Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.

Ninety percent of clinical drug development fails despite implementation of many successful strategies, which raised the question whether certain aspects in target validation and drug optimization are overlooked? Current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity-relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity. We propose structure‒tissue exposure/selectivity-activity relationship (STAR) to improve drug optimization, which classifies drug candidates based on drug's potency/selectivity, tissue exposure/selectivity, and required dose for balancing clinical efficacy/toxicity. Class I drugs have high specificity/potency and high tissue exposure/selectivity, which needs low dose to achieve superior clinical efficacy/safety with high success rate. Class II drugs have high specificity/potency and low tissue exposure/selectivity, which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated. Class III drugs have relatively low (adequate) specificity/potency but high tissue exposure/selectivity, which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked. Class IV drugs have low specificity/potency and low tissue exposure/selectivity, which achieves inadequate efficacy/safety, and should be terminated early. STAR may improve drug optimization and clinical studies for the success of clinical drug development.

Nanomedicine usually refers to nanoparticles that deliver the functional drugs and siRNAs to treat cancer. Recent research has suggested that cancer cells can also make nanoparticles that also deliver functional molecules in promoting cancer metastasis, which is the leading cause of various cancer mortalities. This nanoparticle is called tumor-derived vesicles, or better-known as tumor-derived exosomes (TEXs). TEXs are nanoscale membrane vesicles (30-140 nm) that are released continuously by various types of cancer cells and contain tumor-derived functional biomolecules, including lipids, proteins, and genetic molecules. These endogenous TEXs can interact with host immune cells and epithelial cells locally and systemically. More importantly, they can reprogram the recipient cells in favor of promoting metastasis through facilitating tumor cell local invasion, intravasation, immune evasion, extravasation, and survival and growth in distant organs. Growing evidence suggests that TEXs play a key role in cancer metastasis. Here, we will review the most recent findings of how cancer cells harness TEXs to promote cancer metastasis through modulating vascular permeability, suppressing systemic immune surveillance, and creating metastatic niches. We will also summarize recent research in targeting TEXs to treat cancer metastasis.

By removing a part of the structure, the tooth preparation provides restorative space, bonding surface, and finish line for various restorations on abutment. Preparation technique plays critical role in achieving the optimal result of tooth preparation. With successful application of microscope in endodontics for >30 years, there is a full expectation of microscopic dentistry. However, as relatively little progress has been made in the application of microscopic dentistry in prosthodontics, the following assumptions have been proposed: Is it suitable to choose the tooth preparation technique under the naked eye in the microscopic vision? Is there a more accurate preparation technology intended for the microscope? To obtain long-term stable therapeutic effects, is it much easier to achieve maximum tooth preservation and retinal protection and maintain periodontal tissue and oral function health under microscopic vision? Whether the microscopic prosthodontics is a gimmick or a breakthrough in obtaining an ideal tooth preparation should be resolved in microscopic tooth preparation. This article attempts to illustrate the concept, core elements, and indications of microscopic minimally invasive tooth preparation, physiological basis of dental pulp, periodontium and functions involved in tool preparation, position ergonomics and visual basis for dentists, comparison of tooth preparation by naked eyes and a microscope, and comparison of different designs of microscopic minimally invasive tooth preparation techniques. Furthermore, a clinical protocol for microscopic minimally invasive tooth preparation based on target restorative space guide plate has been put forward and new insights on the quantity and shape of microscopic minimally invasive tooth preparation has been provided.

The primary cilium is a microtubule-based sensory organelle. The molecular mechanism that regulates ciliary dynamics remains elusive. Here, we report an unexpected finding that MLN4924, a small molecule inhibitor of NEDD8-activating enzyme (NAE), blocks primary ciliary formation by inhibiting synthesis/assembly and promoting disassembly. This is mainly mediated by MLN4924-induced phosphorylation of AKT1 at Ser473 under serum-starved, ciliary-promoting conditions. Indeed, pharmaceutical inhibition (by MK2206) or genetic depletion (via siRNA) of AKT1 rescues MLN4924 effect, indicating its causal role. Interestingly, pAKT1-Ser activity regulates both ciliary synthesis/assembly and disassembly in a MLN4924 dependent manner, whereas pAKT-Thr determines the ciliary length in MLN4924-independent but VHL-dependent manner. Finally, MLN4924 inhibits mouse hair regrowth, a process requires ciliogenesis. Collectively, our study demonstrates an unexpected role of a neddylation inhibitor in regulation of ciliogenesis via AKT1, and provides a proof-of-concept for potential utility of MLN4924 in the treatment of human diseases associated with abnormal ciliogenesis.

