Mechanisms of Accumulation and Biological Consequences of Polynuclear Platinum Compounds

The novel trinuclear complex, BBR3464 has undergone Phase II clinical trials and been shown to have greater cytotoxicity and cellular uptake than clinical anticancer platinum drugs such as cisplatin, oxaliplatin and carboplatin. The clinical efficacy of cisplatin, oxaliplatin and carboplatin is limited due to acquired resistance and dose limiting side effects. The three major pharmacological factors contributing to the intrinsic cytotoxicity of, and cellular resistance to, platinum drugs are (i) cellular uptake and efflux of platinum; (ii) the frequency and nature of Pt-DNA adducts; and (iii) deactivating metabolic reactions with sulfur-containing nucleophiles. Since decreased cellular uptake of platinum drugs is a common feature of resistant cells, investigating mechanisms of cellular uptake and efflux is of a great importance in the field of cancer biology. The mechanisms of uptake of Platinum drugs are diverse and complex. Similar to cisplatin, BBR3464 v as shown to use copper transporter hCTR1 and ATP7B for influx and efflux respectively. Organic cation transporters (OCT) did not play an important role in BBR3464 cellular uptake, however, desipramine, an OCT inhibitor had synergistic effects on platinun drugs-induced cytotoxicity. This effect is of high clinical relevance since desipramine, an antidepressant, is being used in prostate cancer patients for the treatment of neuropathic pain. The mechanism of this interaction was further addressed.Due to the high charge of BBR3464, studies have shown that its DNA binding has a non-covalent component. To examine the non covalent component, labile chloride leaving groups were replaced by non labile ammonia groups. Besides having higher cellular accumulation than BBR3464, the non covalent analogue, AH78, had a different mechanism of action in cells and showed promising results in vivo. These data confirm the validity of searching for new chemotypes outside the cisplatin structural class to aid in the treatment of recurrent, cisplatin-resistant cancers

18F-FDG PET Predicts Hematologic Toxicity in Patients with Locally Advanced Anal Cancer Treated With Chemoradiation

Purpose: Hematologic toxicity (HT) during chemoradiation therapy (CRT) for anal cancer can lead to treatment breaks that compromise efficacy. We hypothesized that CRT-induced HT correlates with changes in active bone marrow (ABM) characterized by pre-/post-CRT positron emission tomography (PET)/computed tomography. Methods and materials: Data from 36 patients with anal cancer who were treated with 18F-fluorodeoxyglucose PET/computed tomography scans 2 weeks before and 6 to 16 weeks after CRT were analyzed. Complete blood counts with differential within 2 weeks from, weekly during, and 2 week after treatment were obtained. HT was defined as baseline complete blood count change to nadir and posttreatment recovery. Total bone marrow was segmented into 2 subregions: lumbosacral (LS) pelvis (L5 vertebrae, sacrum, and coccyx) and lower pelvis (LP) (ilium, femoral head/neck, and greater and lesser trochanter). PET ABM was characterized as the volume having standard uptake value (SUV) greater than the mean uptake of unirradiated extrapelvic bone marrow. PET variables of pre-/post-CRT and HT predictors were analyzed by linear regression. Results: Average pelvic ABM was significantly reduced from 52% to 41% in pre- to post-CRT PET scans for all patients (P = .0012). Regional analysis indicated significant post-CRT reduction of LS-ABM (P 50 Gy) in terms of acute hematologic ΔWBC (P = .021) and ΔANC(P = .028). HT increased with increasing volume of ABM receiving 40 Gy. The results also suggest that ABM V40 Gy ≤ 20% to 25% may significantly reduce the risk of HT. Conclusions: HT was significantly associated with ΔABM in patients with anal cancer who were treated with CRT. LS-ABM was a robust surrogate for evaluating CRT-induced HT. Our results suggest implementation of ABM dosimetric constraints, V40 Gy ≤ 20-25%, may significantly reduce HT and lead to decreased treatment delays associated with clinical outcomes

Is there an advantage to delivering breast boost in the lateral decubitus position?

