Long-term risks of cardiovascular death among older patients with major hematological malignancies: a population-based cohort study from SEER database.

BACKGROUND: The objective of this study was to identify the risk of cardiovascular disease (CVD)-related death in older patients with major hematological malignancies (HM). METHODS: This study included 103,102 older patients diagnosed with 7 major types of HM between 1975 and 2018 (median follow-up: 2.7 years) from the Surveillance, Epidemiology, and End Result (SEER) database. The proportion of deaths, Fine-Gray sub-distribution hazards regression model, standardized mortality ratios (SMR) and absolute excess risk (AER) were used to evaluate the risk of CVD-related death. RESULTS: For older patients with HM, CVD-related death ranked as the second leading cause of death, surpassed only by primary malignancy. Compared to the general older population, older patients with HM had higher SMR and AER of CVD-related deaths (SMR: 1.16-1.81; AER: 41.24-308.99), heart disease-related deaths (SMR: 1.19-1.90; AER: 39.23-274.69), and cerebrovascular dis-ease-related deaths (SMR: 0.99-1.66; AER: -0.35 -24.15). The proportion of deaths and cumulative mortality increased with the passage of survival time, especially in Hodgkin lymphoma patients with stage I/II and those aged ≥85 years with chronic lymphocytic leukemia, surpassing primary malignancy. The risk of CVD-related death varied among different HM types. CONCLUSIONS: For older patients with HM, long-term cardiovascular risk management needs to be focused on while addressing the primary malignancy. IMPACT: Our results emphasize the need to manage long-term cardiovascular risk in older patients with HM, especially in those identified as high-risk cases.

Xiaoer-Feire-Qing granules alleviate pyretic pulmonary syndrome induced by Streptococcus pneumoniae in young rats by affecting the lungs and intestines: An in vivo study based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine (TCM) Xiaoer-Feire-Qing granules (XEFRQ) has been used to treat pyretic pulmonary syndrome (PPS) in children for many years. The function of the lungs is considered to be closely related to the large intestine in TCM. PURPOSE: We aimed to investigate the effects of XEFRQ on PPS and the underlying mechanisms via network pharmacology and animal experiments. METHODS: The TCMSP platform was used to identify the ingredients and potential targets of XEFRQ. The GeneCards, OMIM, and TTD databases were used to predict PPS-associated targets. Cytoscape 3.9.1 was employed to construct the protein-protein interaction network, and target prediction was performed by GO and KEGG analyses. For the animal experiment, a PPS model was constructed by three cycles of nasal drip of Streptococcus pneumoniae (STP; 0.5 mL/kg). The animals were randomly divided into the following four groups according to their weight (n = 10 rats per group): the blank group, the model group, the XEFRQ-L (16.3 g/kg) group, and the XEFRQ-H (56.6 g/kg) group. Rats in the blank group and the model group were given 0.5% CMC-Na by gavage. The general conditions of the rats were observed, and their food-intake, body weight, and body temperature were recorded for 14 days. After the intervention of 14 days, serum was collected to detect inflammatory cytokines (TNF-α, IL-1ß, and PGE2) and neurotransmitters (5-HT, SP, and VIP). H&E staining was used to observe the pathological morphology of lung and colon tissue. AQP3 expression was detected by Western blot. In addition, the gut microbiota in cecal content samples were analyzed by 16S rDNA high-throughput sequencing. RESULTS: Our network analysis revealed that XEFRQ may alleviate PPS injury by affecting the levels of inflammatory cytokines and neurotransmitters and mitigating STP-induced PPS.In vivo validation experiments revealed that XEFRQ improved STP-induced PPS and reduced the expression of inflammatory cytokines and neurotransmitters. Notably, XEFRQ significantly decreased the protein expression levels of AQP3, which was associated with dry stool. Our gut microbiota analysis revealed that the relative abundance of [Eubacterium]_ruminantium_group, Colidextribacter, Romboutsia, and Oscillibacter was decreased, which means XEFRQ exerts therapeutic effects against PPS associated with these bacteria. CONCLUSION: Our results demonstrate that XEFRQ alleviates PPS by affecting the lungs and intestines, further guiding its clinical application.

Excessively Delayed Radiation Changes After Proton Beam Therapy for Brain Tumors: Report of Two Cases.

