Human ß-defensin-1 affects the mammalian target of rapamycin pathway and autophagy in colon cancer cells through long non-coding RNA TCONS_00014506.

BACKGROUND: Colorectal cancer has a low 5-year survival rate and high mortality. Human ß-defensin-1 (hBD-1) may play an integral function in the innate immune system, contributing to the recognition and destruction of cancer cells. Long non-coding RNAs (lncRNAs) are involved in the process of cell differentiation and growth. AIM: To investigate the effect of hBD-1 on the mammalian target of rapamycin (mTOR) pathway and autophagy in human colon cancer SW620 cells. METHODS: CCK8 assay was utilized for the detection of cell proliferation and determination of the optimal drug concentration. Colony formation assay was employed to assess the effect of hBD-1 on SW620 cell proliferation. Bioinformatics was used to screen potentially biologically significant lncRNAs related to the mTOR pathway. Additionally, p-mTOR (Ser2448), Beclin1, and LC3II/I expression levels in SW620 cells were assessed through Western blot analysis. RESULTS: hBD-1 inhibited the proliferative ability of SW620 cells, as evidenced by the reduction in the colony formation capacity of SW620 cells upon exposure to hBD-1. hBD-1 decreased the expression of p-mTOR (Ser2448) protein and increased the expression of Beclin1 and LC3II/I protein. Furthermore, bioinformatics analysis identified seven lncRNAs (2 upregulated and 5 downregulated) related to the mTOR pathway. The lncRNA TCONS_00014506 was ultimately selected. Following the inhibition of the lncRNA TCONS_00014506, exposure to hBD-1 inhibited p-mTOR (Ser2448) and promoted Beclin1 and LC3II/I protein expression. CONCLUSION: hBD-1 inhibits the mTOR pathway and promotes autophagy by upregulating the expression of the lncRNA TCONS_00014506 in SW620 cells.

Empowerment-Led Guided Self-Help Intervention for Symptom Burden in Breast Cancer Women Treated With Ovarian Function Suppression: A Randomized Trial Protocol.

Background: Ovarian function suppression (OFS) treatment causes breast cancer patients' estrogens to fall rapidly to postmenopausal levels, and the 5-year treatment duration and 28-day treatment cycles place a heavy physical and psychological symptom burden on them, which in turn directly or indirectly affects the survival benefit. Managing symptom burden early in treatment is critical, but OFS-related studies have yet to be seen. Self-management is essential for patients' symptom burden. However, self-help management is hampered by patients' lack of knowledge, skills, motivation, etc. Guided self-help intervention (GSH) provides a feasible approach. Empowerment theory is a promising theoretical framework to guide self-management. Methods: A prospective two-arm parallel randomized controlled single-blind clinical trial will be conducted to investigate the effect of symptom burden GSH based on empowerment theory in breast cancer patients in the early stages of OFS treatment. A block randomization method is used to allocate 144 patients to either the control or intervention group. The program is conducted according to the OFS return-to-hospital treatment cycle. The intervention group will receive a total of two rounds and five sessions of empowering GSH, lasting at least 15 weeks in total; the control group will receive only usual nursing care. Symptom burden and related metrics will be assessed at baseline and 1, 3, and 6 months after OFS treatment, and changes between and within groups will be explored. This paper adhered to the SPIRIT and CONSORT guidelines. Conclusion: These results will help to validate the GSH in symptom burden management for breast cancer patients in OFS treatment early stages. It enriches its symptom burden management research and may provide implications for the whole cycle of OFS treatment patients.

Upregulation of p300 in paclitaxel-resistant TNBC: implications for cell proliferation via the PCK1/AMPK axis.

