Search

The benzoxaborinine scaffold, a homologue of benzoxaborole with an additional carbon atom in the boracycle, shows significant potential in developing new therapeutic agents. This study reports the synthesis, inhibition assays against four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, and anti-melanoma evaluation of 7-aryl(thio)ureido-substituted benzoxaborinines. Some derivatives, particularly compound 11, exhibited potent inhibitory activity (below 65 nM) against hCA IX and XII and stronger antiproliferative effects than SLC-0111on human melanoma cells under hypoxia. Crystallographic studies of benzoxaborinine 3adducts with hCA I and II demonstrated the binding mode of this chemotype, revealing that although both benzoxaborinine 3and benzoxaborole 10share a similar zinc-binding mode, the expanded ring in benzoxaborinine led to a different orientation within the active site. These findings suggest that benzoxaborinines hold promise for designing novel carbonic anhydrase inhibitors.

Context/ObjectivePerceived job quality is a key indicator of sustainable work among persons with spinal cord injuries (PwSCI). This study aimed at (a) describing three indicators of perceived job quality (i.e.job satisfaction, job performance, and work stress) among working PwSCI, and (b) identifying whether and how different person-job match dimensions (i.e.interest congruence, demands-abilities fit, needs-supplies fit, and effort-reward imbalance) as well as sociodemographic and health-related factors (e.g.age, sex, SCI-related characteristics, pain problems, and depressive symptoms) are associated with perceived job quality.DesignCross-sectional, self-report survey.SettingCommunity.Participants549 working-age PwSCI who participated in the 2017 community survey of the Swiss Spinal Cord Injury Cohort study and reported being engaged in paid work.Outcome measuresJob satisfaction, job performance, and work stress.ResultsHigher interest congruence, better needs-supplies fit and lower effort-reward imbalance, as well as female sex, were associated with higher job satisfaction, while higher effort-reward imbalance, poorer demands-abilities fit (underqualification), and – surprisingly – better needs-supplies fit were associated with higher work stress. Moreover, underqualification, worse needs-supplies fit as well as pain, depressive symptoms, and language region were associated with lower job performance.ConclusionIntegrating individuals in jobs that match their abilities, interests and needs, and which adequately reward their efforts may contribute to better job quality among PwSCI. Beyond that, common secondary health conditions and comorbidities such as pain and depressive symptoms should receive particular attention in interventions that aim to promote job quality and ultimately sustainable work in the SCI population.

Graphical Abstract:

Objectives.Musculoskeletal (MSK) complaints are prevalent in law enforcement officers (LEOs), but research that examines their risk factors is limited. This study aimed to identify the self-reported MSK complaint prevalence and perceived causes in LEOs. Methods.The Nordic musculoskeletal questionnaire was used to identify the 12-month and 7-day prevalence of MSK ‘trouble’ (ache, pain, discomfort) for nine body sites. The perceived cause, participant characteristics and occupational role were reported. Body fat percentage was measured using bioelectrical impedance. Results.Complete submissions of 186 questionnaires were received (80% male, median age 40.6 years, interquartile range 10.1). Eighty-six per cent of officers reported having an MSK complaint in the last 12 months, where lower back, shoulder and neck complaint prevalence was 59.1, 48.4 and 42.5%, respectively. The occupational role was associated with the site and presence of complaints (p < 0.05), where armed officers presented with more shoulder, lower back and hip/thigh complaints. Age, sex and body fat did not impact complaint prevalence. Participants mainly attributed their complaints to occupation equipment or to sport and exercise. Conclusion.MSK complaints were highly prevalent in this cohort, particularly armed officers. Further research is required to establish the impact of these complaints and how they can be mitigated.

