OBJECTIVE: The aim of this study was to develop and validate a predictive nomogram model for long-term rebleeding events in patients with hemorrhagic moyamoya disease (HMMD). METHODS: In total, 554 patients with HMMD from the Fifth Medical Center of the Chinese PLA General Hospital (5-PLAGH cohort) were included and randomly divided into training (390 patients) and internal validation (164 patients) sets. An independent cohort from the First Medical Center and Eighth Medical Center of Chinese PLA General Hospital (the 1-PLAGH and 8-PLAGH cohort) was used for external validation (133 patients). Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression algorithm were used to identify significant factors associated with rebleeding, which were used to develop a nomogram for predicting 5- and 10-year rebleeding. RESULTS: Intraventricular hemorrhage was the most common type of cerebral hemorrhage (39.0% of patients in the 5-PLAGH cohort and 42.9% of the 1-PLAGH and 8-PLAGH cohort). During the mean ± SD follow-up period of 10.4 ± 2.9 years, 91 (16.4%) patients had rebleeding events in the 5-PLAGH cohort. The rebleeding rates were 12.3% (68 patients) at 5 years and 14.8% (82 patients) at 10 years. Rebleeding events were observed in 72 patients (14.3%) in the encephaloduroarteriosynangiosis (EDAS) surgery group, whereas 19 patients (37.3%) experienced rebleeding events in the conservative treatment group. This difference was statistically significant (p < 0.001). We selected 4 predictors (age at onset, number of episodes of bleeding, posterior circulation involvement, and EDAS surgery) for nomogram development. The concordance index (C-index) values of the nomograms of the training cohort, internal validation cohort, and the external validation cohort were 0.767 (95% CI 0.704-0.830), 0.814 (95% CI 0.694-0.934), and 0.718 (95% CI 0.661-0.775), respectively. The nomogram at 5 years exhibited a sensitivity of 48.1% and specificity of 87.5%. The positive and negative predictive values were 38.2% and 91.3%, respectively. The nomogram at 10 years exhibited a sensitivity of 47.1% and specificity of 89.1%. The positive and negative predictive values were 48.5% and 88.5%, respectively. CONCLUSIONS: EDAS may prevent rebleeding events and improve long-term clinical outcomes in patients with HMMD. The nomogram accurately predicted rebleeding events and assisted clinicians in identifying high-risk patients and devising individual treatments. Simultaneously, comprehensive and ongoing monitoring should be implemented for specific patients with HMMD throughout their entire lifespan.
BACKGROUND: Members of the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing (NLRP) family regulate various physiological and pathological processes. However, none have been shown to regulate actin cap formation or spindle translocation during the asymmetric division of oocyte meiosis I. NLRP4E has been reported as a candidate protein in female fertility, but its function is unknown. METHODS: Immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were employed to examine the localization and expression levels of NLRP4E and related proteins in mouse oocytes. small interfering RNA (siRNA) and antibody transfection were used to knock down NLRP4E and other proteins. Immunoprecipitation (IP)-mass spectrometry was used to identify the potential proteins interacting with NLRP4E. Coimmunoprecipitation (Co-IP) was used to verify the protein interactions. Wild type (WT) or mutant NLRP4E messenger RNA (mRNA) was injected into oocytes for rescue experiments. In vitro phosphorylation was employed to examine the activation of steroid receptor coactivator (SRC) by NLRP4E. RESULTS: NLRP4E was more predominant within oocytes compared with other NLRP4 members. NLRP4E knockdown significantly inhibited actin cap formation and spindle translocation toward the cap region, resulting in the failure of polar body extrusion at the end of meiosis I. Mechanistically, GRIN1, and GANO1 activated NLRP4E by phosphorylation at Ser429 and Thr430; p-NLRP4E is translocated and is accumulated in the actin cap region during spindle translocation. Next, we found that p-NLRP4E directly phosphorylated SRC at Tyr418, while p-SRC negatively regulated p-CDC42-S71, an inactive form of CDC42 that promotes actin cap formation and spindle translocation in the GTP-bound form. CONCLUSIONS: NLRP4E activated by GRIN1 and GANO1 regulates actin cap formation and spindle translocation toward the cap region through upregulation of p-SRC-Tyr418 and downregulation of p-CDC42-S71 during meiosis I.
