Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

During the development of therapeutic microRNAs (miRNAs or miRs), it is essential to define their pharmacological actions. Rather, miRNA research and therapy mainly use miRNA mimics synthesized in vitro. After experimental screening of unique recombinant miRNAs produced in vivo, three lead antiproliferative miRNAs against human NSCLC cells, miR-22-3p, miR-9-5p, and miR-218-5p, were revealed to target folate metabolism by bioinformatic analyses. Recombinant miR-22-3p, miR-9-5p, and miR-218-5p were shown to regulate key folate metabolic enzymes to inhibit folate metabolism and subsequently alter amino acid metabolome in NSCLC A549 and H1975 cells. Isotope tracing studies further confirmed the disruption of one-carbon transfer from serine to folate metabolites by all three miRNAs, inhibition of glucose uptake by miR-22-3p, and reduction of serine biosynthesis from glucose by miR-9-5p and -218-5p in NSCLC cells. With greater activities to interrupt NSCLC cell respiration, glycolysis, and colony formation than miR-9-5p and -218-5p, recombinant miR-22-3p was effective to reduce tumor growth in two NSCLC patient-derived xenograft mouse models without causing any toxicity. These results establish a common antifolate mechanism and differential actions on glucose uptake and metabolism for three lead anticancer miRNAs as well as antitumor efficacy for miR-22-3p nanomedicine, which shall provide insight into developing antimetabolite RNA therapies.

Lipotoxicity,caused by intracellular lipid accumulation,accelerates the degenerative process of cellular senescence,which has implications in cancer development and therapy.Previously,camitine palmi-toyltransferase 1C (CPT1C),a mitochondrial enzyme that catalyzes carnitinylation of fatty acids,was found to be a critical regulator of cancer cell senescence.However,whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown.An LC/MS-based lipidomic analysis of PANC-1,MDA-MB-231,HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C.Cellular lipotoxicity was further confirmed by lipotoxicity assays.Significant changes were found in the lipidome of CPT1 C-depleted cells,including major alterations in fatty acid,diacylglycerol,triacylglycerol,oxidative lipids,cardiolipin,phosphatidylglycerol,phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin.This was coincident with changes in expressions of mRNAs involved in lipogenesis.Histological and biochemical analyses revealed higher lipid accumulation and increased malondialde-hyde and reactive oxygen species,signatures of lipid peroxidation and oxidative stress.Reduction of ATP synthesis,loss of mitochondrial transmembrane potential and down-regulation of expression of mito-chondriogenesis gene mRNAs indicated mitochondrial dysfunction induced by lipotoxicity,which could further result in cellular senescence.Taken together,this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence,suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.

Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, and its prognosis depends on the balance between hepatocyte death and regeneration. Sirtuin 6 (SIRT6) has been reported to protect against oxidative stress-associated DNA damage. But whether SIRT6 regulates APAP-induced hepatotoxicity remains unclear. In this study, the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment, respectively.

Objective: To evaluate the relationship between bolus volume and hyoid displacement in dysphagia patients with nasopharyngeal carcinoma after radiation therapy. Methods: Twenty-three nasopharyngeal carcinoma patients with dysphagia were recruited and their swallowing of 3, 5, 10 and 20ml of liquid food was studied fluoroscopically. The vertical and horizontal displacement of the hyoid as well as its time in motion were measured, and the relationship between the bolus volume, hyoid displacement and time in motion time was evaluated. Results: The largest vertical displacement of the hyoid (1.01±0.65cm) was observed when swallowing a 10ml bolus. The hyoid showed the smallest average horizontal displacement (0.39±0.34cm), when swallowing a 3ml bolus. The average motion time of the hyoid was (2.11±0.65) seconds. It was shorter when swallowing a 10 or 20ml bolus than when dealing with a smaller one. Hyoid motion time was negatively correlated with the horizontal displacement of the hyoid bone, and the volume of a swallow was negatively correlated with the hyoid motion time but positively correlated with the penetration-aspiration scale score. Conclusion Bolus volume affects hyoid displacement and hyoid motion time in nasopharyngeal carcinoma patients with dysphagia after radiation therapy. For patients with a penetration-aspiration scale score of 5 or less, the optimum bolus volume is 5 to 10ml.

