Epidemiological and survival analysis of triple-negative breast cancer cases in a retrospective multicenter study.

INTRODUCTION: This is a retrospective study with data collected from breast cancer cases from five major Apollo Hospitals across India, as part of a biobanking process. One aspect of our study focused specifically on data from triple-negative breast cancer (TNBC) cases. The aim of this study was to analyze epidemiology, treatment options, and survival of the patients with TNBC. Our goal was to draw conclusions on the preponderance of the disease and also to understand the outcomes using the existing therapy options. MATERIALS AND METHODS: Data were collected after due ethical clearances and were coded with regard to patient identifiers to protect patient privacy. Data were not only from the various departments of the respective hospitals and the treating physicians but also from the follow-up made by hospital staff and social workers. RESULTS: About 20% of all cases of breast cancer comprised TNBC. Although the disease is generally thought to be an early onset disease, there was no major difference in the median age of diagnosis of TNBC compared to other breast cancer cases. More than 85% of the TNBC cases were of early stage disease with <4% of the cases of metastatic cancer. Data on follow-up were somewhat sporadic as a good number of cases were lost to follow-up, but from the available data, recurrence rate was about 11%. Death, when it occurred, was mostly in the early periods of treatment with 35% of the events occurring before 3 years. The overall survival rates beyond 3 years were more than 86%. CONCLUSIONS: Data and sample collection are an ongoing process, so we expect this data set to be enriched with more cases and longer duration of follow-up in a year. Preliminary analysis sheds light on the potential of such a collection both for understanding the epidemiology of the disease and also for conducting future studies with an eye toward improving treatment outcomes.

Total hip Replacement in Crowe type IV dysplastic hips - average 5 year follow-up and literature review.

This is a retrospective study of 29 patients (34 hips) of Crowe grade IV dysplastic hips aged between 19 and 75 years who underwent THR for osteoarthritis secondary to DDH. The hips were evaluated radiologically for Sharp's acetabular angle, cup inclination, loosening, and ectopic bone formation. Clinically the results were evaluated by pre and postoperative -Harris hip scoring. The mean acetabular angle was 60.8° (range, 45°-68°) preoperatively. In 18 hips, subtrochanteric femoral osteotomy was performed. Pre-operatively, the mean leg length discrepancy was 5 cm (range, 2-8 cm). -Correction within 1 cm was possible in all patients -except in 4 patients. The mean Harris hip Score was 40.80 (32-45.90) preoperatively and 87.96 (74.78-94.72) at last follow-up. THR is successful in high dislocation dysplastic hips. Although there is no gold standard technique of THR in dysplastic hips and treatment of each patient should be individualized. Level of evidence : IV.

Pregnancy concomitant with metastatic adult granulosa cell tumor.

INTRODUCTION: Metastatic adult granulosa cell tumor of the ovary is rarely encountered with pregnancy. CASE REPORT AND RESULTS: Primigravida (26 years) presented at 20 weeks of gestation with acute abdomen and clinical evidence of supraclavicular lymphadenopathy and ascites. She was diagnosed of adult granulosa cell tumor (AGCT) of the right ovary following right salpingoophrectomy done 1 month prior to conception. Fine needle aspiration cytology of supraclavicular lymph node, revealed it to be a metastatic AGCT. Chemotherapy was given antepartum and she delivered a healthy preterm baby at 30 weeks. Subsequently, she had optimal debulking surgery following 6 cycles of cisplatin-based chemotherapy. Baby at 10 months of age was with normal milestones. CONCLUSIONS: The case is an unusual presentation of metastatic adult granulosa cell tumor at child bearing age. Although rapidly progressing, successful prolongation of pregnancy till 30 weeks of gestation was possible with the judicious use of chemotherapy. Fetal and maternal outcomes were favorable.

Interactions of silver nanoparticles with primary mouse fibroblasts and liver cells.

