IFRD1 promotes tumor cells "low-cost" survival under glutamine starvation via inhibiting histone H1.0 nucleophagy.

Glutamine addiction represents a metabolic vulnerability of cancer cells; however, effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of interferon-related developmental regulator 1 (IFRD1) in the adaptive survival of hepatocellular carcinoma (HCC) cells during glutamine starvation. IFRD1 is induced under glutamine starvation to inhibit autophagy by promoting the proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. Conversely, targeting IFRD1 in the glutamine-deprived state increases autophagy flux, triggering cancer cell exhaustive death. This effect largely results from the nucleophilic degradation of histone H1.0 and the ensuing unchecked increases in ribosome and protein biosynthesis associated with globally enhanced chromatin accessibility. Intriguingly, IFRD1 depletion in preclinical HCC models synergizes with the treatment of the glutaminase-1 selective inhibitor CB-839 to potentiate the effect of limiting glutamine. Together, our findings reveal how IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, further highlighting the potential of IFRD1 as a therapeutic target in anti-cancer applications.

UBE2O reduces the effectiveness of interferon-α via degradation of IFIT3 in hepatocellular carcinoma.

Interferon (IFN) exerts its effects through interferon-stimulated genes (ISGs), but its efficacy is limited by interferon resistance, which can be caused by the ubiquitination of key proteins. UBE2O was initially identified as a promising therapeutic target based on data from the TCGA and iUUCD 2.0 databases. Through the inhibition of UBE2O, interferon α/ß signaling and overall interferon signaling were activated. Integrating data from proteomic, mass spectrometry, and survival analyses led to the identification of IFIT3, a mediator of interferon signaling, as a ubiquitination substrate of UBE2O. The results of in vitro and in vivo experiments demonstrated that the knockdown of UBE2O can enhance the efficacy of interferon-α by upregulating IFIT3 expression. K236 was identified as a ubiquitination site in IFIT3, and the results of rescue experiments confirmed that the effect of UBE2O on interferon-α sensitivity is dependent on IFIT3 activity. ATO treatment inhibited UBE2O and increased IFIT3 expression, thereby increasing the effectiveness of interferon-α. In conclusion, these findings suggest that UBE2O worsens the therapeutic effect of interferon-α by targeting IFIT3 for ubiquitination and degradation.

The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity.

In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the non-genetic responses of tumors to chemotherapy, but the mechanisms involved are poorly understood. Here, we establish a multifarious role for SMC4 in the switching of colorectal cancer cells to a diapause-like state. SMC4 attenuation promotes the expression of three investment phase glycolysis enzymes increasing lactate production while also suppressing PGAM1. Resultant high lactate levels increase ABC transporter expression via histone lactylation, rendering tumor cells insensitive to chemotherapy. SMC4 acts as co-activator of PGAM1 transcription, and the coordinate loss of SMC4 and PGAM1 affects F-actin assembly, inducing cytokinesis failure and polyploidy, thereby inhibiting cell proliferation. These insights into the mechanisms underlying non-genetic chemotherapy resistance may have significant implications for the field, advancing our understanding of aerobic glycolysis functions in tumor and potentially informing future therapeutic strategies.

Diagnosis based on electromagnetic navigational bronchoscopy-guided biopsied peripheral lung lesions in a 10-year-old girl: A case report.

BACKGROUND: Electromagnetic navigational bronchoscopy (ENB) is an emerging diagnostic tool that enables practitioners to biopsy peripheral lung tissues that were previously only accessible under computed tomography (CT) guidance. However, few studies have investigated ENB use in children. Here, we report a case of a 10-year-old girl with peripheral lung lesions who complained of a 7-d persistent fever. She was diagnosed with Streptococcus parasanguinis infection based on findings obtained using ENB-guided transbronchial lung biopsy (TBLB). CASE SUMMARY: A 10-year-old girl presented with constitutional symptoms of cough and fever of 7 days' duration. Chest CT scans detected peripheral lung lesions and no endobronchial lesions. TBLB performed under the guidance of an ENB Lungpro navigation system was safe, well-tolerated, and effective for biopsying peripheral lung lesions. Examination of biopsied samples indicated the patient had a pulmonary Streptococcus parasanguinis infection, which was treated with antibiotics instead of more invasive treatment interventions. The patient's symptoms resolved after she received a 3-wk course of oral linezolid. Comparisons of pre-treatment and post-treatment CT scans revealed absorption of some lung lesions within 7 mo of hospital discharge. CONCLUSION: ENB-guided TBLB biopsying of peripheral lung lesions in this child is a safe, well-tolerated, and effective alternative to conventional interventions.

