Repetition Detection in a Dynamic String

A string UU for a non-empty string U is called a square. Squares have been well-studied both from a combinatorial and an algorithmic perspective. In this paper, we are the first to consider the problem of maintaining a representation of the squares in a dynamic string S of length at most n. We present an algorithm that updates this representation in n^o(1) time. This representation allows us to report a longest square-substring of S in O(1) time and all square-substrings of S in O(output) time. We achieve this by introducing a novel tool - maintaining prefix-suffix matches of two dynamic strings. We extend the above result to address the problem of maintaining a representation of all runs (maximal repetitions) of the string. Runs are known to capture the periodic structure of a string, and, as an application, we show that our representation of runs allows us to efficiently answer periodicity queries for substrings of a dynamic string. These queries have proven useful in static pattern matching problems and our techniques have the potential of offering solutions to these problems in a dynamic text setting

Sufficient Conditions for Efficient Indexing Under Different Matchings

The most important task derived from the massive digital data accumulation in the world, is efficient access to this data, hence the importance of indexing. In the last decade, many different types of matching relations were defined, each requiring an efficient indexing scheme. Cole and Hariharan in a ground breaking paper [Cole and Hariharan, SIAM J. Comput., 33(1):26-42, 2003], formulate sufficient conditions for building an efficient indexing for quasi-suffix collections, collections that behave as suffixes. It was shown that known matchings, including parameterized, 2-D array and order preserving matchings, fit their indexing settings. In this paper, we formulate more basic sufficient conditions based on the order relation derived from the matching relation itself, our conditions are more general than the previously known conditions

The k-Mappability Problem Revisited

The k-mappability problem has two integers parameters m and k. For every subword of size m in a text S, we wish to report the number of indices in S in which the word occurs with at most k mismatches. The problem was lately tackled by Alzamel et al. [Mai Alzamel et al., 2018]. For a text with constant alphabet ? and k ? O(1), they present an algorithm with linear space and O(nlog^{k+1}n) time. For the case in which k = 1 and a constant size alphabet, a faster algorithm with linear space and O(nlog(n)log log(n)) time was presented in [Mai Alzamel et al., 2020]. In this work, we enhance the techniques of [Mai Alzamel et al., 2020] to obtain an algorithm with linear space and O(n log(n)) time for k = 1. Our algorithm removes the constraint of the alphabet being of constant size. We also present linear algorithms for the case of k = 1, |?| ? O(1) and m = ?(?n)

Influence of companion diagnostics on efficacy and safety of targeted anti-cancer drugs: systematic review and meta-analyses

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Companion diagnostics aim to identify patients that will respond to targeted therapies, therefore increasing the clinical efficacy of such drugs. Less is known about their influence on safety and tolerability of targeted anti-cancer agents. [Methods and findings]: Randomized trials evaluating targeted agents for solid tumors approved by the US Food and Drug Administration since year 2000 were assessed. Odds ratios (OR) and and 95% confidence intervals (CI) were computed for treatment-related death, treatment-discontinuation related to toxicity and occurrence of any grade 3/4 adverse events (AEs). The 12 most commonly reported individual AEs were also explored. ORs were pooled in a meta-analysis. Analysis comprised 41 trials evaluating 28 targeted agents. Seventeen trials (41%) utilized companion diagnostics. Compared to control groups, targeted drugs in experimental arms were associated with increased odds of treatment discontinuation, grade 3/4 AEs, and toxic death irrespective of whether they utilized companion diagnostics or not. Compared to drugs without available companion diagnostics, agents with companion diagnostics had a lower magnitude of increased odds of treatment discontinuation (OR = 1.12 versus 1.65, p < 0.001) and grade 3/4 AEs (OR = 1.09 versus 2.10, p < 0.001), but no difference in risk of toxic death (OR = 1.40 versus 1.27, p = 0.69). Differences between agents with and without companion diagnostics were greatest for diarrhea (OR = 1.29 vs. 2.43, p < 0.001), vomiting (OR = 0.86 vs. 1.44, p = 0.005), cutaneous toxicity (OR = 1.82 vs. 3.88, p < 0.001) and neuropathy (OR = 0.64 vs. 1.60, p < 0.001). [Conclusions]: Targeted drugs with companion diagnostics are associated with improved safety, and tolerability. Differences were most marked for gastrointestinal, cutaneous and neurological toxicity.Ministry of Economy and Competitiveness of Spain (BFU2012-39151 and RD12/0036/0003 to AP), and the AECC (to AP). Fondo de Investigación Sanitaria (PI13/01444) and CRIS Cancer Foundation and ACEPAIN (to AO).Peer Reviewe

25-Hydroxy vitamin-D, obesity, and associated variables as predictors of breast cancer risk and tamoxifen benefit in NSABP-P1.

Observational studies suggest that host factors are associated with breast cancer risk. The influence of obesity, vitamin-D status, insulin resistance, inflammation, and elevated adipocytokines in women at high risk of breast cancer is unknown. The NSABP-P1 trial population was used for a nested case-control study. Cases were drawn from those who developed invasive breast cancer and controls selected from unaffected participants (≤4 per case) matched for age, race, 5 year Gail score, and geographic location of clinical center as a surrogate for latitude. Fasting serum banked at trial enrolment was assayed for 25-hydroxy vitamin-D (25OHD), insulin, leptin (adipocytokine), and C-reactive protein (CRP, marker of inflammation). Logistic regression was used to test for associations between study variables and the risk of invasive breast cancer. Two hundred and thirty-one cases were matched with 856 controls. Mean age was 54, and 49% were premenopausal. There were negative correlations for 25OHD with body mass index (BMI), insulin, CRP, and leptin. BMI ≥ 25 kg/m(2) was associated with higher breast cancer risk (odds ratio [OR] 1.45, p = 0.02) and tamoxifen treatment was associated with lower risk (OR = 0.44, p &lt; 0.001). Suboptimal 25OHD (&lt;72 nmol/l) did not influence breast cancer risk (OR = 1.06, p = 0.76). When evaluated as continuous variables, 25OHD, insulin, CRP, and leptin levels were not associated with breast cancer risk (all p &gt; 0.34). In this high risk population, higher BMI was associated with a greater breast cancer risk. Serum levels of 25OHD, insulin, CRP, and leptin were not independent predictors of either breast cancer risk or tamoxifen benefit

