[68Ga]Ga-FAPI-04 PET/MR imaging strategy in management of Krukenberg tumors (KTs) from gastric signet-ring-cell carcinoma: to overcome limitation of [68Ga]Ga-FAPI-04 PET imaging in KTs.

PURPOSE: To compare performance of whole-body [68Ga]Ga-FAPI-04 and [18F]FDG PET imaging in the detection of Krukenberg tumors (KTs), primary site and extra-ovarian metastases of gastric signet-ring-cell carcinoma (GSRCC), and evaluate the value of [68Ga]Ga-FAPI-04 PET/MR imaging strategy and its potential impact on the management of KTs from GSRCC. METHODS: Twelve patients with twenty-three KTs from GSRCC, who underwent both [68Ga]Ga-FAPI-04 pelvic PET/MR and whole-body [68Ga]Ga-FAPI-04 and [18F]FDG PET imaging were retrospectively analyzed. [68Ga]Ga-FAPI-04 and [18F]FDG uptakes were compared by using Wilcoxon signed-rank test or paired t test. McNemar's test was used to compare lesion detectability between two modalities. Two-tailed P<0.05 was considered statistically significant. Immunohistochemistry staining was utilized to analyze the fibroblast activation protein (FAP) expression in KTs. RESULTS: A total of 12 patients with 23 KTs from GSRCC (8 synchronous and 4 metachronous) were evaluated. [68Ga]Ga-FAPI-04 was superior to [18F]FDG PET in detecting primary sites of GSRCC (100% [11/11] vs. 18.2% [2/11], p = 0.002), involved lymph nodes (90.9% [10/11] vs. 54.5% [6/11], p = 0.046) and peritoneal metastases (100% [12/12] vs. 41.7% [5/12], p = 0.008), with higher SUVmax and TBR (all p < 0.005). Both tracers had limited value in identifying KTs, with 100% false negative rate on [68Ga]Ga-FAPI-04 PET and a low detection rate of 8.7% on [18F]FDG PET. Fap immunohistochemistry showed negative or slight FAP expression in neoplastic signet ring cells and ovarian stroma. [68Ga]Ga-FAPI-04 PET/MR imaging strategy greatly improved the detection rate of Krukenberg tumors (87%, 20/23). After adding diffusion-weighted imaging (DWI), the detection rate was further improved (87.5% vs. 100%, p = 0.083). [68Ga]Ga-FAPI-04 PET/MR imaging strategy either upgraded TNM staging or changed treatment management in twelve patients. CONCLUSIONS: [68Ga]Ga-FAPI-04 PET outperformed [18F]FDG PET in detecting primary site and most extra-ovarian metastases of GSRCC, but both tracers had limited value in identifying Krukenberg tumors. Pelvis MRI should be applied to compensate the limitation of [68Ga]Ga-FAPI-04 PET imaging to identify Krukenberg tumours. The [68Ga]Ga-FAPI-04 PET/MR imaging strategy has the potential to impact treatment decisions for GSRCC patients with KTs.

Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of <12% due to the lack of effective treatments. Novel treatment strategies are urgently needed. Here, PKMYT1 is identified through genome-wide CRISPR screens as a non-mutant, genetic vulnerability of PDAC. Higher PKMYT1 expression levels indicate poor prognosis in PDAC patients. PKMYT1 ablation inhibits tumor growth and proliferation in vitro and in vivo by regulating cell cycle progression and inducing apoptosis. Moreover, pharmacological inhibition of PKMYT1 shows efficacy in multiple PDAC cell models and effectively induces tumor regression without overt toxicity in PDAC cell line-derived xenograft and in more clinically relevant patient-derived xenograft models. Mechanistically, in addition to its canonical function of phosphorylating CDK1, PKMYT1 functions as an oncogene to promote PDAC tumorigenesis by regulating PLK1 expression and phosphorylation. Finally, TP53 function and PRKDC activation are shown to modulate the sensitivity to PKMYT1 inhibition. These results define PKMYT1 dependency in PDAC and identify potential therapeutic strategies for clinical translation.

Rare myxoid pleomorphic liposarcoma: a case report and literature review.

