Effect of pre-plasma on terahertz radiation from two-color laser plasma filaments in a collinear geometry.

Terahertz (THz) radiation from air plasma in the presence of pre-plasma in a collinear geometry is investigated experimentally, where the pre-plasma is formed by a pre-pulse with a Gaussian beam profile and the measured THz radiation is driven by a main laser pulse. The pre-plasma has a de-focusing effect for the main pulse passing through it, which reduces the effective length of the plasma filament formed by the main laser pulse for THz radiation. It is found that only the part not overlapped by the pre-plasma can actually produce THz radiation. Thus, the amplitude of the THz pulse driven by the main pulse can be modified by changing the spatial separation between two plasma filaments. The experimental observations are qualitatively in agreement with our numerical simulation results. It is also found that the change of the time delay between the pre-pulse and the main pulse does not change the THz radiation amplitude for a given spatial separation. This study suggests a practical way for the manipulation of THz waves through an interaction between laser plasma filaments.

[Fire dragon cupping in prevention and treatment of chemotherapy-induced nausea and vomiting in breast cancer: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy and safety of fire dragon cupping in prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in breast cancer. METHODS: Sixty breast cancer patients receiving medium-high emetogenic chemotherapy regimen were randomly divided into an observation group (30 cases, 3 cases dropped out) and a control group (30 cases, 3 cases dropped out). In both groups, 5 mg tropisetron hydrochloride was given intravenously on the day of chemotherapy and 1st to 3rd days after chemotherapy. In the observation group, fire dragon cupping on the abdomen was applied on 1st, 3rd and 5th days after chemotherapy. The incidence of nausea, vomiting, loss of appetite, abdominal pain, abdominal distension, the severity of nausea, vomiting on 1st to 6th days after chemotherapy, and the duration of nausea, vomiting, loss of appetite were observed in the two groups. The self-rating anxiety scale (SAS) score, general comfort questionnaire scale (GCQ) score before and after treatment and remedy antiemetic medication were observed in the two groups, and the safety was evaluated. RESULTS: On 2nd to 6th days after chemotherapy, the number of patients with nausea, loss of appetite and abdominal distension and nausea scores in the observation group were lower than those in the control group (P<0.05). On 1st to 3rd days after chemotherapy, the number of patients with vomiting and vomiting scores in the observation group were lower than those in the control group (P<0.05). The duration of nausea, vomiting and loss of appetite in the observation group were shorter than those in the control group (P<0.05). In the observation group, there was no significant difference in SAS and GCQ scores before and after treatment (P>0.05). After treatment, the GCQ score in the control group was decreased compared with that before treatment (P<0.05). After treatment, there was no significant difference in SAS and GCQ scores between the two groups (P>0.05). There was no significant difference in the number of patients using remedy medication between the two groups (P>0.05). No adverse reaction occurred during treatment in both groups. CONCLUSION: Fire dragon cupping can effectively reduce the incidence of nausea, vomiting, loss of appetite and the severity of nausea, vomiting related to chemotherapy in breast cancer, and improve patient comfort, and have good safety.

Based on Immune Microenvironment and Genomic Status, Exploring Immunotherapy in Advanced Hidradenocarcinoma: A Retrospective Analysis.

There are no standard treatment guidelines for hidradenocarcinoma, and the immune microenvironment and genomic data are very limited. Thus, in this study the immune microenvironment and genomic indicators in hidradenocarcinoma was investigated, and immunotherapy for hidradenocarcinoma was initially explored. Forty-seven hidradenocarcinoma patients were retrospectively collected. Immunohistochemical staining was performed to identify CD3/CD8+ T cells and programmed death ligand-1 expression. In total, 89.4% and 10.6% of samples had Immunoscores of 0-25% and 25-70%. Tumour proportion score distribution was as follows: tumour proportion score < 1% in 72.4%, 1-5% in 17.0%, and > 5% in 10.6%. Combined positive score distribution was as follows: combined positive score < 1 in 63.8%, 1-5 in 14.9%, and > 5 in 21.3%. Next-generation sequencing revealed that TP53 (33%), PI3KCA (22%), and ERBB3 (22%) were the most frequently mutated genes. The PI3K-Akt signalling pathway, growth, and MAPK signalling pathways were significantly enriched. Five patients had a low TMB (< 10 muts/Mb), and 9 patients had MSS. Three patients treated with immune combined with chemotherapy achieved significant tumour regression, and the progression-free survival was 28.8 months. In conclusion, the hidradenocarcinoma immune microenvironment tends to be noninflammatory. Evidence-based targets for targeted therapy are lacking. Immunotherapy combined with chemotherapy may be better for most advanced hidradenocarcinoma patients with a noninflammatory microenvironment.