Actins , Meiosis , Oocytes , cdc42 GTP-Binding Protein , Animals , Oocytes/metabolism , Mice , Female , Actins/metabolism , Actins/genetics , cdc42 GTP-Binding Protein/metabolism , cdc42 GTP-Binding Protein/genetics , Phosphorylation , Spindle Apparatus/metabolism
INTRODUCTION: The inverted nipple is a condition that affects approximately 10% of women and can have negative cosmetic and psychological implications. Surgical correction is a common approach to address this concern; however, this method can lead to complications, such as nipple necrosis. As comprehensive guidelines are currently lacking for postoperative nipple necrosis management, this study reports our experience in the management of postoperative nipple necrosis following initial attempt at surgical management. METHODS: A retrospective chart review was conducted and included female patients who experienced postoperative nipple necrosis after inverted nipple correction between 2018 and 2021. Cases of recurrent nipple retraction following partial necrosis and cases of complete nipple necrosis were evaluated. Recurrent nipple retraction was managed using various inverted nipple correction techniques, while complete necrosis required a modified C-V flap for nipple reconstruction. RESULTS: A total of 25 patients with a total of 42 affected nipples were included. Thirteen cases (26 nipples) experienced recurrent nipple retraction following partial necrosis, while 12 cases (16 nipples) exhibited complete necrosis. No significant predictive variables for these complications were found. Notably, all patients achieved successful healing following single-stage surgical repair. At 6 months postoperation, the treated nipples exhibited satisfactory healing and appearance and an absence of infection or papillary necrosis. Seven reconstructed nipples showed a mean loss of projection (2.7 ± 0.98) compared with only 2 nipples in the inverted nipple correction group. CONCLUSIONS: Distinguishing between recurrent nipple retraction after partial necrosis and complete nipple necrosis is crucial and should be taken into consideration when managing patients following inverted nipple correction.
OBJECTIVE: The Glasgow Coma Scale-Pupils (GCS-P) score has been suggested to better predict patient outcomes compared with GCS alone, while avoiding the need for more complex clinical models. This study aimed to compare the prognostic ability of GCS-P versus GCS in a national cohort of traumatic subdural hematoma (SDH) patients. METHODS: Patient data were obtained from the National Trauma Data Bank (2017-2019). Inclusion criteria were traumatic SDH diagnosis with available data on presenting GCS score, pupillary reactivity, and discharge disposition. Patients with severe polytrauma or nonsurvivable head injury at presentation were excluded. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of GCS-P versus GCS scores for inpatient mortality prediction were evaluated across the entire cohort, as well as in subgroups based on age and traumatic brain injury (TBI) type (blunt vs penetrating). Calibration curves were plotted based on predicted probabilities and actual outcomes. RESULTS: A total of 196,747 traumatic SDH patients met the study inclusion criteria. Sensitivity (0.707 vs 0.702), specificity (0.821 vs 0.823), and AUC (0.825 vs 0.814, p < 0.001) of GCS-P versus GCS scores for prediction of inpatient mortality were similar. Calibration curve analysis revealed that GCS scores slightly underestimated inpatient mortality risk, whereas GCS-P scores did not. In patients > 65 years of age with blunt TBI (51.9%, n = 102,148), both GCS-P and GCS scores underestimated inpatient mortality risk. In patients with penetrating TBI (2.4%, n = 4,710), the AUC of the GCS-P score was significantly higher (0.902 vs 0.851, p < 0.001). In this subgroup, both GCS-P and GCS scores underestimated inpatient mortality risk among patients with lower rates of observed mortality and overestimated risk among patients with higher rates of observed mortality. This effect was more pronounced in the GCS-P calibration curve. CONCLUSIONS: The GCS-P score provides better short-term prognostication compared with the GCS score alone among traumatic SDH patients with penetrating TBI. The GCS-P score overestimates inpatient mortality risk among penetrating TBI patients with higher rates of observed mortality. For penetrating TBI patients, which comprised 2.4% of our SDH cohort, a low GCS-P score should not justify clinical nihilism or forgoing aggressive treatment.
