Neuroblastoma and its Target Therapies: A Medicinal Chemistry Review.

Neuroblastoma (NB) is a childhood malignant tumour belonging to a group of embryonic tumours originating from progenitor cells of the sympathoadrenal lineage. The heterogeneity of NB is reflected in the survival rates of those with low and intermediate risk diseases who have survival rates ranging from 85 to 90 %. However, for those identified with high-risk Stage 4 NB, the treatment options are much more limited. For this group, current treatment consists of immunotherapy (monoclonal antibodies) in combination with anti-cancer drugs and has a 40 to 50 % survival rate. The purpose of this review is to summarise NB research from a medicinal chemistry perspective and to highlight advances in targeted drug therapy in the field. The review examines the medicinal chemistry of a number of drugs tested in research, some of which are currently under clinical trial. It concludes by proposing that future medicinal chemistry research into NB should consider other possible target therapies and adopt a multi-target drug approach rather than a one-drug-one-target approach for improved efficacy and less drug-drug interaction for the treatment of NB Stage 4 (NBS4) patients.

The effects of aging and frailty on inpatient glycemic control by continuous glucose monitoring in patients with type 2 diabetes.

BACKGROUND: Older adults with diabetes in the hospital are generally managed similarly to younger adults, however, it is unknown if the degree of frailty can affect glucose control among hospitalized patients. METHODS: We examined glycemic parameters derived from continuous glucose monitoring (CGM) in older adults with type 2 diabetes and frailty who were hospitalized in non-acute settings. Data was pooled from 3 prospective studies using CGM including 97 patients wearing Libre CGM sensors and 166 patients wearing Dexcom G6 CGM. Glycemic parameters (time in range (TIR) 70-180; time below range (TBR) <70 and 54 mg/dl) by CGM were compared between 103 older adults ≥60 years and 168 younger adults <60 years. Frailty was assessed using validated laboratory and vital signs frailty index FI-LAB (n = 85), and its effect on hypoglycemia risk was studied. RESULTS: Older adults, as compared to younger adults, had significantly lower admission HbA1c (8.76% ± 1.82 vs. 10.25% ± 2.29, p < 0.001), blood glucose (203.89 ± 88.65 vs. 247.86 ± 124.17 mg/dl, p = 0.003), mean daily BG (173.9 ± 41.3 vs. 183.6 ± 45.0 mg/dl, p = 0.07) and higher percent TIR 70-180 mg/dl (59.0 ± 25.6% vs. 51.0 ± 26.1%, p = 0.02) during hospital stay. There was no difference in hypoglycemia occurrence between older and younger adults. Higher FI-LAB score was associated with higher % CGM < 70 mg/dl (0.204) and % CGM < 54 mg/dl (0.217). CONCLUSION: Older adults with type 2 diabetes have better glycemic control prior to admission and during hospital stay compared to younger adults. Frailty is associated with longer presence of hypoglycemia in non-acute hospital settings.

Triple Negative Breast Cancer: 10-Year Survival Update of The Applied Treatment Strategy in Kuwait.

BACKGROUND: Triple negative breast cancer (TNBC) is recognized as a distinct clinical and biological entity of poor outcome for almost two decades, yet its treatment strategy still needs to be better specified. The study aim is to update the 10-year survival data of our TNBC patients and to find its association with different treatment modalities. PATIENTS AND METHODS: We updated the 10-year survival data of 359 women diagnosed with TNBC between 1999 and 2009 in the Kuwait Cancer Control Center (KCCC). The overall survival (OS), disease free survival (DFS), distant metastasis free survival (DMFS) and loco-regional recurrence free survival (LRFS) were estimated using Kaplan Meier method. Survival was correlated with different prognostic factors and treatment modalities. Statistical significance was calculated using the log-rank test and defined as p < 0.05. Cox regression is used for Multivariate analysis. RESULTS: TNBC represented 12% of breast cancer in Kuwait with a median age of 48 years. The stage distribution was as follow: stage I, II, III, IV in 15%, 43%, 35% and 7% of patients respectively. Regarding surgery, 33% had Conservative surgery; 67% had mastectomy; 82% had axillary clearance. Chemotherapy was neoadjuvant in 25%, adjuvant in 56% and palliative in 5% of patients. Two-thirds of patients (67%) received adjuvant radiotherapy. After a median follow-up of 108 months, the 10-year OS, DFS, DMFS and LRFS were 66%, 59%, 72% and 77% respectively. The 10-year OS was 92%, 80%, 49% and 0% for Stage I, II, III and IV respectively (p =< 0.0001). OS was significantly worse with the presence of lymphovascular invasion (LVI) with p = 0.003. OS was not significantly affected by age, grade or treatment modality. In multivariate analysis, the clinical stage and LVI were still significant (P<0.0001 and 0.04 respectively). CONCLUSION: In the absence of biological biomarkers, clinical stage and LVI seem to be the only significant prognostic factors for survival of TNBC patients in our study population. Timing of chemotherapy as well as the extent of surgery do not seem to affect the TNBC patients' outcome.

