3D genomic mapping reveals multifocality of human pancreatic precancers.

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.

Unveiling the emerging role of curcumin to alleviate ochratoxin A-induced muscle toxicity in grass carp (Ctenopharyngodon idella): in vitro and in vivo studies.

BACKGROUND: Ochratoxin A (OTA), a globally abundant and extremely hazardous pollutant, is a significant source of contamination in aquafeeds and is responsible for severe food pollution. The developmental toxicity of OTA and the potential relieving strategy of natural products remain unclear. This study screened the substance curcumin (Cur), which had the best effect in alleviating OTA inhibition of myoblast proliferation, from 96 natural products and investigated its effect and mechanism in reducing OTA myotoxicity in vivo and in vitro. METHODS: A total of 720 healthy juvenile grass carp, with an initial average body weight of 11.06 ± 0.05 g, were randomly assigned into 4 groups: the control group (without OTA and Cur), 1.2 mg/kg OTA group, 400 mg/kg Cur group, and 1.2 mg/kg OTA + 400 mg/kg Cur group. Each treatment consisted of 3 replicates (180 fish) for 60 d. RESULTS: Firstly, we cultured, purified, and identified myoblasts using the tissue block culture method. Through preliminary screening and re-screening of 96 substances, we examined cell proliferation-related indicators such as cell viability and ultimately found that Cur had the best effect. Secondly, Cur could alleviate OTA-inhibited myoblast differentiation and myofibrillar development-related proteins (MyoG and MYHC) in vivo and in vitro and improve the growth performance of grass carp. Then, Cur could also promote the expression of OTA-inhibited protein synthesis-related proteins (S6K1 and TOR), which was related to the activation of the AKT/TOR signaling pathway. Finally, Cur could downregulate the expression of OTA-enhanced protein degradation-related genes (murf1, foxo3a, and ub), which was related to the inhibition of the FoxO3a signaling pathway. CONCLUSIONS: In summary, our data demonstrated the effectiveness of Cur in alleviating OTA myotoxicity in vivo and in vitro. This study confirms the rapidity, feasibility, and effectiveness of establishing a natural product screening method targeting myoblasts to alleviate fungal toxin toxicity.

Delayed hearing loss after cochlear implantation: Re-evaluating the role of hair cell degeneration.

Delayed loss of residual acoustic hearing after cochlear implantation is a common but poorly understood phenomenon due to the scarcity of relevant temporal bone tissues. Prior histopathological analysis of one case of post-implantation hearing loss suggested there were no interaural differences in hair cell or neural degeneration to explain the profound loss of low-frequency hearing on the implanted side (Quesnel et al., 2016) and attributed the threshold elevation to neo-ossification and fibrosis around the implant. Here we re-evaluated the histopathology in this case, applying immunostaining and improved microscopic techniques for differentiating surviving hair cells from supporting cells. The new analysis revealed dramatic interaural differences, with a > 80 % loss of inner hair cells in the cochlear apex on the implanted side, which can account for the post-implantation loss of residual hearing. Apical degeneration of the stria further contributed to threshold elevation on the implanted side. In contrast, spiral ganglion cell survival was reduced in the region of the electrode on the implanted side, but apical counts in the two ears were similar to that seen in age-matched unimplanted control ears. Almost none of the surviving auditory neurons retained peripheral axons throughout the basal half of the cochlea. Relevance to cochlear implant performance is discussed.

Functional Exercise Capacity and Perceived Exertion in Patients with Empty Nose Syndrome.