Millijoule Terahertz Radiation from Laser Wakefields in Nonuniform Plasmas.

We report the experimental measurement of millijoule terahertz (THz) radiation emitted in the backward direction from laser wakefields driven by a femtosecond laser pulse of few joules interacting with a gas target. By utilizing frequency-resolved energy measurement, it is found that the THz spectrum exhibits two peaks located at about 4.5 and 9.0 THz, respectively. In particular, the high frequency component emerges when the drive laser energy exceeds 1.26 J, at which electron acceleration in the forward direction is detected simultaneously. Theoretical analysis and particle-in-cell simulations indicate that the THz radiation is generated via mode conversion from the laser wakefields excited in plasma with an up-ramp profile, where radiations both at the local electron plasma frequency and its harmonics are produced. Such intense THz sources may find many applications in ultrafast science, e.g., manipulating the transient states of matter.

[Cystic fibrosis primarily presenting with pseudo-Bartter syndrome: a report of three cases and literature review]. / 以假性Bartter综合征为主要表现的囊性纤维化患儿3ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

OBJECTIVES: To summarize the clinical characteristics and genetic variations in children with cystic fibrosis (CF) primarily presenting with pseudo-Bartter syndrome (CF-PBS), with the aim to enhance understanding of this disorder. METHODS: A retrospective analysis was performed on the clinical data of three children who were diagnosed with CF-PBS in Hunan Children's Hospital from January 2018 to August 2023, and a literature review was performed. RESULTS: All three children had the onset of the disease in infancy. Tests after admission showed hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, and genetic testing showed the presence of compound heterozygous mutation in the CFTR gene. All three children were diagnosed with CF. Literature review obtained 33 Chinese children with CF-PBS, with an age of onset of 1-36 months and an age of diagnosis of 3-144 months. Among these children, there were 29 children with recurrent respiratory infection or persistent pneumonia (88%), 26 with malnutrition (79%), 23 with developmental retardation (70%), and 18 with pancreatitis or extrapancreatic insufficiency (55%). Genetic testing showed that c.2909G>A was the most common mutation site of the CFTR gene, with a frequency of allelic variation of 23% (15/66). CONCLUSIONS: CF may have no typical respiratory symptoms in the early stage. The possibility of CF-PBS should be considered for infants with recurrent hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, especially those with malnutrition and developmental retardation. CFTR genetic testing should be performed as soon as possible to help with the diagnosis of CF.

Peripheral NK cells identified as the predictor of response in extensive-stage small cell lung cancer patients treated with first-line immunotherapy plus chemotherapy.

PURPOSE: Although immunotherapy improves outcomes in extensive-stage small-cell lung cancer (ES-SCLC), the search for biomarkers predicting treatment success is crucial. Natural killer (NK) cells are potential indicators in various cancers, however, their precise role in ES-SCLC prognosis remains unclear. METHODS: In this retrospective study, 33 patients with ES-SCLC treated with first-line immuno-chemotherapy were enrolled. The peripheral NK cell percentage and its longitudinal dynamics were analyzed using flow cytometry. Progression-free survival (PFS) and overall survival (OS) were calculated as hazard ratio (HR) and compared statistically. RESULTS: The median PFS was better in the group with normal baseline NK cell levels than the low group (7.0 vs. 4.6 months; HR = 0.17; 95% CI 0.07-0.41; P < 0.0001), but there was no association with OS (14.9 vs. 10.3 months; HR = 0.55; 95% CI 0.23-1.31; P = 0.171). Furthermore, the NK cell% for 95.0% of patients increased after immunochemotherapy in the clinical response group (P = 0.0047), which led to a better median PFS (6.3 vs. 2.1 months; HR = 0.23; 95% CI 0.05-0.98; P < 0.0001) and OS (14.9 vs. 5.9 months; HR = 0.20; 95% CI 0.04-1.02; P < 0.0001). Similar trends were observed with NK cell% changes up to disease progression, improving PFS (6.5 vs. 4.3; HR = 0.41; 95% CI 0.12-0.92; P = 0.0049) and OS (17.4 vs. 9.7; HR = 0.42; 95% CI 0.17-1.02; P < 0.0001). CONCLUSION: In patients with ES-SCLC, the percentage and changes in peripheral NK cells can predict the response to combined immunotherapy and chemotherapy.

