Quinacrine has anticancer activity in breast cancer cells through inhibition of topoisomerase activity

The small molecule Quinacrine (QC, a derivative of 9-aminoacridine), an anti-malaria drug, displays activity against cancer cell lines and can simultaneously suppress nuclear factor-κB (NF-κB) and activate p53 signaling. In this study, we investigated the anticancer mechanism underlying these drug activities in breast cancer cell lines. QC caused a dose-dependent decrease of both anchorage dependent and independent growth of breast cancer cells (MCF-7 and MDA-MB-231) without affecting normal breast epithelial cells (MCF-10A), as evident from clonogenic cell survival, [3-(4,5-dimethylthiazol-2yl-)-2,5-diphenyl tetrazolium bromide] viability, wound healing and soft agar growth. QC activated the proapoptotic marker Bax, PARP cleavage, p53 and its downstream target, p21 (Cip1/Waf1) and downregulated the antiapoptotic marker Bcl-xL and relative luciferase activity of NF-κB in MCF-7 cells. Results of DAPI nuclear staining and FACS analysis show that QC increased apoptosis in a dose-dependent manner. QC caused apoptosis by increasing the cell population in S-phase and simultaneously decreasing the G1 and G2/M populations. A dose-dependent increase of DNA damage as measured by the comet assay was seen in MCF-7 cells after exposure to QC. With regards to the mechanism of DNA damage, we found that QC inhibited topoisomerase activity in MCF-7 cells by increasing the unwinding of supercoiled DNA. Collectively, the results demonstrate that QC has efficient anticancer potential against breast cancer cells via not only an induction of p53 and p21 but also an induction of S phase arrest, DNA damage and inhibition of topoisomerase activity.     

Heavy metal pollution of river Yamuna in the industrially developing state of Haryana

Heavy metal concentrations viz. Fe, Ni, Pb, Cd, Co, Zn in the river Yamuna flowing along the state of Haryana through Delhi have been reported selecting 16 stations covering the upstream and downstream stations for major industrial complexes of the state. While Fe, Ni and Co concentrations exceeded the maximum permissible limits prescribed for drinking all along the river, the Cd concentrations crossed the acceptable standards in Delhi downstream. The Pb concentrations declined in the eutrophicated Delhi downstream while Zn concentrations remained within desirable limits throughout. Peak concentrations were recorded in Delhi downstream for Fe and at Sonepat-Gohana downstream for Ni, Co & Zn, which matched with the type of industrial inputs viz. Iron-works and the electroplating, galvanizing & cycle industries, respectively. The status of heavy metal pollution of the river has been discussed with respect to possible impacts on human health and aquatic life.     

Nasogastric tube knotting over the epiglottis: a cause of respiratory distress

IMPLICATIONS: Nasogastric tube placement can cause ulceration and bleeding from the nose, pharynx, esophagus, and stomach. Its accidental placement into the tracheopulmonary system may lead to pneumothorax, hemothorax, or even death. We report a case of its knotting over the epiglottis, leading to life-threatening respiratory distress.     

Comparison of prostate set‐up accuracy and margins with off‐line bony anatomy corrections and online implanted fiducial‐based corrections

The aim of the study was to determine prostate set‐up accuracy and set‐up margins with off‐line bony anatomy‐based imaging protocols, compared with online implanted fiducial marker‐based imaging with daily corrections. Eleven patients were treated with implanted prostate fiducial markers and online set‐up corrections. Pretreatment orthogonal electronic portal images were acquired to determine couch shifts and verification images were acquired during treatment to measure residual set‐up error. The prostate set‐up errors that would result from skin marker set‐up, off‐line bony anatomy‐based protocols and online fiducial marker‐based corrections were determined. Set‐up margins were calculated for each set‐up technique using the percentage of encompassed isocentres and a margin recipe. The prostate systematic set‐up errors in the medial–lateral, superior–inferior and anterior–posterior directions for skin marker set‐up were 2.2, 3.6 and 4.5 mm (1 standard deviation). For our bony anatomy‐based off‐line protocol the prostate systematic set‐up errors were 1.6, 2.5 and 4.4 mm. For the online fiducial based set‐up the results were 0.5, 1.4 and 1.4 mm. A prostate systematic error of 10.2 mm was uncorrected by the off‐line bone protocol in one patient. Set‐up margins calculated to encompass 98% of prostate set‐up shifts were 11–14 mm with bone off‐line set‐up and 4–7 mm with online fiducial markers. Margins from the van Herk margin recipe were generally 1–2 mm smaller. Bony anatomy‐based set‐up protocols improve the group prostate set‐up error compared with skin marks; however, large prostate systematic errors can remain undetected or systematic errors increased for individual patients. The margin required for set‐up errors was found to be 10–15 mm unless implanted fiducial markers are available for treatment guidance.     

