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Abstract Molecular similarities between embryonic and malignant cells can be exploited to target tumors through specific signatures absent in healthy adult tissues. One such embryonic signature tumors express is oncofetal chondroitin sulfate (ofCS), which supports disease progression and dissemination in cancer. Here, we report the identification and characterization of phage display-derived antibody fragments recognizing two distinct ofCS epitopes. These antibody fragments show binding affinity to ofCS in the low nanomolar range across a broad selection of solid tumor types in vitro and in vivo with minimal binding to normal, inflamed, or benign tumor tissues. Anti-ofCS antibody drug conjugates and bispecific immune cell engagers based on these targeting moieties disrupt tumor progression in animal models of human and murine cancers. Thus, anti-ofCS antibody fragments hold promise for the development of broadly effective therapeutic and diagnostic applications targeting human malignancies.

Abstract Drug delivery is the process or method of delivering a pharmacological product to have therapeutic effects on humans or animals. The use of nanoparticles to deliver medications to cells is driving the present surge in interest in improving human health. Green nanodrug delivery methods are based on chemical processes that are acceptable for the environment or that use natural biomaterials such as plant extracts and microorganisms. In this study, zinc oxide-superparamagnetic iron oxide-silver nanocomposite was synthesized via green synthesis method using Fusarium oxysporum fungi mycelia then loaded with sorafenib drug. The synthesized nanocomposites were characterized by UV-visibile spectroscopy, FTIR, TEM and SEM techniques. Sorafenib is a cancer treatment and is also known by its brand name, Nexavar. Sorafenib is the only systemic medication available in the world to treat hepatocellular carcinoma. Sorafenib, like many other chemotherapeutics, has side effects that restrict its effectiveness, including toxicity, nausea, mucositis, hypertension, alopecia, and hand-foot skin reaction. In our study, 40 male albino rats were given a single dose of diethyl nitrosamine (DEN) 60 mg/kg b.wt., followed by carbon tetrachloride 2 ml/kg b.wt. twice a week for one month. The aim of our study is using the zinc oxide-superparamagnetic iron oxide-silver nanocomposite that was synthesized by Fusarium oxysporum fungi mycelia as nanocarrier for enhancement the sorafenib anticancer effect.

Summary: Impaired sleep is a common aspect of aging and often precedes the onset of Alzheimer’s disease. Here, we compare the effects of sleep deprivation in young wild-type mice and their APP/PS1 littermates, a murine model of Alzheimer’s disease. After 7 h of sleep deprivation, both genotypes exhibit an increase in EEG slow-wave activity. However, only the wild-type mice demonstrate an increase in the power of infraslow norepinephrine oscillations, which are characteristic of healthy non-rapid eye movement sleep. Notably, the APP/PS1 mice fail to enhance norepinephrine oscillations 24 h after sleep deprivation, coinciding with an accumulation of cerebral amyloid-β protein. Proteome analysis of cerebrospinal fluid and extracellular fluid further supports these findings by showing altered protein clearance in APP/PS1 mice. We propose that the suppression of infraslow norepinephrine oscillations following sleep deprivation contributes to increased vulnerability to sleep loss and heightens the risk of developing amyloid pathology in early stages of Alzheimer’s disease.

Objective To estimate the effectiveness of vaccination with a monovalent covid-19 mRNA vaccine containing the omicron XBB.1.5 subvariant against severe covid-19 disease in Denmark, Finland, and Sweden.Design Target trial emulation based on registry data.Setting Denmark, Finland, and Sweden, 1 October 2023 to 21 April 2024.Participants Source population of 3 898 264 individuals eligible for vaccination with the XBB.1.5 containing covid-19 mRNA vaccine at the start of the study on 1 October 2023. Study cohort comprised 1 876 282 recipients of an XBB.1.5 containing vaccine during the study period matched with 1 876 282 non-recipients. Individuals were aged ≥65 years (mean age 75.4 years, standard deviation 7.4 years) and had received at least four doses of a previous covid-19 vaccine.Main outcome measures Cumulative incidences of hospital admissions and deaths related to covid-19 in a follow-up period of 24 weeks after immunisation (defined as one week after vaccination) in recipients of an XBB.1.5 containing covid-19 mRNA vaccine and matched non-recipients. Cumulative incidences were used to calculate comparative vaccine effectiveness (1−risk ratio) and risk differences.Results The associated comparative vaccine effectiveness was 57.9% (95% confidence interval (CI) 49.9% to 65.8%) against hospital admission for covid-19 (1085 v 2635 events) and 75.2% (70.6% to 79.9%) against deaths related to covid-19 disease (348 v 1458 events) after 24 weeks of follow-up. This result corresponded to 154.7 (95% CI 78.3 to 231.0) hospital admissions for covid-19 and 120.3 (110.5 to 130.2) deaths prevented per 100 000 individuals who were vaccinated with an XBB.1.5 containing vaccine. The associated comparative vaccine effectiveness was similar irrespective of sex, age group (65-74 v ≥75 years), number of doses of previous covid-19 vaccines, subgroup of co-administered seasonal influenza vaccines, and period of when either the omicron XBB or BA.2.86 sublineage was predominant. Although the observed reduction in risk was highest during the first weeks after vaccination, comparative vaccine effectiveness was well maintained after 24 weeks of follow-up.Conclusions In this study, in adults aged ≥65 years, vaccination with a monovalent XBB.1.5 containing covid-19 mRNA vaccine was associated with reduced rates of hospital admissions for covid-19 and deaths related to covid-19, during the autumn and winter of 2023-24 in Denmark, Finland, and Sweden.