Primary cells are ideal for in vitro toxicity studies since they closely resemble tissue environment. Here, we report a detailed study on the in vitro interactions of 7-20 nm spherical silver nanoparticles (SNP) with primary fibroblasts and primary liver cells isolated from Swiss albino mice. The intended use of silver nanoparticles is in the form of a topical antimicrobial gel formulation for the treatment of burns and wounds. Upon exposure to SNP for 24 h, morphology of primary fibroblasts and primary liver cells remained unaltered up to 25 microg/mL and 100 microg/mL SNP, respectively, although with minor decrease in confluence. IC(50) values for primary fibroblasts and primary liver cells as revealed by XTT assay were 61 microg/mL and 449 microg/mL, respectively. Ultra-thin sections of primary cells exposed to 1/2 IC(50) SNP for 24 h, visualized under Transmission electron microscope showed the presence of dark, electron dense, spherical aggregates inside the mitochondria, and cytoplasm, probably representing the intracellular SNP. When the cells were challenged with approximately 1/2 IC(50) concentration of SNP (i.e. 30 microg/mL and 225 microg/mL for primary fibroblasts and primary liver cells, respectively), enhancement of GSH (approximately 1.2 fold) and depletion of lipid peroxidation (approximately 1.4 fold) were seen in primary fibroblasts which probably protect the cells from functional damage. In case of primary liver cells; increased levels of SOD ( approximately 1.4 fold) and GSH ( approximately 1.1 fold) as compared to unexposed cells were observed. Caspase-3 activity assay indicated that the SNP concentrations required for the onset of apoptosis were found to be much lower (3.12 microg/mL in primary fibroblasts, 12.5 microg/mL in primary liver cells) than the necrotic concentration (100 microg/mL in primary fibroblasts, 500 microg/mL in primary liver cells). These observations were confirmed by CLSM studies by exposure of cells to 1/2 IC(50) SNP (resulting in apoptosis) and 2 x IC(50)) cells (resulting in necrosis). These results clearly suggest that although silver nanoparticles seem to enter the eukaryotic cells, cellular antioxidant mechanisms protect the cells from possible oxidative damage. This property, in conjunction with the finding that primary cells possess much higher SNP tolerance than the concentration in the gel (approximately 20 microg/g), indicates preliminary safety of the formulation and warrants further study for possible human application.

Antioxidant activity of an aminothiazole compound: possible mechanisms.

Oceans are among the richest natural sources of many bioactive compounds. Several of these compounds have shown pharmacological activities for many diseases. Dendrodoine (5-[(3-N-dimethylamino)-1,2,4-thiadiazolyl]-3-indanyl methanone) is an alkaloid extracted from the marine tunicate Dendrodoa grossularia. Aminothiazoles have a wide range of biological activities including anti-tumor and antioxidant properties. The aim of our study was to examine the antioxidant ability of an aminothiazole derivative, dendrodoine analogue (DA) [(4-amino-5-benzoyl-2-(4-methoxy phenylamino) thiazole] which has been chemically synthesized and is similar to dendrodoine. In all the biochemical assays used in our study, corresponding to different levels of protection, DA showed concentration dependent antioxidant ability. DA (3.07 microM) showed an ability to inhibit 2,2'-azobis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) radical formation to the extent of 0.17 microM of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). The ferric complex reducing ability of 3.07 microM DA was equivalent to 110 microM Trolox. 3.07 microM DA gave 84% protection against deoxyribose degradation, a measure of hydroxyl radical scavenging. DA also has an ability to scavenge NO radical, 3.07 microM DA effecting 20% scavenging. Concentration dependent inhibition of lipid peroxidation and protein oxidation induced by 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) and ascorbate-Fe2+ was observed with low concentrations of DA (1.5-3.07 microM). Mechanistic studies using pulse radiolysis revealed that DA scavenges peroxyl radicals with a bimolecular rate constant of 3 x 10(8)M(-1)s(-1). Moreover, the initially formed nitrogen-centered radical gets transformed into sulfur-centered radical before furnishing any final product. Our results indicated that DA can be a free radical scavenger and potential antioxidant for future application.

Cellular responses induced by silver nanoparticles: In vitro studies.