Delayed cerebral necrosis is a well-known complication of radiation therapy (RT). Because of its irreversible nature, it should be avoided if possible, but avoidance occurs at the expense of potentially compromised tumor control, despite the use of the modern advanced technique of conformal RT that minimizes radiation to normal brain tissue. Risk factors for radiation-induced cerebral necrosis include a higher dose per fraction, larger treatment volume, higher cumulative dose, and shorter time interval (for re-irradiation). The same principle can be applied to proton beam therapy (PBT) to avoid delayed cerebral necrosis. However, conversion of PBT radiation energy into conventional RT is still short of clinical support, compared to conventional RT. Herein, we describe two patients with excessively delayed cerebral necrosis after PBT, in whom follow-up MRI showed no RT-induced changes prior to 3 years after treatment. One patient developed radiation necrosis at 4 years after PBT to the resection cavity of an astroblastoma, and the other developed brainstem necrosis that became symptomatic 6 months after its first appearance on the 3-year follow-up brain MRI. We also discuss possible differences between radiation changes after PBT versus conventional RT.

Empowering pancreatic tumor homing with augmented anti-tumor potency of CXCR2-tethered CAR-NK cells.

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising immunotherapy for solid cancers; however, their effectiveness against pancreatic cancer is limited by the immunosuppressive tumor microenvironment. In particular, low NK cell infiltration poses a major obstacle that reduces cytotoxicity. The current study aimed to enhance the tumor-homing capacity of CAR-NK cells by targeting the chemokine-chemokine receptor axis between NK and pancreatic cancer cells. To this end, data from a chemokine array and The Cancer Genome Atlas pan-cancer cohort were analyzed. Pancreatic cancer cells were found to secrete high levels of ligands for C-X-C motif receptor 1 (CXCR1) and CXCR2. Subsequently, we generated anti-mesothelin CAR-NK cells incorporating CXCR1 or CXCR2 and evaluated their tumor-killing abilities in 2D cancer cell co-culture and 3D tumor-mimetic organoid models. CAR-NK cells engineered with CXCR2 demonstrated enhanced tumor killing and strong infiltration of tumor sites. Collectively, these findings highlight the potential of CXCR2-augmented CAR-NK cells as a clinically relevant modality for effective pancreatic cancer treatment. By improving their infiltration and tumor-killing capabilities, these CXCR2-augmented CAR-NK cells have the potential to overcome the challenges posed by the immunosuppressive tumor microenvironment, providing improved therapeutic outcomes.

Incidental detection of ground glass nodules and primary lung cancer in patients with breast cancer: prevalence and long-term follow-up on chest computed tomography.

Background: Patients with breast cancer have a higher risk of developing lung cancer than the general population. The study aimed to evaluate the prevalence of ground glass nodule (GGN) and risk factors for GGN growth in patients with breast cancer and to evaluate the prevalence and pathologic features of lung cancer. Methods: We retrospectively reviewed the clinical data and chest computed tomography (CT) of 1,384 patients diagnosed with breast cancer who underwent chest CT between January 2008 and December 2022. We evaluated the prevalence of GGNs and their size changes on follow-up chest CT with volume doubling time (VDT) and identified independent risk factors associated with the growth of GGN using multivariable logistic regression analyses. Furthermore, the prevalence and pathologic features of lung cancer were also evaluated. Results: We detected persistent GGNs in 69 of 1,384 (5.0%) patients. The initial diameter of GGNs was 6.3±3.6 mm on average, with primarily (85.5%) pure GGNs. Among them, 27 (39.1%) exhibited interval growth with a median VDT of 1,006.0 days (interquartile range, 622.0-1,528.0 days) during the median 959.0 days (interquartile range, 612.0-1,645.0 days) follow-up period. Older age (P=0.026), part-solid nodules (P=0.006), and total number of GGNs (≥2) (P=0.007) were significant factors for GGN growth. Lung cancer was confirmed in 13 of 1,384 patients (0.9%), all with adenocarcinoma, including one case of minimally invasive adenocarcinoma. The cancers demonstrated a high rate of epidermal growth factor receptor (EGFR) mutation (69.2%). Conclusions: Persistent GGNs in breast cancer patients with high-risk factors should be adequately monitored for early detection and treatment of lung cancer.