Mature teratoma is a common tumor that can undergo malignant transformation, either in ovarian or extragonadal sites. While adenocarcinoma superimposed on sacrococcygeal teratoma is rare, mucinous variants have been reported in only five cases. Here, we present a case of a young girl with disseminated metastasis of mucinous carcinoma, initially of unknown primary origin. Further investigation by a dedicated multidisciplinary team (MDT) revealed a focus of mucinous carcinoma (intestinal type) in a sacrococcygeal teratoma incompletely resected five years earlier. The patient is currently undergoing second-line chemotherapy after experiencing side-effects on the first-line regimen. Pathologists, gynecologic oncologists, and surgical oncologists should exercise caution when dealing with locally aggressive teratomas, thoroughly searching for malignant components and conducting short-term follow-up.

Abstract Background The malaria protein VAR2CSA binds oncofetal chondroitin sulfate (ofCS), a unique chondroitin sulfate, expressed on almost all mammalian cancer cells. Previously, we produced a bispecific construct targeting ofCS and human T cells based on VAR2CSA and anti-CD3 (V-aCD3Hu). V-aCD3Hu showed efficacy against xenografted tumors in immunocompromised mice injected with human immune cells at the tumor site. However, the complex effects potentially exerted by the immune system as a result of the treatment cannot occur in mice without an immune system. Here we investigate the efficacy of V-aCD3Mu as a monotherapy and combined with immune checkpoint inhibitors in mice with a fully functional immune system. Methods We produced a bispecific construct consisting of a recombinant version of VAR2CSA coupled to an anti-murine CD3 single-chain variable fragment. Flow cytometry and ELISA were used to check cell binding capabilities and the therapeutic effect was evaluated in vitro in a killing assay. The in vivo efficacy of V-aCD3Mu was then investigated in mice with a functional immune system and established or primary syngeneic tumors in the immunologically “cold” 4T1 mammary carcinoma, B16-F10 malignant melanoma, the pancreatic KPC mouse model, and in the immunologically “hot” CT26 colon carcinoma model. Results V-aCD3Mu had efficacy as a monotherapy, and the combined treatment of V-aCD3Mu and an immune checkpoint inhibitor showed enhanced effects resulting in the complete elimination of solid tumors in the 4T1, B16-F10, and CT26 models. This anti-tumor effect was abscopal and accompanied by a systemic increase in memory and activated cytotoxic and helper T cells. The combined treatment also led to a higher percentage of memory T cells in the tumor without an increase in regulatory T cells. In addition, we observed partial protection against re-challenge in a melanoma model and full protection in a breast cancer model. Conclusions Our findings suggest that V-aCD3Mu combined with an immune checkpoint inhibitor renders immunologically “cold” tumors “hot” and results in tumor elimination. Taken together, these data provide proof of concept for the further clinical development of V-aCD3 as a broad cancer therapy in combination with an immune checkpoint inhibitor.

Astrocytes act as a dynamic Cl− reservoir regulating Cl− homeostasis in the CNS. Astrocytic Cl− is high and stable during sleep, it is lower during wakefulness and fluctuates in response to sensory input and motor activity. Efflux of Cl− from astrocytes supports inhibitory transmission in the CNS.

Abstract Accurate large‐scale soil moisture (SM) maps are crucial for catchment‐scale hydrological models used for water resource management and warning systems for droughts, floods, and wildfires. SM can be mapped by mobile cosmic‐ray neutron (CRN) systems of moderated detectors at homogeneous landscapes of similar soil and vegetation. In this study, we present a new approach for mobile CRN detection to perform to its full potential, where CRN measurements can also be converted to SM at heterogeneous landscapes. The approach is based solely on thermal and epithermal neutron datasets obtained from mobile dual‐spectra CRN detection, combined with theoretical developments using a particle transport model. For each measurement point, the land cover type is identified using the thermal‐to‐epithermal (T/E) ratio, and the relevant neutron‐count‐to‐soil‐moisture conversion function is estimated from CRN stations located at the main land cover types in the catchment. With this approach, the requirement of collecting 100+ soil samples for each point along the survey route is omitted. We use this T/E‐dependent approach to obtain SM maps from 12 CRN surveys and compare it with a simple approach where only the conversion function from the agricultural site is used. SM by the simple approach is comparable to the estimates of the agricultural stations of a capacitance sensor network, while the estimates of the T/E‐dependent approach also compare well with the heathland and forest stations. With accurate SM estimates for all landcover types, the average error is reduced from 0.089 to 0.038 when comparing CRN SM with space‐borne Soil Moisture Active Passive Mission estimates.

