Factor For Effective Treatment Research Articles

Abstract 6209: O6-methylguanine as the junction of MGMT and PARP1-mediated repair pathways

Abstract Temozolomide is the first-choice DNA alkylating agent and has been commonly used in oncology over the last several decades. The cytotoxicity that temozolomide elicits through the methylation of guanine and adenine residues often becomes the limiting factor in effective treatment. Despite growing evidence of dysregulated alkylating DNA damage repair as a driving force of genome instability leading to cancer, neurological diseases, and premature aging, little is currently known about the coordinated role of PARP1 and MGMT (O6-methylguanine methyltransferase) enzymes in the repair of temozolomide-induced methylated DNA lesions. A major PARP1 function in DNA damage is facilitation of repair of the methylated DNA lesions, N6-methyladenine and N7-methylguanine, via base excision repair (BER); while MGMT restores guanine in O6-methylguanine (O6meG), the most cytotoxic adduct, by a one-step catalysis. It is generally thought that BER and MGMT represent two distinct mechanisms for removing DNA damage induced by alkylating agents; however, using a number of advanced cell-free and cell-based approaches, we provided evidence for direct (DNA-independent) and indirect (through PARylation) interaction between PARP1 and MGMT and demonstrated a functional crosstalk between these repair pathways. Particularly, O6meG repair activity is increased once PARP1 PARylates MGMT. Further, longer (more clinically relevant) exposure to temozolomide induced stronger MGMT PARylation in cells, indicating that the PARP1-MGMT interaction is important for enhanced O6meG repair and cell survival. As PARP1-MGMT complex forms in a variety of cancer cell types, our findings have strong implications for the development of an effective cancer therapy for cells dependent on PARP1 and MGMT mediated DNA repair. Citation Format: Jodie D. Cropper, Dauren S. Alimbetov, Kevin T. Brown, Andrew Robles, Rostislav I. Likhotvorik, James T. Guerra, Yidong Chen, Youngho Kwon, Raushan T. Kurmasheva. O6-methylguanine as the junction of MGMT and PARP1-mediated repair pathways. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6209.

Molecular Docking and Molecular Dynamics Studies Reveal Secretory Proteins as Novel Targets of Temozolomide in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is a tumor of glial origin and is the most malignant, aggressive and prevalent type, with the highest mortality rate in adult brain cancer. Surgical resection of the tumor followed by Temozolomide (TMZ) therapy is currently available, but the development of resistance to TMZ is a common limiting factor in effective treatment. The present study investigated the potential interactions of TMZ with several secretory proteins involved in various molecular and cellular processes in GBM. Automated docking studies were performed using AutoDock 4.2, which showed an encouraging binding affinity of TMZ towards all targeted proteins, with the strongest interaction and binding affinity with GDF1 and SLIT1, followed by NPTX1, CREG2 and SERPINI, among the selected proteins. Molecular dynamics (MD) simulations of protein-ligand complexes were performed via CABS-flex V2.0 and the iMOD server to evaluate the root-mean-square fluctuations (RMSFs) and measure protein stability, respectively. The results showed that docked models were more flexible and stable with TMZ, suggesting that it may be able to target putative proteins implicated in gliomagenesis that may impact radioresistance. However, additional in vitro and in vivo investigations can ascertain the potential of the selected proteins to serve as novel targets for TMZ for GBM treatment.

Type V collagen alpha 1 chain promotes the malignancy of glioblastoma through PPRC1-ESM1 axis activation and extracellular matrix remodeling

Glioblastoma (GBM) is a fatal cancer. Existing therapies do not have significant efficacy for GBM patients. Previous studies have shown that the collagen family is involved in the regulation of the extracellular environment of cancer cells, and these conditions could become an important factor for effective treatment. Therefore, we screened various collagen types and observed that the type V collagen α1 chain (COL5A1) gene plays a pivotal role in GBM. We further examined whether the overexpression of COL5A1 is common in mesenchymal subtypes and is related to the survival rate of GBM patients through several in silico cohorts. In addition, our cohort also showed a consistent trend in COL5A1 protein levels. Most importantly, we validated the cell mobility, metastatic ability and actin polymerization status caused by COL5A1 with two-way models. Based on these results, we established a transcriptomics dataset based on COL5A1. Moreover, PPRC1, GK and ESM1 were predicted by ingenuity pathway analysis (IPA) to be transcription factors or to participate downstream. We investigated the involvement of COL5A1 in extracellular remodeling and the regulation of actin filaments in the metastasis of GBM. Our results indicate that the COL5A1−PPRC1−ESM1 axis may represent a novel therapeutic target in GBM.