Fragment crystallizable gamma receptors (FcγRs) mediate various cellular responses with significant cardiovascular implications. They contribute to the anticancer activity of trastuzumab (TRZ), a recombinant humanized monoclonal antibody that interferes with human epidermal growth factor receptor 2 (HER2), thereby blocking its physiological function in cardiac cells. This is responsible for cardiac complications that hamper TRZ clinical application. In this study we investigated the involvement of FcγRs in the TRZ cardiotoxicity. We used a recombinant antigen-binding fragment (Fab) of TRZ (rFab-HER2) to examine whether the absence of the Fc region resulted in fewer cardiomyocyte toxicity while preserving TRZ’s ability to inhibit HER2. When exposed to rFab-HER2, AC16 human adult ventricular cardiomyocytes were less vulnerable to damage and death, than to TRZ. Specifically, TRZ exhibited cytotoxicity at a lower concentration (150 µg/mL, corresponding to ~1 µM) compared to rFab-HER2 (250 µg/mL, corresponding to ~5 µM). Like TRZ, rFab-HER2 negatively modulated HER2 levels in cardiomyocyte (without inducing cytotoxic activity in BJ human fibroblast cells that either did not express or express very low levels of HER2) and inhibited the downstream ERK/AKT cascades. But rFab-HER2 did not alter cardiomyocyte mitochondrial dynamic balance, and affect apoptosis and inflammation, while it limited cytosolic and mitochondrial ROS indicators. On contrary, the Fc region (50−250 μg/mL) exerted direct cytotoxic action on cardiomyocytes (but not on human fibroblasts that lacked Fc receptors). TRZ (150 μg/mL) markedly upregulated the expression level of FcγRIIA (a FcγRs strongly involved in TRZ-induced antibody-dependent cellular toxicity) in cardiomyocytes, whereas the Fab fragment (150 μg/mL) had no effect. Our results demonstrate that Fc region plays an important pathogenic role in TRZ-induced cardiomyocyte toxicity. In addition, targeting FcγRIIA might contribute to the off-target effects of TRZ therapy.

The recent acceleration of commercial, private and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit, concomitant with the largest-ever number of crewed missions entering space and preparations for exploration-class (lasting longer than one year) missions. Such rapid advancement into space from many new companies, countries and space-related entities has enabled a ‘second space age’. This era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, and encompass multi-omic, single-cell and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics, as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this Perspective, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration, Japan Aerospace Exploration Agency, European Space Agency and other space agencies, and detail the entrance of the commercial spaceflight sector (including SpaceX, Blue Origin, Axiom and Sierra Space) into aerospace medicine and space biology, the first aerospace medicine biobank, and various upcoming missions that will utilize these tools to ensure a permanent human presence beyond low Earth orbit, venturing out to other planets and moons.

In the last decades, carbonic anhydrases (CAs) have become the top investigated innovative pharmacological targets and, in particular, isoforms IX and XII have been widely studied due to the evidence of their overexpression in hypoxic tumors. The frantic race to find new anticancer agents places the quick preparation of large libraries of putative bioactive compounds as the basis of a successful drug discovery and development programme. In this context, multi-component and, in general, one-step reactions are becoming very popular and, among them, Biginelli's reaction gave clean and easy-to-isolate products. Thus, we synthesized a series of Biginelli's products (10–17a–b) and similar derivatives (20–21) bearing the benzenesulfonamide moiety, which is known to inhibit CA enzymes. Through the stopped-flow technique, we were able to assess their ability to inhibit the targeted CAs IX and XII in the nanomolar range with promising selectivity over the physiologically relevant isoforms I and II. Crystallography studies and docking simulations helped us to gain insight into the interaction patterns established in the enzyme–inhibitor complex. From a chemical similarity-based screening of in-house libraries of compounds, a diphenylpyrimidine (23) emerged. The surprisingly potent inhibitory activity of 23for CAs IX and XII along with its strong antiproliferative effect on two (triple-negative breast cancer MDA-MB-231 and glioblastoma U87MG) cell lines laid the foundation for further investigation, again confirming the key role of CAs in cancer.

A hybrid cellulose-based programmable nanoplatform for applications in precision radiation oncology is described. Here, sugar heads work as tumor targeting moieties and steer the precise delivery of radiosensitizers, i.e.gold nanoparticles (AuNPs) into triple negative breast cancer (TNBC) cells. This “Trojan horse” approach promotes a specific and massive accumulation of radiosensitizers in TNBC cells, thus avoiding the fast turnover of small-sized AuNPs and the need for high doses of AuNPs for treatment. Application of X-rays resulted in a significant increase of the therapeutic effect while delivering the same dose, showing the possibility to use roughly half dose of X-rays to obtain the same radiotoxicity effect. These data suggest that this hybrid nanoplatform acts as a promising tool for applications in enhancing cancer radiotherapy effects with lower doses of X-rays.

