Continuous Schedule Research Articles

A hybrid local search algorithm for the continuous energy-constrained scheduling problem

AbstractWe consider the continuous energy-constrained scheduling problem (CECSP). A set of jobs has to be processed on a continuous, shared resource. A schedule for a job consists of a start time, completion time, and a resource consumption profile. The goal is to find a schedule such that each job does not start before its release time, is completed before its deadline, satisfies its full resource requirement, and respects its lower and upper bounds on resource consumption during processing. The objective is to minimize the total weighted completion time. We present a hybrid local search approach, using simulated annealing and linear programming, and compare it to a mixed-integer linear programming (MILP) formulation. We show that the hybrid local search approach matches the MILP formulation in solution quality for small instances and is able to find a feasible solution for larger instances in reasonable time.

Analysis of the Liner Shipping Network Structure of the Asia–Europe Main Trunk Route Using Social Network Analysis

Due to COVID-19, the shipping market has faced uncertainty, and the possibility of changes in port routes has increased. The purpose of this study was to analyze the network of container liner shipping routes between Asia and Europe. In particular, this research focused on a global risky situation—the COVID-19 pandemic. The data examined encompassed Asia–Europe route schedules from January 2018 to October 2021, which exhibited significant fluctuations due to the COVID-19 pandemic originating in 2019. To access this problem, utilizing concepts of centrality from social network analysis (SNA), namely degree centrality and betweenness centrality, this analysis incorporated route capacity as a weighted factor. The findings revealed that the port of Rotterdam held the highest degree of centrality in 2018, 2019, and 2021, while Shanghai claimed the highest degree of centrality in 2020. Singapore exhibited the highest betweenness centrality. Asian ports wielded greater influence during the COVID-19 pandemic compared to European ports. Furthermore, Singapore emerged as a pivotal mediator in the Asia–Europe routes, playing a significant role within the global supply chain. Results showed that the port could be put into an unstable situation. Therefore, the managers of port and shipping companies should be ready to minimize risk. From an academic perspective, it is difficult to integrate and analyze container liner schedules as they are monthly updated. This study therefore analyzed continuous schedules to examine dynamic changes in schedules. By adopting SNA, we presented changes in connectivity over multiple periods. This study addressed questions stakeholders may have had about route changes during the global crisis, contributing to sustainable container transportation. This study provides a general understanding of Asia–Europe container scheduling for decision makers. Using market schedules, this research analyzed the connections, and evaluated and compared each port.

Perspectives of Undergraduate Students on the Academic Workload and Suicidal thoughts at Nigerian University

This study examined the impact of academic activities on suicidal thoughts among undergraduate students of Nnamdi Azikiwe University, Awka. The study adopted a descriptive survey research design. The population comprised of 100 students in Nnamdi Azikiwe University, Awka. The study selected respondents using a simple random sampling technique. Instrument for data collection was a 20 item structured questionnaire titled Perceived Effects of Academic Activities on Suicidal Thoughts Questionnaire (PEAASTQ). The instrument was validated by three experts from the Faculty of Education in Nnamdi Azikiwe University, Awka. The instrument's reliability was established using the Cronbach Alpha coefficient that yielded coefficient values of 0.86 from section A, 0.96 from section B, 0.80 from section C, and 0.96 from section D, indicating that the instrument was valid. The data collected for the study were analyzed using mean and standard deviation. Findings from the study showed that the students agreed that excess academic workload can lead to depression, limit someone's social life, and contribute to suicidal thoughts among undergraduate students and that unplanned, d changes in academic workload negatively impact on someone's mental well-being. Based on these findings, the study recommends among others that there should be an extension of academic sessions to allow for a more balanced and manageable workload throughout the semester. These can help prevent burnout and reduce the cumulative stress of a continuous academic schedule.

Towards sustainable production with resource efficiency: An empirical study of steelmaking continuous casting scheduling

Traditional heavy industries that are energy-intensive have much potential for energy saving and carbon emission reduction. Focusing on the production scheduling of steelmaking continuous casting, this study aims to propose a twin transformation strategy and investigate the impact on sustainable indicators while considering resource efficiency and productivity. Continuous casting is energy-intensive and the bottleneck for steelmaking. The batching and sequencing of the charges are crucial for energy resource management. This study developed a hybrid genetic algorithm that integrated charge batching decisions to minimize makespan and the total weighted tardiness for continuous casting while minimizing energy consumption for a circular supply chain. An empirical study is conducted to estimate the validity of this approach under various scenarios in real settings. The results have shown practical viability of the developed solution that has been implemented in this case company, while the developed solutions can be effectively employed in other industries for sustainability.

