Polyethylene glycol crosslinked decellularized single liver lobe scaffolds with vascular endothelial growth factor promotes angiogenesis in vivo.

BACKGROUND: Improving the mechanical properties and angiogenesis of acellular scaffolds before transplantation is an important challenge facing the development of acellular liver grafts. The present study aimed to evaluate the cytotoxicity and angiogenesis of polyethylene glycol (PEG) crosslinked decellularized single liver lobe scaffolds (DLSs), and establish its suitability as a graft for long-term liver tissue engineering. METHODS: Using mercaptoacrylate produced by the Michael addition reaction, DLSs were first modified using N-succinimidyl S-acetylthioacetate (SATA), followed by cross-linking with PEG as well as vascular endothelial growth factor (VEGF). The optimal concentration of agents and time of the individual steps were identified in this procedure through biomechanical testing and morphological analysis. Subsequently, human umbilical vein endothelial cells (HUVECs) were seeded on the PEG crosslinked scaffolds to detect the proliferation and viability of cells. The scaffolds were then transplanted into the subcutaneous tissue of Sprague-Dawley rats to evaluate angiogenesis. In addition, the average number of blood vessels was evaluated in the grafts with or without PEG at days 7, 14, and 21 after implantation. RESULTS: The PEG crosslinked DLS maintained their three-dimensional structure and were more translucent after decellularization than native DLS, which presented a denser and more porous network structure. The results for Young's modulus proved that the mechanical properties of 0.5 PEG crosslinked DLS were the best and close to that of native livers. The PEG-VEGF-DLS could better promote cell proliferation and differentiation of HUVECs compared with the groups without PEG cross-linking. Importantly, the average density of blood vessels was higher in the PEG-VEGF-DLS than that in other groups at days 7, 14, and 21 after implantation in vivo. CONCLUSIONS: The PEG crosslinked DLS with VEGF could improve the biomechanical properties of native DLS, and most importantly, their lack of cytotoxicity provides a new route to promote the proliferation of cells in vitro and angiogenesis in vivo in liver tissue engineering.

Disorders in angiogenesis and redox pathways are main factors contributing to the progression of rheumatoid arthritis: a comparative proteomics study.

OBJECTIVE: To clarify the pathogenesis of rheumatoid arthritis (RA) by comparing protein expression in fibroblast-like synoviocytes (FLS) from patients with RA with that in FLS from normal subjects, using proteomics analysis. METHODS: Proteins extracted from primary cultures of FLS obtained from 50 patients with RA and 10 normal subjects were analyzed by automated 2-dimensional nano-electrospray ionization liquid chromatography tandem mass spectometry. Differentially expressed proteins were screened by 2-sample t-test (P < 0.05) and fold change (>1.5), based on the bioinformatics analysis. The expression of vasculature development-related proteins (Thy-1, connective tissue growth factor [CTGF], and thrombospondin 1 [TSP-1]) and redox-related proteins (superoxide dismutase 2 [SOD2]) in synovial tissue was confirmed by real-time polymerase chain reaction and Western blotting. The effect of Thy-1 and CTGF knockdown on Thy-1, CTGF, TSP-1, and vascular endothelial growth factor (VEGF) was analyzed by RNA interference experiments. RESULTS: According to the criteria of having >1 unique peptide per protein present and a false discovery rate of ≤5%, 1,060 proteins were identified from patients with RA, and 1,292 proteins were identified from normal subjects, from which 100 differentially expressed proteins were screened out from the RA proteins. Of these, 46 proteins were up-regulated, and the remaining 54 proteins were down-regulated. Gene ontology and pathway analyses showed that 6 vasculature development-related proteins were up-regulated, including Thy-1, CTGF, and TSP-1, while 11 redox-related proteins were down-regulated, including SOD2. The results were consistent with those obtained using mass spectrometry. Thy-1, VEGF, CTGF, and TSP-1 were down-regulated after Thy-1 knockdown, and VEGF and CTGF were down-regulated after CTGF knockdown. Recombinant human CTGF could enhance proliferation and Transwell migration of human umbilical vein endothelial cells. CONCLUSION: Up-regulation of vasculature development-related proteins and down-regulation of redox-related proteins in FLS are predominant factors that may contribute to the pathogenesis of RA.

Reverse facial artery flap to reconstruct the medium-sized defects in the middle facial region following cancer ablation.