Stigmasterol Exerts an Anti-Melanoma Property through Down-Regulation of Reactive Oxygen Species and Programmed Cell Death Ligand 1 in Melanoma Cells.

Cancer immunotherapy as a promising anti-cancer strategy has been widely studied in recent years. Stigmasterol (STIG), a phytosterol, is known to have various pharmacological effects, including anti-inflammatory effects. However, the pharmacological role of STIG on melanoma immunotherapy has not been investigated. The present study demonstrates the anti-melanoma potency of STIG through the regulation of PD-L1 levels. The results reveal that STIG reduces reactive oxygen species (ROS) levels induced by hydrogen peroxide and increases glutathione levels decreased by α-MSH in B16F10 cells. Moreover, STIG significantly decreases melanin content and tyrosinase activities elevated by α-MSH. It also suppresses nitric oxide production induced by α-MSH. Additionally, STIG induces apoptosis with the up-regulation of PARP activation. STIG inhibits IFN-γ-induced PD-L1 expression and STAT1 phosphorylation levels. STIG also reverses the up-regulation of PD-L1 and phosphorylated STAT1 levels augmented by cisplatin, and STIG enhances CD8(+) T-cell-mediated cell death against B16F10 cells. These findings represent the first evidence of pro-apoptotic activity of STIG on melanoma cells through the down-regulation of ROS and PD-L1 pathways. Therefore, STIG may be an effective candidate for melanoma immunotherapy.

Combined DNA Methylation and Gastric Microbiome Marker Predicts Helicobacter pylori-Negative Gastric Cancer.

Background/Aims: While DNA methylation and gastric microbiome are each associated with gastric cancer (GC), their combined role in predicting GC remains unclear. This study investigated the potential of a combined DNA methylation and gastric microbiome signature to predict Helicobacter pylori-negative GC. Methods: In this case-control study, we conducted quantitative methylation-specific polymerase chain reaction to measure the methylation levels of DKK3, SFRP1, EMX1, NKX6-1, MIR124-3, and TWIST1 in the gastric mucosa from 75 H. pylori-negative patients, including chronic gastritis (CG), intestinal metaplasia (IM), and GC. A combined analysis of DNA methylation and gastric microbiome, using 16S rRNA gene sequencing, was performed in 30 of 75 patients. Results: The methylation levels of DKK3, SFRP1, EMX1, MIR124-3, and TWIST1 were significantly higher in patients with GC than in controls (all q<0.05). MIR124-3 and TWIST1 methylation levels were higher in patients with IM than those with CG and also in those with GC than in those with IM (all q<0.05). A higher methylation level of TWIST1 was an independent predictor for H. pylori-negative GC after adjusting for age, sex, and atrophy (odds ratio [OR], 15.15; 95% confidence interval [CI], 1.58 to 145.46; p=0.018). The combination of TWIST1 methylation and GC microbiome index (a microbiome marker) was significantly associated with H. pylori-negative GC after adjusting for age, sex, and atrophy (OR, 50.00; 95% CI, 1.69 to 1,476; p=0.024). Conclusions: The combination of TWIST1 methylation and GC microbiome index may offer potential as a biomarker for predicting H. pylori-negative GC.

Comparative Analysis of CT Findings and Clinical Outcomes in Adult Patients With Disseminated and Localized Pulmonary Nocardiosis.