Empty nose syndrome (ENS) is a complex condition characterized by symptoms such as dyspnea, nasal discomfort, and emotional challenges. This study aimed to evaluate functional exercise capacity and perceived exertion in patients with ENS. Patients with ENS who presented with a range of severe symptoms were prospectively enrolled. Pulmonary function was evaluated using spirometry, and functional exercise capacity was measured via the 6 min walk test (6-MWT). Perceived exertion was quantified using the Borg scale, and cardiopulmonary function was evaluated by monitoring peripheral oxygen saturation (SpO2). These parameters were assessed before and after nasal reconstruction surgery. A total of 44 patients with ENS were enrolled and classified into mild-to-moderate (n = 20) and severe (n = 24) symptom groups. Spirometry results showed no significant differences before and after surgery in the entire cohort. Perceived exertion showed significant postoperative improvement (p = 0.006). The severe ENS symptom group experienced significant improvement in SpO2 (p = 0.013) and perceived exertion (p = 0.002) at the end of the 6-MWT after surgery. Surgical intervention significantly enhanced functional exercise capacity (p = 0.038) in patients with mild-to-moderate ENS symptoms. Surgical reconstruction positively affected perceived exertion and SpO2 at the end of the 6-MWT in patients with ENS. The severity of ENS symptoms, as assessed by SNOT-25 scores, influenced these outcomes. These findings underscore the potential benefits of surgical intervention for enhancing exercise tolerance and respiratory efficiency.

On the Difficulty Predicting Word Recognition Performance After Cochlear Implantation.

HYPOTHESIS: Preimplantation word scores cannot reliably predict postimplantation outcomes. BACKGROUND: To date, there is no model based on preoperative data that can reliably predict the postoperative outcomes of cochlear implantation in the postlingually deafened adult patient. METHODS: In a group of 228 patients who received a cochlear implant between 2002 and 2021, we tested the predictive power of nine variables (age, etiology, sex, laterality of implantation, preimplantation thresholds and word scores, as well as the design, insertion approach, and angular insertion depth of the electrode array) on postimplantation outcomes. Results of multivariable linear regression analyses were then interpreted in light of data obtained from histopathological analyses of human temporal bones. RESULTS: Age and etiology were the only significant predictors of postimplantation outcomes. In agreement with many investigations, preimplantation word scores failed to significantly predict postimplantation outcomes. Analysis of temporal bone histopathology suggests that neuronal survival must fall below 40% before word scores in quiet begin to drop. Scores fall steeply with further neurodegeneration, such that only 20% survival can support acoustically driven word scores of 50%. Because almost all cochlear implant implantees have at least 20% of their spiral ganglion neurons (SGNs) surviving, it is expected that most cochlear implant users on average should improve to at least 50% word recognition score, as we observed, even if their preimplantation score was near zero as a result of widespread hair cell damage and the fact that ~50% of their SGNs have likely lost their peripheral axons. These "disconnected" SGNs would not contribute to acoustic hearing but likely remain electrically excitable. CONCLUSION: The relationship between preimplantation word scores and data describing the survival of SGNs in humans can explain why preimplantation word scores obtained in unaided conditions fail to predict postimplantation outcomes.

Synthesis and Characterization of MnIn2S4/Single-Walled Carbon Nanotube Composites as an Anode Material for Lithium-Ion Batteries.

In this study, we synthesized a transition metal sulfide (TMS) with a spinel structure, i.e., MnIn2S4 (MIS), using a two-step hydrothermal and sintering process. In the context of lithium-ion battery (LIB) applications, ternary TMSs are being considered as interesting options for anode materials. This consideration arises from their notable attributes, including high theoretical capacity, excellent cycle stability, and cost-effectiveness. However, dramatic volume changes result in the electrochemical performance being severely limited, so we introduced single-walled carbon nanotubes (SWCNTs) and prepared an MIS/SWCNT composite to enhance the structural stability and electronic conductivity. The synthesized MIS/SWCNT composite exhibits better cycle performance than bare MIS. Undergoing 100 cycles, MIS only yields a reversible capacity of 117 mAh/g at 0.1 A/g. However, the MIS/SWCNT composite exhibits a reversible capacity as high as 536 mAh/g after 100 cycles. Moreover, the MIS/SWCNT composite shows a better rate capability. The current density increases with cycling, and the SWCNT composite exhibits high reversible capacities of 232 and 102 mAh/g at 2 A/g and 5 A/g, respectively. Under the same conditions, pristine MIS can only deliver reversible capacities of 21 and 4 mAh/g. The results indicate that MIS/SWCNT composites are promising anode materials for LIBs.