Endoscopic interventional therapies for tracheoesophageal fistulas in children: A systematic review.

Methods: An electronic literature search was performed using the keywords "tracheoesophageal fistula," "endoscopic," and "children" in the four major medical databases (Ovid, Embase, PubMed, and Web of Science) right from inception to September 2022. All English language articles describing the endoscopic interventional therapies of TEF in children were reviewed. Two independent researchers screened eligible articles at the title and abstract level. Full texts of potentially relevant articles were then screened again, and reference lists were screened manually to identify additional studies. Relevant data were extracted and analyzed. A synthesis of the relevant data was presented in descriptive form because of the heterogeneity of the included articles. The Chi-Squared test was used with a significance level of 5% (P < 0.05). Results: Among the 1,167 retrieved papers, a total of 46 studies describing 170 TEF patients with an age range of 0.3-175 months were included, including 11 cases of acquired tracheoesophageal fistula, 144 cases of recurrent tracheoesophageal fistula, and 15 cases of congenital tracheoesophageal fistula (H-type TEF). A total of 119 out of 170 fistulas were successfully blocked via endoscopic techniques with an overall success rate of 70.0%, while 48 fistulas failed to close by endoscopic interventions, following which the procedure was converted to open surgery. No obviously severe intraoperative/postoperative complications occurred during the follow-up period, but only a mild esophageal stricture was noticed in six patients and grade II tracheal stenosis in one patient. Two patients died from causes unrelated to endoscopic procedures, with a mortality rate of approximately 1.2%. A comparative assessment of different endoscopic interventional techniques for TEF that detected endotracheal stenting was performed in six patients and one fistula was successfully blocked (16.7%). De-epithelialization alone was performed in 65 patients and the fistula healed in 47 of them (72.3%), with the mean number of successful treatments required being 2.3 times. Chemical sealant injection was administered in 33 patients and success was achieved in 21 (63.6%). The average requirement for endoscopic procedures was 1.5 times. De-epithelialization, in combination with chemical sealant injection, was performed in 62 patients, achieving the highest success rate of 77.4% (48 patients). Other treatment methods were performed in four patients and successfully treatment outcomes were reported in two of them (50.0%). The mean number of successful treatments required was four times, and a treatment was converted to surgery in one patient (25.0%). An assessment of different TEF types showed that 9 out of 15 congenital TEFs, 7 out of 11 acquired TEFs, and 103 out of 144 recurrent TEFs were successfully occluded. A comparison of the success rate across multiple groups showed a significant difference with a score of P < 0.05, while there was no significant difference in the success rate of different TEF-type groups (P > 0.05). Conclusion: Endoscopic intervention is currently a preferred treatment modality for children with TEF because of its less-invasive nature, less complications, and high success rate. Among all interventional techniques, de-epithelialization, in combination with chemical sealant, has a higher success rate than other techniques. However, due to the limited number of cases reported for implementing many kinds of techniques, an ideal endoscopic interventional technique has yet to be devised, often necessitating more treatment applications and close follow-up.

Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy.

