The independent and combined effects of selected risk factors and Arg399Gln XRCC1 polymorphism in the risk of colorectal cancer among an Iranian population.

Background: Several environmental and genetic factors have contributed to the development of colorectal cancer (CRC). We aimed to investigate the independent and combined effects of some selected risk factors and Arg399Gln XRCC1 polymorphism on CRC. Methods: A total of 180 patients with CRC and 160 healthy individuals who were matched for sex, age, and place of residence (Northeast of Iran) participated in this case-control study. Before collecting blood samples and filling out questionnaires, a written consent form was obtained from all participants. Genotypes were determined by RFLP-PCR. The comparison of genotype and allele frequencies was performed using p value based on the results of chi-square test. The odds ratios (OR) and 95% confidence intervals (CI) were calculated by employing a logistic regression model. All statistical calculations were performed using SPSS. Each of the 2- sided p values less than 0.05 were considered statistically significant. Results: The level of literacy, physical activity, consumption of vegetables and fruits, and tea intake of the patients were significantly lower than healthy individuals, but gastrointestinal disorders, family history of cancer, BMI, and fast food consumption were significantly higher in cases than in controls. No significant difference was observed between the 2 groups regarding smoking, opioid addiction, alcohol consumption, diet, fish consumption, and liquid intake, using the kitchen hood, diabetes, and cardiovascular disease. Arg/Gln + Gln/Gln and Arg/Gln genotypes were involved in increased CRC risk (The crude OR =1.781 with a 95% CI of 1.156-2.744 and OR = 1.690 with a 95% CI of 0.787-3.630). Also, Gln/Gln genotype was more frequent in CRC group than in control group. However, none of the risk factors interacted with polymorphism, and thus did not have an effect on CRC. Conclusion: Some risk factors, such as reducing the consumption of vegetables and fruits or reducing physical activity as well as polymorphism of the XRCC1 Arg399Gln alone, increase the risk of CRC, but they do not interact with each other.

DMRFusion: A differentially methylated region detection tool based on the ranked fusion method.

DNA methylation is an important epigenetic modification involved in many biological processes and diseases. Computational analysis of differentially methylated regions (DMRs) could explore the underlying reasons of methylation. DMRFusion is presented as a useful tool for comprehensive DNA methylation analysis of DMRs on methylation sequencing data. This tool is designed base on the integration of several ranking methods; Information gain, Between versus within Class scatter ratio, Fisher ratio, Z-score and Welch's t-test. In this study, DMRFusion on reduced representation bisulfite sequencing (RRBS) data in chronic lymphocytic leukemia cancer displayed 30 nominated regions and CpG sites with a maximum methylation difference detected in the hypermethylation DMRs. We realized that DMRFusion is able to process methylation sequencing data in an efficient and accurate manner and to provide annotation and visualization for DMRs with high fold difference score (p-value and FDR<0.05 and type I error: 0.04).

A potent multifunctional ZIF-8 nanoplatform developed for colorectal cancer therapy by triple-delivery of chemo/radio/targeted therapy agents.

