Intron Retention of DDX39A Driven by SNRPD2 is a Crucial Splicing Axis for Oncogenic MYC/Spliceosome Program in Hepatocellular Carcinoma.

RNA splicing is a dynamic molecular process in response to environmental stimuli and is strictly regulated by the spliceosome. Sm proteins, constituents of the spliceosome, are key components that mediate splicing reactions; however, their potential role in hepatocellular carcinoma (HCC) is poorly understood. In the study, SNRPD2 (PD2) is found to be the most highly upregulated Sm protein in HCC and to act as an oncogene. PD2 modulates DDX39A intron retention together with HNRNPL to sustain the DDX39A short variant (39A_S) expression. Mechanistically, 39A_S can mediate MYC mRNA nuclear export to maintain high MYC protein expression, while MYC in turn potentiates PD2 transcription. Importantly, digitoxin can directly interact with PD2 and has a notable cancer-suppressive effect on HCC. The study reveals a novel mechanism by which DDX39A senses oncogenic MYC signaling and undergoes splicing via PD2 to form a positive feedback loop in HCC, which can be targeted by digitoxin.

Laparoscopic spleen-preserving total pancreatectomy for the treatment of low-grade malignant pancreatic tumors: Two case reports and review of literature.

BACKGROUND: Function-preserving pancreatectomy can improve the long-term quality of life of patients with benign or low-grade malignant tumors, such as intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms. However, there is limited literature on laparoscopic spleen-preserving total pancreatectomy (L-SpTP) due to technical difficulties. CASE SUMMARY: Patient 1 was a 51-year-old male diagnosed with IPMN based on preoperative imaging, showing solid nodules in the pancreatic head and diffuse dilation of the main pancreatic duct with atrophy of the distal pancreas. We performed L-SpTP with preservation of the splenic vessels, and the postoperative pathology report revealed IPMN with invasive carcinoma. Patient 2 was a 60-year-old male with multiple cystic lesions in the pancreatic head and body. L-SpTP was performed, and intraoperatively, the splenic vein was injured and required ligation. Postoperative pathology revealed a mucinous cystic tumor of the pancreas with low-grade dysplasia. Both patients were discharged on postoperative day 7, and there were no major complications during the perioperative period. CONCLUSION: We believe that L-SpTP is a safe and feasible treatment for low-grade malignant pancreatic tumors, but more case studies are needed to evaluate its safety, efficacy, and long-term outcomes.

Risk assessment and strontium isotopic tracing of potentially toxic metals in creek sediments around a uranium mine, China.

The contamination of creek sediments near industrially nuclear dominated site presents significant environmental challenges, particularly in identifying and quantifying potentially toxic metal (loid)s (PTMs). This study aims to measure the extent of contamination and apportion related sources for nine PTMs in alpine creek sediments near a typical uranium tailing dam from China, including strontium (Sr), rubidium (Rb), manganese (Mn), lithium (Li), nickel (Ni), copper (Cu), vanadium (V), cadmium (Cd), zinc (Zn), using multivariate statistical approach and Sr isotopic compositions. The results show varying degrees of contamination in the sediments for some PTMs, i.e., Sr (16.1-39.6 mg/kg), Rb (171-675 mg/kg), Mn (224-2520 mg/kg), Li (11.6-78.8 mg/kg), Cd (0.31-1.38 mg/kg), and Zn (37.1-176 mg/kg). Multivariate statistical analyses indicate that Sr, Rb, Li, and Mn originated from the uranium tailing dam, while Cd and Zn were associated with abandoned agricultural activities, and Ni, Cu, and V were primarily linked to natural bedrock weathering. The Sr isotope fingerprint technique further suggests that 48.22-73.84% of Sr and associated PTMs in the sediments potentially derived from the uranium tailing dam. The combined use of multivariate statistical analysis and Sr isotopic fingerprint technique in alpine creek sediments enables more reliable insights into PTMs-induced pollution scenarios. The findings also offer unique perspectives for understanding and managing aqueous environments impacted by nuclear activities.

Occurrence and genotypic identification of Blastocystis sp., Enterocytozoon bieneusi, and Giardia duodenalis in dairy cattle in Heilongjiang Province, China.

