QSAR modeling and molecular docking studies of 2-oxo-1, 2-dihydroquinoline-4- carboxylic acid derivatives as p-glycoprotein inhibitors for combating cancer multidrug resistance.

Multidrug resistance (MDR) proteins related to the ATP-binding cassette family are found in a very wide range of human tumors and result in therapeutic failure. The overexpression of efflux pumps such as ABCB1 is one of the mechanisms of MDR. This paper aims to develop a reliable quantitative structure-activity relationship (QSAR) model that best describes the correlation between the activity and the molecular structures in order to predict the inhibitory biological activity towards ABCB1. In this regard, a series of quinoline derivatives of 18 compounds were analyzed using different linear and non-linear machine learning (ML) regression methods including k-nearest neighbors (KNN), decision tree (DT), back propagation neural networks (BPNN) and gradient boosting-based (GB) methods. Their aim is to explain the origin of the activity of these investigated compounds and therefore, design new quinoline derivatives with higher effect on ABCB1. A total of 16 ML predictive models were developed on different number of 2D and 3D descriptors and were evaluated using the coefficient of determination (R2) and the root mean squared error (RMSE) statistical metrics. Among all developed models, A GB-based model in particular catboost achieved the highest predictive quality, with one descriptor, expressed by R2 and RMSE of 95% and 0.283 respectively. Molecular docking studies against the target crystal structure of the outward-facing p-glycoprotein (6C0V) revealed significant binding affinities via both hydrophobic and H-bond interactions with the relevant compounds. The 17 has shown the highest binding energy of -9.22 kcal/mol. Therefore, it can suggest that 17 may prove to be a valuable potential lead structure for the design and synthesis of more potent P-glycoprotein inhibitors for combination used with anti-cancer drugs for cancer multidrug resistance management.

High temperature rise dominated cracking mechanisms in ultra-ductile and tough titanium alloy.

Extensive use of titanium alloys is partly hindered by a lack of ductility, strain hardening, and fracture toughness. Recently, several ß-metastable titanium alloys were designed to simultaneously activate both transformation-induced plasticity and twinning-induced plasticity effects, resulting in significant improvements to their strain hardening capacity and resistance to plastic localization. Here, we report an ultra-large fracture resistance in a Ti-12Mo alloy (wt.%), that results from a high resistance to damage nucleation, with an unexpected fracture phenomenology under quasi-static loading. Necking develops at a large uniform true strain of 0.3 while fracture initiates at a true fracture strain of 1.0 by intense through-thickness shear within a thin localized shear band. Transmission electron microscopy reveals that dynamic recrystallization occurs in this band, while local partial melting is observed on the fracture surface. Shear band temperatures of 1250-2450 °C are estimated by the fusible coating method. The reported high ductility combined to the unconventional fracture process opens alternative avenues toward Ti alloys toughening.

Quantification by aberration corrected (S)TEM of boundaries formed by symmetry breaking phase transformations.

The present contribution gives a review of recent quantification work of atom displacements, atom site occupations and level of crystallinity in various systems and based on aberration corrected HR(S)TEM images. Depending on the case studied, picometer range precisions for individual distances can be obtained, boundary widths at the unit cell level determined or statistical evolutions of fractions of the ordered areas calculated. In all of these cases, these quantitative measures imply new routes for the applications of the respective materials.

Direct imaging of boron segregation at dislocations in B:diamond heteroepitaxial films.

A thin film of heavily B-doped diamond has been grown epitaxially by microwave plasma chemical vapor deposition on an undoped diamond layer, on top of a Ir/YSZ/Si(001) substrate stack, to study the boron segregation and boron environment at the dislocations present in the film. The density and nature of the dislocations were investigated by conventional and weak-beam dark-field transmission electron microscopy techniques, revealing the presence of two types of dislocations: edge and mixed-type 45° dislocations. The presence and distribution of B in the sample was studied using annular dark-field scanning transmission electron microscopy and spatially resolved electron energy-loss spectroscopy. Using these techniques, a segregation of B at the dislocations in the film is evidenced, which is shown to be intermittent along the dislocation. A single edge-type dislocation was selected to study the distribution of the boron surrounding the dislocation core. By imaging this defect at atomic resolution, the boron is revealed to segregate towards the tensile strain field surrounding the edge-type dislocations. An investigation of the fine structure of the B-K edge at the dislocation core shows that the boron is partially substitutionally incorporated into the diamond lattice and partially present in a lower coordination (sp(2)-like hybridization).

Dislocation-mediated relaxation in nanograined columnar palladium films revealed by on-chip time-resolved HRTEM testing.