A four-gene signature predicts overall survival of patients with esophageal adenocarcinoma.

Background: Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis. Thus, this study aimed to identify a prognostic molecular signature to predict the overall survival (OS) of patients with EAC. Methods: The mRNA microarray data sets GSE13898 and GSE26886 were downloaded from the Gene Expression Omnibus (GEO) database. RNA sequencing profile and clinical data of EAC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) between EAC tissues and adjacent non-cancerous tissues were obtained using R software. DEGs associated with prognosis of OS were assessed by univariate Cox analysis, and a prognostic signature was built using stepwise multivariate Cox analysis. Time-dependent receiver operating characteristic (ROC) analysis and stratification analysis were conducted to evaluate its predictive performance. Functional enrichment analysis was performed for genes co-expressed with the signature to explore its biological functions in EAC. Results: A total of 336 genes were identified to be differentially expressed between EAC tissues and adjacent non-cancerous tissues. After univariate and multivariate Cox regression analysis, four genes (ALAD, ABLIM3, IL17RB and IFI6) were screened out to construct a prognostic signature. According to this signature, patients could be assigned into high-risk and low-risk group with significantly different OS (P=4.92e-05<0.0001). Multivariate Cox regression analysis suggested that the four-gene signature served as an independent factor in OS prediction. In the time-dependent ROC analysis, the areas under the curves (AUCs) were 0.804, 0.792 and 0.695 for 1-, 3- and 5-year survival prediction, respectively, suggesting a good performance. Functional enrichment analysis showed that the signature was mainly clustered in cell proliferation related biological processes or pathways. Conclusions: The four-gene signature identified in the current study may be a potential prognostic factor for predicting OS of EAC patients.

Analysis of Caregiver Burden and Influencing Factors in Autologous Hematopoietic Stem Cell Transplantation Patients with Bendamustine Preconditioning.

This paper comprehensively analyzes the caregiver burden and its influencing factors on primary caregivers in autologous hematopoietic stem cell transplantation (Auto-HSCT) with bendamustine preconditioning. Auto-HSCT refers to the transplantation of cells back to the patient, aiming to eliminate tumor cells and prolong the patient's life. Bendamustine, while enhancing the success rate of transplantation, has drawn considerable attention to the primary caregivers of patients. Due to the complex nature of the transplantation process, patients have diverse caregiving needs, which caregivers must address to support the entire treatment journey. The caregiver burden of primary caregivers is influenced by various factors, including the patient's disease condition, various aspects of the caregiver as an individual, and psychological factors. The article emphasizes the need for personalized care plans and psychological support to minimize caregiver burden and improve overall quality of life. This study has positive implications for optimizing the implementation of Auto-HSCT therapy.

Different effects of TCBPA exposure on liver cancer cells and liver cells: two sides of the coin.

Tetrachlorobisphenol A (TCBPA), widely used as a substitute for tetrabromobisphenol A (TBBPA), has been detected in various environmental media. Therefore, a detailed evaluation of the toxicological properties of TCBPA is necessary. In this study, we used hepatoma and normal liver cell models in vitro to investigate the effects of TCBPA. Our findings indicate that TCBPA promotes the proliferation of liver cancer cells, as evidenced by MTT and EdU assays, and enhances the expression levels of molecules related to hepatoma proliferation. Further investigation into the molecular mechanism revealed that TCBPA-induced hepatoma proliferation is regulated by an NLRP3-mediated inflammatory process. Additionally, TCBPA was found to promote the epithelial-mesenchymal transition (EMT) process in liver cancer cells. Conversely, TCBPA inhibited the proliferation of normal liver cells. Mechanistic studies showed that TCBPA induced cell pyroptosis in normal liver cells by evaluating a series of related markers, including NLRP3, IL-1ß, ASC, GASDMD, and Caspase 1. In vivo models further showed that TCBPA causes liver tissue damage. In summary, this study demonstrates that TCBPA has a dual effect: promoting the occurrence and development of liver tumor cells in vitro, while inhibiting the proliferation of normal liver cells, like two sides of a coin. These opposite cellular outcomes are regulated by NLRP3-mediated inflammatory processes, providing valuable insights for evaluating the potential health impacts of TCBPA.

