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Even as machine learning exceeds human-level performance on many applications, the generality, robustness, and rapidity of the brain's learning capabilities remain unmatched. How cognition arises from neural activity is the central open question in neuroscience, inextricable from the study of intelligence itself. A simple formal model of neural activity was proposed in Papadimitriou et al. (2020) and has been subsequently shown, through both mathematical proofs and simulations, to be capable of implementing certain simple cognitive operations via the creation and manipulation of assemblies of neurons. However, many intelligent behaviors rely on the ability to recognize, store, and manipulate temporal sequences of stimuli (planning, language, navigation, to list a few). Here we show that in the same model, sequential precedence can be captured naturally through synaptic weights and plasticity, and, as a result, a range of computations on sequences of assemblies can be carried out. In particular, repeated presentation of a sequence of stimuli leads to the memorization of the sequence through corresponding neural assemblies: upon future presentation of any stimulus in the sequence, the corresponding assembly and its subsequent ones will be activated, one after the other, until the end of the sequence. If the stimulus sequence is presented to two brain areas simultaneously, a scaffolded representation is created, resulting in more efficient memorization and recall, in agreement with cognitive experiments. Finally, we show that any finite state machine can be learned in a similar way, through the presentation of appropriate patterns of sequences. Through an extension of this mechanism, the model can be shown to be capable of universal computation. Taken together, these results provide a concrete hypothesis for the basis of the brain's remarkable abilities to compute and learn, with sequences playing a vital role. [ABSTRACT FROM AUTHOR]

Introduction: Detection of PIK3CA mutations in primary tumors and liquid biopsy samples is of increasing importance for treatment decisions and therapy resistance in many types of cancer. The aim of the present study was to directly compare the efficacy of a relatively inexpensive ultrasensitive real-time PCR with the well-established and highly sensitive technology of ddPCR for the detection of the three most common hotspot mutations of PIK3CA , in exons 9 and 20, that are all of clinical importance in various types of cancer. Patients and methods: We analyzed 42 gDNAs from primary tumors (FFPEs), 29 plasma-cfDNA samples, and 29 paired CTC-derived gDNAs, all from patients with ER+ metastatic breast cancer, and plasma from 10 healthy donors. The same blood draws were used for CTC isolation using EpCAM beads for positive immunomagnetic enrichment. All FFPEs and plasma-cfDNA samples were analyzed in parallel for PIK3CA mutations by ultrasensitive real-time PCR assay and droplet digital PCR. Results: In gDNAs from FFPEs, using ultrasensitive real-time PCR, the p.E545K mutation was detected in 22/42(52.4%), and the p.E542K and p.H1047R mutations were detected in 14/42(33.3%) and 16/42(38.1%), respectively. Using ddPCR, the p.E545K mutation was detected in 22/42(52.4%), p.E542K in 17/42(40.5%), and p.H1047R in 19/42(45.2%) samples, revealing a concordance between the two methodologies of 81%, 78.6% and 78.6% for each mutation respectively. In plasma-cfDNA, using ultrasensitive real-time PCR, the p.E545K mutation was detected in 11/29(38%) and both p.E542K and p.H1047R mutations in 2/29(6.9%).In the same plasma-cfDNA samples using ddPCR, p.E545K was detected in 1/29(3.5%), p.E542K in 2/29(6.9%), and p.H1047R in 3/29(10.5%) samples, revealing a concordance of 65.5%,100% and 93.1% for each mutation respectively. In paired CTC-derived gDNAs p.E545K was detected in 11/29(38%), p.E542K in 3/29(10.3%), and p.H1047R in 7/29(24.1%) samples. Conclusions: This low-cost, high-throughput and ultrasensitive real-time PCR assay provides accurate and specific detection of PIK3CA hotspot mutations in liquid biopsy samples and gives similar results to ddPCR. This assay can be performed in labs where digital PCR instrumentation is not available. In CTC-derived gDNA and paired plasma-cfDNA, PIK3CA mutations detected were not identical, revealing that CTC and plasma-cfDNA give complementary information. [ABSTRACT FROM AUTHOR]

