In this paper, we study the performance of static solutions for two-stage adjustable robust linear optimization problems with uncertain constraint and objective coefficients and give a tight ...characterization of the adaptivity gap. Computing an optimal adjustable robust optimization problem is often intractable since it requires to compute a solution for all possible realizations of uncertain parameters (Feige et al. in Lect Notes Comput Sci 4513:439–453,
2007
). On the other hand, a static solution is a single (here and now) solution that is feasible for all possible realizations of the uncertain parameters and can be computed efficiently for most dynamic optimization problems. We show that for a fairly general class of uncertainty sets, a static solution is optimal for the two-stage adjustable robust linear packing problems. This is highly surprising in view of the usual perception about the conservativeness of static solutions. Furthermore, when a static solution is not optimal for the adjustable robust problem, we give a tight approximation bound on the performance of the static solution that is related to a measure of non-convexity of a transformation of the uncertainty set. We also show that our bound is at least as good (and in many case significantly better) as the bound given by the symmetry of the uncertainty set (Bertsimas and Goyal in Math Methods Oper Res 77(3):323–343,
2013
; Bertsimas et al. in Math Oper Res 36(1):24–54,
2011
).
In this paper, we study the performance of static solutions in two-stage adjustable robust packing linear optimization problem with uncertain constraint coefficients. Such problems arise in many ...important applications such as revenue management and resource allocation problems where demand requests have uncertain resource requirements. The goal is to find a two-stage solution that maximizes the worst case objective value over all possible realizations of the second-stage constraints from a given uncertainty set. We consider the case where the uncertainty set is
column-wise
and
constraint-wise
(any constraint describing the set involve entries of only a single column or a single row). This is a fairly general class of uncertainty sets to model constraint coefficient uncertainty. We show that the two-stage adjustable robust problem is
Ω
(
log
n
)
-hard to approximate. On the positive side, we show that a static solution is an
O
(
log
n
·
min
(
log
Γ
,
log
(
m
+
n
)
)
)
-approximation for the two-stage adjustable robust problem where
m
and
n
denote the numbers of rows and columns of the constraint matrix and
Γ
is the maximum possible ratio of upper bounds of the uncertain constraint coefficients. Therefore, for constant
Γ
, surprisingly the performance bound for static solutions and therefore, the adaptivity gap matches the hardness of approximation for the adjustable problems. Furthermore, in general the static solution provides nearly the best efficient approximation for the two-stage adjustable robust problem.
Abstract
Parasitic nematodes are major human and agricultural pests, and benzimidazoles are amongst the most important broad-spectrum anthelmintic drug class used for their control. Benzimidazole ...resistance is now widespread in many species of parasitic nematodes in livestock globally and an emerging concern for the sustainable control of human soil-transmitted helminths. β-tubulin is the major benzimidazole target, although other genes may influence resistance. Among the 6 Caenorhabditis elegans β-tubulin genes, loss of ben-1 causes resistance without other apparent defects. Here, we explored the genetics of C. elegans β-tubulin genes in relation to the response to the benzimidazole derivative albendazole. The most highly expressed β-tubulin isotypes, encoded by tbb-1 and tbb-2, were known to be redundant with each other for viability, and their products are predicted not to bind benzimidazoles. We found that tbb-2 mutants, and to a lesser extent tbb-1 mutants, were hypersensitive to albendazole. The double mutant tbb-2 ben-1 is uncoordinated and short, resembling the wild type exposed to albendazole, but the tbb-1 ben-1 double mutant did not show the same phenotypes. These results suggest that tbb-2 is a modifier of albendazole sensitivity. To better understand how BEN-1 mutates to cause benzimidazole resistance, we isolated mutants resistant to albendazole and found that 15 of 16 mutations occurred in the ben-1 coding region. Mutations ranged from likely nulls to hypomorphs, and several corresponded to residues that cause resistance in other organisms. Null alleles of ben-1 are albendazole-resistant and BEN-1 shows high sequence identity with tubulins from other organisms, suggesting that many amino acid changes could cause resistance. However, our results suggest that missense mutations conferring resistance are not evenly distributed across all possible conserved sites. Independent of their roles in benzimidazole resistance, tbb-1 and tbb-2 may have specialized functions as null mutants of tbb-1 or tbb-2 were cold or heat sensitive, respectively.
Transcriptional timing is inherently influenced by gene length, thus providing a mechanism for temporal regulation of gene expression. While gene size has been shown to be important for the ...expression timing of specific genes during early development, whether it plays a role in the timing of other global gene expression programs has not been extensively explored. Here, we investigate the role of gene length during the early transcriptional response of human fibroblasts to serum stimulation. Using the nascent sequencing techniques Bru-seq and BruUV-seq, we identified immediate genome-wide transcriptional changes following serum stimulation that were linked to rapid activation of enhancer elements. We identified 873 significantly induced and 209 significantly repressed genes. Variations in gene size allowed for a large group of genes to be simultaneously activated but produce full-length RNAs at different times. The median length of the group of serum-induced genes was significantly larger than the median length of all expressed genes, housekeeping genes, and serum-repressed genes. These gene length relationships were also observed in corresponding mouse orthologs, suggesting that relative gene size is evolutionarily conserved. The sizes of transcription factor and microRNA genes immediately induced after serum stimulation varied dramatically, setting up a cascade mechanism for temporal expression arising from a single activation event. The retention and expansion of large intronic sequences during evolution have likely played important roles in fine-tuning the temporal expression of target genes in various cellular response programs.