Nd:YAG water mist laser treatment for giant gestational gingival tumor: A case report.

BACKGROUND: This case of gestational gingival tumor is huge and extremely rare in clinical practice. As the growth location of this gingival tumor is in the upper anterior tooth area, it seriously affects the pregnant woman's speech and food, causing great pain to the patient. The use of Nd:YGA water mist laser to remove the gingival tumor resulted in minimal intraoperative bleeding, minimal adverse reactions, and good postoperative healing, which is worthy of clinical promotion and application. CASE SUMMARY: The patient, a pregnant woman, reported a large lump in her mouth on the first day of postpartum treatment. Based on medical history and clinical examination, the diagnosis was diagnosed as gestational gingival tumor. Postoperative pathological biopsy also confirmed this diagnosis. The use of Nd:YAG water mist laser to remove the tumor resulted in minimal intraoperative bleeding, clear surgical field of view, short surgical time, and good postoperative healing. CONCLUSION: In comparison to traditional surgery, Nd:YAG water mist laser surgery is minimally invasive, minimizes cell damage, reduces bleeding, ensures a clear field of vision, and virtually eliminates postoperative edema, carbonization, and the risk of cross infection. It has unique advantages in oral soft tissue surgery for pregnant patients. Therefore, the clinical application of Nd:YAG water mist laser for the treatment of gestational gingival tumors is an ideal choice.

Genetic underpinnings explored: OPA1 deletion and complex phenotypes on chromosome 3q29.

BACKGROUND: Copy number variations (CNVs) have emerged as significant contributors to the elusive genetic causality of inherited eye diseases. In this study, we describe a case with optic atrophy and a brain aneurysm, in which a de novo CNV 3q29 deletion was identified. CASE PRESENTATION: A 40-year-old female patient was referred to our department after undergoing aneurysm transcatheter arterial embolization for a brain aneurysm. She had no history of systemic diseases, except for unsatisfactory best-corrected visual acuity (BCVA) since elementary school. Electrophysiological tests confirmed the findings in retinal images, indicating optic nerve atrophy. Chromosomal microarray analysis revealed a de novo deletion spanning 960 kb on chromosome 3q29, encompassing OPA1 and six neighboring genes. Unlike previously reported deletions in this region associated with optic atrophy, neuropsychiatric disorders, and obesity, this patient displayed a unique combination of optic atrophy and a brain aneurysm. However, there is no causal relationship between the brain aneurysm and the CNV. CONCLUSION: In conclusion, the optic atrophy is conclusively attributed to the OPA1 deletion, and the aneurysm could be a coincidental association. The report emphasizes the likelihood of underestimating OPA1 deletions due to sequencing technology limitations. Recognizing these constraints, healthcare professionals must acknowledge these limitations and consistently search for OPA1 variants/deletions in Autosomal Dominant Optic Atrophy (ADOA) patients with negative sequencing results. This strategic approach ensures a more comprehensive exploration of copy-number variations, ultimately enhancing diagnostic precision in the field of genetic disorders.

Declined flesh quality resulting from niacin deficiency is associated with elevated glycolysis and impaired mitochondrial homeostasis in grass carp (Ctenopharyngodon idella).

