The potential association between metabolic disorders and pulmonary tuberculosis: a Mendelian randomization study.

BACKGROUND: Metabolic disorders (MetDs) have been demonstrated to be closely linked to numerous diseases. However, the precise association between MetDs and pulmonary tuberculosis (PTB) remains poorly understood. METHOD: Summary statistics for exposure and outcomes from genome-wide association studies (GWASs) for exposures and outcomes were obtained from the BioBank Japan Project (BBJ) Gene-exposure dataset. The 14 clinical factors were categorized into three groups: metabolic laboratory markers, blood pressure, and the MetS diagnostic factors. The causal relationship between metabolic factors and PTB were analyzed using two-sample Mendelian Randomization (MR). Additionally, the direct effects on the risk of PTB were investigated through multivariable MR. The primary method employed was the inverse variance-weighted (IVW) model. The sensitivity of this MR analysis was evaluated using MR-Egger regression and the MR-PRESSO global test. RESULTS: According to the two-sample MR, HDL-C, HbA1c, TP, and DM were positively correlated with the incidence of active TB. According to the multivariable MR, HDL-C (IVW: OR 2.798, 95% CI 1.484-5.274, P = 0.001), LDL (IVW: OR 4.027, 95% CI 1.140-14.219, P = 0.03) and TG (IVW: OR 2.548, 95% CI 1.269-5.115, P = 0.009) were positively correlated with the occurrence of PTB. TC (OR 0.131, 95% CI 0.028-0.607, P = 0.009) was negatively correlated with the occurrence of PTB. We selected BMI, DM, HDL-C, SBP, and TG as the diagnostic factors for metabolic syndrome. DM (IVW, OR 1.219, 95% CI 1.040-1.429 P = 0.014) and HDL-C (IVW, OR 1.380, 95% CI 1.035-1.841, P = 0.028) were directly correlated with the occurrence of PTB. CONCLUSIONS: This MR study demonstrated that metabolic disorders, mainly hyperglycemia, and dyslipidemia, are associated with the incidence of active pulmonary tuberculosis.

Expression of nuclear receptor co­activator 7 protein is associated with poor prognosis of breast cancer.

Nuclear receptor coactivator 7 (NCOA7) is an estrogen receptor binding protein. Its role in breast cancer progression has so far remained elusive. The present study aimed to determine the expression levels of NCOA7 in breast tumor samples and confirmed its potential utility as a breast cancer prognostic biomarker. The expression of NCOA7 was detected by immunohistochemical staining in 241 breast cancer tumor samples and 163 adjacent normal tissue samples. The association of NCOA7 expression with the clinicopathological characteristics and overall survival were statistically analyzed. Cell proliferation was determined by Cell Counting Kit-8 and colony-formation assays. Cell migration was detected using wound-healing and Transwell assays. NCOA7 was positively expressed in 44% of breast tumor tissues. The expression of NCOA7 was positively associated with tumor size (T-stage; P=0.005) and lymph node metastasis (N-stage; P=0.008). Additional statistical analysis indicated that the expression of NCOA7 was associated with patient age, tumor size and lymph node metastasis in patients with triple-negative breast cancer (TNBC) compared with that in patients with non-TNBC. The overall survival of patients with NCOA7-positive breast cancer was significantly lower than that of patients with NCOA7-negative breast cancer (P=0.006). Among the patients with lymph node metastasis, the overall survival was reversely associated with the expression of NCOA7 (P=0.042). Furthermore, knockdown of NCOA7 expression in breast cancer T47D and MCF7 cells significantly inhibited both cell proliferation and migration, suggesting that this protein may exert a role in driving breast cancer progression. Taken together, these results indicate that the expression of NCOA7 is associated with poor prognosis of breast cancer and suggest that this protein may be a driver for metastasis and a potential therapeutic target for advanced breast cancer.

STK10 mutations block erythropoiesis in acquired pure red cell aplasia via impairing ribosome biogenesis.