Reduced ErbB4 Expression in Immune Cells of Patients with Relapsing Remitting Multiple Sclerosis

Background. There is an insufficient remyelination in the lesions of multiple sclerosis (MS). One of the factor that was found to promote remyelination is neuregulin-1 which is the ligand of ErbB4. Immune cells have been implicated in neurogenesis and oligodendrogenesis. Aims. We studied the expression of ErbB4 in the immune cells of patients with relapsing remitting (RR) multiple sclerosis (MS) and healthy controls. Methods. ErB4 expression in immune cells was studied by flow cytometry without stimulation or with stimulation with anti-CD3 and anti-CD28 monoclonal antibodies or in the presence of interferon-g or TNF-α as well as by immunoprecipitation and Western blot, and its mRNA was studied by real-time PCR. Results. We found reduced levels of ErbB4 in the total PBMCs and in T cells, monocytes, and B cells of RR MS patients. Similarly, the ErbB4 RNA levels were reduced in the immune cells of patients with RR-MS. Stimulation via CD3 and CD28 significantly upregulated the expression of ErbB4 on immune cells healthy individuals. This effect was weaker in the patients group. Conclusion. ErbB4 may play a role in the proliferation of oligodendrocyte progenitor cells, differentiation of oligodendrocytes, and remyelination, and, therefore, the reduced ErbB4 expression in immune cells of patients with RR-MS may contribute to insufficient remyelination that occurs in the disease

Activation of the PI3K/mTOR/AKT pathway and survival in solid tumors: systematic review and meta-analysis

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Aberrations in the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/AKT pathway are common in solid tumors. Numerous drugs have been developed to target different components of this pathway. However the prognostic value of these aberrations is unclear. [Methods]: PubMed was searched for studies evaluating the association between activation of the PI3K/mTOR/AKT pathway (defined as PI3K mutation [PIK3CA], lack of phosphatase and tensin homolog [PTEN] expression by immunohistochemistry or western-blot or increased expression/activation of downstream components of the pathway by immunohistochemistry) with overall survival (OS) in solid tumors. Published data were extracted and computed into odds ratios (OR) for death at 5 years. Data were pooled using the Mantel-Haenszel random-effect model. [Results]: Analysis included 17 studies. Activation of the PI3K/mTOR/AKT pathway was associated with significantly worse 5-year survival (OR:2.12, 95% confidence intervals 1.42-3.16, p<0.001). Loss of PTEN expression and increased expression/ activation of downstream components were associated with worse survival. No association between PIK3CA mutations and survival was observed. Differences between methods for assessing activation of the PI3K/mTOR/AKT pathway were statistically significant (p = 0.04). There was no difference in the effect of up-regulation of the pathway on survival between different cancer sites (p = 0.13). [Conclusion]: Activation of the PI3K/AKT/mTOR pathway, especially if measured by loss of PTEN expression or increased expression/activation of downstream components is associated with poor survival. PIK3CA mutational status is not associated with adverse outcome, challenging its value as a biomarker of patient outcome or as a stratification factor for patients treated with agents acting on the PI3K/AKT/mTOR pathway.Work in A.O. lab is supported by grant PI13/01444 from ISCIII and Diputación de Albacete. Work in A.P. lab is supported by the Fundación Científica de la AECC and the Ministry of Economy and Competitiveness (BFU2012-39151) and Red Temática de Investigación Cooperativa en Cáncer. A.O. and A.P. receive support from CRIS Cancer foundation.Peer Reviewe

Fragility of randomized trials supporting cancer drug approvals stratified by approval pathway and review designations

Background: It has been suggested that the results from fragile trials are less likely to translate into benefit in routine clinical practice. Methods: We searched the Food and Drug Administration (FDA) archives to identify drug approvals for solid organ malignancies between 2010 and 2019. We calculated the Fragility Index (FI) supporting each approval, using methods to account for time-to-event. We compared FI and trial and approval characteristics using Mann-Whitney U and Kruskal-Wallis test. Using logistic regression, we examined study characteristics associated with withdrawal of consent or lost to follow-up (WCLFU) exceeding the calculated FI. Results: The median FI among 125 included studies was 23 (range 1-322). The FI was ≤10 in 35 studies (28%), 11-20 in 21 (17%), and >20 in 69 (55%). The median FI/Nexp was 7.7% (range 0.1-51.7%). The median FI was significantly lower among approvals processed through the accelerated vs regular pathway (5.5 vs 25, p = 0.001), but there was no difference in median FI/Nexp. The WCLFU exceeded FI in 42% of studies. Overall survival endpoints were more likely to have a WCLFU exceeding FI (OR 3.16, p = 0.003). WCLFU exceeding FI was also associated with a lesser magnitude of effect (median HR 0.69 vs 0.55, p FI. Conclusion: The median FI among all trials was 23, and WCLFU exceeded FI in 42%. Comparative trials in solid tumors supporting approval through the accelerated pathway are more fragile compared to trials approved through the regular pathway, an observation likely explained by a lower sample size in the experimental arm