Energy metabolism exerts profound impacts on flesh quality. Niacin can be transformed into nicotinamide adenine dinucleotide (NAD), which is indispensable to energy metabolism. To investigate whether niacin deficiency could affect energy metabolism and flesh quality, six diets with graded levels of 0.49, 9.30, 21.30, 33.30, 45.30 and 57.30 mg/kg niacin were fed to grass carp (Ctenopharyngodon idella) for 63 days. The results showed that niacin deficiency declined flesh quality by changing amino acid and fatty acid profiles, decreasing shear force, increasing cooking loss and accelerating pH decline. The accelerated pH decline might be associated with enhanced glycolysis as evident by increased hexokinase (HK), pyruvate kinase (PK) and lactic dehydrogenase (LDH) activities, and mitochondrial dysfunction as evident by destroyed mitochondrial morphology, impaired respiratory chain complex I and antioxidant ability. Based on PWG and cooking loss, the niacin requirements for sub-adult grass carp were 31.95 mg/kg and 29.66 mg/kg diet, respectively.

LAMC1 attenuates neuronal apoptosis via FAK/PI3K/AKT signaling pathway after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The poor prognosis in patients with subarachnoid hemorrhage (SAH) is often attributed to neuronal apoptosis. Recent evidence suggests that Laminin subunit gamma 1 (LAMC1) is essential for cell survival and proliferation. However, the effects of LAMC1 on early brain injury after SAH and the underlying mechanisms are unknown. The current study aimed to reveal the anti-neuronal apoptotic effect and the potential mechanism of LAMC1 in the rat and in the in vitro SAH models. METHODS: The SAH model of Sprague-Dawley rats was established by endovascular perforation. Recombinant LAMC1 (rLAMC1) was administered intranasally 30 min after modeling. LAMC1 small interfering RNA (LAMC1 siRNA), focal adhesion kinase (FAK)-specific inhibitor Y15 and PI3K-specific inhibitor LY294002 were administered before SAH modeling to explore the neuroprotection mechanism of rLAMC1. HT22 cells were cultured and stimulated by oxyhemoglobin to establish an in vitro model of SAH. Subsequently, SAH grades, neurobehavioral tests, brain water content, blood-brain barrier permeability, western blotting, immunofluorescence, TUNEL, and Fluoro-Jade C staining were performed. RESULTS: The expression of endogenous LAMC1 was markedly decreased after SAH, both in vitro and in vivo. rLAMC1 significantly reduced the brain water content and blood-brain barrier permeability, improved short- and long-term neurobehavior, and decreased neuronal apoptosis. Furthermore, rLAMC1 treatment significantly increased the expression of p-FAK, p-PI3K, p-AKT, Bcl-XL, and Bcl-2 and decreased the expression of Bax and cleaved caspase -3. Conversely, knockdown of endogenous LAMC1 aggravated the neurological impairment, suppressed the expression of Bcl-XL and Bcl-2, and upregulated the expression of Bax and cleaved caspase-3. Additionally, the administration of Y15 and LY294002 abolished the protective roles of rLAMC1. In vitro, rLAMC1 significantly reduced neuronal apoptosis, and the protective effects were also abolished by Y15 and LY294002. CONCLUSION: Exogenous LAMC1 treatment improved neurological deficits after SAH in rats, and attenuated neuronal apoptosis in both in vitro and in vivo SAH models, at least partially through the FAK/PI3K/AKT pathway.

Using Smartphone Chatbot for Postoperative Care after Intravitreal Injection during COVID-19 Period: A Retrospective Cohort Study.