Blastocystis sp., Enterocytozoon bieneusi, and Giardia duodenalis are three common zoonotic intestinal parasites, and cattle are important hosts of these three intestinal protozoa. In this study, 1632 fecal samples were collected from dairy farms in Heilongjiang Province, China, and screened for Blastocystis sp., E. bieneusi, and G. duodenalis using polymerase chain reaction. Of these, 149 (9.13%) were positive for three zoonotic pathogens, including 104 (6.40%), 22 (1.35%), and 23 (1.41%) for Blastocystis sp., E. bieneusi, and G. duodenalis, respectively. Based on partial SSU rRNA gene sequencing analysis, 104 positive samples of Blastocystis sp. were found, and a total of nine known subtypes were identified, including ST10 (61), ST3 (18), ST14 (6), ST26 (7), ST24 (3), ST25 (2), ST1 (2), ST5 (2), and ST21 (1). Among these, three subtypes (ST1, ST3, and ST5) were recognized as zoonotic subtypes, and two subtypes (ST10 and ST14) were specific to animals. All 23 Giardia duodenalis-positive samples belonged to assemblage E (n = 23) based on sequenced beta-giardin (bg) and triosephosphate isomerase (tpi) genes. Three known genotypes of E. bieneusi, namely J (n = 9), I (n = 6), and BEB4 (n = 7), were identified by sequence analysis of the internal transcriptional spacer region gene. Our study provides basic data for prevention and control in Heilongjiang Province; however, further research is required to better understand the prevalence and public health significance of these pathogens in the Heilongjiang region.

Establishment and characterization of a highly metastatic hepatocellular carcinoma cell line.

The prevalence of alcohol-related hepatocellular carcinoma (HCC) has been increasing during the last decade. Cancer research requires cell lines suitable for both in vitro and in vivo assays. However, there is a lack of cell lines with a high in vivo metastatic capacity for this HCC subtype. Herein, a new HCC cell line was established, named HCC-ZJ, using cells from a patient diagnosed with alcohol-related HCC. The karyotype of HCC-ZJ was 46, XY, del (p11.2). Whole-exome sequencing identified several genetic variations in HCC-Z that occur frequently in alcohol-associated HCC, such as mutations in TERT, CTNNB1, ARID1A, CDKN2A, SMARCA2, and HGF. Cell counting kit-8 assays, colony formation assays, and Transwell assays were performed to evaluate the proliferation, migration, and sensitivity to sorafenib and lenvatinib of HCC-Z in vitro. HCC-ZJ showed a robust proliferation rate, a weak foci-forming ability, a strong migration capacity, and a moderate invasion tendency in vitro. Finally, the tumorigenicity and metastatic capacity of HCC-Z were evaluated using a subcutaneous xenograft model, an orthotopic xenograft model, and a tail-veil injection model. HCCZJ exhibited strong tumorigenicity in the subcutaneous xenograft and orthotopic tumor models. Moreover, HCC-ZJ spontaneously formed pulmonary metastases in the orthotopic tumor model. In summary, a new HCC cell line derived from a patient with alcohol-related HCC was established, which showed a high metastatic capacity and could be applied for in vitro and in vivo experiments during pre-clinical research.Highlights• An alcohol-related HCC cell line, HCC-ZJ, was established• HCC-ZJ was applicable for in vitro functional experiment and gene editing• HCC-ZJ was applicable for in vivo tumor growth and spontaneous metastasis models.

Distribution and migration of uranium, chromium, and accompanying metal(loid)s in soil-plants system around a uranium hydrometallurgical area.

