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Background: Disruption of circadian processes has been linked to cancer initiation, progression, metastasis, resistance, and mortality. Clock proteins are an emerging target for therapy in breast cancer. Circadian rhythms are controlled by a network of transcription/translation feedback loops primarily driven by BMAL and CLOCK and the transcriptional repressors period (PER1-3) and cryptochrome (CRY1-2). We investigated the molecular and clinical associations of clock genes in breast cancer. Methods: A total of 9563 breast tumors underwent molecular profiling (Caris Life Sciences). Analyses included next-generation sequencing of DNA (592 genes-NextSeq, WES-NovaSeq) and RNA (NovaSeq). Clock gene Score (CS) was determined using expression of clock pathway gene Z scores (positives of BMAL, CLOCK and negatives of PER1/2 and CRY1/2) and then stratified into quartiles. xCell was used to quantify immune cell infiltration in the tumor microenvironment (TME). ER/PR was tested by IHC and HER2 was tested by either IHC or CISH. Significance was determined as P values adjusted for multiple comparison (Q) of < 0.05. Real-world survival information was obtained from insurance claims data and was calculated from either tissue collection to last contact or time on treatment (TOT); comparison was done by Kaplan-Meier test. Results: TNBC had the highest median CS score, while HR+/HER2- had the lowest CS (0.96 vs 0.26 q Citation Format: Priya Jayachandran, Yasmine Baca, Joanne Xiu, Yuanzhong Pan, Phil Walker, Francesca Battaglin, Hiroyuki Arai, Moh’d Khushman, Janice Lu, Darcy Spicer, Shannon Mumenthaler, Richard Goldberg, Benjamin Weinberg, Emil Lou, Michael Hall, Arielle L. Heeke, W. Michael Korn, Steve A. Kay, Heinz-Josef Lenz, Evanthia T. Roussos Torres. Clock Genes in Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-06.

Considerable evidence suggests that psychosocial variables can shape the course of bipolar disorder. Here, though, we focus on the more specific idea that the social environment can predict the course of mania. We systematically review evidence from longitudinal studies concerning how social support, family interactions, traumatic life events, and recent life events relate to the age of onset, the frequency of episode recurrence, and the severity of manic symptoms. Although we find some evidence that the course of mania can be worsened by social environmental factors, the links are specific. Among social variables, some studies indicate that conflict and hostility are predictive, but more general social relationship qualities have not been found to predict mania. Some research indicates that childhood trauma, and recent life events involving goal attainment or sleep disruption can predict mania. Taken together, the profile of variables involving recent exposure that are most predictive include those that are activating, reward-related, or sleep-disrupting, which fits with general psychological hypotheses of behavioral activation and sleep disruption as important for mania. We discuss gaps in the literature, and we note future directions for research, including the need for more integrative, longitudinal research on a fuller range of social and biological risk variables.

Background: Elevated circulating growth differentiation factor 15 (GDF15) and increased GDF15 expression in tumor tissues has been observed in patients with advanced pancreatic cancer (APC). These changes were correlated with poor survival. Effects of GDF15 on tumor progression, metastasis and immune escape may play a role. NGM120, a novel antibody to GFRAL that blocks the effects of GDF15, has resulted both in antitumor and anti-cachexia effects in experimental models. Here we report updated findings of the ongoing Phase 1b study with NGM120 in patients with APC. Methods: Metastatic pancreatic cancer patients with elevated serum GDF15 were treated with NGM120 (30 or 100 mg, s.c., q4wks) in a 1st line setting in combination with Gem/nab-paclitaxel. Primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetics, preliminary evidence of antitumor activity (RECIST) and anti-cachexia effects. Results: Eight patients received NGM120 in combination with Gem/nab-paclitaxel. Median age was 67 years, all patients had advanced disease. NGM120 was well tolerated with no dose-limiting toxicities. Most of the AEs or SAEs observed were Gem/nab-paclitaxel related and none of them attributed to NGM 120 treatment. As of data cut off on March 25, 2022, preliminary results include 3 patients with PR (extending >32 wks), 3 patients SD; 2 patients discontinued early (before first post-dose scan) due to toxicity attributed to Gem/nab-paclitaxel. Among the 6 evaluable patients, the disease control rate (DCR) is 100%, mPFS has not been reached, 12-month survival rate (12-month OS) is 83.3%. Over the course of the study, 5/6 of the patients gained or maintained their body weight (BW) and 5/6 of the patients gained or maintained their lean body mass (LBM) based on maximum change from baseline. Conclusions: NGM120 given in combination with Gem/nab-paclitaxel to patients with APC resulted in a 50% ORR (3 PR in 6 evaluable patients), 100% DCR, 83.3% 12-month OS and a “not reached” mPFS. Compared to historical Gem/nab-paclitaxel data, these findings are encouraging and support the potential role of NGM120 in the treatment of patients with APC. The positive effects on BW and LBM is also encouraging compared to the historical cachexia rate of 30% observed within 12 weeks of starting first-line chemotherapy in APC. A sign of NGM120 engages the GDF15-GFRAL pathway in managing body weight regulation. A Ph2a study is ongoing to further evaluate NGM120 in combination with Gem/nab-paclitaxel in the 1st line setting for the treatment of APC. Citation Format: Andrew Hendifar, Efrat Dotan, Benjamin Weinberg, Edward Kim, Peter Hosein, Jian Luo, Jiping Zha, Alex DePaoli, Vladimir Hanes, Cecilia Tranmuchowski, Kefei Zhou, Carol Tseng, Hsiao Lieu. Initial results of a cohort of advanced pancreatic cancer patients in a phase 1b Study of NGM120, a first-in-class anti-GDNF Family Receptor Alpha Like (GFRAL) antibody [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR006.

