Serine Supports Epithelial and Immune Cell Function in Colitis.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that are largely driven by immune cell activity, and mucosal healing is critical for remission. Serine is a nonessential amino acid that supports epithelial and immune cell metabolism and proliferation; however, whether these roles affect IBD pathogenesis is not well understood. Herein, the study showed that serine synthesis increased selectively in the epithelial cells of colons from patients with IBD and murine models of colitis. Inhibiting serine synthesis impaired colonic mucosal healing and increased susceptibility to acute injury in mice, effects associated with diminished epithelial cell proliferation. Dietary removal of serine similarly sensitized mice to acute chemically induced colitis but ameliorated inflammation in chronic colitis models. The anti-inflammatory effect of exogenous serine depletion in chronic colitis was associated with mitochondrial dysfunction of macrophages, resulting in impaired nucleotide production and proliferation. Collectively, these results suggest that serine plays an important role in both epithelial and immune cell biology in the colon and that modulating its availability could impact IBD pathogenesis.

Keratin 17 modulates the immune topography of pancreatic cancer.

BACKGROUND: The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival. METHODS: Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs. RESULTS: K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8+ T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations. CONCLUSIONS: Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.

Enhancing gestational diabetes mellitus risk assessment and treatment through GDMPredictor: a machine learning approach.

BACKGROUND: Gestational diabetes mellitus (GDM) is a serious health concern that affects pregnant women worldwide and can lead to adverse pregnancy outcomes. Early detection of high-risk individuals and the implementation of appropriate treatment can enhance these outcomes. METHODS: We conducted a study on a cohort of 3467 pregnant women during their pregnancy, with a total of 5649 clinical and biochemical records collected. We utilized this dataset as our training dataset to develop a web server called GDMPredictor. The GDMPredictor utilizes advanced machine learning techniques to predict the risk of GDM in pregnant women. We also personalize treatment recommendations based on essential biochemical indicators, such as A1MG, BMG, CysC, CO2, TBA, FPG, and CREA. Our assessment of GDMPredictor's effectiveness involved training it on the dataset of 3467 pregnant women and measuring its ability to predict GDM risk using an AUC and auPRC. RESULTS: GDMPredictor demonstrated an impressive level of precision by achieving an AUC score of 0.967. To tailor our treatment recommendations, we use the GDM risk level to identify higher risk candidates who require more intensive care. The GDMPredictor can accept biochemical indicators for predicting the risk of GDM at any period from 1 to 24 weeks, providing healthcare professionals with an intuitive interface to identify high-risk patients and give optimal treatment recommendations. CONCLUSIONS: The GDMPredictor presents a valuable asset for clinical practice, with the potential to change the management of GDM in pregnant women. Its high accuracy and efficiency make it a reliable tool for doctors to improve patient outcomes. Early identification of high-risk individuals and tailored treatment can improve maternal and fetal health outcomes http://www.bioinfogenetics.info/GDM/ .

The effectiveness of community ageing in place, advancing better living for elders as a biobehavioural environmental approach for disability among low-income older adults: a systematic review and meta-analysis.

BACKGROUND: community ageing in place, advancing better living for elders (CAPABLE), which is a biobehavioural environmental approach by addressing individual capacities and the home environment, aims to reduce the impact of disability among low-income older adults. OBJECTIVE: this meta-analysis aims to elucidate the efficacy of the CAPABLE program on related outcomes in low-income older adults. METHODS: a systematic search of MEDLINE/PubMed, CINAHL and EMBASE was conducted for articles published up to August 2022. A systematic review and meta-analysis were performed to calculate the pooled effect sizes of the efficacy of the CAPABLE program on home safety hazards, activities of daily living (ADLs), instrumental ADLs (IADLs), depression, falls efficacy, pain and quality of life. RESULTS: seven studies involving 2,921 low-income older adults (1,117 as the CAPABLE group and 1,804 served as a control) with an average age ranging from 65 to 79 were included in the present meta-analysis. Pre-post effect analyses showed that CAPABLE was significantly associated with lower home safety hazards, ADLs, IADLs, depression, falls efficacy, pain and quality of life. Additionally, there were statistically significant associations between the CAPABLE program with improvements in ADLs, IADLs and quality of life compared with controls. CONCLUSION: CAPABLE intervention may be a promising strategy to reduce health disparities, and disability limitations, and improve the quality of life in low-income community-dwelling older adults who suffer from disabilities by addressing both the person and the environment.