Acquired pure red cell aplasia (PRCA) is anemia associated with the absence of erythroblasts and is characterized by persistent and easy recurrence. However, the underlying mechanisms of acquired PRCA remain obscure, and the role of gene mutations in the pathogenesis of acquired PRCA is not fully characterized. In the present study, we detected thirty newly diagnosed patients with acquired PRCA using whole exome sequencing, and a potential role for STK10 in acquired PRCA was uncovered. The mRNA levels of STK10 in three patients with STK10 mutations were decreased. These three patients had a poor response to immunosuppressive therapy and two died in the follow-up period. Here we report that knockdown of STK10 inhibits erythroid differentiation and promotes apoptosis of K562 cells. We show that knockdown of STK10 resulted in inhibition of ribosome biogenesis and reduced ribosome levels in K562 cells. We also show that the p53 signaling pathway is activated by knockdown of STK10. Our results imply that ribosome biogenesis downregulation together with pathological p53 activation prevents normal erythropoiesis. Our study uncovers a new pathophysiological mechanism leading to acquired PRCA driven by STK10 mutations.

Releasing characteristics of toxic chemicals from polystyrene microplastics in the aqueous environment during photoaging process.

Microplastics (MPs) are pervasive in the environment and inevitably undergo photoaging due to UV irradiation. This study delved into the dynamic releasing and transformation process of toxic chemicals from polystyrene microplastics (PS MPs) during photoaging, a subject that remains underexplored. It was revealed that photoaging led to substantial alterations in the physicochemical properties of PS MPs, initiating polymer chain scission and facilitating the release of a large number of toxic chemicals, including numerous organic compounds and several inorganic compounds. The kinetic analysis revealed a dynamic release pattern for PS MPs, where under varying UV intensities (2, 5, and 10 mW/cm2), the release rate (kDOC) initially increased and then decreased, peaking at a total irradiation energy of approximately 7 kW·h/m2. Furthermore, chemicals in leachate were transformed into compounds with smaller molecular weight, higher oxidized and greater unsaturated state over the prolonged photoaging. This transformation was primarily attributed to two reasons. Firstly, the aged PS MPs released chemicals with higher oxidized state compared to the pristine MPs. Secondly, the chemicals previously released underwent further reactions. Besides, among the complex leachate generated by aged PS MPs, the organic chemicals characterized by small molecular weight and high oxidized state exhibited notable acute toxicity, whereas heavy metal ions showed lesser toxicity, and anions were non-toxic. This study shed more light on the photoaging process of PS MPs, releasing characteristics of organic chemicals, and the potential environmental risks associated with plastic wastes.

Degradation of the α-Carboxyl Terminus 11 Peptide: In Vivo and Ex Vivo Impacts of Time, Temperature, Inhibitors, and Gender in Rat.

In previous research, a synthetic α-carboxyl terminus 1 (αCT1) peptide derived from connexin 43 (Cx43) and its variant (αCT11) showed beneficial effects in an ex vivo ischemia-reperfusion (I/R) heart injury model in mouse. In an in vivo mouse model of cryo-induced ventricular injury, αCT1 released from adhesive cardiac patches reduced Cx43 remodeling and arrhythmias, as well as maintained cardiac conduction. Whether intravenous injection of αCT1 or αCT11 produces similar outcomes has not been investigated. Given the possibility of peptide degradation in plasma, this study utilized in vivo I/R cardiac injury and ex vivo blood plasma models to examine factors that may limit the therapeutic potential of peptide therapeutics in vivo. Following tail vein administration of αCT11 (100 µM) in blood, no effect on I/R infarct size was observed in adult rat hearts on day 1 (D1) and day 28 (D28) after injury (p > 0.05). There was also no difference in the echocardiographic ejection fraction (EF%) between the control and the αCT11 groups (p > 0.05). Surprisingly, αCT11 in blood plasma collected from these rats was undetectable within ∼10 min after tail vein injection. To investigate factors that may modulate αCT11 degradation in blood, αCT11 was directly added to blood plasma isolated from normal rats without I/R and peptide levels were measured under different experimental conditions. Consistent with in vivo observations, significant αCT11 degradation occurred in plasma within 10 min at 22 and 37 °C and was nearly undetectable by 30 min. These responses were reduced by the addition of protease/phosphatase (PTase/PPTase) inhibitors to the isolated plasma. Interestingly, no significant differences in αCT11 degradation in plasma were noted between male and female rats. We conclude that fast degradation of αCT11 is likely the reason that no beneficial effects were observed in the in vivo I/R model and inhibition or shielding from PTase/PPTase activity may be a strategy that will assist with the viability of peptide therapeutics.