We synthesized new pyrrole and indole derivatives as human carbonic anhydrase (hCA) inhibitors with the potential to inhibit the Wnt/β-catenin signaling pathway. The presence of both N1-(4-sulfonamidophenyl) and 3-(3,4,5-trimethoxyphenyl) substituents was essential for strong hCA inhibitors. The most potent hCA XII inhibitor 15(Ki= 6.8 nM) suppressed the Wnt/β-catenin signaling pathway and its target genes MYC, Fgf20, and Sall4 and exhibited the typical markers of apoptosis, cleaved poly(ADP-ribose)polymerase, and cleaved caspase-3. Compound 15showed strong inhibition of viability in a panel of cancer cells, including colorectal cancer and triple-negative breast cancer cells, was effective against the NCI/ADR-RES DOX-resistant cell line, and restored the sensitivity to doxorubicin (DOX) in HT29/DX and MDCK/P-gp cells. Compound 15is a novel dual-targeting compound with activity against hCA and Wnt/β-catenin. It thus has a broad targeting spectrum and is an anticancer agent with specific potential in P-glycoprotein overexpressing cell lines.

ABSTRACTIntroductionThe therapeutic targeting of the ubiquitin-proteasome pathway (UPP) through inhibitors of the 20S proteasome core proteolytic activities has revolutionized the treatment of hematological malignancies and is paving the way for its extension to solid tumors.Areas coveredThis review covers the progress made in the field of proteasome inhibitors, ranging from the first-generation bortezomib to the latest second-generation inhibitors such as carfilzomib and ixazomib as well as the proteasome inhibitors in clinical phase such as oprozomib and marizomib. The development of selective and potent proteasome inhibitors with improved pharmacological properties is described from the synthesis to their basic biological, and clinical validation.Expert opinionProteasome inhibitors have transformed the treatment landscape for hematological malignancies and hold great promise for cancer therapy. Combination therapies targeting multiple pathways, the development of novel inhibitors or ‘hybrid-inhibitors,’ and the optimization of treatment protocols are key areas for future exploration. The extension of proteasome inhibitors for the treatment of solid tumors, and their ability to pass the blood–brain barrier open new possibilities for treating central nervous system cancers. However, managing adverse effects, particularly those affecting the central nervous system, remains a critical consideration and a strategic ‘working on’ aspect for the near future.

Introduction: Total Hip Arthroplasty (THA) is being increasingly undertaken in younger and more active patients, with many of these patients wanting to return to sport (RTS) after surgery. However, the percentage of patients RTS and time at which they are able to get back to sport following surgery remains unknown. The objective of this meta-analysis was to determine the time patients RTS after THA.Methods: A search was performed on PUBMED, MEDLINE, EMBASE, and the Cochrane Library for trials on THA and RTS, in the English language, published from the inception of the database to October 2020. All clinical trials reporting on to RTS following THA were included. Data relating to patient demographics, methodological quality, RTS, clinical outcomes and complications were recorded. The PRISMA guidelines were used to undertake this study.Results: The initial literature search identified 1720 studies. Of these, 11 studies with 2297 patients matched the inclusion criteria. 3 studies with 154 patients demonstrated an overall pooled proportion of 40.0% (95% CI, 32.5–47.9%) of patients RTS between 2 and 3 months after surgery. 4 studies with 242 patients demonstrated an overall pooled proportion of 76.9% (95% CI, 71.5–82.0) of patients RTS by 6 months after surgery. Pooled proportion analysis from 7 trials with 560 patients demonstrated 93.9% (95% CI, 82.7–99.5%) of patients RTS between 6 and 12 months after surgery.Conclusions: Pooled proportion analysis showed increasingly more patients were able to RTS after THA over the first 1 year after surgery. There remains marked inter and intra-study variations in time for RTS but the pooled analysis shows that over 90% of patients were able to RTS at 6–12 months after THA. These finding will enable more informed discussions between patients and healthcare professionals about time for RTS following THA.