[Research progress on the mechanism of action of mitophagy in the occurrence and development of liver cancer].

Mitophagy, as an important link in maintaining mitochondrial homeostasis and environmental homeostasis in the liver, can remove damaged mitochondria and provide energy through autophagy and other processes. Additionally, it plays a dual role in the occurrence and development of liver cancer and can affect the therapeutic effect of liver cancer through a variety of signaling pathways. This article reviews the relationship between mitophagy and hepatitis B virus infection, liver cancer occurrence and development, liver cancer stem cells, mitochondrial division and fusion, therapeutic resistance and invasiveness of liver cancer, and other aspects.

The global impact of COVID-19 pandemic on the incidence of pediatric new-onset type 1 diabetes and ketoacidosis: A systematic review and meta-analysis.

Viral infections may increase the risk of developing type 1 diabetes (T1D), and recent reports suggest that Coronavirus Disease 2019 (COVID-19) might have increased the incidence of pediatric T1D and/or diabetic ketoacidosis (DKA). Therefore, this meta-analysis aims to estimate the risk of global pediatric new-onset T1D, DKA, and severe DKA before and after the COVID-19 pandemic. A systematic search of MEDLINE/PubMed, CINAHL, Scopus, and EMBASE was conducted for articles published up to March 2022. A random-effects meta-analysis was performed to compare the relative risk of T1D and DKA among pediatric patients with T1D between the COVID-19 pre-pandemic and pandemic periods. We also compared glucose and HbA1c values in children who were newly diagnosed with T1D before and after the COVID-19 pandemic. The global incidence rate of T1D in the 2019 period was 19.73 per 100 000 children and 32.39 per 100 000 in the 2020 period. Compared with pre-COVID-19 pandemic, the number of worldwide pediatric new-onset T1D, DKA, and severe DKA during the first year of the COVID-19 pandemic increased by 9.5%, 25%, and 19.5%, respectively. Compared with pre-COVID-19 pandemic levels, the median glucose, and HbA1c values in newly diagnosed T1D children after the COVID-19 pandemic increased by 6.43% and 6.42%, respectively. The COVID-19 pandemic has significantly increased the risk of global pediatric new-onset T1D, DKA, and severe DKA. Moreover, higher glucose and HbA1c values in newly diagnosed T1D children after the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

Immunogenicity of COVID-19 vaccines in patients with diverse health conditions: A comprehensive systematic review.

It remains unclear how effective COVID-19 vaccinations will be in patients with weakened immunity due to diseases, transplantation, and dialysis. We conducted a systematic review comparing the efficacy of COVID-19 vaccination in patients with solid tumor, hematologic malignancy, autoimmune disease, inflammatory bowel disease, and patients who received transplantation or dialysis. A literature search was conducted twice using the Medline/PubMed database. As a result, 21 papers were included in the review, and seropositivity rate was summarized by specific type of disease, transplantation, and dialysis. When different papers studied the same type of patient group, a study with a higher number of participants was selected. Most of the solid tumor patients showed a seropositivity rate of more than 80% after the second inoculation, but a low seropositivity was found in certain tumors such as breast cancer. Research in patients with certain types of hematological malignancy and autoimmune diseases has also reported low seropositivity, and this may have been affected by the immunosuppressive treatment these patients receive. Research in patients receiving dialysis or transplantation has reported lower seropositivity rates than the general population, while all patients with inflammatory bowel disease have converted to be seropositive. Meta-analysis validating these results will be needed, and studies will also be needed on methods to protect patients with reduced immunity from COVID-19.

Clinical characteristics and prognostic factors of myocarditis associated with the mRNA COVID-19 vaccine.

