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The poxvirus-derived protein vCCI (viral CC chemokine inhibitor) binds almost all members of the CC chemokine family with nanomolar affinity, inhibiting their pro-inflammatory actions. Understanding the affinity and specificity of vCCI could lead to new anti-inflammatory therapeutics. CCL17, also known as TARC, is unusual among CC chemokines by having only micromolar binding to vCCI. We have used sequence analysis and molecular simulations to determine the cause of this weak binding, which identified several locations in CCL17 where mutations seemed likely to improve binding to vCCI. Based on the aforementioned analysis, we expressed and tested multiple mutants of CCL17. We found two single point mutants V44K and Q45R that increased binding affinity to vCCI by 2-3-fold and, in combination, further improved affinity by 7-fold. The CCL17 triple mutant G17R/V44K/Q45R yielded a Kd of 0.25 ± 0.13 μM, a 68-fold improvement in affinity compared to the complex with wild-type CCL17. A quadruple mutant G17R/V44K/Q45R/R57W showed high affinity (0.59 ± 0.09 μM) compared to the wild type but lower affinity than the triple mutant. This work demonstrates that sequence comparisons and molecular simulations can predict chemokine mutations that increase the level of binding to vCCI, an important first step in developing engineered chemokine inhibitors useful for anti-inflammatory therapy.

The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not well understood. Here, we show that CCL28 promotes neutrophil accumulation in the gut of mice infected with Salmonella and in the lung of mice infected with Acinetobacter. Neutrophils isolated from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, on their surface. The functional consequences of CCL28 deficiency varied between the two infections: Ccl28-/- mice were highly susceptible to Salmonella gut infection but highly resistant to otherwise lethal Acinetobacter lung infection. In vitro, unstimulated neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, all processes largely dependent on CCR3. Consistent with the different outcomes in the two infection models, neutrophil stimulation with CCL28 boosted the killing of Salmonella but not Acinetobacter. CCL28 thus plays a critical role in the immune response to mucosal pathogens by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but also exacerbate disease depending on the mucosal site and the infectious agent.

Listeria monocytogenes is a foodborne pathogen that causes listeriosis in humans, the severity of which depends on multiple factors, including intrinsic characteristics of the affected individuals and the pathogen itself. Additionally, emerging evidence suggests that epigenetic modifications may also modulate host susceptibility to infection. Therefore, different clinical outcomes can be expected, ranging from self-limiting gastroenteritis to severe central nervous system and maternal-neonatal infections, and bacteremia. Furthermore, L. monocytogenes is a genetically and phenotypically diverse species, resulting in a large variation in virulence potential between strains. Multilocus sequence typing (MLST) has been widely used to categorize the clonal structure of bacterial species and to define clonal complexes (CCs) of genetically related isolates. The combination of MLST and epidemiological data allows to distinguish hypervirulent CCs, which are notably more prevalent in clinical cases and typically associated with severe forms of the disease. Conversely, other CCs, termed hypovirulent, are predominantly isolated from food and food processing environments and are associated with the occurrence of listeriosis in immunosuppressed individuals. Reports of genetic traits associated with this diversity have been described. The Food and Agriculture Organization (FAO) is encouraging the search for virulence biomarkers to rapidly identify the main strains of concern to reduce food waste and economical losses. The aim of this review is to comprehensively collect, describe and discuss the methodologies used to discriminate the virulence potential of L. monocytogenes CCs. From the exploration of in vitro and in vivo models to the study of expression of virulence genes, each approach is critically explored to better understand its applicability and efficiency in distinguishing the virulence potential of the pathogen. [ABSTRACT FROM AUTHOR]

Sarath S Nair,1 Jyothi Nagesh,1 Shambhavi C,2 Anshul Singh,1 Shirley Lewis,1 Umesh Velu,1 Deepika Chenna3 1Department of Radiation Oncology, Kasturba Medical College Manipal MAHE, Manipal, Karnataka, India; 2Department of Medical Radiation Physics Program, MCHP Manipal, MAHE, Manipal, Karanataka, India; 3Department of Immunohematology and Blood Transfusion, Kasturba Medical College Manipal MAHE, Manipal, Karnataka, IndiaCorrespondence: Jyothi Nagesh, Email jyothi.nagesh@manipal.eduObjective: To identify a suitable approach for blood irradiation other than the commonly used water medium and to study the impact of different algorithm dose computations.Methods: Water is the commonly used medium for blood irradiation. In this study computed tomography scans were taken with locally made blood irradiation phantoms other than water, by using air, rice powder and thermocole using parallel beam for 25 Gy. Plans were recalculated for different algorithms such as collapsed cone (CC), Monte Carlo (MC) and pencil beam (PB). The dose–volume parameters and measured doses were collected and analyzed for each medium and algorithm.Findings: The monitor unit (MU) for rice powder and water are close (2461± 57 and 2469± 61, respectively), with a maximum dose of 28.0± 1.8 and 28.0± 1.9 Gy. The PB algorithm resulted in lower monitor unit values regardless of the medium used, generating values of 2418, 2406, 2382, and 2362 for water, rice powder, air, and Thermocol, respectively. A significant increase in dose was observed irrespective of the medium used when the MC algorithm was employed, with a maximum of 30.26 Gy in rice powder; a smaller dose was used when the CC algorithm was employed, with 26.3 Gy in water medium. The average maximum doses of all groups were equal using the one-way Anova statistical test. Regarding the impact of field size, rice powder appears to have consistent doses across various field sizes, with slight increases as field size grows, which is similar to water.Novelty/Applications: While water is the conventional medium, this study highlights the potential benefits of rice powder, such as eliminating the risks associated with bubble formation and water spillage, which can lead to equipment malfunction and safety hazards. Although previous studies have explored rice powder as a bolus and tissue-equivalent material, this study uniquely applies this knowledge to blood irradiation, an area where rice powder has not been thoroughly investigated.Keywords: computed tomography, collapsed cone, Monte Carlo, pencil beam, monitor units, MU, treatment planning station.

[Display omitted] In this study, a flexible, free-standing Fe-doped CoP nanoarrays electrode for superior lithium-ion storage has been successfully fabricated. The electrode combines the advantages of a Fe-doping and a flexible carbon cloth (CC) support, resulting in a high specific capacity (1356 mAh/g at 0.2 A/g) and excellent cycling stability (1138 mAh/g after 100 cycles). The cyclic voltammetry (CV) curves at different scan rates investigate the outstanding lithium storage behavior of Fe-CoP-NAs/CC which indicates a combined influence of diffusion behavior and capacitance behavior on the electrochemical process. The galvanostatic intermittent titration technique (GITT) analyzes the diffusion kinetics of Li+ which indicates the fast diffusion kinetics in the Fe-CoP/NAs/CC anode. The assembled Fe-CoP-NAs/CC//LiFePO 4 battery exhibits a remarkable capacity of 325.2 mAh/g even at 5 A/g. And the battery also has good cycle stability, and still provides 498.1 mAh/g specific capacity after 200 cycles. Moreover, the Fe-CoP-NAs/CC//LiFePO 4 soft-pack battery can continuously power the LEDs when it is bent at various angles which demonstrates its potential for use in wearable devices. [ABSTRACT FROM AUTHOR]

