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Baljit Singh

Publications and source records attributed to Baljit Singh.

At least 19 recordsLinked to original sources
PubMed2026

Molecular evaluation of residual disease following neoadjuvant chemotherapy in triple-negative breast cancer CALGB 40603 (Alliance).

BACKGROUNDDespite therapeutic advances in early-stage triple-negative breast cancer (TNBC), residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and obstacle to improving patient outcomes.METHODSTo better characterize RD and identify survival-associated features, we performed comprehensive transcriptomic profiling of 340 pretreatment stage II/III TNBCs and 70 matched posttreatment RD samples from the randomized CALGB 40603 (Alliance) phase II clinical trial. To explore preclinical treatment strategies for RD, patient-derived xenograft (PDX) mouse models mimicking RD were treated with antibody-drug conjugates (ADCs).RESULTSOur study shows prognostic genomic features measured pretreatment may differ from prognostic features measured posttreatment from RD specimens. Patients with a genomic PAM50 subtype of basal-like in RD specimens had a poor survival outcome, and their matching pretreatment tumors were characterized by elevated chromosomal amplifications of oncogenic drivers and significantly reduced B and T cell expression features. Paired analyses of basal-like RD and matched pretreatment tumors revealed further lymphocyte depletion in RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a basal-like and conventional chemotherapy-resistant PDX model, resembling basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response.CONCLUSIONRD biology differs from pretreatment tumors, with basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Preclinical modeling suggests this high-risk group may benefit from adjuvant ADC therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT00861705.FUNDINGNIH NCI U10CA180821 (Alliance for Clinical Trials in Oncology), NCI U24CA176171 (Alliance for Clinical Trials in Oncology), NCI UG1CA233373 (Alliance for Clinical Trials in Oncology), NCI Breast SPORE program P50-CA058223; Susan G. Komen SAC-160074; Breast Cancer Research Foundation BCRF-23-127; NIH NCI R01-CA229409; UNC LCCC Triple Negative Breast Cancer Center.

Humans↗
PubMed2003

Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland.

It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.

Animals↗
PubMed2003

Expression of vascular adhesion protein-1 in normal and inflamed mice lungs and normal human lungs.

Recently, vascular adhesion protein-1 (VAP-1) was implicated in adhesion and transmigration of lymphocytes across endothelial cells in liver and other organs. There is very little information on VAP-1 expression in normal and inflamed lungs. Therefore, we conducted a study to localize VAP-1 in normal mice and human lungs and in two distinct murine models of lung inflammation. Normal mice and human lungs revealed VAP-1 expression in the endothelium of large and mid-sized pulmonary vessels but not in alveolar septae, airway epithelium or blood cells. Mice that lack the lpr(-/-) gene and develop extensive lymphocytic infiltration in their lungs showed VAP-1 expression similar to the normal mice lungs. Mice subjected to cecal ligation and puncture developed acute lung inflammation and showed VAP-1 not only in endothelial cells but also in inflammatory cells in perivascular areas at 72 h after the procedure. We concluded that VAP-1 expression may contribute to the functional heterogeneity of endothelial cells within the lung to create distinct sites for the recruitment of inflammatory cells. Furthermore, since VAP-1 is expressed over a longer period of time in inflamed lungs, it may even be a suitable target for drug delivery and therapeutic manipulations.

Aged↗
PubMed2003

Formulation and stability of surface-tethered DNA-gold-dendron nanoparticles.

The formulation of plasmid DNA on 100 nm gold nanoparticles surface-tethered via cationic dendrons, and the behaviour of the complex in cell culture media, is described in this communication. Adsorption of dendrons onto gold nanoparticles in water resulted in the generation of positively charged nanoparticles with a corresponding small increase in particle size. Addition of plasmid DNA did not markedly reduce the surface potential but resulted in a approximately 10-20% increase in hydrodynamic diameter. More dramatic effects were seen in the presence of cell culture media that, overall, drastically increased the apparent size of the gold-dendron-DNA nanoparticles and reduced the surface potential of the colloids, the presence of serum components partially ameliorating these effects possibly due to steric stabilisation. Release of the surface-tethered DNA was reduced in cell culture media compared to water. This reduced detachment of DNA coupled with the flocculation of the carrier which would likely inhibit endocytosis, demonstrates the importance of testing drug delivery systems with relevant physiologically based fluids prior to their use in vivo studies.