BACKGROUND: Multimodal cancer therapy has garnered significant interest due to its ability to target tumor cells from various perspectives. The advancement of novel nano-delivery platforms represents a promising approach for improving treatment effectiveness while minimizing detrimental effects on healthy tissues. METHODS: This study aimed to develop a multifunctional nano-delivery system capable of simultaneously delivering an anti-cancer drug, a radiosensitizer agent, and a targeting moiety (three-in-one) for the triple combination therapy of colorectal cancer (CRC). This unique nano-platform, called Apt-PEG-DOX/ZIF-8@GQD, encapsulated both doxorubicin (DOX) and graphene quantum dots (GQDs) within the zeolitic imidazolate framework-8 (ZIF-8). To enhance the safety and anti-cancer potential of the platform, heterobifunctional polyethylene glycol (PEG) and an epithelial cell adhesion molecule (EpCAM) aptamer were conjugated with the system, resulting in the formation of targeted Apt-PEG-DOX/ZIF-8@GQD NPs. The physical and chemical characteristics of Apt-PEG-DOX/ZIF-8@GQD were thoroughly examined, and its therapeutic efficacy was evaluated in combination with radiotherapy (RT) against both EpCAM-positive HT-29 and EpCAM-negative CHO cells. Furthermore, the potential of Apt-PEG-DOX/ZIF-8@GQD as a tumor-specific, radio-enhancing, non-toxic, and controllable delivery system for in vivo cancer treatment was explored using immunocompromised C57BL/6 mice bearing human HT-29 tumors. RESULTS: The large surface area of ZIF-8 (1013 m2 g-1) enabled successful loading of DOX with an encapsulation efficiency of approximately ∼90%. The synthesis of Apt-PEG-DOX/ZIF-8@GQD resulted in uniform particles with an average diameter of 100 nm. This targeted platform exhibited rapid decomposition under acidic conditions, facilitating an on-demand release of DOX after endosomal escape. In vitro experiments revealed that the biocompatible nano-platform induced selective toxicity in HT-29 cells by enhancing X-ray absorption. Moreover, in vivo experiments demonstrated that the therapeutic efficacy of Apt-PEG-ZIF-8/DOX@GQD against HT-29 tumors was enhanced through the synergistic effects of chemotherapy, radiotherapy, and targeted therapy, with minimal side effects. CONCLUSION: The combination of Apt-PEG-DOX/ZIF-8@GQD with RT as a multimodal therapy approach demonstrated promising potential for the targeted treatment of CRC and enhancing therapeutic effectiveness. The co-delivery of DOX and GQD using this nano-platform holds great promise for improving the outcome of CRC treatment.

Safety evaluation of the trastuzumab biosimilar in Iranian women with HER2-positive breast cancer undergoing adjuvant chemotherapy: a post-marketing surveillance.

BACKGROUND: Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). This post-marketing surveillance evaluates the safety of a trastuzumab biosimilar (AryoTrust), produced by AryoGen Co. Iran in Iranian women with HER2-positive non-metastatic breast cancer (BC). RESEARCH DESIGN AND METHODS: The patients who had undergone adjuvant chemotherapy regimens received trastuzumab every 3 weeks for nine cycles. The study started in February 2017 and finished in August 2022. Data regarding safety were collected using booklets and then analyzed. RESULTS: A total of 597 women with a mean ±SD age of 48.13 ± 10.18 years underwent 5,313 injection cycles. They received pre-study chemotherapies consisting of anthracyclines, taxanes, both, or other medications in 6.70, 7.20, 82.41, and 2.01% of the cases, respectively. One hundred and thirty-nine patients experienced at least one adverse event (AE). The most common AEs were decreased ejection fraction (EF, 5.7%), peripheral neuropathy (5.36%), and nausea (5.19%). Meningioma was the only life-threatening serious AE. Furthermore, bone pain and infusion-related reactions were the two most common grade three AEs. Nevertheless, the mean EF of patients did not change notably during the study. CONCLUSIONS: The results demonstrate that this trastuzumab biosimilar is a generally well tolerated and safe treatment for HER2-positive BC. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT06021379.

Flow cytometric assessment of DNA double-strand break and repair kinetics in prediction of intrinsic radiosensitivity.