To analyze the clinical presentation and outcomes of myocarditis after administration of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccine. Nine case series and 15 case reports (74 patients) of myocarditis after administration of the BNT162b2 or mRNA-1273 vaccine were reviewed from PubMed, Scopus, Embase, and Web of Science. We analyzed clinical manifestations, diagnostic findings, and outcomes. In addition, we performed a pooled analysis and investigated risk factors leading to admission to the intensive care unit and recovery with conservative care. Most patients were male (94.6%), and the median age (range) was 17.6 (14-70) years. Patients who received the BNT162b2 (n = 58, 78.4%) vaccine presented fewer systemic symptoms and left ventricular dysfunction than mRNA-1273 recipients. Although patients under 20 years experienced more fever and myalgia, they had better ejection fraction and less prominent myocardial inflammation in magnetic resonance imaging than older patients. The clinical course of all patients was favorable without mortality, and one-third of patients resolved with conservative care alone. Risk factor analyses revealed that patients with gastrointestinal symptoms required intensive care (odds ratio: 20.3, 95% confidence interval 1.90-217, p = 0.013). The risk of fatality in myocarditis subjected to mRNA vaccination seems to be low. However, patients with gastrointestinal symptoms received more intensive care, and a significant proportion of patients recovered with conservative management.

Approaching the adiabatic timescale with machine learning.

The control and manipulation of quantum systems without excitation are challenging, due to the complexities in fully modeling such systems accurately and the difficulties in controlling these inherently fragile systems experimentally. For example, while protocols to decompress Bose-Einstein condensates (BECs) faster than the adiabatic timescale (without excitation or loss) have been well developed theoretically, experimental implementations of these protocols have yet to reach speeds faster than the adiabatic timescale. In this work, we experimentally demonstrate an alternative approach based on a machine-learning algorithm which makes progress toward this goal. The algorithm is given control of the coupled decompression and transport of a metastable helium condensate, with its performance determined after each experimental iteration by measuring the excitations of the resultant BEC. After each iteration the algorithm adjusts its internal model of the system to create an improved control output for the next iteration. Given sufficient control over the decompression, the algorithm converges to a solution that sets the current speed record in relation to the adiabatic timescale, beating out other experimental realizations based on theoretical approaches. This method presents a feasible approach for implementing fast-state preparations or transformations in other quantum systems, without requiring a solution to a theoretical model of the system. Implications for fundamental physics and cooling are discussed.

[Estimating the disease burden of seasonal influenza in China, 2006-2019].

Objective: To estimate the health impact and economic burden of seasonal influenza in mainland China. Methods: From systematic literature reviews, we collected the influenza-associated excess influenza-like-illness (ILI) outpatient consultation rates, hospitalization rates of severe acute respiratory infections (SARI) and respiratory excess mortality, 2006-2017. Using these data, as well as demographic data (2019), the number of influenza-associated excess ILI outpatient consultations, SARI hospitalizations and respiratory excess deaths were estimated. Then using per capita economic burden of influenza-associated outpatient consultations and hospitalizations, as well as the productivity loss of influenza-related premature deaths, the annual influenza-associated total economic burden was estimated. All costs were adjusted to 2019 using the consumer price index. Results: The annual influenza-associated excess ILI outpatient consultations, SARI hospitalizations and excess respiratory deaths were 3 million, 2.34 million, 0.09 million, respectively. The total economic burden was 26.38 billion CNY, accounting for 0.266‰ GDP in 2019, of which the hospitalization-related economic burden accounted for the highest proportion (86.4%, 22.79 billion CNY), followed by the outpatient-related economic burden (11.3%, 2.97 billion CNY), and the indirect economic burden of productivity loss of premature deaths was the lowest (2.4%, 0.62 billion CNY). Largest economic burden was observed in East China (10.51 billion CNY) and smallest observed in Northeast China (0.38 billion CNY). Conclusion: The health burden of influenza-related outpatient visits and hospitalizations were substantial. The economic burden of influenza-related SARI hospitalization was higher than that of influenza-related outpatients and pre-mature deaths. The highest economic burden of influenza occurred in the East China.

[Chlorpromazine hydrochloride plays a tumor suppressive role in diffuse large B lymphoma by promoting the expression of S1PR2].