BACKGROUND: Pulmonary nocardiosis is a rare opportunistic infection with occasional systemic dissemination. This study aimed to investigate the computed tomography (CT) findings and prognosis of pulmonary nocardiosis associated with dissemination. METHODS: We conducted a retrospective analysis of patients diagnosed with pulmonary nocardiosis between March 2001 and September 2023. We reviewed the chest CT findings and categorized them based on the dominant CT findings as consolidation, nodules and/or masses, consolidation with multiple nodules, and nodular bronchiectasis. We compared chest CT findings between localized and disseminated pulmonary nocardiosis and identified significant prognostic factors associated with 12-month mortality using multivariate Cox regression analysis. RESULTS: Pulmonary nocardiosis was diagnosed in 75 patients, of whom 14 (18.7%) had dissemination, including involvement of the brain in 9 (64.3%) cases, soft tissue in 3 (21.4%) cases and positive blood cultures in 3 (21.4%) cases. Disseminated pulmonary nocardiosis showed a higher frequency of cavitation (64.3% vs. 32.8%, P = 0.029) and pleural effusion (64.3% vs. 29.5%, P = 0.014) compared to localized infection. The 12-month mortality rate was 25.3%. The presence of dissemination was not a significant prognostic factor (hazard ratio [HR], 0.80; confidence interval [CI], 0.23-2.75; P = 0.724). Malignancy (HR, 9.73; CI, 2.32-40.72; P = 0.002), use of steroid medication (HR, 3.72; CI, 1.33-10.38; P = 0.012), and a CT pattern of consolidation with multiple nodules (HR, 4.99; CI, 1.41-17.70; P = 0.013) were associated with higher mortality rates. CONCLUSION: Pulmonary nocardiosis with dissemination showed more frequent cavitation and pleural effusion compared to cases without dissemination, but dissemination alone did not affect the mortality rate of pulmonary nocardiosis.

Prognostic factors for postoperative papillary thyroid cancer with unexplained elevated Tg: A retrospective study.

Objective: This study aimed to investigate the underlying reasons for unexplained elevated thyroglobulin (Tg) in postoperative papillary thyroid cancer (PTC) patients according to follow-up results post RAT and to explore the long-term clinical outcomes and prognostic factors associated with these patients. Methods: From April 2016 to June 2019, a retrospective study was conducted on postoperative PTC patients who underwent RAT at our institution. Patients with preablative stimulated thyroglobulin (psTg) > 10 ng/mL but no structurally evident disease were enrolled. The causal categorization for elevated Tg was analyzed 6 months post RAT and the long-term therapeutic responses were assessed at the end of follow-up. To identify risk factors influencing recurrence-free survival (RFS), both univariate and multivariate Cox regression analysis were employed. Kaplan-Meier method was utilized for plotting survival curves. Results: A cohort of 165 subjects was enrolled for the analyses. Based on the results of a six-month follow-up, the postoperative unexplained elevated Tg among 165 patients could be ultimately attributed to thyroid remnant in 13.94% (23/165), biochemical disease in 60.00% (99/165), and structural disease in 26.06% (43/165). With a median follow-up of 58 months, 51 (30.91%), 34 (20.60%), 21 (12.73%), and 59 (35.76%) of the 165 patients achieved ER, IDR, BIR and SIR, respectively. Univariate analysis showed that N stage, TNM stage and suppressed Tg 6 months post RAT may be prognostic factors affecting RFS. Multivariate analysis showed that N1b stage [HR:2.749, P = 0.003] and II/III stage [HR:2.910, P = 0.001] were independent risk factors for RFS. Conclusion: The proportion of 165 postoperative PTC patients with unexplained elevated Tg developing structural disease within nearly 5 years was over 30%. Patients with N1b stage and higher TNM stage were more likely to develop structural disease.

Bone metastasis in non-small-cell lung cancer: genomic characterization and exploration of potential targets.

Background: Bone metastasis (BM) seriously affects the quality of life and reduces the survival time of patients with non-small-cell lung cancer (NSCLC). The genomic characteristics and potential targets of BMs are yet to be fully explored. Objective: To explore the genetic characteristics and potential targets of BM in NSCLC. Design: In all, 83 patients with NSCLC were retrospectively selected in this study. Genomic characterization of BMs was explored with the analysis of NGS results from primary tumors and BMs in 6 patients, then combined with NGS results of lung tumors in 16 patients with initial recurrence in bone to analyze mutations potentially associated with BMs, and finally, the correlation was further validated in 61 postoperative patients. Methods: The next generation sequencing (NGS) was performed to identify genomic differences between pulmonary primary tumors and BM. Fluorescence in situ hybridization and immunohistochemistry were performed in postoperative tumor tissues from patients who had undergone radical surgery to validate the predictive role of molecular targets for BM. The correlation between cyclin-dependent kinase 4 (CDK4) and BM was evaluated by Pearson's chi-square test. The university of alabama at birminghan cancer data analysis portal (UALCAN) was carried out for the detection of CDK4 expression in lung cancer and the relationship between CDK4 and clinicopathological parameters. The relationship between prognosis and CDK4 expression was analyzed by the Kaplan-Meier plotter. Results: The rate of gene amplification was increased (24% versus 36%) while gene substitution/indel was decreased (64% versus 52%) in BMs. The BM-specific mutations were analyzed in 16 recurrent patients which revealed the highest incidence of CDK4 amplification (18.8%). According to the Kaplan-Meier plotter database, the NSCLC patients with high CDK4 gene expression showed poor overall survival (OS) and recurrence-free survival (RFS) (p < 0.05). The incidence of CDK4 amplification tended to be higher in recurrent patients compared to the patients without BM (18.8% versus 4.7%, p = 0.118). Conclusion: Compared to the primary tumors of NSCLC, the genome of BMs showed an increased proportion of amplification and a decreased proportion of gene substitution/indel. Furthermore, the CDK4 amplification ratio seemed to be elevated in NSCLC patients with BM which may be associated with poor OS and RFS.

