12,866 research outputs found
The Role of SAHA in Attenuating Liver Fibrosis
No full textChronic liver disease (CLD) is one of the leading causes of morbidity and mortality globally. There are approximately 1.5 billion cases of CLD worldwide, with 4.5 million cases in the United States alone. Most types of CLD are a result of a wound healing process that leads to extracellular matrix deposition and scar tissue formation, or liver fibrosis. When left untreated, liver fibrosis may progress to cirrhosis or hepatocellular carcinoma, and ultimately liver failure, thereby requiring liver transplantation. Unfortunately, the only treatment available for liver fibrosis is removal of the causative agent. This highlights the importance of finding novel therapeutic targets and repurposing drugs to treat liver fibrosis. Histone deacetylase inhibitors (HDACi) have been reported to be beneficial in diseases of fibrosis. Vorinostat, or suberoylanilide hydroxamic acid (SAHA), a pan HDACi used to treat T-cell lymphoma, was reported to inhibit hepatic stellate cell activation and liver fibrosis. However, the mechanism behind this attenuation has yet to be explored in detail. We previously published that overexpression of a redox regulator, Glutaredoxin-1 (Glrx) is protective in liver fibrosis. Therefore, I investigated whether SAHA inhibits hepatic stellate cell activation by upregulating Glrx. I first confirmed SAHA’s inhibition of both human and mouse hepatic stellate cell activation and attenuation of liver fibrosis in a carbon tetrachloride mouse model. SAHA also significantly upregulated the expression of Glrx in both mouse and human hepatic stellate cells. Knockdown of GLRX partially attenuated SAHA’s inhibitory effect on HSC activation. Based on these results, I conclude that SAHA’s inhibition of hepatic stellate cell activation may be Glrx-dependent
Testing Equivalence to Design Polynomials
No full textAn n-variate polynomial g of degree d is a (n,d,t) design polynomial if the degree of the gcd of every pair of monomials of g is at most t-1. The power symmetric polynomial PSym_{n,d} : = ∑_{i = 1}ⁿ x^d_i and the sum-product polynomial SP_{s,d} : = ∑_{i = 1}^{s}∏_{j = 1}^{d} x_{i,j} are instances of design polynomials for t = 1. Another example is the Nisan-Wigderson design polynomial NW, which has been used extensively to prove various arithmetic circuit lower bounds. Given black-box access to an n-variate, degree-d polynomial f() ∈ [], how fast can we check if there exist an A ∈ GL(n, ) and a ∈ ⁿ such that f(A+) is a (n,d,t) design polynomial? We call this problem "testing equivalence to design polynomials", or alternatively, "equivalence testing for design polynomials".
In this work, we present a randomized algorithm that finds (A, ) such that f(A+) is a (n,d,t) design polynomial, if such A and exist, provided t ≤ d/3. The algorithm runs in (nd)^O(t) time and works over any sufficiently large of characteristic 0 or > d. As applications of this test, we show two results - one is structural and the other is algorithmic. The structural result establishes a polynomial-time equivalence between the graph isomorphism problem and the polynomial equivalence problem for design polynomials. The algorithmic result implies that Patarin’s scheme (EUROCRYPT 1996) can be broken in quasi-polynomial time if a random sparse polynomial is used in the key generation phase.
We also give an efficient learning algorithm for n-variate random affine projections of multilinear degree-d design polynomials, provided n ≥ d⁴. If one obtains an analogous result under the weaker assumption "n ≥ d^ε, for any ε > 0", then the NW family is not VNP-complete unless there is a VNP-complete family whose random affine projections are learnable. It is not known if random affine projections of the permanent are learnable.