Simple Summary: The standard of care for most women with advanced ovarian cancer is primary cytoreduction followed by platinum-based chemotherapy and paclitaxel. However, the use of neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy is not inferior, according to prospective randomized trials. Ovarian cancer has a low mutational load but exhibits a high detection rate of molecular alterations in various genes. It remains unclear whether this is an intrinsic feature of ovarian cancer or if it is due to the administration of a platinum combination during NACT. Our study aimed to determine whether NACT affects the tumor's molecular profile. Any modifications in these areas would need to be identified in the initial therapeutic planning, especially in the era of poly (ADP-ribose) polymerase (PARP) inhibitors. Background: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy is a therapeutic choice for women with advanced ovarian cancer. Whether NACT affects the tumor's molecular profile has not been determined. Methods: This was a retrospective study of patients with advanced-stage epithelial ovarian cancer treated with NACT at oncology departments affiliated with the Hellenic Cooperative Oncology Group (HeCOG). Tumor molecular profiling was performed on formalin-fixed and paraffin-embedded (FFPE) tumor pre- and post-NACT tissues. Homologous recombination deficiency (HRD), tumor-infiltrating lymphocytes (TILs), tumor molecular alterations, and tumor mutational burden (TMB) via next-generation sequencing analysis were assessed. Results: Overall, tumors from 36 patients were assessed, and molecular profiling was evaluated in 20 paired tumor samples. HRD positivity exhibited no significant change between pre- and post-NACT tumors. The BRCA1/2 mutational status remained constant, irrespective of the treatment administration. Pre-NACT tumors tended to exhibit a lower percentage of intratumoral TILs compared to post-NACT tumors (p = 0.004). Differences in the mutation profile between pre- and post-treatment tissue were observed in 33.33% (6/18) of the cases. The mean tumor cell content (TCC) (p-value: 0.0840) and the mean genomic instability score (p-value: 0.0636) decreased slightly numerically after therapy. A moderate inverse relationship was observed between the pre-NACT TMB and the chemotherapy response score (p-value: 0.038), indicating this correlation is statistically significant. Conclusion: This study provides insights into the effect of NACT on the tumor molecular landscape. While BRCA1/2 and HRD status remained stable, an increase in TIL proportion and changes in the mutational profiles were observed post-treatment. [ABSTRACT FROM AUTHOR]

Background/Aim: The application of next generation sequencing (NGS) technology in the genetic investigation of hereditary cancer is important for clinical surveillance, therapeutic approach, and reducing the risk of developing new malignancies. The aim of the study was to explore genetic predisposition in individuals referred for hereditary cancer. Materials and Methods: A total of 8,261 individuals were referred for multigene genetic testing, during the period 2020-2023, in the laboratory, and underwent multigene genetic testing using NGS. Among the examined individuals, 56.17% were diagnosed with breast cancer, 6.77% with ovarian cancer, 2.88% with colorectal cancer, 1.91% with prostate cancer, 6.43% were healthy with a significant family history of cancer, while 3.06% had a different type of cancer and 0.21% had not provided any information. Additionally, in 85 women with breast cancer we performed whole exome sequencing analysis. Results: 20% of the examined individuals carried a pathogenic variant. Specifically, 54.8% of the patients had a pathogenic variant in a clinically significant gene (BRCA1, BRCA2, PALB2, RAD51C, PMS2, CDKN2A, MLH1, MSH2, TP53, MSH6, APC, RAD51D, PTEN, RET, CDH1, MEN1, and VHL). Among the different types of pathogenic variants detected, a significant percentage (6.52%) represented copy number variation (CNV). With WES analysis, the following findings were detected: CTC1: c.880C>T, p.(Gln294*); MLH3: c.405del, p.(Asp136Metfs*2), PPM1D: c.1426_1430del, p.(Glu476Leufs*3), and SDHB: c.395A>G, p.(His132Arg). Conclusion: Comprehensive multigene genetic testing is necessary for appropriate clinical management of pathogenic variants’ carriers. Additionally, the information obtained is important for determining the risk of malignancy development in family members of the examined individuals. [ABSTRACT FROM AUTHOR]

The rich literature on online Bayesian selection problems has long focused on so-called prophet inequalities, which compare the gain of an online algorithm to that of a "prophet" who knows the future. An equally natural, though significantly less well-studied, benchmark is the optimum online algorithm, which may be omnipotent (i.e., computationally unbounded), but not omniscient. What is the computational complexity of the optimum online? How well can a polynomial-time algorithm approximate it? Motivated by applications in ride hailing, we study the above questions for the online stochastic maximum-weight matching problem under vertex arrivals. For this problem, a number of 1/2 -competitive algorithms are known. This is the best possible ratio for this problem, as it generalizes the original single-item prophet inequality problem. We present a polynomial-time algorithm, which approximates the optimal online algorithm within a factor of 0.51—strictly more than the best-possible constant against a prophet. In contrast, we show that it is PSPACE-hard to approximate this problem within some universal constant α<1. Funding: Financial support from the National Science Foundation [Grants CCF1763970, CCF1812919, and CCF191070], the Office of Naval Research [Grant N000141912550], and Cisco Research is gratefully acknowledged. [ABSTRACT FROM AUTHOR]