Sleep is critical for daily functioning. One important function of sleep is the consolidation of memories, a process that makes them stronger and less vulnerable to interference. The neural mechanisms underlying the benefit of sleep for memory can be investigated using polysomnography (PSG). PSG is a combination of physiological recordings including signals from the brain (EEG), eyes (EOG), and muscles (EMG) that are used to classify sleep stages. In this protocol, we describe how PSG can be used in conjunction with behavioral memory assessments, actigraphy, and parent-report to examine sleep-dependent memory consolidation. The focus of this protocol is on early childhood, a period of significance as children transition from biphasic sleep (consisting of a nap and overnight sleep) to monophasic sleep (overnight sleep only). The effects of sleep on memory performance are measured using a visuospatial memory assessment across periods of sleep and wakeful-rest. A combination of actigraphy and parent report is used to assess sleep rhythms (i.e., characterizing children as habitual or non-habitual nappers). Finally, PSG is used to characterize sleep stages and qualities of those stages (such as frequencies and the presence of spindles) during naps. The advantage of using PSG is that it is the only tool currently available to assess sleep quality and sleep architecture, pointing to the relevant brain state that supports memory consolidation. The main limitations of PSG are the length of time it takes to prepare the recording montage and that recordings are typically taken over one sleep bought. These limitations can be overcome by engaging young participants in distracting tasks during application and combining PSG with actigraphy and self/parent-report measures to characterize sleep cycles. Together, this unique combination of methods allows for investigations into how naps support learning in preschool children.

Strategic decisions regarding fuels used to meet the University of Virginia's current and future steam demand require an in-depth understanding of the operations of the University of Virginia's Main Heat Plant. The current mix of fossil fuels that the Main Heat Plant depends on to heat the University is constrained in numerous ways, including: the University of Virginia's natural gas allotments, the contractual curtailments on natural gas set by the City of Charlottesville, the University of Virginia's commitment to reducing greenhouse gas emissions, and financial costs. This paper focuses on developing an 8760 (24 hours × 365 days) model that compares multiple what-if scenarios on key measures through simulating the performance of the plant during a year at one hour increments. These scenarios evaluate the effects of changes to the aforementioned constraints and also to increases in demand. Operators at the Main Heat Plant will use the model through an interface that allows them to observe the performance of the system and explore different alternatives by selecting specific scenarios. Summary graphics for parameters such as greenhouse gas emissions, fuel usage, and cost provide decision makers in the plant and in University of Virginia administration with information needed to make strategic decisions regarding the Main Heat Plant and related fuel agreements. The simulated results were validated through a comparison against actual data collected from July 2016 to June 2017, resulting in 65% of modeled fuel states, matching the historical fuel states for the same periods.

Many problems consist in splitting a set of objects into different groups so that each group verifies some properties. In practice, a partitioning is often encoded by an array mapping each object to its group numbering. In fact, the group number of an object does not really matter, and one can simply rename each group to obtain a new encoding. That is what we call the symmetry of the search space in a partitioning problem. This property may be prejudicial for optimization methods such as evolutionary algorithms (EA) which require some diversity during the search. This paper aims at providing a theoretical framework for breaking this symmetry. We define an equivalence relation on the encoding space. This leads us to define a non-trivial search space which eliminates symmetry. We define polynomially computable tools such as equality test, a neighborhood operator and a distance metric applied on the set of partitionings. This work has been applied to the graph coloring problem (GCP). A new distance has been proposed, which is quicker to compute and closer to the problem structure. Computing this distance has been reduced to the linear assignment problem which can be solved polynomially. Using this distance, the analysis of the landscape of the GCP has been carried out.

