Dietary Folate and Cofactors Accelerate Age-dependent p16 Epimutation to Promote Intestinal Tumorigenesis.

The extent to which non-genetic environmental factors, such as diet, contribute to carcinogenesis has been long debated. One potential mechanism for the effects of environmental factors is through epigenetic modifications that affect gene expression without changing the underlying DNA sequence. However, the functional cooperation between dietary factors and cancer-causing epigenetic regulation is largely unknown. Here, we use a mouse model of age-dependent p16 epimutation, in which the p16 gene activity is directly controlled by promoter DNA methylation. We show p16 epimutation is modulated by folate and cofactors in dietary supplementation, which leads to increased colon cancer risk. Importantly, our findings provide functional evidence concerning the safety of folate fortification in the general population. SIGNIFICANCE: Our study demonstrates that dietary folate and cofactors modulate tumor-suppressor gene methylation to increase intestinal tumorigenesis. Our findings highlight the need for monitoring the long-term safety of folate fortification in high-risk individuals.

Whole-process nursing management for laparo-gastroscopic esophagectomy.

Background: Advances in surgical, anesthesia, and nursing techniques have allowed the development of laparo-gastroscopic esophagectomy (LGE) as a minimally invasive treatment of esophageal cancer. This study summarizes the experience of patient whole-process nursing management for patients who received LGE. Methods: The implementation of LGE at Zhongshan Hospital, Fudan University, was initiated in June 2020. The procedure is indicated for patients with thoracic conditions that can compromise the outcomes of traditional surgical procedures, and is performed coordinately by thoracic surgeons and endoscopists. A whole-process nursing protocol covering peri-operative patient management was proposed based on the LGE procedure. The operative outcomes were analyzed in this study. Results: The data of 10 consecutive patients who received LGE and the whole-process nursing protocol were analyzed, and all patients were compliant with the nursing protocol. Intra-operatively, there were no complications or conversions to other surgical methods. Post-operatively, pulmonary complications occurred in 2 cases [1 patient experienced aspiration, underwent preventive tracheotomy, and was discharged on postoperative day (POD) 10; 1 patient developed a left pleural effusion requiring puncture and drainage, and was discharged on POD 7]. The 30-day mortality was not recorded from the primary LGE cohort. Conclusions: The whole-process nursing protocol showed safety and feasibility for patients who underwent LGE. In the future, more specialized and whole-process nursing management will be carried out for patients undergoing such operations.

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy.

ONC201 was originally discovered as TNF-Related Apoptosis Inducing Ligand (TRAIL)-inducing compound TIC10. ONC201 appears to act as a selective antagonist of the G protein coupled receptor (GPCR) dopamine receptor D2 (DRD2), and as an allosteric agonist of mitochondrial protease caseinolytic protease P (ClpP). Downstream of target engagement, ONC201 activates the ATF4/CHOP-mediated integrated stress response leading to TRAIL/Death Receptor 5 (DR5) activation, inhibits oxidative phosphorylation via c-myc, and inactivates Akt/ERK signaling in tumor cells. This typically results in DR5/TRAIL-mediated apoptosis of tumor cells; however, DR5/TRAIL-independent apoptosis, cell cycle arrest, or antiproliferative effects also occur. The effects of ONC201 extend beyond bulk tumor cells to include cancer stem cells, cancer associated fibroblasts and immune cells within the tumor microenvironment that can contribute to its efficacy. ONC201 is orally administered, crosses the intact blood brain barrier, and is under evaluation in clinical trials in patients with advanced solid tumors and hematological malignancies. ONC201 has single agent clinical activity in tumor types that are enriched for DRD2 and/or ClpP expression including specific subtypes of high-grade glioma, endometrial cancer, prostate cancer, mantle cell lymphoma, and adrenal tumors. Synergy with radiation, chemotherapy, targeted therapy and immune-checkpoint agents has been identified in preclinical models and is being evaluated in clinical trials. Structure-activity relationships based on the core pharmacophore of ONC201, termed the imipridone scaffold, revealed novel potent compounds that are being developed. Imipridones represent a novel approach to therapeutically target previously undruggable GPCRs, ClpP, and innate immune pathways in oncology.