This retrospective clinical study assessed the reliability of the reverse facial artery flap to reconstruct the medium-sized defects in the middle facial region following cancer ablation.Fifteen medium-sized defects were repaired with reversed facial artery flap following cancer surgery. The ages of the patients ranged from 2 to 69 years; 9 were male and 6 were female. The primary lesions included palate (5 cases), maxillary gingival (6 cases), cheek or buccal mucosa (3 case), and upper lip (1 case). The size of the skin paddle varied from 4.0 cm × 6.0 cm to 5.0 cm × 10.0 cm. Direct closure was achieved at all donor sites. Fourteen of the 15 flaps survived. No donor-site problems occurred. Two patients appeared to have temporary injury of facial nerve after operation. The follow-up period ranged from 8 to 36 months; 1 patient died as a result of local recurrence and 1 patient developed cervical recurrence.Consequently, it has been demonstrated that the reversed facial artery flap had reliable blood supply and can reliably and conveniently be used for reconstruction of the medium-sized defects, especially in the middle third of oral and maxillofacial region.

Connective tissue growth factor, a regulator related with 10-hydroxy-2-decenoic acid down-regulate MMPs in rheumatoid arthritis.

10-hydroxy-2-decenoic acid (10H2DA) is suggested to be a potential medication for rheumatoid arthritis (RA) by activation of matrix metalloproteinases (MMPs) via mitogen-activated protein kinase signaling pathways. The aim of the present work was to seek differentially expressed proteins in rheumatoid arthritis synovial fibroblasts (RASFs) treated with 10H2DA by comparative proteomics analysis. Two-dimensional electrophoresis (2-DE) and LC-MS/MS were performed to identify changes in protein expression after 24-h 10H2DA treatment. Differentially expressed proteins were identified by real-time PCR and Western blot analysis. Influence of down-regulation of connective tissue growth factor (CTGF) expression on MMPs was studied by RNAi. Ten proteins were up-regulated and 9 proteins were down-regulated after 24-h 10H2DA treatment. A total of 19 differentially expressed proteins were identified and found to be associated with glycolysis, lipid metabolism, cell adhesion, ATP synthesis, oxidation reduction, and anti-apoptosis. CTGF, a member of the C-terminal cystein-rich proteins (CCN) family, was down-regulated after 24-h 10H2DA treatment. MMPs were down-regulated after RNAi (CTGFi). These results suggest that CTGF is a regulator factor in the expression of MMPs, and 10H2DA down-regulate the concentration of MMPs probably by down-regulating the expression of CTGF.

Posttraumatic stress disorder of Red Cross nurses in the aftermath of the 2008 Wenchuan China Earthquake.

This study investigated the symptoms, psychological distress characteristics, and related factors in China Red Cross disaster relief nurses following the 2008 Wenchuan Earthquake in China that began on May 12 and lasted to June 23, 2008. A sample of 210 exposed nurses and a reference group of 236 nonexposed Red Cross nurses were surveyed within 1 year after the catastrophic earthquake. They were given a self-report questionnaire to assess demographics, posttraumatic stress disorder, and depression symptoms. Exposed nurses reported higher psychological distress on all aspects than nonexposed nurses. Scores on the Traumatic Stress Symptom Checklist were predicted by the avoidance of traumatic thoughts during the earthquake, personality traits, prior disaster experience, and preexisting stress, and other background factors were associated with scores on measures of psychological distress in exposed nurses. The conclusion indicated that disaster relief nurses experienced psychological distress and that immediate psychological intervention should be initiated.

Correction: PCL NGCs integrated with urolithin-A-loaded hydrogels for nerve regeneration.

Correction for 'PCL NGCs integrated with urolithin-A-loaded hydrogels for nerve regeneration' by Xue-Han Jin et al., J. Mater. Chem. B, 2022, https://doi.org/10.1039/D2TB01624A.

PCL NGCs integrated with urolithin-A-loaded hydrogels for nerve regeneration.

Inflammation and oxidative stress are among the leading causes of poor prognosis after peripheral nerve injury (PNI). Urolithin-A (UA), an intermediate product produced by the catabolism of ellagitannins in the gastrointestinal tract, has anti-inflammatory, antioxidant, and immunomodulatory properties for inflammation, oxidative damage, and aging-related diseases. Hence, we prepared UA-loaded hydrogels and embedded them in the lumen of PCL nerve guide conduits (NGCs). The hydrogels continuously released appropriate doses of UA into the microenvironment. Based on in vitro studies, UA facilitates cell proliferation and reduces oxidative damage. Besides, the experimental evaluation revealed good biocompatibility of the materials involved. We implanted NGCs into rat models to bridge the sciatic nerve defects in an in vivo study. The sciatic functional index of the PCL/collagen/UA group was comparable to that of the autograft group. Additionally, the consequences of electrophysiological, gastrocnemius muscle and nerve histology assessment of the PCL/collagen/UA group were better than those in the PCL and PCL/collagen groups and close to those in the autograft group. In this study, UA sustained release via the PCL/collagen/UA NGC was found to be an effective alternative treatment for PNI, validating our hypothesis that UA could promote regeneration of nerve tissue.