Adsorption↗
PubMed2003

Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer.

Numerous studies have demonstrated that overexpression of Met, the hepatocyte growth factor(HGF) receptor, plays an important role in tumorigenesis. Met activation can either occur through ligand-independent or -dependent mechanisms, both of which are mediated by a series of proteases and modulators. We studied the protein expression of several components of the HGF/Met pathway on a cohort of 330 node-negative breast carcinomas using a tissue microarray annotated with 30-year, disease-specific patient follow-up data. We examined HGF, matriptase (an activator of HGF expressed on mammary epithelial cell surfaces), HAI-I (the cognate inhibitor of matriptase), and the Met receptor itself. Our studies demonstrate tight correlation between the expression of HGF, matriptase, and Met in breast carcinoma. High-level expression of Met, matriptase, and HAI-I were associated with poor patient outcome. Met and HAI-I showed independent prognostic value when compared with traditional breast markers in a multivariate analysis. Intriguingly, antibodies against the intracellular but not the extracellular domain of Met were prognostic, suggesting that overexpression of the cytoplasmic-tail of Met, perhaps through cleavage or truncating mutation, may play an important role in breast cancer progression.

Breast Neoplasms↗
PubMed2003

Characterization of matriptase expression in normal human tissues.

Matriptase is a type II transmembrane serine protease that has been implicated in the progression of epithelium-derived tumors. The role of this protease in the biology of normal epithelial cells remains to be elucidated. Matriptase mRNA has been detected by Northern analysis in tissues rich in epithelial cells, and the protein is expressed in vivo in normal and cancerous breast, ovarian, and colon tissues. However, a systematic analysis of the distribution of matriptase protein and mRNA in normal human tissues rich in epithelium has not been reported. In this study we characterized the expression of the protease in a wide variety of normal human tissues using a tissue microarray and whole tissue specimens. Significant immunoreactivity and mRNA expression were detected in the epithelial components of most epithelium-containing tissues. Matriptase expression was found in all types of epithelium, including columnar, pseudostratified columnar, cuboidal, and squamous. Distinct spatial distributions of reactivity were observed in the microanatomy of certain tissues, however. This suggests that although matriptase is broadly expressed among many types of epithelial cells, its activity within a tissue may be regulated in part at the protein and mRNA levels during the differentiation of selected epithelia.

Epithelium↗
PubMed2003

A prospective randomized pilot study to evaluate predictors of response in serial core biopsies to single agent neoadjuvant doxorubicin or paclitaxel for patients with locally advanced breast cancer.

INTRODUCTION: Response to neoadjuvant chemotherapy for locally advanced breast cancer can be correlated with long-term outcomes. Surrogate end-point biomarkers may be used to assess response to the treatment. Most reported studies assessed the effects of combination chemotherapy. We assessed the feasibility of obtaining serial core breast biopsies, and correlated rates of apoptosis, proliferation, and expression of related proteins at baseline, during, and after neoadjuvant single agent chemotherapy for locally advanced breast cancer with response. EXPERIMENTAL DESIGN: Women with a histologically confirmed unresected T(3) or T(4) infiltrating carcinoma of the breast were eligible. The first 20 patients received three cycles of doxorubicin 90 mg/m(2) followed by three cycles of paclitaxel 250 mg/m(2), or the reverse. Nine women received four cycles of each (doxorubicin 60 mg/m(2) and paclitaxel 175 mg/m(2)). Cycles were administered 14 days apart with filgastrim. End points included: (a). clinical and pathological response; (b). serial apoptotic [terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling] and proliferation (immunohistochemistry, IHC) rates; and (c). expression (IHC) of estrogen receptor, HER2, bcl2, and p53. RESULTS: From April 1997 to June 2001, 29 women were randomized. Twelve patients (42%) had a clinical complete response (cCR), and 16 (55%) had a clinical partial response. Five women (17%) had a pathological complete response, 7 (24%) had microscopic residual disease, and 17 (58%) had macroscopic residual disease. Higher baseline apoptosis and proliferation were associated with an improved pathological response (P = 0.006 and 0.003, respectively). Among 14 evaluable patients, apoptosis increased in women who had a cCR to the first agent but not in women without a cCR. Estrogen receptor-positive patients had a worse pathological response (P = 0.004). CONCLUSIONS: The selected regimen is efficacious. It is feasible to obtain serial core biopsies that are informative for studies of apoptosis and IHC. This clinical design can serve as a model for combining standard chemotherapy and novel agents.