BACKGROUND & AIMS: The tumour microenvironment (TME) is a crucial mediator of cancer progression and therapeutic outcome. The TME subtype correlates with patient response to immunotherapy in multiple cancers. Most previous studies have focused on the role of different cellular components in the TME associated with immunotherapy efficacy. However, the specific structure of the TME and its role in immunotherapy efficacy remain largely unknown. METHODS: We combined spatial transcriptomics with single-cell RNA-sequencing and multiplexed immunofluorescence to identify the specific spatial structures in the TME that determine the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC) receiving anti-PD-1 treatment. RESULTS: We identified a tumour immune barrier (TIB) structure, a spatial niche composed of SPP1+ macrophages and cancer-associated fibroblasts (CAFs) located near the tumour boundary, which is associated with the efficacy of immune checkpoint blockade. Furthermore, we dissected ligand‒receptor networks among malignant cells, SPP1+ macrophages, and CAFs; that is, the hypoxic microenvironment promotes SPP1 expression, and SPP1+ macrophages interact with CAFs to stimulate extracellular matrix remodelling and promote TIB structure formation, thereby limiting immune infiltration in the tumour core. Preclinically, the blockade of SPP1 or macrophage-specific deletion of Spp1 in mice led to enhanced efficacy of anti-PD-1 treatment in mouse liver cancer, accompanied by reduced CAF infiltration and increased cytotoxic T-cell infiltration. CONCLUSIONS: We identified that the TIB structure formed by the interaction of SPP1+ macrophages and CAFs is related to immunotherapy efficacy. Therefore, disruption of the TIB structure by blocking SPP1 may be considered a relevant therapeutic approach to enhance the therapeutic effect of immune checkpoint blockade in HCC. IMPACT AND IMPLICATIONS: Only a limited number of patients with hepatocellular carcinoma (HCC) benefit from tumour immunotherapy, which significantly hinders its application. Herein, we used multiomics to identify the spatial structure of the tumour immune barrier (TIB), which is formed by the interaction of SPP1+ macrophages and cancer-associated fibroblasts in the HCC microenvironment. This structure constrains immunotherapy efficacy by limiting immune cell infiltration into malignant regions. Preclinically, we revealed that blocking SPP1 or macrophage-specific deletion of Spp1 in mice could destroy the TIB structure and sensitize HCC cells to immunotherapy. These results provide the first key steps towards finding more effective therapies for HCC and have implications for physicians, scientists, and drug developers in the field of HCC.

Targeting SLP2-mediated lipid metabolism reprograming restricts proliferation and metastasis of hepatocellular carcinoma and promotes sensitivity to Lenvatinib.

SLP2, a protein located on mitochondrial, has been shown to be associated with mitochondrial biosynthesis. Here we explored the potential mechanisms by which SLP2 regulates the development of hepatocellular carcinoma. SLP2 could bind to the c-terminal of JNK2 to affect the ubiquitinated proteasomal degradation pathway of JNK2 and maintain the protein stability of JNK2. The increase of JNK2 markedly increases SREBP1 activity, promoting SREBP1 translocation into the nucleus to promote de novo lipogenesis. Alteration of the JNK2 C-terminal disables SLP2 from mediating SLP2-enhanced de novo lipogenesis. YTHDF1 interacts with SLP2 mRNA in a METTL3/m6A-dependent manner. In a spontaneous HCC animal model, SLP2/c-Myc/sgP53 increases the incidence rate of spontaneous HCC, tumor volume, and tumor number. Importantly, statistical analyses show that levels of SLP2 correlate with tumor sizes, tumor metastasis, overall survival, and disease-free survival of the patients. Targeting the SLP2/SREBP1 pathway effectively inhibits proliferation and metastasis of HCC tumors with high SLP2 expression in vivo combined with lenvatinib. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic SLP2, providing a mechanistic link between de novo lipogenesis and HCC.

MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation.

BACKGROUND: Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. Some glycolytic enzymes such as PKM2, the dominant pyruvate kinase in cancer cells, have been shown to engage in non-glycolytic functions that contribute to tumor metabolism. However, the precise mechanisms are not completely understood. METHODS: The role of MNX1-AS1 in hepatocellular carcinoma progression was assessed both in vitro and in vivo. Northern blotting, RNA pulldown, mass spectrometry, RNA-binding protein immunoprecipitation, ChIP, luciferase reporter assays, RNA FISH and immunofluorescence staining were used to explore the detail molecular mechanism of MNX1-AS1 in hepatocellular carcinoma (HCC). RESULTS: Here we dissect how MNX1-AS1, a long non-coding RNA (lncRNA), reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the cell nucleus. We found that MNX1-AS1 expression was frequently overexpressed in HCC-derived cell lines and tissues compared to their normal hepatic cell counterparts, a finding consistent with its status as pan-cancer expressed lncRNA. In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. In response to EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, GLUT1 and PDK1) are upregulated though the coactivator function of PKM2. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in xenograft models, indicative of the significant contribution of MNX1-AS1 to tumorigenic phenotypes. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. CONCLUSIONS: Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.

Morphologic Change of In Vivo Porcine Liver Under 13 mm Hg Pneumoperitoneum Pressure.