OBJECTIVE: To explore the role of p300 in the context of paclitaxel (PTX) resistance in triple-negative breast cancer (TNBC) cells, focusing on its interaction with the phosphoenolpyruvate carboxykinase 1 (PCK1)/adenosine monophosphate-activated protein kinase (AMPK) pathway. METHODS: The expression of p300 and PCK1 at the messenger ribonucleic acid (mRNA) level was detected using a quantitative polymerase chain reaction. The GeneCards and GEPIA databases were used to investigate the relationship between p300 and PCK1. The MDA-MB-231/PTX cell line, known for its PTX resistance, was chosen to understand the specific role of p300 in such cells. The Lipofectamine™ 3000 reagent was used to transfer the p300 small interfering RNA and the overexpression of PCK1 plasmid into MDA-MB-231/PTX. The expression levels of p300, PCK1, 5'AMPK and phosphorylated AMPK (p-AMPK) were determined using the western blot test. RESULTS: In TNBC cancer tissue, the expression of p300 was increased compared with TNBC paracancerous tissue (P < 0.05). In the MDA-MB-231 cell line of TNBC, the expression of p300 was lower than in the PTX-resistant TNBC cells (MDA-MB-231/PTX) (P < 0.05). The PCK1 expression was decreased in the TNBC cancer tissue compared with TNBC paracancerous tissue, and the PCK1 expression was reduced in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05) indicating that PCK1 was involved in the resistance function. Additionally, p-AMPK was decreased in MDA-MB-231/PTX compared with MDA-MB-231 (P < 0.05). The adenosine triphosphate (ATP) level was also detected and was significantly lower in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05). Additionally, cell proliferation increased significantly in MDA-MB-231/PTX at 48 and 72 h (P < 0.05) suggesting that MDA-MB-231/PTX cells obtained the resistance function which was associated with AMPK and ATP level. When p300 was inhibited, p-AMPK and ATP levels elevated in MDA-MB-231/PTX (P < 0.05). When PCK1 was suppressed, the ATP consumption rate decreased, and cell proliferation increased (P < 0.05). However, there were no changes in p300. CONCLUSIONS: In MDA-MB-231/PTX, p300 can inhibit p-AMPK and ATP levels by inhibiting PCK1 expression. Our findings suggest that targeting p300 could modulate the PCK1/AMPK axis, offering a potential therapeutic avenue for overcoming PTX resistance in TNBC.

Recurrent and persistent fever after SARS-CoV-2 infection in patients with follicular lymphoma: A case series.

Although persistent or recurrent COVID-19 infection is well described in some immunosuppressed patient cohort, to date, there have been no reports of this phenomenon in the context of repeatedly negative SARS-CoV-2 testing in the upper respiratory tract. We reported six patients with follicular lymphoma who developed recurrent symptomatic COVID-19 infection. They tested persistently negative for SARS-CoV-2 on pharyngeal swabs and ultimately confirmed by bronchoalveolar lavage fluid metagenomics next-generation sequencing. All six patients presented with lymphopenia and B-cell depletion, and five of them received the anti-cluster of differentiation 20 treatment in the last year. Persistent fever was the most common symptom and bilateral ground-glass opacities were the primary pattern on chest computed tomography. A relatively long course of unnecessary and ineffective antibacterial and/or antifungal treatments was administered until the definitive diagnosis. Persistent fever subsided rapidly with nirmatrelvir/ritonavir treatment. Our case highlighted that recurrent COVID-19 infection should be suspected in immunocompromised patients with persistent fever despite negative pharyngeal swabs, and urgent bronchoalveolar lavage fluid testing is necessary. Treatment with nirmatrelvir/ritonavir appeared to be very effective in these patients.

Tumor immunotherapy resistance: Revealing the mechanism of PD-1 / PD-L1-mediated tumor immune escape.

Tumor immunotherapy, an innovative anti-cancer therapy, has showcased encouraging outcomes across diverse tumor types. Among these, the PD-1/PD-L1 signaling pathway is a well-known immunological checkpoint, which is significant in the regulation of immune evasion by tumors. Nevertheless, a considerable number of patients develop resistance to anti-PD-1/PD-L1 immunotherapy, rendering it ineffective in the long run. This research focuses on exploring the factors of PD-1/PD-L1-mediated resistance in tumor immunotherapy. Initially, the PD-1/PD-L1 pathway is characterized by its role in facilitating tumor immune evasion, emphasizing its role in autoimmune homeostasis. Next, the primary mechanisms of resistance to PD-1/PD-L1-based immunotherapy are analyzed, including tumor antigen deletion, T cell dysfunction, increased immunosuppressive cells, and alterations in the expression of PD-L1 within tumor cells. The possible ramifications of altered metabolism, microbiota, and DNA methylation on resistance is also described. Finally, possible resolution strategies for dealing with anti-PD-1/PD-L1 immunotherapy resistance are discussed, placing particular emphasis on personalized therapeutic approaches and the exploration of more potent immunotherapy regimens.