Abstract Background Covid-19 vaccination is the main strategy to reduce SARS-CoV-2 transmission, mortality and morbidity. This study aimed to examine sociodemographic differences in Covid-19 vaccine uptake among all individuals invited for Covid-19 vaccination in Denmark. Methods This study was designed as a nationwide register-based cohort study. The study population included all Danish residents aged 12 years or above in Denmark between December 27, 2020 and October 20, 2021. Individuals who died during the study period before receiving an invitation for Covid-19 vaccination were excluded. Associations between sociodemographic factors and Covid-19 vaccination uptake were analyzed using logistic regression models adjusting for age, sex, immigration status, educational level, disposable income and history of SARS-CoV-2 infection. Results The study population included 5,164,558 individuals. The overall vaccination coverage was 87.1% by October 20, 2021. In the full adjusted logistic regression models, the highest ORs for non-vaccination were observed among individuals aged 12–24 years (OR: 8.99 (95% CI: 8.76–9.23)), descendants of non-western immigrants (OR: 5.26 (95% CI: 5.18–5.33)), individuals who never had a PCR-test performed (OR: 2.93 (95% CI: 2.90–2.96)), individuals with primary school as highest completed educational level (OR: 2.87 (95% CI: 2.83–2.91)) and individuals with disposable income

Highlights ● NAFLD is deliberated a complicated health problem owing to its growing prevalence, complex pathogenesis, and difficulty to diagnose. ● It is crucial to find an efficient noninvasive and affordable biomarker for earlier identification and staging of NAFLD. ● Ultimate role of miRNA-34a in lipid metabolism dysregulation may lead to NAFLD. ● MiRNA-34a and MiRNA-192 are broadly stated to play a role in the development of NAFLD and NASH.

Sleep is not homogenous but contains a highly diverse microstructural composition influenced by neuromodulators. Prior methods used to measure neuromodulator levels in vivo have been limited by low time resolution or technical difficulties in achieving recordings in a freely moving setting, which is essential for natural sleep. In this protocol, we demonstrate the combination of electroencephalographic (EEG)/electromyographic (EMG) recordings with fiber photometric measurements of fluorescent biosensors for neuromodulators in freely moving mice. This allows for real-time assessment of extracellular neuromodulator levels during distinct phases of sleep with a high temporal resolution.

Abstract Background Frailty is a clinical condition characterized by increased vulnerability to adverse health outcomes. Elderly people are screened for frailty as part of preventative care. However, the risk factors for frailty among older adults who undergo Ningen Dock, a comprehensive medical checkup, remain unclear. Thus, this cross-sectional study aims to identify the risk factors for frailty in older adults who received Ningen Dock. The study included 372 participants over 65 years of age who underwent Ningen Dock at the Health Care Center of Gunma Chuo Hospital between April 2019 and March 2020. Frailty was defined using the Kihon Checklist, a basic checklist. Clinical variables were obtained from Ningen Dock records, a vascular function test, and a questionnaire on medication, among others. Multivariate ordinal logistic regression models were used to assess risk factors. Results Prevalence for frailty and pre-frailty was 12.6% and 26.6%, respectively. The mean age of participants was 72.0 ± 5.1 years old, and 43.5% were female. Compared with systolic blood pressure (SBP) ≥ 130 mmHg, the odds ratios for the 100–129 mmHg and < 100 mmHg groups were 2.43 (P = 0.020) and 8.95 (P 0.6 mg/dL. Compared with an exercise habit of ≥ 4 metabolic equivalents (METs), the odds ratio for < 2 METs/week was 2.45 (P < 0.001). The odds ratio for the cardio-ankle vascular index (CAVI) ≥ 9 group was 1.84 (P = 0.020) compared to < 9. Conclusions In older adults who received Ningen Dock, SBP < 100 mmHg, medications ≥ 7, serum iron ≤ 85 μg/dL, total bilirubin ≤ 0.6 mg/dL, exercise habits < 2 METs, and CAVI ≥ 9 were associated with frailty.

Abstract Background and aims Gestational diabetes mellitus is well-defined as glucose intolerance first documented during pregnancy. In this study, we examined the possible associations between I/D polymorphism of the angiotensin-converting enzyme gene, the M235T variant of angiotensinogen gene, and the rs7950226 polymorphism of the ARNT-like protein-1 (BMAL1) gene and the risk for diabetes in Egyptian pregnant women. Subjects and methods This study recruited 160 gestational diabetes cases and 165 controls. Genomic DNA was derived from peripheral blood leukocytes and ACE gene (I/D) genotyping was performed using the method of polymerase chain reaction and the polymerase chain reaction-based restriction fragment length polymorphism was used for identifying the M235T variant of AGT gene and the rs7950226 polymorphism of the BMAL1. Results The II, ID, and DD genotypes of the ACE gene have significant differences in cases compared to controls (P = 0.000 and X 2 = 81.77). The M235T polymorphism of the AGT gene was increased with gestational diabetes risk. Furthermore, the AA genotype of the BMAL1 rs7950226 gene was significantly related to the gestational diabetes risk (P = 0.000 and X 2 = 52.82). Furthermore, the allele frequencies of the three variants have significant variances between cases and control. Conclusion This study suggested significant associations between ACE (DD), AGT (TT), and BMAL1 rs7950226 (AA) gene polymorphisms with gestational diabetes susceptibility and there was a possibility to identify that II + MM + GG as protective haplotypes and DD + TT + AA as risk haplotypes for gestational diabetes.