Background: The purpose of this study was to compare the change in depth of target volume and dosimetric parameters between the supine and lateral decubitus positions for breast boost treatment with electron beam therapy.Methods: We analyzed 45 patients who were treated, between 2009-2010, with whole breast radiation (WBRT) followed by a tumor bed boost in the lateral decubitius position. Tumor bed volume, distance from skin to the maximal depth of the tumor bed, D90 (dose covering 90% of the tumor bed volume), maximal dose, electron energy and doses to heart and lungs were compared. Additional variables of body mass index (BMI) and tumor bed location were also analyzed to see if there was a benefit limited to any subgroup.Results: Median BMI for the 45 patients treated was 30.6 (20.6-42.4). When comparing the supine scan to the lateral decubitus scan, there was no significant difference in the tumor bed volume (p = 0.116). There was a significant difference between depth to the tumor bed in the supine scan and lateral decubitus scan (p < 0.001). The mean maximum doses and D90 between the two scans were 110.7 (100.0-133.0)% vs 106.1 (95.1-116.9)% (p < 0.05) and 93.9 (81.3-01.0-101.0)% vs. 98.2 (89.1-108.0)% (p = 0.004) respectively. There was no difference in dose delivered to the lungs or heart between the two scans (p = 0.848 and p = 0.992 respectively). On subset analysis, there was a difference in depth to tumor that was seen across all BMI classes, including normal (p ≤ 0.001, overweight (p ≤ 0.001) and obese (p ≤ 0.001). The majority of patients had a tumor in the upper outer quadrant (77.8%) and on subset analysis, there was a significant difference in tumor bed volume (p < 0.01), depth to tumor (p < 0.01), tumor bed coverage [D90] (p < 0.05), maximum dose (p < 0.05) and energy (p < 0.001) for this location.Conclusions: Delivering a tumor bed boost in the lateral decubitus position reduces the distance to the tumor bed allowing for a lower energy treatment to be used to treat breast cancer. It improves coverage and decreases maximal dose to the target volume, all of which would help reduce skin morbidities and should be considered for patients with upper outer quadrant disease, irrespective of BMI status. © 2012 Kannan et al.; licensee BioMed Central Ltd

Non-traditional platinum compounds for improved accumulation, oral bioavailability, and tumor targeting

The five platinum anticancer compounds currently in clinical use conform to structure–activity relationships formulated (M. J. Cleare and J. D. Hoeschele, Bioinorg. Chem., 1973, 2, 187–210) shortly after the discovery that cis-diamminedichloroplatinum(II), cisplatin, has antitumor activity in mice. These compounds are neutral platinum(II) species with two am(m)ine ligands or one bidentate chelating diamine and two additional ligands that can be replaced by water through aquation reactions. The resulting cations ultimately form bifunctional adducts on DNA. Information about the chemistry of these platinum compounds and correlations of their structures with anticancer activity have provided guidance for the design of novel anticancer drug candidates based on the proposed mechanisms of action. This article discusses advances in the synthesis and evaluation of such non-traditional platinum compounds, including cationic and tumor-targeting constructs.National Cancer Institute (U.S.) (Grant CA34992

Assessment of Spatiotemporal Changes of NO2 Using TROPOMI Sensor in Khuzestan Province, Iran