A new spider mite elicitor triggers plant defence and promotes resistance to herbivores.

Herbivore-associated elicitors (HAEs) are active molecules produced by herbivorous insects. Recognition of HAEs by plants induces defence that resist herbivore attacks. We previously demonstrated that the tomato red spider mite Tetranychus evansi triggered defence in Nicotiana benthamiana. However, our knowledge of HAEs from T. evansi remains limited. Here, we characterize a novel HAE, Te16, from T. evansi and dissect its function in mite-plant interactions. We investigate the effects of Te16 on spider mites and plants by heterologous expression, virus-induced gene silencing assay, and RNA interference. Te16 induces cell death, reactive oxygen species (ROS) accumulation, callose deposition, and jasmonate (JA)-related responses in N. benthamiana leaves. Te16-mediated cell death requires a calcium signalling pathway, cytoplasmic localization, the plant co-receptor BAK1, and the signalling components SGT1 and HSP90. The active region of Te16-induced cell death is located at amino acids 114-293. Moreover, silencing Te16 gene in T. evansi reduces spider mite survival and hatchability, but expressing Te16 in N. benthamiana leaves enhances plant resistance to herbivores. Finally, Te16 gene is specific to Tetranychidae species and is highly conserved in activating plant immunity. Our findings reveal a novel salivary protein produced by spider mites that elicits plant defence and resistance to insects, providing valuable clues for pest management.

The effect of semaglutide on blood pressure in patients with type-2 diabetes: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the blood pressure (BP) lowering ability of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), in individuals with type-2 diabetes (T2D). METHODS: Randomized controlled trials (RCTs) comparing subcutaneous or oral semaglutide with placebo or other antihyperglycemic agents (AHAs) in T2D patients were identified by searching PubMed, Embase, Web of Science, ClinicalTrials.gov and Cochrane Library. These screened studies included the outcomes of interest: systolic and/or diastolic BP. Weighted mean differences (WMDs) and 95 % confidence intervals (CIs) were used to present the meta-analysis results. Pooled and sensitivity analyses were performed, and the risk of bias was evaluated. RESULTS: Twenty-nine RCTs with a total of 26985 participants were recruited in the final analysis. The WMD in change from baseline in systolic BP (SBP) of semaglutide versus placebo or other AHAs was -2.31 mmHg (95% CI: -3.11 to -1.51), while that for diastolic BP (DBP) was 0.09 mmHg (95% CI: -0.16 to 0.33). It also reduced glycated hemoglobin A1c (HbA1c) by 0.75% (95% CI: -0.92 to -0.58) and body weight loss by 2.80 kg (95% CI: -3.51 to -2.08). The reduction in SBP was similar for subcutaneous and oral administration of semaglutide, with -2.36 (95% CI: -3.38 to -1.35) and -2.50 (95% CI: -3.48 to -1.53), respectively. CONCLUSIONS: In T2D, SBP decreased significantly in the semaglutide group compared with placebo or other active controls. According to the efficacy results from this meta-analysis, subcutaneous and oral semaglutide have similar SBP-reducing effects. Therefore, the treatment of T2D patients with subcutaneous semaglutide or oral preparations is beneficial for reducing SBP.

The Dosage Recommendation of Cyclosporin in Children with Hemophagocytic Lymphohistiocytosis based on Population Pharmacokinetic Model.

OBJECTIVES: Cyclosporin is one of the therapeutic regimens for hemophagocytic lymphohistiocytosis (HLH); however, the optimal dosage of cyclosporine in children with HLH is unknown. It has been found that piperacillin-tazobactam affects the cyclosporine pharmacokinetic process in pediatric HLH patients. Thus, the purpose of the present study was to recommend cyclosporin dosage for pediatric HLH with and without piperacillin- tazobactam. METHODS: A previously established cyclosporine population pharmacokinetic model for pediatric HLH patients has been used in this study to recommend optimal dosage based on Monte Carlo simulation. The pediatric HLH patients have been included in eight weight groups (5, 10, 20, 30, 40, 50, 60, 70 kg) for sixteen dosages (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 mg/kg), split into one dose or two doses. RESULTS: The optimal cyclosporin dosages for children having HLH without piperacillin-tazobactam have been found to be 15, 13, 12, 11, 10, and 9 mg/kg, split into two doses for weights of 5-7, 7-10, 10-20, 20-28, 28-45, and 45-70 kg, respectively. For children with HLH, optimal cyclosporin dosages with piperacillin-tazobactam have been found to be 8 and 7 mg/kg, split into two doses for weights of 5-20 and 20-70 kg, respectively. CONCLUSION: It is the first time that the cyclosporin dosage regimens for HLH in children have been developed based on Monte Carlo simulation, and the initial dosage optimizations of cyclosporine in pediatric HLH patients have been recommended.

Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity.

Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA-nanobody complexes revealed atomic details of antigen-antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

Comprehensive energy efficiency optimization algorithm for steel load considering network reconstruction and demand response.

Industrial loads are usually energy intensive and inefficient. The optimization of energy efficiency management in steel plants is still in the early stage of development. Considering the topology of power grid, it is an urgent problem to improve the operation economy and load side energy efficiency of steel plants. In this paper, a two-level collaborative optimization method is proposed, which takes into account the dynamic reconstruction cost, transmission loss cost, energy cost and demand response benefit. The upper level objective is the optimization of topology in the grid structure to optimize the power loss and dynamic reconstruction costs of the grid. The lower level is the energy cost considering demand response, real time price and dynamic demand response price. Firstly, the mathematical models of stable load, impact load and the steel production line load are built. The key parameters are identified by the Back Propagation neural network algorithm according to the actual production data. Secondly, considering the constraints of grid structure and load operation capacity, the impact of dynamic grid loss and real-time dynamic electricity price on the energy efficiency of the whole grid are analyzed in depth. The optimal operation model considering the dynamic reconfiguration and grid tramission loss of distribution network is built. Taking a steel plant park in Northeast China as an example, it is proved that the optimization model can improve energy efficiency on the load side by optimizing energy consumption and demand response participation time on load side. The energy cost is reduced by 17.77% on the load side, the network loss is reduced by 1.8%, and the operating cost of the power grid is reduced by 26.2%, which has a positive effect on improving energy utilization efficiency, reducing distribution network loss, and improving overall economic efficiency.

Phosphorylcholine-grafted graphene oxide loaded with irinotecan for potential oncology therapy.

2-Methacryloyloxyethyl phosphorylcholine (MPC) zwitterions were modified onto self-made graphene oxide (GO) through the atom transfer radical polymerization method. The chemical structures of the products were verified using Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, nuclear magnetic resonance spectroscopy (NMR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), etc. It was found that the modified GO (GO-PCn) is well dispersed in water with an average hydrodynamic diameter of about 170 nm. By utilizing the 2D planar structure of this modified graphene, the irinotecan@GO-PCn composite can be loaded with about 20% of irinotecan via π-π stacking interaction and exhibit pH-sensitive drug release performance, releasing faster in the acidic environment. The in vitro cytotoxicity assessments confirmed that GO-PCn composed of phosphorylcholine moiety represented low cytotoxicity and acted as a certain effect on reducing the acute toxicity of irinotecan, which established a foundation for further studies of the system in oncology therapy.

Value of ultrasound guided biopsy combined with Xpert Mycobacterium tuberculosis/resistance to rifampin assay in the diagnosis of chest wall tuberculosis.

BACKGROUND: The thoracic wall lesions, particularly chest wall tuberculosis, and chest wall tumors and other pyogenic wall and actinomycetes infections, almost always present as a diagnostic challenge. AIM: To explore the value of ultrasound-guided biopsy combined with the Xpert Mycobacterium tuberculosis/resistance to rifampin (MTB/RIF) assay to diagnose chest wall tuberculosis. METHODS: We performed a retrospective study of patients with chest wall lesions from March 2018 to March 2021. All patients received the ultrasound-guided biopsy for pathology examination, acid-fast Bacillus staining, mycobacterial culture, and Xpert MTB/RIF analysis. The sensitivity, specificity, and area under the curve (AUC) were calculated for these diagnostic tests, either individually or combined. Rifampicin resistance results were compared between the mycobacterial culture and the Xpert MTB/RIF assay. RESULTS: In 31 patients with the chest wall lesion biopsy, 22 patients were diagnosed with chest wall tuberculosis. Of them, 3, 6, and 21 patients tested positive for mycobacterial culture, acid-fast stain, and Xpert MTB/RIF assay, respectively. The rifampicin resistance results of the 3 culture-positive patients were consistent with their Xpert MTB/RIF assay results. When considering the sensitivity, specificity, and AUC value, the Xpert MTB/RIF assay (95.5%, 88.9%, and 0.92, respectively) was a better choice than the acid-fast Bacillus stain (27.3%, 100.0%, and 0.64, respectively) and mycobacterial culture (13.6%, 100.0%, 0.57, respectively). No complications were reported during the procedure. CONCLUSION: Ultrasound guided biopsy combined with Xpert MTB/RIF has high value in the diagnosis of chest wall tuberculosis, and can also detect rifampicin resistance.