Efficacy and safety of polymyxin B in carbapenem-resistant gram-negative organisms infections

ObjectiveTo investigate how to use polymyxin B rationally in order to produce the best efficacy and safety in patients with carbapenem-resistant gram-negative organisms (CRO) infection.MethodsThe clinical characteristics and microbiological results of 181 patients caused by CRO infection treated with polymyxin B in the First Affiliated Hospital from July 2018 to May 2020 were retrospectively analyzed. The bacterial clearance rate, clinical efficacy, adverse drug reactions and 28 days mortality were evaluated.ResultsThe overall effective rate of 181 patients was 49.72%, the total bacterial clearance rate was 42.0%, and the 28 day all-cause mortality rate was 59.1%. The effective rate and bacterial clearance rate in the group of less than 24 h from the isolation of CRO to the use of polymyxin B were significantly higher than those in the group of more than 24 h. Logistics multivariate regression analysis showed that the predictive factors for effective treatment of CRO with polymyxin B were APACHEII score, duration of polymyxin B treatment, combination of polymyxin B and other antibiotics, and bacterial clearance. 17 cases (9.36%) of acute kidney injury were considered as polymyxin B nephrotoxicity and 4 cases (23.5%) recovered after polymyxin B withdrawal. After 14 days of polymyxin B use, 3 cases of polymyxin B resistance appeared, and there were 2 cases of polymyxin B resistance in the daily dose 1.5 mg/kg/day group.ConclusionFor CRO infection, the treatment of polymyxin B should be early, combined, optimal dose and duration of treatment, which can achieve better clinical efficacy and microbial reactions, and reduce the adverse reactions and drug resistance.

Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months. Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy. Temozolomide (TMZ) is the first-choice chemotherapeutic agent in GBM; however, the development of resistance to TMZ often becomes the limiting factor in effective treatment. While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance, many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathways, autophagy, epigenetic modifications, microRNAs, and extracellular vesicle production. This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance.

Correlation between radiographic sagittal alignment, range of motion, muscle strength, and quality of life in adults with spinal deformities.

[Purpose] The aims of this study were to examine the relationship between range of motion/muscle strength of the spine and lower limbs with 1) radiographic sagittal alignment and 2) quality of life of participants with spinal deformities to adequately target the appropriate factors for effective treatment. [Participants and Methods] This study used an observational cross-sectional correlational design. Participants with spinal deformities and low back pain were recruited for the study. The dependent variables were range of motion/muscle strength of the spine and lower limbs, sagittal alignment, and quality of life. [Results] Regarding alignment, significant correlations were found between hip extension range of motion and sagittal vertebral axis; between occiput-to-wall distance and thoracolumbar kyphosis; and between back extensor endurance and pelvic tilt and pelvic incidence-lumbar lordosis mismatch, also known as the calculated (pelvic incidence) minus (lumbar lordosis) value. With regards to quality of life, significant correlations were found between pain-related disorders and lumbar spine range of motion, and between gait disturbance and knee and hip extension ranges of motion. [Conclusion] Our findings suggest that these factors should be targeted for assessment and treatment of adults with spinal deformities.

Applications of Machine Learning in Fatty Live Disease Prediction.

: Fatty liver disease (FLD) is considered the most prevalent form of chronic liver disease worldwide. The prediction of fatty liver disease is an important factor for effective treatment and reduce serious health consequences. We, therefore construct a prediction model based on machine learning algorithms. A dataset was developed with ten attributes that included 994 liver patients in which 533 patients were females and others were male. Random Forest (RF), Support Vector Machine (SVM), Artificial Neural Network (ANN), and Logistic Regression (RF) data mining technique with 10-fold cross-validation was used in the proposed model for the prediction of fatty liver disease. The performances were evaluated with accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. In this proposed model, logistic regression technique provides a better result (Accuracy 76.30%, sensitivity 74.10%, and specificity 64.90%) among all other techniques. This study demonstrates that machine learning models particularly logistic regression model provides a higher accurate prediction for fatty liver diseases based on medical data from electronic medical. This model can be used as a valuable tool for clinical decision making.