Objective: To investigate the effect of chlorpromazine hydrochloride on proliferation, apoptosis and cell cycle arrest of human diffuse large B lymphoma cells and its possible mechanism. Methods: In January 2019, OCI-LY3 and TMD8 cells were treated with different concentrations of chlorpromazine hydrochloride for 72 h, the proliferations were detected by Alamar Blue assay. The apoptosis and cell cycle arrest of OCI-LY3 and TMD8 cells were detected by flow cytometry with FITC annexin V/PI (propidium iodide) double staining and PI, respectively. The mRNA levels of cyclin-dependent kinase inhibitor P21, P27, CyclinD1 and S1PR2 were detected by RTqPCR. The protein levels of P21, P27 and S1PR2 were detected by Western blot. Results: With the increase of chlorpromazine hydrochloride concentration, the proliferation inhibition rates of OCI-LY3 and TMD8 cells increased at 72 hours, apoptosis and G1 cell cycle arrest increased at 24 hours. Compared with the control group, the expression levels of P21, P27 and SIPR2 mRNA in OCI-LY3 and TMD8 cells were increased at 10 µmol/L chlorpromazine after 12 hours treatment (P<0.05) . And there was no significant difference in the expression of CyclinD1 mRNA (P>0.05) . There was a similar increase in protein levels of P21, P27 and SIPR2 in OCI-LY3 and TMD8 cells after 24 hours of treatment (P<0.05) . Conclusion: Chlorpromazine hydrochloride at a specific concentration may inhibit the proliferation of ABC diffuse large B lymphoma cells by promoting the expression of S1PR2, and promote cell apoptosis and G1 phase cell cycle arrest.

Arterial ischemic stroke in non-neonate children: Diagnostic and therapeutic specificities.

Pediatric arterial ischemic stroke (AIS) is a severe condition, with long-lasting devastating consequences on motor and cognitive abilities, academic and social inclusion, and global life projects. Awareness about initial symptoms, implementation of pediatric stroke code protocols using MRI first and only and adapted management in the acute phase, individually tailored recanalization treatment strategies, and multidisciplinary rehabilitation programs with specific goal-centered actions are the key elements to improve pediatric AIS management and outcomes. The main cause of pediatric AIS is focal cerebral arteriopathy, a condition with unilateral focal stenosis and time-limited course requiring specific management. Sickle cell disease and moyamoya angiopathy patients need adapted screening and therapeutics.

[AMG-102 inhibits proliferation and induces apoptosis of laryngeal squamous cell carcinoma cells by regulating c-Met/PI3K/Akt pathway].

Objective: To investigate the effects of c-Met inhibitor AMG-102 on the proliferation and apoptosis of laryngeal squamous carcinoma Hep-2 cells and the underlying mechanism. Methods: Laryngeal squamous carcinoma cell line Hep-2 cells were treated with 2.5, 5 and 10 µmol/L AMG-102, respectively. The proliferation activities of Hep-2 cells were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT). The apoptotic rate of Hep-2 cells was detected by flow cytometry analysis and Hoechst staining. The mRNA expression levels of apoptosis-related genes were detected by real-time quantitative polymerase Chain reaction (RT-qPCR), and the protein expressions of c-Met/PI3K/AKT pathway were detected by western blot. Results: Compared with the control group, the proliferation rates of Hep-2 cells treated with 2.5, 5 and 10 µmol/L AMG-102 for 24 hours were (89.8±1.1)%, (79.8±1.0)% and (69.1±1.2)%, respectively; for 48 hours were (76.8±2.0)%, (60.2±1.1)% and (49.8±1.2)%, respectively; for 72 hours were (50.1±2.0)%, (41.5±1.1)% and (33.6±1.0), respectively, with significant differences (all P<0.05). The apoptotic rates of Hep-2 cells treated with 2.5, 5 and 10 µmol/L AMG-102 for 48 hours were (16.09±1.53)%, (27.51±2.02)% and (36.57±1.42)%, respectively, which were significantly higher than (3.62±0.10) % in the control group (all P<0.05). After treated with 2.5, 5 and 10 µmol/L AMG-102 for 48 hours, the relative expression levels of Bcl-2 mRNA in Hep-2 cells were 0.58±0.13, 0.38±0.12 and 0.20±0.13, respectively; the relative protein expression of p-Met were 80.0±3.8, 50.6±4.2 and 28.5±1.3, respectively; the relative protein expression of p-PI3K were 87.1±0.9, 54.2±1.2 and 21.0±1.2, respectively; the relative protein expression of p-AKT were 98.7±5.6, 56.9±3.2 and 32.2±4.3, respectively; which were significantly lower than those in the control group (all P<0.05). The relative expression levels of Bax mRNA were 1.78±0.13, 2.37±0.14 and 3.05±0.13, respectively, and the relative expression levels of caspase-3 mRNA were 1.98±0.14, 2.47±0.14 and 3.15±0.13, respectively, which were significantly higher than those in the control group (all P<0.05). Conclusion: c-Met inhibitor AMG-102 could inhibit the proliferation and induce apoptosis of laryngeal squamous carcinoma Hep-2 cells by regulating the c-Met/PI3K/Akt pathway.