Ti3C2Tx MXene-Coated Electrospun PCL Conduits for Enhancing Neurite Regeneration and Angiogenesis.

An electrical signal is the key basis of normal physiological function of the nerve, and the stimulation of the electric signal also plays a very special role in the repair process of nerve injury. Electric stimulation is shown to be effective in promoting axonal regeneration and myelination, thereby promoting nerve injury repair. At present, it is considered that electric conduction recovery is a key aspect of regeneration and repair of long nerve defects. Conductive neural scaffolds have attracted more and more attention due to their similar electrical properties and good biocompatibility with normal nerves. Herein, PCL and MXene-PCL nerve guidance conduits (NGCs) were prepared; their effect on nerve regeneration was evaluated in vitro and in vivo. The results show that the NGCs have good biocompatibility in vitro. Furthermore, a sciatic nerve defect model (15 mm) of SD rats was made, and then the fabricated NGCs were implanted. MXene-PCL NGCs show similar results with the autograft in the sciatic function index, electrophysiological examination, angiogenesis, and morphological nerve regeneration. It is possible that the conductive MXene-PCL NGC could transmit physiological neural electric signals, induce angiogenesis, and stimulate nerve regeneration. This paper presents a novel design of MXene-PCL NGC that could transmit self-originated electric stimulation. In the future, it can be combined with other features to promote nerve regeneration.

Bilateral plate fixation for type C distal humerus fractures: experience at a single institution.

Type C fractures of the distal humerus are difficult to treat and typically require open anatomical reduction and internal fixation. Here we describe our experience treating patients with type C distal humerus fractures using a trans-olecranon approach with bilateral plate fixation. Fifty-six patients (30 males, 26 females; mean age 49.8 years) were treated over a period of six years. Thirteen fractures were open and 43 closed; all were caused by falls or traffic accidents. All operations were performed successfully with no intraoperative complications. Mean duration of follow-up was 30 months (range 6-70). Mean duration of fracture healing was 2.8 months (range 2-4). Forty-seven out of 56 patients (84%) suffered no postoperative complications. One patient exhibited symptoms of ulnar nerve injury following surgery (nine exhibited symptoms before and after surgery). Two patients had mild cubitus varus deformities, four delayed olecranon osteotomy site healing, and two heterotopic ossifications. In summary, complications were minimal and outcomes satisfactory in patients with type C distal humerus fractures who underwent bilateral plate fixation via a trans-olecranon approach.

Biomechanical analysis of the closed reduction internal fixation with cannulated screw of femoral neck fractures.

ABSTRACT: The influencing factors in closed reduction internal fixation with cannulated screw of femoral neck fractures have not been well investigated. This study evaluated these factors in patients with femoral neck fractures.Fifty-seven patients (36 males and 21 females) diagnosed with femoral neck fracture with the average age of 52.44 ±â€Š15.04 years who underwent closed reduction internal fixation with cannulated screw were included in this study. Data were collected through case report reviews, phone call follow-ups, and outpatient follow-ups to evaluate pre- and postoperative radiograph images. Statistical analysis was performed using Garden classification, binary and multinomial logistic regression analysis by including factors such as patient's age, gender, fracture type, time to fixation, reduction quality, functional recovery period, removal of cannulated screw, and preoperative traction. Logistic regression analysis revealed that age and reduction quality was statistically significant (P < .05) to clinical outcome and other factors were not statistically significant.The main factors affecting clinical outcomes were functional recovery and reduction quality. The biomechanical effects of fixation provide a good foundation for fracture healing. Patient's conditions should be carefully evaluated before selecting reduction procedures to reach an optimal surgical outcome.

γδ T/Interleukin-17A Contributes to the Effect of Maresin Conjugates in Tissue Regeneration 1 on Lipopolysaccharide-Induced Cardiac Injury.