BACKGROUND: During COVID-19 pandemic period, it was difficult for the patients regular and scheduled follow-up in outpatient department, especially when lock-down. However, early detection of patients with initial infection or other serious conditions after ocular surgeries, such as intravitreous injection (IVI) for age-related macular degeneration (AMD). OBJECTIVE: We accessed a postoperative care chatbot system (PCCS) in smartphone for patients to self-report postoperative symptoms/signs with an instant bidirectional feedback system. METHODS: During the COVID-19 level 3 epidemic alert in July 2021 in Taiwan, the PCCS alerted the patient to report and grade six ocular symptoms/signs associated with ocular inflammation or retinal detachment. Patients used the PCCS for 7 days postoperatively to assess their symptoms/signs per day after receiving an alert. The data automatically collected using a cloud computer system judged the grade and sent messages to medical staff for further medical assistance. User's satisfaction questionnaire was collected on the 7th day. RESULTS: One hundred and eighty-five patients participated in this study. There were 26 reports (3.03%) of symptom grade deterioration (increased blurred vision, eye swelling, nausea, and floater/flash) in 12 patients (6.5%). No gender difference for the earlier medical consultation. One case occurred endophthalmitis and improved after 2 times prompt IVI antibiotics. 87% of patients were satisfied or very satisfied to communicate their symptoms instantly with the app, willing to use it again and considered it could improve quality of care. The incidence of earlier medical consultation is 3.8% (7/185) and the incidence of endophthalmitis is 0.5% (1/185). CONCLUSIONS: The chatbot system, designed for self-reporting postoperative symptoms and providing instant bidirectional feedback on smartphones, could be beneficial for enhancing early medical consultation without gender differences in AMD patients who receiving intravitreal injections. It achieves satisfactory response from patients.

A meta-analysis of the association between RBP4 rs3758539 genotype and metabolic syndrome factors.

AIM: To explore the link between the RBP4 rs3758539 genotype and metabolic syndrome risk factors and whether the impact of this genetic variation displays any potential race discrepancy. MATERIALS AND METHODS: This meta-analysis followed the PRISMA guidelines and was registered with PROSPERO (registration no. CRD42023407999). PubMed, Web of Science, Embase, Cochrane Library, Google Scholar, Airiti Library and CINAHL databases were used for the study search until October 2023. We evaluated the methodological quality using the Joanna Briggs Institute checklist and determined the correlation using a random-effects meta-analysis. RESULTS: The results indicated that individuals with the rs3758539 GA/AA genotype had a higher risk profile, including lower high-density lipoprotein levels [correlation: -0.045, 95% confidence interval (CI): -0.080 to -0.009, p = .015, I2 = 46.9%] and higher body mass index (correlation: 0.117, 95% CI: 0.036-0.197, p = .005, I2 = 82.0%), body fat (correlation: 0.098, 95% CI: 0.004-0.191, p = .041, I2 = 64.0%), and low-density lipoprotein levels (correlation: 0.074, 95% CI: 0.010-0.139, p = .024, I2 = 0%), of developing metabolic syndrome than those with the GG genotype. The subgroup analysis maintained a significantly positive correlation between the rs3758539 GA/AA genotype and body mass index (correlation: 0.163, 95% CI: 0.031-0.289, p = .016, I2 = 88.9%) but a negative correlation with high-density lipoprotein levels (correlation: -0.047, 95% CI: -0.087 to -0.006, p = .025, I2 = 65.7%) in the Asian group only. CONCLUSION: The current meta-analysis supports a significant link between the RBP4 rs3758539 GA/AA genotype and the metabolic syndrome.

Developmental characteristics and accuracy of autism screening among two-year-old toddlers in the ECHO program.