Listeria monocytogenes is a foodborne pathogen that causes listeriosis in humans, the severity of which depends on multiple factors, including intrinsic characteristics of the affected individuals and the pathogen itself. Additionally, emerging evidence suggests that epigenetic modifications may also modulate host susceptibility to infection. Therefore, different clinical outcomes can be expected, ranging from self-limiting gastroenteritis to severe central nervous system and maternal-neonatal infections, and bacteremia. Furthermore, L. monocytogenes is a genetically and phenotypically diverse species, resulting in a large variation in virulence potential between strains. Multilocus sequence typing (MLST) has been widely used to categorize the clonal structure of bacterial species and to define clonal complexes (CCs) of genetically related isolates. The combination of MLST and epidemiological data allows to distinguish hypervirulent CCs, which are notably more prevalent in clinical cases and typically associated with severe forms of the disease. Conversely, other CCs, termed hypovirulent, are predominantly isolated from food and food processing environments and are associated with the occurrence of listeriosis in immunosuppressed individuals. Reports of genetic traits associated with this diversity have been described. The Food and Agriculture Organization (FAO) is encouraging the search for virulence biomarkers to rapidly identify the main strains of concern to reduce food waste and economical losses. The aim of this review is to comprehensively collect, describe and discuss the methodologies used to discriminate the virulence potential of L. monocytogenes CCs. From the exploration of in vitro and in vivo models to the study of expression of virulence genes, each approach is critically explored to better understand its applicability and efficiency in distinguishing the virulence potential of the pathogen.

CC (CC) remains a significant global health concern, imposing a substantial health burden on women worldwide due to its high incidence and mortality rates. To address this issue, there is a need for ongoing research to uncover the underlying molecular mechanisms of CC and to discover novel diagnostic and therapeutic strategies. Recent progress in non-coding RNAs (ncRNAs) has opened new avenues for investigation, and circular RNAs (circRNAs) have emerged as molecules with diverse roles in various cellular processes. These circRNAs are distinct in structure, forming a closed loop, setting them apart from their linear counterparts. They are intricately involved in regulating different aspects of cellular functions, particularly in cell growth and development. Remarkably, circRNAs can have varying functions, either promoting or inhibiting oncogenic processes, depending on the specific cellular context. Recent studies have identified abnormal circRNAs expression patterns associated with CC, indicating their significant involvement in disease development. The differing circRNAs profiles linked to CC present promising opportunities for early detection, precise prognosis evaluation, and personalized treatment strategies. In this comprehensive review, we embark on a detailed exploration of CC-related circRNAs, elucidating their distinct roles and providing insights into the intricate molecular mechanisms governing CC's onset and progression. A growing body of evidence strongly suggests that circRNAs can serve as valuable biomarkers for early CC detection and hold potential as therapeutic targets for intervention. By delving into the complex interplay between circRNAs and CC, we are paving the way for innovative, individualized approaches to combat this serious disease, with the goal of reducing its impact on women's health globally and improving patient outcomes. As our understanding of circRNAs in the context of CC continues to deepen, the outlook for breakthroughs in diagnosis and treatment becomes increasingly promising.

Nodding syndrome (NS) is a mostly East African pediatric epileptiform encephalopathy of unknown etiology that shares some clinical features with measles-associated subacute sclerosing panencephalitis (SSPE) and progressive rubella panencephalitis. Two independent studies in northern Uganda identified an association between NS and prior measles infection, while an earlier study in South Sudan found an inverse association. We report preliminary serologic analyses of antibodies to measles (MV), rubella (RV), HSV-1, and CMV viruses in northern Ugandan children with NS and Household (HC) and Community (CC) Controls. Only MV-positive titers were significantly different (3-fold and > 2-fold) in NS relative to HC and HC + CC, respectively. While these results are consistent with greater prior measles infection in Ugandan persons with NS, further studies are needed to determine whether Measles virus (MV) plays any role in the etiology and pathogenesis of NS. Resolving this issue will be invaluable for the thousands of children at risk for this devastating yet often neglected condition.

In an exploratory trial treating "long COVID" with the CCR5-binding antibody leronlimab, we observed significantly increased blood cell surface CCR5 in treated symptomatic responders but not in nonresponders or placebo-treated participants. These findings suggest an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab. Clinical Trials Registration. NCT04678830.

Background: The aim of this study is to evaluate comparative biomechanical fixation provided with the BDSF method with the conventional CC screw fixation for treatment of femoral neck fractures with three parallel cannulated screws. Methods: This is a prospective cohort study. There were two teams of surgeons out of which one team operated the patients with BDSF technique and second with conventional CC screw fixation technique; thus, the patients were randomly distributed into two groups. Patients were included in the study as per the following inclusion and exclusion criteria. Results: Union was achieved in 15 (83.33%) patients managed by conventional CC screw technique, while union was achieved in 11 (91.67%) patients managed by BDSF technique in the present study. The average Harris hip score in present study was 90 score in patients managed by BDSF technique, while the average Harris hip score in present study was 80 score in patients managed by BDSF technique. Conclusion: Both BDSF and conventional CC screw fixation are good fixation methods for fracture neck of femur. But functional outcome and fracture union rates are better with BDSF Technique. Although, there are some minor problems noted in BDSF technique such as outer cortical fracture at the entry point of beam screw and opening up of anterior cortex of oblique fracture patterns. Thus, BDSF method provides reliable fixation in which early mobilization and partial weight bearing of the patient may be allowed. [ABSTRACT FROM AUTHOR]

Radical surgical intervention, chemoradiotherapy and immune therapy implicated for patients with cervical cancer (CC) can result in significant morphofunctional, psychological, sexual disorders and social maladjustment. To optimize treatment and rehabilitation for CC patients, a routing approach has been established. This approach involves the patient's journey during diagnosis and treatment with well-defined timed stages. Additionally, a rehabilitation program with lifelong follow-up has been implemented. Prior to commencing therapy, undertaking rehabilitation after oncogynecological treatment during the stage spanning from diagnosis to therapy initiation contributes to enhancing the quality of life (QoL) for CC patients.

Technology for Cloud Computing (CC) has advanced, so Cloud Computing creates a variety of cloud services. Users may receive storage space from the provider as Cloud storage services are quite practical; many users and businesses save their data in cloud storage. Data confidentiality becomes a larger risk for service providers when more information is outsourced to Cloud storage. Hence in this work, a Ciphertext and Elliptic Curve Cryptography (ECC) with Identity-based encryption (CP-IBE) approaches are used in the cloud environment to ensure data security for a healthcare environment. The revocation problem becomes complicated since characteristics are used to create cipher texts and secret keys; therefore, a User revocation algorithm is introduced for which a secret token key is uniquely produced for each level ensuring security. The initial operation, including signature, public audits, and dynamic data, are sensible to Sybil attacks; hence, to overcome that, a Sybil Attack Check Algorithm is introduced, effectively securing the system. Moreover, the conditions for public auditing using shared data and providing typical strategies, including the analytical function, security, and performance conditions, are analyzed in terms of accuracy, sensitivity, and similarity.