Abstract Liquid metal catalysts have recently attracted attention for synthesizing high‐quality 2D materials facilitated via the catalysts’ perfectly smooth surface. However, the microscopic catalytic processes occurring at the surface are still largely unclear because liquid metals escape the accessibility of traditional experimental and computational surface science approaches. Hence, numerous controversies are found regarding different applications, with graphene (Gr) growth on liquid copper (Cu) as a prominent prototype. In this work, novel in situ and in silico techniques are employed to achieve an atomic‐level characterization of the graphene adsorption height above liquid Cu, reaching quantitative agreement within 0.1 Å between experiment and theory. The results are obtained via in situ synchrotron X‐ray reflectivity (XRR) measurements over wide‐range q‐vectors and large‐scale molecular dynamics simulations based on efficient machine‐learning (ML) potentials trained to first‐principles density functional theory (DFT) data. The computational insight is demonstrated to be robust against inherent DFT errors and reveals the nature of graphene binding to be highly comparable at liquid Cu and solid Cu(111). Transporting the predictive first‐principles quality via ML potentials to the scales required for liquid metal catalysis thus provides a powerful approach to reach microscopic understanding, analogous to the established computational approaches for catalysis at solid surfaces.

BackgroundIndividuals with a prior Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection have a moderate to high degree of protection against reinfection, though seemingly less so when the Omicron variant of SARS-CoV-2 started to circulate. The aim of this study was to evaluate the vaccine effectiveness (VE) against SARS-CoV-2 reinfection, Coronavirus Disease 2019 (COVID-19)-related hospitalization, and COVID-19-related death, in individuals with prior SARS-CoV-2 infection, and to assess the effect of time since vaccination during periods with different dominant SARS-CoV-2 variants.Methods and findingsThis study used a nationwide cohort design including all individuals with a confirmed SARS-CoV-2 infection, who were alive, and residing in Denmark between 1 January 2020 and 31 January 2022. Using Danish nationwide registries, we obtained information on SARS-CoV-2 infections, COVID-19 vaccination, age, sex, comorbidity, staying at hospital, and country of origin. The study population included were individuals with prior SARS-CoV-2 infection. Estimates of VE against SARS-CoV-2 reinfection with 95% confidence intervals (CIs) were calculated using a Poisson regression model and adjusted for age, sex, country of origin, comorbidity, staying at hospital, calendar time, and test incidence using a Cox regression model. The VE estimates were calculated separately for three periods with different dominant SARS-CoV-2 variants (Alpha (B.1.1.7), Delta (B.1.617.2), or Omicron (B.1.1.529)) and by time since vaccination using unvaccinated as the reference. In total, 148,527 person-years and 44,192 SARS-CoV-2 infections were included for the analysis regarding reinfections. The study population comprised of 209,814 individuals infected before or during the Alpha period, 292,978 before or during the Delta period, and 245,530 before or during the Omicron period. Of these, 40,281 individuals had completed their primary vaccination series during the Alpha period (19.2%), 190,026 during the Delta period (64.9%), and 158,563 during the Omicron period (64.6%). VE against reinfection following any COVID-19 vaccine type administered in Denmark, peaked at 71% (95% CI: -Inf to 100%) at 104 days or more after vaccination during the Alpha period, 94% (95% CI: 92% to 96%) 14 to 43 days after vaccination during the Delta period, and 60% (95% CI: 58% to 62%) 14 to 43 days after vaccination during the Omicron period. Waning immunity following vaccination was observed and was most pronounced during the Omicron period. Due to too few events, it was not possible to estimate VE for hospitalization and death. Study limitations include potentially undetected reinfections, differences in health-seeking behavior, or risk behavior between the compared groups.ConclusionsThis study shows that in previously infected individuals, completing a primary vaccination series was associated with a significant protection against SARS-CoV-2 reinfection compared with no vaccination. Even though vaccination seems to protect to a lesser degree against reinfection with the Omicron variant, these findings are of public health relevance as they show that previously infected individuals still benefit from COVID-19 vaccination in all three variant periods.