Inflammatory bowel disease (IBD) causes chronic inflammation of the digestive system and can affect both humans and household pets like dogs. Despite extensive research, a definitive cure remains elusive. This study investigates the therapeutic potential of apple-derived extracellular vesicles (ADEVs) in canine IBD. ADEVs, isolated from 'Golden Delicious' apples, were orally administered to dogs with IBD over a ten-day period. Microbiota analysis, clinical assessments, endoscopic examinations, and ultrasound imaging showed a significant reduction in disease severity and post-treatment symptoms. The results indicate that ADEVs regulate intestinal microorganism growth and interact with host cells. In particular IgA and calprotectine level riched physiological level, as well as microbiota and intestinal mucose. These results can explained thanks to the soothing effect of ADEVs on IBD may be due to a synergistic regulatory impact on both intestinal flora and the host's inflammatory response. Overall, these findings suggest a promising new avenue for IBD treatment.

Cancer-associated fibroblasts (CAF) are important constituents of the tumor microenvironment (TME) and are major drivers of tumorigenesis. Yet, therapies aiming at eliminating CAF have failed to cure patients. This setback has raised questions regarding whether CAF exclusively favour cancer progression, or if they may also assume tumor-suppressor functions. In the present study, we used proteomics and single cell RNA-sequencing analysis to examine the CAF landscape in hepatocellular carcinoma (HCC). We thereby unveil three major CAF populations in HCC, one of which specifically expressing the prolargin protein. This CAF subpopulation (further termed as CAF_Port) shared a strong transcriptomic signature with portal liver fibroblasts. We further show that CAF_Port deposit prolargin in the TME and that its levels are lower in tumors as compared to the peritumoral region. Mechanistically, aggressive cancer cells degraded prolargin using matrix metalloprotease activity. Survival analysis of 188 patients revealed that high prolargin protein levels correlate with good patient outcome (HR = 0.37; p= 0.01). In vivo, co-injection of cancer cells with fibroblasts silenced for prolargin, led to faster tumor development (5-fold; p= 0.01), mainly due to stronger angiogenesis. Using protein-protein interaction study and structural modelling, we further demonstrate that prolargin binds and inhibits the activity of several pro-agiogenic proteins, including hepatocyte and fibroblast growth factors. In conclusion, prolargin is angiogenesis modulator and CAF-derived tumor suppressor in HCC. Stabilizing prolargin levels in the CAF_Port subpopulation may revert their tumor-antagonizing properties, warranting exploration in further pre-clinical studies.

Alterations in KRAS have been identified as the most recurring somatic variants in the multiple myeloma (MM) mutational landscape. Combining DNA and RNA sequencing, we studied 756 patients and observed KRAS as the most frequently mutated gene in patients at diagnosis; in addition, we demonstrated the persistence or de novo occurrence of the KRAS aberration at disease relapse. Small-molecule inhibitors targeting KRAS have been developed; however, they are selective for tumors carrying the KRASG12C mutation. Therefore, there is still a need to develop novel therapeutic approaches to target the KRAS mutational events found in other tumor types, including MM. We used AZD4785, a potent and selective antisense oligonucleotide that selectively targets and downregulates all KRAS isoforms, as a tool to dissect the functional sequelae secondary to KRAS silencing in MM within the context of the bone marrow niche and demonstrated its ability to significantly silence KRAS, leading to inhibition of MM tumor growth, both in vitro and in vivo, and confirming KRAS as a driver and therapeutic target in MM.

Alterations in KRAS have been identified as the most recurring somatic variants in the multiple myeloma (MM) mutational landscape. Combining DNA and RNA sequencing, we studied 756 patients and observed KRAS as the most frequently mutated gene in patients at diagnosis; in addition, we demonstrated the persistence or de novo occurrence of the KRAS aberration at disease relapse. Small-molecule inhibitors targeting KRAS have been developed; however, they are selective for tumors carrying the KRASG12Cmutation. Therefore, there is still a need to develop novel therapeutic approaches to target the KRAS mutational events found in other tumor types, including MM. We used AZD4785, a potent and selective antisense oligonucleotide that selectively targets and downregulates all KRAS isoforms, as a tool to dissect the functional sequelae secondary to KRAS silencing in MM within the context of the bone marrow niche and demonstrated its ability to significantly silence KRAS, leading to inhibition of MM tumor growth, both in vitro and in vivo, and confirming KRAS as a driver and therapeutic target in MM.