Despite the well-accepted view that chronic inflammation contributes to the pathogenesis of Duchenne muscular dystrophy (DMD), the function and regulation of eosinophils remain an unclear facet of type II innate immunity in dystrophic muscle. We report the observation that group 2 innate lymphoid cells (ILC2s) are present in skeletal muscle and are the principal regulators of muscle eosinophils during muscular dystrophy. Eosinophils were elevated in DMD patients and dystrophic mice along with interleukin (IL)-5, a major eosinophil survival factor that was predominantly expressed by muscle ILC2s. We also find that IL-33 was upregulated in dystrophic muscle and was predominantly produced by fibrogenic/adipogenic progenitors (FAPs). Exogenous IL-33 and IL-2 complex (IL-2c) expanded muscle ILC2s and eosinophils, decreased the cross-sectional area (CSA) of regenerating myofibers, and increased the expression of genes associated with muscle fibrosis. The deletion of ILC2s in dystrophic mice mitigated muscle eosinophilia and impaired the induction of IL-5 and fibrosis-associated genes. Our findings highlight a FAP/ILC2/eosinophil axis that promotes type II innate immunity, which influences the balance between regenerative and fibrotic responses during muscular dystrophy.

Abstract Objective Classical Cox proportional hazard models tend to overestimate the event probability in a competing risk setup. Due to the lack of quantitative evaluation of competitive risk data for colon cancer (CC), the present study aims to evaluate the probability of CC-specific death and construct a nomogram to quantify survival differences among CC patients. Methods Data on patients diagnosed with CC between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database. Patients were divided into a training dataset for the establishment of the model and a validation dataset to evaluate the performance the model at a ratio of 7:3. To evaluate the ability of multiple variables to predict cause-specific death in CC patients, univariate and multivariate analyses with Fine-Gray models were performed to screen the predictors of cause-specific death, and a nomogram for predicting cause-specific mortality was constructed. Then, the receiver operating characteristic (ROC) curve and the calibration curve were plotted to evaluate the prognostic performance of the nomogram. Results The dataset was randomly divided into a training (n = 16,655) dataset and a validation (n = 7,139) dataset at a ratio of 7:3. In the training dataset, variables including pathological subtypes of tumors, pathological grading (degree of differentiation), AJCC staging, T-staging, surgical type, lymph node surgery, chemotherapy, tumor deposits, lymph node metastasis, liver metastasis, and lung metastasis were identified as independent risk factors for cause-specific death of CC patients. Among these factors, the AJCC stage had the strongest predictive ability, and these features were used to construct the final model. In the training dataset, the consistency index (C-index) of the model was 0.848, and the areas under the receiver operating characteristic curve (AUC) at 1, 3, and 5 years was 0.852, 0.861, and 0.856, respectively. In the validation dataset, the C-index of the model was 0.847, and the AUC at 1 year, 3 years, and 5 years was 0.841, 0.862, and 0.852, respectively, indicating that this nomogram had an excellent and robust predictive performance. Conclusion This study can help clinical doctors make better clinical decisions and provide better support for patients with CC.

Technology for Cloud Computing (CC) has advanced, so Cloud Computing creates a variety of cloud services. Users may receive storage space from the provider as Cloud storage services are quite practical; many users and businesses save their data in cloud storage. Data confidentiality becomes a larger risk for service providers when more information is outsourced to Cloud storage. Hence in this work, a Ciphertext and Elliptic Curve Cryptography (ECC) with Identity-based encryption (CP-IBE) approaches are used in the cloud environment to ensure data security for a healthcare environment. The revocation problem becomes complicated since characteristics are used to create cipher texts and secret keys; therefore, a User revocation algorithm is introduced for which a secret token key is uniquely produced for each level ensuring security. The initial operation, including signature, public audits, and dynamic data, are sensible to Sybil attacks; hence, to overcome that, a Sybil Attack Check Algorithm is introduced, effectively securing the system. Moreover, the conditions for public auditing using shared data and providing typical strategies, including the analytical function, security, and performance conditions, are analyzed in terms of accuracy, sensitivity, and similarity. [ABSTRACT FROM AUTHOR]

This research paper presents a novel digital color image encryption approach that ensures high-level security while remaining simple and efficient. The proposed method utilizes a composite key r and x of 128-bits to create a small in-dimension private key (a chaotic map), which is then resized to match the color matrix dimension. The proposed method is uncomplicated and can be applied to any image without any modification. Image quality, sensitivity analysis, security analysis, correlation analysis, quality analysis, speed analysis, and attack robustness analysis are conducted to prove the efficiency and security aspects of the proposed method. The speed analysis shows that the proposed method improves the performance of image cryptography by minimizing encryption–decryption time and maximizing the throughput of the process of color cryptography. The results demonstrate that the proposed method provides better throughput than existing methods. Overall, this research paper provides a new approach to digital color image encryption that is highly secure, efficient, and applicable to various images. [ABSTRACT FROM AUTHOR]

Progressive lung fibrosis is a major cause of mortality in systemic sclerosis (SSc) patients, but the underlying mechanisms remain unclear. We demonstrate that immune complexes (ICs) activate human monocytes to promote lung fibroblast migration partly via osteopontin (OPN) secretion, which is amplified by autocrine monocyte colony stimulating factor (MCSF) and interleukin-6 (IL-6) activity. Bulk and single-cell RNA sequencing demonstrate that elevated OPN expression in SSc lung tissue is enriched in macrophages, partially overlapping with CCL18 expression. Serum OPN is elevated in SSc patients with interstitial lung disease (ILD) and prognosticates future lung function deterioration in SSc cohorts. Serum OPN levels decrease following tocilizumab (monoclonal anti-IL-6 receptor) treatment, confirming the connection between IL-6 and OPN in SSc patients. Collectively, these data suggest a plausible link between autoantibodies and lung fibrosis progression, where circulating OPN serves as a systemic proxy for IC-driven profibrotic macrophage activity, highlighting its potential as a promising biomarker in SSc ILD.

Regulatory T cells (Treg) are abundant in human and mouse pancreatic cancer. To understand the contribution to the immunosuppressive microenvironment, we depleted Tregs in a mouse model of pancreatic cancer. Contrary to our expectations, Treg depletion failed to relieve immunosuppression and led to accelerated tumor progression. We show that Tregs are a key source of TGFβ ligands and, accordingly, their depletion reprogramed the fibroblast population, with loss of tumor-restraining, smooth muscle actin-expressing fibroblasts. Conversely, we observed an increase in chemokines Ccl3, Ccl6, and Ccl8 leading to increased myeloid cell recruitment, restoration of immune suppression, and promotion of carcinogenesis, an effect that was inhibited by blockade of the common CCL3/6/8 receptor CCR1. Further, Treg depletion unleashed pathologic CD4+ T-cell responses. Our data point to new mechanisms regulating fibroblast differentiation in pancreatic cancer and support the notion that fibroblasts are a heterogeneous population with different and opposing functions in pancreatic carcinogenesis. SIGNIFICANCE: Here, we describe an unexpected cross-talk between Tregs and fibroblasts in pancreatic cancer. Treg depletion resulted in differentiation of inflammatory fibroblast subsets, in turn driving infiltration of myeloid cells through CCR1, thus uncovering a potentially new therapeutic approach to relieve immunosuppression in pancreatic cancer.See related commentary by Aykut et al., p. 345.This article is highlighted in the In This Issue feature, p. 327.

ObjectiveTo investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD).MethodsPatients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm.ResultsBaseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only).ConclusionIn a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.