Lycopene Prevents Phthalate-Induced Cognitive Impairment via Modulating Ferroptosis.

Di-(2-ethylhexyl) phthalate (DEHP) is frequently used as a plasticizer in industrial and agricultural products. DEHP can cause severe neurotoxicity, such as impaired learning and memory function. Lycopene (LYC) as a carotenoid exerts excellent antioxidant capacity and therapeutic effects in neurodegenerative diseases. However, whether LYC can prevent the cognitive impairment induced by DEHP and the specific mechanisms are unclear. In the present study, the behavioral test results suggested that LYC alleviated the learning and memory impairment induced by DEHP. The histopathological data revealed that LYC attenuated DEHP-induced disordered arrangement of the neurons in the CA1 and CA3 regions of the hippocampus tissue. Moreover, LYC inhibited the occurrence of DEHP-induced ferroptosis via regulating iron metabolism, inhibiting lipid peroxidation, and activating the cysteine transporter and nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (NrF2/HO-1) signaling pathway. Overall, the study contributes novel perspectives into the potential mechanisms of LYC preventing phthalate-induced cognitive impairment in the hippocampus.

The expression of Nramp1 modulates the uptake of Mycobacterium tuberculosis by macrophages through alternating inflammatory responses.

Natural-resistance-associated macrophage protein-1 (NRAMP1) is a transmembrane protein of the mammalian SLC11 gene family. Previously, genome-wide association study (GWAS) have shown that the single nucleotide polymorphisms (SNPs) of NRAMP1 are associated with human susceptibility to tuberculosis (TB), and the detection of clinical samples have demonstrated that the expression levels of NRAMP1 are concomitant with the susceptibility to TB in humans and cows, but underlying mechanism is unknown. In this study, we completed a series of experiments to investigate how the expression of Nramp1 affects the infection of macrophages with Mycobacterium tuberculosis (Mtb). We found that the increase of Nramp1 expression induced the decrease of Mtb infection efficiency and the higher-level expression of pro-inflammatory cytokines and chemokines, However, the knockdown of Nramp1 promoted the efficiency of bacilli infection to macrophages and induced lower-levels of expression of pro-inflammatory cytokines and chemokines. Collectively, the results in this study demonstrated that the levels of Nramp1 expression affect Mtb infection of macrophage and regulate pro-inflammatory responses of macrophages to Mtb infection, indicating the population with the low-expression level of NRAMP1 predispose to Mtb infection and TB development, and suggesting SNPs in NRAMP1 modulate the host susceptibility to TB through its regulation of NRAMP1 expression.

[Current status of animal experiment report of acupuncture intervention in chronic fatigue syndrome based on ARRIVE guidelines and GSPC list].

OBJECTIVE: To analyze the current status of animal experiments of acupuncture in intervening chronic fatigue syndrome, so as to search formethods to improve the quality of animal experiment reports. METHODS: From the databases, such as CNKI, VIP, Wanfang, SinoMed, PubMed, Web of Science, Embase and Cochrane Library, the literature of animal experiment on acupuncture treatment for chronic fatigue syndrome was searched from January 1st, 2011 to April 2nd, 2022. Data were extracted according to the animal research reporting in vivo experiment (ARRIVE) guidelines 2.0 and gold standard publication checklist (GSPC), and statistical analysis was performed using Excel 2019. RESULTS: A total of 16 studies were finally included. The satis-faction rate of essential items in the ARRIVE guidelines 2.0 is 41.76%，while the satisfaction rate of recommended items is only 27.73% and of the GSPC is 25.89%. Out of 16 studies, 13 of them explained the reasons for animal exclusion in the experiment, 8 provided specific randomized methods, 8 described detailed information on animal species, strains, and quantities, 3 basically indicated that they had passed ethical review, 7 explained the limitations of the research. All 16 studies reported the main findings and elucidated their potential clinical or scientific value. CONCLUSION: Current animal studies on acupuncture in intervening the chronic fatigue syndrome are of certain limitation. Descriptions of multiple items are incomplete or missing, which prevents rea-ders from assessing reliability and authenticity of the animal experiment. It is recommended that in future research, experimental design, execution and report should be carried out according to the report guidelines for animal experiment to improve research quality.