A suggested guiding panel of seromarkers for efficient discrimination between primary and secondary human hepatocarcinoma.

Although alpha-fetoprotein (AFP) is a golden diagnostic marker for hepatocellular carcinoma (HCC), its value is debatable. Differentiation between primary and secondary hepatocarcinomas (HC) relying on AFP is confusing, does not exceed 20 % in the later. To find alternative markers other than AFP to differentiate between primary and secondary HC from colorectal carcinoma (CRC) and breast (BC) and lung cancers (LC), 60 individuals were recruited: group 1, healthy volunteers; group 2, with primary; and group 3, with secondary HC. Carcinoembryonic antigen (CEA), total glycosaminoglycans (TGAGs), total sialic acid (TSA), free glucosamine (FGA), leucine aminopeptidase (LAP), 5'-nucleotidase (5'-NU) activities, and AFP were estimated in sera, in addition to liver histology. CEA, TGAGs, TSA, and FGA were elevated in secondary HC among CRC primary cancers, while LAP, 5'-NU activities, and AFP were elevated in primary HCC. We concluded that a new panel can be used to differentiate primary from secondary HC better than AFP, speculating the primary cancer. AFP, LAP, and 5'-NU predominated in primary, while CEA, TGAGs, TSA, and FGA, in secondary HC. Elevation of 5'-NU, LAP, TGAGs, TSA, and FGA to CEA indicated that primary source of HC is CRC. Association of TGAGs, TSA, and FGA only to CEA indicated that the primary cancer is breast. Elevation of TGAGs, TSA, and FGA, with other normal parameters, indicated that the primary cancer is lung. A guiding table is recommended in the oncology laboratory, for management and follow-up, and having more expected level of sensitivity than AFP.

Rat model of burn wound healing: effect of Botox.

Animal models of burn play a crucial role in studying the mechanisms of burn wound progression and the factors that regulate various stages of healing. In this study, using a rat model, we assessed the effect of Botox in the healing process through parameters like transepidermal water loss (TEWL), histological alterations, transforming growth factor beta (TGF-beta1) and tumor necrosis factor alpha (TNF-alpha). Fifty Sprague-Dawley rats were inflicted with 5 cm2 second degree burn and divided into 2 groups; one group was injected intralesionally with Botox and the other with saline. Daily observation and transepidermal water loss measurement were performed. Biopsies were taken on days 0, 3, 8, 14, and 28 for histology and polymerase chain reaction, testing TGF-beta and TNF-alpha. The results showed no significant difference in TEWL except for slightly better preservation of moisture with Botox. Histology revealed relatively better and faster regeneration with Botox, delayed lower grade inflammation, and increase in fibroblasts. TNF-alpha had an acute increase of 21-fold then tapered down while TGF-beta levels increased on day 3 after TNF-alpha, peaked on day 8 and then started to decrease until complete healing. Botox improved the healing process and the cosmetic appearance of burn scar.

Measured and Calculated Dose to the Junction between Supraclavicular Field and Tangential Fields Using Different Techniques in Post-Mastectomy Radiotherapy.

UNLABELLED: Appropriately delivered post-operative radiotherapy is an integral part in the multidisciplinary approach for the treatment of invasive breast cancer. THE AIM OF THE WORK: Is to find the most effective simple way to achieve homogeneous dose distribution to the junction of the supraclavicular beam and tangential beams, in absence of CT planning facilities, through measurement/calculation of dose using different techniques. MATERIAL AND METHODS: Alderson human phantom was planned and irradiated through 4 different techniques. Technique I, simple abutment of fields; technique II, table rotation in tangential fields; technique III, table rotation in tangential beams and half beam block in supraclavicular field; and technique IV, simple triangular block in supraclavicular field. Dose to the junctional area was both measured using film dosimetry, and calculated using CT planning (Precise plan). RESULTS: Simple abutment of fields resulted in a significant junctional overdose in both measured (125%) and calculated (171% to 20% of junctional volume) dose. Best results were seen in technique III (table rotation and half beam block) where the measured dose was 89% and calculated dose was 89% to 20% of junctional volume. Technique II and IV resulted in 120%, 120% measured dose and 128%, 138% calculated dose to 20% of volume of junctional area, respectively. CONCLUSION: Table rotation in tangential beams and half beam block in supraclavicular beam seems to be an effective and simple method to prevent junctional overlap in the sitting of post-mastectomy radiotherapy for breast cancer in case of absence of CT-based treatment planning and conformal radiotherapy. KEY WORDS: Radiotherapy - Postmastectomy - Supraclavicular field - Tangential field.