Background To consolidate literature reports of serious late gastrointestinal toxicities after hypofractionated radiation treatment of pancreatic cancer and attempt to derive normal tissue complication probability (NTCP) parameters using the Lyman-Kutcher-Burman model. Methods Published reports of late grade 3 or greater gastrointestinal toxicity after hypofractionated treatment of pancreatic cancer were reviewed. The biologically equivalent dose in 1.8 Gy fractions was calculated using the EQD model. NTCP parameters were calculated using the LKB model assuming 1–5 % of the normal tissue volume was exposed to the prescription dose with α/β ratios of 3 or 4. Results A total of 16 human studies were examined encompassing a total of 1160 patients. Toxicities consisted of ulcers, hemorrhages, obstructions, strictures, and perforations. Non-hemorrhagic and non-perforated ulcers occurred at a rate of 9.1 % and were the most commonly reported toxicity. Derived NTCP parameter ranges were as follows: n = 0.38–0.63, m = 0.48–0.49, and TD50 = 35–95 Gy. Regression analysis showed that among various study characteristics, dose was the only significant predictor of toxicity. Conclusions Published gastrointestinal toxicity reports after hypofractionated radiotherapy for pancreatic cancer were compiled. Median dose was predictive of late grade ≥ 3 gastrointestinal toxicity. Preliminary NTCP parameters were derived for multiple volume constraints.

A 28-year-old female who underwent live donor liver transplantation 3 years prior presented after percutaneous liver biopsy with abdominal and shoulder pain, nausea, vomiting, and elevated liver enzymes. Computed tomography (CT) showed an intrahepatic and subcapsular hematoma. There was a progressive increase in liver enzymes, bilirubin, and INR and a decline in hemoglobin. Subsequent CT imaging revealed flattening of the portal vein consistent with compression by the enlarging hematoma. Liver failure ensued and the patient required urgent retransplantation. The explant demonstrated ischemic necrosis of greater than 90% of the liver parenchyma. We report this case of “Hepatic Compartment Syndrome” leading to fulminant hepatic failure.

Nowadays, in the heuristic and metaheuristics community, there is a schism between researchers who say: "we proved experimentally that a given heuristic provides good results on a given problem and we can guess that it is enough general to be applied for other problems", and those who claim: "the No Free Lunch theorem (NFL) proves that there exists no absolute efficient heuristic". The formers suspect the existence of a structure in the solved problem and that structure can occur in other problems. The latters fear that heuristics are especially adapted for the testbed problem this paper addresses structural aspect of combinatorial optimization problems. In a first time, we recall some related works which provide a frame to our work. Particularly, we recall the existence of deceptive problems which are proved to be hard to optimize, the definitions of the five scenarios of knowledge in optimization problem, and some works which already discuss the reach of NFL theorem. In the next part, we give a short overview of how NFL works and discuss its significance with regards to complexity. This leads to the observation that the notion of structure of optimization problems is missing in NFL use. Then, we prove that k-coloring problems respect such a notion of structure, for any k. In the last part we discuss the relevance of our work on four points: the polynomial reduction of NP-complete problems and structure preservation, the connection between our work and the study which squeeze NFL using neighborhood search operators, the position of our study on the five scenarios of knowledge, and finally the difference between metaheuristics and heuristics.

The Axl protein belongs to a subfamily of receptor tyrosine kinase and has been implicated in a large variety of cancers like colorectal, prostate, mesothelioma, breast, etc., beginning from its overexpression initially detected in chronic myeloid leukemia. Hence Axl presents as a novel and promising target for multiple cancer models. Meanwhile chimeric antigen receptor (CAR) is already a developed platform technology used in genetically modified T cells in order to make them recognize and elicit an immune response against cancer cells. Here we designed 3 single-chain variable fragments from existing monoclonal antibodies against Axl and constructed them into third-generation CARs. For testing, we transduced these CARs into Jurkat T cells and primary CD4 T cells. We cultured the cells in different doses of Axl and assayed the level of their activation using flow cytometry and ELISA. All 3 CARs demonstrated functional efficacy in being able to recognize the antigen and produced successful activation. This was detected by increase in GFP expression, cloned downstream of the NFAT promoter in the Jurkat T cell line. Furthermore the primary T cell experiment demonstrated increased secretion of IFNγ for all 3 CARs and IL-2 for 2 CARs. Our study confirmed the successful construction of 3 new therapeutic CARs against the novel cancer antigen, Axl, with varying levels of activation. This can now be utilized in a switchable CAR system to deliver a tunable therapeutic immune response.

This paper presents a new approach, the COSEARCH approach, for solving the Problem of Assigning Frequencies (FAP) on antennas of a cellular telecommunication network. The COSEARCH approach is a co-evolutionist method in which complementary meta-heuristics, such as genetic algorithm (GA) or tabu search (TS), cooperate in parallel via an adaptive memory (AM). We introduce an original encoding and two new cross-over operators suited to FAP. COSEARCH for the FAP is compared with other studies and its efficiency is revealed on both medium and large instances.