UNASSIGNED: To assess leukemia risk in occupational populations exposed to low levels of benzene.
UNASSIGNED: Leukemia incidence data from the Chinese Benzene Cohort Study were fitted using the Linearized multistage (LMS) model. Individual benzene exposure levels, urinary S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t, t-MA) were measured among 98 benzene-exposed workers from factories in China. Subjects were categorized into four groups by rounding the quartiles of cumulative benzene concentrations (< 3, 3-5, 5-12, ≥12 mg/m3·year, respectively). The risk of benzene-induced leukemia was assessed using the LMS model, and the results were validated using the EPA model and the Singapore semi-quantitative risk assessment model.
UNASSIGNED: The leukemia risks showed a positive correlation with increasing cumulative concentration in the four exposure groups (excess leukemia risks were 4.34, 4.37, 4.44 and 5.52 × 10-4, respectively; Ptrend < 0.0001) indicated by the LMS model. We also found that the estimated leukemia risk using urinary t, t-MA in the LMS model was more similar to those estimated by airborne benzene compared to S-PMA. The leukemia risk estimated by the LMS model was consistent with both the Singapore semi-quantitative risk assessment model at all concentrations and the EPA model at high concentrations (5-12, ≥12 mg/m3·year), while exceeding the EPA model at low concentrations (< 3 and 3-5 mg/m3·year). However, in all four benzene-exposed groups, the leukemia risks estimated by these three models exceeded the lowest acceptable limit for carcinogenic risk set by the EPA at 1 × 10-6.
UNASSIGNED: This study demonstrates the utility of the LMS model derived from the Chinese benzene cohort in assessing leukemia risk associated with low-level benzene exposure, and suggests that leukemia risk may occur at cumulative concentrations below 3 mg/m3·year.

Harness® is a commercial herbicide that contains acetochlor at a concentration of 84% as an active ingredient. Ubiquitous, persistent, and substantial uses of Harness® in agricultural processes have resulted in the pollution of nearby water sources, posing a threat to various aquatic biotas, including fish. The effects of Harness® toxicity on fish health are little known. So, this study aimed to describe the impact of herbicide Harness® on the oxidative stress and reproductive and thyroid performance of male and female tilapia (Oreochromis niloticus) and also investigate the prospective role of the natural antioxidant lycopene supplementation in dismissing the adverse properties of Harness®. Antioxidant enzyme (catalase, superoxide dismutase, and total antioxidant capacity) and hormone measurements (T, E2, T3, and T4) were carried out, and gonadal and thyroid follicle histological sections were examined as a method to investigate the effects of Harness® toxicity on fish. Male and female tilapia were exposed to 10 μmol/L and 100 μmol/L of Harness® and treated with 10 mg lycopene/kg for 15 days of exposure. Our results demonstrated that the antioxidant enzyme activity was altered by Harness exposure and serum T for both males and females dropped; also, female E2 levels decreased, but male E2 increased. Exposure to higher dose of Harness® induced elevation in both T3 and T4 levels, although the low exposure dose stimulated T4 levels. Harness® exposure prompted histological variations and degenerative changes in testicular, ovarian, and thyroid follicle tissues. Lycopene supplement administration diminished oxidative stress induced by Harness®, alleviating its endocrine disparaging effects by neutralizing T3, T4, T, and E2 and ameliorating the histological structure of gonadal and thyroid tissues. In conclusion, lycopene supplementation was preformed to normalize the alterations and oxidative damage caused by Harness® in Nile tilapia, suggesting that lycopene-supplemented diet functioned as potent antioxidants and had the ability to alleviate oxidative stress and thyroid and reproductive toxicity caused by herbicide Harness®. Moreover, it is crucial to take appropriate care when consuming herbicides to defend the aquatic environment.