Liver fibrosis automatic diagnosis utilizing dense-fusion attention contrastive learning network.

BACKGROUND: Liver fibrosis poses a significant public health challenge given its elevated incidence and associated mortality rates. Diffusion-Weighted Imaging (DWI) serves as a non-invasive diagnostic tool for supporting the identification of liver fibrosis. Deep learning, as a computer-aided diagnostic technology, can assist in recognizing the stage of liver fibrosis by extracting abstract features from DWI images. However, gathering samples is often challenging, posing a common dilemma in previous research. Moreover, previous studies frequently overlooked the cross-comparison information and latent connections among different DWI parameters. Thus, it is becoming a challenge to identify effective DWI parameters and dig potential features from multiple categories in a dataset with limited samples. PURPOSE: A self-defined Multi-view Contrastive Learning Network is developed to automatically classify multi-parameter DWI images and explore synergies between different DWI parameters. METHODS: A Dense-fusion Attention Contrastive Learning Network (DACLN) is designed and used to recognize DWI images. Concretely, a multi-view contrastive learning framework is constructed to train and extract features from raw multi-parameter DWI. Besides, a Dense-fusion module is designed to integrate feature and output predicted labels. RESULTS: We evaluated the performance of the proposed model on a set of real clinical data and analyzed the interpretability by Grad-CAM and annotation analysis, achieving average scores of 0.8825, 0.8702, 0.8933, 0.8727, and 0.8779 for accuracy, precision, recall, specificity and F-1 score. Of note, the experimental results revealed that IVIM-f, CTRW-ß, and MONO-ADC exhibited significant recognition ability and complementarity. CONCLUSION: Our method achieves competitive accuracy in liver fibrosis diagnosis using the limited multi-parameter DWI dataset and finds three types of DWI parameters with high sensitivity for diagnosing liver fibrosis, which suggests potential directions for future research.

Effectiveness of Resistance Band Use in Conjunction With Tai Chi Among Older Adults With Prefrailty to Improve Functional Fitness, Quality of Life, and Heart Rate Variability.

PURPOSE: The current randomized controlled trial aimed to bolster the physical fitness of prefrail older adults, potentially delaying their need for admission to care facilities and enhancing their overall well-being. METHOD: The experimental group received a physical fitness intervention comprising resistance band use and tai chi three times per week for 12 weeks, whereas the control group received frailty-related health education. Thirty-four male participants completed the study. RESULTS: A total of seven items had statistically significant differences at 12- and 16-week posttest, respectively: frailty index (p = 0.03; p = 0.03); Instrumental Activities of Daily Living Scale (p < 0.001; p < 0.001); and physical fitness, back (p < 0.001; p < 0.001); physical fitness, arm curl (p = 0.02; p < 0.001); physical activity (p < 0.001; p = 0.009); quality of life, physiological (p = 0.04; p < 0.001); and heart rate variability (p < 0.001; p < 0.001). CONCLUSION: Results revealed substantial improvements in physical fitness, frailty conditions, self-care abilities, and quality of life, but not balance or lower limb flexibility, for the experimental group. Therefore, exercise interventions may effectively improve prefrail older adults' quality of life. [Journal of Gerontological Nursing, 50(5), 19-26.].

A novel ESIPT fluorescent probe for early detection and assessment of ferroptosis-mediated acute kidney injury via peroxynitrite fluctuation.

