BACKGROUND: Tidal peritoneal dialysis (TPD) provides better fluid flow mechanics and is more comfortable for the patient, owing to fewer alarms and less pain during inflow and outflow. The long-term characteristics of patients with TPD were not evident. In this randomized controlled follow-up study, we aimed to explore the characteristics of patients with TPD, compared to IPD.
METHODS: A total of 85 patients were randomized to either IPD or 70% TPD between January 2019 and December 2020, and all patients were followed up on December 2021. The characteristics of patients between the two groups were analyzed using a t-test or chi-square as appropriate. The overall survival and technical survival were analyzed using Kaplan-Meier analysis.
RESULTS: Forty-two patients were assigned to IPD, and 43 patients were assigned to TPD. The basal characteristics of patients were not different between the two groups. In an average of 16 months of follow-up, 19 patients died, and 25 patients dropped out of peritoneal dialysis. The two groups had no difference in overall survival and technical survival. TPD was associated with high urine volume (p = 0.001), lower blood urea nitrogen (p = 0.002), lower phosphorus (p = 0.004), and fewer cycler alarms (p < 0.001). The chance of patients reporting abdominal fullness was higher in patients with TPD (p = 0.001).
CONCLUSIONS: In the randomized, controlled, follow-up study, TPD may preserve residual renal function and is associated with lower urea nitrogen and phosphorus in chronic peritoneal dialysis patients. TPD is associated with fewer cycler alarms but may increase the chance of patients reporting abdominal distension.

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UNASSIGNED: Hydrophobic tagging (HyT) technology presents a distinct therapeutic strategy diverging from conventional small molecule drugs, providing an innovative approach to drug design. This review aims to provide an overview of the HyT literature and future outlook to offer guidance for drug design.
UNASSIGNED: In this review, the authors introduce the composition, mechanisms and advantages of HyT technology, as well as summarize the detailed applications of HyT technology in anti-cancer, neurodegenerative diseases (NDs), autoimmune disorders, cardiovascular diseases (CVDs), and other fields. Furthermore, this review discusses key aspects of the future development of HyT molecules.
UNASSIGNED: HyT emerges as a highly promising targeted protein degradation (TPD) strategy, following the successful development of proteolysis targeting chimeras (PROTAC) and molecular glue. Based on exploring new avenues, modification of the HyT molecule itself potentially enhances the technology. Improved synthetic pathways and emphasis on pharmacokinetic (PK) properties will facilitate the development of HyT. Furthermore, elucidating the biochemical basis by which the compound\'s hydrophobic moiety recruits the protein homeostasis network will enable the development of more precise assays that can guide the optimization of the linker and hydrophobic moiety.

Targeted protein degradation (TPD) is a rapidly expanding field, with various PROTACs (proteolysis-targeting chimeras) in clinical trials and molecular glues such as immunomodulatory imide drugs (IMiDs) already well established in the treatment of certain blood cancers. Many current approaches are focused on oncology targets, leaving numerous potential applications underexplored. Targeting proteins for degradation offers a novel therapeutic route for targets whose inhibition remains challenging, such as protein aggregates in neurodegenerative diseases. This mini review focuses on the prospect of utilizing TPD for neurodegenerative disease targets, particularly PROTAC and molecular glue formats and opportunities for novel CNS E3 ligases. Some key challenges of utilizing such modalities including molecular design of degrader molecules, drug delivery and blood brain barrier penetrance will be discussed.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands joined by a linker, enabling them to simultaneously bind with an E3 ligase and a protein of interest (POI) and trigger proteasomal degradation of the POI. Limitations of PROTAC include lack of potent E3 ligands, poor cell selectivity, and low permeability. AS1411 is an antitumor aptamer specifically recognizing a membrane-nucleus shuttling nucleolin (NCL). Here, we repurpose AS1411 as a ligand for an E3 ligase mouse double minute 2 homolog (MDM2) via anchoring the NCL-MDM2 complex. Then, we construct an AS1411-NCL-MDM2-based PROTAC (ANM-PROTAC) by conjugating AS1411 with large-molecular-weight ligands for \"undruggable\" oncogenic STAT3, c-Myc, p53-R175H, and AR-V7. We show that the ANM-PROTAC efficiently penetrates tumor cells, recruits MDM2 and degrades the POIs. The ANM-PROTAC achieves tumor-selective distribution and exhibits excellent antitumor activity with no systemic toxicity. This is a PROTAC with built-in tumor-targeting and cell-penetrating capacities.

Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review focuses on drug discovery with respect to bifunctional and molecular glue degraders within the ubiquitin proteasome system, including analysis of mechanistic concepts and discovery approaches, with an overview of current clinical and pre-clinical degrader status in oncology, neurodegenerative and inflammatory disease.

Kelch-like proteins (KLHLs) are a large family of BTB-containing proteins. KLHLs function as the substrate adaptor of Cullin 3-RING ligases (CRL3) to recognize substrates. KLHLs play pivotal roles in regulating various physiological and pathological processes by modulating the ubiquitination of their respective substrates. Mounting evidence indicates that mutations or abnormal expression of KLHLs are associated with various human diseases. Targeting KLHLs is a viable strategy for deciphering the KLHLs-related pathways and devising therapies for associated diseases. Here, we comprehensively review the known KLHLs inhibitors to date and the brilliant ideas underlying their development.

PROTAC is a rapidly developing engineering technology for targeted protein degradation using the ubiquitin-proteasome system, which has promising applications for inflammatory diseases, neurodegenerative diseases, and malignant tumors. This paper gives a brief overview of the development and design principles of PROTAC, with a special focus on PROTAC-based explorations in recent years aimed at achieving controlled protein degradation and improving the bioavailability of PROTAC, as well as TPD technologies that use other pathways such as autophagy and lysosomes to achieve targeted protein degradation.

UNASSIGNED: Chronic pain is associated with poor tactile acuity, commonly measured with the 2-point discrimination (TPD) test. Although poor tactile acuity across chronic pain conditions is well established, less is known in acute pain.
UNASSIGNED: Recent conflicting findings in experimentally induced neck and back pain led us to conduct a TPD investigation in experimentally induced limb pain. We hypothesised altered TPD during experimental upper limb pain, but we did not speculate on the direction of the change.
UNASSIGNED: Thirty healthy subjects immersed their dominant hand in a circulating cold-water bath at 7°C (cold pressor test [CPT]). Two-point discrimination was measured at baseline (pre-CPT), during pain (during-CPT), and after withdrawal from the water (post-CPT) in 3 different sites: (1) the dominant forearm, (2) dominant arm and (3) contralateral forearm.
UNASSIGNED: Repeated-measures analysis of variance revealed a significant main effect of time (F(2,56) = 4.45, P = 0.02, ηp2 = 0.14) on TPD; in all 3 sites, TPD values decreased (ie, tactile acuity improved) during pain. Interestingly, the contralateral forearm followed a similar pattern to the dominant (ie, painful) forearm, and furthermore was the only site that exhibited any correlation with pain, albeit in an intriguing direction (r = 0.57, P = 0.001), ie, the greater the pain the worse the tactile acuity.
UNASSIGNED: The improvements in tactile acuity during experimentally induced limb pain may reflect a protective response. The changes in the corresponding site in the contralateral limb may reflect a protective spinal cross talk. Such a response, together with the interesting relationship between tactile acuity and pain, warrant further inquiry.

Histone demethylases play a critical role in gene transcription regulation and have been implicated in cancer. Numerous reports have highlighted the overexpression of histone demethylases, such as LSD1 and JmjC, in various malignant tumor tissues, identifying them as effective therapeutic targets for cancer treatment. Despite many histone demethylase inhibitors entering clinical trials, their clinical efficacy has been limited. Therefore, combination therapies based on histone demethylase inhibitors, along with other modulators like dual-acting inhibitors, have gained significant attention and made notable progress in recent years. In this review, we provide an overview of recent advances in drug discovery targeting histone demethylases, focusing specifically on drug combination therapy and histone demethylases-targeting dual inhibitors. We discuss the rational design, pharmacodynamics, pharmacokinetics, and clinical status of these approaches. Additionally, we summarize the co-crystal structures of LSD1 inhibitors and their target proteins as well as describe the corresponding binding interactions. Finally, we also provided the challenges and future directions for utilizing histone demethylases in cancer therapy, such as PROTACs and molecular glue etc.