The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 T cell progenitors that differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

UNASSIGNED: The present research aimed to study the relationship between body mass index (BMI), sex hormones, leptin, and irisin in children and adolescents with different body types.
UNASSIGNED: In this study, a stratified cluster random sampling method was used to select students aged 8-15 years from two 9-year schools as the research subjects. Based on a case-control study, 183 overweight/obese students were selected. After using sex and age matching to create a matched sample of normal-weighted students, a total of 366 students, including 214 boys (58.5%) and 152 girls (41.5%) were included. We measured their height and weight and calculated their body mass index BMI. Afterward, their concentrations of leptin, irisin, oestradiol (E2), and testosterone (T) in the serum were detected.
UNASSIGNED: There were significant differences in T, E2, leptin, and irisin between normal-weighted boys and girls (p < 0.05). There were statistically significant differences in T, E2, and irisin between overweight/obese boys and girls (p < 0.05). Overweight/obese students had higher concentrations of irisin and leptin than normal-weight students (p < 0.05). The direct effect of BMI on irisin was not statistically significant in either normal or overweight/obese students, but their indirect effects via leptin were statistically significant (for normal-weight boys and girls, standardized indirect effect coefficient: 0.29 and 0.38, respectively; for overweight/obese boys and girls, standardized indirect effect coefficient: 0.36 and 0.34, respectively). There was a negative pathway of E2 → leptin → irisin in normal-weight boys (standardized indirect effect coefficient: -0.24) and a negative pathway of T → leptin → irisin in overweight/obese boys (standardized indirect effect coefficient: -0.27).
UNASSIGNED: The indirect effects of BMI on irisin via leptin exist in children and adolescents of different body types. E2 was negatively correlated with leptin in normal-weight boys, whereas T was negatively correlated with leptin in overweight/obese boys.

Human herpesvirus 6 (HHV-6) reactivation can occur in patients who are highly immunosuppressed, including those who have undergone hematopoietic stem cell transplantation (HSCT). HHV-6 encephalitis is a severe manifestation that is well described in the HSCT population. Chimeric antigen receptor T-cell (CAR-T) therapy is a novel cancer-directed immunotherapy that results in severe immunosuppression. Patients undergoing CAR-T therapy may be at risk for HHV-6 encephalitis, which can be difficult to distinguish from a common adverse effect of CAR-T therapy, neurotoxicity. Herein, we describe 2 patients diagnosed with HHV-6 encephalitis after CAR-T therapy and discuss the diagnostic approach and differential diagnosis for altered mental status after CAR-T therapy. Diagnosing HHV-6 encephalitis can be difficult in this patient population as altered mental status is common after CAR-T therapy and may be attributed to CAR-T-associated neurotoxicity.

Schuurs-Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopmental disorder is a rare disorder characterized by intellectual disability, abnormal craniofacial features and congenital malformations. SHMS is an autosomal dominant hereditary disease caused by pathogenic variants in the PACS1 gene. PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth. So far, only 54 patients with SHMS have been reported. In this work, we report on seven new identified SHMS individuals with the classical c.607C > T: p.Arg206Trp PACS1 pathogenic variant and review clinical and molecular aspects of all the patients reported in the literature, providing a summary of clinical findings grouped as very frequent (≥75% of patients), frequent (50-74%), infrequent (26-49%) and rare (less than ≤25%).

Muscular dystrophies are a group of heterogeneous clinical and genetic disorders. Two siblings presented with characteristics like muscular dystrophy, abnormal white matter, and elevated serum creatine kinase level. The high throughput of whole exome sequencing (WES) makes it an efficient tool for obtaining a precise diagnosis without the need for immunohistochemistry. WES was performed in the two siblings and their parents, followed by prioritization of variants and validation by Sanger sequencing. Very rare variants with moderate to high predicted impact in genes associated with neuromuscular disorders were selected. We identified two pathogenic missense variants, c.778C>T (p.H260Y) and c.2987G>A (p.C996Y), in the LAMA2 gene (NM_000426.3), in the homozygous state in two siblings, and in the heterozygous state in their unaffected parents, which were confirmed by Sanger sequencing. Variant c.2987G>A has not been reported previously. These variants may lead to a change in the structure and function of laminin-α2, a member of the family of laminin-211, which is an extracellular matrix protein that functions to stabilize the basement membrane of muscle fibers during contractions. Overall, WES enabled an accurate diagnosis of both patients with LAMA2-related muscular dystrophy and expanded the spectrum of missense variants in LAMA2.