Periprosthetic infection and mechanical loosening are two leading causes of implant failure in orthopedic surgery that have devastating consequences for patients both physically and financially. Hence, advanced prostheses to simultaneously prevent periprosthetic infection and promote osseointegration are highly desired to achieve long-term success in orthopedics. In this study, we proposed a multifunctional three-dimensional printed porous titanium alloy prosthesis coated with imidazolium ionic liquid. The imidazolium ionic liquid coating exhibited excellent bacterial recruitment property and near-infrared (NIR) triggered photothermal bactericidal activity, enabling the prosthesis to effectively trap bacteria in its vicinity and kill them remotely via tissue-penetrating NIR irradiation. In vivo anti-infection and osseointegration investigations in infected animal models confirmed that our antibacterial prosthesis could provide long-term and sustainable prevention against periprosthetic infection, while promoting osseointegration simultaneously. It is expected to accelerate the development of next-generation prostheses and improve patient outcomes after prosthesis implantation.
BACKGROUND: The role of high socioeconomic status (SES) as an established risk factor for melanoma has been well documented in Western countries and regions. However, research on the association between melanoma and SES in China remains limited. This study aimed to investigate the association between SES and melanoma incidence and stage in China. METHODS: Five measures of SES were accessed, including education level, ethnic background, per capita household income, occupation, and medical insurance coverage. A scoring system based on the Kuppuswamy Socio-Economic Scale was used to create a quantitative assessment of SES. To improve clarity and precision, we refined the language in the original text. Clinical stage at diagnosis was classified according to the Chinese Society Oncology Melanoma Guidelines. RESULTS: A total of 122 patients with pathologic melanoma were enrolled in this study from January 2013 to December 2017. Of these patients, 58 (48%) were male and 64 (52%) were female, with a mean age of 59.23 ± 9.91 years. Patients in the age groups of 45-59 and 60-73 had a higher incidence of melanoma compared to other age groups. Acral lentiginous melanoma was the most commonly observed subtype, accounting for 48% of cases. Patients with a low level of education (middle school and below) and a low level of monthly household income (<3000 CNY) had a higher risk of developing melanoma, as did those who were unemployed. Interestingly, a higher proportion of melanoma diagnoses were made in patients with medical insurance than those without. However, no significant differences in melanoma staging were found based on education level (P = 0.153), monthly household income (P = 0.507), occupation (P = 0.687), or insurance status (P = 0.537). According to the Kuppuswamy Socio-Economic Scale, there were 0 in upper class, 50 in upper middle class, 44 in lower middle class, 28 in upper lower class, 0 in lower class. The mean K-score was 13.85. No statistically significant interaction was observed between K-score and tumor stage. CONCLUSIONS: Patients with lower SES have a higher risk of developing melanoma. However, no significant differences were found in melanoma staging based on SES.
The effect of Levilactobacillus brevis as a starter in northeastern sauerkraut fermentation is still unknown, and further evaluation is worthwhile. Hence, this study aimed to evaluate the effect of autochthonous L. brevis inoculation on the bacterial community succession and formation of flavor and harmful substances in sauerkrauts. Inoculation with L. brevis lowered the pH and increased the total acid content of sauerkrauts (P < 0.05). The nitrite content of the inoculated sauerkraut was significantly lower than that of control (P < 0.05). Moreover, the spoilage bacteria of the inoculated sauerkraut were decreased and nitrogen metabolism was improved. The contents of aldehydes, alcohols, esters, acids, and alkanes increased significantly (P < 0.05), and the sensory attributes such as aroma, sourness, and gloss were also improved. L. brevis was positively and negatively correlated with flavor metabolites and nitrite, respectively, which proved to be a potential starter culture to manufacture sauerkraut.
