Robust Regression via Hard Thresholding

We study the problem of Robust Least Squares Regression (RLSR) where several response variables can be adversarially corrupted. More specifically, for a data matrix X \in R^{p x n} and an underlying model w*, the response vector is generated as y = X'w* + b where b \in R^n is the corruption vector supported over at most C.n coordinates. Existing exact recovery results for RLSR focus solely on L1-penalty based convex formulations and impose relatively strict model assumptions such as requiring the corruptions b to be selected independently of X. In this work, we study a simple hard-thresholding algorithm called TORRENT which, under mild conditions on X, can recover w* exactly even if b corrupts the response variables in an adversarial manner, i.e. both the support and entries of b are selected adversarially after observing X and w*. Our results hold under deterministic assumptions which are satisfied if X is sampled from any sub-Gaussian distribution. Finally unlike existing results that apply only to a fixed w*, generated independently of X, our results are universal and hold for any w* \in R^p. Next, we propose gradient descent-based extensions of TORRENT that can scale efficiently to large scale problems, such as high dimensional sparse recovery and prove similar recovery guarantees for these extensions. Empirically we find TORRENT, and more so its extensions, offering significantly faster recovery than the state-of-the-art L1 solvers. For instance, even on moderate-sized datasets (with p = 50K) with around 40% corrupted responses, a variant of our proposed method called TORRENT-HYB is more than 20x faster than the best L1 solver.Comment: 24 pages, 3 figure

Locally Non-linear Embeddings for Extreme Multi-label Learning

The objective in extreme multi-label learning is to train a classifier that can automatically tag a novel data point with the most relevant subset of labels from an extremely large label set. Embedding based approaches make training and prediction tractable by assuming that the training label matrix is low-rank and hence the effective number of labels can be reduced by projecting the high dimensional label vectors onto a low dimensional linear subspace. Still, leading embedding approaches have been unable to deliver high prediction accuracies or scale to large problems as the low rank assumption is violated in most real world applications. This paper develops the X-One classifier to address both limitations. The main technical contribution in X-One is a formulation for learning a small ensemble of local distance preserving embeddings which can accurately predict infrequently occurring (tail) labels. This allows X-One to break free of the traditional low-rank assumption and boost classification accuracy by learning embeddings which preserve pairwise distances between only the nearest label vectors. We conducted extensive experiments on several real-world as well as benchmark data sets and compared our method against state-of-the-art methods for extreme multi-label classification. Experiments reveal that X-One can make significantly more accurate predictions then the state-of-the-art methods including both embeddings (by as much as 35%) as well as trees (by as much as 6%). X-One can also scale efficiently to data sets with a million labels which are beyond the pale of leading embedding methods