A systematic study on the in vitro interactions of 7-20 nm spherical silver nanoparticles (SNP) with HT-1080 and A431 cells was undertaken as a part of an on-going program in our laboratory to develop a topical antimicrobial agent for the treatment of burn wound infections. Upon exposure to SNP (up to 6.25 microg/mL), morphology of both the cell types remained unaltered. However, at higher concentrations (6.25-50 microg/mL) cells became less polyhedral, more fusiform, shrunken and rounded. IC(50) values for HT-1080 and A431 as revealed by XTT assay were 10.6 and 11.6 microg/mL, respectively. When the cells were challenged with approximately 1/2 IC(50) concentration of SNP (6.25 microg/mL), clear signs of oxidative stress, i.e. decreased GSH ( approximately 2.5-folds in HT-1080, approximately 2-folds in A431) and SOD ( approximately 1.6-folds in HT-1080, 3-folds in A431) as well as increased lipid peroxidation ( approximately 2.5-folds in HT-1080, approximately 2-folds in A431) were seen. Changes in the levels of catalase and GPx in A431 cells were statistically insignificant in both cell types. DNA fragmentation in SNP-exposed cells suggested apoptosis. When the apoptotic thresholds of SNP were monitored with caspase-3 assay the concentrations required for the onset of apoptosis were found to be much lower (0.78 microg/mL in HT-1080, 1.56 microg/mL in A431) than the necrotic concentration (12.5 microg/mL in both cell types). These results can be used to define a safe range of SNP for the intended application as a topical antimicrobial agent after appropriate in vivo studies.

Can dose reduction to one parotid gland prevent xerostomia?--A feasibility study for locally advanced head and neck cancer patients treated with intensity-modulated radiotherapy.

AIMS: Dryness of the mouth is one of the most distressing chronic toxicities of radiation therapy in head and neck cancers. In this study, parotid function was assessed in patients with locally advanced head and neck cancers undergoing intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Parotid function was assessed with the help of a questionnaire and parotid scintigraphy, especially with regards to unilateral sparing of the parotid gland. MATERIALS AND METHODS: In total, 19 patients were treated with compensator-based IMRT between February 2003 and March 2004. The dose to the clinical target volume ranged between 66 and 70 Gy in 30-35 fractions to 95% of the isodose volume. Ipsilateral high-risk neck nodes received an average dose of 60 Gy and the contralateral low-risk neck received a dose of 54-56 Gy. Eight of 19 patients also received concomitant chemotherapy. RESULTS: Subjective toxicity to the parotid glands was assessed with the help of a questionnaire at 0, 3 and 6 months and objective toxicity was assessed with parotid scintigraphy at 0 and 3 months. The mean dose to the ipsilateral parotid gland ranged from 19.5 to 52.8 Gy (mean 33.14 Gy) and the mean dose to the contralateral gland was 11.1-46.6 Gy (mean 26.85 Gy). At a median follow-up of 13 months, 9/19 patients had no symptoms of dryness of the mouth (grade I), 8/19 had mild dryness of the mouth (grade II) and only 2/19 had grade III xerostomia, although the parotid gland could only be spared on one side in most of the patients. CONCLUSIONS: Minimising the radiation dose to one of the parotid glands with the help of IMRT in patients with advanced head and neck cancers can prevent xerostomia in most patients and parotid scintigraphy is a useful method of documenting xerostomia.

Right atrial trans-septal approach for left atrial myxomas--nine-year experience.