OBJECTIVE: Diabetes is often linked to poorer outcomes in patients with moyamoya disease (MMD). However, experience has shown that certain individuals with diabetes have favorable outcomes after encephaloduroarteriosynangiosis (EDAS). The authors aimed to develop a nomogram to predict good neoangiogenesis in patients with MMD and type 2 diabetes mellitus (T2DM) to aid neurosurgeons in the identification of suitable candidates for EDAS. METHODS: Adults with MMD and T2DM who underwent EDAS between June 2004 and December 2018 were included in the analysis. In total, 126 patients (213 hemispheres) with MMD and T2DM from the Fifth Medical Centre of the Chinese PLA General Hospital were included and randomly divided into training (152 hemispheres) and internal validation (61 hemispheres) cohorts at a ratio of 7:3. Univariate logistic and least absolute shrinkage and selection operator regression analyses were used to identify the significant factors associated with good neoangiogenesis, which were used to develop a nomogram. The discrimination, calibration, and clinical utility were assessed. RESULTS: A total of 213 hemispheres in 126 patients were reviewed, including 152 (71.36%) hemispheres with good postoperative collateral formation and 61 (28.64%) with poor postoperative collateral formation. The authors selected 4 predictors (FGD5 rs11128722, VEGFA rs9472135, Suzuki stage, and internal carotid artery [ICA] moyamoya vessels) for nomogram development. The C-indices of the nomogram in the training and internal validation cohorts were 0.873 and 0.841, respectively. The nomogram exhibited a sensitivity of 84.5% and specificity of 81.0%. The positive and negative predictive values were 92.1% and 66.7%, respectively. The calibration curves indicated high predictive accuracy, and receiver operating characteristic curve analysis showed the superiority of the nomogram. The decision-making analysis validated the fitness and clinical application value of this nomogram. Then a web-based calculator to facilitate clinical application was generated. CONCLUSIONS: The nomogram developed in this study accurately predicted neoangiogenesis in patients with MMD and T2DM after EDAS and may assist neurosurgeons in identifying suitable candidates for indirect revascularization surgery.
Bile acid homeostasis is critical to human health. Low-level exposure to antibiotics has been suggested to potentially disrupt bile acid homeostasis by affecting gut microbiota, but relevant data are still lacking in humans, especially for the level below human safety threshold. We conducted a cross-sectional study in 4247 Chinese adults by measuring 34 parent antibiotics and their metabolites from six common categories (i.e., tetracyclines, qinolones, macrolides, sulfonamides, phenicols, and lincosamides) and ten representative bile acids in fasting morning urine using liquid chromatography coupled to mass spectrometry. Daily exposure dose of antibiotics was estimated from urinary concentrations of parent antibiotics and their metabolites. Urinary bile acids and their ratios were used to reflect bile acid homeostasis. The estimated daily exposure doses (EDED) of five antibiotic categories with a high detection frequency (i.e., tetracyclines, qinolones, macrolides, sulfonamides, and phenicols) were significantly associated with urinary concentrations of bile acids and decreased bile acid ratios in all adults and the subset of 3898 adults with a cumulative ratio of antibiotic EDED to human safety threshold of less than one. Compared to a negative detection of antibiotics, the lowest EDED quartiles of five antibiotic categories and four individual antibiotics with a high detection frequency (i.e., ciprofloxacin, ofloxacin, trimethoprim, and florfenicol) in the adults with a positive detection of antibiotics had a decrease of bile acid ratio between 6.6% and 76.6%. Except for macrolides (1.2×102 ng/kg/day), the medians of the lowest EDED quartile of antibiotic categories and individual antibiotics ranged from 0.32â¯ng/kg/day to 10â¯ng/kg/day, which were well below human safety thresholds. These results suggested that low-level antibiotic exposure could disrupt bile acid homeostasis in adults and existing human safety thresholds may be inadequate in safeguarding against the potential adverse health effects of low-level exposure to antibiotics.
BACKGROUND: Cancer surveillance data are essential to help understand where gaps exist and progress is being made in cancer control. We sought to summarize the expected impact of cancer in Canada in 2024, with projections of new cancer cases and deaths from cancer by sex and province or territory for all ages combined. METHODS: We obtained data on new cancer cases (i.e., incidence, 1984-2019) and deaths from cancer (i.e., mortality, 1984-2020) from the Canadian Cancer Registry and Canadian Vital Statistics Death Database, respectively. We projected cancer incidence and mortality counts and rates to 2024 for 23 types of cancer, overall, by sex, and by province or territory. We calculated age-standardized rates using data from the 2011 Canadian standard population. RESULTS: In 2024, the number of new cancer cases and deaths from cancer are expected to reach 247 100 and 88 100, respectively. The age-standardized incidence rate (ASIR) and mortality rate (ASMR) are projected to decrease slightly from previous years for both males and females, with higher rates among males (ASIR 562.2 per 100 000 and ASMR 209.6 per 100 000 among males; ASIR 495.9 per 100 000 and ASMR 152.8 per 100 000 among females). The ASIRs and ASMRs of several common cancers are projected to continue to decrease (i.e., lung, colorectal, and prostate cancer), while those of several others are projected to increase (i.e., liver and intrahepatic bile duct cancer, kidney cancer, melanoma, and non-Hodgkin lymphoma). INTERPRETATION: Although the overall incidence of cancer and associated mortality are declining, new cases and deaths in Canada are expected to increase in 2024, largely because of the growing and aging population. Efforts in prevention, screening, and treatment have reduced the impact of some cancers, but these short-term projections highlight the potential effect of cancer on people and health care systems in Canada.
