Soluble guanylate cyclase agonist, isoliquiritigenin attenuates renal damage and aortic calcification in a rat model of chronic kidney failure.

AIMS: Chronic kidney disease (CKD) is a growing fatal health problem worldwide associated with vascular calcification. Therapeutic approaches are limited with higher costs and poor outcomes. Adenine supplementation is one of the most relevant CKD models to human. Insufficient Nitric Oxide (NO)/ cyclic Guanosine Monophosphate (cGMP) signaling plays a key role in rapid development of renal fibrosis. Natural products display proven protection against CKD. Current study therefore explored isoliquiritigenin, a bioflavonoid extracted from licorice roots, potential as a natural activator for soluble Guanylate Cyclase (sGC) in a CKD rat model. MATERIALS AND METHODS: 60 male Wistar rats were grouped into Control group (n = 10) and the remaining rats received adenine (200 mg/kg, p.o) for 2 wk to induce CKD. They were equally sub-grouped into: Adenine untreated group and 4 groups orally treated by isoliquiritigenin low or high dose (20 or 40 mg/kg) with/without a selective sGC inhibitor, ODQ (1-H(1,2,4)oxadiazolo(4,3-a)-quinoxalin-1-one, 2 mg/kg, i.p) for 8 wk. KEY FINDINGS: Long-term treatment with isoliquiritigenin dose-dependently and effectively amended adenine-induced chronic renal and endothelial dysfunction. It not only alleviated renal fibrosis and apoptosis markers but also aortic calcification. Additionally, this chalcone neutralized renal inflammatory response and oxidative stress. Isoliquiritigenin beneficial effects were associated with up-regulation of serum NO, renal and aortic sGC, cGMP and its dependent protein kinase (PKG). However, co-treatment with ODQ antagonized isoliquiritigenin therapeutic impact. SIGNIFICANCE: Isoliquiritigenin seems to exert protective effects against CKD and vascular calcification by activating sGC, increasing cGMP and its downstream PKG.

Eligibility criteria to cisplatin in head and neck squamous cell carcinoma: Egyptian expert opinion.

Introduction: The use of cisplatin in clinical practice in the management of head and neck squamous cell carcinoma (HNSCC) is limited by its toxicity and acquired resistance, which makes the decision-making process of its prescription multifactorial. Methods: An Egyptian expert panel (comprising nine Egyptian oncologists) meeting was held after a comprehensive literature review on the use of cisplatin in HNSCC. The panel aimed to develop a consensus on evidence-based recommendations for receiving cisplatin in the chemoradiotherapy management of HNSCC in Egyptian clinical practice. Results: The panel indicated that an Eastern Cooperative Oncology Group Performance Status (ECOG PS) > 2, creatinine clearance (CCR) < 50 ml/min, neuropathy grade ≥ 2, pre-existing hearing loss or tinnitus ≥2, hematological problems (platelets < 100,000/mm3, neutrophils < 1500/mm, and hemoglobin < 9 g/dl), and heart failure of New York Heart Association Classes III or IV (even if cardiovascular therapy is optimized); are all absolute contraindications to receiving cisplatin. On the other hand, relative contraindications to cisplatin according to the panel were an ECOG PS of 2, age more than 70 years, CCR between 50 and 60 ml/min, grade 1 neuropathy, grade 1 hearing loss, involuntary weight loss of ≥20% of body weight, Child-Pugh Scores B and C, previous induction chemotherapy, and heart failure of New York Heart Association Classes I or II with left ventricular ejection fraction ≤50%. The panel agreed that the socioeconomic status of patients should be considered when prescribing cisplatin to HNSCC patients. Conclusion: Our discussion resulted in a set of evidence-based recommendations for cisplatin eligibility criteria in patients of HNSCC in Egypt.

Carvedilol ameliorates dexamethasone-induced myocardial injury in rats independent of its action on the α1-adrenergic receptor.