The mouse T-box transcription factors T and Tbx6 are co-expressed in the primitive streak and have unique domains of expression; T is expressed in the notochord, while Tbx6 is expressed in the presomitic mesoderm. T-box factors are related through a shared DNA binding domain, the T-domain, and can therefore bind to similar DNA sequences at least in vitro We investigated the functional similarities and differences of T and Tbx6 DNA binding and transcriptional activity in vitro and their interaction genetically in vivo We show that at one target, Dll1, the T-domains of T and Tbx6 have different affinities for the binding sites present in the mesoderm enhancer. We further show using in vitro assays that T and Tbx6 differentially affect transcription with Tbx6 activating expression tenfold higher than T, that T and Tbx6 can compete at target gene enhancers, and that this competition requires a functional DNA binding domain. Next, we addressed whether T and Tbx6 can compete in vivo First, we generated embryos that express Tbx6 at greater than wild-type levels embryos and show that these embryos have short tails, resembling the T heterozygous phenotype. Next, using the dominant-negative TWis allele, we show that Tbx6+/- TWis/+ embryos share similarities with embryos homozygous for the Tbx6 hypomorphic allele rib-vertebrae, specifically fusions of several ribs and malformation of some vertebrae. Finally, we tested whether Tbx6 can functionally replace T using a knockin approach, which resulted in severe T null-like phenotypes in chimeric embryos generated with ES cells heterozygous for a Tbx6 knockin at the T locus. Altogether, our results of differences in affinity for DNA binding sites and transcriptional activity for T and Tbx6 provide a potential mechanism for the failure of Tbx6 to functionally replace T and possible competition phenotypes in vivo.

Port workers are exposed to a wide range of occupational hazards that can cause injuries and occupational diseases. Among these, exposure to benzene is one of the most important but least studied. The highest occupational exposures for port workers occur during the filling and loading of gasoline, and cleaning of tanks and receptacles. The aim of the study was to evaluate occupational exposure to low levels of benzene by measuring trans,trans-muconic acid (t,t-MA) in urine samples from workers operating at fuelling stations in a tourist port of Southern Italy. The overall sample was composed of 43 port workers of a tourist port in Southern Italy. In 2018, each participant provided two (morning and evening) urine samples for the determination of urinary t,t-MA. Urinary excretion of t,t-MA was always higher at the end of the work shift than at the beginning with significant difference (p = 0.002). In smokers, median t,t-MA urinary excretion is higher than non-smokers both at the beginning (90.5 μg/g creatinine vs. 61.45 μg/g creatinine) and at the end of the work shift (128.2 μg/g creatinine vs. 89.5 μg/g creatinine). Urinary excretion of t,t-MA is higher at the end of the work shift than at the beginning in both smokers and non-smokers, but the difference is significantly higher in non-smokers (p = 0.003) than in smokers (p = 0.05). In conclusion, our results showed that the role of inhaled benzene at fuelling stations in a tourist port can be relevant. On the basis of these results and the known adverse effects of benzene on human health, we encourage the use of personal protective equipment in the fuelling area of ports in order to minimize exposure to benzene to workers.

OBJECTIVE: Temporomandibular joint has been considered one of the most complex joints in human body. Dental articulation hinged upon temporomandibular joint is essential and fundamentally important for dental restoration design and prosthetic/orthodontic occlusion analysis. As digital dentistry rapidly grows, a complete digital work flow requires the use of a digital articulator for occlusion analysis. However, commercial CAD/CAM systems do not provide any method to verify the modeling accuracy of a digital articulator. There is also a lack of detail and generalized mathematical modeling of the digital articulator for simulating the jaw movement.
METHODS: This paper presents the development of a digital articulator by mathematically modeling a general dental articulator which simulates the relative jaw motion between the maxilla and mandible. As the digital articulator moves, the digital upper teeth move relatively to the digital lower teeth, thus simulating the occlusal path with teeth collision detection function. To verify the accuracy of our modeled digital articulator, an improved optical tracking method is proposed to measure the pose of a mechanical articulator with 6 degrees of freedom and compare that with the digital articulator.
RESULTS: The digital articulator system proposed in this paper achieves the following functions: 1. Digitalize the dental articulator with verified precision. Combined with dental design software, restorations can be designed with more efficiency and accuracy. 2. Provide an improved optical tracking method which can compare the movement error between the mechanical articulator and digital articulator. Thus the accuracy of the digital articulation can be verified. The result shows the error of our system is controlled under sub-millimeter which provides sufficient accuracy for the design of restoration under static and dynamic occlusion conditions.
CONCLUSIONS: We develop a general digital articulator which can simulate jaw movement between opposing teeth and an improved optical tracking method to verify the accuracy of the digital articulator. The modeling and accuracy verification of the digital articulator shows that there is a systematic and reliable way to replace traditional mechanical articulator and can close the gap for digital restoration fabrication.