We report a case of a middle-aged woman with a rapidly growing abdominal mass that was diagnosed as myxoid pleomorphic liposarcoma, a recently recognised, rare and aggressive subtype of liposarcoma. The tumour exhibits a combination of histological features from both myxoid liposarcoma and pleomorphic liposarcoma. Genetic analysis revealed mutations in TP53 and RB1, along with widespread loss of heterozygosity. However, no DDIT3 gene translocation or MDM2/CDK4 gene amplification was detected. These genetic characteristics can be used to distinguish this type of liposarcoma from others. Two unusual gene fusion/rearrangements, CREB5::TERT fusion and ETV1::LFNG rearrangement, were identified. The patient underwent complete removal of the tumour without the use of radiotherapy or chemotherapy. No recurrence was observed during the follow-up period of 18 months.

Clinical and Pathologic Predictors of Tumor Deposits in Colorectal Cancer.

BACKGROUND: Tumor deposits (TDs) are a special metastatic pattern of colorectal cancer (CRC). This study aims to explore the pathological characteristics of TD and find out the risk factors of TD in CRC. METHODS: TDs cases of CRC were selected and validated by HE staining. The correlation between TDs and T stages, N stages, and microsatellite instability was calculated by the chi-squared (χ2) test. RESULTS: A total of 2553 patients with colorectal cancer undergoing intestinal resection were included in this study. Two hundred fifty-nine cases of TDs patients were included. The positive rate of TDs was 1.9% (2/105) in T1, 3.8% (10/266) in T2, 11% (231/2305) in T3, and 22.8% (16/77) in T4. T3 and T4 were more prone to TDs than T1 and T2, but there was no difference between T3 and T4. The positive rate of TDs was 7.2% (107/1491) in N0, 14.3% (152/1062) in N + , and N + was more prone to TDs than N0. The positive rate of TDs was 10.5% (256/2432) in MSS, 2.5% (3/121) in MSI, and MSS was more prone to TDs than MSI. Multivariate analysis showed lymph node invasion, T stage, and MSS were independent risk factors for TDs. CONCLUSION: Lymph node invasion, T stage, and MSS were independent risk factors for TDs.

Diffuse large B-cell lymphoma with continuously elevated immunoglobulin M following treatment: a case report with pathologic, immunophenotypic, and molecular analyses.

A rare subtype of diffuse large B-cell lymphoma (DLBCL) has been reported to be accompanied by elevated immunoglobulin M (IgM) paraprotein in the serum at diagnosis, called as IgMs-DLBCL. The monoclonal IgM paraprotein disappears soon after treatment in most of these patients. Here, we described a DLBCL patient with continuously elevated IgM following therapy. A 59-year-old male was diagnosed with DLBCL (GCB subtype per Hans algorithm, stage IA) with involvement of the right cervical lymph node. After six cycles of immuno-chemotherapy with the R-CHOP regimen, complete metabolic remission was achieved, but an elevated level of serum IgM persisted. To investigate the origin of elevated IgM, pathologic, immunophenotypic, and molecular analyses of lymph node and bone marrow (BM) samples were performed pre- and post-treatment. BM infiltration of lymphoplasmacytic cells, and a typical immunophenotypic profile by flow cytometry supported the diagnosis of Waldenström macroglobulinemia (WM). The MCD subtype of DLBCL was identified by next-generation sequencing of the lymph node at initial diagnosis characterized by co-occurring point mutations in MYD88 L265P and CD79B. Additionally, two different dominant clonotypes of the immunoglobulin heavy chain (IGH) were detected in the lymph node and BM by IGH sequencing, which was IGHV 3-11*06/IGHJ 3*02 and IGHV 3-11*06/IGHJ 6*02, respectively, speculating to be two independent clonal origins. This study will provide a panoramic understanding of the origin or biological characteristics of DLBCL co-occurring with WM.

Blockade of TNF-α/TNFR2 signalling suppresses colorectal cancer and enhances the efficacy of anti-PD1 immunotherapy by decreasing CCR8+ T regulatory cells.