The current study aimed to investigate the cardiotoxic effect of dexamethasone-high-dose in rats, the therapeutic effect of carvedilol and the role of α1-adrenergic receptor (α1AR). The experiment involved 6 groups: control, dexamethasone (10 mg/kg), carvedilol (10 mg/kg), phenylephrine (1 mg/kg), phenylephrine plus carvedilol and propranolol (30 mg/kg). Drugs and vehicles were given for 7 days. Dexamethasone was given with the drugs in the last 4 groups. On the 8th-day and after overnight fasting, serum and cardiac samples were collected. Serum levels of cardiac troponin I and creatine kinase-myoglobin as well as cardiac levels of diacylglycerol, malondialdehyde, kinase activity of Akt, transforming growth factor-ß, Smad3 and alpha smooth muscle actin were measured. Cardiac samples were also used for histopathological examination using hematoxylin-eosin and Sirius red stains, in addition to immunohistochemical examination using ß-arrestin2 antibody. Dexamethasone induced cardiac injury via increasing oxidative stress, apoptosis and profibrotic signals. Carvedilol significantly reduced the dexamethasone-induced cardiotoxicity. Using phenylephrine, a competitive α1-agonist, with carvedilol potentiated the cardioprotective actions of carvedilol. Propranolol, a ß-blocker without activity on α1ARs, showed higher cardiac protection than carvedilol. Dexamethasone-high-dose upregulates cardiac oxidative stress, apoptotic and profibrotic signals and induces cardiac injury. Blocking the α1-adrenergic receptor by carvedilol attenuates its cardioprotective effects against dexamethasone-induced cardiotoxicity.

Mitigation of dexamethasone-induced nephrotoxicity by modulating the activity of adrenergic receptors: Implication of Wnt/ß-arrestin2/ß-catenin pathway.

The present study aimed to investigate the role of α and ß-adrenergic receptors (ßARs) in mediation or modulation of the dexamethasone-induced nephrotoxicity by using different pharmacological interventions. Nephrotoxicity was induced by subcutaneous injection of dexamethasone (10 mg/kg) for 7 days in Wistar albino rats. Eight groups were used: control; dexamethasone; carvedilol; phenylephrine; carvedilol and phenylephrine; propranolol; doxazosin; propranolol and doxazosin. At the end of experiment, rats were euthanized and blood, urine and kidney samples were collected. Serum and urinary creatinine and urinary total protein levels were measured. Also, the renal tissue levels of diacylglycerol (DAG); Akt kinase activity, malondialdehyde (MDA), NADPH oxidase 2 (NOX2), transforming growth factor-ß (TGF-ß), Wnt3A and ß-catenin were recorded. Furthermore, histopathological and ß-arrestin2-immunohistochemical examinations of renal tissues were performed. Results: Dexamethasone induced glomerular damage, proteinuria, renal oxidative stress and upregulated the renal Wnt/ß-arrestin2/ß-catenin pathway and the profibrotic signals. Blocking the α1 and ßARs by carvedilol reduced the dexamethasone-induced nephrotoxicity. Pre-injection of phenylephrine did not reduce the reno-protective action of carvedilol. Blocking the ßARs only by propranolol reduced the dexamethasone-induced nephrotoxicity to the same extent of carvedilol group. Blocking the α1ARs only by doxazosin reduced dexamethasone-induced nephrotoxicity to a higher extent than other treatments. However, combined use of propranolol and doxazosin did not synergize the reno-protective effects of doxazosin. Conclusion: Dexamethasone induces nephrotoxicity, possibly, by upregulating the Wnt/ß-arrestin2/ß-catenin pathway. Blocking either α1ARs or ßARs can effectively protect against the dexamethasone-induced nephrotoxicity. However, combined blocking of α1ARs and ßARs does not synergize the reno-protective effects.

Thymoquinone upregulates miR-125a-5p, attenuates STAT3 activation, and potentiates doxorubicin antitumor activity in murine solid Ehrlich carcinoma.