[The study of self-constructed brainstem fiber bundle by neurosurgeon through using 3D-Slicer software].

Objective: To explore the methods and appliaction value for self-constructing brainstem fiber bundles by neurosurgeon through 3D-Slicer software in neurosurgical preoperative planning. Methods: The DCIOM format imaging data of 31 patients with neurosurgical brainstem lesions were collected who admitted to Neurosurgery Department at the First Affiliated Hospital of Chongqing Medical University from June 2018 to May 2019 and imported into the 3D-Slicer software system. The neurosurgery specialists independently constructed the fiber bundles to generate two-dimensional Fraction Anisotropy maps, Directionally Encoded Color maps and three-dimensional fiber bundle tracing maps. Building a preopertive virtual pathological anatomical imaging system and understanding the three-dimensional pathological anatomical relationship between lesions and brain stem fiber bundles to develop an accurate surgical approach and simulate surgicalprocedures before surgery. Results: All cases were reconstructed by neurosurgeon, and the self-constructed 3D virtual images were used to develop the surgical plan. All the operations were successfully completed under the assistance of microsurgical techniques and neuroendoscopy while avoiding fiber bundles as much as possible, and the total or subtotal tumor was achieved without damage to the fiber bundle. After operation, the symptoms of new brainstem fiber bundle injury were mild. 31 patients were followed up 3 months after operation without obvious symptoms of brainstem fiber bundle injury, and 31 patients were followed up 6 months after operation without obvious symptoms of brainstem fiber bundle injury. Conclusions: Constructing brainstem fiber bundles by neurosurgeon can accurately and purposefully reconstruct the shape of brainstem fiber bundles, so that neurosurgeons can more accurately understand the three-dimensional pathological anatomical relationship between tumor and brain stem fiber bundles. In order to formulate the surgical plan in a more reasonable way, choose the optimal surgical approach, understand the location of the "relative safe area" , and be more confident to avoid damage to the brain stem fiber bundle while achieving subtotal or total resection of the tumor,also the nerve function of the patient is preserved as much as possible.

[A pilot study of transcranial alternating current stimulation in the treatment of drug-naive adult patients with major depressive disorder].

Objective: To explore the efficacy, adverse reactions, feasibility, and acceptability of transcranial alternating current stimulation (tACS) treating drug-naive adult patients with major depressive disorder (MDD), and provide basis for further study with a large sample. Methods: The study was performed in the Neuromodulation laboratory, Department of Neurology of Xuanwu Hospital, Capital Medical University (Beijing, China) from July, 2017 to June, 2018. Thirty Eligible first-episode MDD outpatients were randomized 1∶1 to receive active tACS or sham intervention. The tACS was administered in a 40 minute, 77.5 Hz frequency, 15 mA session with one forehead (Fp1, Fpz, and Fp2, in the 10/20 international placement system, 4.45 cm×9.53 cm) and two mastoid (3.18 cm×3.81 cm) stimulation for 20 times in 4 consecutive weeks at fixed day time frame once daily from Monday through Friday, with weekends off (week 4), followed by 4 weeks with no tACS treatment (week 8). By utilizing the Hamilton rating scale for depression-17 item (HRSD-17) to assess the depressive severity of MDD patients, adverse events were administered by the treatment-emergent adverse events, the Young mania rating scale, and the self-made common questionnaire on cranial electrical stimulation. The primary efficacy outcome was the remission rate defined as HRSD-17 score ≤7 at week 8. Secondary outcomes included the rates of remission at week 4 and response at weeks 4 and 8. Safety was assessed by evaluation of adverse events. Also the proportions of participants accepting the intervention and this study procedure were evaluated at weeks 4 and 8. Results: Thirty MDD patients completed the study, and both groups had no statistical differences on their demographic characteristics (P>0.05). At week 8, the active group had a remission rate of 10/15, which was higher than 3/15 in the sham group (P<0.05). Also, the remission rate (14/15) in the active group was higher than 5/15 of the sham group at week 4 (P<0.05). For the response rates, significant differences were found between groups at week 8. For safety, both groups showed no severe adverse events and no mania/hypomania. One participant per group had 2 times of tinnitus cerebri during the intervention days. All patients accepted the intervention and the study procedure. Conclusions: The pilot study indicated that tACS with 77.5 Hz and 15 mA may have a therapeutic effect on depressive symptoms. It is well-tolerated and safe, as well as feasible and acceptable for adults with MDD.