Genomic characterization and potential targets of bone metastasis in non-small cell lung cancer NGS was performed on the matched primary tumors and bone metastases to explore the differences in the genomes of bone metastases, and it was found that gene amplification increased in bone metastases. Combined with the results of NGS in NSCLC patients with the first postoperative recurrence site in the bone, it was found that CDK4 amplification expression increased in bone metastases. Finally, the correlation between bone metastasis and CDK4 amplification was verified by expanding the sample.

TonEBP/NFAT5 expression is associated with cisplatin resistance and migration in macrophage-induced A549 cells.

BACKGROUND: Macrophages promote angiogenesis, metastasis, and drug resistance in several cancers. Similarly, TonEBP/NFAT5 induces metastasis in renal carcinoma and colon cancer cells. However, the role of this transcription factor and that of macrophages in lung cancer cells remains unclear. Therefore, this study investigated the effects of macrophages and TonEBP/NFAT5 expression on cisplatin resistance and migration in A549 lung adenocarcinoma cells. RESULTS: A549 cells were cultured alone or indirectly co-cultured with THP-1-derived macrophages using a transwell culture chamber. Cisplatin-induced cell death was markedly decreased and migration increased in co-cultured A549 cells. Macrophage-conditioned media (CM) showed a similar effect on drug resistance and migration. Cisplatin-induced apoptosis, DNA fragmentation, and cleaved apoptotic proteins PARP and caspase-3 were markedly reduced in macrophage CM-induced A549 cells. Here, ERK, p38, JNK, and NF-κB activities were increased by macrophage CM. Furthermore, the proteins involved in cisplatin resistance and cancer cell migration were identified using specific inhibitors of each protein. ERK and NF-κB inhibition considerably reduced cisplatin resistance. The increase in macrophage CM-induced migration was partially reduced by treatment with ERK, JNK, and NF-κB inhibitors. TonEBP/NFAT5 expression was increased by macrophages, resulting in increased cisplatin resistance, cell migration, and invasion. Moreover, RNAi-mediated knockdown of TonEBP/NFAT5 reduced cisplatin resistance, migration, and invasion in macrophage CM-induced A549 cells. CONCLUSIONS: These findings demonstrate that paracrine factors secreted from macrophages can change A549 cells, resulting in the induction of drug resistance against cisplatin and migration. In addition, the TonEBP/NFAT5 ratio, increased by macrophages, is an important regulator of the malignant transformation of cells.

A newly discovered glycosyltransferase gene UGT88A1 affects growth and polysaccharide synthesis of Grifola frondosa.