BAK1 protects the receptor-like kinase BIR2 from SNIPER2a/b-mediated degradation to promote pattern-triggered immunity in Nicotiana benthamiana.

The detection of microbial infections by plants induces the rapid formation of immune receptor complexes at the plasma membrane. However, how this process is controlled to ensure proper immune signaling remains largely unknown. Here, we found that the Nicotiana benthamiana membrane-localized leucine-rich repeat receptor-like kinase BAK1-INTERACTING RLK 2 (NbBIR2) constitutively associates with BRI1-ASSOCIATED RECEPTOR KINASE 1 (NbBAK1) in vivo and in vitro and promotes complex formation with pattern recognition receptors. In addition, NbBIR2 is targeted by 2 RING-type ubiquitin E3 ligases, SNC1-INFLUENCING PLANT E3 LIGASE REVERSE 2a (NbSNIPER2a) and NbSNIPER2b, for ubiquitination and subsequent degradation in planta. NbSNIPER2a and NbSNIPER2b interact with NbBIR2 in vivo and in vitro and are released from NbBIR2 upon treatment with different microbial patterns. Furthermore, accumulation of NbBIR2 in response to microbial patterns is tightly associated with NbBAK1 abundance in N. benthamiana. NbBAK1 acts as a modular protein that stabilizes NbBIR2 by competing with NbSNIPER2a or NbSNIPER2b for association with NbBIR2. Similar to NbBAK1, NbBIR2 positively regulates pattern-triggered immunity and resistance to bacterial and oomycete pathogens in N. benthamiana, whereas NbSNIPER2a and NbSNIPER2b have the opposite effect. Together, these results reveal a feedback regulatory mechanism employed by plants to tailor pattern-triggered immune signaling.

Polypyrimidine tract binding protein 1 (PTBP1) contains a novel regulatory sequence, the rBH3, that binds the prosurvival protein MCL1.

The maturation of RNA from its nascent transcription to ultimate utilization (e.g., translation, miR-mediated RNA silencing, etc.) involves an intricately coordinated series of biochemical reactions regulated by RNA-binding proteins (RBPs). Over the past several decades, there has been extensive effort to elucidate the biological factors that control specificity and selectivity of RNA target binding and downstream function. Polypyrimidine tract binding protein 1 (PTBP1) is an RBP that is involved in all steps of RNA maturation and serves as a key regulator of alternative splicing, and therefore, understanding its regulation is of critical biologic importance. While several mechanisms of RBP specificity have been proposed (e.g., cell-specific expression of RBPs and secondary structure of target RNA), recently, protein-protein interactions with individual domains of RBPs have been suggested to be important determinants of downstream function. Here, we demonstrate a novel binding interaction between the first RNA recognition motif 1 (RRM1) of PTBP1 and the prosurvival protein myeloid cell leukemia-1 (MCL1). Using both in silico and in vitro analyses, we demonstrate that MCL1 binds a novel regulatory sequence on RRM1. NMR spectroscopy reveals that this interaction allosterically perturbs key residues in the RNA-binding interface of RRM1 and negatively impacts RRM1 association with target RNA. Furthermore, pulldown of MCL1 by endogenous PTBP1 verifies that these proteins interact in an endogenous cellular environment, establishing the biological relevance of this binding event. Overall, our findings suggest a novel mechanism of regulation of PTBP1 in which a protein-protein interaction with a single RRM can impact RNA association.

Case Report: Lung adenocarcinoma associated with germline ERCC2 frameshift mutation.