A bathtub model with nonlinear velocity–density relation

The bathtub model is an applicable and effective tool for simulating the characteristics of traffic dynamics in downtown areas during morning rush hour, especially the characteristics of hypercongested traffic. In order to reduce the complexity of the research, previous studies have adopted a linear velocity–density relationship. This has limitations in analyzing the cost and duration of hypercongestion in traffic dynamics. In this paper, we develop a bathtub model with one kind of nonlinear velocity–density Relation, i.e., Pipes–Munjal Relation, based on continuous scheduling preferences and analyze its solutions in both no-toll user equilibrium and social optimum states. Due to the intractability in solving this bathtub model, there exists local analytical solutions, but for a complete solution of the model, only numerical solutions are available. The results indicate that as the value of n increases, the model can simulate traffic dynamics with higher cost and longer duration of hypercongestion under equilibrium, and can simulate traffic states with lower system cost under social optimum. We also explore the results of implementing optimal time-varying toll to realize social optimum. This study expands the relevant theories of bathtub models and provides a new perspective for traffic congestion.

An open-label, single-arm, dose escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of the ATR inhibitor SC0245 in advanced solid malignancies.

e15126 Background: Ataxia telangiectasia and Rad3-related (ATR) is a critical protein that senses DNA damage and is an integral part of the DNA damage repair pathway.SC0245, a novel and orally administered small molecule ATR inhibitor, is being developed for advanced solid malignancies. In vitro, SC0245 is highly potent against the ATR/ATRIP(h) enzyme with IC50 values ranging from 14 to 43 nM and has potent antiproliferative activity against a wide range of human cancers. This is the first report of an ongoing first-in-human study of SC0245 monotherapy in patients (pts) with advanced solid malignancies. Methods: An accelerated titration design was used to increase doses in the first two dose levels (40mg and 80mg once daily (QD) continuous, 21 days/cycle) followed by a standard “3+3” design in the remainder of the study (continuous schedule: 120mg and 160mg QD, 21 days/cycle; or intermittent schedule: 200mg, 240mg, 300mg QD, 160mg, 200mg and 260mg twice daily (BID), 3 days on and 4 days off, repeat every week x 4 weeks, 28 days/cycle). Tumor assessments are being performed every 8 weeks using RECIST v1.1. Results: As of the data cut-off-date of January 10, 2024, 27 pts (median age, 56; male, 48.1%) were enrolled and treated with SC0245 doses of 1, 1, 4, 4, 4, 2, 4, 3 and 4 pts in 40, 80, 120, 160, 200, 240 and 300mg QD, and 160 and 200mg BID cohort, respectively. No DLTs have been observed to date. Most TEAEs have been Grade 1 or 2 in severity. TEAEs experienced in ≥25% pts include: leukopenia and thrombocytopenia (9/27, 33.3%, each), and anemia, increased conjugated bilirubin and constipation (8/27, 29.6%, each). There were no ≥ Grade 3 TEAEs experienced in more than 2 pts. There were neither dose adjustment nor treatment discontinuation due to TRAEs. Eleven of 21 pts who were evaluable for tumor assessment had stable disease as their best response, with seven pts having reductions in target lesions. The PK characteristics of SC0245 indicated fast oral absorption (median Tmax, 0.5~2.0 h), a long half-life (mean t1/2,16.1~36.4 h) and high intersubject variability. The relationship between SC0245 exposure and dose was nonlinear with minimal accumulation after cumulative treatment in some pts. Additionally, SC0245 exposure and relevant PK parameters have reached the range associated with efficacy in preclinical studies. Conclusions: SC0245 exhibited favorable safety and PK characteristics when administered intermittently at doses up to 200mg BID in pts with advanced solid cancers. SC0245 appeared to induce less hematological toxicity than other ATR inhibitors at relevant doses. Based on these preliminary data, SC0245 will be developed in combination with other anti-tumor agents that may have synergies with ATR inhibitors such as topoisomerase 1 inhibitors and DNA damaging agents. Clinical trial information: CTR20210769.

A phase I study of highly potent oral ATR inhibitor (ATRi) tuvusertib plus oral PARP inhibitor (PARPi) niraparib in patients with solid tumors.