The above algorithms are obtained by using the vector space decomposition framework, introduced by Kayal and Saha (STOC 2019) and Garg, Kayal and Saha (FOCS 2020), for learning non-degenerate arithmetic circuits. A key technical difference between the analysis in the papers by Garg, Kayal and Saha (FOCS 2020) and Bhargava, Garg, Kayal and Saha (RANDOM 2022) and the analysis here is that a certain adjoint algebra, which turned out to be trivial (i.e., diagonalizable) in prior works, is non-trivial in our case. However, we show that the adjoint arising here is triangularizable which then helps in carrying out the vector space decomposition step
Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent
No full textIntroduction: \ud
Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence. The caspase 8 inhibitor FLIP is an anti-apoptotic protein over-expressed in several cancer types including MPM. The histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) is currently being evaluated in relapsed mesothelioma. We examined the roles of FLIP and caspase 8 in regulating SAHA-induced apoptosis in MPM. \ud
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Methods: \ud
The mechanism of SAHA-induced apoptosis was assessed in 7 MPM cell lines and in a multicellular spheroid model. SiRNA and overexpression approaches were used, and cell death was assessed by flow cytometry, Western blotting and clonogenic assays. Results: RNAi-mediated FLIP silencing resulted in caspase 8-dependent apoptosis in MPM cell line models. SAHA potently down-regulated FLIP protein expression in all 7 MPM cell lines and in a multicellular spheroid model of MPM. In 6/7 MPM cell lines, SAHA treatment resulted in significant levels of apoptosis induction. Moreover, this apoptosis was caspase 8-dependent in all six sensitive cell lines. SAHA-induced apoptosis was also inhibited by stable FLIP overexpression. In contrast, down-regulation of HR23B, a candidate predictive biomarker for HDAC inhibitors, significantly inhibited SAHA-induced apoptosis in only 1/6 SAHA-sensitive MPM cell lines. Analysis of MPM patient samples demonstrated significant inter-patient variations in FLIP and caspase 8 expressions. In addition, SAHA enhanced cisplatin-induced apoptosis in a FLIP-dependent manner. \ud
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Conclusions: \ud
These results indicate that FLIP is a major target for SAHA in MPM and identifies FLIP, caspase 8 and associated signalling molecules as candidate biomarkers for SAHA in this disease. © 2011 Elsevier Ltd. All rights reserved
Scolytoplatypus lopchuensis Maiti & Saha
No full text11. Scolytoplatypus lopchuensis Maiti & Saha * Scolytoplatypus lopchuensis Maiti & Saha, 2009: 90. Thai distribution: N: Chiang Mai. New to Thailand. New record: Chiang Mai, Doi Inthanon NP, Checkpoint 2, 18° 31.55' N, 98° 29.94' E, 1700 m, MT, 8–15.v.2007 (Y. Areeluck) (1). Other distribution: India (W. Bengal). (2) Taxonomy: In their description of the male, Maiti and Saha (2009) fail to mention the prosternum, which is a valuable taxonomic character in Scolytoplatypus (Beaver & Gebhardt 2006). It is broadly flattened posteriorly, but tapers anteriorly to a sharp point which is more strongly sclerotised. The tapering part bears long, backwardly pointing hairs, and at the tip on each side, a small tuft of short, forwardly pointing hairs. Maiti and Saha (2009) do not mention also the extremely long tufts of hairs on the anterior coxae. These are longer than in any other species of Scolytoplatypus known to us, the longest hairs extending two-thirds of the body length. Biology: Maiti and Saha (2009) list three host species in three different families (Lauraceae, Rutaceae, Symplocaceae). Given the localities listed by Maiti & Saha (2009), and above, probably a montane species. Illustrations: D (Maiti & Saha 2009).Published as part of Beaver, R. A., Sittichaya, W. & Liu, L-Y., 2014, A Synopsis of the Scolytine Ambrosia Beetles of Thailand (Coleoptera: Curculionidae: Scolytinae), pp. 1-82 in Zootaxa 3875 (1) on pages 17-18, DOI: 10.11646/zootaxa.3875.1.1, http://zenodo.org/record/513058
Prostate 25-hydroxyvitamin D-1alpha-hydroxylase is up-regulated by suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor
No full textProstatic 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-OHase) is up-regulated by epidermal growth factor (EGF) and down-regulated by 1alpha,25-dihydroxyvitamin D [1alpha,25(OH)2D] at the promoter level in an autocrine/paracrine fashion, suggesting that local production of 1alpha,25(OH)2D could provide an important cell growth regulatory mechanism. Gene expressions depend on the acetylation status of the histone tails of chromatin, which is regulated by histone acetyltransferases and histone deacetylases (HDAC). A number of HDAC inhibitors, including suberolylanilide hydroxamic acid (SAHA), can inhibit tumor growth in vitro and in vivo. Moreover, SAHA increases the expression of genes which modulate cell cycle progression, tumor suppression, differentiation and apoptosis. Therefore, whether SAHA might also regulate 1alpha-OHase activity in PZ-HPV-7 prostate cells was investigated. SAHA at 10 microM up-regulated 1alpha-OHase activity approximately two-fold as analyzed by the formation of 3H-1alpha,25(OH)2D3 from 3H-25-hydroxyvitamin D3 using high performance liquid chromatography. SAHA (10 microM) also stimulated 1alpha-OHase mRNA expression as measured by real-time polymerase chair reaction, and promoter activity determined by luciferase reporter gene assay. The findings suggest that another important action of SAHA may be to up-regulate the expression of the 1alpha-OHase gene that controls the synthesis of 1alpha,25(OH)2D which in turn regulates prostate growth and differentiation in an autocrine/paracrine fashion
Improved Approximation Algorithms for Dyck Edit Distance and RNA Folding
No full textThe Dyck language, which consists of well-balanced sequences of parentheses, is one of the most fundamental context-free languages. The Dyck edit distance quantifies the number of edits (character insertions, deletions, and substitutions) required to make a given length-n parenthesis sequence well-balanced. RNA Folding involves a similar problem, where a closing parenthesis can match an opening parenthesis of the same type irrespective of their ordering. For example, in RNA Folding, both () and )( are valid matches, whereas the Dyck language only allows () as a match. Both of these problems have been studied extensively in the literature. Using fast matrix multiplication, it is possible to compute their exact solutions in time O(n^2.687) (Chi, Duan, Xie, Zhang, STOC'22), and a (1+ε)-multiplicative approximation is known with a running time of Ω(n^2.372).