The mechanisms underlying sepsis-induced cardiomyopathy (SIC) remain poorly understood, and there are no specific therapeutics for SIC. We investigated the effects of maresin conjugates in tissue regeneration 1 (MCTR1) on SIC and explored its potential mechanisms. The experiments were conducted using an endotoxemia model induced by lipopolysaccharide (LPS). Mice were given MCTR1 intravenously 6 h after LPS stimulation. Echocardiography was performed to assess cardiac function 12 h after LPS administration. Treatment with MCTR1 significantly enhanced cardiac function and reduced LPS-induced increase of mRNA expression levels of inflammation cytokines. Transcriptomic analysis indicated that MCTR1 inhibited neutrophil chemotaxis via the IL-17 signaling pathway. We confirmed that MCTR1 reduced the expressions of neutrophil chemoattractants and neutrophil infiltration in the LPS-stimulated hearts. MCTR1 also resulted in a considerable reduction in IL-17A production mainly derived from γδ T cells. Moreover, our results provided the first evidence that neutralizing IL-17A or depletion of γδ T cells markedly decreased neutrophil recruitment and enhanced cardiac function in LPS-induced cardiac injury. These results suggest that MCTR1 alleviates neutrophil infiltration thereby improves cardiac function in LPS-induced cardiac injury via the IL-17 signaling pathway. Thus, MCTR1 represented a novel therapeutic strategy for patients with SIC.

Dexmedetomidine promotes inflammation resolving through TGF-ß1 secreted by F4/80+Ly6G+ macrophage.

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist, which can regulate inflammatory responses. However, whether DEX interferes with the inflammation resolving remains unclear. Here, we reported the effects of DEX on zymosan-induced generalized inflammation in mice during resolution. Mice were administered intraperitoneally with DEX after the initiation of sepsis. The resolution interval (Ri), a vital resolution indice, decreased from twelve hours to eight hours after the administration of DEX. The induction of peritoneal pro-inflammatory interleukin [IL] - 1ß and tumour necrosis factor-α (TNF-α) appeared to be inhibited. Of interest, the anti-inflammatory transforming growth factor-ß1 (TGF-ß1) but not IL-10 levels were up-regulated at twenty-four hours in the DEX group along with 1.0 mg/mice zymosan A (ZyA) treatment. The expression levels of multiple genes related to protective immune processes and clearance functions were detected and revealed the same trends. DEX markedly increased the F4/80+Ly6G+ macrophage population. Additionally, the adequate apoptotic neutrophil clearance from injury after DEX installation could be reverse by opsonization or co-instillation of TGF-ß1 neutralizing antibody in vivo, promoting the inflammation-resolution programs. In conclusion, DEX post-treatment, via the increase of F4/80+Ly6G+ macrophages, provokes further secretion of TGF-ß1, leading to the attenuated cytokine storm and accelerated inflammation resolving.

Survivin shRNA induces caspase-3-dependent apoptosis and enhances cisplatin sensitivity in squamous cell carcinoma of the tongue.

Survivin is a member of the inhibitor of apoptosis protein (IAP) family; it is overexpressed in most cancer tissues and induces resistance to chemotherapy. In this study, we investigated whether a short hairpin RNA (shRNA) targeting survivin can induce apoptosis and enhance chemosensitivity to cisplatin in squamous cell carcinoma of the tongue. Results showed that chemosensitivity to cisplatin was surviving dependent in three cell lines (Tca8113, Bca885, and MCF7); higher survivin mRNA expression levels were associated with lower sensitivity to cisplatin. A plasmid-containing survivin shRNA was constructed and transfected into cell line Tca8113. Survivin shRNA inhibited expression of survivin mRNA and protein (63% and 65% inhibition, respectively), significantly inhibited cell proliferation, and enhanced chemosensitivity to cisplatin (p < 0.05). Apoptosis and caspase-3 activity were induced when cells were treated with survivin shRNA and/or cisplatin. Survivin shRNA induced caspase-3-dependent apoptosis and enhanced chemosensitivity to cisplatin in these tongue squamous cell carcinoma cell lines.

Extended supraclavicular fasciocutaneous island flap based on the transverse cervical artery for head and neck reconstruction after cancer ablation.