Histone deacetylase (HDAC) overexpression has been documented in various cancers and may be associated with worse outcomes. Data from early-phase studies of advanced non-small cell lung cancer ...(NSCLC) suggest encouraging antitumor activity with the combination of an HDAC inhibitor and either platinum-based chemotherapy or an EGFR inhibitor; however, toxicity is a limiting factor in the use of pan-HDAC inhibitors. Selective inhibition of HDAC6 may represent a potential therapeutic target and preclinical studies revealed immunomodulatory effects with HDAC6 inhibition, suggesting the potential for combination with immune checkpoint inhibitors. This phase Ib, multicenter, single-arm, open-label, dose-escalation study investigated the HDAC6 inhibitor ACY-241 (citarinostat) plus nivolumab in patients with previously treated advanced NSCLC who had not received a prior HDAC or immune checkpoint inhibitor.
The orally administered ACY-241 dose was escalated (180, 360, or 480 mg once daily). Nivolumab was administered at 240 mg (day 15 of cycle 1, then every 2 weeks thereafter). The primary endpoint was to determine the maximum tolerated dose (MTD) of ACY-241 plus nivolumab. Secondary endpoints included safety, tolerability, and preliminary antitumor activity. Pharmacodynamics was an exploratory endpoint.
A total of 18 patients were enrolled, with 17 patients treated. No dose-limiting toxicities (DLTs) occurred with ACY-241 at 180 or 360 mg; 2 DLTs occurred at 480 mg. The MTD of ACY-241 was 360 mg. The most common grade ≥ 3 treatment-emergent adverse events were dyspnea (n = 3; 18%) and pneumonia (n = 3; 18%). At the 180-mg dose, 1 complete response and 2 partial responses (PRs) were observed. At the 360-mg dose, 3 PRs were observed; 1 patient achieved stable disease (SD) and 1 experienced progressive disease (PD). At the 480-mg dose, no responses were observed; 1 patient achieved SD and 3 experienced PD. Acetylation analyses revealed transient increases in histone and tubulin acetylation levels following treatment. An increase in infiltrating total CD3
T cells was observed following treatment.
The study identified an MTD for ACY-241 plus nivolumab and the data suggest that the combination may be feasible in patients with advanced NSCLC. Responses were observed in patients with advanced NSCLC.
https://clinicaltrials.gov/ct2/show/NCT02635061 (identifier, NCT02635061).
Citarinostat (CC-96241; previously ACY-241), an oral inhibitor of histone deacetylases (HDACs) with selectivity for HDAC6, has demonstrated synergistic anticancer activity with paclitaxel in multiple ...solid tumor models. Combination therapy using citarinostat with paclitaxel was evaluated in this phase Ib 3 + 3 dose-escalation study in patients with advanced solid tumors.
Patients with previously treated advanced solid tumors received citarinostat 180, 360, or 480 mg once daily on days 1 to 21 plus paclitaxel 80 mg/m
on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was determination of the maximum tolerated dose (MTD). Secondary endpoints included safety, antitumor activity, pharmacokinetics, and pharmacodynamics.
Twenty patients were enrolled and received study treatment; 15 had received prior taxane therapy. No dose-limiting toxicities were reported at any dose; therefore, the MTD was not identified. Citarinostat 360 vs 480 mg was associated with reduced incidence and severity of neutropenia. Three patients experienced a confirmed partial response and 13 achieved stable disease. Pharmacokinetic parameters were linear up to citarinostat 360 mg, the dose at which the highest levels of histone and tubulin acetylation were observed in peripheral blood mononuclear cells.
The combination of citarinostat plus paclitaxel showed an acceptable safety profile, with no unexpected or dose-limiting toxicities and potential evidence of antitumor activity in patients with heavily pretreated advanced solid tumors. Citarinostat 360 mg once daily is considered the recommended phase II dose for use in combination with paclitaxel 80 mg/m
every 3 of 4 weeks. This trial is registered on ClinicalTrials.gov (NCT02551185).
This phase II bridging study assessed the safety and efficacy of nab-paclitaxel/gemcitabine (Metastatic Pancreatic Adenocarcinoma Clinical Trial MPACT regimen) in Chinese patients with metastatic ...pancreatic cancer (MPC).
This 3-part sequential study evaluated nab-paclitaxel 125 mg/m
plus gemcitabine 1000 mg/m
on days 1, 8, and 15 every 4 weeks. Part 1 evaluated safety. Part 2 evaluated efficacy using Simon's optimal 2-stage design: if >2 responses were observed in Stage 1 (n = 28), 54 additional patients would be enrolled in Stage 2. If >9 responses were observed, the study was complete. Otherwise, nab-paclitaxel/gemcitabine would be compared with gemcitabine alone in Part 3. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR), overall survival (OS), and safety.