Adjuvants, Immunologic↗
PubMed2002

Oncogenic beta-catenin is required for bone morphogenetic protein 4 expression in human cancer cells.

Somatic cell gene targeting was used to create an isogenic set of human colon cancer cells that differs only in the presence or absence of their endogenous activated beta-catenin oncogene. Affymetrix Genechip expression profiling of parental cells and gene-targeted derivatives identified numerous novel genes whose expression was dependent on the presence of oncogenic beta-catenin. The transforming growth factor-beta family member bone morphogenetic protein 4 (BMP4), whose receptor is mutated in a rare inherited gastrointestinal cancer predisposition syndrome, was the most highly differentially expressed gene. Additional experiments revealed that the oncogenic allele of beta-catenin specifically is absolutely required for BMP4 expression and secretion by human cancer cells and that BMP4 is overexpressed and secreted by human colon cancer cells with mutant adenomatous polyposis coli genes. These data identify the presence of regulatory interactions between the Wnt and BMP signaling pathways in cancer pathogenesis, providing an intriguing connection between the sporadic and inherited forms of a common human malignancy.

Bone Morphogenetic Protein 4↗
PubMed2002

Continuous mandibular nerve block for pain relief. A report of two cases.

PURPOSE: Mandibular nerve block allows surgery to be performed on the mandible. However, pain in the postoperative period needs to be treated with opioids or non-steroidal anti-inflammatory agents which have undesirable side effects. We examine the feasibility of continuous mandibular nerve block with 0.25% bupivacaine top-ups using a catheter for intraoperative and postoperative pain relief in two patients with a fracture of the mandible. METHODS: Using the lateral extraoral approach, the mandibular nerve was approached with an 18-gauge indwelling iv cannula in two patients undergoing repair of a fractured mandible under general anesthesia. After removing the needle, an 18-gauge epidural catheter was inserted into the cannula which was then removed. The catheter was tunnelled subcutaneously to emerge at the lateral aspect of the forehead. Two to 4 mL bupivacaine 0.25% were injected on a 12-hr basis and the catheter was kept in place for seven days. RESULTS: Both patients had excellent pain relief and no parenteral or oral analgesics were required throughout the postoperative period. No side effects were noted. CONCLUSIONS: Continuous mandibular nerve block with 2-4 mL 0.25% bupivacaine top-ups injected twice a day through a catheter provides excellent pain relief in patients with a fracture of the mandible. This method may have implications for the management of pain of other etiology in the mandibular region.

Aged↗
PubMed2002

Subdural block complicating spinal anesthesia?

IMPLICATIONS: Features suggestive of subdural block appeared after an apparently normal subarachnoid block. The long bevel of the reusable Quincke-type spinal needle may have contributed to the development of this complication. We propose that spinal needles should have a smaller bevel to minimize the possibility of such a complication.

Anesthesia, Spinal↗
PubMed2002

Role of cadmium in the regulation of AR gene expression and activity.