[Expression level and prognostic value of PD-L1 in microsatellite instability-high gastric cancer].

Objective: To study the clinicopathological features and PD-L1 expression of microsatellite instability-high (MSI-H) gastric cancer. Methods: The clinicopathological data of the 2 472 patients who had undergone radical surgical resection and been performed immunohistochemical staining of four major mismatch repair (MMR) proteins (MLH1, PMS2, MSH2 and MSH6) from March 2014 to December 2018 at Peking University Cancer Hospital were collected. One hundred and seventy-one patients showed mismatch repair-deficient (dMMR), and microsatellite instability of these patients were detected with polymerase chain reaction (PCR). Then, taken PCR results as the standard, PD-L1 was assessed using immunohistochemistry (IHC) in the MSI-H gastric cancers. Results: MSI-H (vs. MSI-L) in gastric cancers was associated with female gender, advanced age, gastric-antrum location, intestinal type, lesion diameter exceeding 5 cm, absence of lymph node metastasis and positive PD-L1 expression (P<0.05, respectively). Combined positive score (CPS) was an independent risk factor (P=0.026, HR=8.385, 95%CI=1.293-54.367). Although no relationship between PD-L1 expression pattern and prognosis was observed,"diffuse-pattern" of the PD-L1 expression was related to lymphatic-vascular invasion (P=0.007) and infiltration depth (P=0.04). Among the patients with MSI-H and PD-L1 positive gastric cancer, the patients who experienced recurrence or died all had the pattern of "diffuse" PD-L1 expression. Also, regarding the expression level and staining pattern of PD-L1, the metastasis lesion of lymph node had a high coincidence with primary site (P=0.45). Conclusions: MSI-H gastric cancer shows distinctive clinicopathological characteristics. The CPS can be used as a prognostic indicator in MSI-H gastric cancers, while the "diffuse-pattern" of PD-L1 expression could possibly be used as a prognostic indicator. The patients with advanced gastric cancer could obtain the expression level and staining pattern of PD-L1 using the biopsy material of metastatic lesions.

Blue light disrupts the circadian rhythm and create damage in skin cells.

On a daily basis, the skin is exposed to many environmental stressors and insults. Over a 24-h natural cycle, during the day, the skin is focused on protection; while at night, the skin is focused on repairing damage that occurred during daytime and getting ready for the next morning. Circadian rhythm provides the precise timing mechanism for engaging those different pathways necessary to keep a healthy skin through clock genes that are present in all skin cells. The strongest clue for determining cellular functions timing is through sensing light or absence of light (darkness). Here, we asked the question if blue light could be a direct entrainment signal to skin cells and also disrupt their circadian rhythm at night. Through a reporter assay for per1 transcription, we demonstrate that blue light at 410 nm decreases per1 transcription in keratinocytes, showing that epidermal skin cells can sense light directly and control their own clock gene expression. This triggers cells to "think" it is daytime even at nighttime. Elsewhere, we measured different skin cell damage because of blue light exposure (at different doses and times of exposure) vs. cells that were kept in full darkness. We show an increase in ROS production, DNA damage and inflammatory mediators. These deleterious effects can potentially increase overall skin damage over time and ultimately accelerates ageing.