BACKGROUND: Clinically, the total and residual liver volume must be accurately calculated before major hepatectomy. However, liver volume might be influenced by pneumoperitoneum during surgery. Changes in liver volume change also affect the accuracy of simulation and augmented reality navigation systems, which are commonly first validated in animal models. In this study, the morphologic changes in porcine livers in vivo under 13 mm Hg pneumoperitoneum pressure were investigated. MATERIALS AND METHODS: Twenty male pigs were scanned with contrast-enhanced computed tomography without pneumoperitoneum and with 13 mm Hg pneumoperitoneum pressure. RESULTS: The surface area and volume of the liver and the vascular diameter of the aortic lumen, inferior vena cava lumen, and portal vein lumen were measured. There were statistically significant differences in the surface area and volume of the liver (P=0.000), transverse diameter of the portal vein (P=0.038), longitudinal diameter of the inferior vena cava (P=0.033), longitudinal diameter of the portal vein (P=0.036), vascular cross-sectional area of the inferior vena cava (P=0.028), and portal vein (P=0.038) before and after 13 mm Hg pneumoperitoneum pressure. CONCLUSIONS: This study indicated that the creation of pneumoperitoneum at 13 mm Hg pressure in a porcine causes liver morphologic alterations affecting the area and volume, as well as the diameter of a blood vessel.

Comprehensive Characterization of RNA Processing Factors in Gastric Cancer Identifies a Prognostic Signature for Predicting Clinical Outcomes and Therapeutic Responses.

RNA processing converts primary transcript RNA into mature RNA. Altered RNA processing drives tumor initiation and maintenance, and may generate novel therapeutic opportunities. However, the role of RNA processing factors in gastric cancer (GC) has not been clearly elucidated. This study presents a comprehensive analysis exploring the clinical, molecular, immune, and drug response features underlying the RNA processing factors in GC. This study included 1079 GC cases from The Cancer Genome Atlas (TCGA, training set), our hospital cohort, and two other external validation sets (GSE15459, GSE62254). We developed an RNA processing-related prognostic signature using Cox regression with the least absolute shrinkage and selection operator (LASSO) penalty. The prognostic value of the signature was evaluated using a multiple-method approach. The genetic variants, pathway activation, immune heterogeneity, drug response, and splicing features associated with the risk signature were explored using bioinformatics methods. Among the tested 819 RNA processing genes, we identified five distinct RNA processing patterns with specific clinical outcomes and biological features. A 10-gene RNA processing-related prognostic signature, involving ZBTB7A, METTL2B, CACTIN, TRUB2, POLDIP3, TSEN54, SUGP1, RBMS1, TGFB1, and PWP2, was further identified. The signature was a powerful and robust prognosis factor in both the training and validation datasets. Notably, it could stratify the survival of patients with GC in specific tumor-node-metastasis (TNM) classification subgroups. We constructed a composite prognostic nomogram to facilitate clinical practice by integrating this signature with other clinical variables (TNM stage, age). Patients with low-risk scores were characterized with good clinical outcomes, proliferation, and metabolism hallmarks. Conversely, poor clinical outcome, invasion, and metastasis hallmarks were enriched in the high-risk group. The RNA processing signature was also involved in tumor microenvironment reprogramming and regulating alternative splicing, causing different drug response features between the two risk groups. The low-risk subgroup was characterized by high genomic instability, high alternative splicing and might benefit from the immunotherapy. Our findings highlight the prognostic value of RNA processing factors for patients with GC and provide insights into the specific clinical and molecular features underlying the RNA processing-related signature, which may be important for patient management and targeting treatment.

Multi-organ metastasis as destination for breast cancer cells guided by biomechanical architecture.