Prescriptions from Traditional Chinese Medicine compared with salbutamol and montelukast for the treatment of pediatric asthma: a randomized controlled trial.

OBJECTIVE: To compare the effects of a series of Traditional Chinese Medicine (TCM) empirical prescriptions with salbutamol and montelukast (SM) in children with asthma. METHODS: A total of 182 children with asthma were randomized into the TCM group (n = 97) or SM group (n = 85). Patients in the TCM group were treated with a series of TCM prescriptions, whereas those in the SM group received salbutamol and montelukast; both groups received their respective treatment for 12 weeks. Asthma control, changes in scores of TCM symptom patterns, and asthma symptom control (SC) scores after treatment were compared between the two groups. RESULTS: A higher percentage of patients in the TCM group had asthma control compared with those in the SM group (91.67% and 76.83%, respectively, P = 0.006). Scores for abnormal feces (P < 0.001), hyperhidrosis (P < 0.001), and tongue appearance (P = 0.001) in the TCM group were significantly better than those in the SM group. However, the total scores of TCM symptom patterns and SC scores did not differ significantly between the two groups (P > 0.05). CONCLUSION: Compared with salbutamol and montelukast, the TCM prescriptions tested were better for symptom control in children with asthma.

Effect of Traditional Chinese Medicine on Inflammatory Mediators in Pediatric Asthma.

Objective. To observe the effects of empirical prescriptions of traditional Chinese medicine (TCM) on inflammatory mediators in pediatric asthma and to explore the underlying molecular mechanism in the treatment of asthma. Methods. A total of 182 children with asthma were randomly placed into either the TCM group (n = 97) or the salbutamol and montelukast (SM) group (n = 85). Patients in the TCM group were treated with a series of empirical prescriptions of TCM, while those in the SM group received salbutamol and montelukast. Both groups received their respective treatment for 12 weeks. There were 35 patients in TCM group and 34 patients in SM group providing venous blood. Real-time PCR was used to determine the mRNA expression levels of interleukin- (IL-) 10, IL-17, matrix metalloproteinase-9 (MMP-9), and transforming growth factor ß1 (TGF-ß1) in peripheral blood mononuclear cells before and after treatment. Enzyme-linked immunosorbent assay was used to measure the levels of IL-10, IL-17, MMP-9, and TGF-ß1 in peripheral blood before and after treatment. Results. The mRNA expression of TGF-ß1 in the SM group was downregulated (P = 0.00) after treatment. No significant differences were found between the TCM group and the SM group after treatment (P > 0.05). In the TCM group, the levels of IL-10, IL-17, and MMP-9 significantly decreased after treatment (P = 0.01, 0.04, and 0.03, resp.). In the SM group, IL-17, MMP-9, and TGF-ß1 levels significantly decreased after treatment (P = 0.00, 0.03, and 0.00, resp.). There was no significant difference between the two groups regarding the levels of IL-10, IL-17, TGF-ß1, and MMP-9 (P > 0.05). The difference of the level of IL-17 was negatively correlated with the change of C-ACT score in TCM group and SM group. Conclusion. TCM has a regulatory effect on the balance of some inflammatory mediators in pediatric asthma.

Uvangoletin induces mitochondria-mediated apoptosis in HL-60 cells in vitro and in vivo without adverse reactions of myelosuppression, leucopenia and gastrointestinal tract disturbances.