BackgroundThe continued occurrence of more contagious Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants and waning immunity over time require ongoing reevaluation of the vaccine effectiveness (VE). This study aimed to estimate the effectiveness in 2 age groups (12 to 59 and 60 years or above) of 2 or 3 vaccine doses (BNT162b2 mRNA or mRNA-1273) by time since vaccination against SARS-CoV-2 infection and Coronavirus Disease 2019 (COVID-19) hospitalization in an Alpha-, Delta-, or Omicron-dominated period.Methods and findingsA Danish nationwide cohort study design was used to estimate VE against SARS-CoV-2 infection and COVID-19 hospitalization with the Alpha, Delta, or Omicron variant. Information was obtained from nationwide registries and linked using a unique personal identification number. The study included all previously uninfected residents in Denmark aged 12 years or above (18 years or above for the analysis of 3 doses) in the Alpha (February 20 to June 15, 2021), Delta (July 4 to November 20, 2021), and Omicron (December 21, 2021 to January 31, 2022) dominated periods. VE estimates including 95% confidence intervals (CIs) were calculated (1-hazard ratio∙100) using Cox proportional hazard regression models with underlying calendar time and adjustments for age, sex, comorbidity, and geographical region. Vaccination status was included as a time-varying exposure. In the oldest age group, VE against infection after 2 doses was 90.7% (95% CI: 88.2; 92.7) for the Alpha variant, 82.3% (95% CI: 75.5; 87.2) for the Delta variant, and 39.9% (95% CI: 26.3; 50.9) for the Omicron variant 14 to 30 days since vaccination. The VE waned over time and was 73.2% (Alpha, 95% CI: 57.1; 83.3), 50.0% (Delta, 95% CI: 46.7; 53.0), and 4.4% (Omicron, 95% CI: -0.1; 8.7) >120 days since vaccination. Higher estimates were observed after the third dose with VE estimates against infection of 86.1% (Delta, 95% CI: 83.3; 88.4) and 57.7% (Omicron, 95% CI: 55.9; 59.5) 14 to 30 days since vaccination. Among both age groups, VE against COVID-19 hospitalization 14 to 30 days since vaccination with 2 or 3 doses was 98.1% or above for the Alpha and Delta variants. Among both age groups, VE against COVID-19 hospitalization 14 to 30 days since vaccination with 2 or 3 doses was 95.5% or above for the Omicron variant. The main limitation of this study is the nonrandomized study design including potential differences between the unvaccinated (reference group) and vaccinated individuals.ConclusionsTwo vaccine doses provided high protection against SARS-CoV-2 infection and COVID-19 hospitalization with the Alpha and Delta variants with protection, notably against infection, waning over time. Two vaccine doses provided only limited and short-lived protection against SARS-CoV-2 infection with Omicron. However, the protection against COVID-19 hospitalization following Omicron SARS-CoV-2 infection was higher. The third vaccine dose substantially increased the level and duration of protection against infection with the Omicron variant and provided a high level of sustained protection against COVID-19 hospitalization among the +60-year-olds.

BackgroundThe number of single-living workers separated from their spouses and families has been increasing due to the need to create a balance between life and work. Workers are assigned everywhere in globalized workplaces while also caring for their family members in the context of Japan’s aging society. At the same time, the mental and health status of persons living separately from their families is a matter of concern. The development of interpersonal communication means using information and communications technology (ICT) tools and the internet is remarkable, enabling simultaneous 2-way communication across distances and national borders. The easy accessibility to simultaneous communication is expected to improve the psychosocial status of isolated family members. ObjectiveThis study aims to clarify the health benefits of ICT by using a psychosocial health assessment, the characteristics of ICT tools, and the frequency of communication among the workers and their families who live separately. MethodsThis was a cross-sectional study planned and conducted in Japan. Study participants, including adults who live separately from other family members or have separately living family members due to work, were recruited to answer a web response survey about ICT usage status, health status, and life and society evaluation. This study recruited 73 participants divided into 2 groups by their communication tools and frequencies, and their separated life, health, and psychosocial status were statistically compared. ResultsAmong the 73 study participants, 15 were categorized in the high communication–skilled (HCS) group that used both types of ICT tools to communicate frequently: “live,” such as video chat and voice call, and “nonlive,” such as SMS text message service and email. A simple comparison between the HCS and reference groups showed significant differences in the cohesion with the neighborhood (P=.03), perceived social position (P=.01), and happiness (P.99; current smoking, P=.37), and dyadic trust in family members living separately (P=.80). Further, in a multivariate regression analysis adjusted for confounding factors, such as educational history, age, gender, and job status, poor subjective health showed a prevalence odds ratio of less than 1 (OR 0.17, 95% CI 0.03-1.02). The HCS group showed significant positive relationships in the cohesion score with the neighborhood (P=.01; β=2.40, 95% CI 0.56-4.24), perceived social position (P=.03; β=1.17, 95% CI 0.11-2.23), and happiness score (P=.002; β=1.46, 95% CI 0.58-2.34) in the same multivariate regression models. ConclusionsThis study suggested that people who frequently communicate with separated family members by taking advantage of various ICT tools can maintain a better mental state and better social relations among those who live alone and are separated from their families.

Abstract As an immune evasion and survival strategy, the Plasmodium falciparum malaria parasite has evolved a protein named VAR2CSA. This protein mediates sequestration of infected red blood cells in the placenta through the interaction with a unique carbohydrate abundantly and exclusively present in the placenta. Cancer cells were found to share the same expression of this distinct carbohydrate, termed oncofetal chondroitin sulfate on their surface. In this study we have used a protein conjugation system to produce a bispecific immune engager, V-aCD3, based on recombinant VAR2CSA as the cancer targeting moiety and an anti-CD3 single-chain variable fragment linked to a single-chain Fc as the immune engager. Conjugation of these two proteins resulted in a single functional moiety that induced immune mediated killing of a broad range of cancer cells in vitro and facilitated tumor arrest in an orthotopic bladder cancer xenograft model.