Background/Aim: Oxaliplatin, a platinum-based chemotherapy used in the treatment of colorectal cancer, induces acute neurotoxicity following infusion. The aim of this study was to establish whether alterations in axonal excitability develop progressively with higher cumulative doses and whether there is a recovery in motor axons after each cycle of treatment. Patients and Methods: Twenty consecutive patients with a colorectal cancer diagnosis, referred from the Oncology Department of Aretaieion Hospital of Athens, were enrolled in this study between October 2018 and May 2019. None of the participants had diabetes, alcohol abuse, known neuropathy or were previously treated with another neo-adjuvant therapy. Threshold Tracking techniques and Qtrac software were used for assessing axonal excitability in motor axons. Excitability recordings were undertaken before and immediately after the end of oxaliplatin infusion. Results: Statistically significant changes were found (p<0.01) in axonal excitability (relative refractory period, refractoriness at 2 ms and 2.5 ms, subexcitability and super-excitability) before and after oxaliplatin infusion. No statistically significant changes (p>0.05) were found in threshold electrotonus and strengthduration parameters before and after oxaliplatin infusion. We also did not find statistically significant differences (p>0.05) between means of excitability parameters before infusion at each cycle. Conclusion: Our study confirms oxaliplatin-induced acute neurotoxicity following infusion and suggests that motor axons recover between repeat infusion cycles. [ABSTRACT FROM AUTHOR]

Tumors harboring homologous recombination deficiency (HRD) are considered optimal candidates for poly(ADP-ribose) polymerase 1 (PARP) inhibitor treatment. Such deficiency can be detected by analyzing breast cancer type (BRCA)1/2 gene mutations, as well as mutations in other genes of the homologous recombination pathway. The algorithmic measurement of the HRD effect by identifying genomic instability (GI) has been used as biomarker. As compared with the direct measurement of somatic gene alterations, this approach increases the number of patients who could benefit from PARP inhibitor treatment. In the present study, the performance of the Oncoscan CNV assay, accompanied by appropriate bioinformatic algorithms, was evaluated for its performance in GI calculation and was compared with that of a validated next-generation sequencing (NGS) test (myChoice HRD test). In addition, the clinical utility of the GI score (GIS) and BRCA1/2 tumor analysis were investigated in a cohort of 444 patients with ovarian cancer. For that reason, single nucleotide polymorphism (SNP) arrays and appropriate bioinformatics algorithms were used to calculate GIS in 29 patients with ovarian cancer with known GIS status using a validated NGS test. Furthermore, BRCA1/2 analysis results were compared between the aforementioned assay and the amplicon-based Oncomine™ BRCA Research Assay. BRCA1/2 analysis was performed in 444 patients with ovarian cancer, while GIS was calculated in 175 BRCA1/2-negative cases. The bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis (RediScore), and the OncoscanR pipeline exhibited a high overall agreement with the validated test (93.1%). In addition, the Oncomine NGS assay had a 100% agreement with the validated test. The BRCA1/2 mutation frequency was 26.5% in the examined patients with ovarian cancer. GIS was positive in 40% of the BRCA1/2-negative cases. The RediScore bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis is a viable and effective approach for HRD calculation in patients with ovarian cancer, offering a positive prediction for PARP inhibitor responsiveness in 55% of the patients. [ABSTRACT FROM AUTHOR]

The Nash equilibrium—a, combination of choices by the players of a game from which no self-interested player would deviate—is the predominant solution concept in game theory. Even though every game has a Nash equilibrium, it is not known whether there are deterministic behaviors of the players who play a game repeatedly that are guaranteed to converge to a Nash equilibrium of the game from all starting points. If one assumes that the players’ behavior is a discrete-time or continuous-time rule whereby the current mixed strategy profile is mapped to the next, this question becomes a problem in the theory of dynamical systems. We apply this theory, and in particular Conley index theory, to prove a general impossibility result: There exist games, for which all game dynamics fail to converge to Nash equilibria from all starting points. The games which help prove this impossibility result are degenerate, but we conjecture that the same result holds, under computational complexity assumptions, for nondegenerate games. We also prove a stronger impossibility result for the solution concept of approximate Nash equilibria: For a set of games of positive measure, no game dynamics can converge to the set of approximate Nash equilibria for a sufficiently small yet substantial approximation bound. Our results establish that, although the notions of Nash equilibrium and its computation-inspired approximations are universally applicable in all games, they are fundamentally incomplete as predictors of long-term player behavior. [ABSTRACT FROM AUTHOR]

