Cell cycle machinery in oncology: A comprehensive review of therapeutic targets.

The cell cycle is tightly regulated to ensure controlled cell proliferation. Dysregulation of the cell cycle machinery is a hallmark of cancer that leads to unchecked growth. This review comprehensively analyzes key molecular regulators of the cell cycle and how they contribute to carcinogenesis when mutated or overexpressed. It focuses on cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, checkpoint kinases, and mitotic regulators as therapeutic targets. Promising strategies include CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib for breast cancer treatment. Other possible targets include the anaphase-promoting complex/cyclosome (APC/C), Skp2, p21, and aurora kinase inhibitors. However, challenges with resistance have limited clinical successes so far. Future efforts should focus on combinatorial therapies, next-generation inhibitors, and biomarkers for patient selection. Targeting the cell cycle holds promise but further optimization is necessary to fully exploit it as an anti-cancer strategy across diverse malignancies.

Endoscopic third ventriculostomy for management of hydrocephalus associated with Chiari malformation type II in children.

BACKGROUND: Hydrocephalus is commonly associated with Chiari malformation (CM) particularly CM type II. The traditional treatment of hydrocephalus in these patients has been cerebrospinal fluid diversion by shunts. Endoscopic third ventriculostomy (ETV) has emerged as an alternative procedure in these patients. PURPOSE: Assessment of the clinical and radiological outcomes of ETV in the management of hydrocephalus in children with CM II. METHODS: This is a prospective study conducted on 18 patients with CM II associated with hydrocephalus admitted to Cairo University hospitals between January 2020 and June 2021. These patients had been managed surgically by ETV. Clinical outcome was assessed based on improvement of manifestations of increased intracranial pressure while radiological outcome was based on the findings of postoperative computed tomography. In cases with early failure, serial lumbar puncture (LP) was performed for 2 days. RESULTS: ETV was performed as a secondary procedure in 4 cases. The overall success rate of the procedure was 72%, and its success rate as a secondary procedure was 100%. Serial LP was effective in decreasing early failure in 44.4% of cases. Radiological regression of hydrocephalic changes was detected in 50% of the cases. CONCLUSION: ETV is an efficient and safe procedure in the treatment of hydrocephalus in children with Chiari malformation II, particularly when performed as a secondary procedure. Serial LP following the procedure increases the success rate in patients with early failure.

M2BPGi for assessing liver fibrosis in patients with hepatitis C treated with direct-acting antivirals.

BACKGROUND: Assessing liver fibrosis is important for predicting the efficacy of direct-acting antivirals (DAAs) and patient prognosis. Non-invasive techniques to assess liver fibrosis are becoming important. Recently, serum Mac-2 binding protein glycosylation isomer (M2BPGi) was identified as a non-invasive marker of liver fibrosis. AIM: To investigate the diagnostic accuracy of M2BPGi in assessing liver fibrosis in patients with chronic hepatitis C (CHC) treated with DAAs. METHODS: From December 2017 to August 2018, 80 treatment-naïve adult patients with CHC who were eligible for DAAs therapy were consecutively enrolled in this observational cohort study. For 12 weeks, 65 patients were treated with sofosbuvir/daclatasvir, and 15 patients were treated with sofosbuvir/daclatasvir and a weight-based dose of ribavirin at knowledge and technology association for hepatitis C management clinic, Cairo, Egypt. We measured serum M2BPGi levels, PAPAS index, fibrosis-4 (FIB-4) score and liver stiffness measurements (LSM) at baseline and 12 weeks after the end of treatment. Serum M2BPGi levels were measured using enzyme-linked immunosorbent assay. RESULTS: All patients achieved sustained virologic response (SVR12) (100%). Serum M2BPGi levels, LSM, FIB-4 score and PAPAS index decreased significantly at SVR12 (P < 0.05). Serum M2BPGi levels correlated positively with LSM at baseline and SVR12 (P < 0.001). At baseline, compared with the FIB-4 score and PAPAS index, M2BPGi was the best marker to distinguish patients with grade F4 fibrosis (AUC = 0.801, P < 0.001), patients with grade F2 from grade F0-1 fibrosis (AUC = 0.713, P = 0.012), patients with grade F3-4 from grade F0-2 fibrosis (AUC = 0.730, P < 0.001), and patients with grade F2-4 from grade F0-1 fibrosis (AUC = 0.763, P < 0.001). At SVR12, M2BPGi had the greatest AUCs for differentiating patients with grade F4 fibrosis (AUC = 0.844, P < 0.001), patients with grade F3 from grade F0-2 fibrosis (AUC = 0.893, P = 0.002), patients with grade F3-4 from grade F0-2 fibrosis (AUC = 0.891, P < 0.001), and patients with grade F2-4 from grade F0-1 fibrosis (AUC = 0.750, P < 0.001). CONCLUSION: M2BPGi is a reliable marker for the non-invasive assessment and prediction of liver fibrosis regression in patients with CHC who achieved an SVR with DAAs therapy.