Family history is an established risk factor for lung cancer. Previous studies have found that germline genetic alterations, such as those in EGFR, BRCA1, BRCA2, CHEK2, CDKN2A, HER2, MET, NBN, PARK2, RET, TERT, TP53, and YAP1, are associated with an increased risk of developing lung cancer. The study reports the first of a lung adenocarcinoma proband with germline ERCC2 frameshift mutation c.1849dup (p. A617Gfs*32). Her family cancer history review demonstrated that her two healthy sisters, a brother with lung cancer, and three healthy cousins were positive for ERCC2 frameshift mutation, which might contribute to increased cancer risk. Our study highlights the necessity of performing comprehensive genomic profiling in discovering rare genetic alterations, early cancer screening, and monitoring for patients with family cancer history.

Identification of a novel mutation in the FGF10 gene in a Chinese family with obvious congenital lacrimal duct dysplasia in lacrimo-auriculo-dento-digital syndrome.

AIM: To identify the pathogenic gene variant in a family with lacrimo-auriculo-dento-digital syndrome [LADD (MIM 149730)] showing congenital lacrimal duct dysplasia as the main clinical manifestation and lay the foundation for future research on the pathogenic gene. METHODS: Ophthalmological examinations, including slit-lamp biomicroscopy and lacrimal duct probing, and computed tomography dacryocystography (CT-DCG) were performed for all participants. The family pedigree was drawn, genetic features were analyzed, and the genomic DNA of the subjects was extracted. Pathogenic genes were screened via whole exome sequencing (WES) and confirmed using Sanger sequencing. RESULTS: Six patients belonged to this three-generation family, and their clinical manifestations included congenital nasolacrimal duct obstruction, congenital absence of lacrimal puncta and canaliculi, lacrimal fistulae, and limb deformities. This pattern indicates autosomal dominant inheritance. Diagnosis was based on the clinical characteristics of LADD syndrome, which presented in all the patients in this family. A novel frameshift mutation in the FGF10 gene (NM_004465.1), c.234dupC (p.Trp79Leus*15), was identified in all patients via WES. The variant was confirmed by Sanger sequencing and classified as a "pathogenic mutation" according to the American College of Medical Genetics and Genomics (ACMG) variant interpretation guidelines. CONCLUSION: A novel frameshift mutation in the FGF10 gene is found in all patients. This finding helps this family with LADD syndrome receiving a more accurate clinical diagnosis and genetic counseling by extending the mutation range of the FGF10 gene.

Development and validation of a coagulation-related genes prognostic model for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high incidence and mortality worldwide, which seriously threatens people's physical and mental health. Coagulation is closely related to the occurrence and development of HCC. Whether coagulation-related genes (CRGs) can be used as prognostic markers for HCC remains to be investigated. METHODS: Firstly, we identified differentially expressed coagulation-related genes of HCC and control samples in the datasets GSE54236, GSE102079, TCGA-LIHC, and Genecards database. Then, univariate Cox regression analysis, LASSO regression analysis, and multivariate Cox regression analysis were used to determine the key CRGs and establish the coagulation-related risk score (CRRS) prognostic model in the TCGA-LIHC dataset. The predictive capability of the CRRS model was evaluated by Kaplan-Meier survival analysis and ROC analysis. External validation was performed in the ICGC-LIRI-JP dataset. Besides, combining risk score and age, gender, grade, and stage, a nomogram was constructed to quantify the survival probability. We further analyzed the correlation between risk score and functional enrichment, pathway, and tumor immune microenvironment. RESULTS: We identified 5 key CRGs (FLVCR1, CENPE, LCAT, CYP2C9, and NQO1) and constructed the CRRS prognostic model. The overall survival (OS) of the high-risk group was shorter than that of the low-risk group. The AUC values for 1 -, 3 -, and 5-year OS in the TCGA dataset were 0.769, 0.691, and 0.674, respectively. The Cox analysis showed that CRRS was an independent prognostic factor for HCC. A nomogram established with risk score, age, gender, grade, and stage, has a better prognostic value for HCC patients. In the high-risk group, CD4+T cells memory resting, NK cells activated, and B cells naive were significantly lower. The expression levels of immune checkpoint genes in the high-risk group were generally higher than that in the low-risk group. CONCLUSIONS: The CRRS model has reliable predictive value for the prognosis of HCC patients.