La peau est exposée chaque jour à de nombreux facteurs de stress et traumatismes environnementaux. Pendant un cycle naturel de 24 heures, dans la journée, la peau est axée sur sa protection, tandis que la nuit, elle se concentre sur la réparation des lésions survenues pendant la journée en préparation du lendemain matin. Le rythme circadien assure un mécanisme de cadencement temporel précis pour engager les différentes voies nécessaires au maintien d'une peau saine à travers les gènes de l'horloge interne qui sont présents dans toutes les cellules cutanées. La perception de la lumière ou l'absence de lumière (obscurité) est le plus fort indice pour déterminer le cadencement des fonctions cellulaires. Nous nous sommes ici posé la question de savoir si la lumière bleue serait un signal d'entraînement direct pour les cellules de la peau également capable de perturber leur rythme circadien la nuit. À travers un essai utilisant un gène rapporteur pour la transcription de per1, nous démontrons que la lumière bleue à 410 nm diminue la transcription de per1 dans les kératinocytes, montrant que les cellules épidermiques peuvent détecter directement la lumière et contrôler l'expression de leurs propres gènes horloges. Cela incite les cellules à « penser ¼ que la journée a commencé, même pendant la nuit. Par ailleurs, nous avons mesuré différentes lésions des cellules cutanées suite à l'exposition à la lumière bleue (à différentes doses et durées d'exposition) par rapport aux cellules qui étaient maintenues dans une obscurité complète. Nous montrons une augmentation de la production d'espèces réactives de l'oxygène (ROS), des lésions de l'ADN et des médiateurs inflammatoires. Ces effets délétères peuvent potentiellement augmenter les lésions cutanées globales au fil du temps et en accélérer ultérieurement le vieillissement.

[Effect of c-Met inhibitor AMG-102 on radiosensitivity in laryngeal squamous carcinoma cells].

Objective: To investigate the effect of c-Met inhibitor AMG-102 on proliferation and radiosensitivity in laryngeal squamous carcinoma cells. Methods: The effects of AMG-102 on proliferation and radiosensitivity of laryngeal squamous carcinoma cell lines Hep-2 and KBV200 were detected by 3-(4, 5-dimethy-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assay and colony formation assay, respectively. The apoptosis of Hep-2 and KBV200 cells was detected by flow cytometry. The expression levels of c-Met, phospho-Met (p-Met), cleaved caspase-3 and Akt/p-Akt, Erk/p-Erk were detected by Western blot. Specific small interfering RNA targeting c-Met or plasmid of c-Met were transfected into Hep-2 and KBV200 cells to investigate the cell sensitivity to AMG-102. Results: Compared with KBV200 cells, Hep-2 cells were more sensitive to AMG-102 with IC(50) of 14 and 9 µmol/L, respectively. The relative expression levels of c-Met and p-Met proteins in Hep-2 cells were 194.48±0.57 and 177.76±1.53, respectively, which were significantly higher than those in KBV200 cells (171.24±1.00 and 115.37±0.56, respectively, P<0.001 for both). Exogenous hepatocyte growth factor (HGF) was added to increase the expression level of p-Met protein in KBV200 cells. The results showed that AMG-102 significantly reduced the expression of p-Met in KBV200 cells treated with HGF (P<0.001). Compared with the dimethyl sulfoxide (DMSO) group, AMG-102 treatment combined with radiotherapy significantly increased the radiosensitivity of Hep-2 cells (SER=1.28, P<0.001). However, AMG-102 had little effect on the radiosensitivity of KBV200 cells (SER=1.18, P=0.002). Compared with the 4 Gy radiotherapy alone group and the 5 µmol/L of AMG-102 alone treatment group, the apoptosis rate of Hep-2 cells in the combined treatment group was significantly increased. Meanwhile, the expression level of cleaved caspase-3 protein was also markedly increased. However, there were no significant changes in the apoptotic rate and cleaved caspase-3 expression in each treatment group of KBV200 cells. Compared with DMSO treatment group, the expression levels of p-Met, p-Akt and p-Erk were significantly decreased in the 4 Gy radiotherapy group, 5 µmol/L of AMG-102 treatment group and combined treatment group of Hep-2 cells. And the levels of p-Met, p-Akt and p-Erk in the combined treatment group were significantly lower than those in the 4 Gy radiotherapy alone group and 5 µmol/L of AMG-102 treatment alone group. By contrast, in KBV200 cells, the expression of p-Met, p-Akt and p-Erk in each group was not changed. The relative expression of p-Met in Hep-2 cells before and after radiotherapy at 30 min, 1 h, 4 h, 8 h, 24 h were 99.89±0.61, 138.62±1.00, 163.07±5.00, 87.80±1.85, 90.67±0.65 and 94.09±1.41, respectively. The level of p-Met was slightly increased after radiotherapy at 30 min and 1 h (P<0.001 for all), whereas it was significantly decreased from 4 h to 24 h after radiotherapy (P<0.05 for all). By contrast, the expression of p-Met in KBV200 cells did not change with time after radiotherapy (P>0.05). The sensitivity of Hep-2 cells to AMG-102 was decreased after silencing of c-Met, while the sensitivity of KBV200 cells to AMG-102 was not significantly changed (P>0.05). Moreover, the radiosensitivity of Hep-2 cells in c-Met knockdown group had a slightly increasing trend (SER=1.07, P=0.068). After the treatment with 10 µmol/L of AMG-102, the proliferation rate of c-Met ectopically expressed KBV200 cells was 60.05%±3.23%, It was significantly lower than that of the blank control 90.08%±1.04% and siRNA negative control (90.12%±1.01%, P<0.001). The results suggested that the overexpression of c-Met in KBV200 cells increased the radiosensitivity to AMG-102, whereas depletion of c-Met resulted in resistance to AMG-102 in Hep-2 cells. Furthermore, the radiosensitivity of KBV200 cells that overexpressed c-Met showed a decreased trend (SER=0.7, P=0.005). Conclusions: c-Met inhibitor AMG-102 has a significant inhibitory effect on the proliferation of c-Met overexpressing laryngeal squamous carcinoma cells, leading to increased radiosensitivity. It suggests that molecular targeted therapy against c-Met receptor is more effective in c-Met overexpressed subtype of laryngeal squamous cell carcinoma.