3018 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase and poly-ADP ribose polymerases (PARPs) are crucial components in the DNA damage response (DDR). Combining tuvusertib and niraparib may synergistically enhance synthetic lethality and increase apoptosis. Part B1 of the DDRiver Solid Tumors 301 study (NCT04170153) assessed this combination. Methods: Part B1 of this open-label multicenter dose-escalation phase Ib trial enrolled unselected patients with metastatic or locally advanced unresectable solid tumors refractory to standard treatment. The primary objective was to determine safety (including maximum tolerable dose and recommended dose(s) for expansion [RDE]). Secondary and tertiary objectives included determination of the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of different dosing regimens of tuvusertib plus niraparib. Multiple continuous and intermittent schedules were explored with tuvusertib doses ranging from 90–180 mg once-daily (QD) and niraparib doses from 100–200 mg QD. A partial ordering continual reassessment method was used to identify the RDEs. Results: As of 02 January 2024, 43 patients had been enrolled (all with baseline body weight <77kg or platelet count <150,000/mm3); 13 patients remained on treatment. Ten (26.3%) patients had dose-limiting toxicities (DLTs). The most common DLT was grade 3 anemia requiring blood transfusion (n=4; 10.5%); the most frequent grade ≥3 treatment-emergent adverse events were anemia (n=18; 41.9%), platelet count decrease (n=6; 14.0%) and fatigue (n=4; 9.3%). The PK of tuvusertib when combined with niraparib was consistent with that of tuvusertib monotherapy, suggesting a lack of any clinically meaningful mutual drug–drug interactions. Dose-dependent ɣ-H2AX inhibition (proximal PD marker) was observed at tuvusertib doses ≥130 mg QD. Preliminary efficacy data show 5 (15.6%) responses (3 confirmed) by RECIST v1.1 in 32 evaluable patients: 2 in patients with epithelial ovarian cancer (EOC; 1 with BRCA1-mutant [ BRCA1m] PARPi-resistant EOC, 1 with BRCA-wild type homologous recombination deficiency-positive EOC) and 1 each in patients with non-small cell lung cancer, estrogen receptor-positive HER2-negative BRCA1m breast cancer, and BRCA1m PARPi-resistant pancreatic cancer. Tuvusertib 180 mg QD and niraparib 100 mg QD or tuvusertib 90 mg QD and niraparib 200 mg QD, both given in a 1 week on/1 week off schedule, were identified as RDEs. Conclusions: The combination of tuvusertib plus niraparib, each administered on a 1 week on/1 week off schedule, has a manageable safety profile and is suitable for further investigation. A combination study in patients with PARPi-resistant EOC is planned. Clinical trial information: NCT04170153 .

Abstract PO2-02-13: A Mechanical Conditioning gene expression (MeCo) score detects the patients that benefit from neoadjuvant anti-fibrotic therapy in early HER2-negative breast cancer (HER2negBC)