Neoplasms , Registries , Humans , Canada/epidemiology , Neoplasms/epidemiology , Neoplasms/mortality , Male , Female , Incidence , Sex Distribution , Forecasting , Middle Aged , Aged , Age Distribution , Adult , Mortality/trends
As an important precursor of secondary inorganic aerosols (SIAs), ammonia (NH3) plays a key role in fine particulate matter (PM2.5) formation. In order to investigate its impacts on haze formation in the North China Plain (NCP) during winter, NH3 concentrations were observed at a high-temporal resolution of 1 min by using the SP-DOAS in Tai'an from December 2021 to February 2022. During the observation period, the average NH3 concentration was 11.84 ± 5.9 ppbv, and it was determined as an ammonia-rich environment during different air quality conditions. Furthermore, the average concentrations of sulfate (SO42-), nitrate (NO3-) and ammonium (NH4+) were 9.54 ± 5.97 µg/m3, 19.09 ± 14.18 µg/m3 and 10.72 ± 6.53 µg/m3, respectively. Under the nitrate-dominated atmospheric environment, aerosol liquid water content (ALWC) was crucial for NH3 particle transformation during haze aggravation, and the gas-particle partitioning of ammonia played an important role in the SIAs formation. The reconstruction of the molecular composition further indicated that ammonium nitrate (NH4NO3) plays a dominant role in the increase of PM2.5 during haze events. Consequently, future efforts to mitigate fine particulate pollution in this region should focus on controlling NH4NO3 levels. In ammonia-rich environments, NO3- formation is more dependent on the concentration of nitric acid (HNO3). The sensitive analysis of TNO3 (HNO3 + NO3-) and NHX (NH3 + NH4+) reduction using the thermodynamic model suggested that the NO3- concentration decreases linearly with the reduction of TNO3. And the concentration of NO3- decreases rapidly only when NHX is reduced by 50-60 %. Reducing NOX emissions is the most effective way to alleviate nitrate pollution in this region.
BACKGROUND: Extracellular ATP-AMP-adenosine metabolism plays a pivotal role in modulating tumor immune responses. Previous studies have shown that the conversion of ATP to AMP is primarily catalysed by Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), a widely studied ATPase, which is expressed in tumor-associated immune cells. However, the function of ATPases derived from tumor cells themselves remains poorly understood. The purpose of this study was to investigate the role of colon cancer cell-derived ATPases in the development and progression of colon cancer. METHODS: Bioinformatic and tissue microarray analyses were performed to investigate the expression of ATPase family members in colon cancer. An ATP hydrolysis assay, high-performance liquid chromatography (HPLC), and CCK8 and colony formation assays were used to determine the effects of ENTPD2 on the biological functions of colon cancer cells. Flow cytometric and RNA-seq analyses were used to explore the function of CD8+ T cells. Immunoelectron microscopy and western blotting were used to evaluate the expression of ENTPD2 in exosomes. Double-labelling immunofluorescence and western blotting were used to examine the expression of ENTPD2 in serum exosomes and colon cancer tissues. RESULTS: We found that ENTPD2, rather than the well-known ATPase CD39, is highly expressed in cancer cells and is significantly positively associated with poor patient prognosis in patients with colon cancer. The overexpression of ENTPD2 in cancer cells augmented tumor progression in immunocompetent mice by inhibiting the function of CD8+ T cells. Moreover, ENTPD2 is localized primarily within exosomes. On the one hand, exosomal ENTPD2 reduces extracellular ATP levels, thereby inhibiting P2X7R-mediated NFATc1 nuclear transcription; on the other hand, it facilitates the increased conversion of ATP to adenosine, hence promoting adenosine-A2AR pathway activity. In patients with colon cancer, the serum level of exosomal ENTPD2 is positively associated with advanced TNM stage and high tumor invasion depth. Moreover, the level of ENTPD2 in the serum exosomes of colon cancer patients is positively correlated with the ENTPD2 expression level in paired colon cancer tissues, and the ENTPD2 level in both serum exosomes and tissues is significantly negatively correlated with the ENTPD2 expression level in tumor-infiltrating CD8+ T cells. CONCLUSION: Our study suggests that exosomal ENTPD2, originated from colon cancer cells, contributes to the immunosuppressive microenvironment by promoting ATP-adenosine metabolism. These findings highlight the importance of exosome-derived hydrolytic enzymes as independent entities in shaping the tumor immune microenvironment.