Objective: Classical Cox proportional hazard models tend to overestimate the event probability in a competing risk setup. Due to the lack of quantitative evaluation of competitive risk data for colon cancer (CC), the present study aims to evaluate the probability of CC-specific death and construct a nomogram to quantify survival differences among CC patients. Methods: Data on patients diagnosed with CC between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database. Patients were divided into a training dataset for the establishment of the model and a validation dataset to evaluate the performance the model at a ratio of 7:3. To evaluate the ability of multiple variables to predict cause-specific death in CC patients, univariate and multivariate analyses with Fine-Gray models were performed to screen the predictors of cause-specific death, and a nomogram for predicting cause-specific mortality was constructed. Then, the receiver operating characteristic (ROC) curve and the calibration curve were plotted to evaluate the prognostic performance of the nomogram. Results: The dataset was randomly divided into a training (n = 16,655) dataset and a validation (n = 7,139) dataset at a ratio of 7:3. In the training dataset, variables including pathological subtypes of tumors, pathological grading (degree of differentiation), AJCC staging, T-staging, surgical type, lymph node surgery, chemotherapy, tumor deposits, lymph node metastasis, liver metastasis, and lung metastasis were identified as independent risk factors for cause-specific death of CC patients. Among these factors, the AJCC stage had the strongest predictive ability, and these features were used to construct the final model. In the training dataset, the consistency index (C-index) of the model was 0.848, and the areas under the receiver operating characteristic curve (AUC) at 1, 3, and 5 years was 0.852, 0.861, and 0.856, respectively. In the validation dataset, the C-index of the model was 0.847, and the AUC at 1 year, 3 years, and 5 years was 0.841, 0.862, and 0.852, respectively, indicating that this nomogram had an excellent and robust predictive performance. Conclusion: This study can help clinical doctors make better clinical decisions and provide better support for patients with CC. [ABSTRACT FROM AUTHOR]

Multiparental populations (MPPs) encompass greater genetic diversity than traditional experimental crosses of two inbred strains, enabling broader surveys of genetic variation underlying complex traits. Two such mouse MPPs are the Collaborative Cross (CC) inbred panel and the Diversity Outbred (DO) population, which are descended from the same eight inbred strains. Additionally, the F1 intercrosses of CC strains (CC-RIX) have been used and enable study designs with replicate outbred mice. Genetic analyses commonly used by researchers to investigate complex traits in these populations include characterizing how heritable a trait is, i.e. its heritability, and mapping its underlying genetic loci, i.e. its quantitative trait loci (QTLs). Here we evaluate the relative merits of these populations for these tasks through simulation, as well as provide recommendations for performing the quantitative genetic analyses. We find that sample populations that include replicate animals, as possible with the CC and CC-RIX, provide more efficient and precise estimates of heritability. We report QTL mapping power curves for the CC, CC-RIX, and DO across a range of QTL effect sizes and polygenic backgrounds for samples of 174 and 500 mice. The utility of replicate animals in the CC and CC-RIX for mapping QTLs rapidly decreased as traits became more polygenic. Only large sample populations of 500 DO mice were well-powered to detect smaller effect loci (7.5-10%) for highly complex traits (80% polygenic background). All results were generated with our R package musppr, which we developed to simulate data from these MPPs and evaluate genetic analyses from user-provided genotypes. [ABSTRACT FROM AUTHOR]

Background: Chylous Ascites is a rare condition. It develops as a result of iatrogenic injury to the cisterna chyli, thoracic duct, or their major tributaries. It leads to an increase in chyle release. Subsequently, obstruction of lymphatic return from abdomen. It is more prevalent after major abdominal procedures involving retro-peritoneum. Case Presentation: A 65 years old female patient was admitted with a history of pain at epigastric and left upper abdominal quadrant via the emergency department at King Hussein Medical Centre. She was planned for elective Whipple's procedure for cancer head of pancreas. This case report considers the impact of intraoperative injury to major lymphatic system leading to chylous ascites and death following her pancreatic resection. Retrospective evaluation of her records revealed an intraoperative iatrogenic injury to the cisterna chyli had occurred during Whipple's Procedure. The injured lymphatic duct was discovered and repaired intraoperatively. The chyle drainage was resolved temporarily after 3 weeks of conservative management. Despite its resolution, it recurred after massive upper GI bleeding, which was managed operatively after failed endoscopic and embolization. The patient failed to recover and died as a direct result of her poor general condition due to the effects of an iatrogenic injury of Cisterna Chyli. We report this case of intraoperative injury to the cisterna chyli, subsequent development of chylous ascites, and its post-operative sequelae. This article considers, even if discovered and repaired intraoperatively, the impact of such injury on development of postoperative chylous ascites, nutritional insufficiency, poor prognosis, and subsequent death. Conclusion: Chylous ascites is a rare complication of Whipple's Procedure. It usually progresses due to iatrogenic operational trauma to a significant lymphatic channel. Even if such injury to cisterna chyli is discovered and managed intraoperatively, it carries a poor prognosis and subsequent death. [ABSTRACT FROM AUTHOR]

With almost 2 million new HIV infections worldwide each year, the prevention of HIV infection is critical for stopping the pandemic. The only approved form of pre-exposure prophylaxis is a costly daily pill, and it is recognized that several options will be needed to provide protection to the various affected communities around the world. In particular, many at-risk people would benefit from a prevention method that is simple to use and does not require medical intervention or a strict daily regimen. We show that silk fibroin protein can be formulated into insertable discs that encapsulate either an antibody (IgG) or the potent HIV inhibitor 5P12-RANTES. Several formulations were studied, including silk layering, water vapor annealing and methanol treatment to stabilize the protein cargo and impact the release kinetics over weeks. In the case of IgG, high concentrations were released over a short time using methanol treatment, with more sustained results with the use of water vapor annealing and layering during device fabrication. For 5P12-RANTES, sustained release was obtained for 31 days using water vapor annealing. Further, we show that the released inhibitor 5P12-RANTES was functional both in vitro and in ex vivo colorectal tissue. This work shows that silk fibroin discs can be developed into formidable tools to prevent HIV infection.

CCL28 is a mucosal chemokine that has been involved in various responses, including IgA production. We have analyzed its production in human tissues using a comprehensive microarray database. Its highest expression is in the salivary gland, indicating that it is an important component of saliva. It is also expressed in the trachea, bronchus, and in the mammary gland upon onset of lactation. We have also characterized a Ccl28-/- mouse that exhibits very low IgA levels in milk, and the IgA levels in feces are also reduced. These observations confirm a role for the CCL28/CCR10 chemokine axis in the recruitment of IgA plasmablasts to the lactating mammary gland. CCL28 is also expressed in the vomeronasal organ. We also detected olfactory defects (anosmia) in a Ccl28-/- mouse suggesting that CCL28 is involved in the function/development of olfaction. Importantly, Ccl28-/- mice are highly susceptible to Salmonella enterica serovar Typhimurium in an acute model of infection, indicating that CCL28 plays a major role in innate immunity against Salmonella in the gut. Finally, microbiome studies revealed modest differences in the gut microbiota between Ccl28-/- mice and their cohoused wild-type littermates. The latter observation suggests that under homeostatic conditions, CCL28 plays a limited role in shaping the gut microbiome.