Objectives: To enhance the efficiency of radiotherapy (RT), implementation of individual-based treatment is essential. In this way, determining individual intrinsic radiosensitivity (IRS) can be useful to achieve minimal adverse effects of RT. The present study aimed to identify IRS of breast cancer (BC) patients through determination of radiation-induced DNA double-strand breaks (DSBs), repair kinetics, and acute normal tissue complications induced by RT. Materials and Methods: DSBs induction and its repair kinetics in 50 BC patients' lymphocytes were analyzed by flow cytometric analysis of H2AX Ser-139 phosphorylation at 30 min, 3 and 24 hr after in vitro irradiation. In vivo skin dosimetry was done by GAFChromic films and acute skin toxicity was scored by radiation oncologists according to the criteria of Radiation Therapy and Oncology Group (RTOG) in all patients with similar prescribed treatment. Results: The average surface dose for patients ranged from 0.92 to 1.9 Gy and correlation analysis showed no significant relationship with weekly acute skin reactions. Formation of γH2AX after 30 min, slope of dose-response curve and repair kinetics of DSBs after 3 and 24 hr (intrinsic radiosensitivity) were significantly correlated with the RTOG scores following irradiation (clinical radiosensitivity) (r=0.48 and P-value<0.0001, r=0.72 and P-value<0.0001, r=0.48 and P-value<0.001, and finally r=0.53 and P-value<0.001, respectively; (using Pearson's correlation test). Conclusion: Flow cytometric analysis of DNA DSBs by γH2AX measurement has the potential to be developed into a clinical predictor for identifying the overreactor patients prior to RT. Our result suggests that the slope-related quantity based on the linear pattern of the dose-response curve has the merit to predict overreactor patients with a sensitivity of 89% and a specificity of 94%.

Radiobiological comparison between Cobalt-60 and Iridium-192 high-dose-rate brachytherapy sources: Part I-cervical cancer.

PURPOSE: This study aimed to compare the biological effective doses (BEDs) to clinical target volume (CTV) and organs at risk (OARs) for cervical cancer patients treated with high-dose-rate (HDR) Iridium-192 (192 Ir) or Cobalt-60 (60 Co) brachytherapy (BT) boost and to determine if the radiobiological differences between the two isotopes are clinically relevant. METHODS: Considering all radiosensitivity parameters and their reported variations, the BEDs to CTV and OARs during HDR 60 Co/192 Ir BT boost were evaluated at the voxel level. The anatomical differences between individuals were also taken into account by retrospectively considering 25 cervical cancer patients. The intrafraction repair, proliferation, hypoxia-induced radiosensitivity heterogeneity, relative biological effectiveness (RBE), and source aging dose-rate variation were also taken into account. The comparisons in CTV were performed based on equivalent uniform BED (EUBED). RESULTS: Considering nominal parameters with no RBE correction, the CTV EUBEDs were almost similar with a median ratio of ∼1.00 (p < 0.00001), whereas RBE correction resulted in 3.9%-5.5% (p = 0.005, median = 4.8%) decrease for 60 Co with respect to 192 Ir. For OARs, the median values of D2cc (in EQD23 ) for 60 Co were lower than that of 192 Ir up to 9.2% and 11.3% (p < 0.00001) for nominal parameters and fast repair conditions, respectively. In addition, for a nominal value (reported range) of radiosensitive parameters, the CTV EUBED differences of up to 6% (5%-10%) were assessed for HDR-BT component. CONCLUSION: The RBE values are the most important cause of discrepancies between the two sources. By comparing BED/EUBEDs to CTV and OARs between 60 Co and 192 Ir sources, this numerical study suggests that a dose escalation to ∼4% is feasible and safe while sparing well the surrounding normal tissues. This 4% dose escalation should be benchmarked with clinical evidences (such as the results of clinical trials) before it can be used in clinical practice.

Polymorphisms of XRCC3 and XRCC7 and Colorectal Cancer Risk in Khorasan Razavi Province, Iran.

Background: Colorectal cancer (CRC) is highly prevalent cancer, which should be genetically studied among different peoples of the world. Objective: The aim of this study was to evaluate the effect of XRCC3T241M, XRCC3 A17893G and, for the first time, XRCC7 I3434T polymorphisms on CRC risk in Khorasan Razavi Province, Iran. Materials and Methods: In this case-control study, 180 patients with CRC and 160 sex- and age-matched healthy controls were studied. Genotypes were determined by RFLP-PCR and ARMS-PCR. Results: The incidence of CRC was observed to be significantly more in a heterozygous XRCC3 C/T genotype than in the CC genotype (OR 2.210, 95% CI 1.073-4.548, p=0.030). In the case of the XRCC7 I3434T polymorphism, CRC risk was significantly (4.3 fold) higher in I/T+T/T variant subjects compared to the I/I genotype (OR 4.394, 95% CI 2.721-7.096, p=0.000). Moreover, the XRCC3 A17893G polymorphism did not correlate with CRC. In addition, there was no significant difference between the distribution of genotypes of the three studied polymorphisms with demographic and clinicopathological features in the CRC patients. Conclusion: Polymorphisms of XRRC3 and XRCC7 genes are involved in CRC and should be considered as a risk factor.