PURPOSE: This clinical study assessed a pedicled supraclavicular fasciocutaneous island flap (SFIF) based on the transverse cervical artery that was extended to include shoulder skin for reconstructing the head and neck. PATIENTS AND METHODS: Pedicled SFIFs extended to include the shoulder skin based on the cutaneous feeder vessels and perforator vessels in the deep fascia of the transverse cervical artery were designed for 24 patients with defects of the head and neck after cancer ablation. Preoperative 3-dimensional computed tomographic angiography was performed in all patients. The patients consisted of 15 men and 9 women ranging in age from 24 to 73 years. RESULTS: The primary lesions included squamous cell carcinoma of the tongue, buccal mucosa, floor of the mouth, oropharynx, palate, and lower gingiva. Three-dimensional computed tomographic angiography showed that the transverse cervical artery arose from the thyrocervical trunk in 13 cases and from the subclavian artery in 11 cases. The diameter of the artery ranged from 0.15 to 0.24 cm. The size of flaps ranged from 4 × 8 cm to 6 × 12 cm, and the mean length of the vascular pedicle was approximately 18.5 cm. Of the flaps, 23 survived completely, for a success rate of 95.8%. Three patients underwent radiotherapy, and the follow-up period ranged from 3 to 12 months. One patient died of local tumor recurrence, and cervical recurrences developed in 3 patients. CONCLUSION: An SFIF extended to include the shoulder skin based on the cutaneous feeder vessels and perforator vessels in the deep fascia of the transverse cervical artery is a useful, viable option for defects of the head and neck after cancer ablation.

Submental flap for reconstructing tongue defect with V-Y advancement flap for repairing submental defect.

OBJECTIVE: To assess the reliability of the facial-submental artery island flap for reconstructing tongue defects and the aesthetic benefits of using two V-Y islanded flaps for repairing the resulting submental defect. STUDY DESIGN: Case series with chart review. SETTING: Patient with tongue cancer, younger patient, cosmetic outcome. SUBJECTS AND METHODS: Thirty-three tongue defects were repaired with facial-submental artery island flaps, and the submental defects were repaired with two V-Y advancement flaps. The ages of the patients ranged from 28 to 57 years; 19 were men and 14 were women. All of the lesions were tongue squamous cell carcinoma. The size of the facial-submental artery island flap ranged from 3.5x7.0 to 5.0x8.0 cm. The size of the V-Y advancement flaps ranged from 3.0x3.0 to 4.0x4.0 cm. Direct closure was achieved at all donor sites. RESULTS: The facial-submental artery island flaps and V-Y advancement flaps survived in 93.9 percent and 97.0 percent, respectively. The patients were followed for 12 to 26 months. The functional results in terms of speech and swallowing were good, and the aesthetic outcomes using two V-Y advancement flaps to repair the submental defects were satisfactory. Two patients with extracapsular lymph node spread developed local recurrence: One is alive with disease and the other is dead. CONCLUSIONS: The facial-submental artery island flap is a simple, reliable flap that is preferred for reconstructing tongue defects. Using two V-Y advancement flaps for repairing the donor site defect improves the cosmetic outcome in the submental region.

The trapezius osteomyocutaneous island flap for reconstructing hemimandibular and oral defects following the ablation of advanced oral malignant tumours.

OBJECTIVE: This study presents an effective repair method for the hemimandibular and oral defects produced during the ablation of advanced oral malignant tumours. METHODS: Nine patients (five males and four females ranging in age from 18 to 74 years; mean age 51.3 years) with advanced oral malignant tumours were treated at our institution. Trapezius osteomyocutaneous island flaps (TOIFs) including the acromion, spine, and part of the medial scapular border were used to repair the hemimandibular and oral defects. RESULTS: No major flap failure occurred. Donor-site problems have been minimal, with limited shoulder motion in all patients. The functional results in terms of speech, swallowing, and facial contour were satisfactory. The patients were followed for 6-24 months (average 15.2 months): six of them are alive with no disease, two alive with disease; and one has died of a lung metastasis. CONCLUSION: The TOIF is large, simple, and reliable, and is preferred for reconstructing hemimandibular and oral defects.

Double-column fixation for type C fractures of the distal humerus in the elderly.