Two-stage stratified designs with survival outcomes and adjustment for misclassification in predictive biomarkers.

Biomarker stratified clinical trial designs are versatile tools to assess biomarker clinical utility and address its relationship with clinical endpoints. Due to imperfect assays and/or classification rules, biomarker status is prone to errors. To account for biomarker misclassification, we consider a two-stage stratified design for survival outcomes with an adjustment for misclassification in predictive biomarkers. Compared to continuous and/or binary outcomes, the test statistics for survival outcomes with an adjustment for biomarker misclassification is much more complicated and needs to take special care. We propose to use the information from the observed biomarker status strata to construct adjusted log-rank statistics for true biomarker status strata. These adjusted log-rank statistics are then used to develop sequential tests for the global (composite) hypothesis and component-wise hypothesis. We discuss the power analysis with the control of the type-I error rate by using the correlations between the adjusted log-rank statistics within and between the design stages. Our method is illustrated with examples of the recent successful development of immunotherapy in nonsmall-cell lung cancer.

Identification of New Markers of Angiogenic Sprouting Using Transcriptomics: New Role for RND3.

BACKGROUND: New blood vessel formation requires endothelial cells to transition from a quiescent to an invasive phenotype. Transcriptional changes are vital for this switch, but a comprehensive genome-wide approach focused exclusively on endothelial cell sprout initiation has not been reported. METHODS: Using a model of human endothelial cell sprout initiation, we developed a protocol to physically separate cells that initiate the process of new blood vessel formation (invading cells) from noninvading cells. We used this model to perform multiple transcriptomics analyses from independent donors to monitor endothelial gene expression changes. RESULTS: Single-cell population analyses, single-cell cluster analyses, and bulk RNA sequencing revealed common transcriptomic changes associated with invading cells. We also found that collagenase digestion used to isolate single cells upregulated the Fos proto-oncogene transcription factor. Exclusion of Fos proto-oncogene expressing cells revealed a gene signature consistent with activation of signal transduction, morphogenesis, and immune responses. Many of the genes were previously shown to regulate angiogenesis and included multiple tip cell markers. Upregulation of SNAI1 (snail family transcriptional repressor 1), PTGS2 (prostaglandin synthase 2), and JUNB (JunB proto-oncogene) protein expression was confirmed in invading cells, and silencing JunB and SNAI1 significantly reduced invasion responses. Separate studies investigated rounding 3, also known as RhoE, which has not yet been implicated in angiogenesis. Silencing rounding 3 reduced endothelial invasion distance as well as filopodia length, fitting with a pathfinding role for rounding 3 via regulation of filopodial extensions. Analysis of in vivo retinal angiogenesis in Rnd3 heterozygous mice confirmed a decrease in filopodial length compared with wild-type littermates. CONCLUSIONS: Validation of multiple genes, including rounding 3, revealed a functional role for this gene signature early in the angiogenic process. This study expands the list of genes associated with the acquisition of a tip cell phenotype during endothelial cell sprout initiation.

The clinical significance of SNAIL, TWIST, and E-Cadherin expression in gastric mesentery tumor deposits of advanced gastric cancer.

