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Biomedical subjects

Sandeep Singh

Publications and source records attributed to Sandeep Singh.

At least 19 recordsLinked to original sources
PubMed2026

Decreased TXNRD1 is associated with resistance to tagraxofusp in blastic plasmacytoid dendritic cell neoplasms, as seen in phase II.

Tagraxofusp is a CD123-targeted therapy comprised of a recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin payload. It is the first approved treatment specifically for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). To identify biomarkers of response, bone marrow samples from 12 BPDCN patients who were treated with tagraxofusp in the pivotal phase II trial (NCT02113982) were profiled longitudinally using a gene panel and single-cell RNA sequencing. Residual tumor cells following tagraxofusp expressed lower levels of TXNRD1 that would reduce the efficacy of tagraxofusp. In support of this, enzymatic inhibition of TXNRD1 resulted in higher viability of CAL-1 BPDCN cells following tagraxofusp. Responders had either wild-type or missense TET2 mutations, while transient and non-responders had at least one truncating TET2 mutation. Examples of these mutations within the catalytic domain of TET2 were constructed and transduced into cells. Missense and truncating mutants displayed reduced sensitivities to hypomethylating agents and prolonged S-phase stasis. These results suggest that the levels of TXNRD1 interact with intrinsic TET2 truncating mutations within the bone marrow to modulate patient response to tagraxofusp.

Female↗
PubMed2007

Gadd45alpha does not modulate the carboplatin or 5-fluorouracil-induced apoptosis in human papillomavirus-positive cells.

Gadd45alpha is shown to be induced by a wide spectrum of DNA-damaging agents and implicated in negative regulation of cell growth by causing G2-M arrest or induction of apoptosis. In the present study, we explored the involvement of p53 in the promoter activation of Gadd45alpha as well as the role of Gadd45alpha in carboplatin (Carb) or 5-fluorouracil (5-FU)-induced apoptosis in human papillomavirus virus (HPV)-positive HEp-2 and HeLa cells. We report that Carb or 5-FU upregulate Gadd45alpha and p53 in both these cells. Transient transfection of chloramphenicol acetyl transferase (CAT)-reporter construct driven by Gadd45alpha promoter clearly indicated that Gadd45alpha upregulation was mediated through activation of its promoter. Inhibition of p53 function by dominant-negative-p53 expression partially suppressed the activation of Gadd45alpha promoter. Further, the induction of apoptosis was assessed by detection of poly (ADP-ribose) polymerase (PARP) cleavage by Western blot analysis. Inhibition of upregulated Gadd45alpha expression by antisense expression vector did not modulate the Carb or 5-FU-induced apoptosis. Overall, we conclude that Gadd45alpha promoter activation partially depends on p53 function in HPV-positive cells. Moreover, Gadd45alpha protein does not modulate Carb or 5-FU-induced apoptosis in these cells.

Antimetabolites, Antineoplastic↗
PubMed2006

p53 regulates ERK activation in carboplatin induced apoptosis in cervical carcinoma: a novel target of p53 in apoptosis.

In general, the activation of extracellular recognition kinase (ERK) cascade is implicated in exerting tumorigenic effects. Conversely, recent studies suggest that ERK activation may also have role in DNA-damage induced apoptosis [Wang, X., Martindale, J.L. and Holbrook, N.J. (2000) Requirement for ERK activation in cisplatin-induced apoptosis. J. Biol. Chem. 275, 39435-39443; Schweyer S., Soruri A., Meschter O., Heintze A., Zschunke F., Miosge N., Thelen P., Schlott T., Radzun H.J. and Fayyazi, A. (2004) Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation. Br. J. Cancer 91, 589-598]. Here we observed an essential requirement of ERK activation in carboplatin (Carb) induced apoptosis in SiHa and CaSki cells. Under similar treatment conditions p53 was also involved in Carb induced apoptosis in these cells. Therefore, we investigated the relation between p53 and ERK in Carb induced apoptosis in these cells. Abrogation of p53 transactivation activity by pifithrin alpha or dominant-negative mutant of p53 resulted in decrease in activation of ERK in Carb treated cells. The present study for the first time proposes that p53 may act as one of the upstream regulators of ERK activation for the induction of apoptosis in Carb treated cervical cancer cells.

Antineoplastic Agents↗
PubMed2006

Reversible atrial fibrillation secondary to a mega-oesophagus.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it increases in prevalence with advancing age to about 5% in people older than 65 years. CASE PRESENTATION: We present a rare case of atrial fibrillation secondary to a mega-oesophagus occurring in an 84-year-old Caucasian woman. The patient had a history of progressive dysphagia and the accumulation of food debris lead to mega-oesophagus. CONCLUSION: The diagnosis was made by barium swallow and electrocardiogram; evacuations of 300 ml of the food debris lead to complete resolution of the arrhythmia. The possible aetiology leading to this AF is discussed.

Journal Article↗
PubMed2006

Laryngocele: a rare complication of surgical tracheostomy.

BACKGROUND: A laryngocele is usually a cystic dilatation of the laryngeal saccule. The etiology behind its occurrence is still unclear, but congenital and acquired factors have been implicated in its development. CASE PRESENTATION: We present a rare case of laryngocele occurring in a 77-year-old Caucasian woman. The patient presented with one month history of altered voice, no other associated symptoms were reported. The medical history of the patient included respiratory failure secondary to childhood polio at the age of ten; the airway management included a surgical tracheostomy. Flexible naso-laryngoscopy revealed a soft mass arising from the posterior pharyngeal wall obscuring the view of the posterior commissure and vocal folds. The shape of the mass altered with respiration and on performing valsalva maneuver. A plain lateral neck radiograph revealed a large air filled sac originating from the laryngeal cartilages and extending along the posterior pharyngeal wall. The patient was then treated by endoscopic laser marsupialization and reviewed annually.We discuss the complications of tracheostomy and the pathophysiology of laryngoceles and in particular the likely aetiological factors in this case. CONCLUSION: A laryngocele presenting in a female patient with tracheostomy is extremely rare and has not been to date reported in the world literature. A local mechanical condition may be the determinant factor in the pathogenesis of the disease.

Aged↗
PubMed2006

Methyl-beta-cyclodextrin enhances the susceptibility of human breast cancer cells to carboplatin and 5-fluorouracil: involvement of Akt, NF-kappaB and Bcl-2.

The response rates of extensively used chemotherapeutic drugs, carboplatin (Carb) or 5-fluorouracil (5-FU) are relatively disappointing because of considerable side effects associated with their high-dose regimen. In the present study, we determined whether treatment with a cholesterol depleting agent, methyl-beta-cyclodextrin (MCD), enhances the weak efficacy of low doses of Carb or 5-FU in human breast cancer cells. Data demonstrate that pretreatment with MCD significantly potentiates the cytotoxic activity of Carb and 5-FU in both MCF-7 and MDA-MB-231. Furthermore, we explored the molecular basis of enhanced cytotoxicity, and our data revealed that low-dose treatment with these drugs in MCD pretreated cells exhibited significantly decreased Akt phosphorylation, NF-kappaB activity and down-regulation in expression of anti-apoptotic protein Bcl-2. In addition, MCD pretreated cells demonstrated an increased intracellular drug accumulation as compared to cells treated with drugs alone. Taken together, our data provide the basis for potential therapeutic application of MCD in combination with other conventional cytotoxic drugs to facilitate reduction of drug dosage that offers a better chemotherapeutic approach with low toxicity.

Adjuvants, Pharmaceutic↗
PubMed2006

A novel paclitaxel-eluting porous carbon-carbon nanoparticle coated, nonpolymeric cobalt-chromium stent: evaluation in a porcine model.

OBJECTIVES: We aimed to evaluate the response of porcine coronary arteries to a novel paclitaxel-eluting porous carbon-carbon nanoparticle coated, nonpolymeric cobalt chromium stent. BACKGROUND: Polymer based drug-eluting stents significantly reduce restenosis. However, the indefinite presence of polymer is thought to initiate and sustain inflammation and contribute to the occurrence of late complications. METHODS: Sixteen carbon-carbon coated, nonpolymeric cobalt chromium stents with two different doses of paclitaxel (eight of each) were implanted in porcine coronary arteries. In addition, eight cobalt chromium stents coated with a biodegradable polymer were also studied. Animals were sacrificed 6 weeks after stent implantation and histomorphometric analysis was performed. Results were compared among the three groups of stents. RESULTS: The cobalt chromium stents coated with carbon-carbon with low and medium doses of paclitaxel both showed acceptable performance characteristics, with respect to endothelialization, neointimal hyperplasia, percentage diameter stenosis, inflammatory response, and tendency to fibrin deposition, when compared to historical data with the Cypher stent. On the other hand, the stents coated with poly(lactide) and poly(lactide-co-glycolide) biodegradable polymers and 0.7 microg/mm2 paclitaxel showed poor performance. There was a significant tendency to poor endothelialization, greater neointimal hyperplasia, percentage diameter stenosis, greater inflammatory response, and tendency to fibrin deposition (P < 0.01 for all parameters). CONCLUSIONS: This preclinical evaluation demonstrates the safety and efficacy of a novel cobalt chromium stent with a carbon-carbon coating and low and medium doses of paclitaxel.

