The neoantigens derived from transposable elements - A hidden treasure for cancer immunotherapy.

Neoantigen-based therapy is a promising approach that selectively activates the immune system of the host to recognize and eradicate cancer cells. Preliminary clinical trials have validated the feasibility, safety, and immunogenicity of personalized neoantigen-directed vaccines, enhancing their effectiveness and broad applicability in immunotherapy. While many ongoing oncological trials concentrate on neoantigens derived from mutations, these targets do not consistently provoke an immune response in all patients harboring the mutations. Additionally, tumors like ovarian cancer, which have a low tumor mutational burden (TMB), may be less amenable to mutation-based neoantigen therapies. Recent advancements in next-generation sequencing and bioinformatics have uncovered a rich source of neoantigens from non-canonical RNAs associated with transposable elements (TEs). Considering the substantial presence of TEs in the human genome and the proven immunogenicity of TE-derived neoantigens in various tumor types, this review investigates the latest findings on TE-derived neoantigens, examining their clinical implications, challenges, and unique advantages in enhancing tumor immunotherapy.

Association between Cardiometabolic index and cognitive function: a cross-sectional study in a diabetic-based population.

BACKGROUND: Diabetes is a significant risk factor for cognitive impairment. Therefore early identification of cognitive impairment in diabetic patients is particularly important. The aim of this study was to assess the relationship between Cardiometabolic index（CMI） and cognitive function in a diabetic population. METHODS: A cross-sectional study was conducted by collecting information from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Multiple linear regression models were used to investigate the correlation between CMI and low cognitive function in a diabetic population. Threshold effects analysis and fitted smoothing curves were used to describe the nonlinear links. Interaction tests and subgroup analyses were also performed. RESULTS: A total of 1050 people participated in this study, including 561 men and 489 women. In the fully corrected model, CMI was positively associated with low cognitive performance as assessed by CERAD W-L, AFT and DSST [OR=1.37 (1.14, 1.72),P=0.0074], [OR=1.21 (1.04, 1.51),P=0.0126] and [OR=1.27 (1.08, 1.63),P= 0.0253]. Our study found that diabetic patients with higher CMI were at greater risk of developing low cognitive function. The effect of the subgroups on the positive association of CMI with cognitive impairment was not significant. A non-linear association between low cognitive performance and CMI was determined by CERAD W-L, AFT and DSST (log likelihood ratio < 0.05). In addition our also study found that CMI was a better predictor of cognitive impairment in diabetes than WWI. CONCLUSION: Increased CMI is associated with an increased risk of cognitive impairment in people with diabetes.CMI can be used as a new anthropometric measure for predicting cognitive impairment in diabetes.

Case report and literature analysis: pancreatic hepatoid carcinoma with multiple lymph node metastases progressing to liver metastasis after pancreaticoduodenectomy.

Hepatoid carcinoma is an extrahepatic primary tumor displaying characteristics reminiscent of hepatocellular carcinoma differentiation, which is found in various organs, such as the stomach, ovaries, gallbladder, and pancreas. Reports of pancreatic hepatoid carcinoma remain scarce. Consequently, understanding of this disease remains a priority, with no established consensus on its diagnosis and management. Here, we reported the case of a 45-year-old woman diagnosed with hepatoid carcinoma located in the pancreatic head, accompanied by multiple lymph node metastases. Following pancreaticoduodenectomy, the patient developed liver metastases within 3 months. Subsequently, she underwent adjuvant therapy consisting of Teysuno and Durvalumab following microwave ablation for the liver metastases. Remarkably, the patient has survived for one year without significant disease progression. This case underscores the potential efficacy of immunotherapy as a promising treatment option for pancreatic hepatoid carcinoma. Further research and clinical trials are warranted to explore the optimal management strategies for this rare and challenging malignancy.

Atramacrolodes A-D (1-4), Four Undescribed Eudesmane-type Sesquiterpenes from the Rhizome of Atractylodes macrocephala.

Four undescribed sesquiterpenes, atramacrolodes A-D (1-4), along with six known compounds 5-10 were isolated from the rhizome of Atractylodes macrocephala. Compound 3 possessed a new skeleton based on an unprecedented carton-carton connection. Their structures were determined by UV, IR, HRESIMS, NMR spectra, 13C NMR calculation with DP4+ analysis, and the comparison of experimental and calculated ECD spectra. Compounds 5 and 8 showed protective effects against paracetamol-induced liver cell injury.

The fibrosis-4 index is a prognostic factor for cholangiocarcinoma patients who received immunotherapy.