The extraction and utilization of uranium (U) ores have led to the release of significant amounts of potentially toxic metal(loid)s (PTMs) into the environment, constituting a grave threat to the ecosystem. However, research on the distribution and migration mechanism of U, chromium (Cr), and their accompanying PTMs in soil-plant system around U hydrometallurgical area remains insufficient and poorly understood. Herein, the distribution, migration, and risk level of PTMs were evaluated in soil and plant samples around U hydrometallurgical area, Northern Guangdong, China. The results demonstrated that the maximum content of U and Cr found in the analyzed soils were up to 84.2 and 238.9 mg/kg, respectively. These values far exceed the soil background values in China and other countries. The highest content of U (53.6 mg/kg) was detected in Colocasia antiquorum Schott, and the highest content of Cr (349.5 mg/kg) was observed in Pteridium aquilinum, both of which were enriched in their roots. The risk assessment of PTMs demonstrated that the study area suffered from severe pollution (PN > 3), especially from U, Cr, Th, and As, suggesting the non-negligible anthropogenic impacts. Hence, in light of the significant ecological hazard posed by the U hydrometallurgical area, it is imperative to implement appropriate restoration measures to ensure the human health and maintain the stability of the ecosystem.

Assessment of potential zoonotic transmission of Giardia duodenalis from dogs and cats.

Giardia duodenalis is one of the major causes of diarrhea among humans, especially in young children. Statistical analysis revealed that the pooled prevalence of G. duodenalis in humans, dogs, and cats was 9.72% (10,921/112383), 15.60% (7510/48140), and 14.53% (1125/7740), respectively. Unquestionably, the canine-specific assemblages C and D and the feline-specific assemblage F were the dominant genotypes in dogs and cats, respectively. Additionally, the prevalence of zoonotic G. duodenalis assemblages (A and B) in dogs and cats was 23.07% (875/3792) and 41.42% (169/408), respectively, implying that the potential transmission of G. duodenalis from dogs and cats to human infection cannot be ignored. The highest frequency of potentially zoonotic assemblages was found among working dogs (3.55%, 25/705) and the 1-5 age group (22.92%, 11/48). In summary, dogs and cats have a significant role in the zoonotic transmission of G. duodenalis due to their close contact with humans and the higher frequency presence of zoonotic assemblages. Further studies are necessary to explore the presence of G. duodenalis among humans and animals and in environmental samples. Researchers should adopt a one-health approach to gain a deeper understanding of G. duodenalis in dogs and cats and potential transmission routes to humans.

Analyses of Factors Associated with Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Review.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is the exacerbation of a range of respiratory symptoms during the stable phase of chronic obstructive pulmonary disease (COPD). AECOPD is thus a dangerous stage and key event in the course of COPD, as its deterioration and frequency seriously affects the quality of life of patients and shortens their survival. Acute exacerbations occur and develop due to many factors such as infection, tobacco smoke inhalation, air pollution, comorbidities, airflow limitation, various biomarkers, history of previous deterioration, natural killer cell abnormalities, immunoglobulin G deficiency, genetics, abnormal muscle and nutritional status, negative psychology, and seasonal temperature changes. There is relatively limited research on the impact of the role of standardized management on the alleviation of AECOPD. However, with the establishment of relevant prevention and management systems and the promotion of artificial intelligence technology and Internet medical approaches, long-term effective and standardized management of COPD patients may help to achieve the quality of life and disease prognosis in COPD patients and reduce the risk of AE.

Kinesin family member 18B activates mTORC1 signaling via actin gamma 1 to promote the recurrence of human hepatocellular carcinoma.

The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is frequently reported to be hyperactivated in hepatocellular carcinoma (HCC) and contributes to HCC recurrence. However, the underlying regulatory mechanisms of mTORC1 signaling in HCC are not fully understood. In the present study, we found that the expression of kinesin family member 18B (KIF18B) was positively correlated with mTORC1 signaling in HCC, and the upregulation of KIF18B and p-mTOR was associated with a poor prognosis and HCC recurrence. Utilizing in vitro and in vivo assays, we showed that KIF18B promoted HCC cell proliferation and migration through activating mTORC1 signaling. Mechanistically, we identified Actin gamma 1 (γ-Actin) as a binding partner of KIF18B. KIF18B and γ-Actin synergistically modulated lysosome positioning, promoted mTORC1 translocation to lysosome membrane, and prohibited p70 S6K from entering lysosomes for degradation, which finally led to the enhancement of mTORC1 signaling transduction. Moreover, we found that KIF18B was a direct target of Forkhead box M1, which explains the potential mechanism of KIF18B overexpression in HCC. Our study highlights the potential of KIF18B as a therapeutic target for the treatment of HCC.