Enrichment of regulatory T cells (Tregs) in the tumour microenvironment (TME) has been recognized as one of the major factors in the initiation and development of resistance to immune checkpoint inhibitors. C-C motif chemokine receptor 8 (CCR8), a marker of activated suppressive Tregs, has a significant impact on the functions of Tregs in the TME. However, the regulatory mechanism of CCR8 in Tregs remains unclear. Here, we reveal that a high level of TNF-α in the colorectal cancer (CRC) microenvironment upregulates CCR8 expression in Tregs via the TNFR2/NF-κB signalling pathway and the FOXP3 transcription factor. Furthermore, in both anti-PD1-responsive and anti-PD1-unresponsive tumour models, PD1 blockade induced CCR8+ Treg infiltration. In both models, Tnfr2 depletion or TNFR2 blockade suppressed tumour progression by reducing CCR8+ Treg infiltration and thus augmented the efficacy of anti-PD1 therapy. Finally, we identified that TNFR2+CCR8+ Tregs but not total Tregs are positively correlated with adverse prognosis in CRC and gastric cancer. Our work reveals the regulatory mechanisms of CCR8 in Tregs and identifies TNFR2 as a promising target for immunotherapy.

Overexpressed transferrin receptor implied poor prognosis and relapse in gastrointestinal stromal tumors.

Ferroptosis, as a novel-induced programmed cell death, plays critical roles in the pathogenesis of cancers. However, the promising biomarkers of ferroptosis in gastrointestinal stromal tumor (GIST) remain to be elucidated. Herein, the expression of ferroptosis-related genes was analyzed in GIST. Among the 64 ferroptosis-related genes, transferrin receptor (TFRC) expression presented a remarkable upregulation in high-risk patients through Gene Expression Omnibus (GEO) dataset analysis, as well as its significant change after imatinib was treated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of TFRC-relevant genes revealed that TFRC expression was closely associated with cell growth pathways and metabolism-related pathways. Furthermore, patients at high risk of recurrence were more likely to exhibit high TFRC expression by immunohistochemistry. Additionally, high TFRC expression indicated an undesirable state of patient relapse, which could serve as a powerful significant independent predictor of recurrence-free survival (RFS). In summary, we systematically summarize the expression characteristics and clinical relevance of TFRC and show that TFRC can be used as a prognostic factor, which can be considered a potential therapeutic target in GIST.

Synchronous primary colorectal mucinous adenocarcinoma and pancreatic ductal adenocarcinoma: A case report.

The present study reports a rare case of synchronous colorectal mucinous adenocarcinoma (CMAC) and pancreatic ductal adenocarcinoma (PDAC). A 61-year-old man complained of hematochezia for half a month. Colonoscopy and biopsy in a local hospital revealed mucinous adenocarcinoma in the sigmoid colon, and a subsequent abdominal computed tomography examination in Ren Ji Hospital (Shanghai, China) identified an unexpectedly hypovascular lesion in the body and tail of the pancreas, in addition to a mass in the colon. The patient then underwent combined surgery consisting of a distal pancreaticosplenectomy and a sigmoidectomy, and the postoperative pathological tests confirmed the co-occurrence of CMAC and PDAC. Next-generation sequencing demonstrated no deleterious germline mutations, but did find some critical somatic mutations concerning both tumors. The patient received 12 cycles of a combination of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (modified FOLFIRINOX regimen) as adjuvant chemotherapy thereafter. Complete remission was achieved at 1 year after the surgery. To the best of our knowledge, this is the first documented case of such synchronous malignances (CMAC and PDAC) in the literature, and its publication therefore improves our overall understanding in this field.

SIGLEC10+ macrophages drive gastric cancer progression by suppressing CD8+ T cell function.

Existing immune checkpoint inhibitors focus on activating T cells and show limited effectiveness in gastric cancer (GC). SIGLEC10 is identified as a novel tumor-associated macrophage-related immune checkpoint in other cancer types. However, its immunosuppressive role and clinical significance in GC remain unclear. In this study, we find a dominant expression of SIGLEC10 on CD68+ macrophages in GC. SIGLEC10 can suppress the proliferation and function of tumor-infiltrating CD8+ T cells in vitro via the Akt/P38/Erk signaling pathway. Furthermore, in ex vivo and in vivo models, SIGLEC10 blockade promotes CD8+ T cell effector function. Finally, SIGLEC10+ macrophages are positively correlated with the adverse prognosis of GC. Our study highlights that SIGLEC10 directly suppresses T cell function and serves as a promising target for immunotherapy and suggests SIGLEC10+ macrophages as a novel potential predictor of the clinical prognosis of GC.

Identification of novel urine proteomic biomarkers for high stamina in high-altitude adaptation.