Analysis of factors influencing treatment outcomes of halo nevus

Objective To investigate clinical characteristics of halo nevus, and to explore factors influencing its treatment outcome. Methods A prospective study was conducted in 250 patients with halo nevus from February 2016 to November 2016 to analyze the factors influencing treatment outcomes. Results There were a total of 293 lesions in the 250 patients, including 219 (87.6%) patients with solitary lesions and 31 (12.4%) with multiple lesions. Among these lesions, 154 (52.6%) occurred on the trunk, and 127 (43.3%) occurred on the face and neck. The diameters of the lesions ranged from 5 mm to 20 mm. Not all the halo nevi spontaneously subsided in 248 (99.2%) of the 250 patients, and 122 (48.8%) of the patients were complicated by vitiligo. Univariate logistic regression analysis showed that age, number of lesions, complication by vitiligo and therapeutic methods were factors influencing the treatment outcome of halo nevus. Multivariate logistic regression analysis revealed that age ≤ 19 years or ≥ 40 years, disease duration > 1 year, solitary lesions, absence of vitiligo and nevus removal were independent factors for effective treatment of halo nevus. Conclusions Most of halo nevi cannot subside spontaneously. CO2 laser or surgical excision combined with externally applied agents is effective for the treatment of halo nevus. For halo nevus patients without vitiligo, it′s preferred to remove the halo nevi. For halo nevus patients with vitiligo, nevi should be removed in the stable stage of vitiligo. Relapse often occurs in patients with multiple halo nevi or large-area vitiligo, so close follow-up is needed. Key words: Vitiligo; Treatment outcome; Nevus; Root cause analysis; Halo nevus

Eureka!!! Sewing to Moonbeams

A thermoreversible nanopolymer enables a new method of creating sutureless vascular-vascular connections without trauma to the tissue.

The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth

Aims: To describe perinatal factors associated with later morbidity among extremely preterm children at 30 months of age corrected for prematurity. Population: Of 308 surviving children born at ⩽25 weeks...

Behavioral Interventions: Effective and Adaptable for the Treatment of Pregnant Cocaine-Dependent Women

We examined the effectiveness of behavioral interventions in the treatment of cocaine-dependent pregnant women. The study was carried out in four stages: (1) the unique needs of substance-abusing women were examined to identify effective treatment factors, (2) behavioral interventions found to be effective in other cocaine-dependent populations were identified, (3) strategies from these two elements were combined in an ongoing treatment-study of cocaine-dependent pregnant women (the Pregnancy Project), and (4) outcome data in a group of 35 women who participated in the Pregnancy Project were examined. The rate of retention in treatment was high, as was compliance with prenatal care for those women who remained in treatment. A high rate of compliance with prenatal care was associated with good perinatal outcome. There was a relatively high rate of cocaine abstinence during treatment, at birth, and in the early period following birth of the baby. Many of the patients especially appreciated the individually based, self-empowering aspects of the behavioral counseling interventions. We concluded that behavioral interventions, within a woman-friendly treatment program, are an important treatment option to consider.

Factors attenuating growth promoting effect of growth hormone therapy for Turner's syndrome.

Nine patients with Turner's syndrome aged 7 to 13 years were treated with recombinant human growth hormone (hGH) at a dose of 0.5 or 1.0 U/kg/w for 1 year. In five of them the growth rate was accelerated from 3.3 +/- 0.6 (SD) to 6.5 +/- 0.5 cm/y (group A), whereas 4 had a reduced rate of growth promotion (3.4 +/- 0.3 to 4.6 +/- 0.4 cm/y) (group B). Analysis of factors affecting growth response to hGH revealed 3 major parameters: (1) age of initiating hGH therapy (A, 9.5 +/- 2.1 vs B, 13.3 +/- 0.4 yrs, P less than 0.01), (2) basal LH (A, 3.2 +/- 2.4 vs, B, 44.9 +/- 17.8 mIU/ml, P less than 0.001) and FSH levels (A, 14.7 +/- 15.4 vs B, 131 +/- 49 mIU/ml; P less than 0.01) and (3) somatomedin-C (SM-C) producing capacity: coefficient of correlation to growth rate, r = 0.80, P less than 0.01). No remarkable changes were observed in the results of glucose tolerance, thyroid state, calcium metabolism and liver function tests. These results indicate that patient's age is the most crucial factor in effective treatment with hGH, and in adolescent girls, gonadal failure with a limited increase in SM-C production attenuates the growth promoting potency of hGH.