Objective: To explore the relationships among the epithelial to mesenchymal transition (EMT)-related factors (SNAIL, TWIST, and E-Cadherin) and clinicopathological parameters and gastric mesangial tumor deposits (TDs) in advanced gastric cancer (AGC) patients and their value in gastric cancer prognosis judgment. Materials and Methods: The data of 190 patients who underwent radical resection of ACG were analyzed retrospectively, including 75 cases of TDs (+) and 115 cases of TDs (-). The expression of EMT-related transforming factors Snail, Twist, and E-cadherin in the primary tumor, paracancerous normal tissues, and TDs was detected by immunohistochemistry. Results: SNAIL and TWIST were overexpressed in primary tumors and TDs, whereas E-Cadherin was down-expressed in primary tumors. SNAIL was correlated significantly with tumor differentiation, lymph node metastases, and TDs (P < 0.05); TWIST was correlated strongly with tumor location, lymph node metastases, and TDs (P < 0.05); E-Cadherin was correlated closely with tumor differentiation and lymph node metastases (P < 0.05). Kaplan-Meier curves showed that SNAIL expression was correlated with DFS (P < 0.05), and TWIST expression was correlated with OS (P < 0.05). Tumor differentiation, lymph node metastasis, and TWIST expression were prognostic-independent risk factors of AGC patients (P < 0.05). Conclusion: The occurrence and development of gastric cancer and the formation of TDs may be related to EMT, analyzing the expression of EMT-related transforming proteins may be helpful to judge the prognosis of gastric cancer.

Lysine demethylase KDM3A alleviates hyperoxia-induced bronchopulmonary dysplasia in mice by promoting ETS1 expression.

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease among neonates, with increasing morbidity and mortality. This study aims to investigate the effect and mechanism of lysine demethylase 3A (KDM3A) on hyperoxia-induced BPD. Hyperoxia-induced BPD mouse and alveolar epithelial cell models were constructed. The effects of hyperoxia on lung development were evaluated by histological and morphological analysis. The levels of KDM3A, E26 transformation specific-1 (ETS1), H3 lysine 9 dimethylation (H3K9me2), and endoplasmic reticulum (ER) stress-related indexes were quantified by RT-qPCR, Western blot, and IF staining. Cell apoptosis was assessed by flow cytometry and TUNEL staining. Transfection of oe-ETS1, oe-KDM3A, and sh-ETS1 was applied in hyperoxia-induced alveolar epithelial cells to explore the mechanism of the KDM3A/ETS1 axis in hyperoxia-induced apoptosis. KDM3A inhibitor IOX1 was applied to validate the in vivo effect of KDM3A in hyperoxia-induced BPD mice. The results displayed that hyperoxia-induced BPD mice showed reduced body weight, severe destruction of alveolar structure, decreased radial alveolar count (RAC), and increased mean linear intercept (MLI) and mean alveolar diameter (MAD). Further, hyperoxia induction down-regulated ETS1 expression, raised ER stress levels, and increased apoptosis rate in BPD mice and alveolar epithelial cells. However, transfection of oe-ETS1 improved the above changes in hyperoxia-induced alveolar epithelial cells. Moreover, transfection of oe-KDM3A up-regulated ETS1 expression, down-regulated H3K9me2 expression, inhibited ER stress, and reduced apoptosis rate in hyperoxia-induced alveolar epithelial cells. In addition, transfection of sh-ETS1 reversed the inhibitory effect of KDM3A on hyperoxia-induced apoptosis by regulating ER stress. In vivo experiments, KDM3A inhibitor IOX1 intervention further aggravated BPD in newborn mice. In a word, KDM3A alleviated hyperoxia-induced BPD in mice by promoting ETS1 expression.

Modulating the tumoral SPARC content to enhance albumin-based drug delivery for cancer therapy.

Insufficient delivery of therapeutic agents into solid tumors by systemic administration remains a major challenge in cancer treatment. Secreted protein acidic and rich in cysteine (SPARC) has high binding affinity to albumin and has been shown to enhance the penetration and uptake of albumin-based drug carriers in tumors. Here, we developed a strategy to alter the tumor microenvironment (TME) by upregulating SPARC to enhance the delivery efficiency of albumin-based drug carriers into tumors. We prepared albumin nanoparticles encapsulating an NF-κB controllable CRISPR activation system (SP-NPs). SP-NPs achieved tumor-selective SPARC upregulation by responding to the highly activated NF-κB in tumor cells. Whereas a single dose of SP-NPs only modestly upregulated SPARC expression, serial administration of SP-NPs created a positive feedback loop that induced progressive increases in SPARC expression as well as tumor cell uptake and tumor penetration of the nanoparticles in vitro, in organoids, and in subcutaneous tumors in vivo. Additionally, pre-treatment with SP-NPs significantly enhanced the anti-tumor efficacy of Abraxane, a commercialized albumin-bound paclitaxel nanoformulation. Our data provide evidence that modulating SPARC in the TME can enhance the efficiency of albumin-based drug delivery to solid tumors, which may result in new strategies to increase the efficacy of nanoparticle-based cancer drugs.