Abstract Aim Antioxidant therapy for with vitamin E appears to be effective for the treatment of nonalcoholic fatty liver disease (NAFLD). However, the mechanism of action and optimal therapeutic dosage is unclear. The present study was undertaken to examine whether the effects of α‐tocopherol (α‐Toc) on NAFLD are dose‐dependent in a diet‐induced obese model. Methods Male mice were fed standard chow, high‐fat (HF) diet, HF diet with low‐dose, or with high dose of α‐Toc supplementation. Histological findings, triglyceride content, and the levels of protein expression related to fatty acid synthesis/oxidation such as carnitine palmitoyltransferase I (CPT‐1) of liver were evaluated. In addition, 2‐tetradecylglycidic acid (TDGA), a CPT‐1 inhibitor, was administered to mice fed HF diet with low‐dose of α‐Toc. Finally, HepG2 cells in fat‐loaded environment were treated with 0–50 μM α‐Toc. Results Treatment of low‐dose of α‐Toc decreased HF‐induced hepatic fat accumulation, but this finding was not observed in treatment of high dose of α‐Toc. HF‐induced reduction of CPT‐1 was attenuated with low‐dose of α‐Toc but not with high dose of α‐Toc. TDGA suppressed the improvement of histological findings in liver induced by low‐dose of α‐Toc treatment. CPT‐1 expression in HepG2 cells increased in response to low‐dose of α‐Toc, but not in high dose. Conclusions Dual action of α‐Toc on CPT‐1 protein levels was observed. The effect of vitamin E on NAFLD may be not be dose‐dependent.

Gastrointestinal stromal tumours (GISTs) are the most frequent mesenchymal tumours of the gastrointestinal tract, but they are rare in children. We report a case of a recurrent GIST that was first diagnosed in a 10 years old girl and underwent antrectomy. After 11 years, she again complained of vomiting and abdominal pain. Upper gastrointestinal endoscopy revealed a submucosal lesion in the posterior gastric wall. Computed tomography of the chest, abdomen and pelvis confirmed the absence of distant metastasis or enlarged lymph nodes. She underwent wide local excision with a safety margin and reconstruction. Pathologic examination of the excised mass confirmed the diagnosis of recurrent GIST. She is doing well without evidence of third recurrence or metastasis after 13 months of follow-up with a multidisciplinary team till present. GISTs are very uncommon in paediatric patients and patients should be managed in the context of a clinical trial and in tertiary centres familiar with the treatment of the disease.

BackgroundThe recommendations in several countries to stop using the ChAdOx1 vaccine has led to vaccine programs combining different Coronavirus Disease 2019 (COVID-19) vaccine types, which necessitates knowledge on vaccine effectiveness (VE) of heterologous vaccine schedules. The aim of this Danish nationwide population-based cohort study was therefore to estimate the VE against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and COVID-19-related hospitalization and death following the first dose of the ChAdOx1 vaccine and the combination of the ChAdOx1/mRNA vaccines.Methods and findingsAll individuals alive in or immigrating to Denmark from 9 February 2021 to 23 June 2021 were identified in the Danish Civil Registration System. Information on exposure, outcomes, and covariates was obtained from Danish national registries. Poisson and Cox regression models were used to calculate crude and adjusted VE, respectively, along with 95% confidence intervals (CIs) against SARS-CoV-2 infection and COVID-19-related hospitalization or death comparing vaccinated versus unvaccinated individuals. The VE estimates were adjusted for calendar time as underlying time and for sex, age, comorbidity, country of origin, and hospital admission. The analyses included 5,542,079 individuals (97.6% of the total Danish population). A total of 144,360 individuals were vaccinated with the ChAdOx1 vaccine as the first dose, and of these, 136,551 individuals received an mRNA vaccine as the second dose. A total of 1,691,464 person-years and 83,034 SARS-CoV-2 infections were included. The individuals vaccinated with the first dose of the ChAdOx1 vaccine dose had a median age of 45 years. The study population was characterized by an equal distribution of males and females; 6.7% and 9.2% originated from high-income and other countries, respectively. The VE against SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine was 88% (95% CI: 83; 92) 14 days after the second dose and onwards. There were no COVID-19-related hospitalizations or deaths among the individuals vaccinated with the combined vaccine schedule during the study period. Study limitations including unmeasured confounders such as risk behavior and increasing overall vaccine coverage in the general population creating herd immunity are important to take into consideration when interpreting the results.ConclusionsIn this study, we observed a large reduction in the risk of SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine, compared with unvaccinated individuals.

The discovery of new inorganic magnesium electrolytes may act as a foundation for the rational design of novel types of solid-state batteries. Here we investigated a new type of organic-inorganic metal hydride, isopropylamine magnesium borohydride, Mg(BH4)2∙(CH3)2CHNH2, with hydrophobic domains in the solid state, which appear to promote fast Mg2+ ionic conductivity. A new synthetic strategy was designed by combination of solvent-based methods and mechanochemistry. The orthorhombic structure of Mg(BH4)2∙(CH3)2CHNH2 was solved ab initio by the Rietveld refinement of synchrotron X-ray powder diffraction data and density functional theory (DFT) structural optimization in space group I212121 (unit cell, a = 9.8019(1) Å, b = 12.1799(2) Å and c = 17.3386(2) Å). The DFT calculations reveal that the three-dimensional structure may be stabilized by weak dispersive interactions between apolar moieties and that these may be disordered. Nanoparticles and heat treatment (at T > 56 °C) produce a highly conductive composite, σ(Mg2+) = 2.86 × 10−7, and 2.85 × 10−5 S cm−1 at −10 and 40 °C, respectively, with a low activation energy, Ea = 0.65 eV. Nanoparticles stabilize the partially eutectic molten state and prevent recrystallization even at low temperatures and provide a high mechanical stability of the composite.