Effects of Exercise and Ferulic Acid on Alpha Synuclein and Neuroprotective Heat Shock Protein 70 in An Experimental Model of Parkinsonism Disease.

BACKGROUND & OBJECTIVE: This study investigated the effects of ferulic acid (FR), muscle exercise (Ex) and combination of them on rotenone (Rot)-induced Parkinson disease (PD) in mice as well as their underlying mechanisms. METHOD: 56 male C57BL/6 mice were allocated into 8 equal groups, 1) Normal control (CTL), 2) FR (mice received FR at 20 mg/kg/day), 3) Ex (mice received swimming Ex) and 4) Ex + FR (mice received FR and Ex), 5) Rot (mice received Rot 3 mg/Kg i.p. for 70 days), 6) ROT+ FR (mice received Rot + FR at 20 mg/kg/day), 7) ROT+ Ex (mice received Rot + swimming Ex) and 8) ROT+ Ex + FR (mice received Rot + FR and Ex). ROT group showed significant impairment in motor performance and significant reduction in tyrosine hydroxylase (TH) density and Hsp70 expression (p< 0.05) with Lewy bodies (alpha synuclein) aggregates in corpus striatum. Also, ROT+FR, ROT+EX and ROT + Ex+ FR groups showed significant improvement in behavioral and biochemical changes, however the effect of FR alone was more potent than Ex alone (p< 0.05) and addition of Ex to FR caused no more significant improvement than FR alone. CONCLUSION: We concluded that, FR and Ex improved the motor performance in rotenone-induced PD rodent model which might be due to increased Hsp70 expression and TH density in corpus striatum and combination of both did not offer more protection than FR alone.

Telmisartan attenuates N-nitrosodiethylamine-induced hepatocellular carcinoma in mice by modulating the NF-κB-TAK1-ERK1/2 axis in the context of PPARγ agonistic activity.

Hepatocellular carcinoma (HCC) is characterized by bad prognosis and is the second most common reason for cancer-linked mortality. Treatment with sorafenib (SRF) alone increases patient survival by only a few months. A causal link has been determined between angiotensin II (Ang-II) and HCC. However, the mechanisms underlying the tumorigenic effects of Ang-II remain to be elucidated. N-Nitrosodiethylamine was utilized to examine the effects of telmisartan (TEL) (15 mg/kg), SRF (30 mg/kg), and a combination of these two agents on HCC mice. Downregulation of NF-кBP65 mRNA expression and inhibition of the phosphorylation-induced activation of both ERK1/2 and NF-кB P65 were implicated in the anti-tumor effects of TEL and SRF. Consequent regression of malignant changes and improvements in liver function associated with reduced levels of AFP, TNF-α, and TGF-ß1 were also confirmed. Anti-proliferative, anti-metastatic, and anti-angiogenic effects of treatment were indicated by reduced hepatic cyclin D1 mRNA expression, reduced MMP-2 levels, and reduced VEGF levels, respectively. TEL, but not SRF, demonstrated agonistic activity for PPARγ receptors, as evidenced by increased PPARγ DNA binding activity, upregulation of CD36, and HO-1 mRNA expression followed by increased liver antioxidant capacity. Both TEL and SRF inhibited TAK1 phosphorylation-induced activation, indicating that TAK1 might act as a central mediator in the interaction between ERK1/2 and NF-кB. TEL, by modulating the ERK1/2, TAK1, and NF-кB signaling axis in the context of PPARγ agonistic activity, exerted anti-tumor effects and increased tumor sensitivity to SRF. Therefore, TEL is an encouraging agent for further clinical trials regarding the management of HCC.