Several tumor types have been efficiently treated with PARP inhibitors (PARPis), which are now approved for the treatment of ovarian, breast, prostate, and pancreatic cancers. The BRCA1/2 genes and mutations in many additional genes involved in the HR pathway may be responsible for the HRD phenomenon. The aim of the present study was to investigate the association between genomic loss of heterozygosity (gLOH) and alterations in 513 genes with targeted and immuno-oncology therapies in 406 samples using an NGS assay. In addition, the %gLOHs of 24 samples were calculated using the Affymetrix technology in order to compare the results obtained via the two methodologies. HR variations occurred in 20.93% of the malignancies, while BRCA1/2 gene alterations occurred in 5.17% of the malignancies. The %LOH was highly correlated with alterations in the BRCA1/2 genes, since 76.19% (16/21) of the BRCA1/2 positive tumors had a high %LOH value (p = 0.007). Moreover, the LOH status was highly correlated with the TP53 and KRAS statuses, but there was no association with the TMB value. Lin's concordance correlation coefficient for the 24 samples simultaneously examined via both assays was 0.87, indicating a nearly perfect agreement. In conclusion, the addition of gLOH analysis could assist in the detection of additional patients eligible for treatment with PARPis. [ABSTRACT FROM AUTHOR]

The brain is a complex system comprising a myriad of interacting neurons, posing significant challenges in understanding its structure, function, and dynamics. Network science has emerged as a powerful tool for studying such interconnected systems, offering a framework for integrating multiscale data and complexity. To date, network methods have significantly advanced functional imaging studies of the human brain and have facilitated the development of control theory-based applications for directing brain activity. Here, we discuss emerging frontiers for network neuroscience in the brain atlas era, addressing the challenges and opportunities in integrating multiple data streams for understanding the neural transitions from development to healthy function to disease. We underscore the importance of fostering interdisciplinary opportunities through workshops, conferences, and funding initiatives, such as supporting students and postdoctoral fellows with interests in both disciplines. By bringing together the network science and neuroscience communities, we can develop novel network-based methods tailored to neural circuits, paving the way toward a deeper understanding of the brain and its functions, as well as offering new challenges for network science. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is one of the deadliest cancers worldwide; late diagnosis and drug resistance are two major factors often responsible for high morbidity and treatment failure. Epithelial-to-mesenchymal transition (EMT) is a dynamic process that has been closely linked with cancer. Long non-coding RNAs (lncRNAs) have been also associated with several cancer-related mechanisms, including EMT. We conducted a literature search in the PubMed database in order to sum up and discuss the role of lncRNAs in regulating OC-related EMT and their underlying mechanisms. Seventy (70) original research articles were identified, as of 23 April 2023. Our review concluded that the dysregulation of lncRNAs is highly associated with EMT-mediated OC progression. A comprehensive understanding of lncRNAs' mechanisms in OC will help in identifying novel and sensitive biomarkers and therapeutic targets for this malignancy. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy (NACT) for certain breast cancer (BC) subtypes confers significant tumor regression rates and a survival benefit for patients with a complete pathologic response. Clinical and preclinical studies have demonstrated that immune-related factors are responsible for better treatment outcomes, and thus, neoadjuvant immunotherapy (IO) has emerged as a means to further improve patient survival rates. Innate immunological "coldness", however, of specific BC subtypes, especially of the luminal ones, due to their immunosuppressive tumor microenvironment, hinders the efficacy of immune checkpoint inhibitors. Treatment policies aiming to reverse this immunological inertia are, therefore, needed. Moreover, radiotherapy (RT) has been proven to have a significant interplay with the immune system and promote anti-tumor immunity. This "radiovaccination" effect could be exploited in the neoadjuvant setting of BC and significantly enhance the effects of the already established clinical practice. Modern stereotactic irradiation techniques directed to the primary tumor and involved lymph nodes may prove important for the RT-NACT-IO combination. In this review, we provide an overview and critically discuss the biological rationale, clinical experience, and ongoing research underlying the interplay between neoadjuvant chemotherapy, anti-tumor immune response, and the emerging role of RT as a preoperative adjunct with immunological therapeutic implications in BC. [ABSTRACT FROM AUTHOR]