This study investigated the cytotoxic effect of uvangoletin on HL-60 cells, and the effects of uvangoletin on myelosuppression, leucopenia, gastrointestinal tract disturbances and the possible cytotoxic mechanisms by using CCK-8, flow cytometry, western blot, xenograft, cyclophosphamide-induced leucopenia, copper sulfate-induced emesis and ethanol-induced gastric mucosal lesions assays. The results of CCK-8, flow cytometry and western blot assays indicated that uvangoletin showed the cytotoxic effect on HL-60 cells and induced the apoptosis of HL-60 cells by downregulating the expression levels of anti-apoptotic proteins (Survivin, Bcl-xl and Bcl-2), upregulating the expression levels of pro-apoptotic proteins (Smac, Bax, Bad, c-caspase-3 and c-caspase-9), and promoting the release of cytochrome c from mitochondria to cytoplasm. Further, the results of xenograft assay suggested that uvangoletin inhibited the HL-60-induced tumor growth without adverse effect on body weight of nude mice in vivo by regulating the expression levels of above apoptotic proteins. The results indicated that the reductions of WBCs count and thighbone marrow granulocytes percentage in cyclophosphamide-induced leucopenia assay, the incubation period and number of emesis in copper sulfate-induced emesis assay and the gastric mucosal lesions in ethanol-induced gastric mucosal lesions assay were not exacerbated or reversed by uvangoletin. In conclusion, the research preliminarily indicated that uvangoletin induced apoptosis of HL-60 cells in vitro and in vivo without adverse reactions of myelosuppression, leucopenia and gastrointestinal tract disturbances, and the pro-apoptotic mechanisms may be related to mitochondria-mediated apoptotic pathway.

Agonistic induction of PPARγ reverses cigarette smoke-induced emphysema.

The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator-activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Pparg(flox/flox) mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg(flox/flox) mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema.

A quantification model of Traditional Chinese Medicine syndromes in children with idiopathic precocious puberty and early puberty.

OBJECTIVE: To establish a quantification model of Traditional Chinese Medicine (TCM) syndromes by sampling patients undergoing idiopathic precocious puberty (IPP) and early puberty. METHODS: A questionnaire for classifying and quantifying TCM syndromes was designed and administered. All the results were analyzed; the relationship between 3 types of syndrome and 47 symptoms were summated. Meanwhile, the frequency distribution of each symptom or sign was aggregated. Fuzzy mathematics was used to develop a quantification model ofTCM syndromes. RESULTS: We found that precocious puberty had 3 types of syndrome, including hyperactivity of fire due to Yin deficiency (Syndrome I), depressed liver Qi transforming into fire (Syndrome II), and end retention of damp heat (Syndrome III). In the IPP group, Syndrome I was the most common principal syndrome (100%). Forty-six patients (43.81%) were diagnosed with Syndrome I accompanied by Syndrome II and 11 (10.48%) were diagnosed with Syndrome I accompanied by Syndrome III. In the early puberty group, Syndrome I was also the main syndrome (98.39%). The degrees of most symptoms were mild to moderate. Reddened tongue was the most common tongue manifestation (62.86% prevalence) in the IPP group. The most common pulse manifestations were slippery pulse, thread pulse, and taut pulse. The Asymptotic Normalization Coefficient (ANC) method was used to quantify the TCM syndromes in 167 cases. Diagnostic accuracy rate reached 91%, comparable to expert diagnosis. CONCLUSION: We find that there are 3 types of syndrome in the IPP group and in the early puberty group. Syndrome I (hyperactivity of fire due to Yin deficiency) is the main syndrome in the two groups. ANC may be an appropriate for quantification model of TCM syndromes.

Regulatory effects of stage-treatment with established Chinese herbal formulas on inflammatory mediators in pediatric asthma.

OBJECTIVE: To explore the regulatory effects of established Chinese herbal formulas on inflammatory mediators released during asthma attacks, and to elucidate the molecular mechanism of Traditional Chinese Medicine in the treatment of asthma. METHODS: Seventy-five asthmatic children were randomly divided into a Chinese medication group (45 cases) and a Western medication control group (30 cases). Patients in the Chinese medication group were treated with a series of established Chinese herbal formulas, whereas the Western medication control group received a leukotriene receptor antagonist and a bronchial relaxant. Real-time PCR was used to determine the mRNA expression levels of interleukin (IL)-4, cysteinyl leukotriene receptor 1 (CysLTR1), and interferon (IFN)-gamma in peripheral blood mononuclear cells before and after treatment. Enzyme-linked immunosorbent assay was used to measure the peripheral blood levels of IL-4, leukotriene (LTE)-4, and INF-gamma before and after treatment. RESULTS: After treatment, the mRNA expression levels of IL-4 and CysLTR1 were down-regulated (P< 0.01) and the mRNA expression levels of IFN-gamma were up-regulated (P < 0.05) in the Chinese medication and Western medication groups; no significant difference was found between the two groups. In the Chinese medication group, IL-4 blood level was decreased and it was significantly different from that in the Western medication group (P < 0.05); there was also a significant increase in IFN-gamma blood levels after treatment with Chinese medication (P < 0.05). There were no significant differences in LTE-4 blood levels between the two groups before and after treatment (P > 0.05). CONCLUSION: Chinese medication has a regulatory effect on leukotriene receptor gene expression and the imbalance of Th1/Th2 immune cells during asthma attacks in pediatric patients.