Abstract Background: Extracellular matrix (ECM) stiffness in the tumor microenvironment is associated with aggressive features that lead to adverse clinical outcomes, including metastasis. Mechanical conditioning (MC) is the phenomenon whereby cancer cells that have grown in a fibrotic-like stiff ECM acquire aggressive features which can be maintained after metastasis in distant sites (Cell Rep.; 35:109293). MeCo Score is a gene expression signature that measures the response to ECM stiffness in early tumors which is associated with subsequent metastasis. We sought to study whether MeCo Score is associated with pathologic complete response (pCR) in early HER2negBC, and whether anti-fibrotic treatment with nintedanib (a multikinase VEGFR1-3, FGFR1-3 and PDGFRA/B inhibitor approved for idiopathic lung fibrosis) is able to mitigate the impact of MC. Methods: Baseline tumor samples from patients (N=130) from a randomized phase II clinical trial (Clin Cancer Res 23: 1432-42) in early HER2negBC trial comparing weekly paclitaxel monotherapy (85 mg/m2 x 12 courses; N=65; Arm A) versus the same treatment plus nintedanib (150 mg p.o. bid, continuous schedule; Arm B) were analyzed by RNAseq. MeCo Score was computed as previous described (Cell Rep.; 35:109293), and intrinsic PAM50 subtypes were determined using the R package genefu. Clinical, demographic and pathologic variables were gathered for all patients; pCR was graded according to the Residual Cancer Burden (RCB) score, RCB=0. Regression models were built using the variables RCB, T, N, G, age, intrinsic subtype, Ki67, MeCo Score and treatment arm. Bi-variate correlations were analyzed with the Pearson coefficient. All statistic tests were two-sided. Results: MeCo Score was successfully determined in 76 women (50% from each arm); the average score was 0.34 (range: 0.052 – 0.617). Of them, 48.6% were Luminal A, 34.2% Luminal B, 14.5% Basal-like, and 2.7% Normal according to PAM50. Median age was 49 y.o. (range: 30.6 – 79.2); tumor size distribution was T1:3.0%; T2:68.2%; T3:24.3%; T4: 4.5%; 47% of the patients were N0, 47% were N1 and 6% were N2. Most patients (85%) were ER and/or PR positive; 15% were “triple-negative”. Histological grade distribution was G1/G2/G3: 15%/62%/23%. The average Ki67 was 28.7% (range: 1%-98%). pCR was 10.8% and 4.5% in arms A and B. The average MeCo Score by intrinsic subtype was 0.26 (LumA); 0.43 (LumB) and 0.38 (Basal), LumB vs LumA P< 0.001; LumB vs Basal: P=0.037. We did not find correlation between MeCo Score and G, T, N, age or Ki67, neither in the Luminal subgroup or the whole cohort. In Arm A, patients with high MeCo Score (i.e., above median) had a 0% pCR rate compared to 10.5% pCR rate for those with low MeCo Score (P=0.035); however, in the nintedanib arm (Arm B) no differences were found: 10.5% versus 11.1% pCR rate in high versus low MeCo Score (P=0.4). Conclusions: Among early HER2negBC, Luminal B cases display the highest MeCo Scores. MeCo Score was independent of all classic prognostic variables. High MeCo Score is associated with lack of pCR to neoadjuvant paclitaxel monotherapy, but concurrent administration of the anti-fibrotic agent nintedanib rescues this association. Citation Format: Miguel Quintela-Fandino, Adam Watson, Adam Grant, Gus Mouneimne, Maria J. Bueno, Silvana Mouron. A Mechanical Conditioning gene expression (MeCo) score detects the patients that benefit from neoadjuvant anti-fibrotic therapy in early HER2-negative breast cancer (HER2negBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-02-13.

Abstract PO3-20-03: First-in-human global study of RLY-2608, a pan-mutant and isoform selective PI3Kα inhibitor, as a single agent in patients with advanced solid tumors and in combination with fulvestrant in patients with advanced breast cancer

Abstract Background: Oncogenic mutations in PI3Kα are common driver events in ER+ breast cancer and other solid tumors. Alpelisib, a non-mutant selective PI3Kα inhibitor, is effective in ER+ breast cancer thus validating PI3Kα as a therapeutic target. Inhibition of wild-type PI3Kα results in toxicity including hyperglycemia which limits tolerability and drug exposure. RLY-2608, a novel, oral allosteric PI3Kα inhibitor, is uniquely designed to overcome these limitations via mutant- and isoform-selective PI3Kα inhibition for greater target coverage, improved tolerability, and antitumor activity. Initiated in December 2021, ReDiscover is the ongoing, first-in-human study to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of RLY-2608 monotherapy in PIK3CA-mutant advanced solid tumor patients (pts) and of RLY-2608 plus fulvestrant in pts with PIK3CA-mutant, HR+HER2-BC. At AACR 2023, dose escalation data for RLY-2608 was reported and demonstrated encouraging target inhibition and anti-tumor activity (including partial response), across PIK3CA genotypes with minimal impact on glucose homeostasis. To date, pts have received RLY-2608 at doses of 100–2000 mg/day, with no reported dose-limiting toxicities; the MTD has not been reached. These proof-of-mechanism data indicate that RLY-2608 is the first allosteric, pan-mutant selective PI3Kα inhibitor and that RLY-2608 has broad therapeutic potential in PIK3CA-driven cancers. Methods: Enrollment is ongoing in this global, multi-center, dose escalation/expansion study of RLY-2608 as a single agent in adults who have advanced solid tumors and are refractory, intolerant, or have declined standard therapy; and RLY-2608 in combination with fulvestrant in previously treated pts with HR+/HER2– MBC. Eligibility criteria include presence of PIK3CA mutation (blood or tumor) per local assessment, ECOG performance status 0–1, evaluable disease per RECIST 1.1 and no prior PI3K inhibitor (except in expansion combination group 2). RLY-2608 is administered on a continuous schedule with 4-week cycles. Adverse events (AEs) per CTCAE v5, PK, biomarkers (pAKT, mutant ctDNAs and insulin pathway markers) and anti-tumor activity are assessed serially. Dose escalation employs a Bayesian Optimal Interval design to identify the MTD and/or the recommended Phase 2 dose (RP2D). Following dose escalation, expansion cohorts will enroll patients with select PIK3CA-mutated solid tumors for treatment with RLY-2608 monotherapy and patients with HR+/HER2– MBC for treatment with RLY-2608 and fulvestrant. The primary endpoints are MTD/RP2D and AE profile for single agent and combination; key secondary endpoints are PIK3CA genotype in blood and tumor, PK, biomarkers, and overall response rate. ReDiscover (NCT05216432) is enrolling worldwide. For further information, contact clinicaltrials@relaytx.com. Funding source: This study is funded by Relay Therapeutics, Cambridge, MA, United States. Citation Format: Andreas Varkaris, Komal Jhaveri, Elena Garralda Cabanas, Lucia Sanz, Janice Kim, Cesar A. Perez, Erika Hamilton, Alexander I. Spira, Kari Wisinski, Angel Guerrero, Jason Henry, Jordi Rodon Ahnert, Gege Tan, Xiaoyan Li, Diana Hummel, Tamieka Hunter, Alison Timm, Ramin Samadani, Erika Puente-Poushnejad, Eunice Kwak, Brenton G. Mar, Alison M. Schram. First-in-human global study of RLY-2608, a pan-mutant and isoform selective PI3Kα inhibitor, as a single agent in patients with advanced solid tumors and in combination with fulvestrant in patients with advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-03.