Adenosine Triphosphate , Adenosine , Apyrase , CD8-Positive T-Lymphocytes , Colonic Neoplasms , Exosomes , Humans , Exosomes/metabolism , Adenosine/metabolism , Adenosine Triphosphate/metabolism , Colonic Neoplasms/pathology , Colonic Neoplasms/metabolism , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , Apyrase/metabolism , Apyrase/genetics , Animals , Mice , Cell Line, Tumor , Male , Female , Metabolic Reprogramming , Receptor, Adenosine A2A
To explore the intrinsic mechanism of pure organic room temperature and clustering-induced phosphorescence and investigate mechanochromism and structural-function relationships, here, 4-(2-(9H-carbazol-9-yl)phenyl)-2-amino-6-methoxypyridine-3,5-dicarbonitrile (Lo-CzAD), 4-(3-(9H-carbazol-9-yl)phenyl)-2-amino-6-methoxypyridine-3,5-dicarbonitrile (Lm-CzAD), and 4-(4-(9H-carbazol-9-yl)phenyl)-2-amino-6-methoxypyridine-3,5-dicarbonitrile (Lp-CzAD) were designed and synthesized by choosing self-made carbazole and 3, 5-dicyanopyridine (DCP) unit as electron acceptor and electron donor in sequence. Compared with crystals Lm-CzAD and Lp-CzAD, crystal Lo-CzAD shows better room temperature phosphorescence (RTP) performance, with RTP lifetimes of 187.16 ms, as well as afterglows 1s, which are attributed to twisted carbazole unit and donor-acceptor (D-A) molecular conformation, big crystal density and spin orbit coupling constant ξ (S1 â T1 and S1 â T2), as well as intermolecular H type stacking and small ξ (S0 â T1). By choosing urea and PPh3 as host materials and tuning doping ratio, four doping systems were successfully constructed, significantly improving RTP performance of Lo-CzAD and Lp-CzAD, as well as showing different fluorescence and RTP. The lifetimes and afterglows of pure organic Urea/Lo-CzAD and Urea/Lp-CzAD systems are up to 478.42 ms, 5 s, 261.66 ms and 4.5 s in turn. Moreover, Lo-CzAD and Lp-CzAD show time-dependent RTP in doping systems due to monomer and aggregate dispersion, as well as clustering-induced phosphorescence. Based on the different luminescent properties, multiple information encryptions were successfully constructed.
OBJECTIVE: There is limited consensus regarding management of spinal epidural abscesses (SEA), particularly in patients without neurologic deficits. Several models have been created to predict failure of medical management in patients with SEA. We evaluate the external validity of five predictive models in an independent cohort of patients with SEA. METHODS: 176 patients with SEA between 2010 and 2019 at our institution were identified, and variables relevant to each predictive model were collected. Published prediction models were used to assign probability of medical management failure to each patient. Predicted probabilities of medical failure and actual patient outcomes were used to create Receiver Operating Characteristic (ROC) curves, with the area under the ROC curve (AUROC) used to quantify a model's discriminative ability. Calibration curves were plotted using predicted probabilities and actual outcomes. The Spiegelhalter Z-test was used to determine adequate model calibration. RESULTS: One model (Kim et al.) demonstrated good discriminative ability and adequate model calibration in our cohort (ROC = 0.831, p-value = 0.83). Parameters included in the model were age >65, diabetes, MRSA infection, and neurologic impairment. Four additional models did not perform well for discrimination or calibration metrics (Patel et al., ROC=0.580, p=<0.0001; Shah et al., ROC=0.653, p=<0.0001; Baum et al., ROC=0.498, p=<0.0001; Page et al., ROC=0.534, p=<0.0001). CONCLUSION: Only one published predictive model demonstrated acceptable discrimination and calibration in our cohort, suggesting limited generalizability of the evaluated models. Multi-institutional data may facilitate the development of widely applicable models to predict medical management failure in patients with SEA.
