Induction of breast cancer cell apoptosis by novel thiouracil-fused heterocyclic compounds through boosting of Bax/Bcl-2 ratio and DFT study.

Breast cancer is a common public health disease causing mortality worldwide. Thus, providing novel chemotherapies that tackle breast cancer is of great interest. In this investigation, novel pyrido[2,3-d]pyrimidine derivatives 3,4,(6a-c),(8a,b),9-20 were synthesized and characterized using a variety of spectrum analyses. The geometric and thermal parameters of the novel thiouracil derivatives 3,4,6a,(8a,b),11,12,17,18, 19 were measured using density functional theory (DFT) via DFT/B3LYP/6-31 + G(d,p) basis set. All synthesized compounds were evaluated by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) method using MCF-7 and MDA-MB-231 breast cancerous cells, compound 17 had the maximum anticancer activity against both breast cancerous cells, recording the lowest half-maximal inhibitory concentration (IC50) values (56.712 µg/mL for MCF-7 cells and 48.743 µg/mL for MDA-MB-231 cells). The results were confirmed in terms of the intrinsic mechanism of apoptosis, where compound 17 had the highest percentage in the case of both cancer cells and recorded Bax (Bcl-2 associated X)/Bcl-2 (B-cell lymphoma 2) ratio 17.5 and 96.667 for MCF-7 and MDA-MB-231 cells, while compound 19 came after 17 in the ability for induction of apoptosis, where the Bax/Bcl-2 ratio was 15.789 and 44.273 for both cancerous cells, respectively. Also, compound 11 recorded a high Bax/Bcl-2 ratio for both cells. The safety of the synthesized compounds was applied on normal WI-38 cells, showing minimum cytotoxic effect with undetectable IC50. Compounds 17, 11, and 19 recorded a significant increase of p53 upregulated modulator of apoptosis (PUMA) expression levels in the cancerous cells. The DFT method was also used to establish a connection between the experimentally determined values of the present investigated compounds and their predicted quantum chemical parameters. It was concluded that Compounds 17, 11, and 19 had anti-breast cancer potential through the induction of apoptotic Bax/Bcl-2 and PUMA expression levels.

Efficacy of lubiprostone for functional constipation treatment in adolescents and children: Randomized controlled trial.

OBJECTIVES: Adolescent and pediatric functional constipation (FC) is a common clinical problem. Currently, data on lubiprostone for the treatment of pediatric FC are scarce. This study investigated the efficacy and safety of lubiprostone in the treatment of pediatric FC. METHODS: In a single-blinded, randomized controlled study, we included 280 patients aged 8-18 years with FC. Patients were randomized either to a weight-based lubiprostone dose (n = 140) or conventional laxatives (n = 140), including lactulose, bisacodyl, or sodium picosulfate, for 12 weeks, followed by 4 weeks posttreatment follow-up. RESULTS: Improvement in constipation was achieved in 128 (91.4%) patients in the lubiprostone group, and in 48 (34.3%) patients of the conventional therapy group (p < 0.001) and was sustained after treatment discontinuation. One quarter of the lubiprostone group experienced the first spontaneous bowel motion within 48 h after dose initiation. A total of 75.7% of the lubiprostone group could achieve and sustain Bristol stool form of 3 or 4 during the last 4 weeks of therapy and through the 4 weeks of follow-up versus 50 (35.7%) patients in the conventional therapy group (p < 0.001). No life-threatening adverse drug reactions were encountered, and no treatment-related discontinuation. Mild self-limited colicky abdominal pain and headache were the most prevalent side effects in the lubiprostone group. CONCLUSIONS: Lubiprostone is an effective and well-tolerated pharmacotherapy for youthful age and pediatric age groups, which may alter the paradigm of pediatric FC treatment.

Effect of neuromuscular electrical stimulation and early physical activity on ICU-acquired weakness in mechanically ventilated patients: A randomized controlled trial.

BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is common in critically ill patients and increases the duration of mechanical ventilation (MV) and weaning time. Early mobilization, range of motion (ROM) exercises, and neuromuscular electrical stimulation (NMES) can prevent ICU-AW by maintaining muscle mass. However, studies highlighting the effects of combining NMES with early physical activity in ICU patients are limited. AIM: To evaluate the effect of NMES and early physical activity on ICU-AW in mechanically ventilated patients. DESIGN: A single-blinded randomized controlled trial was conducted in Alexandria, Egypt. METHOD: Patients were randomly assigned to one of four groups: NMES, ROM, combined therapy (ROM + NMES), or conventional care (control group). The Medical Research Council (MRC) scale was used to assess the ICU-AW for the study patients over a 7-day period. The duration of the patient's MV and ICU stays were recorded. RESULTS: Of the 180 patients who were assessed for eligibility, 124 were randomly assigned to one of four groups: 32 patients in ROM exercises, 30 in NMES, 31 in combined therapy (ROM + NMES), and 31 in the control group. On day 7, ROM + NMES and NMES groups showed higher MRC scores than ROM and control groups (50.37 ± 2.34, 49.77 ± 2.19, 44.97 ± 3.61, and 41.10 ± 3.84, respectively). ANOVA test results indicated significant differences (p < .001) across the four groups. ICU-AW occurred in 0% of the ROM + NMES group, 60% of the ROM group, 13% of the NMES group, and 100% of the control group (p < .001). The MV duration (in days) in the ROM + NMES group was shorter (12.80 ± 3.800) than in the ROM, NMES, or control groups (21.80 ± 4.460, 18.73 ± 4.748, and 20.70 ± 3.932, respectively). ICU-LOS was shorter in the ROM + NMES group (17.43 ± 3.17 days) compared with the ROM group (22.53 ± 4.51 days), the NMES group (21.10 ± 5.0 days), and the control group (21.50 ± 4.42 days) with significant differences (p < .001) between the four groups. CONCLUSION: Daily sessions of NMES and early physical activity were well tolerated, preserved muscle strength, prevented ICU-AW, and decreased the duration of the MV and ICU stay. RELEVANCE TO CLINICAL PRACTICE: The findings of this study support the use of NMES and early physical exercises by critical care nurses as part of routine care for critically ill patients.