Metronomic chemotherapy in hematology: Lessons from preclinical and clinical studies to build a solid rationale for future schedules

Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting multiple targets and reducing toxicity of antineoplastic drugs. This minireview will summarize preclinical and clinical studies on cytotoxic drugs given at weekly, daily, or at continuous metronomic schedules alone or in combination with novel targeted agents for hematological malignancies, including lymphoma, multiple myeloma, and leukemia. Most of the preclinical in vitro and in vivo studies have reported a significant benefit of both mCHEMO monotherapy and combinatorial regimens compared with chemotherapy at the maximum tolerated dose. However, the combination of mCHEMO with targeted drugs is still little explored in the hematologic clinical setting. Data obtained from preclinical studies on low dose metronomic chemotherapy in hematological malignancies clearly suggested the possibility to clinically investigate more tolerable and effective strategies for the treatment of patients with advanced hematological malignancies, or at least for those frail and elderly patients, who are not eligible or resistant to standard treatments.

Butyrate promotes kidney resilience through a coordinated kidney protective response in tubular cells

Acute kidney injury (AKI) is common in hospitalized patients and increases short-term and long-term mortality. Treatment options for AKI are limited. Gut microbiota products such as the short-chain fatty acid butyrate have anti-inflammatory actions that may protect tissues, including the kidney, from injury. However, the molecular mechanisms of tissue protection by butyrate are poorly understood. Treatment with oral butyrate for two weeks prior to folic acid-induced AKI and during AKI improved kidney function and decreased tubular injury and kidney inflammation while stopping butyrate before AKI was not protective. Continuous butyrate preserved the expression of kidney protective factors such as Klotho, PGC-1α and Nlrp6 which were otherwise downregulated. In cultured tubular cells, butyrate blunted the maladaptive tubular cell response to a proinflammatory milieu, preserving the expression of kidney protective factors. Kidney protection afforded by this continuous butyrate schedule was confirmed in a second model of nephrotoxic AKI, cisplatin nephrotoxicity, where the expression of kidney protective factors was also preserved. To assess the contribution of preservation of kidney protective factors to kidney resilience, recombinant Klotho was administered to mice with cisplatin-AKI and shown to preserve the expression of PGC-1α and Nlrp6, decrease kidney inflammation and protect from AKI. In conclusion, butyrate promotes kidney resilience to AKI and decreases inflammation by preventing the downregulation of kidney protective genes such as Klotho. This information may be relevant to optimize antibiotic management during hospitalization.