Detecting early-stage esophageal squamous cell carcinoma (ESCC) and precancerous lesions is critical for improving survival. Here, we conduct whole-genome bisulfite sequencing (WGBS) on 460 cfDNA samples from patients with non-metastatic ESCC or precancerous lesions and matched healthy controls. We develop an expanded multimodal analysis (EMMA) framework to simultaneously identify cfDNA methylation, copy number variants (CNVs), and fragmentation markers in cfDNA WGBS data. cfDNA methylation markers are the earliest and most sensitive, detectable in 70% of ESCCs and 50% of precancerous lesions, and associated with molecular subtypes and tumor microenvironments. CNVs and fragmentation features show high specificity but are linked to late-stage disease. EMMA significantly improves detection rates, increasing AUCs from 0.90 to 0.99, and detects 87% of ESCCs and 62% of precancerous lesions with >95% specificity in validation cohorts. Our findings demonstrate the potential of multimodal analysis of cfDNA methylome for early detection and monitoring of molecular characteristics in ESCC.
Biomarkers, Tumor , DNA Copy Number Variations , DNA Methylation , Early Detection of Cancer , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Precancerous Conditions , Humans , Esophageal Squamous Cell Carcinoma/genetics , Esophageal Squamous Cell Carcinoma/diagnosis , Precancerous Conditions/genetics , Precancerous Conditions/diagnosis , Precancerous Conditions/pathology , Esophageal Neoplasms/genetics , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/pathology , Male , Early Detection of Cancer/methods , Female , Biomarkers, Tumor/genetics , Middle Aged , Aged , Epigenome , Cell-Free Nucleic Acids/genetics , Cell-Free Nucleic Acids/blood , Whole Genome Sequencing/methods , Tumor Microenvironment/genetics
Precise polyamine metabolism regulation is vital for cells and organisms. Mutations in spermine synthase (SMS) cause Snyder-Robinson intellectual disability syndrome (SRS), characterized by significant spermidine accumulation and autophagy blockage in the nervous system. Emerging evidence connects polyamine metabolism with other autophagy-related diseases, such as Tauopathy, however, the functional intersection between polyamine metabolism and autophagy in the context of these diseases remains unclear. Here, we altered SMS expression level to investigate the regulation of autophagy by modulated polyamine metabolism in Tauopathy in Drosophila and human cellular models. Interestingly, while complete loss of Drosophila spermine synthase (dSms) impairs lysosomal function and blocks autophagic flux recapitulating SRS disease phenotype, partial loss of dSms enhanced autophagic flux, reduced Tau protein accumulation, and led to extended lifespan and improved climbing performance in Tauopathy flies. Measurement of polyamine levels detected a mild elevation of spermidine in flies with partial loss of dSms. Similarly, in human neuronal or glial cells, partial loss of SMS by siRNA-mediated knockdown upregulated autophagic flux and reduced Tau protein accumulation. Importantly, proteomics analysis of postmortem brain tissue from Alzheimer's disease (AD) patients showed a significant albeit modest elevation of SMS level. Taken together, our study uncovers a functional correlation between polyamine metabolism and autophagy in AD: SMS reduction upregulates autophagy, suppresses Tau accumulation, and ameliorates neurodegeneration and cell death. These findings provide a new potential therapeutic target for AD.
Autophagy , Spermine Synthase , tau Proteins , Animals , tau Proteins/metabolism , Humans , Spermine Synthase/metabolism , Spermine Synthase/genetics , Drosophila melanogaster/metabolism , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Tauopathies/metabolism , Tauopathies/pathology , Neurons/metabolism , Neurons/pathology , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/genetics , Spermidine/metabolism , Disease Models, Animal , Lysosomes/metabolism , Drosophila/metabolism , Mental Retardation, X-Linked
The core of tumor cell metabolism is the management of energy metabolism due to the extremely high energy requirements of tumor cells. The purine nucleotide synthesis pathway in cells uses the purinosomes as an essential spatial structural complex. In addition to serving a crucial regulatory role in the emergence and growth of tumors, it contributes to the synthesis and metabolism of purine nucleotides. The significance of purine metabolism in tumor cells is initially addressed in this current article. The role of purinosomes as prospective therapeutic targets is then reviewed, along with a list of the signaling pathways that play in the regulation of tumor metabolism. A thorough comprehension of the function of purinosomes in the control of tumor metabolism can generate fresh suggestions for the creation of innovative cancer treatment methods.