Background: Khuzestan province is one of the largest industrial provinces in Iran, with high air pollution. One of the main air pollutants is nitrogen dioxide (NO2) in the atmosphere, which is linked to several epidemiological and environmental effects. Thus, spatial and temporal monitoring of NO2 is crucial for land managers. So, the aim of this study was the spatiotemporal evaluation of NO2 in Khuzestan Province, Iran, using Sentinel 5 (TROPOMI). Methods: Initially, the amount of tropospheric NO2 concentration was estimated in each month. In the next step, using ArcMap software, the monthly average of tropospheric NO2 was extracted from 12 months. Moreover, the location of 100 important air pollutant industries in the Khuzestan Province was extracted using Google Earth image. Thus, using the monthly average NO2 concentrations and the location of the cities and industries, the monthly average pollution of this pollutant was extracted for the cities and industries. Finally, the cities and industries of air pollution in Khuzestan Province were prioritized based on of tropospheric NO2 concentration. Findings: The maximum concentrations of this gas was in Bavi, Ahvaz, Abadan, and Mahshahr cities; and respectively, this gas had the lowest values of NO2 in Izeh, Lali, and Baghmalek cities. Moreover, in the cold months of the year, Khorramshahr and Mahshahr had higher concentrations of NO2 in comparison to the warm months of the year. The results of the spatial analysis revealed that the highest concentration of NO2 was in the Farabi Petrochemical Company, Khuzestan Steel Company, Ghadir, and Razi Petrochemicals, respectively. Conclusion: According to the findings of this study, it can be deduced the influence of local emission sources of NO2 in Khuzestan Province is related to population density, high traffic of motor vehicles, and industrial activities

Accuracy assessment and improvement of SRTM, ASTER, FABDEM, and MERIT DEMs by polynomial and optimization algorithm : A case study (Khuzestan Province, Iran)

Satellite digital elevation models (DEMs) are used for decision-making in various fields. Therefore, evaluating and improving vertical accuracy of DEM can increase the quality of end products. This article aimed to increase the vertical accuracy of most popular satellite DEMs (i.e., the ASTER, Shuttle Radar Topography Mission [SRTM], Forest And Buildings removed Copernicus DEM [FABDEM], and Multi-Error-Removed Improved-Terrain [MERIT]) using the particle swarm optimization (PSO) algorithm. For this purpose, at first, the vertical error of DEMs was estimated via ground truth data. Next, a second-order polynomial was applied to model the vertical error in the study area. To select the polynomial with the highest accuracy, employed for vertical error modeling, the coefficients of the polynomial have been optimized using the PSO algorithm. Finally, the efficiency of the proposed algorithm has been evaluated by other ground truth data and in situ observations. The results show that the mean absolute error (MAE) of SRTM DEM is 4.83 m while this factor for ASTER DEM is 5.35 m, for FABDEM is 4.28, and for MERIT is 3.87. The obtained results indicated that the proposed model could improve the MAE of vertical accuracy of SRTM, ASTER, FABDEM, and MERIT DEMs to 0.83, 0.51, 0.37, and 0.29 m, respectively. © 2023 the author(s), published by De Gruyter.CC-BY 4.0</p

Study of Effectiveness of Human Factors Engineering Interference in Cumulative Trauma Disorders Rate Decreasing in the Tehran South Health Center 2005-2006

Introduction: Up to now accomplished many investigations about cumulative trauma disorders (CTD) accession. For the most part sitting pattern and unsuitable task posture has been specified reason of these complications. In the publicized stats from a foreign source ambit of 44 percent of people who worked with computer has been afflict to the CTD's. The aim of this paper is to find and measurement of CTD and ergonomic intervention and investigation rate of this intervention's effect in the Tehran south health center. This center use paperless system. Methods: In this research Nordic questionnaire distribute between 68 persons of the center to determine CTD's. By technical expert inspection specified reason of complications. Observantly to state methods reason which create more severity and frequency CTD's has been recognized and interference with human factors engineering. For the more efficiency of interference Anthropometry has been used for all of Work stations and for any person designed a significant posture. Results: results that obtained before interference indicate that were CTD's complications at more of employees which 90 percent of them suffered of up spine pain. Also 27.4 percent of them had shoulder pain and 20.4 percent had neck pain. After the interference these measures decreased. And complaint of employee decreased 40.8 percent to up spine pain. Also for the shoulder pain it reached to 22 and neck pain 17.6 percent. With state test identified that there are significant difference between CTD after and before of intervention (p<0.005). Conclusion: Being unsuitable task posture is main cause of CTD's in the Work stations. We can prevent to increasing these complications in the work place by simple approach like adjustment in the desk and chair height, correct performance working training and doing simple exercise

Is there an advantage to delivering breast boost in the lateral decubitus position?