A majority of breast cancer patients die of widespread aggressive multidrug-resistant tumors. Aspartate ß-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase and oncofetal antigen involved in embryogenesis. To illustrate if ASPH could be targeted for metastatic breast cancer, embedded and on-top three-dimensional (3-D) cultures, 3-D invasion, mammosphere formation, immunofluorescence, immunohistochemistry, Western blot, co-IP and microarray were conducted. In vitro metastasis was developed to imitate how cancer cells invade basement membrane at the primary site, transendothelially migrate, consequently colonize and outgrow at distant sites. Orthotopic and experimental pulmonary metastatic (tail vein injection) murine models were established using stable breast cancer cell lines. Cox proportional hazards regression models and Kaplan-Meier plots were applied to assess clinical outcome of breast cancer patients. In adult non-cancerous breast tissue, ASPH is undetectable. Pathologically, ASPH expression re-emerged at ductal carcinoma in situ (DCIS), and enhanced with disease progression, from early-stage invasive ductal carcinoma (IDC) to late-stage carcinoma. ASPH at moderate to high levels contribute to aggressive molecular subtypes, early relapse or more frequent progression and metastases, whereas substantially shortened overall survival and disease-free survival of breast cancer patients. Through direct physical interactions with A disintegrin and metalloproteinase domain-containing protein (ADAM)-12/ADAM-15, ASPH could activate SRC cascade, thus upregulating downstream components attributed to multifaceted metastasis. ASPH-SRC axis initiated pro-invasive invadopodium formation causing breakdown/disorganization of extracellular matrix (ECM), simultaneously potentiated epithelial-mesenchymal transition (EMT), induced cancer stem cell markers (CD44 and EpCAM), enhanced mammosphere formation and intensified 3-dimentional invasion. Oncogenic SRC upregulated matrix metallopeptidases (MMPs) were assembled by invadopodia, acting as executive effectors for multi-step metastasis. ASPH-SRC signal guided multi-organ metastases (to lungs, liver, bone, spleen, lymph nodes, mesentery or colon) in immunocompromised mice. Malignant phenotypes induced by ASPH-SRC axis were reversed by the third-generation small molecule inhibitor (SMI) specifically against ß-hydroxylase activity of ASPH in pre-clinical models of metastatic breast cancer. Collectively, ASPH could activate ADAMs-SRC-MMPs cascades to promote breast cancer tumor progression and metastasis. ASPH could direct invadopodium construction as a biomechanical sensor and pro-metastatic outlet. ASPH-mediated cancer progression could be specifically/efficiently subverted by SMIs of ß-hydroxylase activity. Therefore, ASPH emerges as a therapeutic target for breast cancer.

Low CBS expression can identify patients who benefit from adjuvant chemotherapy in gastric cancer.

Aim: To explore the clinical significance of Cystathionine beta-synthase (CBS) expression in gastric cancer (GC).Research design and methods: CBS expression and clinicopathological/follow-up information of patients with gastric cancer undergoing operation were collected from The Cancer Genome Atlas (TCGA) database. The association of CBS expression with patients' overall survival (OS) was determined in the entire cohort and different subgroups. Validation was performed in two external cohorts from NCBI Gene Expression Omnibus (GEO) database. The estimated drug response of the tumors with different CBS expressions was characterized. The potential CBS-related cellular pathways in chemoresistance were explored.Results: High CBS was associated with poor OS in patients receiving adjuvant chemotherapy (ACT) but not those without ACT. And ACT was associated with favorable OS in patients with low CBS expression but not those with high CBS expression. The results were verified in two external cohorts. Drug response prediction suggested that patients with low CBS expression showed high sensitivity to 5-Fluorouracil. Gene Set Enrichment Analysis (GSEA) suggested that CBS might contribute to GC chemoresistance via modulating many cellular pathways, including down-regulating apoptosis and P53 pathways while up-regulating DNA repair pathway.Conclusion: Low CBS expression can predict the benefit from ACT in GC.

Inhibition of TGFß1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy.

Aims: Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may be attenuated in fibrotic livers. However, the molecular mechanisms responsible for this process are largely unknown. It is widely acknowledged that the TGFß1 signaling axis plays a major role in liver fibrosis. Therefore, the aims of this study were to elucidate the underlying mechanism of liver regeneration during ALPPS with or without fibrosis, specifically focusing on TGFß1 signaling. Approach: ALPPS was performed in rat models with N-diethylnitrosamine-induced liver fibrosis and no fibrosis. Functional liver remnant regeneration and expression of TGFß1 were analyzed during the ALPPS procedures. Adeno-associated virus-shTGFß1 and the small molecule inhibitor LY2157299 (galunisertib) were used separately or in combination to inhibit TGFß1 signaling in fibrotic rats. Results: Liver regeneration following ALPPS was lower in fibrotic rats than non-fibrotic rats. TGFß1 was a key mediator of postoperative regeneration in fibrotic liver. Interestingly, AAV-shTGFß1 accelerated the regeneration of fibrotic functional liver remnant and improved fibrosis, while LY2157299 only enhanced liver regeneration. Moreover, combination treatment elicited a stronger effect. Conclusions: Inhibition of TGFß1 accelerated regeneration of fibrotic liver, ameliorated liver fibrosis, and improved liver function following ALPPS. Therefore, TGFß1 is a promising therapeutic target in ALPPS to improve fibrotic liver reserve function and prognosis.

Upregulated mH2A1 serves as an unfavorable prognostic indicator and promotes the progress of hepatocellular carcinoma (HCC).