BACKGROUND: Acute kidney injury (AKI) poses a severe risk to public health, mostly manifested by damage and death of renal tubular epithelial cells. However, routine blood examination, a conventional approach for clinical detection of AKI, is not available for identifying early-stage AKI. Plenty of reported methods were lack of early biomarkers and real time evaluation tools, which resulted in a vital challenge for early diagnosis of AKI. Therefore, developing novel probes for early detection and assessment of AKI is exceedingly crucial. RESULTS: Based on ESIPT mechanism, a new fluorescent probe (MEO-NO) with 2-(2'-hydroxyphenyl) benzothiazole (HBT) derivatives as fluorophore has been synthesized for dynamic imaging peroxynitrite (ONOO-) levels in ferroptosis-mediated AKI. Upon the addition of ONOO-, MEO-NO exhibited obvious fluorescence changes, a significant Stokes shift (130 nm) and rapid response (approximately 45 s), and featured exceptional sensitivity (LOD = 7.28 nM) as well as high selectivity from the competitive species at physiological pH. In addition, MEO-NO was conducive to the biological depth imaging ONOO- in cells, zebrafish, and mice. Importantly, MEO-NO could monitor ONOO- levels during sorafenib-induced ferroptosis and CP-induced AKI. With the assistance of MEO-NO, we successfully visualized and tracked ONOO- variations for early detection and assessment of ferroptosis-mediated AKI in cells, zebrafish and mice models. SIGNIFICANCE AND NOVELTY: Benefiting from the superior performance of MEO-NO, experimental results further demonstrated that the levels of ONOO- was overexpressed during ferroptosis-mediated AKI in cells, zebrafish, and mice models. The developed novel probe MEO-NO provided a strong visualization tool for imagining ONOO-, which might be a potential method for the prevention, diagnosis, and treatment of ferroptosis-mediated AKI.

Risk of interstitial lung disease with the use of programmed cell death 1 (PD-1) inhibitor compared with programmed cell death ligand 1 (PD-L1) inhibitor in patients with breast cancer: A systematic review and meta-analysis.

Background: Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have become integral elements within the current landscape of breast cancer treatment modalities; however, they are associated with interstitial lung disease (ILD), which is rare but potentially fatal. Notably, only a few studies have compared the difference in ILD incidence between PD-1 and PD-L1 inhibitors. Therefore, this study aimed to assess the discrepancies regarding ILD risk between the two immune checkpoint inhibitors. We also reported three cases of ILD after PD-1 inhibitor treatment. Methods: We comprehensively searched PubMed, EMBASE, and the Cochrane Library to identify clinical trials that investigated PD-1/PD-L1 inhibitor treatment for patients with breast cancer. Pooled overall estimates of incidence and risk ratio (RR) were calculated with a 95% confidence interval (CI), and a mirror group analysis was performed using eligible studies. Results: This meta-analysis included 29 studies with 4639 patients who received PD-1/PD-L1 inhibitor treatment. A higher ILD incidence was observed among 2508 patients treated with PD-1 inhibitors than among 2131 patients treated with PD-L1 inhibitors (0.05 vs. 0.02). The mirror group analysis further revealed a higher ILD event risk in patients treated with PD-1 inhibitors than in those treated with PD-L1 inhibitors (RR = 2.34, 95% CI, 1.13-4.82, P = 0.02). Conclusion: Our findings suggest a greater risk of ILD with PD-1 inhibitors than with PD-L1 inhibitors. These findings are instrumental for clinicians in treatment deliberations, and the adoption of more structured diagnostic approaches and management protocols is necessary to mitigate the risk of ILD.

Dissection, Histological Processing, and Gene Expression Analysis of Murine Supraclavicular Brown Adipose Tissue.

Brown adipose tissue (BAT)-mediated thermogenesis plays an important role in the regulation of metabolism, and its morphology and function can be greatly impacted by environmental stimuli in mice and humans. Currently, murine interscapular BAT (iBAT), which is located between two scapulae in the upper dorsal flank of mice, is the main BAT depot used by research laboratories to study BAT function. Recently, a few previously unknown BAT depots were identified in mice, including one analogous to human supraclavicular brown adipose tissue. Unlike iBAT, murine supraclavicular brown adipose tissue (scBAT) is situated in the intermediate layer of the neck and thus cannot be accessed as readily. To facilitate the study of newly identified mouse scBAT, presented herein is a protocol detailing the steps to dissect intact scBAT from postnatal and adult mice. Due to scBAT's small size relative to other adipose depots, procedures have been modified and optimized specifically for processing scBAT. Among these modifications is the use of a dissecting microscope during tissue collection to increase the precision and homogenization of frozen scBAT samples to raise the efficiency of subsequent qPCR analysis. With these optimizations, the identification of, morphological appearance of, and molecular characterization of the scBAT can be determined in mice.

Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate.

Background/Aims: : The histological characteristics and natural history of precirrhotic primary biliary cholangitis (PBC) with portal hypertension (PH) are unclear. Our aim was to clarify the prevalence, risk factors, and histological characteristics of precirrhotic PBC patients with PH. Methods: : This retrospective study compared the clinical features, histological characteristics, and response to ursodeoxycholic acid (UDCA) between the PH and non-PH groups of precirrhotic PBC patients. Results: : Out of 165 precirrhotic PBC patients, 40 (24.2%) also had PH. According to histological stage 1, 2 and 3 disease, 5.3% (1/19), 17.3% (17/98), and 45.8% (22/48) of patients also had PH, respectively. Precirrhotic PBC with PH was significantly positively correlated with bile duct loss, degree of cytokeratin 7 positivity, and degree of fibrosis in the portal area, but significantly negatively correlated with lymphoid follicular aggregation. Compared to the non-PH group, patients in the PH group showed a higher prevalence of obliterative portal venopathy, incomplete septal fibrosis, portal tract abnormalities and non-zonal sinusoidal dilatation (p<0.05). In addition, patients with PH were more likely to present with symptoms of jaundice, ascites, epigastric discomfort, a poorer response to UDCA, and more decompensation events (p<0.05). High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values were risk factors for precirrhotic PBC with PH. Conclusions: : Approximately 24.2% of precirrhotic PBC patients have PH, which is histologically related to the injury of bile ducts. High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values are associated with increased risk of precirrhotic PBC with PH.

Prognostic Implications of Circulating Plasma Cell Percentage in Multiple Myeloma and Primary Plasma Cell Leukemia Defined by New Criteria.

INTRODUCTION: The definition of primary plasma cell leukemia (pPCL) has been revised from ≥20% to ≥5% circulating plasma cells (CPC). However, the precise prognosis associated with CPC remains controversial. This study aimed to investigate prognostic biomarkers for myeloma patients based on CPC presence. METHODS: A comprehensive analysis was conducted on 309 consecutive patients diagnosed with either multiple myeloma or pPCL, utilizing peripheral blood smears stained with Wright-Giemsa. RESULTS: Patients were grouped by CPC percentage: 0% (221, 71.5%), 1-4% (49, 15.9%), 5-19% (16, 5.2%), ≥20% (23, 7.4%). CPC >5% correlated with unfavorable characteristics, including anemia, renal dysfunction, and advanced International Staging System. Common cytogenetic abnormalities such as 1q21 amplification, 17p deletion, and Myc rearrangement were prevalent among CPC-positive patients. Median progression-free survival (PFS) and overall survival (OS) were shorter in patients with CPC ≥5% (29.47 vs. 10.03 months; 64.10 vs. 12.30 months). Additionally, PFS and OS were shorter in CPC-positive patients without autologous hematopoietic stem cell transplantation (ASCT) and those with response < partial remission to the first-line regimen. Furthermore, an association emerged between soft tissue-related extramedullary disease and inferior PFS, while Myc rearrangement correlated with abbreviated OS. CONCLUSION: Biological characteristics displayed greater aggressiveness in patients with positive CPC, leading to significantly shorter PFS and OS. The presence of CPC, ASCT, and overall response rate were independent prognostic factors. While no new threshold for pPCL with CPCs is proposed, but Myc rearrangements and CPC positivity could serve as ultra-high-risk factors for multiple myeloma.

Comparison of human leukocyte antigen in patients with paroxysmal nocturnal hemoglobinuria of different clone sizes.