High-efficiency removal of arsenic(III) from wastewater using combined copper ferrite@biochar and persulfate.

Arsenic (As) is a potentially toxic element with variable valence states. Due to high toxicity and bioaccumulation, As can pose a severe threat to the quality of the ecology as well as human health. In this work, As(III) in water was effectively removed by biochar-supported copper ferrite magnetic composite with persulfate. The copper ferrite@biochar composite exhibited higher catalytic activity than copper ferrite and biochar. The removal of As(III) could reach 99.8% within 1 h under the conditions of initial As(III) concentration at 10 mg/L, initial pH at 2-6, and equilibrium pH at 10. The maximum adsorption capacity of As(III) by copper ferrite@biochar-persulfate was 88.9 mg/g, achieving superior performance than mostly reported the metal oxide adsorbents. By means of a variety of characterization techniques, it was found that ∙OH acted as the main free radical for removing As(III) in the copper ferrite@biochar-persulfate system and the major mechanisms were oxidation and complexation. As a natural fibre biomass waste-derived adsorbent, ferrite@biochar presented a high catalytic efficiency and easy magnetic separation for As(III) removal. This study highlights the great potential of copper ferrite@biochar-persulfate application in As(III) wastewater treatment.

An Alternating Magnetic Field-Controlled Drug Delivery System Based on 4,4'-Azobis (4-cyanovaleric Acid)-Functioned Fe3O4@Chitosan Nanoparticles.

Herein, we designed chitosan-coated Fe3O4 nanocomposites for the control release of drugs by an alternating magnetic field (AMF). The chitosan-coated Fe3O4 nanoparticles (Fe3O4@CS) were prepared by a alkaline co-precipitation method, and then, the model drug toluidine blue (TB) was covalently grafted onto the surface of the nanocomposite by a two-step amide reaction with the thermosensitive molecule 4,4'-azobis (4-cyanovaleric acid) (ACVA) as the linker group. The prepared nanocomposites were superparamagnetic and showed high magnetization saturation (about 54.0 emu g-1). In vitro hydrothermal release studies showed that most parts of the TB would be effectively enclosed within the nanocarriers at lower ambient temperatures (23 or 37 °C) due to the molecular bonding of ACVA. The results of kinetic fitting of hydrothermal release data showed that TB released from nanoparticles followed first-order kinetics (R2 > 0.99) and the Korsemeyer-Peppas model (R2 > 0.99, n < 0.5). Most importantly, a single magnetron release experiment demonstrated an approximately linear relationship between the cumulative release of the drug and the duration of action of AMF (R2 = 0.9712). Moreover, the increase in the cumulative release of the drug can be controlled by controlling the switch of the AMF generation device. Therefore, the ACVA-modified Fe3O4@CS nanocarrier designed in this study is a promising model for drug delivery that enables the control of drug release dose by AMF.

Staple line lockstitch reinforcement decreases clinically relevant pancreatic fistula following distal pancreatectomy: Results of a propensity score matched retrospective analysis.

Background: Postoperative pancreatic fistula (POPF) remains the primary complication of distal pancreatectomies. We aimed to review whether staple line reinforcement with continuous lockstitches would lead to decreased grade B and C pancreatic fistula in patients undergoing distal pancreatectomy. Methods: This retrospective study enrolled consecutive patients scheduled to undergo distal pancreatectomy at a large tertiary hospital. A comparison was conducted between lockstitch reinforcement and non-reinforcement for remnant closure during distal pancreatectomies from August 2016 to February 2021. Propensity score matching was applied to balance the two groups with covariates including abdominal and back pain, diabetes mellitus, and estimated blood loss. The primary outcome was POPF rate. Results: A total of 153 patients were enrolled in the study (89 lockstitch reinforcements, 64 non-reinforcements), of whom 128 patients (64 per group) were analyzed after propensity score matching (1:1). The total POPF rate was 21.9%. POPF was identified in 12.5% (8/64) of the patients who underwent resection with lockstitch reinforcement and 31.2% (20/64) of the patients without reinforcement (odds ratio 0.314, 95% confidence interval 0.130-0.760, P=0.010). No deaths occurred in either group. Neither the major complication rate nor the length of hospital stay after surgery differed between the groups. Conclusions: Compared with the use of stapler alone, staple line lockstitch reinforcement for remnant closure during distal pancreatectomy could reduce the POPF rate. Further multicenter randomized clinical trials are required to confirm these results.