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.

Objective To explore the effect of vaginal pressure feedback combined with pelvic floor muscle resistant training on stress urinary incontinence (SUI). Methods 125 women with SUI in our hospital from February, 2014 to May, 2015 were randomized into control group (n=65) and experimental group (n=60). The control group took Kegel exercise, which asked for patients to contract their pelvic floor muscles, while the experimental group first received biofeedback electrical stimulation for 20 minutes with XFT-2002 pelvic floor stimula-tor, then instructed the patients to contract their pelvic floor muscles and pressed the pneumatic probe which placed in vagina according to the voice navigation of XFT-0010 pelvic floor muscle stimulator after they learnt the contraction skill. Both groups received training with 10 seconds' contraction and 10 seconds' rest 30 minutes per day for 30 days in total. They were assessed by GRRUG and International Consulta-tion Incontinence Questionnaire-UI Short Form (ICIQ-SF). Results After treatment, the muscle strength of the pelvic floor (t=-3.570) and the scores of ICIQ (t=4.198) improved significantly in both groups (P<0.01), and was higher in the experimental group than in the control group (t=6.833, t=-2.445, P<0.01), as well as the therapeutic efficiency (Z=63.954, P<0.001). Conclusion Vaginal pressure feedback com-bined with pelvic floor muscle resistant training can further improve stress urinary incontinence in women.

Objective To investigate the effects of surface anesthesia on assisted balloon dilatation when treating dysphagia caused by radiotherapy for nasopharyngeal carcinoma.Methods Fifty-four patients with dysphagia after radiotherapy were divided randomly into an anesthesia group and a non-anesthesia group.The anesthesia group received anesthetics before treatment while the non-anesthesia group did not.All of the patients were treated with low-frequency electrical stimulation and assisted balloon dilatation for 3 weeks.They were then assessed using videofluoroscopy and self-reports of difficulty in swallowing before and after the treatment.Results After the treatment, significant improvement was observed in pharyngeal delay time, in cricopharyngeal opening, and in laryngeal elevation and forwardness.There was also a significant decrease in self-reported swallowing difficulty and failed swallows in both groups compared with before the treatment.The improvements in the non-anesthesia group were significantly greater than in the anesthesia group.After the treatment, the average aspiration rate of the anesthesia group was significantly higher than before treatment and higher than that of the non-anesthesia group.The improvement in oral intake of the non-anesthesia group was significantly better than that of the anesthesia group.Conclusion Balloon dilatation and low-frequency electrical stimulation have a synergistic effect and can improve patients' swallowing after radiation-induced cranial nerve damage, thus promoting survival.Assisted balloon dilatation without anesthesia has a better effect than when surface anesthesia is used.

To analyze the clinical characteristics,imaging and pathological features of 1 case with partial right lung atelectasis and summarize the relevant domestic reports on the false positive of positron emission tomography-computed tomography (PET-CT) and tumor markers.The patient was diagnosed by PET-CT as partial atelectasis and there were progressive increases of CEA,CA199 and CA242.But site of lesion biopsy showed no malignancy.After treatments of anti-inflammatory and eliminating phlegm,the tumor markers returned to normal and the lesion site had excellent re-expansion.The detection of PET-CT plus tumor markers may have false positive probability.The reason is probably related with inflammation and glandular secretion of lesion site.

For more than 40 years primary hepatocytes culture technique has been utilized extensively for assessing effects of drug on metabolizing enzymes (especially cytochromes P450), drug metabolism, drug-drug interactions, and the mechanisms of cytotoxicity and genotoxicity. Human derived primary hepatocytes reserve the metabolism function and enzyme activity of liver. Therefore, this technique has been widely used as a reliable and efficient tool in the drug and xenobiotics evaluation and screen in vitro. This review focuses on primary culture technique of hepatocytes and its application in drug metabolism and toxicology research and evaluation.