Potential Role of Microfibrillar-Associated Protein 4, Fibrotic Indices and Oxidative Stress in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. In an attempt to understand some potential mechanisms of persistence and oncogenicity of Hepatitis C virus (HCV)-related HCC, microfibrillar-associated protein 4 (MFAP4), fibrotic indices and oxidative status biomarkers were assessed in the sera of 50 patients with HCV-associated HCC, 25 patients with HCV-related liver cirrhosis and 15 healthy individuals. Serum oxidized Coenzyme Q10 (CoQ10) and malondialdehyde showed significant elevation in HCC patients compared to the control group (p < 0.001), as well as cirrhotic patients (p < 0.05 and p < 0.001, respectively), while serum glutathione content and superoxide dismutase activity were significantly decreased in HCC patients compared to the control group (p < 0.001). Serum MFAP4, aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4) and Forns index showed significant increase in HCC patients compared to the control group (p < 0.001), while only APRI and FIB-4 were significantly different between HCC and cirrhotic patients (p < 0.05), with a sensitivity of 86% and 92%, respectively, at cut off ≥0.7 for APRI and ≥1.57 for FIB-4. Therefore, increasing oxidative stress and fibrosis might mediate HCV induced cirrhosis and HCC. APRI and FIB-4 may be used as a simple non-expensive formula for the screening of HCC rather than MFAP4.

Toxic Effects of Trichloroethylene on Rat Neuroprogenitor Cells.

Trichloroethylene (TCE) is a common volatile organic solvent which is considered as an ubiquitous environmental pollutant. It is claimed to be a developmental neurotoxicant. Our group evaluated previously its impact on three-dimensional neurospheres in vitro. The current work aims to investigate the neurotoxic effects of a lower concentration of TCE on the same system. To perform the experiment, neural progenitor cells were obtained from the brains of nine newborn rats. Afterward, these cells were cultured in both growth and differentiation media to get the neurospheres. Cell cultures were divided into two groups: group 1 (control), group 2 (exposed to 0.25 µM TCE). Neurospheres were photographed at different durations and assessment of the morphological changes such as proliferation and differentiation of neurospheres was done. In addition, cell viability, apoptosis, and necrosis were analyzed using flow cytometry to clarify the mechanism of involved cytotoxicity. The results revealed that TCE-treated neurospheres showed significantly decreased proliferation on days 7 and 14. These cells failed to show the neurogenic differentiation seen in the neurospheres of the control group. Furthermore, a highly significant decrease in viability and a significant increase in the number of apoptotic cells were observed in the treated cells in comparison to the control group. The present work confirmed that TCE, at very low doses relevant to daily life exposure in humans, caused neurotoxic effects in 3D neurosphere model through the affection of neural proliferation and differentiation as well as disturbance of cell viability and apoptosis.

A Study of Extrapyramidal Manifestations Accompanying Decompensated Viral Hepatic Cirrhosis Patients.

BACKGROUND: Despite the high prevalence of viral hepatic cirrhosis all over the world, the characteristic motor features of related Parkinsonism (extrapyramidal manifestations) are not well described. The current study aimed to characterize such disorder in a sample of Egyptian patients with chronic viral liver disease (CLD), and their clinical correlates. METHODS: Ninety-six (96) patients with CLD were examined for the presence of extrapyramidal signs. Parkinsonism was assessed using the UPDRS-III scale and its sub scores. Ataxia and dystonia were also assessed by related scales. Patients with Parkinsonism were compared to other patients and correlations with clinical features of CLD were done. RESULTS: The clinical diagnosis of extrapyramidal manifestations was justified in 57 patients (59.4%) with predominant akinetic rigid syndrome (ARS) (87.7%). Bradykinesia and axial features were the most frequent signs (89.5% and 70.2%, respectively). 38.6% of patients had postural tremors, whereas only 3.5% had rest tremors. Gait and postural abnormalities were detected in 38.6% and 36.8% respectively. Parkinsonism was associated with advanced hepatic cirrhosis (p=0.02) and increased episodes of hepatic encephalopathy (HE) (p=0.006). Severity of parkinsonian features was correlated to patients' age, age of onset of CLD and rapid progression, while impaired speech and gait were rather correlated to a number of episodes of HE. CONCLUSION: Advanced viral cirrhosis is associated with high prevalence of parkinsonism that is characterized by symmetrical ARS with frequent axial features, postural tremor, gait and postural impairment. Severity of these signs is correlated to age, age of onset, rapid progression and frequency of HE.