Functional localization of cAMP signalling in cardiac myocytes.

The cAMP pathway is of cardinal importance for heart physiology and pathology. The spatial organization of the various components of the cAMP pathway is thought to allow the segregation of functional responses triggered by the different neuromediators and hormones that use this pathway. PDEs (phosphodiesterases) hydrolyse cAMP (and cGMP) and play a major role in this process by preventing cAMP diffusion to the whole cytosol and inadequate target activation. The development of olfactory cyclic nucleotide-gated channels to directly monitor cAMP beneath the plasma membrane in real time allows us to gain new insights into the molecular mechanisms responsible for cAMP homoeostasis and hormonal specificity in cardiac cells. The present review summarizes the recent results we obtained using this approach in adult rat ventricular myocytes. In particular, the role of PDEs in the maintenance of specific cAMP signals generated by beta-adrenergic receptors and other G(s)-coupled receptors will be discussed.

Serum neuron-specific enolase, carnosinase, and their ratio in acute stroke. An enzymatic test for predicting outcome?

BACKGROUND AND PURPOSE: Few admission variables adequately predict neuronal damage and prognosis in individual patients after stroke. Therefore, there is a need for a reliable non-invasive surrogate measure of clinical outcome. METHODS: We have developed a surrogate measure of stroke outcome using the ratio of serum neuron-specific enolase (NSE) to human serum carnosinase (HSC) in 124 patients with acute ischemic or hemorrhagic stroke and 61 matched control subjects. Serum NSE is known to rise and HSC to fall after neuronal injury such as cerebral ischemia. RESULTS: Serum NSE levels were significantly higher and HSC levels lower in the patient group. The NSE/HSC ratio was elevated in patients with stroke: median (semiquartile) hemorrhages, 0.072 (0.033); infarcts, 0.039 (0.026); and control subjects, 0.019 (0.014), P = .0001. Patients with a primary intracerebral hemorrhage had nonsignificantly higher ratios than those with an infarct (P = .082). The NSE/HSC ratio was significantly associated with 90-day outcome measured in two out of three disability and handicap scales: modified Barthel Index (rs = -.34, P = .001), modified Rankin Scale (rs = .30, P = .002), and Lindley Score (rs = .19, P = .057). Patients who died or were institutionalized had higher ratios than those who were discharged home: 0.069 (0.043) versus 0.038 (0.024), P = .011. Correlations between the NSE/HSC ratio and outcome were comparable to those between patient age or consciousness level on admission and clinical outcome. CONCLUSIONS: We believe that measurement of NSE, HSC, or their ratio may be useful in the assessment of patients with acute stroke with respect to diagnosis and prediction of clinical outcome.

Coherence tuned fiber optic sensing system, with self-initialization, based on a multimode laser diode.

In this paper we study the potential of using multimode laser diodes as an alternative to low coherence length sources normally used white light fiber optic interferometric sensors. A simple theoretical model is introduced to demonstrate the autocorrelation function of such sources. An experimental setup of two interferometers in tandem was used to study the coherence properties of the multimode laser diode Mitsubishi ML-4406 and then to demonstrate the possibility of using it in coherence tuned multiplexing systems. The main advantage of using such sources is to launch more optical power into the monomode fiber and hence to improve the system resolution.

High-sensitivity fiber-optic accelerometer.

We describe a novel accelerometer in which the sensing element is a weighted diaphragm. The displacement of the diaphragm produced by acceleration is measured using a miniature hemispherical air-spaced Fabry-Perot interferometer, of which one mirror is mounted on the diaphragm. The interferometer is illuminated by a diode laser and addressed through a monomode optical fiber.

Practical fiber-optic-based submicro-g accelerometer free from source and environmental perturbations.

We describe a novel accelerometer in which the sensing element is a weighted diaphragm designed to have minimal cross coupling. The displacement of the diaphragm, produced by acceleration, is measured by using two miniature hemispherical air-spaced Fabry-Perot interferometers, one constructed on either side of the diaphragm. The output of the two interferometers is processed such that the detrimental effects caused by wavelength drift of the source and variation in temperature of the sensor are reduced by 45.8 and 27.3 dB, respectively, compared with those of a single interferometer.