In breast cancer, there has been evidence of atypical activation of signal transduction and activators of transcription 3 (STAT3). Thymoquinone (TQ) exerts its anti-neoplastic effect through diverse mechanisms, including STAT3 inhibition. The tumor suppressor, microRNA-125a-5p was reported to be downregulated in various breast cancer cells. Therefore, we investigated the influence of TQ and/or doxorubicin on microRNA-125a-5p and its correlation with STAT3 activation as well as tumor growth in mice bearing solid Ehrlich tumors. We found that TQ markedly suppressed inducible and constitutive phosphorylation of STAT3 in tumor tissue without affecting STAT5. Moreover, it attenuated tumor growth, downregulated STAT3 downstream target proteins, and increased the apoptotic activities of caspase-3 and -9. Interestingly, TQ-elicited synergism of doxorubicin anti-neoplastic activity was coupled with upregulation of tumoral microRNA-125a-5p. Taken together, the current findings raise the potential of TQ as a promising chemomodulatory adjuvant to augment mammary carcinoma sensitivity to doxorubicin.

Neoadjuvant FOLFIRINOX followed by Chemoradiotherapy for Middle and Lower Rectal Cancer.

OBJECTIVE: Neoadjuvant concomitant chemoradiotherapy followed by surgical resection is the standard of care in the treatment of rectal cancer. We are investigating the value of adding combination chemotherapy oxaliplatin, irinotecan, leucovorin and fluorouracil (FOLFIRINOX) before neoadjuvant chemoradiotherapy. METHODS: Forty-one patients with middle and lower rectal cancer were included. FOLFORINOX were given every 2 weeks over 2 months (4 cycles) followed by concomitant chemoradiotherapy (CRT). Surgery was done 6-8 weeks after CRT and then adjuvant 4 months of FOLFOX or XELOX were given. The primary end point was sphincter preservation rate. RESULTS: All patients received the four cycles of neoadjuvant chemotherapy FOLFORINOX, 38 patients completed CRT and only 29 patients underwent surgery. 32 patients were available for assessment (29 patients who underwent surgery and three patients who refuse surgery because of no evidence of disease by endoscopy, imaging and biopsy). Sphincter preservation was achieved in twenty-one patients (51.2%). Pathological complete response rate was 24.1%. After a median follow up of 24 months. Median PFS was 20 months and 2-years PFS was 62.3%. The median overall survival of all patients was not reached, while 2-years OS was 76.5%. CONCLUSION: Neoadjuvant FOLFIRINOX followed by CRT for middle and lower rectal cancer is feasible, tolerable with satisfactory sphincter preservation rate. 
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Randomized Pilot Study of 20 Gy in 5 Fractions versus 27 Gy in 3 Fractions Radiotherapy for Treating Painful Bone Metastases: A Single Institution Experience.

PURPOSE: Radiotherapy is a very effective tool in the treatment of painful bone metastases. The aim of this study was to compare the palliative effect of radiotherapy between the standard fractionation schedule 20 Gy over 5 fractions (20Gy/5fr) and the high biological dose schedule 27 Gy over 3 fractions (27Gy/3fr) which is frequently used in Stereotactic body radio-surgery (SBRT). METHODS: Patients were randomized to receive (20Gy/5fr)or (27Gy/3fr). The primary aim of the study was pain relief using the numeric rating scale (NRS), after three months of radiation therapy. Secondary end points include pain relief immediately after finishing radiation therapy (within one week), and narcotic relief after three months of radiation therapy. RESULTS: Twenty-two patients with painful bone metastases were included. 12 patients received (20Gy/5fr) and 10 patients received (27Gy/3fr). Male patients were predominant on both arms (81.8%) with a mean age of 58 years [ranging between 19-72 years]. For pain relief after three months of radiation therapy, partial pain relief was documented in 9 patients (75%) with (20Gy/5fr) and in 8 patients (80%) with (27Gy/3fr) with a p- value of 0.6. Additionally, narcotic relief after three months was equal for both groups. For immediate pain relief, partial pain relief was seen in one patient (8%) with (20Gy/5fr) versus seven patients (70%) with (27Gy/3fr) with a p value of 0.06. The increase in immediate pain relief in the 27Gy arm was numerically but not statistically significant. CONCLUSION: SBRT and standard fractionation radiation therapy had equal effectiveness for pain relief, when the assessment was done after three months of radiation therapy. Interestingly, SBRT had a better immediate pain relief. 
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Raspberry ketone preserved cholinergic activity and antioxidant defense in obesity induced Alzheimer disease in rats.