Comparable outcome of alternative donor and matched sibling donor hematopoietic stem cell transplant for children with acute lymphoblastic leukemia in first or second remission using alemtuzumab in a myeloablative conditioning regimen.

HLA-matched sibling donor (MSD) stem cell transplantation can cure>60% of pediatric patients with acute lymphoblastic leukemia (ALL), but <30% of patients will have a sibling donor. Alternative donor (AD) transplantation can be curative but has a higher risk of graft-versus-host disease (GVHD). The addition of alemtuzumab (Campath 1-H) to AD transplants produces in vivo T cell depletion, which may reduce the risk for GVHD. We now report the outcome for 83 children with ALL (41 MSD, 42 AD) undergoing stem cell transplantation in first or second complete remission. All patients received myeloablative conditioning, including cyclophosphamide, cytarabine arabinoside, and total-body irradiation, with alemtuzumab administered to AD recipients. GVHD prophylaxis consisted of a calcineurin inhibitor with either short-course methotrexate or prednisone. Disease-free survival (DFS) for MSD recipients was 72.3% (95% confidence interval [CI], 55.4%-83.6%) versus 62.4% (95% CI, 45.2%-75.4%) for AD recipients. The 100-day mortality was 7.1% in the AD group and 2.4% in the MSD group. Relapse rates were identical (24%). Treatment-related mortality, principally viral infection, explained the difference in survival. For children undergoing stem cell transplantation (SCT) from alternative donors, alemtuzumab with a myeloablative conditioning regimen resulted in DFS comparable to MSD.

Sensitivity of RECQL4-deficient fibroblasts from Rothmund-Thomson syndrome patients to genotoxic agents.

RECQ helicase protein-like 4 (RECQL4) is a member of the human RECQ family of DNA helicases. Two-thirds of patients with Rothmund-Thomson syndrome (RTS) carry biallelic inactivating mutations in the RECQL4 gene. RTS is an autosomal recessive disorder characterized by poikiloderma, sparse hair, small stature, skeletal abnormalities, cataracts, and an increased risk of cancer. Mutations in two other RECQ helicases, BLM and WRN, are responsible for the cancer predisposition conditions Bloom and Werner syndromes, respectively. Previous studies have shown that BLM and WRN-deficient cells demonstrate increased sensitivity to hydroxyurea (HU), camptothecin (CPT), and 4-nitroquinoline 1-oxide (4NQO). Little is known about the sensitivity of RECQL4-deficient cells to these and other genotoxic agents. The purpose of this study was to determine if RTS cells display any distinct cellular phenotypes in response to DNA damaging agents or replication blocks that could provide insight into the molecular function of the RECQL4 protein. Our results show that primary fibroblasts from RTS patients carrying two deleterious RECQL4 mutations, compared to wild type (WT) fibroblasts, have increased sensitivity to HU, CPT, and doxorubicin (DOX), modest sensitivity to other DNA damaging agents including ultraviolet (UV) irradiation, ionizing radiation (IR), and cisplatin (CDDP), and relative resistance to 4NQO. The RECQ family of DNA helicases has been implicated in the regulation of DNA replication, recombination, and repair. Because HU, CPT, and DOX exert their effects primarily during S phase, these results support a greater role for the RECQL4 protein in DNA replication as opposed to repair of exogenous damage.

Combination of ZD55-MnSOD therapy with 5-FU enhances antitumor efficacy in colorectal cancer.