Grifola frodosa polysaccharides, especially ß-D-glucans, possess significant anti-tumor, antioxidant and immunostimulatory activities. However, the synthesis mechanism remains to be elucidated. A newly discovered glycosyltransferase UGT88A1 was found to extend glucan chains in vitro. However, the role of UGT88A1 in the growth and polysaccharide synthesis of G. frondosa in vivo remains unclear. In this study, the overexpression of UGT88A1 improved mycelial growth, increased polysaccharide production, and decreased cell wall pressure sensitivity. Biomass and polysaccharide production decreased in the silenced strain, and the pressure sensitivity of the cell wall increased. Overexpression and silencing of UGT88A1 both affected the monosaccharide composition and surface morphology of G. frondosa polysaccharides and influenced the antioxidant activity of polysaccharides from different strains. The messenger RNA expression of glucan synthase (GLS), UTP-glucose-1-phosphate uridylyltransferase (UGP), and UDP-xylose-4-epimerase (UXE) related to polysaccharide synthesis, and genes related to cell wall integrity increased in the overexpression strain. Overall, our study indicates that UGT88A1 plays an important role in the growth, stress, and polysaccharide synthesis of G. frondosa, providing a reference for exploring the pathway of polysaccharide synthesis and metabolic regulation. KEY POINTS: •UGT88A1 plays an important role in the growth, stress response, and polysaccharide synthesis in G. frondosa. •UGT88A1 affected the monosaccharide composition, surface morphology and antioxidant activity of G. frondosa polysaccharides. •UGT88A1 regulated the mRNA expression of genes related to polysaccharide synthesis and cell wall integrity.

Human papillomavirus Detection Rates in Bowen's Disease: Correlation with Pelvic and Digital Region Involvement and Specific p53 Immunostaining Patterns.

BACKGROUND: The relationship between human papillomavirus (HPV) and Bowen's disease (BD) is not fully understood. OBJECTIVES: To investigate the differences in HPV detection rates in BD samples across various body regions and analyze the expression patterns of p53, p16, and Ki-67 in relation to HPV presence. METHODS: Tissue samples from patients diagnosed with BD, confirmed through histopathology, were retrospectively collected. Next-generation sequencing was used for HPV DNA detection. Immunohistochemistry (IHC) for p16, p53, and Ki-67 was performed. RESULTS: Out of 109 patients with BD, 21 (19.3%) were HPV-positive. All identified types were α-HPVs, with HPV-16 being the most common. The HPV detection rate was significantly higher in the pelvic (69.2%, P<0.001) and digital (50.0%, P=0.022) areas compared to those in the other regions. HPV presence was significantly correlated with p53 negativity (P=0.002), the p53 "non-overexpression" IHC pattern (P<0.001), and p53-p16 immunostain pattern discordance (P<0.001). Conversely, there was no notable association between HPV presence and p16 positivity, the p16 IHC pattern, or Ki-67 expression. CONCLUSIONS: Our findings suggest the oncogenic role of sexually transmitted and genito-digitally transmitted α-HPVs in pathogenesis of BD in the pelvic and digital regions.

Guidelines for Rational Clinical Use of Fentanyl Transdermal Patch.

Pain is one of the most common clinical symptoms of cancer patients, seriously affecting the quality of life of patients and bringing heavy mental and economic burden to families and society. The treatment of cancer pain in China is facing numerous challenges, one of which includes the irrational usage of analgesic drugs in clinical practice. As a strong opioid analgesic, transdermal fentanyl patch has been widely used due to its convenient clinical application and obvious therapeutic effect. Several basic-level hospitals and even general hospitals in China fail to appropriate the application of drugs in clinical application due to the lack of understanding of the pharmacological characteristics and clinical application of fentanyl transdermal patch by medical staff, seriously affecting the treatment quality. Therefore, it is imperative to strengthen the rational use and management of fentanyl transdermal patches. Accordingly, the initiation by the Cancer Rehabilitation and Palliative Treatment Professional Committee of the Hubei Anti-cancer Association launched the compilation of the "Guidelines for Rational Clinical Use of Fentanyl Transdermal Patch" (from now on referred to as the "Guidelines") in Hubei Province, China. The experts in the preparation group are experts in many disciplines, such as medicine, pharmacy, and nursing. The expert group determines the outline, prepares the required regulations, and revises it repeatedly. Moreover, these experts put forward suggestions for revision to strictly control the accuracy and scientific authenticity of the contents of the "Guide". Finally, all experts of the preparation team certify and finalize the draft. This "Guide" prepared by experts of the Cancer Rehabilitation and Palliative Treatment Professional Committee of the Hubei Anti-cancer Association and the expert advisory group with joint efforts, aims to play a positive role in promoting the rational clinical use of fentanyl transdermal patch, reducing the mental and economic burden of patients, and ensuring medical quality and medical safety.