The aberrant upregulation of exon 10-inclusive SREK1 through SRSF10 acts as an oncogenic driver in human hepatocellular carcinoma.

Deregulation of alternative splicing is implicated as a relevant source of molecular heterogeneity in cancer. However, the targets and intrinsic mechanisms of splicing in hepatocarcinogenesis are largely unknown. Here, we report a functional impact of a Splicing Regulatory Glutamine/Lysine-Rich Protein 1 (SREK1) variant and its regulator, Serine/arginine-rich splicing factor 10 (SRSF10). HCC patients with poor prognosis express higher levels of exon 10-inclusive SREK1 (SREK1L). SREK1L can sustain BLOC1S5-TXNDC5 (B-T) expression, a targeted gene of nonsense-mediated mRNA decay through inhibiting exon-exon junction complex binding with B-T to exert its oncogenic role. B-T plays its competing endogenous RNA role by inhibiting miR-30c-5p and miR-30e-5p, and further promoting the expression of downstream oncogenic targets SRSF10 and TXNDC5. Interestingly, SRSF10 can act as a splicing regulator for SREK1L to promote hepatocarcinogenesis via the formation of a SRSF10-associated complex. In summary, we demonstrate a SRSF10/SREK1L/B-T signalling loop to accelerate the hepatocarcinogenesis.

Synthesis, Antibacterial and Anthelmintic Activity of Novel 3-(3-Pyridyl)-oxazolidinone-5-methyl Ester Derivatives.

In this study, a series of 3-(3-pyridyl)-oxazolidone-5-methyl ester derivatives was synthesized and characterized by 1H NMR, 13C NMR, and LC-MS. The conducted screening antibacterial studies of the new 3-(3-pyridyl)-oxazolidone-5-methyl ester derivatives established that the methyl sulfonic acid esters have broad activity spectrum towards Staphylococcus aureus, Streptococcus pneumoniae, Bacillus subtilis and Staphylococcus epidermidis. Among them, compound 12e has the most potent activity, with an MIC of 16 µg/mL against B.subtilis, and could reduce the instantaneous growth rate of bacteria. Furthermore, molecular docking studies were also simulated for compound 12e to predict the specific binding mode of this compound. In addition, anthelmintic activity of these compounds was also evaluated against adult Indian earthworms (Pheretima posthuman). The results showed that compound 11b had the best effect. These results above can provide experimental reference for the development of novel antibacterial and anthelmintic drugs.

USP5 facilitates non-small cell lung cancer progression through stabilization of PD-L1.

PD-L1(CD274) is a well-known immunosuppressive molecule, which confers immunoescape features to cancer cells and has become one of the major targets in cancer immunotherapies. Understanding the regulatory mechanisms that control PD-L1 protein expression is important for guiding immune checkpoint blockade therapy. Here, we showed that ubiquitin specific peptidase 5 (USP5) was a novel PD-L1 deubiquitinase in non-small cell lung cancer (NSCLC) cells. USP5 directly interacted with PD-L1 and deubiquitinated PD-L1, therefore enhances PD-L1 protein stability. Meanwhile, USP5 protein levels were highly elevated and positively correlated to PD-L1 levels in NSCLC tissues, and were closely correlated with poor prognosis of these patients. In addition, knockdown of USP5 retarded tumor growth in the Lewis lung carcinoma mouse model. Thus, we identified that USP5 was a new regulator of PD-L1 and targeting USP5 is a promising strategy for cancer therapy.

Gastric adenocarcinoma at stage IV with complete remission after neoadjuvant therapy concurrent with adenosquamous carcinoma of the ampulla of Vater: a case report and literature review.