The high-rate sensitivity of nanostructured metallic materials demonstrated in the recent literature is related to the predominance of thermally activated deformation mechanisms favoured by a large density of internal interfaces. Here we report time-resolved high-resolution electron transmission microscopy creep tests on thin nanograined films using on-chip nanomechanical testing. Tests are performed on palladium, which exhibited unexpectedly large creep rates at room temperature. Despite the small 30-nm grain size, relaxation is found to be mediated by dislocation mechanisms. The dislocations interact with the growth nanotwins present in the grains, leading to a loss of coherency of twin boundaries. The density of stored dislocations first increases with applied deformation, and then decreases with time to drive additional deformation while no grain boundary mechanism is observed. This fast relaxation constitutes a key issue in the development of various micro- and nanotechnologies such as palladium membranes for hydrogen applications.

Advanced three-dimensional electron microscopy techniques in the quest for better structural and functional materials.

After a short review of electron tomography techniques for materials science, this overview will cover some recent results on different shape memory and nanostructured metallic systems obtained by various three-dimensional (3D) electron imaging techniques. In binary Ni-Ti, the 3D morphology and distribution of Ni4Ti3 precipitates are investigated by using FIB/SEM slice-and-view yielding 3D data stacks. Different quantification techniques will be presented including the principal ellipsoid for a given precipitate, shape classification following a Zingg scheme, particle distribution function, distance transform and water penetration. The latter is a novel approach to quantifying the expected matrix transformation in between the precipitates. The different samples investigated include a single crystal annealed with and without compression yielding layered and autocatalytic precipitation, respectively, and a polycrystal revealing different densities and sizes of the precipitates resulting in a multistage transformation process. Electron tomography was used to understand the interaction between focused ion beam-induced Frank loops and long dislocation structures in nanobeams of Al exhibiting special mechanical behaviour measured by on-chip deposition. Atomic resolution electron tomography is demonstrated on Ag nanoparticles in an Al matrix.

Okadaic acid and its interaction with sodium, potassium, magnesium and calcium ions: complex formation and transport across a liquid membrane.

Okadaic acid, a macrocyclic polyether compound, was shown to mediate the transfer of Na+, K+, Mg2+ and Ca2+ ions from aqueous solution to an organic phase, with a preference for Na+ ions. A kinetic study of the transport of these ions across a liquid membrane showed that the Na+ ion was more rapidly transported than the other ions and that the Na+ ion flux was dependent on the okadaic acid concentration.

Cancer in the Eastern Region of Saudi Arabia: A population-based study (1987-1988).

This study presents the findings of the first population-based tumor registry in the Eastern region (ER). Data on all cancer sites, in 1987 and 1988, were captured from all health facilities in the ER. A regional population census was obtained from regional health authorities. Cancer deaths were obtained from death registries. Age-specific rate, crude incidence rate (CIR), age-standardized incidence rate (ASR) and relative age-standardized incidence rate (%ASR) were compared with available population-based data from 137 tumor registries. 1559 primary cancer cases were captured. The CIR and ASR/100,000/year for cancer among Saudi males were respectively 59.8 and 125.7. The corresponding rates among Saudi females were 43.6 and 95.5. These rates rank very low on the international scale. Cancer sites with the highest %ASR among Saudi males were lung, lymphomas, leukemias, urinary bladder and tumors of uncertain primary. For Saudi females, these sites were breast, leukemias, tumors of brain and nervous system, thyroid and tumors of uncertain primary. Lung cancer was the leading cause of death from cancer among Saudi males. The first regional population-based cancer registry in Saudi Arabia was established in 1987. The overall cancer ASR in the ER is low. The leading cancer sites with the highest %ASR are lung in Saudi males and breast in Saudi females.

A multicenter study of recombinant human erythropoietin (epoetin alpha) in the management of anemia in cancer patients receiving chemotherapy.

Current evidence suggests that epoetin alpha administration is well tolerated and effective in the management of anemia of cancer and cancer chemotherapy. An open-label, multinational, non-comparative study was conducted in 215 cancer patients with anemia secondary to chemotherapy with platinum- or non-platinum-based combinations. Epoetin alpha was administered s.c. (150 IU/kg three times/week) for a planned period of 16 weeks. The response rate of epoetin alpha, defined as an increase in hemoglobin level of 2 g/dl or more from baseline, was 67%. The rate of response was not related to the chemotherapy regimen administered (platinum or non-platinum based). The percentage of patients transfused and the transfusion rate during epoetin alpha treatment were reduced. Transfusional need was eliminated in 64 (75%) of the 85 patients transfused before the study start, after 1 month of therapy. Quality of life, assessed using a visual analog scale, improved markedly in patients who experienced a hematological response. These patients also experienced a statistically significant (p < 0.0001) improvement in mean WHO performance score. These findings indicate that epoetin alpha is a well tolerated and effective agent which increases hemoglobin concentration and reduces transfusion requirements in anemic cancer patients receiving chemotherapy.