Bax/Bcl-2 expression ratio in prediction of response to breast cancer radiotherapy.

OBJECTIVES: Radiotherapy is one of the most effective modalities of cancer therapy, but clinical responses of individual patients varies considerably. To enhance treatment efficiency it is essential to implement an individual-based treatment. The aim of present study was to identify the mechanism of intrinsic apoptosis pathway on radiosensitivity and normal tissue complications caused by the radiotherapy. MATERIALS AND METHODS: Peripheral blood mononuclear cells from ten breast cancer patients were exposed to 6MV X-rays to deliver 1 and 2 Gy. Expression levels of Bax, Bcl-2, and Bax/Bcl-2 ratio were examined by relative quantitative RT-PCR. All the patients received similar tangential irradiation of the whole breast and conventional fractionation. Skin dosimetry was done by GAFChromic EBT-3 film and clinical radiosensitivity was determined using the acute reactions to radiotherapy of the skin according to Radiation Therapy Oncology Group score. All statistical analyses were performed using GraphPad Prism, version 7.01. RESULTS: In the in-vitro experiment, Bax and Bax/Bcl-2 ratios were significantly increased with 1 and 2 Gy doses (P<0.001 and P<0.0001, respectively). Herein, the notable result was a significant correlation between dose-response curve slope (as an in-vitro radiosensitivity index) and acute skin toxicity score following irradiation (as a clinical radiosensitivity index). There was no significant relationship between skin dose and reactions (P>0.05 for all patients). CONCLUSION: Significant correlation between Bax/Bcl-2 ratio determined before radiation therapy and clinical response in the patients, can be used as a biomarker to identify radiosensitive individuals. However, further studies are required to validate radiation-induced apoptotic biomarkers.

A revised dosimetric characterization of 60Co BEBIG source: From single-source data to clinical dose distribution.

PURPOSE: Although the dosimetric characterization of 60Co BEBIG source can be found in several literature studies, the data sets show major discrepancies and the lack of uncertainty analyses. This study tried to determine an accurate dosimetric data set for this source using Monte Carlo (MC) simulations along with detailed uncertainty analysis. To explore how different dosimetric data sets can make changes in practical situations, clinical dose distributions based on our results were compared with the dose distributions derived from Granero et al. and consensus data sets. METHODS AND MATERIALS: The MC simulations were performed with Monte Carlo N-Particle eXtended code (MCNPX) version 2.6.0 and the TG-43 parameters were estimated adhering to the American Association of Physicists in Medicine (AAPM) and European SocieTy for Radiotherapy and Oncology (ESTRO) 229 report. The dose rate distributions for single-source and two typical clinical cases, including one intracavitary and one interstitial, were calculated using an in-house code on the basis of the TG-43 formalism. RESULTS: The total uncertainties for water dose rate on source transverse axis at 1 cm and 5 cm, air kerma strength, and dose rate constant were evaluated to be 0.10%, 0.09%, 0.04%, and 0.11%, respectively. Meaningful differences were found for the interstitial case in which 22% of clinical target volume (CTV) showed differences from ±1% to ±10% or even larger. CONCLUSIONS: The MC uncertainty was derived about 16 times smaller than the typical MC component stated in TG-138, partly because of large number of histories and partly because the spectra of 60Co and also its photons' attenuation coefficients are adequately accurate. The results showed that in the clinical situations, the applicator geometry and the superposition of single-source dose distributions can reduce the differences observed between several data sets.