Rethinking the usefulness of bone marrow biopsy on treatment decision in CLL patients at diagnosis

We aimed to investigate the role of bone marrow infiltration pattern (BMIP) and bone marrow reticulin fibrosis (BMRF) in determining treatment demand in patients with diagnosis of chronic lymphocytic leukemia (CLL). We retrospectively evaluated the data of 65 patients, who were followed with the diagnosis of CLL at Istanbul Training and Research Hospital, Department of Hematology, between July 2007 and June 2016. The median age of the patients was 64 years (range, 32–83). Twenty-three (35.4%) patients were female, and 42 (64.6%) were male. Early/mild grade BMRF was observed in 46 (70.8%) patients and advanced grade BMRF in 19 (29.2%) patients. Eleven (23.9%) of 46 patients with early/mild grade BMRF and 10 (52.9%) of 19 patients with advanced grade BMRF required treatment during follow-up (p = 0.04). According to the BMIP, 14 (21.5%) patients had diffuse and 51 (78.5%) patients had non-diffuse BMIP. Eleven (78.6%) of 14 patients with diffuse BMIP and 10 (19.6%) of 51 patients with non-diffuse BMIP required treatment during follow-up (p < 0.001). In univariate analysis, both advanced grade BMRF and diffuse BMIP had an impact on occurrence of treatment demand (p = 0.028, HR = 3.535 vs. p < 0.01 HR = 15.033). Multivariate analysis also revealed diffuse BMIP to be effective (p < 0.001, HR 13.089), while advanced grade BMRF failed to significantly influence treatment demand (p = 0.140, HR 2.664). In conclusion, in the light of our findings, it is reasonable to consider that bone marrow biopsy at the time of diagnosis might provide a preliminary information about treatment demand in patients with CLL.     

Synergism from combinations of cisplatin and oxaliplatin with quercetin and thymoquinone in human ovarian tumour models

The development of drug resistance remains one of the major hurdles in cancer chemotherapy, particularly so for ovarian cancer. Combination of drugs acting synergistically in combination can offer a means of overcoming drug resistance. In this study, two tumour-active phytochemicals, quercetin and thymoquinone, were combined with two platinum drugs, cisplatin and oxaliplatin, with the aim of providing a means of overcoming drug resistance. Two human epithelial ovarian cancer cell lines, A2780 and its cisplatin-resistant form (A2780(cisR)) were treated with binary combinations of cisplatin and oxaliplatin with quercetin and thymoquinone using three sequences of administration. Cell viability was quantified using the (MTT) reduction assay. The combined drug action was analysed based on the equations derived by Chou and Talalay (1984). Greatest synergism was observed when the phytochemical was added first followed by platinum drug 2 h later and the least synergism (often additive to antagonistic) was observed when the two compounds were administered as a bolus. It is suggested that the addition of the phytochemical 2 h before platinum drug may sensitize cancer cells to platinum action, thus offering a means of overcoming drug resistance. The results may be highly significant clinically if found to be confirmed in vivo.     

Studies on synthesis, activity and binding with DNA of a new trinuclear platinum compound [{trans-PtCl(NH3)2}2{trans-Pt(thiazole)2}{H2N(CH2)(6NH2}2]Cl3(NO3)

A new trinuclear platinum compound [{trans-PtCl(NH(3))(2)}(2){trans-Pt(thiazole) (2)}{H(2)N(CH(2))(6)NH(2)}(2)]Cl(3) (NO(3)) has been synthesized and characterized. The activity of the compound against three human ovarian cancer cell lines A2780, A2780(cisR) and A2780(ZD0473R), its cell uptake and level of binding with DNA have been determined. JH5 is found to be less active than cisplatin against parent A2780 cell line but more active than cisplatin against the A2780(cisR) and A2780(ZD0473R) resistant cell lines indicated by the lower resistance factors. The results indicate that at the level of its activity JH5 has been better able to overcome mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R) cell lines. JH5 has higher cellular accumulation of platinum than cisplatin in the A2780(cisR) and A2780(ZD0473R) resistant cell lines but lower than cisplatin in the parents A2780 cell line. Cisplatin binds with DNA forming mainly bifunctional intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts that cause local bending of DNA strand. In contrast, JH5 is expected to bind with DNA to form mainly interstrand long-range G-Pt..Pt..Pt(G) adducts that would induce more of a global change in DNA conformation.     

Synthesis of trans-bis-(2-hydroxypyridine)dichloroplatinum(II) and its activity in human ovarian tumour models