[Pancreatitis of hydatid origin]. / Pancréatite d'origine hydatique.

INTRODUCTION: Hydatic cysts of the liver are known to rupture into the biliary tree, but acute pancreatitis is an uncommon consequence. CASE REPORT: A 30-year-old woman who had undergone cholecystectomy 8 years earlier for gall bladder stones was hospitalized because of acute abdominal pain. Acute pancreatitis was diagnosed. Abdominal sonography showed a hydatic cyst. Fifteen days after admission after normalization of the amylasemia, surgical cure was successful. DISCUSSION: This case demonstrates that hepatic material can migrate via the main bile duct and provoke acute pancreatitis. Fistula drainage via the Oddi sphincter can be successful.

[Penetrating injuries of the abdomen. Results of two classical and selective attitudes in the management of 249 wounds]. / Les plaies pénétrantes de l'abdomen. Résultats des 2 attitudes classique et sélective dans la prise en charge de 249 plaies.

The systematic surgical exploration of each abdominal penetrating wound allows an exact out-come of lesions and an adequate treatment without delay. But these advantages are made upon a possibly 30% negative laparotomy. The selective attitude in the management of these abdominal's wounds has permitted to decrease this rate to 5% with a risk of secondary operation for non primary detected lesions in 5%. Our attitude toward 249 penetrative abdominal's wounds was classic and selectable respectively from 86 to 89 and 90 to 93. The results has confirmed the literature's date and especially has shown no significant difference between the two attitude concerning the morbidity and the mortality.

[Hydatid cyst of the psoas muscle]. / Les kystes hydatiques du muscle psoas.

Hydatid cysts in the psoas muscle are unusual. The authors report a case of a hydatid cyst which had developed within the psoas muscle and was detected from a mass in the left iliac fossa which was diagnosed before surgery by ultrasound and a CT scan, which remain the preferred primary examinations for the investigation of masses of this type. The authors discuss the various possible clinical and paraclinical contexts and recommend total pericystectomy of a closed cyst as the best treatment following extraperitoneal iliac surgical opening.

Breast cancer in a low-risk population. The influence of age and menstrual status on disease pattern and survival in Saudi Arabia.

Data on 130 women with invasive breast cancer, seen at our institution between April 1981 and November 1990, were retrospectively reviewed to assess the influence of age and menstrual status on the pattern and prognosis of their disease. Patients were mostly young (median age 40 years) and in 21 patients (16%) the diagnosis was established at the age of 30 years or younger. Eighty-six patients (66%) were under 50 and 82 patients (63%) were pre-menopausal. Pre-menopausal patients were more numerous than expected in stage III and less numerous in stage II. On the other hand, the differences between observed and expected values for both stage I and stage IV in the 2 menopausal groups were not significant. Compared with post-menopausal patients, pre-menopausal patients with 1-3 or greater than 3 positive lymph nodes were more numerous than expected. Differences between pre-menopausal and post-menopausal patients have persisted after categorizing patients into 2 age-groups with a cut-off point at 50 years. Comparable initial assessment and therapeutic modalities were offered to the 2 menopausal groups. At the time of analysis (January, 1991) all patients had a complete follow-up. Over a median follow-up of 46 months, the overall median survival (+/- SE) was 85.7 (+/- 4.4) months with a survival probability (+/- SE) at 5 years of 62% (+/- 5%). The proportional hazard model of Cox has identified advanced stage (stages III and IV) and involvement of lymph nodes as the only independent adverse predictors of survival with estimated hazard rates of 2.9 and 2.8, respectively. Unadjusted analysis, adjusted analysis and stratified survival functions failed to reveal any survival difference based on age or menstrual status. We conclude that, in a low-risk population and despite apparent baseline differences in demographic and disease characteristics between pre-menopausal and post-menopausal breast cancer patients, neither age nor menopausal status had a significant influence on survival. Our results should guide future cancer-care programs in Saudi Arabia.

Community acquired acute bacterial and atypical pneumonia in Saudi Arabia.