Development and multicenter validation of deep convolutional neural network-based detection of colorectal cancer on abdominal CT.

OBJECTIVES: This study aims to develop computer-aided detection (CAD) for colorectal cancer (CRC) using abdominal CT based on a deep convolutional neural network. METHODS: This retrospective study included consecutive patients with colorectal adenocarcinoma who underwent abdominal CT before CRC resection surgery (training set = 379, test set = 103). We customized the 3D U-Net of nnU-Net (CUNET) for CRC detection, which was trained with fivefold cross-validation using annotated CT images. CUNET was validated using datasets covering various clinical situations and institutions: an internal test set (n = 103), internal patients with CRC first determined by CT (n = 54) and asymptomatic CRC (n = 51), and an external validation set from two institutions (n = 60). During each validation, data from the healthy population were added (internal = 60; external = 130). CUNET was compared with other deep CNNs: residual U-Net and EfficientDet. The CAD performances were evaluated using per-CRC sensitivity (true positive/all CRCs), free-response receiver operating characteristic (FROC), and jackknife alternative FROC (JAFROC) curves. RESULTS: CUNET showed a higher maximum per-CRC sensitivity than residual U-Net and EfficientDet (internal test set 91.3% vs. 61.2%, and 64.1%). The per-CRC sensitivity of CUNET at false-positive rates of 3.0 was as follows: internal CRC determined by CT, 89.3%; internal asymptomatic CRC, 87.3%; and external validation, 89.6%. CUNET detected 69.2% (9/13) of CRCs missed by radiologists and 89.7% (252/281) of CRCs from all validation sets. CONCLUSIONS: CUNET can detect CRC on abdominal CT in patients with various clinical situations and from external institutions. KEY POINTS: • Customized 3D U-Net of nnU-Net (CUNET) can be applied to the opportunistic detection of colorectal cancer (CRC) in abdominal CT, helping radiologists detect unexpected CRC. • CUNET showed the best performance at false-positive rates ≥ 3.0, and 30.1% of false-positives were in the colorectum. CUNET detected 69.2% (9/13) of CRCs missed by radiologists and 87.3% (48/55) of asymptomatic CRCs. • CUNET detected CRCs in multiple validation sets composed of varying clinical situations and from different institutions, and CUNET detected 89.7% (252/281) of CRCs from all validation sets.

Structural basis for T cell immunoglobulin and mucin protein 3 and Toxascaris leonina galectin complex.

T-cell immunoglobulin and mucin protein 3 (Tim-3), also known as Hepatitis A virus cellular receptor 2, has been discovered to have a negative regulatory effect on murine T-cell responses. Galectin-9 exhibits various biological effects, including cell aggregation, eosinophil chemoattraction, activation, and apoptosis, observed in murine thymocytes, T-cells, and human melanoma cells. Such approach demonstrated that Galectin-9 acts as a binding partner on Tim-3 and mediates the T-cell inhibitory effects. Tl-gal is a homologous protein to galectin-9, isolated from the adult stage of the canine gastrointestinal nematode parasite Toxascaris leonina. However, molecular mechanism between Tim-3 and galectin-9 is still remain unknown. Here, we describe the cryo-electron microscopy and X-ray structures and interactions of the Tim-3 and Tl-gal complex as well as their biochemical and biophysical characterization. In the structure, Ser46 residue of Tl-gal NCRD was bound to Asp25 residue of hTim-3. Compared to our previous study, the binding site of the complex is the same as the sugar binding site (the Ser46 residue) of Tl-gal. In addition, analysis of the complex structure revealed that the four Tl-gal molecules were in an open form packing and one mTim-3 peptide was bound to one Tl-gal molecule. These observations suggest that how Tl-gal binds hTim3 is essential to understanding the molecular mechanism for the Tim-3-galectin 9 interaction that regulates immune responses. This could potentially serve as a therapeutic target for inflammatory diseases.

Development and validation of CT­based radiomics model of PET-negative residual CT masses: a potential biomarker for predicting relapse­free survival in non-Hodgkin lymphoma patients showing complete metabolic response.