Introduction: We aimed to identify urine biomarkers for screening individuals with adaptability to high-altitude hypoxia with high stamina levels. Although most non-high-altitude natives experience rapid decline in physical ability when ascending to high altitudes, some individuals with high-altitude adaptability continue to maintain high endurance levels. Methods: We divided the study population into two groups: the LC group (low change in endurance from low to high altitude) and HC group (high change in endurance from low to high altitude). We performed blood biochemistry testing for individuals at high altitudes and sea level. We used urine peptidome profiling to compare the HH (high-altitude with high stamina) and HL (high-altitude with low stamina) groups and the LC and HC groups to identify urine biomarkers. Results: Routine blood tests revealed that the concentration of white blood cells, lymphocytes and platelets were significantly higher in the HH group than in the HL group. Urine peptidome profiling showed that the proteins ITIH1, PDCD1LG2, NME1-NME2, and CSPG4 were significantly differentially expressed between the HH and HL groups, which was tested using ELISA. Urine proteomic analysis showed that LRG1, NID1, VASN, GPX3, ACP2, and PRSS8 were urine proteomic biomarkers of high stamina during high-altitude adaptation. Conclusion: This study provides a novel approach for identifying potential biomarkers for screening individuals who can adapt to high altitudes with high stamina.

Clinicopathological analysis of primary thyroid non-Hodgkin lymphoma: a single-center study.

Background: Primary thyroid lymphoma (PTL) is very rare. The aim of this study was to describe the clinical characteristics, pathological features, and survival outcomes of primary thyroid non-Hodgkin lymphoma, including the diagnostic value of clonal immunoglobulin (Ig) gene rearrangements in diagnosing mucosa-associated lymphoid tissue (MALT) lymphoma of the thyroid gland with co-existing Hashimoto thyroiditis (HT). Methods: Paraffin-embedded tissues of patients diagnosed in our institute with PTL between 2007 and 2021 were collected. Clinicopathological features and follow-up data were retrospectively analyzed. Analysis of clonal Ig gene rearrangements were performed in patients with suspected PTL. Results: Of the 22 patients included in our study, 17 were female. The median age at diagnosis was 65.5 years (range, 44-80 years). We detected 11 cases of diffuse large B-cell lymphoma (DLBCL), 10 cases of MALT lymphoma, and 1 case of T-cell lymphoma. A total of 18 patients (81.8%) had early stage (I/II) disease. B-cell lymphoma showed diffuse positivity for CD20 but negative markers for thyroid-origin cells. Double-hit and triple-hit lymphomas were not found in the 8 DLBCL cases, and 2 cases of HT with lymphoid tissue dysplasia were diagnosed with MALT lymphoma with gene rearrangement testing. The median follow-up time was 47 months (range, 4-160 months), and the overall survival was 80% for MALT lymphoma (8 of 10), 72.7% for DLBCL lymphoma (8 of 11), and 100% for T-cell lymphoma (1 of 1). There was no significant difference between the groups. Conclusions: PTL mostly affects middle-aged and older adult females with HT, and its main histological type is non-Hodgkin B-cell lymphoma. For patients with HT along with a histologically benign lymphoepithelial lesion, the identification of clonal Ig gene rearrangements is important for differential diagnosis. The prognosis between DLBCL and MALT is not statistically significant.

Long noncoding RNA SPRY4-IT1 acts as a miR-101-5p sponge to promote gastrointestinal stromal tumor progression by inhibiting ZEB1.