BACKGROUND: Although several studies reported good results of open reduction and internal fixation of displaced fracture of the adult distal humerus, few studies have specifically addressed the results of such surgical fixation in osteoporotic bone in the elderly. METHODS: This study focused on AO type C fractures in the elderly by using 2 plates for fixation of the lateral and medial columns to reconstruct a stable triangular frame of the distal humerus. The study comprised 35 patients, and 32 were available for final evaluation at a mean follow-up of 24.5 months (range, 14-60 months). RESULTS: Mayo Elbow Function Score showed 25 patients (78%) achieved an excellent functional result, and 7 (22%) had a good result. No patients were considered to have a fair or poor result. At the final follow-up, the mean range of flexion to extension of the elbow was 22 degrees (range, 10 degrees -40 degrees) to 125 degrees (range, 100 degrees -140 degrees). All fractures united at average of 3.5 months (range, 2.5-5.3 months). CONCLUSION: Open reduction and internal fixation using double-columned plating is a useful and effective technique in the management of displaced, comminuted, intra-articular fractures of the distal humerus in elderly patients. LEVEL OF EVIDENCE: Level 4; Case series, treatment study.

Expression of inducible nitric oxide synthase and vascular endothelial growth factor in ameloblastoma.

The purposes of this study were to determine the correlation between the expression of inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) in ameloblastoma and to examine the relationships of this expression to angiogenesis and the clinical and biological behaviors of the tumor. Immunohistochemical staining with streptavidin peroxidase was used to analyze iNOS and VEGF expression, and CD34 was used to evaluate microvascular density (MVD) in 35 ameloblastomas (24 primary tumors and 11 recurrences) and 5 malignant ameloblastomas. Ten odontogenic keratocysts (OKCs) served as controls. On relational analysis, positive and VEGF expression and MVD counts increased in this order: OKCs, primary ameloblastoma, recurrent ameloblastoma, and malignant ameloblastoma. Differences between the ameloblastomas and OKCs were significant (P < 0.05). Among ameloblastomas, MVD counts increased with increasing expression of iNOS and VEGF (P < 0.05), and iNOS expression and VEGF expression were positively correlated (r = 0.66, P < 0.05). Inducible nitric oxide synthase expression and VEGF expression may be closely related to the angiogenesis and invasive biological behavior of ameloblastomas.

Value of a smartphone-compatible thermal imaging camera in the detection of peroneal artery perforators: Comparative study with computed tomography angiography.

BACKGROUND: The aim of this study was to investigate the value of a smartphone-compatible thermal imaging camera in the mapping of the peroneal artery perforators. METHODS: Twelve consecutive patients scheduled for fibular flap reconstruction were enrolled. The lower limbs were first studied using smartphone-based dynamic infrared thermography (DIRT). During the rewarming, the hotspots were marked, small rubber markers were taped to the registered sites, and then the patients were sent for a CT scan. The diagnostic performance of smartphone-based DIRT was evaluated by comparing the DIRT findings with CT angiography and intraoperative findings. RESULTS: DIRT detected 42 of the 57 dominant perforators in 24 limbs and resulted in a sensitivity of 73.7% and a positive predictive value of 65.6%. CONCLUSIONS: The sensitivity and positive predictive value of the smartphone-based DIRT are low. Currently, it should be used as an adjunctive tool together with the established imaging techniques.

Intrinsic retinoic acid receptor alpha-cyclin-dependent kinase-activating kinase signaling involves coordination of the restricted proliferation and granulocytic differentiation of human hematopoietic stem cells.

Little is known about the mechanisms by which retinoic acid receptor alpha (RAR alpha) mediates the effects of retinoic acid (RA) to coordinate granulocytic proliferation/differentiation (P/D) transition. Cyclin-dependent kinase-activating kinase (CAK) complex, whose activity in phosphorylation of RAR alpha is determined by its targeting subunit ménage à trois 1 (MAT1), regulates G(1) exit, a cell cycle stage when cells commonly commit to proliferation or to differentiation. We previously found that in myeloid leukemia cells, the lack of RA-induced RAR alpha-CAK dissociation and MAT1 degradation suppresses cell differentiation by inhibiting CAK-dependent G(1) exit and sustaining CAK hyperphosphorylation of RAR alpha. This contrasts with our recent findings about the P/D transition in normal primitive hematopoietic cells, where MAT1 degradation proceeds intrinsically together with granulocytic development, in accord with dynamic expression of aldehyde dehydrogenases (ALDHs) 1A1 and 1B1, which catalyze RA synthesis. Blocking ALDH activity inhibits MAT1 degradation and granulocytic differentiation, whereas loss of RAR alpha phosphorylation by CAK induces RA-target gene expression and granulocytic differentiation. These studies suggest that the subversion of RAR alpha-CAK signaling during normal granulopoiesis is crucial to myeloid leukemogenesis and challenges the current paradigm that RA induces cell differentiation solely by transactivating target genes. Disclosure of potential conflicts of interest is found at the end of this article.