Obesity is a proven risk factor for neurodegenerative disease like Alzheimer's disease (AD). Accumulating evidences suggested that nutritional interventions provide potential for prevention and treatment of AD. The present study aimed to investigate the effect of dietary treatment of obese rats with natural Raspberry ketone (RK) and their relationship with neurodegeneration. Obesity was first induced in 40 male Wistar rats (140-160 g) by feeding high fat diet (HFD) for 16 weeks. Obese rats were then assigned into 4 groups (n = 10 each). (O-AD) is obese induced AD group maintained on HFD for another 6 weeks. OCR is obese group received calorie restricted diet for 6 weeks. OCRRK is obese group received calorie restricted diet and RK (44 mg/kg body weight, daily, orally) for 6 weeks and OCRD is obese group received calorie restricted diet and orlistate (10 mg/kg body weight, daily orally) for 6 weeks. Another 10 normal rats received normal diet were used as normal control group (NC). Body weight, visceral white adipose tissue weight (WAT), lipid profile, oxidative stress markers, adiponectin, cholinergic activity and amyloid extracellular plaques were examined. In addition to histological changes in brain tissues were evaluated.Raspberry ketone (RK) via its antioxidant properties attenuated oxidative damage and dyslipidemia in O-AD group. It inhibited acetylcholinesterase enzyme (AchE) and hence increased acetylcholine level (Ach) in brain tissues of O-AD rats. It is also impeded the upregulation of beta-secretase-1 (BACE-1) and the accumulation of amyloid beta (Aß) plaques which crucially involved in AD. The combination of CR diet with RK was more effective than CR diet with orlistate (antiobese drug) in abrogating the neurodegenerative changes induced by obesity. Results from this study suggested that concomitant supplementation of RK with calorie restricted regimen effectively modulate the neurodegenerative changes induced by obesity and delay the progression of AD.

The Use of the Chuang's Prognostic Scale to Predict the Survival of Metastatic Colorectal Cancer Patients Receiving Palliative Systemic Anticancer Therapy.

BACKGROUND: With the increasing number of agents active against cancer, advanced cancer patients including metastatic colorectal cancer (mCRC) patients may continue receiving palliative systemic anticancer therapy (PSAT) near the end-of-life. Validated palliative prognostic models, such as the Chuang's prognostic scale (CPS), may be helpful in identifying mCRC patients with limited survival who are unlikely to benefit from PSAT. AIM: To test the ability of the CPS to predict the survival of mCRC under treatment with PSAT. METHODS: CPS was prospectively assessed in 36 mCRC patients who were receiving PSAT. The scale is based on eight items: ascites, edema, cognitive impairment, liver and lung metastases, performance status, tiredness, and weight loss. The total CPS score ranges from 0 to 8.5 with the higher score indicating worse prognosis. RESULTS: Patients were divided into two groups using a CPS cutoff score of 5, Group 1 with a CPS score ≤5 and Group 2 with a CPS score >5. Using this cutoff value, 3-month mortality was predicted with a positive predictive value of 71%, a negative predictive value of 77%, a sensitivity of 67%, a specificity of 81% and an overall accuracy of 75%. Group 1 patients had a longer median survival of 149 days (95% confidence interval [CI]: 82-216) in comparison to Group 2 patients who had a median survival of 61 days (95% CI: 35-87). The difference in survival was statistically significant (P = 0.01). CONCLUSION: CPS may be useful in identifying mCRC patients with limited survival who are unlikely to benefit from PSAT.