Treatment of human prostate cancer cells, LNCaP, with cadmium stimulated cell growth. There was a 2.4-fold increase in the population of cells in the S + G(2)M phase by d 4 and a 2.7-fold increase in cell number by d 8. The metal decreased the concentration of AR protein and mRNA (80 and 60%, respectively) and increased the expression of prostate-specific antigen and the homeobox gene, NKX 3.1 (6-fold) that was blocked by an antiandrogen. In addition, cadmium activated the AR in mouse L cells containing an MMTV-luciferase reporter gene (4-fold increase) and in COS-1 cells transfected with wild-type AR and an MMTV-CAT reporter gene (7-fold increase). Cadmium also activated a chimeric receptor (GAL-AR) containing the hormone-binding domain of AR. The metal bound to AR with an equilibrium dissociation constant of 1.19 x 10(-10) M. Cadmium blocked the binding of androgen to the receptor but did not alter its affinity (dissociation constant = 2.8 x 10(-10) M), suggesting that the metal is an inhibitor of hormone binding. In castrated animals, a single, low, environmentally relevant dose of cadmium (20 microg/kg body weight) increased the wet weight of the prostate (1.97- to 3-fold) and the seminal vesicle complex (approximately 1.5-fold) and increased the expression of the androgen-regulated gene, probasin (27-fold). The in vivo effects were also blocked by an antiandrogen.

Androgen-Binding Protein↗
PubMed2002

Localization and characterization of calcineurin in bovine eye.

PURPOSE: There are several aspects of the visual system that may be regulated by Ca2+- and calmodulin (CaM)-stimulated protein phosphatase. In the present study, the distribution and characterization of calcineurin (CaN) in bovine eye was determined. METHODS: Whole bovine eyes were either homogenized for purification or regionally dissected to determine CaN localization and activity. Dissected tissues were homogenized and Western blot analysis performed, using polyclonal anti-CaN antibodies, and assayed using p-nitrophenyl phosphate (PNPP) as a substrate to determine the dephosphorylation activity of CaN. Fresh samples were then prepared for immunohistochemistry and probed with polyclonal anti-CaN antibodies. RESULTS: CaN was found to be present in all eye tissues, although activity and protein expression varied. The highest levels of CaN activity and protein expression were found in the optic nerve, retina, and cornea. Immunohistochemical methods displayed similar results with additional staining of the optic nerve vasculature. Assays of purified CaN demonstrated that bovine eye CaN had regulatory properties similar to CaN isolated from other tissues. Probing eye tissues with CaN A isoform-specific antibodies demonstrated that eye tissues displayed variable distributions of the CaN Aalpha and CaN Abeta isoforms. CONCLUSIONS: The presence of CaN in the bovine eye provides a physiological pathway by which the phosphorylated state of proteins and intracellular Ca2+ concentrations can be coordinated. The authors propose that CaN is involved in the immunologic privilege of the cornea, retinal signal transduction, and the toxic effects of immunosuppressants on the eye. Further in vivo studies of CaN function are necessary to understand the contributions of CaN to ocular physiology.

Animals↗
PubMed2002

Feline mammary adenocarcinoma: tumor size as a prognostic indicator.

Mammary carcinomas and adenocarcinomas (MACs) are relatively common tumors in cats. The postexcisional survival period of affected cats is inversely proportional to tumor size, but the reported median survival periods for different tumor size categories is quite variable. This variability diminishes the prognostic value of reported data. In our study, cats with MACs greater than 3 cm in diameter had a 12-month median survival period, whereas those with MACs less than 3 cm in diameter had a 21-month survival period. Survival periods for cats with MACs smaller than 3 cm ranged from 3 to 54 months; therefore, tumor size alone is of limited prognostic value in cats with MACs smaller than 3 cm in diameter. In cats with MACs larger than 3 cm in diameter, tumor size appears to have much higher prognostic relevance, because this study, as well as others, have indicated that cats with MACs greater than 3 cm in diameter have a poor prognosis, with median survival periods ranging from 4 to 12 months.

Adenocarcinoma↗
PubMed2002

Expression of the serine protease matriptase and its inhibitor HAI-1 in epithelial ovarian cancer: correlation with clinical outcome and tumor clinicopathological parameters.