The impracticality of fast matrix multiplication often makes combinatorial algorithms much more desirable. Unfortunately, it is known that the problems of (exactly) computing the Dyck edit distance and the folding distance are at least as hard as Boolean matrix multiplication. Thereby, they are unlikely to admit truly subcubic-time combinatorial algorithms. In terms of fast approximation algorithms that are combinatorial in nature, the state of the art for Dyck edit distance is an O(log n)-factor approximation algorithm that runs in near-linear time (Saha, FOCS'14), whereas for RNA Folding only an ε n-additive approximation in Õ(n²/ε) time (Saha, FOCS'17) is known.
In this paper, we make substantial improvements to the state of the art for Dyck edit distance (with any number of parenthesis types). We design a constant-factor approximation algorithm that runs in Õ(n^1.971) time (the first constant-factor approximation in subquadratic time). Moreover, we develop a (1+ε)-factor approximation algorithm running in Õ(n²/ε) time, which improves upon the earlier additive approximation. Finally, we design a (3+ε)-approximation that takes Õ(nd/ε) time, where d ≥ 1 is an upper bound on the sought distance.
As for RNA folding, for any s ≥ 1, we design a factor-s approximation algorithm that runs in O(n+(n/s)³) time. To the best of our knowledge, this is the first nontrivial approximation algorithm for RNA Folding that can go below the n² barrier. All our algorithms are combinatorial in nature
SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells
No full textSAHA, an inhibitor of histone deacetylase activity, has been shown to sensitize tumor cells to apoptosis
induced by TRAIL, a member of TNF-family. In this paper we investigated the effect of SAHA/TRAIL
combination in two breast cancer cell lines, the ERa positive MCF-7 and the ERa negative MDA-MB231.
Treatment of MDA-MB231 and MCF-7 cells with SAHA in combination with TRAIL caused detachment of
cells followed by anoikis, a form of apoptosis which occurs after cell detachment, while treatment with
SAHA or TRAIL alone did not produce these effects. The effects were more evident in MDA-MB231 cells,
which were chosen for ascertaining the mechanism of SAHA/TRAIL action. Our results show that SAHA
decreased the level of c-FLIP, thus favouring the interaction of TRAIL with the specific death receptors
DR4 and DR5 and the consequent activation of caspase-8. These effects increased when the cells were
treated with SAHA/TRAIL combination. Because z-IEDT-fmk, an inhibitor of caspase-8, prevented both
the cleavage of the focal adhesion-kinase FAK and cell detachment, we suggest that activation of caspase-
8 can be responsible for both the decrement of FAK and the consequent cell detachment. In addition,
treatment with SAHA/TRAIL combination caused dissipation of DJm, activation of caspase-3 and
decrement of both phospho-EGFR and phospho-ERK1/2, a kinase which is involved in the phosphorylation
of BimEL. Therefore, co-treatment also induced decrement of phospho-BimEL and a concomitant
increase in the dephosphorylated form of BimEL, which plays an important role in the induction of
anoikis.