PURPOSE: PET-negative residual CT masses (PnRCMs) are usually dismissed as nonviable post-treatment lesions in non-Hodgkin lymphoma (NHL) patients showing complete metabolic response (CMR). We aimed to develop and validate computed tomography (CT)-based radiomics model of PET-negative residual CT mass (PnRCM) for predicting relapse-free survival (RFS) in NHL patients showing CMR. METHODS: A total of 224 patients who showed CMR after completing first-line chemotherapy for PET-avid NHL were recruited for model development. Patients with PnRCM were selected in accordance with the Lugano classification. Three-dimensional segmentation was done by two readers. Radiomic scores (RS) were constructed using features extracted using the Least-absolute shrinkage and selection operator analysis among radiomics features of PnRCMs showing more than substantial interobserver agreement (> 0.6). Cox regression analysis was performed with clinical and radiologic features. The performance of the model was evaluated using area under the curve (AUC). For validation, 153 patients from an outside hospital were recruited and analyzed in the same way. RESULTS: In the model development cohort, 68 (30.4%) patients had PnRCM. Kaplan-Meier analysis showed that patients with PnRCM had significantly (p = 0.005) shorter RFS than those without PnRCM. In Kaplan-Meier analysis, the high RS group showed significantly (p = 0.038) shorter RFS than the low-scoring group. Multivariate Cox regression analysis showed that high IPI score [hazard ratio (HR) 2.46; p = 0.02], treatment without rituximab (HR 3.821; p = 0.019) were factors associated with shorter RFS. In estimating RFS, combined model in both development and validation cohort showed AUC values of 0.81. CONCLUSION: The combined model that incorporated both clinical parameters and CT-based RS showed good performance in predicting relapse in NHL patients with PnRCM.

Neutrophil peptide 1 accelerates the clearance of degenerative axons during Wallerian degeneration by activating macrophages after peripheral nerve crush injury.

JOURNAL/nrgr/04.03/01300535-202408000-00036/figure1/v/2023-12-16T180322Z/r/image-tiff Macrophages play an important role in peripheral nerve regeneration, but the specific mechanism of regeneration is still unclear. Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration. However, the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear. This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury. The functions of RAW 264.7 cells were elucidated by Cell Counting Kit-8 assay, flow cytometry, migration assays, phagocytosis assays, immunohistochemistry and enzyme-linked immunosorbent assay. Axonal debris phagocytosis was observed using the CUBIC (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis) optical clearing technique during Wallerian degeneration. Macrophage inflammatory factor expression in different polarization states was detected using a protein chip. The results showed that neutrophil peptide 1 promoted the proliferation, migration and phagocytosis of macrophages, and CD206 expression on the surface of macrophages, indicating M2 polarization. The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention. Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α, -6, -12, and tumor necrosis factor-α in vivo and in vitro. Thus, the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration, which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.

Transformation from acute promyelocytic leukemia in pregnancy to acute myeloid leukemia with MLL-AF9 fusion gene: A case report and literature review.

RATIONALE: Because there are few evidence-based guidelines and an extremely low incidence rate, managing and treating patients who have transitioned from acute promyelocytic leukemia (APL), which was diagnosed during pregnancy, to acute myeloid leukemia (AML), can be difficult. PATIENT CONCERNS: In this case, a 34-year-old pregnant patient was diagnosed with APL in medium-risk group in June 2017. After the all-trans retinoic acid and arsenic trioxide-based full-course treatment, the patients achieved complete remission (CR) and were well-tolerated. After 5 years, the patient complained of fatigue for 3 months. DIAGNOSIS: Bone marrow examination revealed hypercellularity with approximately 50% immunophenotypic abnormal myeloblasts with MLL-AF9 fusion gene. Based on the AML diagnosis criteria of the World Health Organization, the patient was eventually diagnosed with a rare transformation from APL to AML. INTERVENTIONS: The patient was treated with two cycles of induction chemotherapy and an allogeneic hematopoietic stem cell transplantation (allo-HSCT). OUTCOMES: Until now, the patient is in continuous remission with no signs of APL and AML. LESSIONS: Despite the rarity of APL to AML transformation, it is crucial to track the disease's progress and administer treatment on time. It remains uncertain whether the risk stratification and clinical outcomes of secondary AML with MLL-AF9 are equivalent to those of de novo AML with MLL-AF9. The management and treatment of these patients should be personalized and require further observation.