Abstract Background The purpose of this study was to compare the change in depth of target volume and dosimetric parameters between the supine and lateral decubitus positions for breast boost treatment with electron beam therapy. Methods We analyzed 45 patients who were treated, between 2009–2010, with whole breast radiation (WBRT) followed by a tumor bed boost in the lateral decubitius position. Tumor bed volume, distance from skin to the maximal depth of the tumor bed, D90 (dose covering 90% of the tumor bed volume), maximal dose, electron energy and doses to heart and lungs were compared. Additional variables of body mass index (BMI) and tumor bed location were also analyzed to see if there was a benefit limited to any subgroup. Results Median BMI for the 45 patients treated was 30.6 (20.6-42.4). When comparing the supine scan to the lateral decubitus scan, there was no significant difference in the tumor bed volume (p = 0.116). There was a significant difference between depth to the tumor bed in the supine scan and lateral decubitus scan (p  Conclusions Delivering a tumor bed boost in the lateral decubitus position reduces the distance to the tumor bed allowing for a lower energy treatment to be used to treat breast cancer. It improves coverage and decreases maximal dose to the target volume, all of which would help reduce skin morbidities and should be considered for patients with upper outer quadrant disease, irrespective of BMI status.</p

18F-FDG PET Predicts Hematologic Toxicity in Patients with Locally Advanced Anal Cancer Treated With Chemoradiation.

PurposeHematologic toxicity (HT) during chemoradiation therapy (CRT) for anal cancer can lead to treatment breaks that compromise efficacy. We hypothesized that CRT-induced HT correlates with changes in active bone marrow (ABM) characterized by pre-/post-CRT positron emission tomography (PET)/computed tomography.Methods and materialsData from 36 patients with anal cancer who were treated with 18F-fluorodeoxyglucose PET/computed tomography scans 2&nbsp;weeks before and 6 to 16&nbsp;weeks after CRT were analyzed. Complete blood counts with differential within 2&nbsp;weeks from, weekly during, and 2&nbsp;week after treatment were obtained. HT was defined as baseline complete blood count change to nadir and posttreatment recovery. Total bone marrow was segmented into 2 subregions: lumbosacral (LS) pelvis (L5 vertebrae, sacrum, and coccyx) and lower pelvis (LP) (ilium, femoral head/neck, and greater and lesser trochanter). PET ABM was characterized as the volume having standard uptake value (SUV) greater than the mean uptake of unirradiated extrapelvic bone marrow. PET variables of pre-/post-CRT and HT predictors were analyzed by linear regression.ResultsAverage pelvic ABM was significantly reduced from 52% to 41% in pre- to post-CRT PET scans for all patients (P&nbsp;=&nbsp;.0012). Regional analysis indicated significant post-CRT reduction of LS-ABM (P&nbsp;&lt;&nbsp;.0001) and LP-ABM (P&nbsp;=&nbsp;.006). Linear regression analysis identified post-CRT SUVmean, differential ΔSUVmean, and ΔABM as correlating significantly with pre- and posttreatment HT. ΔWBC linearly correlated with ΔABM of LS and LP pelvis (P&nbsp;=&nbsp;.033 and P&nbsp;=&nbsp;.028, respectively). Dosimetrically, ABM was sensitive to higher radiation doses (&gt;50&nbsp;Gy) in terms of acute hematologic ΔWBC (P&nbsp;=&nbsp;.021) and ΔANC(P&nbsp;=&nbsp;.028). HT increased with increasing volume of ABM receiving 40&nbsp;Gy. The results also suggest that ABM V40&nbsp;Gy&nbsp;≤&nbsp;20% to 25% may significantly reduce the risk of HT.ConclusionsHT was significantly associated with ΔABM in patients with anal cancer who were treated with CRT. LS-ABM was a robust surrogate for evaluating CRT-induced HT. Our results suggest implementation of ABM dosimetric constraints, V40&nbsp;Gy&nbsp;≤&nbsp;20-25%, may significantly reduce HT and lead to decreased treatment delays associated with clinical outcomes