BACKGROUND: Rational treatment of pneumonia requires knowledge of the likely aetiological diagnosis in any community. Little is known about the pattern and outcome of pneumonia in Saudi Arabia. METHODS: A total of 567 pneumonic episodes in adult patients from the Al-Qassim area were reviewed retrospectively. RESULTS: Patients had a mean age of 42.7 years, with 103 patients (18%) aged 13 to 20 years and 103 (18%) aged 60 or more. Almost two thirds of the episodes (64%) occurred in men. An aetiological diagnosis was established in 351 (62%) cases, with 145 episodes being due to pneumococcal infection and 129 to Mycoplasma pneumonia. Inhospital mortality was 6% (35 patients). Age over 60 years, aspiration pneumonia, and Gram negative infection were the only factors that independently predicted adverse outcome on adjusted mortality analysis. CONCLUSION: This analysis of pneumonia in the Al-Qassim area indicates the pattern and prognosis of acute bacterial and atypical pneumonia that requires admission to hospital in the central region of Saudi Arabia. It should provide a basis for developing rational treatment for community acquired pneumonia in Saudi Arabia.

Splenectomy for hematological disorders in the Eastern Province of Saudi Arabia.

Splenomegaly is a common clinical disorder in the Kingdom of Saudi Arabia. Its aetiology is variable and includes portal hypertension due to schistosomal periportal hepatic fibrosis, haemoglobinopathies and lymphoproliferative disorders. At King Fahd Hospital of the University, Al-Khobar in the Eastern Province of the Kingdom, splenectomy is performed frequently for various reasons on patients drawn from all the Provinces. This is a report of 104 patients (age range eight months to 65 years) who underwent splenectomy between 1982 and 1987. We reviewed the indications, operative findings, outcome, and complications of the procedure. Patients with hypersplenism formed the largest group (50%) subjected to splenectomy followed by those suffering from the haemoglobinopathies. Chest infection as the most common complication and it mainly affected patients with portal hypertension. Post-operative septicaemia occurred in four cases within six months from the date of splenectomy.

Life events stress in Saudi peptic ulcer patients of the eastern province.

The frequency of stress, as measured by the occurrence of 34 life events in the year preceding evaluation, was compared between 51 Saudis with peptic ulcers, diagnosed endoscopically, and 52 Saudis without peptic ulcer. All subjects were examined at King Fahd Hospital, Al-Khobar, Eastern Saudi Arabia, and were seen between March 1985 and July 1987. The mean number of events, their frequency distribution, and their categorization into areas of activity such as bereavement and other problems relating to health, marital, financial, and undesirable circumstances were similar for both groups. With regard to individual events, the only significant differences between ulcer patients and controls were that more patients had had serious arguments with in-laws or relatives and more controls had had minor personal illness or moderate financial problems. Excessive stress, as measured by life events, does not appear to be evident in Saudi peptic ulcer patients of the Eastern Province. Anxiety and/or depression was significantly more frequent in the group of patients with ulcers.

Public knowledge, misperceptions, and attitudes about cancer in Saudi Arabia.

We interviewed six hundred adults to assess their awareness, attitude and misperceptions about cancer. The mean age (+/- SD) was 31.2 (+/- 8.7) years. Fifty-six percent of the participants were males and 75% were Saudis. Nationality and having a relative who had cancer were found to be insignificant predictors of attained knowledge. Despite a minor difference between males' and females' performance, gender did not influence knowledge. Education was the most significant factor that influenced individuals' knowledge and misperceptions. The most significant difference was noted between those who had university or higher education (level III, 41%) and those who were illiterate or only had primary schooling (level I, 16%). The difference between level I and level II (secondary and high school, 43%) was less obvious. The analysis also showed that individuals who were > 30 years of age generally showed more knowledge and fewer misconceptions about cancer than younger participants. Age, however, together with education deviated only 5% in the variability of the total score. A high level of misperception was observed among all respondents specifically relating to questions regarding side effects of conventional therapy and statements about unproven treatment. This analysis demonstrated that knowledge about cancer was disappointingly poor and the level of misperceptions significantly high. Possessing higher academic credentials alone, is not sufficient to acquire an optimal standard of health knowledge. The data also suggest that there should be comprehensive cancer health education and primary and secondary cancer prevention programs in Saudi Arabia. To achieve this goal, primary care physicians and community cancer centers should work jointly. Brief guidelines are proposed.

Unusual presentation of cancer.

The large bowel is the most frequent primary site for metastases in inguinal hernial sacs. We report four cases, two due to carcinoid of unknown primary, and one each due to adenocarcinoma of colon, stomach and pancreas. We recommend that all hernial sacs, particularly in the elderly, be examined microscopically.