Background: Research of immunotherapy for cholangiocarcinoma has yielded some results, but more clinical data are needed to prove its efficacy and safety. Moreover, there is a need to identify accessible indexes for selecting patients who may benefit from such treatments. Methods: The medical records of 66 cholangiocarcinoma patients who underwent immunotherapy were retrospectively collected. The effectiveness of immunotherapy was assessed by tumor response, progression-free survival (PFS), and overall survival (OS), while safety was evaluated by adverse events during treatment. Univariate and multivariate Cox regression analyses were performed to identify prognostic risk factors for PFS and OS, and Kaplan-Meier curves of potential prognostic factors were drawn. Results: Overall, in this study, immunotherapy achieved an objective response rate of 24.2% and a disease control rate of 89.4% for the included patients. The median PFS was 445 days, and the median OS was 772.5 days. Of the 66 patients, 65 experienced adverse events during treatment, but none had severe consequences. Multivariate Cox analysis indicated that tumor number is a prognostic risk factor for disease progression following immunotherapy in cholangiocarcinoma patients, while tumor differentiation and the fibrosis-4 (FIB-4) index are independent risk factors for OS. Conclusion: In general, immunotherapy for cholangiocarcinoma is safe, with adverse events remaining within manageable limits, and it can effectively control disease progression in most patients. The FIB-4 index may reflect the potential benefit of immunotherapy for patients with cholangiocarcinoma.

FLT3-selective PROTAC: Enhanced safety and increased synergy with Venetoclax in FLT3-ITD mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) patients carrying Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations often face a poor prognosis. While some FLT3 inhibitors have been used clinically, challenges such as short efficacy and poor specificity persist. Proteolytic targeting chimera (PROTAC), with its lower ligand affinity requirement for target proteins, offers higher and rapid targeting capability. Gilteritinib, used as the ligand for the target protein, was connected with different E3 ligase ligands to synthesize several series of PROTAC targeting FLT3-ITD. Through screening and structural optimization, the optimal lead compound PROTAC Z29 showed better specificity than Gilteritinib. Z29 induced FLT3 degradation through the proteasome pathway and inhibited tumor growth in subcutaneous xenograft mice. We verified Z29's minimal impact on platelets in a patient-derived xenografts (PDX) model compared to Gilteritinib. The combination of Z29 and Venetoclax showed better anti-tumor effects, lower platelet toxicity, and lower hepatic toxicity in FLT3-ITD+ models. The FLT3-selective PROTAC can mitigate the platelet toxicity of small molecule inhibitors, ensuring safety and efficacy in monotherapy and combination therapy with Venetoclax. It is a promising strategy for FLT3-ITD+ patients, especially those with platelet deficiency or liver damage.

Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer.

Estrogen receptor α (ERα) plays a pivotal role in the proliferation, differentiation, and migration of breast cancer (BC) cells, and aromatase (ARO) is a crucial enzyme in estrogen synthesis. Hence, it is necessary to inhibit estrogen production or the activity of ERα for the treatment of estrogen receptor-positive (ER+) BC. Herein, we present a new category of dual-targeting PROTAC degraders designed to specifically target ERα and ARO. Among them, compound 18c bifunctionally degrades and inhibits ERα/ARO, thus effectively suppressing the proliferation of MCF-7 cells while showing negligible cytotoxicity to normal cells. In vivo, 18c promotes the degradation of ERα and ARO and inhibits the growth of MCF-7 xenograft tumors. Finally, compound 18c demonstrates promising antiproliferative and ERα degradation activity against the ERαMUT cells. These findings suggest that 18c, being the inaugural dual-targeting degrader for ERα and ARO, warrants further advancement for the management of BC and the surmounting of endocrine resistance.

Modulation of atherosclerosis-related signaling pathways by Chinese herbal extracts: Recent evidence and perspectives.