BACKGROUND: Adenosquamous carcinoma (ASC) of the ampulla of Vater (AmV) is exceedingly rare with more aggressive behavior and worse prognosis than adenocarcinoma. The finding of ASC at the AmV in combination to the gastric adenocarcinoma has never been reported in the literature before. CASE PRESENTATION: An old lady was diagnosed as gastric adenocarcinoma at stage IV with enlargement of supraclavicular lymph nodes by gastroscopy and histopathological evaluation 3 years ago. Afterwards, the patient achieved complete remission after regular chemotherapy. However, the patient manifested yellow sclera and skin, choluria and clay colored stool 3 months ago. Preoperative contrast-enhanced CT, ERCP, MRCP, and PET/CT revealed the presence of an ampullary tumor. The patient then underwent laparoscopic radical gastrectomy and pancreaticoduodenectomy with regional lymph node dissection. Postoperative cytological analyses confirmed the diagnosis of gastric ulcer with complete response to neoadjuvant therapy and ASC at the AmV. The patient's postoperative outcome was uneventful. CONCLUSION: Drawing firm conclusions about the diagnosis of ampullary ASC is difficult because of the difficulty in acquiring both adenocarcinoma and SCC components by fine needle biopsy. The rarity of ASC of the AmV coexistent with gastric carcinoma makes it difficult to elucidate their clinicopathological characteristics, therapeutic strategies and overall prognosis. Surgical resection still remains the main treatment method.

Dysregulation of Wnt/ß-catenin signaling by protein kinases in hepatocellular carcinoma and its therapeutic application.

Wnt/ß-catenin signaling is indispensable for many biological processes, including embryonic development, cell cycle, inflammation, and carcinogenesis. Aberrant activation of the Wnt/ß-catenin signaling can promote tumorigenicity and enhance metastatic potential in hepatocellular carcinoma (HCC). Targeting this pathway is a new opportunity for precise medicine for HCC. However, inhibiting Wnt/ß-catenin signaling alone is unlikely to significantly improve HCC patient outcome due to the lack of specific inhibitors and the complexity of this pathway. Combination with other therapies will be an important next step in improving the efficacy of Wnt/ß-catenin signaling inhibitors. Protein kinases play a key and evolutionarily conserved role in the Wnt/ß-catenin signaling and have become one of the most important drug targets in cancer. Targeting Wnt/ß-catenin signaling and its regulatory kinase together will be a promising HCC management strategy. In this review, we summarize the kinases that modulate the Wnt/ß-catenin signaling in HCC and briefly discuss their molecular mechanisms. Furthermore, we list some small molecules that target the kinases and may inhibit Wnt/ß-catenin signaling, to offer new perspectives for preclinical and clinical HCC studies.

Retrograde artery first approach for "shoulder" pancreatic cancers in minimally invasive distal pancreatectomy.

BACKGROUND: "Shoulder" pancreatic cancer, defined as tumor located at the confluence where the splenic vein meets the portal vein, has specific adjacent anatomies. It's difficult to resect this type of tumor with adequate regional lymphadenectomy. METHODS: We described a new concept of "shoulder" pancreatic cancer, and retrospectively analyzed eleven consecutive cases from September 2019 to April 2020, to assess the safety and efficacy of the retrograde artery first approach in minimally invasive distal pancreatectomy. The primary outcome was set as radical (R0) resection rate. RESULTS: All of the 11 cases achieved R0 resection, with a median of 8 (range 5-32) lymph nodes harvested, given the ratio of embraced splenic vein in 72.7% of the cases, splenic artery embracement in 45.5%, and SMV-PV wall invasion in 27.3%. The maximum tumor size on pathology was 35 (range 20-65) mm. The median operative time was 260 (range 155-470) min, and the median estimated blood loss was 200 (range 50-1000) ml. One case needed intraoperative transfusion. One grade B postoperative pancreatic fistula occurred accompanied with abdominal infection, while the rest of cases recovered uneventful. The median postoperative length of stay was 9 (range 6-20) days. CONCLUSIONS: "Shoulder" pancreatic cancers are clinically significant. Retrograde artery first approach is a potentially safe and effective alternative to achieve a radical resection margin for shoulder pancreatic cancers in minimally invasive era. More evidences are needed in the future.