OBJECTIVES: Research on long noncoding RNAs (lncRNAs) has been conducted in different areas of oncology. Currently, the biological significance of lncRNAs and their regulatory features in gastrointestinal stromal tumors (GIST) remain largely unknown. We have previously identified SPRY4-IT1 overexpression in GIST through lncRNA sequencing of GIST tissues. Coincidentally, SPRY4-IT1 is an intron of the SPRY4 gene, and SPRY4 is specifically highly expressed in GIST. Thus the aim of the present study was to investigate the role of lncRNA SPRY4-IT1 in GIST pathogenesis. METHODS: Herein, we screened for SPRY4-IT1 and analyzed its possible phenotypes using Gene set enrichment analysis (GSEA). The phenotypes of GIST were verified using CCK-8, colony formation, and wound-healing assays. The ceRNA mechanism was determined by the location of lncRNA SPRY4-IT1, and its relationship to the Ago2 protein. The SPRY4-IT1/miR-101-5p/ZEB1 axis was predicted using online software and sequencing. Luciferase and pull-down assays were performed for verification. Pathway-associated and phenotype-associated proteins were detected by western blotting. RESULTS: Sequencing analysis revealed 117 differentially expressed lncRNAs in GIST and normal gastric tissue samples. Accordingly, SPRY4-IT1 was screened out and its phenotype was predicted by GSEA. Mechanistically, SPRY4-IT1 was identified as a competing endogenous RNA (ceRNA) that downregulated miR-101-5p and upregulated ZEB1, which activated extracellular signal-regulated kinase (ERK) signaling to stimulate GIST proliferation, invasion, and epithelial-mesenchymal transition. Although this effect was regulated by a negative feedback loop through SPRY4, it was still controlled by SPRY4-IT1. CONCLUSIONS: In GIST, we revealed a ceRNA mechanism by which SPRY4-IT1 modulates ZEB1 by sponging miR-101-5p, eventually driving tumor cell proliferation, migration, and epithelial-mesenchymal transition (EMT).

Genomic and RNA-Seq profiling of patients with HFrEF unraveled OAS1 mutation and aggressive expression.

BACKGROUND: Heart failure (HF) is a complex pathophysiological state characterized by inadequate delivery of blood and nutrients to the cardiac tissues. It is rarely curable and is commonly associated with a poor prognosis. In this study, we aimed to analyse exomic and RNA-Seq data from patients with HF to identify the key altered pathways in HF. METHODS: Whole blood samples were collected from patients with HF and subjected to whole exome sequencing (WES) and RNA-Seq analysis. The gene expression and RNA-Seq data obtained were verified using gene chip analysis and RT-PCR. RESULTS: Both exomic and RNA-Seq data confirmed the dysregulation of phosphorylation and immune signalling in patients with HF. Specifically, exomic analysis showed that TITIN, OBSCURIN, NOD2, CDH2, MAP3K5, and SLC17A4 mutations were associated with HF, and RNA-Seq revealed that S100A12, S100A8, S100A9, PFDN5, and TMCC2, were upregulated in patients with HF. Additionally, comparison between RNA-seq and WES data showed that OAS1 mutations are associated with HF. CONLCUSION: Our findings indicated that patients with HF show an overall disruption of key phosphorylation and immune signalling pathways. Based on RNA-seq and WES, OAS1 mutations may be primarily responsible for these changes.

Progressive abdominal pain with acute exacerbation due to retroperitoneal follicular dendritic cell sarcoma: a case report with targeted genomic sequencing analysis.

BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare malignancy that arises from follicular dendritic cells and typically presents as a slow-growing painless mass without specific symptoms. Here we report an unusual case of a 55-year-old female with retroperitoneal FDCS who presented with progressive abdominal pain onset and acute exacerbation. METHODS: On CTA, a middle-upper abdominal mass (58*40 mm) was shown with multiple enlarged lymph nodes. After en-bloc resection of the tumor, the patient recovered completely from her symptoms and was discharged without complication. One month later, the patient returned for follow-up and the relevant tests were completed. RESULTS: In this case, CA724 elevated significantly and seemed to be associated with tumor progression. The results of positron emission tomography/computed tomography (PET/CT) and radiological examinations, including magnetic resonance imaging (MRI) and computed tomography angiography (CTA), were discussed to improve our understanding of diagnostic tools on FDCS. Targeted genomic sequencing analysis revealed three novel gene mutations, EPHA3 (nonsense mutation), DDR2 (SNV), and BIRC3 (InDel). CONCLUSION: We reported an unusual case of retroperitoneal FDCS with acute exacerbated abdominal pain. The interpretations of CA724, PET/CT, as well as imaging results deserve further investigation in FDCS. Genomic sequencing revealed three novel gene mutations in FDCS, including EPHA3 (nonsense mutation), DDR2 (SNV), and BIRC3 (InDel).

Calsyntenin-1 Promotes Doxorubicin-induced Dilated Cardiomyopathy in Rats.