Glycosylphosphatidylinositol-anchored protein-deficient hematopoietic stem and progenitor cell development caused by PIGA mutations cannot fully explain the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH). Herein, patients newly diagnosed with PNH at our hospital between April 2019 and April 2021 were recruited. The human leukocyte antigen (HLA) class I and II loci were analyzed, and patients were stratified by PNH clone sizes: small (< 50%) and large (≥ 50%). In 40 patients (29 males; 72.5%), the median PNH clone size was 72%. Thirteen (32.5%) and twenty-seven (67.5%) patients harbored small and large PNH clones, respectively. DRB1*15:01 and DQB1*06:02 had higher frequencies in patients with PNH than in healthy controls (adjusted P-value = 4.10 × 10-4 and 4.10 × 10-4, respectively). Whole HLA class I and II allele contributions differed (P = 0.046 and 0.065, not significant difference) when comparing patients with small and large PNH clones. B*13:01 and C*04:01 allelic frequencies were significantly higher in patients with small clones (P = 0.032 and P = 0.032, respectively). Patients with small clones had higher class II HLA evolutionary divergence (HED) (P = 0.041) and global class I and II HED (P = 0.019). In the entire cohort, 17 HLA aberrations were found in 11 (27.5%) patients. No significant differences in HLA aberrations were found between patients with small or large clones. In conclusion, patients with small clones tended to have a higher frequency of immune attack-associated alleles. A higher HED in patients with small clones may reflect a propensity for T cell-mediated autoimmunity. HLA aberrations were similar between patients with small and large clones.

Dynasore Alleviates LPS-Induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders without available pharmacological therapies. Dynasore is a cell-permeable molecule that inhibits GTPase activity and exerts protective effects in several disease models. However, whether dynasore can alleviate lipopolysaccharide (LPS)-induced ALI is unknown. This study investigated the effect of dynasore on macrophage activation and explored its potential mechanisms in LPS-induced ALI in vitro and in vivo. Methods: Bone marrow-derived macrophages (BMDMs) were activated classically with LPS or subjected to NLRP3 inflammasome activation with LPS+ATP. A mouse ALI model was established by the intratracheal instillation (i.t.) of LPS. The expression of PYD domains-containing protein 3 (NLRP3), caspase-1, and gasdermin D (GSDMD) protein was detected by Western blots. Inflammatory mediators were analyzed in the cell supernatant, in serum and bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assays. Morphological changes in lung tissues were evaluated by hematoxylin and eosin staining. F4/80, Caspase-1 and GSDMD distribution in lung tissue was detected by immunofluorescence. Results: Dynasore downregulated nuclear factor (NF)-κB signaling and reduced proinflammatory cytokine production in vitro and inhibited the production and release of interleukin (IL)-1ß, NLRP3 inflammasome activation, and macrophage pyroptosis through the Drp1/ROS/NLRP3 axis. Dynasore significantly reduced lung injury scores and proinflammatory cytokine levels in both BALF and serum in vivo, including IL-1ß and IL-6. Dynasore also downregulated the co-expression of F4/80, caspase-1 and GSDMD in lung tissue. Conclusion: Collectively, these findings demonstrated that dynasore could alleviate LPS-induced ALI by regulating macrophage pyroptosis, which might provide a new therapeutic strategy for ALI/ARDS.

Label-Free Multiplex Profiling of Exosomal Proteins with a Deep Learning-Driven 3D Surround-Enhancing SERS Platform for Early Cancer Diagnosis.

Identification of protein profiling on plasma exosomes by SERS can be a promising strategy for early cancer diagnosis. However, it is still challenging to detect multiple exosomal proteins simultaneously by SERS since the Raman signals of exosomes detected by conventional colloidal nanocrystals or two-dimensional SERS substrates are incomplete and complex. Herein, we develop a novel three-dimensional (3D) surround-enhancing SERS platform, named 3D se-SERS, for the multiplex detection of exosomal proteins. In this 3D se-SERS, proteins and exosomes are covered with "hotspots" generated by the gold nanoparticles, which surround the analytes densely and three-dimensionally, providing sensitive and comprehensive SERS signals. Combining this 3D se-SERS with a deep learning model, we successfully quantitatively profiled seven proteins including CD63, CD81, CD9, CD151, CD171, TSPAN8, and PD-L1 on the surface of plasma exosomes from patients, which can predict the occurrence and advancement of lung cancer. This 3D se-SERS integrating deep learning technique benefits from high sensitivity and significant multiplexing ability for comprehensive analysis of proteins and exosomes, demonstrating the potential of deep learning-driven 3D se-SERS technology for plasma exosome-based early cancer diagnosis.