BACKGROUND/AIMS: High-resolution methods have advanced esophageal and anorectal manometry interpretation but are incompletely established for intestinal manometry. We characterized normal fasting duodeno-jejunal manometry parameters not measurable by standard techniques using clustered closely-spaced recordings. METHODS: Ten fasting recordings were performed in 8 healthy controls using catheters with 3–4 gastrointestinal manometry clusters with 1–2 cm channel spacing. Migrating motor complex phase III characteristics were quantified. Spatial-temporal contour plots measured propagation direction and velocity of individual contractions. Coupling was defined by pressure peak continuity within clusters. RESULTS: Twenty-three phase III complexes (11 antral, 12 intestinal origin) with 157 (95% CI, 104–211) minute periodicities, 6.99 (6.25–7.74) minute durations, 10.92 (10.68–11.16) cycle/minute frequencies, 73.6 (67.7–79.5) mmHg maximal amplitudes, and 4.20 (3.18–5.22) cm/minute propagation velocities were recorded. Coupling of individual contractions was 39.1% (32.1–46.1); 63.0% (54.4–71.6) of contractions were antegrade and 32.8% (24.1–41.5) were retrograde. Individual phase III contractions propagated > 35 fold faster (2.48 cm/sec; 95% CI, 2.25–2.71) than complexes themselves. Phase III complexes beyond the proximal jejunum were longer in duration (P = 0.025) and had poorer contractile coupling (P = 0.025) than proximal complexes. Coupling was greater with 1 cm channel spacing vs 2 cm (P < 0.001). CONCLUSIONS: Intestinal manometry using clustered closely-spaced pressure ports characterizes novel antegrade and retrograde propagation and coupling properties which degrade in more distal jejunal segments. Coupling is greater with more closely-spaced recordings. Applying similar methods to dysmotility syndromes will define the relevance of these methods.
Catheters ; Fasting ; Intestines ; Jejunum ; Manometry ; Muscle Contraction ; Myoelectric Complex, Migrating ; Periodicity

It is well known that malnutrition is a predictor of mortality in hemodialysis patients. The number of diabetic nephropathy patients is increasing rapidly. This study aimed to investigate nutritional status and nutrient intake according to the presence of diabetes among hemodialysis patients. The nutritional intake and general characteristics of outpatients at Ajou University Hospital (24 with diabetes and 30 without diabetes) were investigated between July and September 2015. Patients' general data were collected, and nutritional status by Patient-Generated Subjective Global Assessment (PG-SGA) was evaluated. Nutrient intakes were assessed according to 3-day food records. There was no significant difference regarding body weight between the two groups. However, the non-diabetic group showed a better nutritional status by Patient-Generated Subjective Global Assessment (PG-SGA) (5.2±4.4 vs. 8.0±4.3 score, non-diabetics vs. diabetics, P<0.05). There was no difference in daily calorie intake (1,473.9±370.5 vs. 1,503.8±397.5 kcal) and protein intake (60.3±19.7 vs. 65.6±20.5 g) in those with diabetes. Intakes of vegetables protein, sodium, potassium, vitamin C, folic acid and fiber were significantly higher in the diabetic group compared to those of the non-diabetic group. There was no difference in daily nutrient intake between the hemodialysis weekday and weekend groups. The non-diabetic group had higher calorie and sodium intakes per meal in the hemodialysis weekday group, but the difference was not significant. Based on these results, intervention should be performed to improve nutritional status in consideration of diabetes and dietary patterns.
Ascorbic Acid ; Body Weight ; Diabetes Mellitus ; Diabetic Nephropathies ; Folic Acid ; Humans ; Malnutrition ; Meals ; Mortality ; Nutritional Status* ; Outpatients ; Potassium ; Prospective Studies* ; Renal Dialysis* ; Sodium ; Vegetables

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that is associated with repetitive head injury and has distinctive neuropathological features that differentiate this disease from other neurodegenerative diseases. Intraneuronal tau aggregates, although they occur in different patterns, are diagnostic neuropathological features of CTE, but the precise mechanism of tauopathy is not known in CTE. We performed whole RNA sequencing analysis of post-mortem brain tissue from patients with CTE and compared the results to normal controls to determine the transcriptome signature changes associated with CTE. The results showed that the genes related to the MAP kinase and calcium-signaling pathways were significantly downregulated in CTE. The altered expression of protein phosphatases (PPs) in these networks further suggested that the tauopathy observed in CTE involves common pathological mechanisms similar to Alzheimer's disease (AD). Using cell lines and animal models, we also showed that reduced PPP3CA/PP2B phosphatase activity is directly associated with increases in phosphorylated (p)-tau proteins. These findings provide important insights into PP-dependent neurodegeneration and may lead to novel therapeutic approaches to reduce the tauopathy associated with CTE.
Alzheimer Disease ; Brain ; Brain Injury, Chronic* ; Cell Line ; Craniocerebral Trauma ; Gene Expression Profiling* ; Humans ; Models, Animal ; Neurodegenerative Diseases ; Phosphoprotein Phosphatases ; Phosphotransferases ; Sequence Analysis, RNA ; Tauopathies* ; Transcriptome*

Wnt3a, one of Wnt family members, plays key roles in regulating pleiotropic cellular functions, including self-renewal, proliferation, differentiation, and motility. Accumulating evidence has suggested that Wnt3a promotes or suppresses tumor progression via the canonical Wnt signaling pathway depending on cancer type. In addition, the roles of Wnt3a signaling can be inhibited by multiple proteins or chemicals. Herein, we summarize the latest findings on Wnt3a as an important therapeutic target in cancer.
Cell Division ; physiology ; Gene Expression Regulation, Neoplastic ; physiology ; Humans ; Neoplasm Proteins ; metabolism ; physiology ; Neoplasms ; genetics ; metabolism ; pathology ; Tumor Cells, Cultured ; Wnt Signaling Pathway ; physiology ; Wnt3A Protein ; metabolism ; physiology