PURPOSE: Matriptase is a type II transmembrane serine protease expressed by cells of surface epithelial origin, including epithelial ovarian tumor cells. Matriptase cleaves and activates proteins implicated in the progression of ovarian cancer and represents a potential prognostic and therapeutic target. The aim of this study was to examine the expression of matriptase, and its inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1), in epithelial ovarian cancer and to assign clinicopathological correlations. EXPERIMENTAL DESIGN: We have determined by immunohistochemistry the expression of matriptase and HAI-1 in 54 epithelial ovarian cancers. Statistical analyses of immunohistochemistry expression data with clinical outcome and clinicopathological parameters were then performed. RESULTS: Of 54 tumors tested, 39 (72%) and 11 (20%) were positive for matriptase and for HAI-1, respectively. All HAI-1-positive tumors were also matriptase positive. Analysis of clinicopathological parameters demonstrated a loss of matriptase associated with stage III/IV tumors as compared with stage I/II tumors (P = 0.030). There was also a loss of HAI-1 expression associated with stage III/IV tumors (P = 0.039). Of 34 stage I/II tumors, 28 (82%) stained positive for matriptase, and 10 (29%) stained positive for HAI-1; 10 (29%) tumors showed coexpression. Of 20 stage III/IV tumors, however, 11 stained positive for matriptase (55%), only 1 of which coexpressed HAI-1 (P = 0.039). CONCLUSIONS: Advanced-stage ovarian tumors that express matriptase are more likely to do so in the absence of its inhibitor, HAI-1, indicating that an imbalance in the matriptase:HAI-1 ratio could be important in the development of advanced disease. Such an imbalance could promote the proteolytic activity of matriptase and, consequently, a more invasive phenotype.

Female↗
PubMed2002

Development and validation of a method for using breast core needle biopsies for gene expression microarray analyses.

PURPOSE: Gene expression microarray technologies have the potential to define molecular profiles that may identify specific phenotypes(diagnosis), establish a patient's expected clinical outcome (prognosis), and indicate the likelihood of a beneficial effect of a specific therapy (prediction). We wished to develop optimal tissue acquisition, processing, and analysis procedures for exploring the gene expression profiles of breast core needle biopsies representing cancer and noncancer tissues. EXPERIMENTAL DESIGN: Human breast cancer xenografts were used to evaluate several processing methods for prospectively collecting adequate amounts of high-quality RNA for gene expression microarray studies. Samples were assessed for the preservation of tissue architecture and the quality and quantity of RNA recovered. An optimized protocol was applied to a small study of core needle breast biopsies from patients, in which we compared the molecular profiles from cancer with those from noncancer biopsies. Gene expression data were obtained using Research Genetics, Inc. Named Genes cDNA microarrays. Data were visualized using simple hierarchical clustering and a novel principal component analysis-based multidimensional scaling. Data dimensionality was reduced by simple statistical approaches. Predictive neural networks were built using a multilayer perceptron and evaluated in an independent data set from snap-frozen mastectomy specimens. RESULTS: Processing tissue through RNALater preserves tissue architecture when biopsies are washed for 5 min on ice with ice-cold PBS before histopathological analysis. Cell margins are clear, tissue folding and fragmentation are not observed, and integrity of the cores is maintained, allowing optimal pathological interpretation and preservation of important diagnostic information. Adequate concentrations of high-quality RNA are recovered; 51 of 55 biopsies produced a median of 1.34 microg of total RNA (range, 100 ng to 12.60 microg). Snap-freezing or the use of RNALater does not affect RNA recovery or the molecular profiles obtained from biopsies. The neural network predictors accurately discriminate between predominantly cancer and noncancer breast biopsies. CONCLUSIONS: The approaches generated in these studies provide a simple, safe, and effective method for prospectively acquiring and processing breast core needle biopsies for gene expression studies. Gene expression data from these studies can be used to build accurate predictive models that separate different molecular profiles. The data establish the use and effectiveness of these approaches for future prospective studies.

Animals↗