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.

Liver is the central hub regulating energy metabolism during feeding-fasting transition. Evidence suggests that fasting and refeeding induce dynamic changes in liver size, but the underlying mechanisms remain unclear. Yes-associated protein (YAP) is a key regulator of organ size. This study aims to explore the role of YAP in fasting- and refeeding-induced changes in liver size. Here, fasting significantly reduced liver size, which was recovered to the normal level after refeeding. Moreover, hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting. Conversely, refeeding promoted hepatocyte enlargement and proliferation compared to fasted state. Mechanistically, fasting or refeeding regulated the expression of YAP and its downstream targets, as well as the proliferation-related protein cyclin D1 (CCND1). Furthermore, fasting significantly reduced the liver size in AAV-control mice, which was mitigated in AAV Yap (5SA) mice. Yap overexpression also prevented the effect of fasting on hepatocyte size and proliferation. Besides, the recovery of liver size after refeeding was delayed in AAV Yap shRNA mice. Yap knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation. In summary, this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition, which provides new evidence for YAP in regulating liver size under energy stress.

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.

Objective:To investigate the effectiveness of basic swallowing training for tracheotomy patients using a speech valve after severe cranial injury.Methods:Thirty brain injury patients were randomly divided into a control group and an observation group, each of 15. In addition to conventional drug therapy, those in the control group were given basic swallowing training, while those in the observation group received the same swallowing training wearing a speech valve. The basic swallowing training included ice stimulation, tongue movement training and cough training twice a day, five days a week, for four weeks. The patients in the observation group were also trained to wear a speech valve on the same schedule. The subjects′ swallowing function was evaluated laryngoscopically using Saito′s dysphagia rating scale and the Rosenbek leakage aspiration rating scale before and after the 4 weeks of treatment.Results:Significant improvement was observed in both groups, with significantly greater improvement in the observation group, on average.Conclusions:Basic swallowing training when wearing a speech valve can improve the swallowing function of patients with severe brain injury after a tracheotomy and reduce aspiration during swallowing.

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.

Objective To study the application value of endoscopic thyroidectomy via total membrane dissection. Methods One hundred and sixteen patients with benign thyroid nodules were given axillo-breast approach endoscopic thyroidectomy via total membrane dissection from January 2014 to December 2016. Results Endoscopic thyroidectomy was completed in all the patients without conversion to open surgery.The operation time was 45-125 min[mean,(65.6 ±36.7)min],the blood loss was 10-220 ml[mean,(43.2 ±22.7)ml],the postoperative drainage volume was 25-305 ml[mean,(95.3 ±53.8)ml], the postoperative drainage time was 2-4 d[mean,(2.3 ±0.7)d)],and the length of hospital stay was 3-6 d[mean,(4.1 ±1.1)d].Short-term twitch occurred in 1 case and seroma occurred in 2 cases.No other complications such as hoarseness,bucking or asphyxia occurred in this series. Conclusion Endoscopic thyroidectomy via total membrane dissection can effectively avoid the injury of recurrent laryngeal nerve and parathyroid gland.

A retrospective study was conducted based on the clinical data of 42 patients of portal hypertension and splenomegaly who underwent laparoscopic splenectomy.The patients were divided into two groups including pedicle priority group and conventional group by different operative method.The operation time and intraoperative blood loss in the pedicle priority group were significantly lower than those in the conventional group (both P ＜ 0.05),and there was no statistically significant difference on the conversion rate of laparotomy,active time postoperation,exhaust time,postoperative hospitalization stay and the incidence of complications (all P ＞ 0.05).Priority processing for splenic pedicle has obvious advantages in laparoscopic splenectomy for portal hypertension and splenomegaly,and it could reduce the difficulty of operation,shorten the operation time and reduce bleeding.

Objective To study the effect of low frequency electric stimulation on tongue muscles in nasopharyngeal carcinoma (NPC) patients after radiation therapy.Methods Forty-three nasopharyngeal carcinoma patients with dysphagia after radiation therapy were randomly divided into a control group of 21 and a test group of 22.The control group received low frequency electric stimulation on external tongue muscles for 15 minutes a day while the test group received low frequency electric stimulation on external tongue muscles for 20 minutes a day,5 days a week for 4 weeks.Before and after the treatment,the range of motion of tongues was evaluated.Results Before the treatment,there was no significant difference between the two groups in all the measurements (P＞0.05).After the treatment,the protraction of the tongue improved significantly in both groups,with a significantly more improvement in the test group than in the control group.Significant improvement was observed in the side-to-side movement of the tongue in the test group,but not in the control group after the treatment.However,no significant improvement was observed in the up-and-down motion of the tongue in both groups after the treatment (P＞0.05).Conclusion Low frequency electric stimulation on internal and external tongue muscles can improve the protractive and side-to-side motion of the tongue in NPC patients after radiotherapy.

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.