Esophageal tuberculosis mimicking submucosal tumor: A rare case.

INTRODUCTION: Esophageal tuberculosis (ET) is a rare form of infectious esophagitis. Here, we present a case of primary ET in an immunocompetent patient with dysphagia. CASE PRESENTATION: Esophagogastroduodenoscopy (EGD) revealed a submucosal tumor (SMT)-like lesion in the distal esophagus. Subsequent endoscopic ultrasonography (EUS) showed ulceration, esophageal wall discontinuities, thickening, and hypoechoic masses. Histopathological analysis confirmed a tuberculoid granuloma within the lesion. Imaging studies ruled out pulmonary tuberculosis and lymph node involvement. The patient received six months of antituberculosis treatment, resulting in significant improvement on follow-up EGD. DISCUSSION: ET is often misdiagnosed due to its rarity and nonspecific symptoms. In this case, the clinical presentation of dysphagia, combined with the characteristic findings on EGD and EUS, led to the diagnosis of primary esophageal tuberculosis. CONCLUSION: Prompt consideration of ET in dysphagia patients with SMT-like lesions and timely initiation of appropriate antituberculosis treatment can improve clinical outcomes and help avoid unnecessary surgeries.

Faslpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus.

Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Faslpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (Sle1homo.lprhet) and compared it with B6.Faslpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly elevated serum ANA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1⍺, IL-2, and IL-27. Taken together, Sle1homo.lprhet strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.

Metachronous primary esophageal squamous cell carcinoma and duodenal adenocarcinoma: A case report and review of literature.

BACKGROUND: The prevalence of multiple primary malignant neoplasms (MPMNs) is increasing in parallel with the incidence of malignancies, the continual improvement of diagnostic models, and the extended life of patients with tumors, especially those of the digestive system. However, the co-existence of MPMNs and duodenal adenocarcinoma (DA) is rarely reported. In addition, there is a lack of comprehensive analysis of MPMNs regarding multi-omics and the tumor microenvironment (TME). CASE SUMMARY: In this article, we report the case of a 56-year-old man who presented with a complaint of chest discomfort and abdominal distension. The patient was diagnosed with metachronous esophageal squamous cell carcinoma and DA in the Department of Oncology. He underwent radical resection and chemotherapy for the esophageal tumor, as well as chemotherapy combined with a programmed death-1 inhibitor for the duodenal tumor. The overall survival was 16.6 mo. Extensive evaluation of the multi-omics and microenvironment features of primary and metastatic tumors was conducted to: (1) Identify the reasons responsible for the poor prognosis and treatment resistance in this case; and (2) Offer novel diagnostic and therapeutic approaches for MPMNs. This case demonstrated that the development of a second malignancy may be independent of the location of the first tumor. Thus, tumor recurrence (including metastases) should be distinguished from the second primary for an accurate diagnosis of MPMNs. CONCLUSION: Multi-omics characteristics and the TME may facilitate treatment selection, improve efficacy, and assist in the prediction of prognosis.

Engineering redirected NF-κB/OIP5 expression programs to enhance tumor responses to chemotherapy in bladder cancer.

Nuclear factor kappa-B (NF-κB), a pivotal transcriptional regulator, plays a crucial role in modulating downstream genes implicated in tumor drug resistance. We establish a programmable system within bladder cancer cells to tailor drug responses by employing a synthetic clustered regularly interspaced short palindromic repeats (CRISPR)-based expression strategy that emulates natural transcriptional regulators. Our investigation uncovers the functional significance of Opa-interacting protein 5 (OIP5), upregulated upon NF-κB activation, as a key regulator governing drug-resistance to vincristine (VCR) treatment in bladder cancer. Through engineered guide RNAs (sgRNAs) targeting OIP5 to integrate NF-κB aptamers, we construct a modular scaffold RNA that encodes both the target locus and regulatory functionality. This engineered CRISPR scaffold RNA effectively responds to VCR stimulus by binding with activated NF-κB. Intriguingly, it redirects NF-κB to attenuate OIP5 expression-a reversal of its original role-while concurrently obstructing multiple NF-κB-mediated drug resistance pathways. This dual action thwarts drug resistance development. Further enhancing therapeutic potential, we develop a versatile nanoparticle system capable of co-delivering CRISPR scaffold RNAs and VCR. This synergistic approach demonstrates potent anti-tumor effects in both in vitro and in vivo settings. Our nanoparticle-mediated combination presents a compelling proof-of-concept, showcasing the utility of engineered CRISPR-based synthetic expression programs to reconfigure cellular drug responses and heighten tumor cell susceptibility to chemotherapy.