Identification and characterization of transporters in human gliomas

Functional overexpression of the ATP binding cassette (ABC) transporters at the cell surface is thought to be responsible for clinical multidrug resistance (MDR) in tumours of the brain. Inhibition of ABC transporters by existing inhibitors has proven to be inconclusive. This research program hypothesized an alternative location for the ABC transporters in glioblastoma cells and also proposed to develop stationary phases for the identification of ABC transporters inhibitors. Expression profile investigation of P-glycoprotein (PGP), multidrug resistant protein 1 (MRP1), multidrug resistant protein 2 (MRP2) and the breast cancer resistant protein (BCRP) in glioblastoma multiforme cell lines and clinical patient specimens suggested varying levels of expression. Localisation studies by confocal microscopy confirmed cell surface expression and also indicated that BCRP was localised at the nucleus of the T98 and LN229 cells. Immunoblots of LN229 nuclear extracts indicated ~ 2 fold higher expression of BCRP as compared to cytoplasmic extracts. Immunohistochemistry studies with clinical samples confirmed the nuclear and perinuclear location of BCRP. IC50 value for Mitoxantrone (MTX); a BCRP substrate was calculated as 0.29 ± 0.020 μM for the LN229 cell line, and pre-treatment with the cell impermeant fumitremorgin C 3 (FTC, 5 μM) slightly reduced the IC50 value to 0.16 ± 0.087 μM. This refractoriness to FTC is in contrast with the literature showing a ~ 6-fold reduction in IC50 value of MTX upon pre-treatment with FTC in human breast cancer MCF-7 cell line with ectopic expression of BCRP. The results supported the notion that the nuclear presence of endogenously expressed BCRP actively extrudes MTX, and that because FTC is not able to inhibit the nuclear BCRP, significant reduction in the IC50 was not observed. The results suggest that the treatment of clinical MDR should be expanded to include inhibition of ABC transporters functioning at the nuclear membrane. Cellular membrane affinity chromatography columns were developed for the study of the MRP1, MRP2 and BCRP using Spodoptera frugiperda (Sf9) cells that had been stably transfected with human Mrp1, Mrp2 or Bcrp cDNA. The resulting columns and a control column were characterized using frontal affinity chromatography using [3H]-etoposide as the marker ligand and etoposide, benzbromarone and MK571 as the displacers on the CMAC(Sf9MRP1) column, etoposide and furosemide on the CMAC(Sf9MRP2) column and etoposide and fumitremorgin C on the CMAC(Sf9BCRP) column. The binding affinities obtained from the chromatographic studies were consistent with the data obtained using non-chromatographic techniques and the results indicate that the immobilized MRP1, MRP2 and BCRP transporters retained their ability to selectively bind known ligands. The results indicated that the CMAC(Sf9MRP1), CMAC(Sf9MRP2) and CMAC(Sf9BCRP) columns can be used for the study of binding to the MRP1, 4 MRP2 and BCRP transporters and that membranes from the Sf9 cell line can be used to prepare CMAC columns. This study expands our knowledge of the ABC transporters and makes a case for the finding that nuclear efflux proteins play a pivotal role in the overall MDR phenotype in CNS tumours. Also the CMAC columns developed and characterised provide a tool to study the binding of potential therapeutic candidates to ABC proteins.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Identification and Characterization of Transporters in Human Gliomas

Functional overexpression of the ATP binding cassette (ABC) transporters at the cell surface is thought to be responsible for clinical multidrug resistance (MDR) in tumours of the brain. Inhibition of ABC transporters by existing inhibitors has proven to be inconclusive. This research program hypothesized an alternative location for the ABC transporters in glioblastoma cells and also proposed to develop stationary phases for the identification of ABC transporters inhibitors. Expression profile investigation of P-glycoprotein (PGP), multidrug resistant protein 1 (MRP1), multidrug resistant protein 2 (MRP2) and the breast cancer resistant protein (BCRP) in glioblastoma multiforme cell lines and clinical patient specimens suggested varying levels of expression. Localisation studies by confocal microscopy confirmed cell surface expression and also indicated that BCRP was localised at the nucleus of the T98 and LN229 cells. Immunoblots of LN229 nuclear extracts indicated ~ 2 fold higher expression of BCRP as compared to cytoplasmic extracts. Immunohistochemistry studies with clinical samples confirmed the nuclear and perinuclear location of BCRP. IC50 value for Mitoxantrone (MTX); a BCRP substrate was calculated as 0.29 ± 0.020 μM for the LN229 cell line, and pre-treatment with the cell impermeant fumitremorgin C 3 (FTC, 5 μM) slightly reduced the IC50 value to 0.16 ± 0.087 μM. This refractoriness to FTC is in contrast with the literature showing a ~ 6-fold reduction in IC50 value of MTX upon pre-treatment with FTC in human breast cancer MCF-7 cell line with ectopic expression of BCRP. The results supported the notion that the nuclear presence of endogenously expressed BCRP actively extrudes MTX, and that because FTC is not able to inhibit the nuclear BCRP, significant reduction in the IC50 was not observed. The results suggest that the treatment of clinical MDR should be expanded to include inhibition of ABC transporters functioning at the nuclear membrane. Cellular membrane affinity chromatography columns were developed for the study of the MRP1, MRP2 and BCRP using Spodoptera frugiperda (Sf9) cells that had been stably transfected with human Mrp1, Mrp2 or Bcrp cDNA. The resulting columns and a control column were characterized using frontal affinity chromatography using [3H]-etoposide as the marker ligand and etoposide, benzbromarone and MK571 as the displacers on the CMAC(Sf9MRP1) column, etoposide and furosemide on the CMAC(Sf9MRP2) column and etoposide and fumitremorgin C on the CMAC(Sf9BCRP) column. The binding affinities obtained from the chromatographic studies were consistent with the data obtained using non-chromatographic techniques and the results indicate that the immobilized MRP1, MRP2 and BCRP transporters retained their ability to selectively bind known ligands. The results indicated that the CMAC(Sf9MRP1), CMAC(Sf9MRP2) and CMAC(Sf9BCRP) columns can be used for the study of binding to the MRP1, 4 MRP2 and BCRP transporters and that membranes from the Sf9 cell line can be used to prepare CMAC columns. This study expands our knowledge of the ABC transporters and makes a case for the finding that nuclear efflux proteins play a pivotal role in the overall MDR phenotype in CNS tumours. Also the CMAC columns developed and characterised provide a tool to study the binding of potential therapeutic candidates to ABC proteins