Objective: This analysis was designed to explore the utility of body mass index (BMI) and calf circumference (CC) values in the diagnosis of sarcopenia. Methods: A cross-sectional analysis of community-dwelling adults ≥50 years old was conducted. An InBody 770 bioimpedance analysis (BIA) device was used for measuring muscle mass, a grip-strength dynamometer was used to assess muscle strength, and a 4 m gait speed (GS) analysis was used to gauge physical function. The Asian Working Group for Sarcopenia (AWGS) 2019 criteria were used to define sarcopenia. The cut-off values for BMI and CC were based on the computed Younden’s index values and AWGS 2019 criteria, respectively. The area under the ROC curves (AUC), specificity, sensitivity, and positive and negative predictive values (PPV and NPV) were calculated to establish the value of BMI and CC for the diagnosis of sarcopenia. Results: In total, the data of 4177 participants ≥50 years of age were analyzed. These included 2668 (63.9%) females and 1509 (36.1%) males. Of these participants, 946 (22.6%) met the criteria for sarcopenia, including 408 (27%) males and 538 (20.2%) females. The sensitivity, specificity, and NPVs obtained when using BMI and CC values to predict sarcopenia were as follows: 84.03%/65.51%/0.90 and 74.76%/83.51%/0.87, respectively, in males; 87.36%/64.12%/0.94 and 78.25%/82.09%/0.93, in females. The respective AUC values for BMI and CC in males were 0.83 (0.80–0.85) and 0.85 (0.83–0.88), while in females they were 0.85 (0.83–0.87) and 0.88 (0.87–0.90). Conclusions: These data suggest that BMI and CC can both serve as accurate predictors of sarcopenic incidence in a multi-ethnic population ≥50 years of age. The specificity values for BMI were relatively low in both males and females, however, underscoring the relative advantages of measuring CC when assessing individual sarcopenia risk.

An exposition is undertaken for the linearity of both stable M/G/1 queue's non-extensive (Rényian)and (Tsallisian) solutions. This current letter provides the mathematical validity for the experimental setup of the information theoretic unification with queueing theory manifested by the Rényian, and Tsallisian linearity profile attained, which is a consequence of the progressive increase of the Shannonian squared coefficient of variation, through the provision of the mathematical proof. Potential applications of Queueing Theory (QT) to Cloud Computing (CC) and Internet of Things(IoT) are given. Closing remarks combined with open problems and future next phase research are provided. [ABSTRACT FROM AUTHOR]

Abstract Purpose Cholecystectomy (XGB) is widely recognized as a risk factor for colon cancer (CC). Continuous exposure of the colonic epithelium to deoxycholic acid (DCA) post-XGB may exert cytotoxic effects and be involved in the progression of CC. However, the functions of the XGB-induced DCA increase and the underlying mechanism remain unclear. Methods Colitis-associated CC (CAC) mouse models constructed by AOM-DSS inducement were used to confirm the effect of XGB on the CC progression. Hematoxylin & eosin staining was performed to assess the tumor morphology of CAC mouse models tissues. Various cell biological assays including EdU, live-cell imaging, wound-healing assays, and flow cytometry for cell cycle and apoptosis were used to evaluate the effect of DCA on CC progression. The correlation among XGB, DCA, and CC and their underlying mechanisms were detected with immunohistochemistry, mass spectrometry, transcriptome sequencing, qRT-PCR, and western blotting. Results Here we proved that XGB increased the plasma DCA level and promoted colon carcinogenesis in a colitis-associated CC mouse model. Additionally, we revealed that DCA promoted the proliferation and migration of CC cells. Further RNA sequencing showed that 120 mRNAs were upregulated, and 118 downregulated in DCA-treated CC cells versus control cells. The upregulated mRNAs were positively correlated with Wnt signaling and cell cycle-associated pathways. Moreover, DCA treatment could reduced the expression of the farnesoid X receptor (FXR) and subsequently increased the levels of β-Catenin and c-Myc in vitro and in vivo. Moreover, the FXR agonist GW4064 decreased the proliferation of CC cells by repressing the expression of β-catenin. Conclusion We concluded that XGB-induced DCA exposure could promote the progression of CC by inhibiting FXR expression and enhancing the Wnt-β-catenin pathway. Video Abstract

Circular-RNA friend leukemia virus integration 1 (circ-FLI1; hsa_circ_0000370) is a noninvasive biomarker for the diagnosis of colon carcinoma (CC). Herein, we intended to investigate its functions and competing endogenous RNA (ceRNA) mechanisms in CC cells. In terms of expression status, circ-FLI1 was abnormally upregulated in CC patients’ tumors and cells, paralleled with DKC1 upregulation and miR-197-3p downregulation. Most strikingly, there was a direct target relationship between miR-197-3p and circ-FLI1 or DKC1 based on the starbase database, dual-luciferase reporter assay, and RNA immunoprecipitation. Functionally, the colony formation assay, MTS method, fluorescence-activated cell sorting method, cell cycle and apoptosis assays, and transwell assays were performed, and the results revealed that interfering circ-FLI1 and re-expressing miR-197-3p could restrict colony formation, cell viability, cell cycle progression, and migration/invasion of CC cells with apoptosis rate elevation; besides, they promoted oxaliplatin (L-OHP)-induced cell viability inhibition. Furthermore, there were counteractive effects between circ-FLI1 silencing and miR-197-3p depletion, miR-197-3p overexpression and DKC1 restoration on regulating CC cell functions and L-OHP resistance. With a xenograft tumor model, the anti-growth role of circ-FLI1 silencing was also found in vivo with or without L-OHP treatment. Collectively, we demonstrated that circ-FLI1 might confer L-OHP resistance and malignant progression of CC presumably through the circ-FLI1/miR-197-3p/DKC1 ceRNA axis.

Abstract Background Cervical cancer (CC) is the fourth aggressive tumor affecting women worldwide. Circular RNA (circRNA) is enrolled in CC process. This study aims to unveil the profiles of circ_101119 (circCDK17) in cell proliferation, migration, invasion, apoptosis and glycolysis in CC. Methods The expression levels of circCDK17, microRNA-1294 (miR-1294) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) mRNA were detected by quantitative real time polymerase chain reaction (qRT-PCR). The protein expression levels of YWHAZ, recombinant glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) were determined by western blot. Cell proliferation, migratory and invasive abilities and apoptosis were illustrated by cell counting kit-8 (CCK-8) assay, transwell assay and flow cytometry analysis, respectively. Cell lactate production, glucose uptake and adenosine 5'-triphosphate (ATP) level were severally elucidated by lactate assay kit, glucose assay kit and ATP detection kit. Results CircCDK17 expression and the mRNA and protein expression levels of YWHAZ were dramatically upregulated, while miR-1294 expression was obviously downregulated in CC tissues or cells compared with control groups. CircCDK17 silencing suppressed cell proliferation, migration, invasion and glycolysis, and induced cell apoptosis in CC; however, miR-1294 inhibitor restrained these effects. Additionally, circCDK17 was a sponge of miR-1294 and miR-1294 bound to YWHAZ. Furthermore, circCDK17 knockdown inhibited tumor formation in vivo. Conclusion CircCDK17 knockdown repressed cell proliferation, migration, invasion and glycolysis, and promoted cell apoptosis via miR-1294/YWHAZ axis in CC. This finding provides a theoretical basis in studying circRNA-mediated therapy in CC.