OBJECTIVE: In this single-center study we reviewed our experience with left atrial myxomas occurring over the past 9 years. METHODS: Sixty-three patients underwent excision of cardiac myxomas between 1995 and 2004. Of these, 56 patients (32 females and 24 males) had left atrial (LA) myxoma. The mean age was 37.80+12.97 years (range 3.5-67 years). Echocardiography was the only diagnostic evaluation done. The preferred approach for resection was right atrial trans-septal. Annual echocardiographic evaluation was undertaken following surgery. Follow-up is current and available in all the survivors (range 4 months-9 years). RESULTS: Clinically 75% of the LA myxomas simulated mitral stenosis. The symptoms were present for 2-6 months before operation. Most (86%) LA myxomas were attached to the fossa ovalis. Few (14%) originated from the LA wall, mitral valve annulus and anterior mitral leaflet. One patient succumbed to low cardiac output and another died of massive embolic stroke following surgery. There were no late deaths. Two patients (3.7%) developed left hemiparesis after operation but recovered completely. There was one (1.9%) recurrence 3 years after surgery. Atrial fibrillation occurred in one patient. Mitral insufficiency which was seen in two (3.7%) patients prior to surgery subsided following excision of the tumor. Postoperatively 94% patients remained without symptoms. CONCLUSION: Owing to the risk of valvular obstruction or embolization early surgery is indicated. Right atrial trans-septal approach is safe and easy. Most patients are asymptomatic following surgery. A yearly follow-up is essential.

Cadmium accumulation and antioxidative responses in the Sesbania drummondii callus.

The effect of cadmium (Cd) on growth, accumulation, and antioxidative response was studied in Sesbania drummondii callus, cultivated on different concentrations of Cd (0-250 microM) for four weeks. Callus growth was comparable to that of the control for concentrations up to 50 microM Cd; however, concentrations higher than 50 microM affected growth. A concentration of 100 microM Cd inhibited growth by 16%, with respect to control. Cd concentration in callus increased with increasing Cd concentrations in the growth medium. Callus accumulated 530 mg Cd kg(-1) of their dry weight at 100 microM Cd concentration. Sesbania callus responded to Cd-induced oxidative stress by modulating antioxidants (glutathione and other non-protein thiols) level and antioxidative enzymes: superoxide dismutase (SOD), ascorbate peroxidase (APX), and glutathione reductase (GR). The content of the glutathione (GSH) and GSH/GSSG ratio first increased up to a concentration of 50 microM Cd and then decreased. The content of other non-protein thiols significantly increased with increasing Cd concentrations in the growth medium. The activities of antioxidative enzymes, SOD, APX, and GR, followed the same trends as antioxidants first increasing up to a concentration of 50 microM Cd and then decreasing. These results suggest that antioxidative defense mechanisms play a significant role in Cd detoxification and accumulation in Sesbania drummondii.

TEM/AFM investigation of size and surface properties of nanocrystalline ceria.

A series of ceria nanoparticles were synthesized by using a microemulsion method. The effect of relative concentration of surfactant/water on the size and the surface roughness of ceria nanoparticles was examined using transmission electron microscopy (TEM) and atomic force microscopy (AFM) respectively. The investigation confirmed a relationship between the size and the roughness properties of the nanoceria as a function of the water to surfactant ratio. With increasing dilution of the surfactant, the size distribution became narrow such that average particle size decreased linearly as the ratio increased without affecting lower size threshold of particles (approximately 10 nm). The surface roughness, on the other hand was found to increase with increasing water to surfactant ratio implying diluted surfactant would provide rougher surface of ceria nanoparticles. The information can be used to tailor the adhesion properties of nanoceria by optimizing the size distribution as well as surface roughness as a function of water to surfactant ratio.

Menstrual-like breakdown and apoptosis in human endometrial explants.

BACKGROUND: Apoptosis occurs in late secretory and menstrual human endometrium and is thought to play an important role in endometrial physiology. Menstrual-like breakdown has been observed in vitro in endometrial explants. The purpose of this study was to assess the role of apoptosis in menstrual-like breakdown in human endometrial explants. METHODS: Human endometrial tissue was obtained during the mid-secretory phase and cultured with or without estrogen and progesterone. The occurrence of breakdown was assessed by histology. Apoptosis was determined by gel electrophoresis for the detection of DNA fragmentation and by immunohistochemistry using the M30 CytoDEATH and anti-cleaved caspase-3 (CASP3) antibodies for the detection of caspase activity. Expression of BCL2 and BAX was quantified using real-time PCR analysis. RESULTS: Apoptosis occurred in human endometrial explants at all time-points studied. Cleaved CASP3 and M30 antigen expression increased in all explants, suggesting the involvement of CASP3 in the apoptosis. Low BCL2:BAX ratios were observed in all samples when compared with pre-culture controls. Estradiol and progesterone supplementation of the culture media reduced or eliminated menstrual-like breakdown but did not affect the degree of apoptosis observed. CONCLUSIONS: The apoptosis observed in endometrium during the late secretory phase and menstrual phase does not appear to be mechanistically related to the tissue breakdown but rather may be involved in the impending remodelling that occurs in the endometrium in the transition from secretory to proliferative phase following the menses.