Eighty-three patients were treated. The prespecified primary endpoint was met: the independently assessed ORR in Stages 1 + 2 was 35% (95% CI, 24.8-46.2); therefore, Part 3 was not initiated. The median DOR was 8.9 months (95% CI, 6.01-8.94). The median OS and progression-free survival were 9.2 (95% CI, 7.6-11.1) and 5.5 (95% CI, 5.29-7.16) months, respectively. The 12-month OS rate was 30%. In an updated analysis, the median OS was 9.3 months and the 12-month OS rate was 32%. Longer OS was observed in patients with baseline neutrophil-to-lymphocyte ratio ≤ 5 vs > 5. The most common grade ≥ 3 adverse events were leukopenia (35%), neutropenia (34%), anemia (15%), thrombocytopenia (10%), and fatigue (13%). Grade 3 peripheral neuropathy occurred in 7% of patients (no grade 4 reported).
The MPACT regimen of nab-paclitaxel/gemcitabine is efficacious in Chinese patients with MPC. No new safety signals were observed.
NCT02135822 , May 8, 2014.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
Using patient data from the electronic health record (EHR) and computer logic, an “electronic phenotype” can be created to identify patients with community-acquired pneumonia (CAP) in ...real time to assist with syndrome-specific antimicrobial stewardship efforts.
1
We adapted and validated the performance of an inpatient CAP electronic phenotype for antimicrobial stewardship interventions.
Methods:
An automated scoring system was created within the EHR (Epic Systems) to identify hospitalized patients with CAP based on the variables and logic listed in Fig. 1B. We adapted a score used by the Michigan Hospital Medicine Safety Consortium (HMS) to identify patients with CAP, with additions made to improve sensitivity (Fig. 1).
1
The score can be displayed in a column within the EHR patient list (Fig. 2). We validated the electronic phenotype via chart review of all hospitalized patients on systemic antimicrobials admitted to a medicine team consecutively between November 8 and 18, 2021. Patients who were readmitted within the validation time frame were excluded. We assessed the performance of the electronic phenotype by comparing the score to manual chart review, where “CAP diagnosis” was defined as (1) mention of “pneumonia” or “CAP” as part of the differential diagnosis in the admission documentation, (2) antimicrobials were started within 48 hours of admission, and (3) radiographic findings were suggestive of pneumonia. After initial evaluation, the scoring system was adjusted, and performance was re-evaluated during prospective audit and feedback performed on EHR CAP–positive patients over 13 days between July 2022 and December 2022.
Results:
We included 191 patients in our initial validation cohort. The CAP score had high sensitivity (95.83%), specificity (92.2%), and negative predictive value (99.35%), though lower positive predictive value (63.89%) was noted (Table 2). The rules were further refined to include bloodstream infection only with
Haemophilus influenza
or
Streptococcus pneumoniae
in rule 2B, and azithromycin was removed from “CAP antibiotics.” After these changes, repeated evaluation of 88 patients with positive CAP EHR score was performed, and only 20 (23%) were considered false-positive results.
Conclusions:
Electronic phenotypes can be used to create automated tools to identify patients with CAP with reasonable performance. Data from this tool can be used to guide more focused antimicrobial stewardship interventions and clinical decision support in the future.
Reference:
Vaughn VM, et al. A statewide collaborative quality initiative to improve antibiotic duration and outcomes in patients hospitalized with uncomplicated community-acquired pneumonia.
Clin Infect Dis
2022;75:460–467.
Disclosures:
None
High-fat diet (HFD)-fed mouse models have been widely used to study early type 2 diabetes. Decreased β-cell glucokinase (GCK) expression has been observed in HFD-induced diabetes. However, owing to ...its crucial roles in glucose metabolism in the liver and in islet β-cells, the contribution of decreased GCK expression to the development of HFD-induced diabetes is unclear. Here, we employed a β-cell-targeted gene transfer vector and determined the impact of β-cell-specific increase in GCK expression on β-cell function and glucose handling
and
Overexpression of GCK enhanced glycolytic flux, ATP-sensitive potassium channel activation and membrane depolarization, and increased proliferation in Min6 cells. β-cell-targeted GCK transduction did not change glucose handling in chow-fed C57BL/6 mice. Although adult mice fed a HFD showed reduced islet GCK expression, impaired glucose tolerance and decreased glucose-stimulated insulin secretion (GSIS), β-cell-targeted GCK transduction improved glucose tolerance and restored GSIS. Islet perifusion experiments verified restored GSIS in isolated HFD islets by GCK transduction. Thus, our data identify impaired β-cell GCK expression as an underlying mechanism for dysregulated β-cell function and glycemic control in HFD-induced diabetes. Our data also imply an etiological role of GCK in diet-induced diabetes.This article has an associated First Person interview with the first author of the paper.
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