PURPOSE: To investigate the role and prognostic value of mH2A1 in the progression of hepatocellular carcinoma (HCC). METHODS: Basing on the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and GEO datasets, the gene expression of mH2A1 and relative clinical characteristics were analyzed to assess the prognostic significant of mH2A1 in HCC. The protein expression of mH2A1 was measured by immunohistochemistry. Stable cell lines and nude mice model were used to investigate the role of mH2A1 in the progression of HCC. RESULTS: In this study, using TCGA-LIHC data and HCC tissue microarray, we found that expression of mH2A1 was higher in tumor tissues than in adjacent normal tissues. These results were validated using the GEO database. Patients with high levels of mH2A1 were predicted to have larger tumor size and more advanced tumor stage and grade. Multivariate analysis revealed that increased mH2A1 expression was an independent prognostic risk factor of shorter overall survival (OS). Experimental results showed that elevated mH2A1 expression promoted the progression of HCC while reduced mH2A1 expression lead to opposite effects in vitro and in vivo. mH2A1 promoted the progression of HCC by regulating cell cycle via AKT. Dysregulated expression of mH2A1 was associated with its DNA methylation status. Two CpG sites (cg01466741 and cg02614129) were negatively correlated with mH2A1 expression. Notably, high methylation of both CpG sites was associated with better OS. CONCLUSION: Based on the above results, we concluded that upregulated mH2A1 in HCC promoted tumor progression and could serve as an unfavorable prognostic indicator.

Identification of a cryptic submicroscopic deletion using a combination of fluorescence in situ hybridization and array comparative genomic hybridization in a t(3;5)(q25;q35)-positive acute myeloid leukemia patient: A case report and review of the literature.

RATIONALE: The advent of high-resolution genome arrays including array comparative genomic hybridization (aCGH) has enabled the detection of cryptic submicroscopic deletions flanking translocation breakpoints in up to 20% of the apparently "balanced" structural chromosomal rearrangements in hematological disorders. However, reports of submicroscopic deletions flanking the breakpoints of t(3;5)(q25;q35) are rare and the clinical significance of submicroscopic deletions in t(3;5) has not been explicitly identified. PATIENT CONCERNS: We present a 47-year-old man with acute myeloid leukemia. G-banding analysis identified t(3;5)(q25;q35). DIAGNOSIS: Array CGH-based detection initially confirmed only the deletion of chromosome 3. Further characterization using fluorescence in situ hybridization identified a cryptic submicroscopic deletion including 5' MLF1-3' NPM1 flanking the breakpoint on the derivative chromosome 3. INTERVENTIONS: The patient started "7+3" induction chemotherapy with cytosine arabinoside and daunorubicin, and subsequently received 2 cycles of high-dose intermittent acronym of cytosine arabinoside or cytarabine. OUTCOMES: The patient did not undergo complete remission and died from an infection due to neutropenia. LESSONS: Haploinsufficiency of NPM1 or other deleted genes, including SSR3, may be responsible for the phenotype of t(3;5)(q25;q35)-positive myeloid neoplasms with submicroscopic deletions.

ABCA8 is regulated by miR-374b-5p and inhibits proliferation and metastasis of hepatocellular carcinoma through the ERK/ZEB1 pathway.

BACKGROUND: ATP binding cassette subfamily A member 8 (ABCA8) belongs to the ATP binding cassette (ABC) transporter superfamily. ABCA8 is a transmembrane transporter responsible for the transport of organics, such as cholesterol, and drug efflux. Some members of the ABC subfamily, such as ABCA1, may inhibit cancer development. However, the mechanism of ABCA8 in the process of cancer activation is still ambiguous. METHODS: The expression of ABCA8 in human hepatocellular carcinoma (HCC) tissues and cell lines was examined using qPCR, immunoblotting, and immunohistochemical staining. The effects of ABCA8 on the proliferation and metastasis of HCC were examined using in vitro and in vivo functional tests. A luciferase reporter assay was performed to explore the binding between microRNA-374b-5p (miR-374b-5p) and the ABCA8 3'-untranslated region (UTR). RESULTS: ABCA8 was frequently down-regulated in HCC and this down-regulation was negatively correlated with prognosis. The overexpression of ABCA8 inhibited growth and metastasis in HCC, whereas the knockdown of ABCA8 exerted the antithetical effects both in vivo and in vitro. ABCA8 was down-regulated by miR-374b-5p; this down-regulation can induce epithelial transformation to mesenchyme via the ERK/ZEB1 signaling pathway and promote HCC progression. CONCLUSION: We exposed the prognostic value of ABCA8 in HCC, and illuminated a novel pathway in ABCA8-regulated inhibition of HCC tumorigenesis and metastasis. These findings may lead to a new targeted therapy for HCC through the regulation of ABCA8, and miR-374b-5p.

lncRNA-SOX2OT promotes hepatocellular carcinoma invasion and metastasis through miR-122-5p-mediated activation of PKM2.