Thorium uptake by wheat at different stages of plant growth.

Data on biogeochemistry of thorium are rather limited. So far little is known about toxic effects of small amounts of the radionuclide on higher plants. In this study the uptake of thorium by wheat seedlings was measured by greenhouse experiments. Germination of wheat seeds for 6 days in the presence of thorium resulted in accumulation of the metal in all parts of the seedlings. When the Th-rich seedlings were transferred to normal soil and were grown there further for 7 days, Th concentrations in roots and leaves decreased significantly (in leaves the Th content decreased up to the level of Th in the control plants). In seeds, however, Th content remained unchanged. An increase of Th content in roots and seeds was also observed as a result of addition of thorium to soil but in this case the concentration of Th in leaves did not change. The accumulation of Th in plants affected the uptake of other elements including essential macro-nutrients. The most strongly affected part of the plants was leaf.

Pregnancy rates following fimbriectomy reversal via neosalpingostomy: a 10-year retrospective analysis.

OBJECTIVE: To establish parameters associated with successful fimbriectomy reversal and to estimate monthly fecundability and cumulative pregnancy rates through life-table analysis. DESIGN: Series report. SETTING: University-based infertility clinic. PATIENT(S): Forty-one women undergoing surgery for tubal sterilization reversal. INTERVENTION(S): Surgical fimbriectomy reversal. MAIN OUTCOME MEASURE(S): Time from sterilization to reversal, laparoscopy vs. laparotomy, uni- vs. bilateral fimbriectomy reversal, Bruhat vs. suture, tubal lengths, postsurgical hysterosalpingogram, ovulation induction, incidence of pregnancy and outcome, and life-table analysis to determine pregnancy rate. RESULT(S): The mean time from sterilization to reversal was 11.5 years. Of the 41 women who underwent fimbriectomy reversal, 6 (14.6%) conceived. Sixteen reversals were performed by laparotomy resulting in 4 (25%) pregnancies, whereas 25 were performed laparoscopically resulting in 2 (8%) pregnancies. Eight had unilateral salpingostomies and 33 bilateral, of which 1 of 8 (12.5%) and 5 of 33 (15.2%) conceived, respectively. Using the Bruhat technique, 1 of 11 (9%) conceived vs. 5 of 30 (16.7%) that underwent reversal using sutures. The mean postoperative tubal length for the 6 women who conceived was 8 cm vs. 6.7 cm in the 35 women who did not conceive. Postoperatively, 26 women received ovulation induction and 1 (3.8%) conceived whereas 5 (33.3%) conceptions occurred in 15 women who did not require ovulation induction. Using life-table analysis with 619 postsurgical cycles, the monthly fecundability was.0097. The cumulative conception rate after 5 years was 31.2%. CONCLUSION(S): Neosalpingostomy for the reversal of fimbriectomy sterilization represents a viable option for fertility restoration. The best candidates for this procedure are spontaneously ovulatory and have a tubal length of more than 7 cm.

Neuroblastoma with concomitant giardiasis: report of a case with diagnosis by fine needle aspiration cytology.