The escalating epidemic of PRRSV-1 in China has prompted widespread concern regarding the evolution of strains, disparities in pathogenicity to herds, and immunological detection of emerging strains. The nucleocapsid (N) protein, as a highly conserved protein with immunogenic properties in PRRSV, is a subject of intensive study. In this research, the recombinant His-N protein was expressed based on the N gene of PRRSV-1 using a prokaryotic expression system and then administered to BALB/c mice. A cell fusion protocol was implemented between SP2/0 cells and splenocytes, resulting in the successful screening of a monoclonal antibody against the N protein, designated as mAb 2D7, by indirect ELISA. Western Blot analysis and Indirect Immunofluorescence Assay (IFA) confirmed that mAb 2D7 positively responded to PRRSV-1. By constructing and expressing a series of truncated His-fused N proteins, a B-cell epitope of N protein, 59-AAEDDIR-65, was identified. A sequence alignment of two genotypes of PRRSV revealed that this epitope is relatively conserved in PRRSV, yet more so in genotype 1. Cross-reactivity analysis by Western blot analysis demonstrated that the B-cell epitope containing D62Y mutation could not be recognized by mAb 2D7. The inability of mAb 2D7 to recognize the epitope carrying the D62Y mutation was further determined using an infectious clone of PRRSV. This research may shed light on the biological significance of the N protein of PRRSV, paving the way for the advancement of immunological detection and development of future recombinant marker vaccine.
During our previous bilateral adrenal vein sampling (AVS) procedure, the authors observed that accessing the left adrenal vein through the antecubital vein was more feasible than the conventional femoral vein. Meanwhile, the femoral vein pathway facilitated access to the right adrenal vein than the antecubital vein pathway. Therefore, the authors hypothesized that simultaneous bilateral AVS via the antecubital combined with the femoral vein pathway could improve the success rate. A total of 94 cases of AVS via the antecubital combined with the femoral vein pathway were performed, while the remaining 20 cases employed the antecubital vein pathway at our center between August 2020 and April 2023. Furthermore, a meta-analysis was conducted in this study using 15 selected articles to determine the success rate of AVS in each center and pathway. The success rate of ACTH-stimulated simultaneous bilateral AVS via the antecubital vein combined with the femoral vein pathway was 92.85% (P = .503) on the right and 95.00% (P < .001) on the left. In the antecubital vein pathway, the success rates were only 25.00% (P < .001) on the right side and 80.00% (P = .289) on the left side. The results of meta-analysis demonstrated a success rate of 78.16% on the right and 94.98% on the left for ACTH-stimulated AVS via the femoral vein pathway. Based on our center's experience, simultaneous bilateral adrenal vein sampling via the combined pathway could improve the success rate of AVS in the short term and shorten the learning curve.
Background Dermatofibrosarcoma protuberans (DFSP) is one of the most challenging cutaneous cancers in surgical clinic practice. Excision with negative margins is essential for effective disease control. However, wide surgical margins and maximal tissue conservation are mutually exclusive. Mohs micrographic surgery conserves tissue but is time-consuming. Thus, we developed a novel specimen radiography system that can be used intraoperatively. Aims To introduce a specimen radiography system for evaluating intraoperative surgical margins in patients with dermatofibrosarcoma protuberans. Methods Since September 2017, we have treated seven biopsy-proven cases of local DFSPs via local excision with surgical margins of 2-4 cm. During operations, the operative specimens were screened using the specimen radiography system. All surgical specimens were pathologically examined intraoperatively. Results Five patients were men and two were women, of median age 36 years. The mean radiographic screening time was 9.7 ± 2.3 min. Radiographically negative margins were confirmed intraoperatively. The minimal margin width ranged from 5.0 to 35.4 mm (mean width 16.9 ± 10.4 mm). The intraoperatively negative radiographic margins were consistent with those revealed by postoperative pathology. The minimal pathological margin width ranged from 4.0 to 34.5 mm (mean 16.6 ± 10.1 mm) and was not significantly different from the intraoperative data. Limitations The sample size was small and positive or negative predictive values were not calculated. Conclusions We introduce a novel method of intraoperative surgical margin assessment for DFSP patients. It may find broad clinical and research applications during oncoplastic surgery.