Monitoring fast‐moving animals—Building a customized camera system and evaluation toolset

Abstract Automated cameras (including camera traps) are an established observation tool, allowing, for example the identification of behaviours and monitoring without harming organisms. However, limitations including imperfect detection, insufficient data storage and power supply restrict the use of camera traps, making inexpensive and customizable solutions desirable. We describe a camera system and evaluation toolset based on Raspberry Pi computers and YOLOv5 that can overcome those shortcomings with its modular properties. We facilitate the set‐up and modification for researchers via detailed step‐by‐step guides. A customized camera system prototype was constructed to monitor fast‐moving organisms on a continuous schedule. For testing and benchmarking, we recorded mason bees (Osmia cornuta) approaching nesting aids on 20 sites. To efficiently process the extensive video material, we developed an evaluation toolset utilizing the convolutional neural network YOLOv5 to detect bees in the videos. In the field test, the camera system performed reliably for more than a week (2 h per day) under varying weather conditions. YOLOv5 detected and classified bees with only 775 original training images. Overall detection reliability varied depending on camera perspective, site and weather conditions, but a high average detection precision (78%) was achieved, which was confirmed by a human observer (80% of algorithm‐based detections confirmed). The customized camera system mitigates several disadvantages of commercial camera traps by using interchangeable components and incorporates all major requirements a researcher has for working in the field including moderate costs, easy assembly and an external energy source. We provide detailed user guides to bridge the gap between ecology, computer science and engineering.

Abstract 5707: Preclinical evaluation of KRLS-017, a potent, highly selective and reversible CDK7 inhibitor with broad antitumor effect in preclinical models, in preparation for a Phase 1 clinical trial in advanced solid tumor malignancies

Abstract KRLS-017 is a potent, selective, and reversible inhibitor of Cyclin Dependent Kinase 7 (CDK7). Its molecular formula is C24H35N5O2Si and its molecular weight is 453.65 Daltons. KRLS-017 is being developed for the treatment of patients with advanced solid tumor malignancies. To differentiate KRLS-017 from other CDK7 inhibitors, we created a reversible inhibitor to allow for treatment schedule optimization and maximization of therapeutic index in clinic. High selectivity of KRLS-017 for CDK7 was confirmed using a panel of 313 recombinant human kinases. The IC50 of KRLS-017 against recombinant human CDK7 was determined to be 16 nM, and no other kinases in the panel showed IC50 values less than 300 nM. Antiproliferative activity of KRLS-017 was investigated in vitro using a broad panel of human tumor cell lines. KRLS-017 showed potent antiproliferative effect across a wide variety of both solid and hematologic tumor types, producing GI50 values <200 nM in 258/302 human tumorcell lines tested. Antitumor activity of KRLS-017 was investigated in vivo using multiple mouse xenograft tumormodels at dose levels ranging from 25 mg/kg to 200 mg/kg using both continuous (daily) andintermittent dosing schedules. Statistically significant tumor growth inhibition was seen at doselevels of 50 mg/kg and higher, with tumor regression observed at 100 mg/kg and 200 mg/kg. Better in vivo tolerability at efficacious doses was observed using intermittent dosing schedules in mouse xenograft models, which led to adoption of an intermittent schedule in the proposed first-in-human phase 1 trial. KRLS-017 is orally bioavailable in mice, rats, and dogs and plasma drug exposure increased in a proportional manner with dose. Comparing first dose and 28th dose in the dog, minimal plasma accumulation was observed, suggesting once daily dosing in humans would be initially tested. Repeat dose 28 day GLP toxicology studies in rat and dog showed adverse effects in highly proliferative bone marrow and gastrointestinal tissues which is consistent with the known mechanism of action for CDK7 and is considered to be monitorable and manageable in the setting of oncology. The clinical development plan for KRLS-017 includes an initial Phase 1 dose escalation study (KRLS-017-101) in patients with refractory solid tumor malignancies to assess pharmacokinetics/pharmacodynamics and to determine an optimal dose level and treatment schedule to test in expansion cohorts. Given the potential of CDK7 inhibitors in the treatment of hormone receptor positive breast cancer, combination work with other agents (such as selective estrogen receptor degraders) is on-going. Citation Format: Alison L. Hannah, Steve Ritland, Thomas Steele, Steven Smith, Ashwin Ram, BT Slingsby, Kapil Dhingra, James Chrisman, Rajesh Dua, Yasunori Tokunaga, Shigeyuki Kono, Yasuhiro Aga. Preclinical evaluation of KRLS-017, a potent, highly selective and reversible CDK7 inhibitor with broad antitumor effect in preclinical models, in preparation for a Phase 1 clinical trial in advanced solid tumor malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5707.