PURPOSE: Doxorubicin is an important cancer chemotherapeutic agent with severe cardiotoxic effects that eventually lead to dilated cardiomyopathy (DCM). Calsyntenin-1(CLSTN1) plays a critical role in the nervous system, but its relevance in cardiovascular diseases is unknown. We investigated the significance of CLSTN1 in doxorubicin-induced DCM. METHODS: CLSTN1 expression in doxorubicin-induced DCM rats and H9c2 cells was determined using western blotting. To further explore the functions of CLSTN1, a cardiac-specific CLSTN1 overexpression rat model was constructed. The rats were subjected to analysis using echocardiographic, hemodynamic, and electrocardiographic parameters. Potential downstream molecules in CLSTN1 overexpression heart tissue were investigated using proteomics and western blotting. Finally, a knockdown of CLSTN1 was constructed to investigate the rescue function on doxorubicin-induced cell toxicity. RESULTS: CLSTN1 protein expression increased drastically in doxorubicin-induced DCM rats and H9c2 cells. Under doxorubicin treatment, CLSTN1 protein-specific overexpression in the heart muscle promoted cardiac chamber enlargement and heart failure, while the knockdown of CLSTN1 reduced doxorubicin-induced cardiomyocyte toxicity in vitro. At the mechanistic level, overexpression of CLSTN1 downregulated SERCA2 expression and increased the phosphorylation levels of PI3K-Akt and CaMK2. CONCLUSION: Our findings demonstrated that CLSTN1 promotes the pathogenesis of doxorubicin-induced DCM. CLSTN1 could be a therapeutic target to prevent the development of doxorubicin-induced DCM.

The nerve-tumour regulatory axis GDNF-GFRA1 promotes tumour dormancy, imatinib resistance and local recurrence of gastrointestinal stromal tumours by achieving autophagic flux.

Complete surgical resection, accessible therapeutic targets and effective tyrosine kinase inhibitors (TKIs) have not completely cured gastrointestinal stromal tumours (GISTs), with most patients suffering from residual tumours and recurrence. The existence of nerve infiltration in GIST provides a way for tumour cells to escape local resection and systemic targeted therapy, which may challenge the previous understanding of its behaviour patterns and inspire the development of more radical excision and more precise targeted therapy. Moreover, tumour dormancy has emerged as a major cause of drug resistance and tumour relapse. Among these pathways, the nerve-tumour regulatory axis GDNF-GFRA1 is activated in GISTs, assists tumour cells in achieving dormancy and protects them from apoptosis under environmental stress by enhancing autophagic flux. The concrete mechanism is that the GDNF-regulating interaction between GFRA1 and the lysosomal calcium channel MCOLN1 activates Ca2+-dependent TFEB signalling. Activated TFEB transcriptionally regulates intracellular lysosome levels, which could achieve feedback upregulation of cellular autophagy flux during TKI treatment. This dormancy-transition axis fills parts of the mechanistic vacancy before the onset of secondary mutations, and strategies for TKIs combined with targeting GFRA1-dependent autophagy have distinct promise as prospective clinical therapies.

Perk heterozygosity ameliorates chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in male rats.

BACKGROUND: Pulmonary hypertension (PH) is a rare and deadly disease characterized by remodeling of the pulmonary vasculature and increased pulmonary artery pressure. hypobaric pulmonary hypertension (HPH) is clinically classified as group 4 of pulmonary hypertension and has a poor prognosis . Previous reports showed that HPH was associated with increased endoplasmic reticulum (ER) stress. The protein kinase R-like endoplasmic reticulum kinase (PERK) is an ER-associated stress protein. However, to date, its physiological effects on HPH and RVF development remains unknown. This study aimed to assess PERK's role in HPH and RV function using in vivo experimental model. METHODS: Perk-knockout male Sprague-Dawley rats were generated and were housed in either a hypobaric chamber or in a normoxic environment. After stimulation for 4 weeks, the hemodynamic parameters of the rats were measured. The heart and lungs were harvested for pathological observation. Blood was collected for the detection of inflammatory indexes. The right ventricle tissue was collected to assess phosphorylated-AKT, ROCK1, ET1, and MMP2 protein expression. RESULTS: WE FIRSTLY GENERATED PERK+/− RATS,: Under normal conditions, Perk+/- rats showed no changes in mPAP(mean pulmonary artery pressure), RVHI(Right ventricular hypertrophy index), cardiomyocyte size and interstitial fibrosis, and pulmonary vascular remodeling. However, in response to chronic hypoxia, Perk+/- rats exhibited decreased in mPAP, RVHI, ventricular fibrosis, and lung remodeling compared to wild-type rats. Perk+/- rats also showed lower expression of phosphor-AKT, ROCK1, ET1, and MMP2 protein in response to chronic hypoxia. CONCLUSIONS: These findings suggest that Perk heterozygosity protects against HPH and Perk may be a suitable target for treating HPH.