PURPOSE: ZD55-MnSOD is an E1B 55 kDa-deleted replication-competent adenovirus and armed with the therapeutic gene MnSOD. The expression of the therapeutic gene MnSOD increases with the selective replication of the oncolytic adenovirus (ZD55) so that ZD55-MnSOD has more significant activity than the replicate defective adenovirus Ad-MnSOD in vitro and in vivo. The tumor cannot be completely eradicated only with ZD55-MnSOD, although ZD55-MnSOD has obvious antitumor activity. 5-fluorouracil (5-FU) is still the most effective adjuvant therapy for patients with colorectal cancer. METHODS: We reasoned that combined treatment of cancer cells with ZD55-MnSOD and 5-FU might have a synergistic effect. In vitro experiments with SW620 colorectal carcinoma cell line demonstrated that it was sensitive to ZD55-MnSOD, especially most sensitive to ZD55-MnSOD plus 5-FU treatment. Treatment with both ZD55-MnSOD and 5-FU could induce more significant apoptosis in cancer cells compared with ZD55-MnSOD or 5-FU alone, respectively. A better antitumor activity was observed by ZD55-MnSOD plus 5-fluorouracil (5-FU) treatment. Tumor growth was greatly inhibited by this combined treatment, and animal survival time increased. CONCLUSION: These results show that, by using the combination therapies, a significant decrease in tumor mass can be achieved, which suggest that ZD55-MnSOD in combination with 5-FU may have potential clinical implications.

A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation derived from the effects of terfenadine, cisapride and E-4031 in the conscious chronic av node--ablated, His bundle-paced dog.

INTRODUCTION: Terfenadine, cisapride, and E-4031, three drugs that prolong ventricular repolarization, were selected to evaluate the sensitivity of the conscious chronic atrioventricular node--ablated, His bundle-paced Dog for defining drug induced cardiac repolarization prolongation. A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation was generated from these data. METHODS: Three male beagle dogs underwent radiofrequency AV nodal ablation, and placement of a His bundle-pacing lead and programmable pacemaker under anesthesia. Each dog was restrained in a sling for a series of increasing dose infusions of each drug while maintained at a constant heart rate of 80 beats/min. RT interval, a surrogate for QT interval in His bundle-paced dogs, was recorded throughout the experiment. RESULTS: E-4031 induced a statistically significant RT prolongation at the highest three doses. Cisapride resulted in a dose-dependent increase in RT interval, which was statistically significant at the two highest doses. Terfenadine induced a dose-dependent RT interval prolongation with a statistically significant change occurring only at the highest dose. The relationship between drug concentration and RT interval change was described by a sigmoid E(max) model with an effect site. Maximum RT change (E(max)), free drug concentration at half of the maximum effect (EC(50)), and free drug concentration associated with a 10 ms RT prolongation (EC(10 ms)) were estimated. A linear correlation between EC(10 ms) and HERG IC(50) values was identified. DISCUSSION: The conscious dog with His bundle-pacing detects delayed cardiac repolarization related to I(Kr) inhibition, and detects repolarization change induced by drugs with activity at multiple ion channels. A clinically relevant sensitivity and a linear correlation with in vitro HERG data make the conscious His bundle-paced dog a valuable tool for detecting repolarization effect of new chemical entities.

[A brief research on the life of Li Lian, the author of Yi shi (Medical history) of the Ming dynasty, and his works].

The dates of birth and death of Li Lian, a medical historian and literati of the Ming dynasty and the writing of Yi shi (Medical History) are studied. Based on the Ming scholar Chen Bo's epitaph and Li Lian's own essays and poets, Li's date of birth is settled as 1488, that of his death, 1566. Thus, the mistakes and missing of these dates of the entry "Li Lian" appeared in three biographical dictionaries are corrected. The family background of Li Lian, a descendant of the "Jin Zhong Li", a family pediatrician of over 200 years, are studied. Comprehensive analysis is made on the date of compilation of Li Lian's Medical History based on the prefaces, epitaphs of Yang Lian and Wang Ao, both Ming officials, and inferred to be around 1529 - 1530.