BACKGROUND: Diagnosis of two pathologies, including a neoplasm and infectious condition, by fine needle aspiration (FNA) cytology in the same patient is rare. CASE: A 2-year-old, male child presented with fever, abdominal pain and abdominal mass. Imaging findings were strongly in favor of a neuroblastoma. FNA smears from the mass revealed fecal material containing numerous trophozoites of Giardia lamblia. FNA was repeated in view of the imaging findings. Repeat smears showed a small round cell tumor with rosettes and background filamentous/fibrillar material consistent with a neuroblastoma. Chemotherapy reduced the mass considerably. Histopathology of the resected residual mass revealed a ganglioneuroma in addition to remnants of neuroblastoma. The patient was free of disease two years after the initiation of chemotherapy. CONCLUSION: When FNA cytology shows an infectious pathology in the clinical and imaging setting of a tumor, FNA should be repeated so that an important component of the diagnosis is not missed.

Structure of GSK3beta reveals a primed phosphorylation mechanism.

GSK3beta was identified as the kinase that phosphorylates glycogen synthase but is now known to be involved in multiple signaling pathways. GSK3beta prefers prior phosphorylation of its substrates. We present the structure of unphosphorylated GSK3beta at 2.7 A. The orientation of the two domains and positioning of the activation loop of GSK3beta are similar to those observed in activated kinases. A phosphate ion held by Arg 96, Arg 180 and Lys 205 occupies the same position as the phosphate group of the phosphothreonine in activated p38gamma, CDK2 or ERK2. A loop from a neighboring molecule in the crystal occupies a portion of the substrate binding groove. The structure explains the unique primed phosphorylation mechanism of GSK3beta and how GSK3beta relies on a phosphoserine in the substrate for the alignment of the beta- and alpha-helical domains.

A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction.

OBJECTIVE: To compare the rates of ovulation and pregnancy after tamoxifen citrate (TMX) or clomiphene citrate (CC) among anovulatory women with infertility. DESIGN: Prospective randomized trial. SETTING: Infertility clinic in a university teaching hospital. PATIENT(S): Eighty-six anovulatory women under 40 years of age undergoing ovulation induction. INTERVENTION(S): The women were assigned randomly to receive either TMX or CC on cycle days 5-9. MAIN OUTCOME MEASURE(S): Rates of ovulation and pregnancy for the two treatment modalities. RESULTS(S): The overall rate of ovulation in the TMX group was 50 of 113 (44.2%) and in the CC group, 41 of 91 (45.1%). There were 10 pregnancies in the TMX group and 6 pregnancies in the CC group. The cycle fecundity per ovulatory cycle was 20.0% in the TMX group and 14.6% in the CC group. CONCLUSION(S): The overall rate of ovulation and pregnancy were similar with TMX and CC. TMX is a suitable alternative agent to CC in the management of anovulatory infertility.

VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent.

Inosine monophosphate dehydrogenase (IMPDH) is an essential rate-limiting enzyme in the purine metabolic pathway, catalyzing the de novo synthesis of guanine nucleotides required for lymphocyte proliferation. IMPDH has therefore been an attractive target for developing immunosuppressive drugs (e.g., CellCept and mizoribine). Here we describe the immunosuppressive activity of VX-497, a novel noncompetitive inhibitor of IMPDH. VX-497 (MW 452.5) is orally bioavailable and inhibits the proliferation of primary human, mouse, rat, and dog lymphocytes at concentrations of approximately 100 nM. The inhibitory effect of VX-497 on lymphocytes is reversed in the presence of exogenous guanosine, but not in the presence of adenosine or uridine, confirming that the antilymphocytic activity of VX-497 is specifically due to inhibition of IMPDH. The antiproliferative effect of VX-497 in cells is also reversed within 48 h of its removal. Based on evaluation of VX-497 in several lymphoid and nonlymphoid cells, the antiproliferative effect of VX-497 is observed to be most pronounced on lymphoid and keratinocyte cells as compared with fibroblasts. In vivo, oral administration of VX-497 inhibits the primary IgM antibody response in a dose-dependent manner, with an ED(50) value of approximately 30-35 mg/kg in mice. Single daily dosing of VX-497 is observed to be as effective as twice-daily dosing in this model of immune activation. These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation.