (TSLP) and IL-31 in skin lesions, and downregulated splenic IL-4 and IL-13 in Per a 2-induced AD mice. This study provides evidence supporting that repeated brushing of aeroallergens to the skin leads to atopic dermatitis phenotypes and oral allergen-specific immune tolerance can ameliorate AD-like symptoms and systemic inflammation and prevent progression of atopic march.

Indoor aeroallergens from American cockroaches and mites initiate atopic march via cutaneous contact in a murine model.

The progression of allergic diseases from atopic dermatitis in childhood to other allergic conditions such as asthma in later life is often referred to as the atopic march. In order to study the relationship between cutaneous sensitization by aeroallergen and atopic march, we established a mouse model to test the hypothesis using American cockroaches and house dust mites as the model allergens. Mice were sensitized via skin with native cockroach extract (CraA) or recombinant Per a 2 and Der p 2 proteins without adjuvant. Each mouse was subjected to a total of three 1-week patching sensitizations with a 2-week interval in between each application. The resulting immunological variables in sera, scratching behavior, airway hyperresponsiveness (AHR), and pathology of skin lesions and nasal mucosa were evaluated. In mice, application of CraA, rPer a 2, and rDer p 2 aeroallergens through skin patching induced significantly high levels of both total IgE and specific IgEs. The epicutaneous sensitization after a subsequent allergen challenge showed a significant increase in scratch bouts, AHR, epidermal thickness, and eosinophil counts in the skin compared with the control mice. In addition, stimulation of murine splenocytes with allergens increased higher levels of Th2 cytokines, anti-inflammatory cytokines, and chemokines excretion. Our study provides evidence supporting that epicutaneous sensitization to aeroallergens also led to nasal and airway symptoms comparable to atopic march as described in humans. We hope this new allergy model will be useful in the development of new preventive and therapeutic strategies aimed at stopping the atopic march.

Artificial intelligence-enabled microbiome-based diagnosis models for a broad spectrum of cancer types.

Microbiome-based diagnosis of cancer is an increasingly important supplement for the genomics approach in cancer diagnosis, yet current models for microbiome-based diagnosis of cancer face difficulties in generality: not only diagnosis models could not be adapted from one cancer to another, but models built based on microbes from tissues could not be adapted for diagnosis based on microbes from blood. Therefore, a microbiome-based model suitable for a broad spectrum of cancer types is urgently needed. Here we have introduced DeepMicroCancer, a diagnosis model using artificial intelligence techniques for a broad spectrum of cancer types. Built based on the random forest models it has enabled superior performances on more than twenty types of cancers' tissue samples. And by using the transfer learning techniques, improved accuracies could be obtained, especially for cancer types with only a few samples, which could satisfy the requirement in clinical scenarios. Moreover, transfer learning techniques have enabled high diagnosis accuracy that could also be achieved for blood samples. These results indicated that certain sets of microbes could, if excavated using advanced artificial techniques, reveal the intricate differences among cancers and healthy individuals. Collectively, DeepMicroCancer has provided a new venue for accurate diagnosis of cancer based on tissue and blood materials, which could potentially be used in clinics.

Multiple accounting and driving factors of water resources use: A case study of Shanghai.

Previous research papers on urban water resources accounting were confined to the perspectives of production and consumption, ignoring the perspective of income. This paper proposes a systems framework to analyze the income, production, and consumption-based water uses and underlying driving forces of a city based on the methods of multi-scale input-output analysis and structural decomposition analysis. A case study is performed for Shanghai as a megacity. The results show that the income, production and consumption-based water uses of Shanghai had decreased from 5.70 billion m3, 10.85 billion m3 and 28.45 billion m3 in 2007 to 2.80 billion m3, 6.20 billion m3 and 24.10 billion m3 in 2017, respectively. Domestic imported primary inputs had emerged as an important virtual water supplier of Shanghai and its share of total supply-side water use had increased from 23.92% in 2007 to 42.95% in 2017. Meanwhile, about 46% and 40% of Shanghai's total consumption-based water use had been imported from other Chinese regions and foreign countries in 2017, respectively. It is revealed that trade played an important role in relieving water use pressure in Shanghai. The factors that had increased the uses of water resources in Shanghai include population, per capita value-added, per capita output, final consumption structure, and per capita final consumption. The factors that had reduced the water uses in Shanghai include technology, value added mix, output structure, value added structure, domestic import, commodity mix, and foreign import. It is suggested that in addition to curbing urban water use from the production side, more targeted water-saving measures should be devised from the supply (e.g., restricting loan to heavy water-consuming enterprises) and consumption sides (e.g., encouraging residents to buy low-water products).

Ride-On Cars With Different Postures and Motivation in Children With Disabilities: A Randomized Controlled Trial.

IMPORTANCE: A child's independent mobility, environments, and mastery motivation are critical factors during early development. OBJECTIVE: To examine the effectiveness of ride-on car (ROC) training with a standing (ROC-Stand) or a sitting posture (ROC-Sit) in enhancing children's mastery motivation and decreasing parenting stress levels. DESIGN: Randomized controlled trial (RCT) with a multiple pretest-posttest design. SETTING: Hospital-based environment in northern Taiwan. PARTICIPANTS: Thirty-nine children with disabilities ages 1 to 3 yr were randomly assigned to ROC-Stand (n = 16), ROC-Sit (n = 12), or conventional therapy (control; n = 11). All groups received 2-hr training sessions two times a week for 12 wk and then a 12-wk follow-up period that involved only regular therapy. MEASURES: Assessments included the Revised Dimensions of Mastery Questionnaire-Chinese version and the Parenting Stress Index. RESULTS: All groups showed significant changes in social persistence with adults, mastery pleasure, and general competence after the intervention. The two ROC training groups showed a significantly greater decrease in parenting stress than the control group. In addition, increased general competence of the ROC-Stand group also strongly correlated with decreased parent-child dysfunctional interaction. CONCLUSIONS AND RELEVANCE: This RCT verifies the effectiveness of ROC training and offers a novel approach to increase children's mastery motivation and decrease parenting stress. What This Article Adds: Providing a large amount of active, exploratory experiences with goal-directed, moderately challenging tasks and cooperation with caregivers may result in the greatest benefits to young children with motor disabilities.

Hip, vertebral, and wrist fracture risks and schizophrenia: a nationwide longitudinal study.

BACKGROUND: Fractures are a great health issue associated with morbidity, quality of life, life span, and health care expenditure. Fractures are correlated with cardiovascular disease, type 2 diabetes mellitus, cerebrovascular disease, and some psychiatric disorders. However, representative national data are few, and longitudinal cohort studies on the association between schizophrenia and the subsequent fracture risk are scant. We designed a nationwide population-based cohort study to investigate the association of schizophrenia with hip, vertebral, and wrist fractures over a 10-year follow-up. METHODS: Data of patients with schizophrenia (International Classification of Diseases, Ninth Revision, Clinical Modification code 295) and matched over January 2000-December 2009) were extracted from Taiwan National Health Insurance Research Database. A Cox proportional-hazards regression model was constructed to calculate hazard ratios (HRs) for fractures between the schizophrenia and control cohorts. RESULTS: Of 2028 people with schizophrenia (mean age: 36.3 years, 49.4% female), 89 (4.4%) reported newly diagnosed fractures-significantly higher than the proportion in the control population (257, 3.2%; P = 0.007). The incidences of hip (1.2%, P = 0.009) and vertebral (2.6%, P = 0.011) fractures were significantly higher in the schizophrenia cohort than in the control cohort. In Cox regression analysis, hip (adjusted HR: 1.78, 95% confidence interval [CI]: 1.08-2.93) and vertebral (adjusted HR: 1.40, 95% CI: 1.01-1.95) fracture risks were significantly higher in patients with schizophrenia. Furthermore, a sex-based subgroup analysis revealed that the risk of hip fracture remained significantly higher in female patients with schizophrenia (HR: 2.68, 95% CI: 1.32-5.44) than in female controls. On the other hand, there was no significant interaction between effects of sex and schizophrenia on the risk of fractures. CONCLUSIONS: Over a 10-year follow-up, hip and vertebral fracture risks were higher in the people with schizophrenia than in the controls. The risk of fractures in patients with schizophrenia does not differ between female and male.

The cytotoxic mechanism of epigallocatechin gallate on proliferative HaCaT keratinocytes.

BACKGROUND: Epigallocatechin gallate (EGCG) is the major ingredient of sinecatechins ointment, approved for the treatment of external genital and perianal warts. However, the molecular mechanism for EGCG's effect on warts resulting from the human papillomavirus (HPV) infection of keratinocytes is not well understood. HPV may survive in proliferative keratinocytes and may be involved in cell cycle regulation and progression. The objective of this study was to investigate the mechanism underlying EGCG's treatment on external genital warts of HPV infection through the cultured keratinocyte cells from the HaCaT cell line. METHODS: MTT and flow cytometry assays were used to measure cell viability and the cell cycle profile, with and without EGCG treatment, for HaCaT keratinocyte cells cultured in a calcium-free medium and 1.8 mM calcium which induced proliferative and differentiated keratinocytes, respectively, for 24 h. The expression levels of cytotoxic proteins and factors were evaluated with the RT-PCR and western blotting analysis. RESULTS: EGCG influenced the proliferation stage but not the differentiation stage of keratinocytes. We suggest that apoptosis and autophagy might be the possible mechanism for the EGCG's effect on the proliferative HaCaT cells. Furthermore, we found that EGCG reduced the protein levels of cyclin D1 and Zac1 (a zinc-finger protein which regulates apoptosis and cell cycle arrest 1) dose-dependently in proliferative as compared to differentiated keratinocytes. It also induced the expression of p21 and DEC1 (differentiated embryo-chondrocyte expressed gene 1), and promoted G1 arrest of cell cycle in proliferative keratinocytes. CONCLUSIONS: These results help clarify the mechanisms of EGCG treatment of HPV-infected keratinocytes and may contribute to new targets, such as Zac1 and DEC1 for external genital and perianal warts.

Opposing Effects of Zac1 and Curcumin on AP-1-Regulated Expressions of S100A7.

ZAC, an encoding gene mapped at chromosome 6q24-q25 within PSORS1, was previously found over-expressed in the lower compartment of the hyperplastic epidermis in psoriatic lesions. Cytokines produced in the inflammatory dermatoses may drive AP-1 transcription factor to induce responsive gene expressions. We demonstrated that mZac1 can enhance AP-1-responsive S100A7 expression of which the encoding gene was located in PSORS4 with HaCaT keratinocytes. However, the mZac1-enhanced AP-1 transcriptional activity was suppressed by curcumin, indicating the anti-inflammatory property of this botanical agent and is exhibited by blocking the AP-1-mediated cross-talk between PSORS1 and PSORS4. Two putative AP-1-binding sites were found and demonstrated to be functionally important in the regulation of S100A7 promoter activity. Moreover, we found curcumin reduced the DNA-binding activity of AP-1 to the recognition element located in the S100A7 promoter. The S100A7 expression was found to be upregulated in the lesioned epidermis of atopic dermatitis and psoriasis, which is where this keratinocyte-derived chemoattractant engaged in the pro-inflammatory feedback loop. Understanding the regulatory mechanism of S100A7 expression will be helpful to develop therapeutic strategies for chronic inflammatory dermatoses via blocking the reciprocal stimuli between the inflammatory cells and keratinocytes.

Stringlike pulse quantification study by pulse wave in 3D pulse mapping.

BACKGROUND: A stringlike pulse is highly related to hypertension, and many classification approaches have been proposed in which the differentiation pulse wave (dPW) can effectively classify the stringlike pulse indicating hypertension. Unfortunately, the dPW method cannot distinguish the spring stringlike pulse from the stringlike pulse so labeled by physicians in clinics. DESIGN: By using a Bi-Sensing Pulse Diagnosis Instrument (BSPDI), this study proposed a novel Plain Pulse Wave (PPW) to classify a stringlike pulse based on an array of pulse signals, mimicking a Traditional Chinese Medicine physician's finger-reading skill. RESULTS: In comparison to PPWs at different pulse taking positions, phase delay Δθand correlation coefficient r can be elucidated as the quantification parameters of stringlike pulse. As a result, the recognition rates of a hypertensive stringlike pulse, spring stringlike pulse, and non-stringlike pulse are 100%, 100%, 77% for PPW and 70%, 0%, 59% for dPW, respectively. CONCLUSIONS: Integrating dPW and PPW can unify the classification of stringlike pulse including hypertensive stringlike pulse and spring stringlike pulse. Hence, the proposed novel method, PPW, enhances quantification of stringlike pulse.