Our findings suggest the potential application of SAHA in combination with TRAIL in clinical trials for
breast cancer
Learning Generalized Depth Three Arithmetic Circuits in the Non-Degenerate Case
No full textConsider a homogeneous degree d polynomial f = T₁ + ⋯ + T_s, T_i = g_i(_{i,1}, …, _{i, m}) where g_i’s are homogeneous m-variate degree d polynomials and _{i,j}’s are linear polynomials in n variables. We design a (randomized) learning algorithm that given black-box access to f, computes black-boxes for the T_i’s. The running time of the algorithm is poly(n, m, d, s) and the algorithm works under some non-degeneracy conditions on the linear forms and the g_i’s, and some additional technical assumptions n ≥ (md)², s ≤ n^{d/4}. The non-degeneracy conditions on _{i,j}’s constitute non-membership in a variety, and hence are satisfied when the coefficients of _{i,j}’s are chosen uniformly and randomly from a large enough set. The conditions on g_i’s are satisfied for random polynomials and also for natural polynomials common in the study of arithmetic complexity like determinant, permanent, elementary symmetric polynomial, iterated matrix multiplication. A particularly appealing algorithmic corollary is the following: Given black-box access to an f = Det_r(L^(1)) + … + Det_r(L^(s)), where L^(k) = (_{i,j}^(k))_{i,j} with _{i,j}^(k)’s being linear forms in n variables chosen randomly, there is an algorithm which in time poly(n, r) outputs matrices (M^(k))_k of linear forms s.t. there exists a permutation π: [s] → [s] with Det_r(M^(k)) = Det_r(L^(π(k))).
Our work follows the works [Neeraj Kayal and Chandan Saha, 2019; Garg et al., 2020] which use lower bound methods in arithmetic complexity to design average case learning algorithms. It also vastly generalizes the result in [Neeraj Kayal and Chandan Saha, 2019] about learning depth three circuits, which is a special case where each g_i is just a monomial. At the core of our algorithm is the partial derivative method which can be used to prove lower bounds for generalized depth three circuits. To apply the general framework in [Neeraj Kayal and Chandan Saha, 2019; Garg et al., 2020], we need to establish that the non-degeneracy conditions arising out of applying the framework with the partial derivative method are satisfied in the random case. We develop simple but general and powerful tools to establish this, which might be useful in designing average case learning algorithms for other arithmetic circuit models
EVALUATION OF HISTONE DEACETYLASE INHIBITOR EFFECTS ON THYROID CANCER
No full textAbstract
Histone deacetylases (HDACs) play a crucial role in the proper regulation of cellular functions through their connection with chromatin and transcriptional regulation. Alterations in HDAC activity have been reported in several types of cancer encouraging development of HDAC inhibitors (HDACis) for cancer treatment. The antitumor activity of HDACi has been demonstrated, in clinical trials, in both solid and non solid neoplasias at doses well tolerated by patients. However, the molecular basis for their tumor selectivity is unknown. Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, having a poor prognosis and being refractory to conventional chemo- and radiotherapy. To the aim to find an innovative therapy for the treatment of ATCs, we studied the effects of two potent HDACis, SAHA and MS-275, on rat thyroid cell lines transformed by the v-ras-Ki oncogene which is frequently mutated in ATCs. We show that: i) HDAC 1 and HDAC 2 are overexpressed in anaplastic thyroid carcinomas compared to normal thyroid; ii) SAHA and MS-275 induce apoptosis selectively in completely transformed rat thyroid cells; iii) TNF-related apoptosis-inducing ligand (TRAIL) is the main mediator of cell death induced by SAHA; iv) SAHA stabilize TRAIL protein by affecting its proteasome-mediated degradation
Stabilization strategies for unstable dynamics.
No full textBACKGROUND: When humans are faced with an unstable task, two different stabilization mechanisms are possible: a high-stiffness strategy, based on the inherent elastic properties of muscles/tools/manipulated objects, or a low-stiffness strategy, based on an explicit positional feedback mechanism. Specific constraints related to the dynamics of the task and/or the neuromuscular system often force people to adopt one of these two strategies. METHODOLOGY/FINDINGS: This experiment was designed such that subjects could achieve stability using either strategy, with a marked difference in terms of effort and control requirements between the two strategies. The task was to balance a virtual mass in an unstable environment via two elastic linkages that connected the mass to each hand. The dynamics of the mass under the influence of the unstable force field and the forces applied through the linkages were simulated using a bimanual, planar robot. The two linkages were non-linear, with a stiffness that increased with the amount of stretch. The mass could be stabilized by stretching the linkages to achieve a stiffness that was greater than the instability coefficient of the unstable field (high-stiffness), or by balancing the mass with sequences of small force impulses (low-stiffness). The results showed that 62% of the subjects quickly adopted the high-stiffness strategy, with stiffness ellipses that were aligned along the direction of instability. The remaining subjects applied the low-stiffness strategy, with no clear preference for the orientation of the stiffness ellipse. CONCLUSIONS: The choice of a strategy was based on the bimanual coordination of the hands: high-stiffness subjects achieved stability quickly by separating the hands to stretch the linkages, while the low-stiffness subjects kept the hands close together and took longer to achieve stability but with lower effort. We suggest that the existence of multiple solutions leads to different types of skilled behavior in unstable environments
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