Due to the availability of several social media platforms and their use in sending text messages, it is necessary to provide an easy and safe way to protect messages from being hacked especially in the presence of intruders and data thieves, and taking into consideration that most of messages are confidential and personal, it is necessary to provide an easy and safe way to protect messages from being hacked. In this research paper, a simple and easy method of message cryptography will be proposed. The method divides a message into blocks with fixed sizes. The block size ranges from 2 to 60. The method uses a secret color image to generate an array with a size equal to the number of resulted blocks. The array will then be used as a private key. Each element of the private key will be used to calculate the number of rotation digits for the associated block in order to apply block rotation left operation. The proposed method will be examined using the parameters: Mean Square Error (MSE), Peak Signal to Noise Ratio (PSNR), Correlation Coefficient (CC), and throughput. The proposed method will be compared with other standard methods of message cryptography, such as Data Encryption Standard (DES), Triple-DES (3DES), Advanced Encryption Standard (AES), and Blow Fish (BF). Experimental results show that the proposed method is enough secured based on using secret image, block size, and calculated Rotation Left Digits (RLD) for each block.

Aim: Here, we investigate the relationship between mid-upper arm circumference (MUAC) and calf circumference (CC) screening indicators of sarcopenia and the risk of pneumonia in stable patients diagnosed with schizophrenia. Method: The study is prospective and includes inpatients with schizophrenia from two mental health centers in Western China. The studied screening indicators, MUAC and CC were assessed in standing patients. The relationship between MUAC and CC as sarcopenia screening indicators with the risk of pneumonia in patients with schizophrenia was analyzed by performing a statistical logistic regression analysis. Result: For this study, 339 patients with schizophrenia, aged 50 years and over were recruited. Moreover, four patients with pneumonia that occurred within 1 week of the relapse of schizophrenia were excluded. As a result, only 335 patients were included in the analysis. Pneumonia has been reported in 82 (24.5%) of all included patients with schizophrenia. Our data analysis confirmed that in the male patients, the higher CC was associated with a lower risk of pneumonia (odds ratio [OR] = 0.751, 95% CI: 0.635-0.889). We have divided men into two cohorts following the values of CC. Our analysis further showed that the patients with CC = 34cm had a lower risk of pneumonia in men (OR = 0.36, 95% CI: 0.163-0.795). Conclusion: We demonstrate that CC is associated with pneumonia risk in stable men with schizophrenia. [ABSTRACT FROM AUTHOR]

The paper proposes the generalized version of the multipolar neutrosophic soft set. The neutrosophic soft set (NSS) is an advanced extension of the neutrosophic set, which accommodates the alternatives' parametrized values. This paper extends the NSS to generalized multipolar NSS and introduces some fundamental operations for generalized multipolar NSS with their necessary properties. We define the correlation coefficient (CC) and weighted correlation coefficient (WCC) for the generalized multi-polar neutrosophic soft set. Several desirable properties for CC and WCC and their relationship are derived. Finally, based on established correlation measures, a decisionmaking algorithm under the neutrosophic environment is stated to tackle uncertain and vague information. The applicability of the proposed algorithm is demonstrated through a case study of the decision-making problem. A comparative analysis with several existing studies reveals the effectiveness of the approach. [ABSTRACT FROM AUTHOR]

Purpose: Cholecystectomy (XGB) is widely recognized as a risk factor for colon cancer (CC). Continuous exposure of the colonic epithelium to deoxycholic acid (DCA) post-XGB may exert cytotoxic effects and be involved in the progression of CC. However, the functions of the XGB-induced DCA increase and the underlying mechanism remain unclear. Methods: Colitis-associated CC (CAC) mouse models constructed by AOM-DSS inducement were used to confirm the effect of XGB on the CC progression. Hematoxylin & eosin staining was performed to assess the tumor morphology of CAC mouse models tissues. Various cell biological assays including EdU, live-cell imaging, wound-healing assays, and flow cytometry for cell cycle and apoptosis were used to evaluate the effect of DCA on CC progression. The correlation among XGB, DCA, and CC and their underlying mechanisms were detected with immunohistochemistry, mass spectrometry, transcriptome sequencing, qRT-PCR, and western blotting. Results: Here we proved that XGB increased the plasma DCA level and promoted colon carcinogenesis in a colitis-associated CC mouse model. Additionally, we revealed that DCA promoted the proliferation and migration of CC cells. Further RNA sequencing showed that 120 mRNAs were upregulated, and 118 downregulated in DCA-treated CC cells versus control cells. The upregulated mRNAs were positively correlated with Wnt signaling and cell cycle-associated pathways. Moreover, DCA treatment could reduced the expression of the farnesoid X receptor (FXR) and subsequently increased the levels of β-Catenin and c-Myc in vitro and in vivo. Moreover, the FXR agonist GW4064 decreased the proliferation of CC cells by repressing the expression of β-catenin. Conclusion: We concluded that XGB-induced DCA exposure could promote the progression of CC by inhibiting FXR expression and enhancing the Wnt-β-catenin pathway. B11_ZgToCHH9ZHiKaTV37K Video Abstract [ABSTRACT FROM AUTHOR]

Objectives: Our objective was to evaluate if SARC-F, SARC-CalF, SARC-F-EBM, calf circumference (CC), mid-upper-arm circumference (MUAC) and Ishii test can be used to accurately screen for sarcopenia in schizophrenic patients. Method: We enrolled schizophrenic patients aged 50 or older, who were regularly taking antipsychotic medications, at two mental health centres. Bioimpedance-based muscle-mass was analysed with an InBody 770 instrument, while muscle strength was measured with a digital grip-strength dynamometer. The physical performance of the patients was gauged from their gait speed over 6 m. Standard AWGS2019 diagnostic criteria were used, and the accuracies of the six screening methods were indicated by the sensitivity, negative predictive value (NPV), and area under receiver operating characteristic curve (AUC). Results: A total of 339 stable schizophrenic patients were enrolled. The overall prevalence of sarcopenia was 53.1%, and the prevalence was 55.6% and 47.66%, respectively, for males and females. The prevalence of sarcopenia obesity in the total population was 16.22%, and that of males and females was 18.97% and 10.28%, respectively. The SARC-F, SARC-CalF, SARC-F-EBM, CC, MUAC and Ishii test sensitivity/NPV in screening for sarcopenia were 41.86%/0.52, 79.07%/0.7, 28.68%/0.51, 78.3%/0.71, 76.74%/0.7, 89.92%/0.84, respectively, in males and 45.1%/0.59, 94.12%/0.91, 54.9%/0.7, 92.16%/60.91, 74.51%/0.77, 96.08%/0.94, respectively, in females. In males, the AUCs of the SARC-F, SARC-CalF, SARC-F-EBM, CC, MUAC and Ishii test were 0.601 (95%CI, 0.528–0.673), 0.754 (95%CI,0.69–0.817), 0.657 (95%CI,0.588–0.727), 0.8 (95%CI, 0.744–0.856), 0.781 (95%CI, 0.721–0.84) and 0.88 (95%CI, 0.837–0.922), respectively, and in females, they were 0.587(95%CI,0.479–0.696), 0.794 (95%CI,0.709–0.878), 0.799 (95%CI,0.71–0.888), 0.893 (95%CI, 0.833–0.953), 0.843 (95%CI, 0.772–0.915) and 0.855 (95%CI, 0.784–0.926), respectively. Conclusion: The prevalence of sarcopenia in schizophrenic patients is high. Clinical doctors should screen for sarcopenia in schizophrenic patients and provide timely interventions to reduce the occurrence of adverse events. The above six tools can be used as screening tools, and the Ishii test is the most suitable for screening. [ABSTRACT FROM AUTHOR]