Tumor cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect, but the involvement of Warburg effect in liver cancer cell metastasis is not well understood. In present study, our results indicate a positive correlation between glucose metabolism level and metastatic potential of hepatocellular carcinoma (HCC). We also observed that a long noncoding RNA-SOX2OT (lncRNA-SOX2OT) can not only increase the metastatic potential of HCC but also promote a pyruvate kinase M2 (PKM2)-mediated activation of glucose metabolism. Inhibition of PKM2 in HCC cells greatly compromises lncRNA-SOX2OT in promoting Warburg effect and metastasis. Furthermore, miR-122-5p was found being a direct target of lncRNA-SOX2OT in regulating PKM2 expression. Thus, our findings reveal that lncRNA-SOX2OT, a regulator of PKM2, could predispose HCC patients to metastases and may serve as a candidate for metastatic prediction and therapies in HCC patients.

Augmented reality navigation for liver resection with a stereoscopic laparoscope.

OBJECTIVE: Understanding the three-dimensional (3D) spatial position and orientation of vessels and tumor(s) is vital in laparoscopic liver resection procedures. Augmented reality (AR) techniques can help surgeons see the patient's internal anatomy in conjunction with laparoscopic video images. METHOD: In this paper, we present an AR-assisted navigation system for liver resection based on a rigid stereoscopic laparoscope. The stereo image pairs from the laparoscope are used by an unsupervised convolutional network (CNN) framework to estimate depth and generate an intraoperative 3D liver surface. Meanwhile, 3D models of the patient's surgical field are segmented from preoperative CT images using V-Net architecture for volumetric image data in an end-to-end predictive style. A globally optimal iterative closest point (Go-ICP) algorithm is adopted to register the pre- and intraoperative models into a unified coordinate space; then, the preoperative 3D models are superimposed on the live laparoscopic images to provide the surgeon with detailed information about the subsurface of the patient's anatomy, including tumors, their resection margins and vessels. RESULTS: The proposed navigation system is tested on four laboratory ex vivo porcine livers and five operating theatre in vivo porcine experiments to validate its accuracy. The ex vivo and in vivo reprojection errors (RPE) are 6.04 ±â€¯1.85 mm and 8.73 ±â€¯2.43 mm, respectively. CONCLUSION AND SIGNIFICANCE: Both the qualitative and quantitative results indicate that our AR-assisted navigation system shows promise and has the potential to be highly useful in clinical practice.

An extra chromosome 9 derived from either a normal chromosome 9 or a derivative chromosome 9 in a patient with acute myeloid leukemia positive for t(9;11)(p21.3;q23.3): A case report.

Translocation (9;11)(p21.3;q23.3) is one of the most common lysine methyltransferase 2A (KMT2A)-rearrangements in de novo and therapy-related acute myeloid leukemia (AML). Numerous in vitro and in vivo studies have demonstrated that the KMT2A/MLLT3 super elongation complex subunit (MLLT3) fusion gene on the derivative chromosome 11 serves a crucial role in leukemogenesis. Trisomy 9 as a secondary chromosome change in patients with t(9;11) is relatively rare. The present study reported a unique case of AML with a chromosome 9 trisomy secondary to t(9;11)(p21.3;q23.3) through the cytogenetic analysis of leukemic blood and bone marrow. Further characterization with fluorescence in situ hybridization and array comparative genomic hybridization analysis revealed that this extra chromosome 9 was either a copy of normal chromosome 9 or a derivative chromosome 9. Conversely with the previously reported favorable outcome of AML patients with t(9;11)(p21.3;q23.3), in the present study, the cells with only translocation persisted, whereas the cells with an extra chromosome 9 disappeared following initial chemotherapy. With this unique case, the present study hypothesized that the extra chromosome 9 could serve a crucial role in AML disease progression and contribute to cellular sensitivity to chemotherapy.