Prevalence of hyperlipidemia among Saudi school children in Riyadh.

BACKGROUND: Coronary heart disease (CHD) constitutes one of the main health problems in Saudi Arabia, but little is known on the lipid profile of the juvenile population. METHODS: We measured the prevalence of high-risk levels of serum lipids in 1390 boys and girls, aged 9 or 12 years, in Riyadh city. RESULTS: High-risk levels of total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG) and triglycerides/high-density lipoprotein (TC/HDL) cholesterol ratio were found in 32.7%, 33.1%, 34.1% and 22.0% of the students. The prevalence of high-risk levels of TG increased with age among boys and girls, while the prevalence of high-risk LDL decreased with age in girls. Mean levels of TC, LDL and the TC/HDL ratio were higher among girls than boys in the 9-year-old age group. Mean levels of TG and the TC/HDL ratio were higher among girls than boys in the 12-year-old age group. CONCLUSIONS: The prevalence of high-risk levels of serum lipids ranged from 32.7% to 34.1%. We emphasize the need to assess the prevalence of other CHD risk factors among our students and design a suitable control program.

Parkinson's disease: is it a toxic syndrome?

Parkinson's disease (PD) is one of the neurodegenerative diseases which we can by certainty identify its pathology, however, this confidence disappeares when talking about the cause. A long history of trials, suggestions, and theories tried linking PD to a specific causation. In this paper, a new suggestion is trying to find its way, could it be toxicology? Can we-in the future-look to PD as an occupational disease, in fact, many clues point to the possible toxic responsibility-either total or partial-in causing this disease. Searching for possible toxic causes for PD would help in designing perfect toxic models in animals.

Fatal suicide cases in Port Said city, Egypt.

In the present study, a retrospective evaluation of suicide cases in the city of Port Said from 1998 to 2004 is done. The demographic data of the cases were evaluated. There were 80 cases of suicide 54 of them (67.5%) involved males. Age distribution showed a predominance in the age range 20-30 years. Methods of suicide included rodenticides intake in 25% of cases, drowning in 18.75%, burns in 16.25%, firearm injuries in 13.75%, jumping from height in 10%, drug intake in 8.75% and hanging in 7.5%. A medico-legal autopsy had been carried out for all cases. In conclusion, we emphasize the importance of rodenticides control as well as necessity of performing a psychological autopsy.

Thyroid disorders and autoantibodies in systemic lupus erythematosus and rheumatoid arthritis patients.

To determine the patterns of thyroid dysfunction and autoantibodies associated with SLE and RA patients, twenty patients with SLE and another group of twenty with RA were studied. The results were compared with those of twenty apparently healthy age- and sex- matched controls. All patients were subjected to complete history taking, thorough clinical examination and joint examination. All patients and controls were subjected to the following investigations: T3, T4, TSH, antithyroglobulin antibodies (ATGAb) and thyroid peroxidase antibodies (TPOAb). Also, complete blood picture, ESR, RF, ANA, CRP and LE cells were done. This study revealed that thyroid disorders were significantly increased in SLE patients (50%) when compared to RA (15%) (P<0.05). In SLE group, 20% had euthyroid sick syndrome, 20% had hypothyroidism (10% subclinical and 10% biochemical), and 10% had hyperthyroidism (5% subclinical and 5% biochemical). However, in RA, 10% had hypothyroidism (subclinical) and 5% had subclinical hyperthyroidism. TPOAb was found in 15% of SLE and 5% of RA patients and 10% of controls, but the titres were higher in SLE and RA patients. Also, ATGAb was found in 5% of SLE, 30% of RA patients and 10% of controls, but the titres were higher in SLE and RA patients. It is concluded that thyroid abnormalities are more implicated with euthyroid sick syndrome and hypothyroidism (subclinical and overt) than hyperthyroidism in SLE patients. SLE and RA were associated with antithyroid antibodies (TPOAb in SLE and ATGAb in RA). Performance of thyroid function tests in patients with SLE, in particular and RA as a part of the biochemical and immunological profiles, may help in early detection of associated thyroid disorders.