Aim: This study investigated the stability of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on 16 common environmental surface materials.Background: SARS-CoV-2 is the causative agent of severe coronavirus disease, a significant public health concern that quickly led to a pandemic. Contamination of environmental surface materials is of concern, with previous studies identifying long-term detection of infectious particles on surfaces. These contaminated surfaces create an increased risk for contact transmission.Methods: Surface materials were inoculated with 10,000 plaque forming units and samples were collected 4, 8, 12, 24, 30, 48, and 168 hours post infection (hpi). Viral titers were determined for each sample and time point using plaque assays. Nonparametric modeling utilized the Turnbull algorithm for interval-censored data. Maximum likelihood estimates for the survival curve were calculated. Parametric proportional hazards regression models for interval censored data were used to explore survival time across the surface materials.Results: There was a sharp decline in recoverable virus after 4 hpi for all tested surfaces. By 12 hpi, infectious SARS-CoV-2 was recoverable from only four surfaces; and by 30 hr, the virus was recoverable from only one surface. There were differences in survival curves based on the materials although some groups of materials are similar, both statistically and practically.Conclusions: While very low amounts of infectious SARS-CoV-2 are recoverable over time, there remains a risk of viral transmission by surface contamination in indoor environments. Individuals and institutions must follow appropriate procedures to decontaminate indoor environment and increase diligence for hand hygiene and personal protective equipment.

Although case reports have suggested an association between severe acute respiratory distress syndrome coronavirus 2 and appendicitis, we found that the overall incidence of appendicitis was stable throughout the pandemic at our tertiary pediatric hospital. Furthermore, we did not find evidence of CoV2 infection in 9 appendicitis tissues. Therefore, we conclude that severe acute respiratory distress syndrome coronavirus 2 infection of the appendix is not a common etiologic cause of pediatric appendicitis

The human fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström macroglobulinemia (WM). WM is still an incurable disease, and patients succumb because of disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 was also confirmed at the protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and noncanonical NF-κB cascades were downregulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3, and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.

The human fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström macroglobulinemia (WM). WM is still an incurable disease, and patients succumb because of disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 was also confirmed at the protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and noncanonical NF-κB cascades were downregulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3, and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.

Study design: Cross-sectional observational study using data from the second community survey of the Swiss Spinal Cord Injury Cohort Study (Survey 2017) conducted between 03/2017 and 03/2018. Objectives: To identify facilitators of and barriers to utilizing SCI-specialized outpatient clinic and inpatient care by individuals with spinal cord injury (SCI). Setting: Community. Methods: Multivariable logistic regression was used to identify factors influencing (1) the attendance at annual check-ups at SCI-specialized treatment facilities, (2) the utilization of SCI-specialized outpatient clinic care by those who utilized any outpatient clinic care, and (3) the utilization of SCI-specialized inpatient care by those who were hospitalized. Multiple imputation was used to account for missing data. Results: Out of 3959 eligible individuals, 1294 completed the questionnaire (response rate 33%). In the last 12 months, 51% of study participants attended the annual check-up, 33% of outpatient clinic care users utilized SCI-specialized outpatient clinic care, and 44% of those who were hospitalized were hospitalized at a SCI center. Annual check-ups were attended less by women, the elderly, and those with nontraumatic SCI. SCI-specialized outpatient clinic care was less likely to be utilized when individuals with SCI were living with cancer, lived farther away from SCI-specialized treatment facilities or in a minority language region. Specialized inpatient care was less likely to be utilized by women and those with incomplete lesions. Conclusions: SCI-specialized outpatient clinic care must be provided near the residence of individuals with SCI, otherwise non-specialized care is utilized. The reasons why women utilize SCI-specialized care less frequently than men merits further investigation.