The effects of Bacillus subtilis on the immunity, mucosal tissue morphology, immune-related gene transcriptions, and intestinal microbiota in flounder (Paralichthys olivaceus) with two feeding methods: Continuous versus discontinuous feeding

Probiotics as dietary additives can improve weight gain, feed efficiency, and disease resistance in cultured fish. In this research, we evaluated and compared the effects of Bacillus subtilis on immunity, mucosal tissue morphology, immune-related gene transcriptions, and intestinal microbiota in flounder (Paralichthys olivaceus) by a 30-day feeding experiment based on a continuous feeding schedule (E1) and a discontinuous feeding schedule (E2). As a result, the use of B. subtilis exerted the best positive effects on survival rate, enzyme activity, mucosal tissue morphology, immune-related gene transcriptions, and intestinal microbiota in flounders. Alkaline phosphatase (AKP), lysozyme (LZM), and superoxide dismutase (SOD) activities in the liver of E2 were higher than those of E1 (P < 0.05). Furthermore, the villi length in the intestinal tract and the fold length in the stomach of E2 were also higher than in E1 (P < 0.05). The il-1 expression levels in the spleen were significantly increased in E2 (P < 0.05) compared to E1. We performed 16 S rRNA sequencing analysis to find that Bacillus in E1 (1.06%) and E2 (1.01%) had higher relative abundances than in E0 (0.053%) at the end of the experiments, indicating that short-term application of B. subtilis with the continuous or discontinuous feeding method can allow both the adaptation of the ecosystem to the presence of probiotics by the establishment of new species in the gut microbiota and the ability these new probiotic species to perform corresponding functions. No significant differences in the ability of probiotic establishment were observed between E1 and E2. Our findings provided a unique perspective to explore the mechanism of immune enhancement with probiotics and to screen the optimal administration strategy in aquaculture application for probiotic use. Together, these results point to some level of enhancement in immune status by continuous and discontinuous feeding after a short-term feeding period, which could be used as a prophylactic strategy for flounder health management.

A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors.

Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56-62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

Quality control of plastic sack products using the DMAIC method at PT. XYZ

PT. XYZ is a company engaged in the production of plastic sacks which are used for various industrial purposes. There are several types of defects in plastic sacks, namely, torn sacks, inappropriate sack brands, and slanted seams. This research aims to determine the level of product defects, factors causing product defects and provide suggestions for improvements to the production process at PT. XYZ. This research uses the six sigma method through the DMAIC stages (Define, Measure, Analyze, Improve and Control). Based on research results, the defect rate for plastic sack products was 2.72%, while the average level was 3.9 sigma. There are several factors that cause defects in plastic sack products, namely human factors, machines, work methods and materials. Proposed improvements to improve product quality at PT. XYZ there are several factors that must be improved, namely, humans are carrying out training and directing employees to follow SOPs, machines are making continuous maintenance schedules according to machine capacity so that they are always in good condition, work method factors the company must make additional SOPs so that work method problems are reduced. In the future, material is tightening the process of checking the inspection of threads that are not good properly.

Continuous PEGasparaginase Dosing Reduces Hypersensitivity Reactions in Pediatric ALL: A Dutch Childhood Oncology Group ALL11 Randomized Trial.

The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule. Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25). Hypersensitivity reactions were defined as allergies, allergic-like reactions, and silent inactivation. Secondary end points were other asparaginase-related toxicities, asparaginase activity and antibody levels, and outcome. During induction, 27 of 818 patients (3.3%) experienced hypersensitivity reactions. After random assignment, 4 of 155 (2.6%) in the continuous treatment arm versus 17 of 157 (10.8%) patients in the noncontinuous treatment arm had hypersensitivity reactions (P < .01), of which two (1.3%) versus 13 (8.3%) were inactivating reactions (P < .01). The occurrence of inactivating hypersensitivity reactions was seven times lower in the continuous arm (odds ratio, 0.15 [0.032-0.653]). In addition, antibody levels were significantly lower in the continuous arm (P < .01). With exception of a lower incidence of increased amylase in the continuous arm, there were no significant differences in total number of asparaginase-associated toxicities between arms. However, the timing of the toxicities was associated with the timing of the asparaginase administrations. No difference in 5-year cumulative incidence of relapse, death, or disease-free survival was found between both treatment arms. A continuous dosing schedule of PEGasp is an effective approach to prevent antibody formation and inactivating hypersensitivity reactions. The continuous PEGasp schedule did not increase toxicity and did not affect the efficacy of the therapy.