Role of high resolution ultrasound/endosonography and elastography in predicting lymph node malignancy.

OBJECTIVE: The objective of this study is to evaluate the role of high resolution ultrasonography (US) and endoscopic ultrasound (EUS)-elastography in predicting malignant lymphadenopathy. PATIENTS AND METHODS: This prospective study included 88 patients who underwent EUS or US examination of different groups of lymph nodes (LNs). The classification as benign or malignant based on the real time elastography pattern and the B-mode US/EUS images was compared with the final diagnosis obtained by EUS or US guided fine-needle aspiration cytology (FNAC), tru-cut biopsy or excisional biopsy and follow-up in benign lesions not indicated for biopsy for at least 12 months. RESULTS: Regarding the echogenicity, 98.3% of the benign LNs were hyperechoic, 1.7% was hypoechoic while 89.7% of the malignant LNs were hypoechoic, 3.4% were heterogenous and 6.9% were hyperechoic. With cut-off value of 1.93, the sensitivity of longitudinal to transverse ratio was 73% and the specificity was 100%. Score 1 elastography had specificity of 100% in diagnosis of benign LNs, sensitivity was 76.3%, positive predictive value (PPV) was 100%, negative predictive value (NPV) was 84.7% while score 2 had a sensitivity of 60%, specificity of 31.5%, PPV of 15.3%, NPV of 79.3%. Score 3 had a sensitivity of 70.2%, specificity of 100%, PPV of 13.8%, NPV of 100% in detecting malignancy while score 4 had a sensitivity of 85.5%, specificity of 100%, PPV of 100%, NPV of 65.5%. CONCLUSION: Elastography is a promising diagnostic modality that may complement standard ultrasound and EUS and help guide FNAC during staging of LNs.

Adjuvant chemotherapy for luminal A breast cancer: a prospective study comparing two popular chemotherapy regimens.

INTRODUCTION: Based on the variable benefit of taxanes in the adjuvant setting of early breast cancer in certain tumor phenotypes, especially in human epidermal growth factor receptor (HER)2-positive and triple-negative disease, and with the observation of a lesser benefit in luminal A, this research article aimed at exploring the value of docetaxel in patients with an estrogen receptor-positive, HER2-negative disease phenotype, who might not derive the same benefits as those with other phenotypes. PATIENTS AND METHODS: This was a randomized prospective study comparing disease-free survival (DFS) and safety profile of sequential adjuvant three cycles Fluorouracil, Epirubicin, Cyclophosphamide followed by three cycles Docetaxel (FEC-D) versus six cycles classic Fluorouracil, Epirubicin, Cyclophosphamide (FEC)-100 in 60 Egyptian women who presented to Dar Al Fouad Hospital during the period June 2007 to July 2008 with (pT1-2 pN0-3 M0). The primary end point was DFS in a follow-up period of 4 years. The secondary end point was toxicity profile. RESULTS: Four-year DFS rates were comparable in both arms: 73.3% ± 8.1% in the FEC-D arm versus 76.5% ± 7.8% in the FEC-100 arm (P = 0.83). N3 and grade III subgroups achieved the worst DFS in both subgroups (P = 0.001 and P = 0.214, respectively). The rate of nausea and vomiting was higher in the FEC-100 arm (P = 0.49), while grade III-IV neutropenia and febrile neutropenia incidence was similar between both arms. CONCLUSION: Sequential adjuvant chemotherapy with FEC followed by docetaxel achieved comparable DFS results to FEC alone in luminal A phenotype subgroups of breast cancer.

Comparative study analyzing survival and safety of bevacizumab/carboplatin/paclitaxel and cisplatin/pemetrexed in chemotherapy-naïve patients with advanced non-squamous bronchogenic carcinoma not harboring EGFR mutation.