Atherosclerotic cardiovascular disease remains a preeminent cause of morbidity and mortality globally. The onset of atherosclerosis underpins the emergence of ischemic cardiovascular diseases, including coronary heart disease (CHD). Its pathogenesis entails multiple factors such as inflammation, oxidative stress, apoptosis, vascular endothelial damage, foam cell formation, and platelet activation. Furthermore, it triggers the activation of diverse signaling pathways including Phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), NF-E2-related factor 2/antioxidant response element (Nrf2/ARE), the Notch signaling pathway, peroxisome proliferator-activated receptor (PPAR), nucleotide oligo-structural domain-like receptor thermoprotein structural domain-associated protein 3 (NLRP3), silencing information regulator 2-associated enzyme 1 (Sirt1), nuclear transcription factor-κB (NF-κB), Circular RNA (Circ RNA), MicroRNA (mi RNA), Transforming growth factor-ß (TGF-ß), and Janus kinase-signal transducer and activator of transcription (JAK/STAT). Over recent decades, therapeutic approaches for atherosclerosis have been dominated by the utilization of high-intensity statins to reduce lipid levels, despite significant adverse effects. Consequently, there is a growing interest in the development of safer and more efficacious drugs and therapeutic modalities. Traditional Chinese medicine (TCM) offers a vital strategy for the prevention and treatment of cardiovascular diseases. Numerous studies have detailed the mechanisms through which TCM active ingredients modulate signaling molecules and influence the atherosclerotic process. This article reviews the signaling pathways implicated in the pathogenesis of atherosclerosis and the advancements in research on TCM extracts for prevention and treatment, drawing on original articles from various databases including Google Scholar, Medline, CNKI, Scopus, and Pubmed. The objective is to furnish a reference for the clinical management of cardiovascular diseases.

Eco-friendly preparation and characterization of high-performance electrothermal graphene-AgNPs/lignocellulose composites.

Graphene-based (Gr-based) electrothermal heaters, due to their light weight, low electrical resistance, high thermal conductivity, and easy accessibility, have attracted widespread attention in the field of electrothermal heating. To achieve a high steady-state temperature in electrothermal heaters under low voltage, here we constructed a Gr-based film with low electrical resistance. Firstly, we employed non-toxic vitamin C to reduce silver nitrate for the in situ chemical deposition of silver nanoparticles (AgNPs) on the Gr surface. The SEM results confirmed that the AgNPs were uniformly deposited on the Gr surface. The synergistic interaction between AgNPs and Gr provided high-speed electrons transport paths for the film. On the other hand, we employed biodegradable lignocellulose fiber (LCF) as a dispersant and film-forming agent. The aromatic ring structure of LCF interacts with Gr via π-π interactions, aiding the dispersion of Gr in aqueous solutions. SEM results revealed that LCF permeated through the surfaces and interstices of the two-dimensional Gr sheets, providing mechanical support for the composite film. This approach enables the creation of freestanding Gr-AgNPs/LCF electrothermal composites. The resistivity and electrothermal results demonstrated that the obtained 20 wt% Gr-based composite film possessed low electrical resistance (5.4 Ω sq-1) and exhibited an outstanding saturated temperature of 214 °C under a very low input voltage of 7 V. The preparation method of this Gr-based composite film is simple, easy to operate, and environmentally friendly, providing a new reference for the preparation of eco-friendly and high-performance resistance heating electronics.

CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma.

Super enhancers (SEs) are genomic regions comprising multiple closely spaced enhancers, typically occupied by a high density of cell-type-specific master transcription factors (TFs) and frequently enriched in key oncogenes in various tumors, including neuroblastoma (NB), one of the most prevalent malignant solid tumors in children originating from the neural crest. Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) is a newly identified super-enhancer-driven gene regulated by master TFs in NB; however, its function in NB remains unclear. Through an integrated study of publicly available datasets and microarrays, we observed a significantly elevated CDK5RAP3 expression level in NB, associated with poor patient prognosis. Further research demonstrated that CDK5RAP3 promotes the growth of NB cells, both in vitro and in vivo. Mechanistically, defective CDK5RAP3 interfered with the UFMylation system, thereby triggering endoplasmic reticulum (ER) phagy. Additionally, we provide evidence that CDK5RAP3 maintains the stability of MEIS2, a master TF in NB, and in turn, contributes to the high expression of CDK5RAP3. Overall, our findings shed light on the molecular mechanisms by which CDK5RAP3 promotes tumor progression and suggest that its inhibition may represent a novel therapeutic strategy for NB.

Establishment of the First National Standard for Neutralizing Antibodies against SARS-CoV-2 XBB Variants.

Neutralizing antibodies (NtAbs) against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are indicators of vaccine efficacy that enable immunity surveillance. However, the rapid mutation of SARS-CoV-2 variants prevents the timely establishment of standards required for effective XBB vaccine evaluation. Therefore, we prepared four candidate standards (No. 11, No. 44, No. 22, and No. 33) using plasma, purified immunoglobulin, and a broad-spectrum neutralizing monoclonal antibody. Collaborative calibration was conducted across nine Chinese laboratories using neutralization methods against 11 strains containing the XBB and BA.2.86 sublineages. This study demonstrated the reduced neutralization potency of the first International Standard antibodies to SARS-CoV-2 variants of concern against XBB variants. No. 44 displayed broad-spectrum neutralizing activity against XBB sublineages, effectively reduced interlaboratory variability for nearly all XBB variants, and effectively minimized the geometric mean titer (GMT) difference between the live and pseudotyped virus. No. 22 showed a broader spectrum and higher neutralizing activity against all strains but failed to reduce interlaboratory variability. Thus, No. 44 was approved as a National Standard for NtAbs against XBB variants, providing a unified NtAb measurement standard for XBB variants for the first time. Moreover, No. 22 was approved as a national reference reagent for NtAbs against SARS-CoV-2, offering a broad-spectrum activity reference for current and potentially emerging variants.