Case report: Dermatofibrosarcoma of the breast.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon neoplasm of the skin and soft tissue, commonly appearing on the trunk and extremities. The occurrence of DFSP in the breast is extremely rare. It has low to intermediate malignant potential with a high rate of local recurrence and invasion. We present a case of a 28-year- old female with a skin lesion on the breast associated with an underlying breast lump. We aim to discuss the sonographic and magnetic resonance findings of breast dermatofibrosarcoma.

Does the Autophagy Related Gene 7 (ATG7) Have a Role in Non-Melanoma Skin Cancer?

PURPOSE: To evaluate the role of autophagy related gene 7 (ATG7) in non-melanoma skin cancer. SUBJECTS AND METHODS: This retrospective and prospective case-control study was performed on 104 patients with non-melanoma skin cancer (NMSC) in addition to 20 apparently healthy subjects matched for age and sex as a control group. Multiple skin biopsies were taken for immunohistochemical evaluation of ATG7 expression. RESULTS: Both epithelial and stromal ATG7 were expressed in all participants while all patients showed nucleocytoplasmic localization and controls showed both cytoplasmic and nucleocytoplasmic expression. In addition, significantly higher H-scores of ATG7 in both epithelium and stroma were detected in patients compared to controls (P<0.001). CONCLUSION: ATG7 nucleocytoplasmic topographic localization might be involved in the pathogenesis of NMSC, which can open the gate for new target therapy for this skin cancer.

Hematopoietic stem cell mobilization into the peripheral circulation in patients with chronic liver diseases.

OBJECTIVE: The present study was aimed to investigate and compare the kinetics of bone marrow-derived hematopoietic stem cells (BMHSC) migration in the peripheral blood and liver in response to liver injury in patients with chronic liver disease (CLD). METHODS: In all, 45 CLD patients staged with Child-Pugh A, B and C and 15 healthy participants were evaluated for the concentration of circulating BMHSC by a flow cytometric analysis of CD133(+) /CD34(+) cells. In addition, homing BMHSC and hepatic progenitors were assessed by the immunohistochemical detection of CD133(+) and OV6(+) cells in liver biopsy specimens from Child-Pugh A and B patients. RESULTS: No significant difference in the percentage of circulating CD133(+) /CD34(+) cells was observed among all groups of patients. In liver tissues, OV6(+) cells increased significantly in Child-Pugh B cases (P < 0.05), while CD133(+) cells were distributed sparsely in the periportal region in Child-Pugh A and B patients. OV6(+) cells were significantly correlated with CD34(+) cells but not with CD133(+) cells in Child-Pugh A and B patients (P < 0.01 and P < 0.05, respectively). CONCLUSIONS: Various degrees of severity in CLD neither evoked the mobilization of BMHSC into the circulation nor triggered their homing into liver tissue, thus excluding extrahepatic stem cell-mediated repair. The recovery process seems to be dependent on proliferating endogenous liver progenitors (OV6(+) cells).

Thrombopoietin level is increased in the serum of asphyxiated neonates: a prospective controlled study.

BACKGROUND: Thrombopoietin (TPO) is a growth factor that controls platelet production. Despite the known association of chronic hypoxia and acute asphyxia with hematologic changes, TPO had not been studied in neonatal asphyxia. OBJECTIVE: To assess TPO concentrations in the serum of asphyxiated and nonasphyxiated neonates, and examine any correlation with the severity of asphyxia. DESIGN/METHODS: This prospective study was carried out on 32 asphyxiated neonates and 30 control subjects admitted at Cairo University Medical Center. Asphyxia was defined if two of the following were found: (1) Apgar score /=-10 and (3) clinical evidence of perinatal asphyxia. Encephalopathy was classified clinically according to Sarnat's stages during the first day of life. Platelet count and TPO level (pg/ml) were measured at 1st, 3rd and 7th day of life. RESULTS: : TPO measured on the first day of life did not differ between cases and controls (900.2+/-526.4 vs 726.6+/-441.9 pg/ml, p=0.2). It increased on the 3rd day of life and was significantly higher in asphyxiated infants compared to controls (1291.4+/-627.9 vs 885.5+/-400.3 pg/ml, respectively; p=0.004). This difference remained significant in a logistic regression model controlling for birth weight, sex and mode of delivery (regression coefficient=476.9+/-146.8; p=0.002). In asphyxiated infants (n=32), encephalopathy was classified as mild (n=17), moderate (n=10) and severe (n=5). TPO correlated with the degree of clinical severity on the 7th day of life (r=0.59, p=0.003). TPO did not differ between survivors (n=24) and nonsurvivors (n=8) within the asphyxia group (1197.1+/-596.8 vs 1613.1+/-605.9 pg/ml; p=0.09). Platelet counts correlated negatively with TPO measured on day 1 (r=-0.415; p=0.02), day 3 (r=-0.64; p=0.001) and day 7 (r=-0.562; p=0.007). CONCLUSIONS: TPO increased and correlated with severity of asphyxia at 3 and 7 days of life. It correlated negatively with the platelet count at all times.