BACKGROUND: The Modified Checklist for Autism in Toddlers (M-CHAT) is a common pediatric screening tool with mixed accuracy findings. Prior evidence supports M-CHAT screening for developmental concerns, especially in toddlers born preterm. This study examined M-CHAT accuracy in a large, nationwide sample. METHODS: 3393 participants from the Environmental influences on Child Health Outcomes (ECHO) program were included. Harmonized M-CHAT (M-CHAT-H) results were compared with parent-reported autism diagnosis and autism-related characteristics to assess accuracy for term and preterm children, together and separately. Generalized estimating equations, clustering for ECHO cohort and controlling for demographic covariates, were used to examine associations between developmental and behavioral characteristics with M-CHAT-H accuracy. RESULTS: Sensitivity of the M-CHAT-H ranged from 36 to 60%; specificity ranged from 88 to 99%. Positive M-CHAT-H was associated with more developmental delays and behavior problems. Children with severe motor delays and more autism-related problems were more likely to have a false-negative M-CHAT-H. Children with fewer behavior problems and fewer autism-related concerns were more likely to have a false-positive screen. CONCLUSION: The M-CHAT-H accurately detects children at low risk for autism and children at increased risk with moderate accuracy. These findings support use of the M-CHAT-H in assessing autism risk and developmental and behavioral concerns in children. IMPACT: Previous literature regarding accuracy of the Modified Checklist for Autism in Toddlers (M-CHAT) is mixed but this study provides evidence that the M-CHAT performs well in detecting children at low risk for autism and consistently detects children with developmental delays and behavioral problems. The M-CHAT moderately detects children at increased risk for autism and remains a useful screening tool. This study examines M-CHAT accuracy in a large-scale, nationwide sample, examining associations between screening accuracy and developmental outcomes. These findings impact pediatric screening for autism, supporting continued use of the M-CHAT while further elucidating the factors associated with inaccurate screens.

Synaptopodin is required for long-term depression at Schaffer collateral-CA1 synapses.

Synaptopodin (SP), an actin-associated protein found in telencephalic neurons, affects activity-dependant synaptic plasticity and dynamic changes of dendritic spines. While being required for long-term depression (LTD) mediated by metabotropic glutamate receptor (mGluR-LTD), little is known about its role in other forms of LTD induced by low frequency stimulation (LFS-LTD) or spike-timing dependent plasticity (STDP). Using electrophysiology in ex vivo hippocampal slices from SP-deficient mice (SPKO), we show that absence of SP is associated with a deficit of LTD at Sc-CA1 synapses induced by LFS-LTD and STDP. As LTD is known to require AMPA- receptors internalization and IP3-receptors calcium signaling, we tested by western blotting and immunochemistry if there were changes in their expression which we found to be reduced. While we were not able to induce LTD, long-term potentiation (LTP), albeit diminished in SPKO, can be recovered by using a stronger stimulation protocol. In SPKO we found no differences in NMDAR, which are the primary site of calcium signalling to induce LTP. Our study shows, for the first time, the key role of the requirement of SP to allow induction of activity-dependant LTD at Sc-CA1 synapses.

Preoperative Vaginal Microbiome as a Predictor of Postoperative Urinary Tract Infection.

This is a single Institute, prospective cohort study. We collected twenty- two postmenopausal women with pelvic organ prolapse planning to undergo vaginal hysterectomy with transvaginal pelvic reconstructive surgery, with or without a concomitant anti-incontinence procedure. Vaginal swabs and urine samples were longitudinally collected at five time points: preoperative consult visit (T1), day of surgery prior to surgical scrub (T2), immediately postoperative (T3), day of hospital discharge (T4), and at the postoperative exam visit (T5). Women experiencing urinary tract infection symptoms provided a sample set prior to antibiotic administration (T6). Microbiome analysis on vaginal and urinary specimens at each time point. Region V3-V5 of the 16S ribosomal RNA gene was amplified and sequenced. Sample DNA was analyzed with visit T1, T2, T5 and T6. Six (27.3%) participants developed postoperative urinary tract infection whose vaginal sample at first clinical visit (T1) revealed beta-diversity analysis with significant differences in microbiome structure and composition. Women diagnosed with a postoperative urinary tract infection had a vaginal microbiome characterized by low abundance of Lactobacillus and high prevalence of Prevotella and Gardnerella species. In our cohort, preoperative vaginal swabs can predict who will develop a urinary tract infection following transvaginal surgery for pelvic organ prolapse.

Aflatoxin B1 inhibited the development of primary myoblasts of grass carp (Ctenopharyngodon idella) by degrading extracellular matrix.