Analysis of Variance↗
PubMed2006

Cardiac resynchronization as therapy for congestive cardiac failure in children dependent on chronic cardiac pacing.

Three patients with heart failure after chronic right ventricular apical pacing were treated with resynchronization. Biventricular pacing was used for two patients, and the other was treated with left univentricular pacing. In all patients, we observed a dramatic improvement of left ventricular dimension, function, and clinical state. We conclude that biventricular or left ventricular pacing is superior to right ventricular apical pacing in children who are pacemaker-dependent.

Adolescent↗
PubMed2005

DNA damaging drugs-induced down-regulation of Bcl-2 is essential for induction of apoptosis in high-risk HPV-positive HEp-2 and KB cells.

DNA damaging chemotherapeutic agents like carboplatin (Carb) and 5-fluorouracil (5-FU), whose effects are mediated through diverse intracellular targets, induce apoptosis in various cancer cells including human papillomavirus (HPV) positive HEp-2 and KB cells. The present work reports the involvement of Bcl-2 in response to the exposure of HEp-2 and KB cells to Carb or 5-FU. We demonstrate that both these drugs are potent inducers of apoptosis. Apoptosis was preceded by decrease in Bcl-2 protein level accompanied by caspase-9 activation and poly(ADP-ribose) polymerase (PARP) cleavage without altering Bax expression. Further analysis revealed down-regulation of Bcl-2 mRNA as well as protein in drugs treated cells. Ectopic expression of Bcl-2 protected cells against drugs mediated DNA damage-induced apoptosis. Overall, data indicates that genotoxic stress leads to down-regulation of Bcl-2 in HEp-2 and KB cells, which plays a decisive role in the outcome of stress in these cells.

Antimetabolites, Antineoplastic↗
PubMed2005

Doxycycline potentiates antitumor effect of cyclophosphamide in mice.

Cyclophosphamide (CPA) is a widely used chemotherapeutic drug in neoplasias. It is a DNA and protein alkylating agent that has a broad spectrum of activity against variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the high-dose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining well-tolerated antibiotic doxycycline (DOX) with CPA and understanding the mechanism of cell killing. Interestingly, we found that DOX significantly enhances the tumor regression activity of CPA on xenograft mice model bearing MCF-7 cells. DOX also potentiates MCF-7 cell killing by CPA in vitro. In presence of DOX (3 microg/ml), the IC50 value of CPA decreased significantly from 10 to 2.5 mM. Additional analyses indicate that the tumor suppressor p53 and p53-regulated proapoptotic Bax were upregulated in vivo and in vitro following CPA treatment in combination with DOX, suggesting that upregulation of p53 may contribute to the enhancement of antitumor effect of CPA by DOX. Furthermore, downregulation of antiapoptotic Bcl-2 was observed in animals treated with CPA and CPA plus DOX when compared to untreated or DOX-treated groups. Our results raise the possibility that this combination chemotherapeutic regimen may lead to additional improvements in treatment of breast cancer.

Animals↗
PubMed2005

Chemosensory processing in the fruit fly, Drosophila melanogaster: generalization of a feeding response reveals overlapping odour representations.

Insects are capable of detecting, and discriminating between, a very large number of odours. The biological relevance of many of those odours, particularly those related to food, must first be learned. Given that the number of sensory receptors and antennal lobe (AL) glomeruli is limited relative to the number of odours that must be detectable, this ability implies that the olfactory system makes use of a combinatorial coding scheme whereby each sensory cell or AL projection neuron can participate in coding for several different odours. An important step in understanding this coding scheme is to behaviourally quantify the degree to which sets of odours are discriminable. Here we evaluate odour discriminability in the fruit fly, Drosophila melanogaster, by first conditioning individual flies to not respond to any of several odorants using a nonassociative conditioning protocol (habituation). We show that flies habituate unconditioned leg movement responses to both mechanosensory and olfactory stimulation over 25 unreinforced trials. Habituation is retained for at least 2 h and is subject to dishabituation. Finally, we test the degree to which the conditioned response generalizes to other odorants based on molecular features of the odorants (e.g. carbon chain length and the presence of a target functional group). These tests reveal predictable generalization gradients across these molecular features. These data substantiate the claim that these features are relevant coding dimensions in the fruit fly olfactory system, as has been shown for other insect and vertebrate species.

