Here we demonstrate the crucial role of CKS1B in multiple myeloma (MM) progression and define CKS1B-mediated SKP2/p27Kip1-independent down-stream signaling pathways. Forced-expression of CKS1B in MM cells increased cell multidrug-resistance. CKS1B activates STAT3 and MEK/ERK pathways. In contrast, SKP2 knockdown or p27Kip1 over-expression resulted in activation of the STAT3 and MEK/ERK pathways. Further investigations showed that BCL2 is a downstream target of MEK/ERK signaling. Stimulation of STAT3 and MEK/ERK signaling pathways partially abrogated CKS1B knockdown induced MM cell death and growth inhibition. Targeting STAT3 and MEK/ ERK signaling pathways by specific inhibitors induced significant MM cell death and growth inhibition in CKS1B-overexpressing MM cells and their combinations resulted in synergy. Thus, our findings provide a rationale for targeting STAT3 and MEK/ERK/ BCL2 signaling in aggressive CKS1B-overexpressing MM.

No abstract

We prove the following strong hardness result for learning: Given a distribution of labeled examples from the hypercube such that there exists a monomial consistent with (1 − ǫ) of the examples, it is NP-hard to find a halfspace that is correct on (1/2 + ǫ) of the examples, for arbitrary constants ǫ > 0. In learning theory terms, weak agnostic learning of monomials is hard, even if one is allowed to output a hypothesis from the much bigger concept class of halfspaces. This hardness result subsumes a long line of previous results, including two recent hardness results for the proper learning of monomials and halfspaces. As an immediate corollary of our result we show that weak agnostic learning of decision lists is NP-hard.Our techniques are quite different from previous hardness proofs for learning. We define distributions on positive and negative examples for monomials whose first few moments match. We use the invariance principle to argue that regular halfspaces (all of whose coefficients have small absolute value relative to the total ℓ 2 norm) cannot distinguish between distributions whose first few moments match. For highly non-regular subspaces, we use a structural lemma from recent work on fooling halfspaces to argue that they are "junta-like" and one can zero out all but the top few coefficients without affecting the performance of the halfspace. The top few coefficients form the natural list decoding of a halfspace in the context of dictatorship tests/Label Cover reductions.We note that unlike previous invariance principle based proofs which are only known to give Unique-Games hardness, we are able to reduce from a version of Label Cover problem that is known to be NP-hard. This has inspired follow-up work on bypassing the Unique Games conjecture in some optimal geometric inapproximability results.Before describing the details of the prior body of work on hardness results for learning, we note that our result subsumes all these results with just one exception (the hardness of learning monomials by t- CNFs [34]). This is because we obtain the optimal inapproximability factor and allow learning of monomials by the much richer class of halfspaces.The results of the paper are noteworthy in the broader context of hardness of approximation. Previously, hardness proofs based on the invariance principle were only known to give Unique-Games

ObjectiveTo develop a model of established respiratory immunity against Pseudomonas aeruginosa pneumonia and to investigate the effects of route and type of nutrition on this immunity. Summary Background DataDiet influences the ability of gut-associated lymphoid tissue (GALT) to maintain mucosal immunity. Complex enteral diets and chow maintain normal GALT populations against established IgA-mediated antiviral respiratory immunity. Both intravenous and intragastric total parenteral nutrition (TPN) produce GALT atrophy, but only intragastric TPN preserves established antiviral immunity. The authors hypothesized that both GALT-depleting diets (intragastric and intravenous TPN) would impair immunity against bacterial pneumonia. Methods P. aeruginosa was administered intratracheally to determine the mortality rate at increasing doses, and liposomes containing P. aeruginosa antigens were used to generate effective respiratory immunization. In the final experiment, mice received liposomes containing P. aeruginosa antigens to establish immunity and then were randomized to chow, complex enteral diets, intragastric TPN, or intravenous TPN. After 5 days of diet, mice received live intratracheal P. aeruginosa, and the death rate was recorded at 24 and 48 hours. ResultsThe LD50 and LD10, were 9 x 107 and 12 x 107, respectively. Immunization reduced the mortality rate from 66% to 12%. This immunization was maintained in mice fed chow or a complex enteral diet and was lost in animals receiving intravenous TPN. Intragastric TPN partially preserved this respiratory immunity. ConclusionsProtection against bacterial pneumonia can be induced by prior antigenic immunization. This protection is lost with intravenous TPN, partially preserved with a chemically defined enteral diet, and completely preserved with chow or complex enteral diets. Both route and type of nutrition influence antibacterial respiratory tract immunity.Nosocomial pneumonia occurs in 10% to 25% of mechanically ventilated patients, accounting for 15% of hospital-acquired infections.' Mortality rates attributable to these pneumonias range from 7% to 30% but can reach 40% to 50% when Pseudomonas or Acinetobacter is the causative organism.2'3 Route and type of nutrition affect the risk of pneumonia in seriously injured patients. Severely injured trauma patients receiving enteral nutrition have significantly fewer pneumonias compared with patients fed parenterally, implying an impairment in mucosal defenses in patients fed Supported by NIH grant 1 ROI GM053439.

No abstract

No abstract

Glutamine-enriched TPN preserved both extraintestinal and intestinal IgA levels and had a normalizing effect on Th2-type IgA-stimulating cytokines.

We construct pseudorandom generators that fool functions of halfspaces (threshold functions) under a very broad class of product distributions. This class includes not only familiar cases such as the uniform distribution on the discrete cube, the uniform distribution on the solid cube, and the multivariate Gaussian distribution, but also includes any product of discrete distributions with probabilities bounded away from 0.Our first main result shows that a recent pseudorandom generator construction of Meka and Zuckerman [MZ09], when suitably modified, can fool arbitrary functions of d halfspaces under product distributions where each coordinate has bounded fourth moment. To ǫ-fool any size-s, depth-d decision tree of halfspaces, our pseudorandom generator uses seed length O((d log(ds/ǫ) + log n) · log(ds/ǫ)). For monotone functions of d halfspaces, the seed length can be improved to O((d log(d/ǫ) + log n) · log(d/ǫ)). We get better bounds for larger ǫ; for example, to 1/polylog(n)-fool all monotone functions of (log n)/ log log n halfspaces, our generator requires a seed of length just O(log n).Our second main result generalizes the work of Diakonikolas et al. [DGJ + 09] to show that bounded independence suffices to fool functions of halfspaces under product distributions. Assuming each coordinate satisfies a certain stronger moment condition, we show that any function computable by a size-s, depth-d decision tree of halfspaces is ǫ-fooled byÕ(d 4 s 2 /ǫ 2 )-wise independence.Our technical contributions include: a new multidimensional version of the classical BerryEsseen theorem; a derandomization thereof; a generalization of Servedio [Ser07]'s regularity lemma for halfspaces which works under any product distribution with bounded fourth moments; an extension of this regularity lemma to functions of many halfspaces; and, new analysis of the sandwiching polynomials technique of Bazzi [Baz09] for arbitrary product distributions.