We report the synthesis and in vitro activity of trans-bis-(2-hydroxypyridine)dichloroplatinum(II) (coded as DH3) in humour ovarian tumour models. The compound is less active than cisplatin against the parent cell line A2780 but more so against the cisplatin-resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) cell line. DH3 is marginally less active than cisplatin against ZD0473-resistant A2780(ZD0473R) cell line but with a much lower resistance factor than cisplatin. DH3 has higher platinum-DNA binding levels than cisplatin in the A2780 and A2780(ZD0473) cell lines and a lower value in the A2780(cisR) cell line. Even though DH3 has a lower activity than cisplatin, the higher platinum-DNA binding levels observed for DH3 than cisplatin in A2780 and A2780(ZD0473R) cell lines may not be entirely unexpected when we note that the two compounds are likely to differ in their nature of binding with DNA. Whereas cisplatin binds with DNA forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH3 is expected to form more 1,2-interstrand Pt(GG) and monofunctional adducts. The higher activity of DH3 than cisplatin in the A2780(cisR) cell line despite its lower level of platinum-DNA binding can also be seen to indicate the complexity of the situation. Although platinum-DNA binding may be an essential requirement for apoptosis, it is not sufficient to cause cell death that is actually brought about by downstream processes in the cycle. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion show that DH3 is less able to prevent BamH1 digestion than is cisplatin, indicating that cisplatin causes a greater conformational change in the DNA than DH3. CONCLUSION: DH3 is less active than cisplatin against the parent cell line A2780, but more so against the cisplatin-resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) cell line.     

Hypoglycaemia in under-five children with diarrhoea

The present study aimed to observe the clinical features ofhypoglycaemia, and identify predictors of hypoglycaemia in under-fivediarrhoeal children requiring hospitalization for close observationand support. Such information could be useful to the cliniciansand policy makers in developing appropriate management protocolsboth for identification of such children and optimizing theirmanagement. We performed a prospective study in 782 under-fivechildren who presented with diarrhoeal illnesses. Blood glucosewas determined when hypoglycaemia was suspected in 598 (62%),and 65 (11%) of them were hypoglycaemic (study group). Fromthe other 533 non-hypoglycaemic children, 195 were randomlyselected as comparison group. Bacteraemia was significantly(P = 0.026) often detected in 17 out of 260 (7%) children asopposed to 3 out of 184 (2%) children who did not have a rapidglucose test performed. Among hypoglycaemic children, 7 (11%)were bacteraemic and among non-hypoglycaemic children 10 (5%)had bacteraemia. In univariate analysis, history of shorter(<72 h) pre-admission duration of diarrhoea (75 vs. 58%,P = 0.01), documented convulsion (28 vs. 11%, P < 0.001),shorter (<72 h) hospitalization (52 vs. 33%, P = 0.01), highercase fatality rate (28 vs. 14%, P = 0.02) were associated withhypoglycaemia. In logistic regression, bacteraemic children(with clinical sepsis) were 4 times more likely to develop hypoglycaemia(OR = 4.2, 95% CI = 1.4–12.9, P = 0.012). Therefore, ina diarrhoeal disease health care service with limited resources,a rapid bedside glucose test may be considered as an inexpensivealternative in the management decisions of diagnosing bacteraemiaand initiating empiric antibiotic treatment.     

Bacterial Mediated Rapid and Facile Synthesis of Silver Nanoparticles and Their Antimicrobial Efficacy against Pathogenic Microorganisms

In the present study, silver nanoparticles (AgNPs), biosynthesized using culture supernatant of bacterial strain Paenarthrobacter nicotinovorans MAHUQ-43, were characterized and their antimicrobial activity was investigated against both Gram-positive Bacillus cereus and Gram-negative bacteria Pseudomonas aeruginosa. Bacterial-mediated synthesized AgNPs were characterized by UV-Visible (UV-Vis) spectrophotometer, field emission-transmission electron microscopy (FE-TEM), energy dispersive X-ray (EDX), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and dynamic light scattering (DLS) analysis. The UV-Vis spectral analysis showed the absorption maxima at 466 nm which assured the synthesis of AgNPs. The FE-TEM analysis revealed the spherical shape of nanoparticles with the size range from 13 to 27 nm. The EDX and XRD analysis ensured the crystalline nature of biosynthesized AgNPs. The FTIR analysis revealed the involvement of different biomolecules for the synthesis of AgNPs as reducing and capping agents. The bacterial-mediated synthesized AgNPs inhibited the growth of pathogenic strains B. cereus and P. aeruginosa and developed a clear zone of inhibition (ZOI). The MIC and MBC for both pathogens were 12.5 µg/mL and 25 µg/mL, respectively. Moreover, field emission scanning electron microscopy analysis revealed that the synthesized AgNPs can destroy the outer membrane and alter the cell morphology of treated pathogens, leading to the death of cells. This study concludes the eco-friendly, facile and rapid synthesis of AgNPs using P. nicotinovorans MAHUQ-43 and synthesized AgNPs showed excellent antimicrobial activity against both Gram-positive and Gram-negative pathogens.     

Localizing moving targets and organs using motion-managed CTs.

Respiration-induced target and organ motion impacts the radiotherapy strategies of some cancers. Various methods and techniques have been used to investigate motion-related radiotherapy issues, including retrospective 4-dimensional (4D) computed tomography (CT), prospective gated CT, and breath-hold CT scans. This paper reviews these methods and, particularly, the method using retrospective 4D CT scans, which has been developed at our institution. Some motion studies based on retrospective 4D CT images of patients are also examined. These studies have led to reduced planning target volume (PTV) margins for a number of patients, because the respiratory motion was observed to be minimal or gated radiotherapy was used. Respiratory motion managed CTs and, particularly, retrospective 4D CTs are proving to be useful for measuring soft tissue motion, identifying patients who could benefit from gated radiotherapy, and evaluating the effects of respiratory motion during radiotherapy.