Abstract Background This study investigates the effects of nano-curcumin on gene expression of insulin and insulin receptor in diabetic rats. Forty female rats were divided into four groups (ten rats for each). The first group was non-diabetic rats acting as negative control and rats of the second group were rendered diabetic by STZ served as positive controls. The third one was induced diabetic and received oral Diamicron for 3 weeks. The fourth was rendered diabetic and administrated oral nano-curcumin for 3 weeks. Results A significant increase of blood glucose was showed in diabetic rats with significant reduction of insulin level compared to non-diabetic controls. The gene expression of insulin and insulin receptor were more significant in diabetic untreated rats compared to the control non-diabetic group. The induction of curcumin as well as Diamicron to diabetic rats normalized significantly their blood sugar level. Also, curcumin-treated rats indicated significant higher in gene expression of insulin and insulin receptor than positive and negative controls. Conclusion The results suggest that nano-curcumin could be used as antidiabetic therapy, induced hypoglycemia, and increase the gene expression of insulin and insulin receptor in STZ-induced diabetic rats. More studies are needed to illustrate the definite mechanism of action of nano-curcumin concerning the upregulation of gene expression of the above-mentioned genes.

Breast cancer is the most common cancer in females, it accounts for one third of all malignancies affecting women. Appropriate biomarkers play significant role in predicting the prognosis and decide the specific therapy to each patient. In this study we aimed at evaluating the value of Ki-67 as a prognostic marker in breast cancer patients and to analyze the associations between Ki-67 and their clinicopathological parameters. This study included 92 patients with developed non metastatic breast cancer and 10 women had benign breast tumor served as controls. We measured the serum level by ELISA technique and tissue expression of Ki-67 by immunohistochemical technique. Our results showed that there were no statistically significant differences in serum Ki-67 levels between the two studied groups. As for Ki-67expression in breast cancer cells, the score increases with increase of tumor size, grade, premenopausal, Ki-67 expression in estrogen and progesterone receptor positive tumors showed lower values than estrogen and progesterone negative tumors, while higher Ki-67 expression was more frequently associated with HER2-positive. In conclusion; our study supports the finding that tissue Ki-67 expression may add prognostic information to that obtained from classical prognostic factors and can provide data of significant value to other important prognostic indicators such as pathological grading, and axillary lymph node involvement. Keywords: Ki-67, Immunohistochemistry, Breast carcinoma, Tumor grade, Prognosis, Cell proliferation

Abstract Background Type 1 diabetes mellitus (T1DM) is a chronic inflammatory disease concerning insulin-producing β-cells destroyed by the conjoined action of auto reactive T cells, inflammatory cytokines and monocytic cells. Recent proof favors crucial role of cellular autoimmunity as well as its mediators in pathogenesis and following T1DM. We aimed to investigate whether IL-1α, IL-1β, or IL-10 an easily available inflammatory marker is associated with T1DM. Results The onset of T1DM was accompanied with elevation serum levels of IL-1α, IL-1β, and IL-10. ROC curve revealed that IL10 > 5.95 pg/ml predicted T1DM with sensitivity and specificity of 96% and 90%, respectively. Conclusion The raise of serum inflammatory cytokines such as IL-1α, IL-1β, and IL-10 of the patient may be exploited as potential markers for development of T1DM. The study proposes that level of inflammatory markers is upregulated in T1DM individual in an age-dependent manner and suggesting activation of the inflammatory immune response system.

Background and aims: Nonalcoholic fatty liver disease (NAFLD) is a complicated disease linked with dietary habitats, obesity, and a range of comorbidities correlated with insulin resistance.Although environmental parameters are essential in deciding risk of the disease, proofs from previous reports sustain the hypothesis that genetics are responsible for NAFLD developmentand progression. Plasma cell antigen-1 (PC-1) and its gene polymorphism are associated with NAFLD progression. Consequently, the object of this study was to detect the usefulness of PC-1 K121Q gene polymorphism in NAFLD progression. Subjects and methods: A total of 87 NAFLD patients were included in the study and subdivided ultrasonographically into 31 patients with grade 1 (mild NAFLD), 26 patients with grade 2 (moderate NAFLD) and 30 patients with grade 3 (severe NAFLD), in addition to 47 normal controls. The detection of PC-1 K121Q gene polymorphism was accomplished by using restriction fragment length polymorphism (RFLP)-PCR. Results: Lipid profile parameters were associated with the incidence of NAFLD. AlthoughPC-1 gene polymorphism didnot significantly change in parallel with NAFLD grades, PC-1 at the genetic and protein level was significantly associated with triacylglycerollevels in NAFLD patients. Conclusion: Lipid profile indices are risk factors for the incidence of NAFLD. Triacylglycerol (TAG) level is the hall-mark in the NAFLD pathogenesis and in the predisposition of PC-1 gene polymorphism. Keywords: NAFLD, Triacylglycerol (TAG), Plasma cell antigen-1 (PC-1)

Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs. This imbalance necessitates LMIC-focused research to ensure that characterization of dementia accurately reflects the involvement and specificities of diverse populations. Development of effective preventive, diagnostic, and therapeutic approaches for dementia in LMICs requires targeted, personalized, and harmonized efforts. Our article represents timely discussions at the 2022 Symposium on Dementia and Brain Aging in LMICs that identified the foremost opportunities to advance dementia research, differential diagnosis, use of neuropsychometric tools, awareness, and treatment options. We highlight key topics discussed at the meeting and provide future recommendations to foster a more equitable landscape for dementia prevention, diagnosis, care, policy, and management in LMICs. HIGHLIGHTS: Two-thirds of persons with dementia live in LMICs, yet research and costs are skewed toward HICs. LMICs expect dementia prevalence to more than double, accompanied by socioeconomic disparities. The 2022 Symposium on Dementia in LMICs addressed advances in research, diagnosis, prevention, and policy. The Nairobi Declaration urges global action to enhance dementia outcomes in LMICs.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

Using student evaluations of teaching (SETs) as a quality assessment tool have long been a highly debated topic among both practitioners and scholars of higher education teaching. Rather than focus on whether SETs provide reliable measurements of quality, we explore what happens when SETs are implemented as or intended as quality development tools. We report from a qualitative study of how higher education teachers and managers perceive and use SETs as part of developing their own teaching, and focus on how the dialogue around teaching, which was intended as a part of the quality assessment procedure, is actualized (or not) in practice.

Background: Stem cells therapy is a new therapeutic approach for pulmonary emphysema. Granulocyte colony-stimulating factor (G-CSF) is effective in tissue regeneration through mobilization of stem cells to different organs. So, in this study we compared the effect of filgrastim (175 amino acid recombinant human G-CSF) versus bone marrow mononuclear cells on apoptosis and repair of air spaces in lipopolysaccharide induced emphysema in C57Bl/6 mice. Methods: The mice were classified into 4 groups: group A: mice not received any treatment, group B: mice received intranasal instillation of lipopolysaccharide repeated three times per week for 8 weeks, group C: mice received a dose of intravenous bone marrow mononuclear cells (0.3 ml of cell suspension at a concentration of 2 × 106 cells/ml) after instillation and evaluated 5 weeks later and group D: mice received subcutaneous filgrastim three subcutaneous injections a week for 7 weeks (100 microgram/kg/injection) after lipopolysaccharide instillation. Imaging analysis was done using imagej program. Results: Concerning the mean of air space equivalent diameter (D0) and (D1), no differences were observed between the bone marrow mononuclear cells treated mice and filgrastim treated mice. As regard apoptotic index, no significant difference was found between filgrastim and BMMNCs treated groups. Conclusion: These results indicate nearly similar effectiveness of both filgrastim and BMMNCs in treatment of lipopolysaccharide induced pulmonary emphysema.

The aim of the present study is to evaluate the association of serum uric acid (UA) levels with the risk of incident hypertension among different age groups in men and women using a single large Japanese general cohort. The present study is based on annual health check-up program in Gunma, Japan. We studied 12,029 participants (mean age, 48 ​± ​9 years old; 31% women) free of prevalent cardiovascular disease and hypertension at baseline (2009). Hypertension was defined by self-report, hypertensive medication use, or measured BP ​> ​140/90 ​mmHg ​at each visit. Discrete proportional hazards regression model was used to evaluate the association of UA level at baseline with incident hypertension through 2012 adjusted for age, gender, baseline blood pressure, and other CVD risk factors among different age decade groups in men and women. During follow-up of 3 years, 12% of the cohort (n ​= ​1457) developed hypertension. UA was strongly associated with incident hypertension in the multivariable model in all participants. In age-stratified analysis, participants below 50 years of age in men had the significant association of UA with incident hypertension, whereas participants above 50 years did not. In women, participants above 40 years had the significant association, whereas participants below 40 years did not. The present data suggest that UA level is an independent predictor for incident hypertension among middle aged men below 50 years old and middle aged and the elderly women above 40 years.

This review article is intended as a practical guide for newcomers to the field of kinetic Monte Carlo (KMC) simulations, and specifically to lattice KMC simulations as prevalently used for surface and interface applications. We will provide worked out examples using the kmos code, where we highlight the central approximations made in implementing a KMC model as well as possible pitfalls. This includes the mapping of the problem onto a lattice and the derivation of rate constant expressions for various elementary processes. Example KMC models will be presented within the application areas surface diffusion, crystal growth and heterogeneous catalysis, covering both transient and steady-state kinetics as well as the preparation of various initial states of the system. We highlight the sensitivity of KMC models to the elementary processes included, as well as to possible errors in the rate constants. For catalysis models in particular, a recurrent challenge is the occurrence of processes at very different timescales, e.g., fast diffusion processes and slow chemical reactions. We demonstrate how to overcome this timescale disparity problem using recently developed acceleration algorithms. Finally, we will discuss how to account for lateral interactions between the species adsorbed to the lattice, which can play an important role in all application areas covered here.