Abstract PR006: Evolution of evolvability

Abstract The purpose of this work is to better understand how the rate of phenotypic adaptation of cells in a tumor affects its ability to survive treatment. Drug resistance is an ongoing problem for maintaining a sustained response in treating advanced cancers. Regardless of their lineage, heritable phenotypic adaptions may be beneficial for the tumor to survive stepwise changes in the environment during tumor growth. There may be further benefit for cells to develop the trait of being adaptable - to respond to large shifts in the microenvironment, survive metastasis to a new organ, and thrive when treatments are applied. Genomic instability and phenotypic redundancy may aid in adaptations, but there may be limits. With too much mutation and deviation from the parental phenotype, cells lose important regulatory and maintenance functions necessary to survive. So is there an optimal rate of evolvability? We use an off-lattice agent-based model to investigate how the rate of change through phenotypic trait space affects tumor growth and response to treatment. We assign cells with different combinations of proliferation rates and migration speeds and test how the variance from the parental cell on division affects the selection of trait combinations over time. During growth, heterogeneity is gained quickly and space matters less if evolvability is forced to continually increase, but there is more selection for proliferative phenotypes and slower evolvability if its rate is allowed to drift freely. We found that tradeoffs generally imposed a greater selection force leading to faster recurrence and the coexistence of proliferation or migration specialists. We compared responses to continuous, intermittent, and adaptive treatment schedules of an anti-proliferative drug. At some point with treatment, there is an optimal evolvability, as larger increases in diversity allows for cells to fall back into a sensitive state and be killed by treatment. We aim to design better treatment strategies that work for tumors with different levels of evolvability by understanding how the rate of tumor evolution affects growth and treatment response. Citation Format: Jill A. Gallaher, Maximilian Strobl, Jeffrey West, Mark Roberston-Tessi, Alexander R. A. Anderson. Evolution of evolvability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR006.

Use of internet of things (IOT) on fish feeding tools with nodemcu

In everyday life whether in the city or in the countryside, there are lots of fish keepers in both large, medium sized ponds or small ones. Raising fish is an activity people who are very popular from the past until now, because ease of maintenance and care that makes most people want to cultivate fish. Fish kept in considered pond must give time to feed so that the fish requires a regular and continuous feeding schedule. ESP8266 NodeMCU is an integrated chip component that designed for today's connected world. these chips offers a complete, unified Wi-Fi networking solution that can used as an application provider or to sell all functions Wi-Fi networking to other application processors. One of its uses namely as an Automatic Fish Feeder Using ESP8266 Based on the Internet of Things (IOT). By using the components of the tool above as well as some supporting software When the tool runs, the fish feeder can automatically work in accordance with the schedule options that have been previously arranged, and capable displays data to web pages in the form of notifications when feed has been given and when the reservoir is empty or exhausted.

Poziotinib treatment in patients with HER2-positive advanced breast cancer who have received prior anti-HER2 regimens.

Poziotinib is an irreversible pan-inhibitor of the human epidermal growth factor receptor (HER) that has shown acceptable tolerability and antitumor activity in phase I and II trials in patients with advanced solid tumors. In the present open-label, multicenter phase II study, we demonstrate safety, tolerability, and preliminary efficacy data from two different dosing schedules in patients with HER2-positive advanced breast cancer. Patients who had received at least two prior HER2-directed therapy lines for advanced disease, received 24mg poziotinib on an intermittent dosing schedule (cohort 1) or 16mg poziotinib once daily on a continuous dosing schedule (cohort 2). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), and time to progression (TTP). Secondary endpoints additionally included safety and pharmacokinetics. A total of 67 patients were enrolled. The ORR was 30% in both groups (p = 0.98). DCR was 60% vs 78% (p = 0.15) and median PFS and TTP were 4.1 vs 4.9months (both p = 0.30) for cohorts 1 and 2, respectively. The most common treatment related adverse events (AEs) of any grade included diarrhea (88% vs 85%, p = 0.76), rash (88% vs 88%, p = 0.96), and stomatitis (64% vs 56%, p = 0.52), with grade 3-4 diarrhea occurring in 33% vs 32% of patients (p = 0.93) and grade 3-4 rash in 27% vs 35% of patients (p = 0.48) in cohort 1 vs cohort 2, respectively. Poziotinib demonstrated evidence of clinical activity in patients with pre-treated HER2-positive advanced breast cancer, although high levels of toxicity may preclude further studies at this time.