Construction and Evaluation of an M2 Macrophage-Related Prognostic Model for Colon Cancer.

Colon cancer (CC) is a primary human malignancy. Recently, the mechanism of the tumor microenvironment (TME) in CC has been a hot topic of research. However, there is uncertainty regarding the contribution of M2 macrophages and related genes to the prognosis for CC. M2 macrophage-related genes (M2RGs) were obtained from The Cancer Genome Atlas (TCGA) database. Immune cell infiltration in CC tissue was assessed by Cibersort. Based on the TCGA-COAD training set, a Least Absolute Shrinkage and Selection Operator (LASSO) Cox risk model was constructed and its efficiency was evaluated by analyzing risk profiles and survival profiles. Using gene set enrichment analysis (GSEA), the functional distinctions between high-risk and low-risk categories were further investigated. Finally, potential immune checkpoints, immunotherapy efficiency, and clinical treatment of high-risk patients were evaluated. A total of 1063 M2RGs were identified in TCGA-COAD, 32 of these were confirmed to be strongly related to overall survival (OS), and 14 of these were picked to construct an OS-oriented prognostic model in CC patients. The M2RG signature had a positive correlation with unfavorable prognosis according to the survival analysis. Correlation analysis revealed that the risk model was positively associated with clinicopathological characteristics, immune cell infiltration, immune checkpoint inhibitor targets, the risk of immune escape, and the efficiency of anti-cancer medications. The risk model created using M2RGs may be useful in predicting the prognosis of CC.

Serum cystatin C for risk stratification of prediabetes and diabetes populations.

BACKGROUND: The association between serum cystatin C level and vascular outcomes has not been fully elucidated in diabetes and is unclear in prediabetes. We aim to evaluate whether cystatin C level predicts future risk for mortality and vascular outcomes in prediabetes and diabetes. METHODS: A total of 85,371 participants with prediabetes and diabetes, and available baseline cystatin C in the UK biobank were included with a 14-year follow-up. Cox hazards models were used to calculate the associations between cystatin C level, mortality (all-cause, cause-specfic mortality) and vascular outcomes (myocardial infarction [MI], stroke, end-stage renal disease [ESRD] and diabetic retinopathy [DR]). The 1136 diabetes subjects in Guangzhou Diabetic Eye Study (GDES) were included for examing the impact of cystatin C on in vivo retinal degeneration and microvascular changes by using SS-OCT and OCTA. RESULTS: The highest cystatin C quartile had increased risks of all-cause (hazard ratio [HR], 2.02; 95% confidence interval [CI] 1.86-2.19), cardiovascular (HR, 2.29; 95% CI 1.97-2.67), cancer (HR, 1.86; 95% CI 1.65-2.10) and other-cause mortality (HR, 2.24; 95% CI 1.90-2.64), MI (HR, 1.40; 95% CI 1.26-1.55), stroke (HR, 1.88; 95% CI, 1.57-2.26), ESRD (HR, 7.33; 95% CI, 5.02-10.71), DR (HR, 1.17; 95% CI 1.03-1.32) than those in the lowest quartile. Adding cystatin C to the conventional model improved C-statistic for all-cause (0.699-0.724), cardiovascular (0.762-0.789), cancer (0.661-0.674) and other-cause mortality (0.675-0.715), MI (0.748-0.750), stroke (0.712-0.718), and ESRD (0.808-0.827). The GDES analysis identified a strong association between increased cystatin C levels and diminished retinal neural layers, as well as microvascular rarefaction in both macular and optic disc regions (all P < 0.05). CONCLUSIONS: Serum cystatin C refines the risk stratification for mortality and vascular outcomes among patients with prediabetes or diabetes.