Novel Targets in a High-Altitude Pulmonary Hypertension Rat Model Based on RNA-seq and Proteomics.

High-altitude pulmonary hypertension (HAPH) is a complication arising from an inability to acclimatize to high altitude and is associated with high morbidity and mortality. We aimed to analyze the effects of macitentan, selexipag, riociguat, and reoxygenation on HAPH, and to screen possible targets of these treatments for future drug screening. Rats were subjected to hypobaric hypoxia for 35 days to induce HAPH, and treated with vehicle or selexipag, macitentan, riociguat, or with reoxygenation, from days 21 to 35. Selexipag, macitentan, and reoxygenation prevented an increase in mean pulmonary artery pressure and hypoxia-induced right ventricular hypertrophy, compared to the vehicle. Riociguat had little effect. RNA-seq and proteomics revealed strong correlations between responses to the three drugs, which had almost identical effects. GO-enrichment revealed that the differentially expressed genes included those involved in metabolic regulation, transcription, and translation. Various molecular pathways were annotated. Selexipag, macitentan, and reoxygenation ameliorated HAPH. Serpina1, Cryz, and Cmc1 were identified, via multi-omics screening, as key genes involved in HAPH. These findings provide new insights into the targeted drug mechanisms in HAPH.

E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non-small cell lung cancer.

Central precocious puberty (CPP), largely caused by germline mutations in the MKRN3 gene, has been epidemiologically linked to cancers. MKRN3 is frequently mutated in non-small cell lung cancers (NSCLCs) with five cohorts. Genomic MKRN3 aberrations are significantly enriched in NSCLC samples harboring oncogenic KRAS mutations. Low MKRN3 expression levels correlate with poor patient survival. Reconstitution of MKRN3 in MKRN3-inactivated NSCLC cells directly abrogates in vitro and in vivo tumor growth and proliferation. MKRN3 knockout mice are susceptible to urethane-induced lung cancer, and lung cell-specific knockout of endogenous MKRN3 accelerates NSCLC tumorigenesis in vivo. A mass spectrometry-based proteomics screen identified PABPC1 as a major substrate for MKRN3. The tumor suppressor function of MKRN3 is dependent on its E3 ligase activity, and MKRN3 missense mutations identified in patients substantially compromise MKRN3-mediated PABPC1 ubiquitination. Furthermore, MKRN3 modulates cell proliferation through PABPC1 nonproteolytic ubiquitination and subsequently, PABPC1-mediated global protein synthesis. Our integrated approaches demonstrate that the CPP-associated gene MKRN3 is a tumor suppressor.

Pathological features of lymph nodes around inferior mesenteric artery in rectal cancer: a retrospective study.

OBJECTIVE: This study aimed to explore the pathological characteristics of lymph nodes around inferior mesenteric artery in rectal cancer and its risk factors and its impact on tumor staging. METHODS: 485 rectal cancer patients underwent proctectomy surgery were collected in this study. Clinical features of patients, including gender, age, BMI, tumor size, pathological type, differentiation, nerve invasion, lymph nodes, tumor marker, and pathological examinations, were analyzed. RESULTS: A total of 485 cases were included in this study. There were 29 cases with IMA-LN metastasis; the metastasis rate was 5.98% (29/485). Positive IMA-LNs were associated with distance from anal verge, CEA, pathological type, differentiation, nerve invasion, T stage, and N stage. Multivariate analysis showed that distance from anal verge, CEA level, differentiation, and T stage were independent risk factors for positive IMA-LNs. CONCLUSION: Distance from anal verge, CEA level, differentiation, and T stage were independent risk factors for positive IMA-LNs. No skip metastasis occurred in IMA-LNs. We should choose the appropriate surgical methods to achieve better oncological results and reduce the incidence of postoperative complications.