Study design: Questionnaire survey conducted in 2017 as part of the Swiss Spinal Cord Injury Cohort Study (SwiSCI). Objectives: To elucidate the use of outpatient health care providers by individuals with chronic spinal cord injury in a situation of free choice and ample supply. Setting: Community, nationwide. Methods: The frequency of visits was compared to that of a survey conducted five years earlier. Using regression tree analysis, the characteristics of individuals with extensive use of health care providers’ services were investigated. Substitution effects, where health care users replace one provider type by another, were quantified using likelihood ratios for positive outcomes. Results: The questionnaire was returned by 1,294 persons (response rate 33%). Participants reported visits to 14 different health care providers within the previous 12 months. Most often visited was the general practitioner (GP) by 82%. Older individuals used fewer health care providers than younger participants. Individuals with spasticity and females visited a broader variety of health care providers than the average user. The participants used fewer providers than they did five years ago. Health care users were not found to be substituting one provider type with another. Conclusions: Individuals with spinal cord injury in Switzerland use a wide array of medical service providers. All providers were used complementary to each other without redundancies between providers. The use of providers is driven by health-related factors and gender. Old age was not as much a driver for high utilization as described in other settings.

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by the destruction of the small and medium bile ducts. Its pathogenesis is still unknown. Despite the genome wide association study findings, the therapies targeting the cytokines pathway, tested so far, have failed. The concept of the biliary epithelium as a key player of the PBC pathogenesis has emerged over the last few years. It is now well accepted that the biliary epithelial cells (BECs) actively participate to the genesis of the damage. The chronic stimulation of BECs via microbes and bile changes the cell phenotype toward an active state, which, across the production of proinflammatory mediators, can recruit, retain, and activate immune cells. The consequent immune system activation can in turn damage BECs. Thus, the crosstalk between both innate and adaptive immune cells and the biliary epithelium creates a paracrine loop responsible for the disease progression. In this review, we summarize the evidence provided in literature about the role of BECs and the immune system in the pathogenesis of PBC. We also dissect the relationship between the immune system and the BECs, focusing on the unanswered questions and the future potential directions of the translational research and the cellular therapy in this area. Review on the crosstalk between biliary epithelial cells and the immune system in the pathogenesis of primary biliary cholangitis.

The relaxation dynamics of disentangled ultrahigh molecular weight polyethylene (UHMWPE) were analyzed by means of torsional rheology in a broad frequency and temperature range. The disentangled specimens were compression-molded at two different temperatures, solid state (125 °C) and melt state (160 °C), and the latter was compared with a melt-state-processed commercial UHMWPE specimen. Three different relaxation processes were observed, namely, αc-, β-, and γ-relaxations, as expected for polyethylene. The relaxation strengths of the αc- and γ-relaxations were found to be dependent on the crystallinity content, verified by means of differential scanning calorimetry. The relaxation molecular dynamics of the γ-relaxation in the solid-state-compressed disentangled sample follows a Vogel–Fulcher–Tammann–Hesse trend, suggesting a dynamic glass-to-rubber transition. The same trend is not found for the γ-relaxation of both melt-state-processed samples, thus suggesting a role of crystalline polydispersity and entanglement density in the free volume of the amorphous segments.

Study design: Cross-sectional survey. Objectives: To evaluate the annual influenza vaccination coverage rate (IVCR) among community-dwelling individuals with spinal cord injury (SCI). Setting: SCI community in Switzerland. Methods: Participants were responders to the influenza vaccination question (n= 492) in the 2012 community survey of the Swiss Spinal Cord Injury (SwiSCI) cohort study. IVCR of SwiSCI participants were compared to the normative Swiss population, sampled in the Swiss Health Survey of 2012 using direct standardization, logistic regression standardization, and a genetic matching approach to control for differences in age, sex, and quarterly period of survey response. Results: Individuals with SCI showed higher crude (26%, 95% confidence interval (CI): 22–30%) and age- and sex-standardized (24%, CI: 23–24%) IVCR than observed in the general population (15% CI, 14–15%). The adjustment for age and sex as well as quarterly period of survey response showed that the standardized IVCR of individuals with SCI (17%; CI: 12–23%) approached that of the general population. Low IVCR of about 10% were found among individuals with SCI younger than 45 years. IVCR were similar between men and women and between individuals with incomplete and complete paraplegia and tetraplegia. Conclusion: The IVCR in individuals with chronic SCI was not higher than in the general population and much lower than guidelines recommend. The improvement of the IVCR is an important target of health policy in SCI in Switzerland as to reduce the evidenced excess burden in respiratory-disease related morbidity and mortality.