Giant Magneto-Impedance (GMI) Effect in Single-Layer Soft Magnetic Film Under Stress.

The stress-induced magnetic anisotropy can significantly affect giant magneto-impedance (GMI) effect of the soft magnetic film. This paper is devoted to the GMI effect of the single layer soft magnetic film implied without and with a stress. By simulating a physical model with MATLAB and COMSOL software, the impedance expression of the single layer soft magnetic film and the relation between external magnetic field and magnetic permeability are deduced. We observed that, without a stress, the sensitive region increased firstly and then decreased with the increasing of the excitation current frequency from 1 MHz to 200 MHz. While the film was subjected to the stress in the direction of the current with one end stressed, the stress on the film was gradually reduced from stressed end to free end. Also, the impedance change rate of the film changed when the stress was added, which is similar to the effect of adding a bias magnetic field on the film. More importantly, the addition of stress σ can induce the bias of the GMI measurement range and improve its sensitivity near zero magnetic fields. This may provide a new way for designing a GMI sensor with higher sensitivity and adjustable measurement range.

The FBXW7 tumor suppressor inhibits breast cancer proliferation and promotes apoptosis by targeting MTDH for degradation.

Metadherin (MTDH) is an oncoprotein and is expressed at high levels in a wide variety of human carcinomas, which represents an important genetic determinant and regulates multiple events in tumorigenesis. MTDH promotes breast cancer cell proliferation and tumorigenesis through the activation of numerous signaling pathways. Currently, the mecha- nism regulating MTDH expression is poorly understood. Here we identified that FBXW7, a component of E3 ubiquitin ligase, targets MTDH for ubiquitin-mediated degradation. Forced overexpression of FBXW7 could decrease the level of MTDH protein, and inhibition of endogenous FBXW7 expression remarkably increases the MTDH protein abundance. More importantly, overexpression of FBXW7 could lead to proliferation arrest and apoptosis in breast cancer cells through targeting MTDH degradation. These data suggest that FBXW7, a tumor suppressor, inhibits breast cancer cell prolifera- tion and promotes apoptosis at least partially through targeting MTDH for proteolysis. This new regulatory mechanism of MTDH by FBXW7 represents a new pathway for malignant phenotype turnover in human breast cancer.