According to the International Agency for Research on Cancer (IARC), aflatoxin B1 (AFB1) has been recognized as a major contaminant in food and animal feed and which is a common mycotoxin with high toxicity. Previous research has found that AFB1 inhibited zebrafish muscle development. However, the potential mechanism of AFB1 on fish muscle development is unknown, so it is necessary to conduct further investigation. In the present research, the primary myoblast of grass carp was used as a model, we treated myoblasts with AFB1 for 24 h. Our results found that 5 µM AFB1 significantly inhibited cell proliferation and migration (P < 0.05), and 10 µM AFB1 promoted lactate dehydrogenase (LDH) release (P < 0.05). Reactive oxygen species (ROS), protein carbonyl (PC) and malondialdehyde (MDA) levels were increased in 15, 5 and 10 µM AFB1 (P < 0.05), respectively. Catalase (CAT), glutathione peroxidase (GPx) and total superoxide dismutase (T-SOD) activities were decreased in 10, 10 and 15 µM AFB1 (P < 0.05), respectively. Furthermore, 15 µM AFB1 induced oxidative damage by Nrf2 pathway, also induced apoptosis in primary myoblast of grass carp. Meanwhile, 15 µM AFB1 decreased MyoD gene and protein expression (P < 0.05). Importantly, 15 µM AFB1 decreased the protein expression of collagen Ⅰ and fibronectin (P < 0.05), and increased the protein levels of urokinase plasminogen activator (uPA), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 2 (MMP-2), and p38 mitogen-activated protein kinase (p38MAPK) (P < 0.05). As a result, our findings suggested that AFB1 damaged the cell morphology, induced oxidative damage and apoptosis, degraded ECM components, in turn inhibiting myoblast development by activating the p38MAPK/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase (MMPs)/extracellular matrix (ECM) signaling pathway.

Germline MLH1 and MSH6 mutations from two Lynch syndrome families identified in a patient with early-onset of endometrial cancer: A case report.

Introduction: Lynch syndrome is caused by a germline mutation in mismatch repair (MMR) genes, leading to the loss of expression of MMR heterodimers, either MLH1/PMS2 or MSH2/MSH6, or isolated loss of PMS2 or MSH6. Concurrent loss of both heterodimers is uncommon, and patients carrying pathogenic variants affecting different MMR genes are rare, leading to the lack of cancer screening recommendation for these patients.Case presentation:Here, we reported a female with a family history of Lynch syndrome with MLH1 c.676C > T mutation. She developed endometrial cancer at 37 years old, with loss of MLH1/PMS2 expression. Immunohistochemical staining on tumor samples incidentally detected the additional loss of MSH6 expression. Whole exome sequencing on genomic DNA from peripheral blood revealed MSH6 c.2731C > T mutation, which was confirmed to be inherited from her mother, who had an early-onset ascending colon cancer without cancer family history. Conclusion: This is a rare case of the Lynch syndrome harboring germline mutations simultaneously in two different MMR genes inherited from two families with Lynch syndrome. The diagnosis of endometrial cancer at the age less than 40 years is uncommon for Lynch syndrome-related endometrial cancer. This suggests an earlier cancer screening for patients carrying two MMR mutations.

Anti-Inflammatory Salicin Derivatives from the Barks of Salix tetrasperma.

The genus Salix L. is traditionally used in folk medicine to alleviate pain caused by various kinds of inflammation. In the present study, 10 undescribed salicin derivatives along with 5 known congeners were isolated from the barks of Salix tetrasperma, and their structures were elucidated by spectroscopic analyses, single-crystal X-ray diffraction, electronic circular dichroism (ECD) calculations, and chemical conversions. Compounds 4-6 significantly inhibited NO production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, and the most active 4 obviously suppressed the production of IL-1ß and IL-6 and decreased iNOS and COX-2 expression in a dose-dependent manner. Further Western blotting analysis revealed that the anti-inflammatory mechanism of 4 is possibly mediated through the MAPK and NF-κB signaling pathways.