Acyclic Monoterpenes↗
PubMed2005

Displaced femoral neck fracture in children and adolescents: closed versus open reduction--a preliminary study.

Twenty-six children and adolescents with displaced femoral neck fractures who were treated surgically from 1992 to 2002 were included in this study. Among them, 14 were male and 12 were female. Altogether, 10 of them had a transcervical type of fracture, and the other 16 had a cervicotrochanteric type of fracture. The average age of the patients was 10.8 years (3-17 years). Seventeen were treated by closed reduction and internal fixation (group A), and nine required open reduction and internal fixation (group B). In group A, there were good results in 11 cases (65%), a fair result in one case (6%), and poor results in 5 cases (29%). In group B, there were good results in seven cases (78%) and fair results in the other two cases (22%). The average fracture union times in groups A and B were 12.6 and 10.2 weeks, respectively. Thus, there was a favorable outcome in group B. However, statistical analysis of data in this preliminary study did not reveal any significant difference in the surgical outcome between the two groups.

Adolescent↗
PubMed2005

The hypoglycaemic activity of fenugreek seed extract is mediated through the stimulation of an insulin signalling pathway.

The in vivo hypoglycaemic activity of a dialysed fenugreek seed extract (FSE) was studied in alloxan (AXN)-induced diabetic mice and found to be comparable to that of insulin (1.5 U kg(-1)). FSE also improved intraperitoneal glucose tolerance in normal mice. The mechanism by which FSE attenuated hyperglycaemia was investigated in vitro. FSE stimulated glucose uptake in CHO-HIRc-mycGLUT4eGFP cells in a dose-dependent manner. This effect was shown to be mediated by the translocation of glucose transporter 4 (GLUT4) from the intracellular space to the plasma membrane. These effects of FSE on GLUT4 translocation and glucose uptake were inhibited by wortmannin, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, and bisindolylmaleimide 1, a protein kinase C (PKC)-specific inhibitor. In vitro phosphorylation analysis revealed that, like insulin, FSE also induces tyrosine phosphorylation of a number of proteins including the insulin receptor, insulin receptor substrate 1 and p85 subunit of PI3-K, in both 3T3-L1 adipocytes and human hepatoma cells, HepG2. However, unlike insulin, FSE had no effect on protein kinase B (Akt) activation. These results suggest that in vivo the hypoglycaemic effect of FSE is mediated, at least in part, by the activation of an insulin signalling pathway in adipocytes and liver cells.

3T3 Cells↗
PubMed2005

Bilateral anterior shoulder dislocation: a case report.

Bilateral anterior shoulder dislocation is a very rare clinical entity. All the cases reported so far highlight a simultaneous bilateral shoulder dislocation. We report an unusual case, where the left shoulder dislocated first due to trauma followed by atraumatic dislocation of the right shoulder. A new manoeuvre--the Spaso Technique was used to reduce the dislocation.

Adult↗
PubMed2005

Anticoagulation in patients with mechanical valves during pregnancy.

Mechanical valve thrombosis is a life-threatening event, while pregnancy is associated with a hypercoagulable state. Thus, in pregnant women with mechanical valves, adequate anticoagulation becomes even more critical. This prospective study was conducted to establish a uniform anticoagulation regimen for these women. A total of 250 pregnancies in 245 women with mechanical heart valves were evaluated. The patients were divided into 2 groups: group 1 (n = 150) took oral warfarin throughout pregnancy and group 2 (n = 100) received subcutaneous heparin in the 1(st) trimester and oral warfarin for the other trimesters. Both groups received heparin at the time of delivery. There were no coumarin-induced fetal malformations. Minor thromboembolic episodes took place in 5 women in group 1 and 3 in group 2. Valve thrombosis occurred in 1 woman in group 2 and led to 1 maternal death in this series. The incidence of spontaneous abortion was similar between the groups. We conclude that warfarin is safe and convenient to use during pregnancy. The teratogenic effects of warfarin during the 1(st) trimester are overstated, and switching to heparin is not mandatory.

Administration, Oral↗