De novo double-hit B-cell precursor leukemia/lymphoma - an unusual presentation as peritoneal lymphomatosis

Peritoneal lymphomatosis (PL) is a rare presentation of extranodal precursor leukemia/lymphoma. The presentation is often non-specific, leading to delayed diagnosis and treatment. In this case, though the preliminary diagnosis was established on ascitic fluid cytology, the disease progressed rapidly, leading to demise before initiating chemotherapy. Immunophenotyping and molecular studies, performed later, established a diagnosis of de novo B-cell precursor leukemia/ lymphoma with MYC, BCL2 rearrangements (Double-hit lymphoma). MYC, BCL2 rearrangements are rarely reported in precursor B-lymphoma/leukemia which carry dismal prognosis. In this report, we illustrate autopsy findings of PL in an elderly gentleman who presented with ascites for evaluation

A Case Series Highlighting the Relative Frequencies of the Common, Uncommon and Atypical/Unusual Hematological Findings on Bone Marrow Examination in Cases of Visceral Leishmaniasis

Introduction: Bone marrow aspiration and biopsy still remains as one of the vital tests for confirmation of diagnosis of visceral Leishmaniasis. The aim of the present study is to assess the relative frequency of common, uncommon and atypical hematological findings in cases of Visceral Leishmaniasis. Materials & Methods: A total of 16 cases of Leishmaniasis diagnosed on Bone marrow examination over a period of two years (2008-2010), were retrieved from the archives and the peripheral blood smear, bone marrow aspiration smears and trephine biopsies were examined for the common, uncommon and atypical features as described in the literature. Results: Out of the total of 16 cases, 10 were pediatric and 6 adult cases. The common findings like pancytopenia, peripheral blood monocytosis, increased histiocytes on aspirate smears and granulomas on biopsies were noted in 12/16 (75%), 9/16 (56.25%), 13/16 (81.2%) and 11/16 (69%) cases respectively. Amongst the uncommon findings, hemophagocytosis was noted in 12/ 16 (75%) cases, plasma cells with inclusions in 6/16 (37.5%) and LD bodies in cells other than histiocytes in 4/16 (25%) cases. The atypical findings included organism aggregates noted in 9/16 (56%) cases, Pelger-Heut cells seen in 4/16 (25%) cases and increased focal vascularity on biopsies in 10/16 (62.5%) cases. The average parasite density (APD) on smears was 3+ and the range of positivity was 1+ to 5+. Conclusion: The knowledge of these morphological clues can assist us in searching for LD bodies and correctly diagnosing the condition without excessive dependence on unnecessary and sophisticated tests