The two oncogenes KRas and Myc cooperate to drive tumorigenesis, but the mechanism underlying this remains unclear. In a mouse lung model of KRasG12D-driven adenomas, we find that co-activation of Myc drives the immediate transition to highly proliferative and invasive adenocarcinomas marked by highly inflammatory, angiogenic, and immune-suppressed stroma. We identify epithelial-derived signaling molecules CCL9 and IL-23 as the principal instructing signals for stromal reprogramming. CCL9 mediates recruitment of macrophages, angiogenesis, and PD-L1-dependent expulsion of T and B cells. IL-23 orchestrates exclusion of adaptive T and B cells and innate immune NK cells. Co-blockade of both CCL9 and IL-23 abrogates Myc-induced tumor progression. Subsequent deactivation of Myc in established adenocarcinomas triggers immediate reversal of all stromal changes and tumor regression, which are independent of CD4+CD8+ T cells but substantially dependent on returning NK cells. We show that Myc extensively programs an immune suppressive stroma that is obligatory for tumor progression.

Despite effective treatment for those living with Human Immunodeficiency Virus (HIV), there are still two million new infections each year. Protein-based HIV entry inhibitors, being highly effective and specific, could be used to protect people from initial infection. One of the most promising of these for clinical use is 5P12-RANTES, a variant of the chemokine RANTES/CCL5. The N-terminal amino acid of 5P12-RANTES is glutamine (Gln; called Q0), a residue that is prone to spontaneous cyclization when at the N-terminus of a protein. It is not known how this cyclization affects the potency of the inhibitor or whether cyclization is necessary for the function of the protein, although the N-terminal region of RANTES has been shown to be critical for receptor interactions, with even small changes having a large effect. We have studied the kinetics of cyclization of 5P12-RANTES as well as N-terminal variations of the protein that either produce an identical cyclized terminus (Glu0) or that cannot similarly cyclize (Asn0, Phe0, Ile0, and Leu0). We find that the half life for N-terminal cyclization of Gln is roughly 20 h at pH 7.3 at 37 °C. However, our results show that cyclization is not necessary for the potency of this protein and that several replacement terminal amino acids produce nearly-equally potent HIV inhibitors while remaining CC chemokine receptor 5 (CCR5) antagonists. This work has ramifications for the production of active 5P12-RANTES for use in the clinic, while also opening the possibility of developing other inhibitors by varying the N-terminus of the protein.

CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer. These disease associations have motivated numerous preclinical studies and clinical trials (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2-chemokine axis. To aid drug discovery efforts, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein-protein interactions, receptor-chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.

A defective chemokine motif in the HIV-1 Tat protein has been hypothesized to alter central nervous system cellular trafficking and inflammation, rendering HIV-1 subtype C less neuropathogenic than B. To evaluate this hypothesis, we compared biomarkers of cellular chemotaxis and inflammation in cerebrospinal fluid (CSF) and serum in individuals infected with HIV-1 subtypes B (n = 27) and C (n = 25) from Curitiba, Brazil. None had opportunistic infections. Chemokines (MCP-1, MIP-1α, MIP-1β, RANTES, IP-10) and cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-10) were measured using the multiplex bead suspension array immunoassays or ELISA HD. CSF and serum biomarker concentrations were compared between subtype B and C groups and HIV-positive and HIV-negative subjects (N = 19) using an independent group t test (unadjusted analysis) and linear regression (adjusted analysis), controlling for nadir CD4 and CSF and plasma HIV RNA suppression. CSF levels of cytokines and chemokines were significantly (p

Cyber threats have been growing tremendously in recent years. There are significant advancements in the threat space that have led towards an essential need for the strengthening of digital infrastructure security. Better security can be achieved by fine-tuning system parameters to the best and optimized security levels. For the protection of infrastructure and information systems, several guidelines have been provided by wellknown organizations in the form of cybersecurity standards. Since security vulnerabilities incur a very high degree of financial, reputational, informational, and organizational security compromise, it is imperative that a baseline for standard compliance be established. The selection of security standards and extracting requirements from those standards in an organizational context is a tedious task. This article presents a detailed literature review, a comprehensive analysis of various cybersecurity standards, and statistics of cyber-attacks related to operating systems (OS). In addition to that, an explicit comparison between the frameworks, tools, and software available for OS compliance testing is provided. An in-depth analysis of the most common software solutions ensuring compliance with certain cybersecurity standards is also presented. Finally, based on the cybersecurity standards under consideration, a comprehensive set of minimum requirements is proposed for OS hardening and a few open research challenges are discussed. [ABSTRACT FROM AUTHOR]

Background: No previous study compared ACOG and DIPSI criteria for diagnosing gestational diabetes (GDM). This study compared diagnostic accuracy of Diabetes in pregnancy study group of India (DIPSI) with Carpenter–Coustan (CC) and National Diabetes Data Group (NDDG) criteria for diagnosis of GDM and correlation with fetomaternal outcome. Methods: A total of 1029 pregnant women underwent 2 h 75 g OGTT in non-fasting state. After 3–7 days, women were called in fasting state and subjected to 100 g OGTT and fasting, 1, 2, 3 h samples were taken. GDM was diagnosed using DIPSI, CC and NDDG criteria. All women were followed till delivery, and fetomaternal outcome was noted. Results: 10.4% (107) women were diagnosed as GDM by DIPSI, 6.4% (66) by CC and 3.1% (32) by NDDG criteria. Sensitivity of DIPSI with CC was 98.48%, specificity was 95.64%, and diagnostic accuracy was 95.82%. Sensitivity of DIPSI with NDDG was 99.89%, specificity was 92.38%, and diagnostic accuracy was 95.52%. Sensitivity of NDDG with CC was 48.48%, specificity was 100%, and diagnostic accuracy was 96.7%. Women with GDM by all three criteria were seen to have a significantly higher proportion of LSCS, higher birth weight and macrosomia compared to normoglycemic women (p value < 0.001). Conclusion: Diagnostic accuracy, sensitivity and specificity of DIPSI are comparable to CC and NDDG criteria; therefore, DIPSI can be recommended for diagnosing GDM with added advantage of low cost, simplicity and convenience. Women diagnosed as GDM by DIPSI, CC and NDDG had significantly higher rate of cesarean delivery, higher birth weight and macrosomia as compared to women with normoglycemia. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc.

Background: Cervical cancer (CC) is the fourth aggressive tumor affecting women worldwide. Circular RNA (circRNA) is enrolled in CC process. This study aims to unveil the profiles of circ_101119 (circCDK17) in cell proliferation, migration, invasion, apoptosis and glycolysis in CC. Methods: The expression levels of circCDK17, microRNA-1294 (miR-1294) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) mRNA were detected by quantitative real time polymerase chain reaction (qRT-PCR). The protein expression levels of YWHAZ, recombinant glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) were determined by western blot. Cell proliferation, migratory and invasive abilities and apoptosis were illustrated by cell counting kit-8 (CCK-8) assay, transwell assay and flow cytometry analysis, respectively. Cell lactate production, glucose uptake and adenosine 5'-triphosphate (ATP) level were severally elucidated by lactate assay kit, glucose assay kit and ATP detection kit. Results: CircCDK17 expression and the mRNA and protein expression levels of YWHAZ were dramatically upregulated, while miR-1294 expression was obviously downregulated in CC tissues or cells compared with control groups. CircCDK17 silencing suppressed cell proliferation, migration, invasion and glycolysis, and induced cell apoptosis in CC; however, miR-1294 inhibitor restrained these effects. Additionally, circCDK17 was a sponge of miR-1294 and miR-1294 bound to YWHAZ. Furthermore, circCDK17 knockdown inhibited tumor formation in vivo. Conclusion: CircCDK17 knockdown repressed cell proliferation, migration, invasion and glycolysis, and promoted cell apoptosis via miR-1294/YWHAZ axis in CC. This finding provides a theoretical basis in studying circRNA-mediated therapy in CC. [ABSTRACT FROM AUTHOR]

Circular-RNA friend leukemia virus integration 1 (circ-FLI1; hsa_circ_0000370) is a noninvasive biomarker for the diagnosis of colon carcinoma (CC). Herein, we intended to investigate its functions and competing endogenous RNA (ceRNA) mechanisms in CC cells. In terms of expression status, circ-FLI1 was abnormally upregulated in CC patients’ tumors and cells, paralleled with DKC1 upregulation and miR-197-3p downregulation. Most strikingly, there was a direct target relationship between miR-197-3p and circ-FLI1 or DKC1 based on the starbase database, dualluciferase reporter assay, and RNA immunoprecipitation. Functionally, the colony formation assay, MTS method, fluorescence-activated cell sorting method, cell cycle and apoptosis assays, and transwell assays were performed, and the results revealed that interfering circ-FLI1 and reexpressing miR-197-3p could restrict colony formation, cell viability, cell cycle progression, and migration/invasion of CC cells with apoptosis rate elevation; besides, they promoted oxaliplatin (L-OHP)-induced cell viability inhibition. Furthermore, there were counteractive effects between circ-FLI1 silencing and miR-197-3p depletion, miR-197-3p overexpression and DKC1 restoration on regulating CC cell functions and L-OHP resistance. With a xenograft tumor model, the anti-growth role of circ-FLI1 silencing was also found in vivo with or without L-OHP treatment. Collectively, we demonstrated that circ-FLI1 might confer L-OHP resistance and malignant progression of CC presumably through the circ-FLI1/miR-197-3p/DKC1 ceRNA axis. [ABSTRACT FROM AUTHOR]

Background: The tumour necrosis factor-α (TNF-α) gene plays an important role in the host immune response, which will influence the development and clearance of cancer. Polymorphism of the TNF-α promoter region is considered to influence its transcription and be a risk factor for tumorigenesis. In the current study, we evaluated the role of TNF-α promoter region polymorphisms in susceptibility to cervical intraepithelial neoplasia (CIN) and cervical cancer (CC). Methods: A total of 2732 subjects, including 1173 healthy controls, 579 patients with CIN and 980 patients with CC in a Chinese Han population, were selected for the current study. Five SNPs in the TNF-α promoter, rs1799964 (− 1031 C>T), rs1800630 (− 863 A>C), rs1799724 (− 857 C>T), rs1800629 (− 308 A>G) and rs361525 (− 238 A>G), were selected and genotyped using TaqMan Assays. The association of these SNPs with CIN and cervical cancer was evaluated among healthy controls, CIN and CC patients. Results: The frequency distribution of rs1800629 and rs361525 alleles was significantly different between the CC group and the control group (P=0.009 and P=0.002). The rs1800629 A allele was found to be a protective factor for CC (OR=0.72; 95% CI=0.56– 0.92). The rs361525 A allele was found to be a risk factor for CC (OR=1.69; 95% CI=1.21– 2.38). After pathological subtyping of CC, the allele distribution of rs1800629 and rs361525 were both significantly different between the cervical squamous cell carcinoma and control groups (P=0.002 and P< 0.001). The rs1800629 A allele was protective factor for cervical squamous cell carcinoma (OR=0.66; 95% CI=0.50– 0.86). The rs361525 A allele was a risk factor for cervical squamous cell carcinoma (OR=1.87; 95% CI=1.32– 2.65). Moreover, the genotypic frequency of rs361525 was significantly different between cervical cancer stage I and stage II (P=0.003). Conclusion: The rs1800629 and rs361525 in the TNF-α promoter are associated with susceptibility to CC in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Peijing Shi,1 Xiaoyong Zhang,1 Chunxiang Lou,1 Yunxia Xue,1 Ruibao Guo,1 Shuzhen Chen2 1Department of Gynaecology, The Third Hospital of Ji’nan, Jinan, People’s Republic of China; 2Department of Pathology, The Third Hospital of Ji’nan, Jinan, People’s Republic of ChinaCorrespondence: Peijing ShiDepartment of Gynaecology, The Third Hospital of Ji’nan, Jinan, Shandong 250132, People’s Republic of ChinaEmail shipeijing223@163.comBackground: Cervical cancer (CC) is a common gynecological tumor that affects women’s health. Circular RNA hsa_circ_0084927 (hsa_circ_0084927) has been reported to be upregulated in CC. However, the role and regulatory mechanism of hsa_circ_0084927 in CC are unclear.Methods: Expression of hsa_circ_0084927, microRNA (miR)-634, and tumor protein D52 (TPD52) mRNA in CC tissues and cells was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, colony formation, cell cycle progression, apoptosis, migration, and invasion of CC cells were determined with cell counting kit-8 (CCK-8), plate clone, flow cytometry, or transwell assays. The levels of cyclin D1, cleaved-caspase-3 (c-caspase 3), matrix metalloproteinase (MMP)-2, MMP-9, and TPD52 protein were evaluated with Western blotting. The targeting relationship between hsa_circ_0084927 or TPD52 and miR-634 was verified via dual-luciferase reporter and/or RNA immunoprecipitation (RIP) assays. Xenograft assay was conducted to confirm the role of hsa_circ_0084927 in vivo.Results: Hsa_circ_0084927 and TPD52 were upregulated while miR-634 was downregulated in CC tissues and cells. Hsa_circ_0084927 silencing reduced tumor growth in vivo and induced cell cycle arrest, apoptosis, and curbed proliferation, colony formation, migration, and invasion of CC cells in vitro. Hsa_circ_0084927 regulated TPD52 expression through sponging miR-634. MiR-634 inhibitor reversed hsa_circ_0084927 knockdown-mediated impact on the malignancy of CC cells. TPD52 elevation abolished the repressive influence of miR-634 mimics on the malignancy of CC cells.Conclusion: Hsa_circ_0084927 accelerated CC advancement via upregulating TPD52 via sponging miR-634, offering a new evidence to support hsa_circ_0084927 as a promising target for CC treatment.Keywords: CC, hsa_circ_0084927, miR-634, TPD52