Therapeutic potential of salidroside in preserving rat cochlea organ of corti from gentamicin-induced injury through modulation of NRF2 signaling and GSK3ß/NF-κB pathway.

Salidroside (SAL) is a phenol glycoside compound found in plants of the Rhodiola genus which has natural antioxidant and free radical scavenging properties. SAL are able to protect against manganese-induced ototoxicity. However, the molecular mechanism by which SAL reduces levels of reactive oxygen species (ROS) is unclear. Here, we established an in vitro gentamicin (GM) ototoxicity model to observe the protective effect of SAL on GM-induced hair cells (HC) damage. Cochlear explants of postnatal day 4 rats were obtained and randomly divided into six groups: two model groups (treatment with 0.2 mM or 0.4 mM GM for 24 h); two 400 µmol/L SAL-pretreated groups pretreatment with SAL for 3 h followed by GM treatment (0.2 mM or 0.4 mM) for 24 h; 400 µmol/L SAL group (treatment with SAL for 24 h); control group (normal cultured cochlear explants). The protective effects of SAL on GM-induced HC damage, and on mRNA and protein levels of antioxidant enzymes were observed. HC loss occurred after 24 h of GM treatment. Pretreatment with SAL significantly reduced GM-induced OHC loss. In cochlear tissues, mRNA and protein levels of NRF2 and HO-1 were enhanced in the GM alone group compared with the SAL pretreatment GM treatment group. SAL may protect against GM-induced ototoxicity by regulating the antioxidant defense system of cochlear tissues; SAL can activate NRF2/HO-1 signaling, inhibit NF-κB activation, activate AKT, and increase inhibitory phosphorylation of GSK3ß to decrease GSK3 activity, all of which exert antioxidant effects.

Optimizing robotic thyroid surgery: lessons learned from an retrospective analysis of 104 cases.

Background: Robotic assistance in thyroidectomy is a developing field that promises enhanced surgical precision and improved patient outcomes. This study investigates the impact of the da Vinci Surgical System on operative efficiency, learning curve, and postoperative outcomes in thyroid surgery. Methods: We conducted a retrospective cohort study of 104 patients who underwent robotic thyroidectomy between March 2018 and January 2022. We evaluated the learning curve using the Cumulative Sum (CUSUM) analysis and analyzed operative times, complication rates, and postoperative recovery metrics. Results: The cohort had a mean age of 36 years, predominantly female (68.3%). The average body mass index (BMI) was within the normal range. A significant reduction in operative times was observed as the series progressed, with no permanent hypoparathyroidism or recurrent laryngeal nerve injuries reported. The learning curve plateaued after the 37th case. Postoperative recovery was consistent, with no significant difference in hospital stay duration. Complications were minimal, with a noted decrease in transient vocal cord palsy as experience with the robotic system increased. Conclusion: Robotic thyroidectomy using the da Vinci system has demonstrated a significant improvement in operative efficiency without compromising safety. The learning curve is steep but manageable, and once overcome, it leads to improved surgical outcomes and high patient satisfaction. Further research with larger datasets and longer follow-up is necessary to establish the long-term benefits of robotic thyroidectomy.

Therapeutic Role of Chinese Medicine Targeting Nrf2/HO-1 Signaling Pathway in Myocardial Ischemia/Reperfusion Injury.

Acute myocardial infarction (AMI), characterized by high incidence and mortality rates, poses a significant public health threat. Reperfusion therapy, though the preferred treatment for AMI, often exacerbates cardiac damage, leading to myocardial ischemia/reperfusion injury (MI/RI). Consequently, the development of strategies to reduce MI/RI is an urgent priority in cardiovascular therapy. Chinese medicine, recognized for its multi-component, multi-pathway, and multi-target capabilities, provides a novel approach for alleviating MI/RI. A key area of interest is the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. This pathway is instrumental in regulating inflammatory responses, oxidative stress, apoptosis, endoplasmic reticulum stress, and ferroptosis in MI/RI. This paper presents a comprehensive overview of the Nrf2/HO-1 signaling pathway's structure and its influence on MI/RI. Additionally, it reviews the latest research on leveraging Chinese medicine to modulate the Nrf2/HO-1 pathway in MI/RI treatment.