PURPOSE: The majority of Egyptian patients with lung cancer present at a late stage of the disease. Bevacizumab/carboplatin/paclitaxel, as well as cisplatin plus pemetrexed, are both standard regimens for advanced non-squamous bronchogenic cancer. This study compares both regimens, in terms of efficacy and toxicity profile, in Egyptian patients. PATIENTS AND METHODS: This is a randomized Phase II study comparing toxicity profile and survival in 41 chemotherapy-naïve patients with stage IIIB or IV non-squamous NSCLC, with an ECOG performance status of 0 to 2. The epidermal growth factor receptor (EGFR) mutation detection was performed prior to treatment of all patients. Patients in the first group received: bevacizumab 7.5 mg/m(2) on Day 1 and Day 15; carboplatin area under the curve-5 on Day 1; and paclitaxel 60 mg/m(2) on Day 1, Day 8, and Day 15 every 4 weeks. In the second group, patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) every 3 weeks. RESULTS: The combination of bevacizumab/carboplatin/paclitaxel demonstrated higher Grade III-IV toxicity than cisplatin/pemetrexed regarding sensory/motor neuropathy (P = 0.06), DVT (P = 0.23), proteinuria (P = 0.23), and hypertension (P = 0.11), as well as Grade II alopecia (P = 0.001); however, no significant difference in toxicities between both arms was recorded regarding nausea and vomiting (P = 0.66), hematological toxicity, febrile neutropenia (P = 1) and fatigue (P = 0.66). Progression-free survival was similar for both treatment arms with a median of 6 months (P = 0.978). Overall median survival was comparable in both arms, 16.07 months versus 16.01 months (P = 0.89). CONCLUSION: Bevacizumab/carboplatin/paclitaxel and cisplatin/pemetrexed provided meaningful and comparable efficacy in advanced non-squamous bronchogenic carcinoma not harboring EGFR mutation. No significant difference in toxicity was observed between both treatment arms, apart from bevacizumab/carboplatin/paclitaxel-related risks as DVT, hypertension, proteinuria, sensory/motor neuropathy, and alopecia.

Comparative study analyzing survival and safety of bevacizumab/carboplatin/paclitaxel versus carboplatin/docetaxel in initial treatment of metastatic Her-2-negative breast cancer.

PURPOSE: In view of the previous reports demonstrating the positive outcome of bevacizumab in metastatic breast cancer, we aimed at comparing the role of bevacizumab-based metronomic combination with taxane (paclitaxel) versus a different taxane (docetaxel)-based regimen in addition to carboplatin as initial treatment for metastatic Her-2-negative breast cancer. PATIENTS AND METHODS: This is a randomized Phase III study comparing the progression-free survival (PFS) and safety in Her-2-negative female patients with initial diagnosis of metastatic breast cancer with World Health Organization performance status of 0-II. Forty-one patients were randomized from September 2008 to July 2009 to receive either; (1) bevacizumab 5 mg/kg day 1 and day 15, carboplatin area under the curve (AUC)-2 day 1, day 8, and day 15, and paclitaxel 60 mg/m(2) day 1, day 8, and day 15 (arm-I); or (2) carboplatin AUC-5 day 1, docetaxel 75 mg/m(2) day 1 (arm-II). The Kaplan-Meier method was used for estimating survival; log-rank test for comparing survival curves. The primary end point was PFS, and secondary end points were overall survival (OS) and safety. RESULTS: PFS was 10 months in arm I versus 10.2 months in arm II (P = 0.9). The OS rate was similar in both arms: 37.6 months for arm I versus 37.4 months for arm II (P = 0.92). The toxicity revealed higher incidence of hypertension and proteinuria in arm I; however, with higher incidence of grade III-IV neutropenia and neutropenic fever in arm II. No treatment-related mortality was recorded. CONCLUSION: Bevacizumab/carboplatin/paclitaxel and carboplatin/docetaxel show comparable PFS and OS with different toxicity profiles.