Proinflammatory and anti-inflammatory cytokine balance in gasoline exhaust induced pulmonary injury in mice

Proinflammatory and anti-inflammatory cytokine balance and associated changes in pulmonary bronchoalveolar lavage fluid (BALF) of unleaded gasoline exhaust (GE) exposed mice were investigated. Animals were exposed to GE (1 L/min of GE mixed with 14 L/min of compressed air) using a flow-past, nose-only, dynamic inhalation exposure chamber for different durations (7, 14, and 21 days). The particulate content of the GE was found to be 0.635, +/-0.10 mg PM/m3. Elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were observed in BALF of GE-exposed mice, but interleukin 1beta(IL-1beta) and the anti-inflammatory cytokine interleukin-10 (IL-10) remained unaffected. GE induced higher activities of alkaline phosphatase (ALP), gamma-glutamyl transferase (gammaGT), and lactate dehydrogenase (LDH) in the BALF, indicating Type II alveolar epithelial cell injury, Clara-cell injury, and general toxicity, respectively. Total protein in the BALF increased after 14 and 21 days of exposure, indicating enhanced alveolar-capillary permeability. However, the difference in the mean was found statistically insignificant in comparison to the compressed air control. Total cell count in the BALF of GE-exposed mice ranged between 0.898 and 0.813x10(6) cells/ml, whereas the compressed air control showed 0.65x10(6) cells/mL. The histopathological changes in GE-exposed lung includes perivascular, and peribronchiolar cuffing of mononuclear cells, migration of polymorphonuclear cells in the alveolar septa, alveolar thickening, and mild alveolar edematous changes indicating inflammation. The shift in pro- and anti-inflammatory cytokine balance and elevation of the pulmonary marker enzymes indicate toxic insult of GE. This study will help in our understanding of the mechanism of pulmonary injury by GE in the light of cytokine profiles, pulmonary marker enzymes, and lung architecture.     

Significance of intracellular arsenic trioxide for therapeutic response in acute promyelocytic leukemia

Arsenic trioxide (As2O3) is an effective drug for treatment of acute promyelocytic leukemia (APL) and malignant tumors. However, it is not commonly known to researchers that sensitivity has been associated with As2O3 concentration in target cells. Cell lines and cell strains of leukemia and solid cancer cells were treated with different concentrations of As2O3, and the concentrations were compared to apoptosis detected by FITC-annexin V and propidium iodide (PI) double staining. Results showed that intracellular and intercellular concentrations of arsenic in different cell lines differed. Our study noted that the cell lines had concentrations of arsenic trioxide in decreasing order, as follows: APL primary cell > K562 > CML primary cell > HL-60 > AML-M2 primary cell > HeLa > H-22. Higher intracellular As2O3 concentrations in cell lines APL, NB4, and K562 can be obtained by treating in culture medium with lower As2O3 concentration for longer times than the transient higher concentration. These results indicate that different leukemia and solid carcinoma cell lines have different intracellular arsenic concentrations, which correlate with different sensitivities to As2O3 in clinical treatment. The intracellular As2O3 concentration is higher; in addition, we note apoptosis, a very important observation in our study. As2O3 inhibited the growth of these cell lines significantly. Novel techniques by maintaining continuous low but effective arsenic levels inside the target leukemic cells in APL may improve the complete remission rate and overall survival with minimum cost and drug toxicity.     

Can Fourier transform infrared spectroscopy at higher wavenumbers (mid IR) shed light on biomarkers for carcinogenesis in tissues?

Fourier transform infrared microspectroscopy (FTIR-MSP) has shown promise as a technique for detection of abnormal cell proliferation and premalignant conditions. In the present study, we investigate the absorbance in the sensitive wavenumber region between 2800 and 3000 cm(-1), which has been known to be due to the antisymmetric and symmetric stretching vibrations of CH2 and CH3 groups of proteins and lipids. We report common biomarkers from this region that distinguish between normal and malignant tissues and cell lines. Based on our findings, we propose that the wavenumber region around 2800 to 3000 cm(-1) in the FTIR spectra of cells and tissues could provide valuable scientific evidence at the onset of premalignancy and may be used for ex vivo and in vitro detection of carcinogenesis. To further examine the utility of these markers in cancer diagnosis and management, they are tested successfully in monitoring the changes occurring in leukemia patients during chemotherapy.     

Preoperative mammotome biopsy of ducts beneath the nipple areola complex.

AIM: To evaluate the role of ultrasound guided mammotome biopsy of the ducts beneath the nipple areola complex (NAC), as a new technique in detecting the occult involvement of the NAC in breast cancer patients prior to nipple preserving subcutaneous mastectomy. METHOD: A prospective study where 33 women requesting nipple preserving mastectomy for invasive or in situ disease were offered the procedure to determine if leaving the nipple was safe. A 5 mm skin incision was made after infiltration with local anaesthetic and the 11G mammotome needle was positioned beneath the nipple under ultrasound guidance which was turned through 360 degrees as the biopsies were taken. The procedures were performed by trained non-radiologists. RESULTS: Thirty-three women had 36 procedures. Seven out of the 36 had a positive mammotome biopsy. Twenty-three patients had 26 NAC preserving mastectomies with immediate reconstruction. Three had bilateral procedures. Ten patients had NAC sacrificed. The histopathology of the mastectomy specimen correlated 100% with the mammotome biopsy. CONCLUSION: Preoperative ultrasound guided mammotome biopsy of the ducts beneath the NAC is a safe, reliable and accurate technique and is evolving as an oncologically safe procedure. The large mammotome needle can be visualized easily under high resolution, near field high frequency scanners and this increases the accuracy of the biopsy. It can replace the traditional frozen section and be used as an alternate. It can be performed safely by an appropriately trained non-radiologist (surgeon/breast clinician).