Structural basis for substrate and antibiotic recognition by Helicobacter pylori isoleucyl-tRNA synthetase.

Helicobacter pylori infection is a global health concern, affecting over half of the world's population. Acquiring structural information on pharmacological targets is crucial to facilitate inhibitor design. Here, we have determined the crystal structures of H. pylori isoleucyl-tRNA synthetase (HpIleRS) in apo form as well as in complex with various substrates (Ile, Ile-AMP, Val, and Val-AMP) or an inhibitor (mupirocin). Our results provide valuable insights into substrate specificity, recognition, and the mechanism by which HpIleRS is inhibited by an antibiotic. Moreover, we identified Asp641 as a prospective regulatory site and conducted biochemical analyses to investigate its regulatory mechanism. The detailed structural information acquired from this research holds promise for the development of highly selective and effective inhibitors against H. pylori infection.

METTL14/miR-29c-3p axis drives aerobic glycolysis to promote triple-negative breast cancer progression though TRIM9-mediated PKM2 ubiquitination.

The energy metabolic rearrangement of triple-negative breast cancer (TNBC) from oxidative phosphorylation to aerobic glycolysis is a significant biological feature and can promote the malignant progression. However, there is little knowledge about the functional mechanisms of methyltransferase-like protein 14 (METTL14) mediated contributes to TNBC malignant progression. Our study found that METTL14 expression was significantly upregulated in TNBC tissues and cell lines. Silencing METTL14 significantly inhibited TNBC cell growth and invasion in vitro, as well as suppressed tumour growth. Mechanically, METTL14 was first found to activate miR-29c-3p through m6A and regulate tripartite motif containing 9 (TRIM9) to promote ubiquitination of pyruvate kinase isoform M2 (PKM2) and lead to its transition from tetramer to dimer, resulting in glucose metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis to promote the progress of TNBC. Taken together, these findings reveal important roles of METTL14 in TNBC tumorigenesis and energy metabolism, which might represent a novel potential therapeutic target for TNBC.

The Effect of Group Identity on Chinese College Students' Social Mindfulness: Testing a Moderated Mediation Model.

Purpose: The current study examined the effect of group identity on social mindfulness, how awe mediates this effect, and lastly how empathy may moderate the various indirect pathway. Methods: A total of 2041 Chinese college students were recruited from different universities or colleges to complete the questionnaire including group identity scale, awe scale, empathy scale and social mindfulness scale. This study was conducted using random and convenient sampling, as well as SPSS and its plugin PROCESS as a statistical tool. Results: The present study showed that group identity was positively associated with awe and social mindfulness. Awe was positively associated with social mindfulness. Empathy further moderated the relationship between group identity and awe, awe and social mindfulness, as well as group identity and social mindfulness. Conclusion: The findings of this study shed light on a correlation between group identity and social mindfulness. Furthermore, this study emphasizes the practical importance of intervening in the empathy level of students who have poor empathy in order to increase their social mindfulness.

Noncovalent interactions between biomolecules facilitated their application in food emulsions' construction: A review.

The use of biomolecules, such as proteins, polysaccharides, saponins, and phospholipids, instead of synthetic emulsifiers in food emulsion creation has generated significant interest among food scientists due to their advantages of being nontoxic, harmless, edible, and biocompatible. However, using a single biomolecule may not always meet practical needs for food emulsion applications. Therefore, biomolecules often require modification to achieve ideal interfacial properties. Among them, noncovalent interactions between biomolecules represent a promising physical modification method to modulate their interfacial properties without causing the health risks associated with forming new chemical bonds. Electrostatic interactions, hydrophobic interactions, and hydrogen bonding are examples of noncovalent interactions that facilitate biomolecules' effective applications in food emulsions. These interactions positively impact the physical stability, oxidative stability, digestibility, delivery characteristics, response sensitivity, and printability of biomolecule-based food emulsions. Nevertheless, using noncovalent interactions between biomolecules to facilitate their application in food emulsions still has limitations that need further improvement. This review introduced common biomolecule emulsifiers, the promotion effect of noncovalent interactions between biomolecules on the construction of emulsions with different biomolecules, their positive impact on the performance of emulsions, as well as their limitations and prospects in the construction of biomolecule-based emulsions. In conclusion, the future design and development of food emulsions will increasingly rely on noncovalent interactions between biomolecules. However, further improvements are necessary to fully exploit these interactions for constructing biomolecule-based emulsions.