Comprehensive analysis based on the disulfidptosis-related genes identifies hub genes and immune infiltration for pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is a prevalent and aggressive malignancy in the digestive tract, requiring accurate prediction and effective treatment strategies. Recently, the discovery of disulfidptosis, a novel form of programmed cell death characterized by abnormal disulfide accumulation, has sparked interest in its role in PAAD. In this study, we aimed to investigate the involvement of disulfidptosis-related genes (DRGs) in PAAD. Using publicly available databases, we conducted a comprehensive analysis exploring the complex relationships between DRGs and important aspects of PAAD, including gene expression, immune response, mutation, drug sensitivity, and functional enrichment. Notably, we observed significant heterogeneity among different disulfidptosis subclusters and identified specific differentially expressed genes in PAAD. Through machine learning techniques, we identified SLC7A11, S100A4, DIAPH3, PRDX1, and SLC7A7 as the most relevant hub genes. We further validated their significance in PAAD by considering their expression patterns, prognostic value, diagnostic potential, diagnostic model, and immune infiltration. This study presents exciting opportunities and challenges in unraveling the underlying mechanisms of PAAD prognosis. It also establishes a foundation for personalized cancer care and the development of innovative immunotherapeutic strategies. By shedding light on the role of DRGs, particularly hub genes, we enhance our understanding and management of PAAD.

Complete blood and urine paraprotein tests as response assessments in multiple myeloma patients treated with bortezomib, cyclophosphamide, and dexamethasone.

Background: This study assessed the effect of standardized efficacy markers on prognosis in patients with newly diagnosed multiple myeloma (MM) during the induction phase of treatment with bortezomib, cyclophosphamide, and dexamethasone (BCD). Methods: We retrospectively analyzed clinical data in 197 newly diagnosed MM patients treated with BCD as front-line regimen at Peking Union Medical College Hospital from January 1, 2013 to December 31, 2018. Results: There were 107 patients with International Staging System (ISS) III and 51 with paraprotein of light chain. Of these, 77 completed nine cycles of the BCD regimen. As the number of treatment cycles increased, the proportions of serum and urine immunofixation electrophoresis (IFE) tests elevated from 40.39% to 62.22% and 16.75% to 37.78%, respectively. More than 90% of intact immunoglobulin chain MM patients were evaluated for blood M protein per cycle, but that of urinary M protein was less than 60%. The detection rate of urinary M protein in light chain MM was more than 70% per cycle. Patients with a very good partial response (VGPR) had longer progression-free survival (PFS) than those with uncertain VGPR (32 vs. 26 months, p = 0.0336). Of the 141 patients who completed at least four cycles without undergoing autologous hematopoietic stem cell transplantation, those who were regularly assessed at every other cycle showed more favorable PFS than those who visited irregularly (27 vs. 22 months, p = 0.059). Conclusion: Urinary M protein detection rate is significantly lower than that in serum, leading to an overestimation of efficacy, premature reduction of treatment intensity, and shortened PFS. Precise response assessments are critical to treatment decisions and clinical diagnoses.

Origin and evolution of pentanucleotide repeat expansions at the familial cortical myoclonic tremor with epilepsy type1 - SAMD12 locus.

Familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1) is caused by (TTTTA)exp(TTTCA)exp repeat expansions in SAMD12, while pure (TTTTA)exp is polymorphic. Our investigation focused on the origin and evolution of pure (TTTTA)exp and (TTTTA)exp(TTTCA)exp at this locus. We observed a founder effect between them. The phylogenetic analysis suggested that the (TTTTA)exp(TTTCA)exp might be generated from pure (TTTTA)exp through infrequent transformation events. Long-read sequencing revealed somatic generation of (TTTTA)exp(TTTCA)exp from pure (TTTTA)exp, likely via long segment (TTTCA) repeats insertion. Our findings indicate close relationships between the non-pathogenic (TTTTA)exp and the pathogenic (TTTTA)exp(TTTCA)exp, with dynamic interconversions. This sheds light on the genesis of pathogenic repeat expansions from ancestral premutation alleles. Our results may guide future studies in detecting novel repeat expansion disorders and elucidating repeat expansion mutational processes, thereby enhancing our understanding of human genomic variation.

Genome-Wide Identification and Transcriptional Analysis of AP2/ERF Gene Family in Pearl Millet (Pennisetum glaucum).

The apetala2/ethylene response factor (AP2/ERF) gene family plays a crucial role in regulating plant growth and development and responding to different abiotic stresses (e.g., drought, heat, cold, and salinity). However, the knowledge of the ERF family in pearl millet remains limited. Here, a total of 167 high-confidence PgERF genes are identified and divided into five subgroups based on gene-conserved structure and phylogenetic analysis. Forty-one pairs of segmental duplication are found using collinear analysis. Nucleotide substitution analysis reveals these duplicated pairs are under positive purification, indicating they are actively responding to natural selection. Comprehensive transcriptomic analysis reveals that PgERF genesare preferentially expressed in the imbibed seeds and stem (tilling stage) and respond to heat, drought, and salt stress. Prediction of the cis-regulatory element by the PlantCARE program indicates that PgERF genes are involved in responses to environmental stimuli. Using reverse transcription quantitative real-time PCR (RT-qPCR), expression profiles of eleven selected PgERF genes are monitored in various tissues and during different abiotic stresses. Transcript levels of each PgERF gene exhibit significant changes during stress treatments. Notably, the PgERF7 gene is the only candidate that can be induced by all adverse conditions. Furthermore, four PgERF genes (i.e., PgERF22, PgERF37, PgERF88, and PgERF155) are shown to be involved in the ABA-dependent signaling pathway. These results provide useful bioinformatic and transcriptional information for understanding the roles of the pearl millet ERF gene family in adaptation to climate change.

Impact of hyperoxia on the gut during critical illnesses.

Molecular oxygen is typically delivered to patients via oxygen inhalation or extracorporeal membrane oxygenation (ECMO), potentially resulting in systemic hyperoxia from liberal oxygen inhalation or localized hyperoxia in the lower body from peripheral venoarterial (VA) ECMO. Consequently, this exposes the gastrointestinal tract to excessive oxygen levels. Hyperoxia can trigger organ damage due to the overproduction of reactive oxygen species and is associated with increased mortality. The gut and gut microbiome play pivotal roles in critical illnesses and even small variations in oxygen levels can have a dramatic influence on the physiology and ecology of gut microbes. Here, we reviewed the emerging preclinical evidence which highlights how excessive inhaled oxygen can provoke diffuse villous damage, barrier dysfunction in the gut, and gut dysbiosis. The hallmark of this dysbiosis includes the expansion of oxygen-tolerant pathogens (e.g., Enterobacteriaceae) and the depletion of beneficial oxygen-intolerant microbes (e.g., Muribaculaceae). Furthermore, we discussed potential impact of oxygen on the gut in various underlying critical illnesses involving inspiratory oxygen and peripheral VA-ECMO. Currently, the available findings in this area are somewhat controversial, and a consensus has not yet to be reached. It appears that targeting near-physiological oxygenation levels may offer a means to avoid hyperoxia-induced gut injury and hypoxia-induced mesenteric ischemia. However, the optimal oxygenation target may vary depending on special clinical conditions, including acute hypoxia in adults and neonates, as well as particular patients undergoing gastrointestinal surgery or VA-ECMO support. Last, we outlined the current challenges and the need for future studies in this area. Insights into this vital ongoing research can assist clinicians in optimizing oxygenation for critically ill patients.