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Complex dynamics of a ring of three unidirectionally-coupled semiconductor lasers are studied with respect to the coupling strength. While uncoupled, the lasers stay in a continuous-wave regime; they begin to oscillate as the coupling strength reaches a certain threshold value. When the coupling further increases, the dynamics exhibit a route to chaos via a sequence of Hopf bifurcations resulting in periodic, quasiperiodic, and chaotic oscillations. In the chaotic range, different synchronization states, ranging from asynchronous behavior to phase and near synchronization, are observed. The analytical solution yields a large number of fixed points. [ABSTRACT FROM PUBLISHER]

Introduction: Heterozygous pathogenic variants in NTRK2 (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of NTRK2-related disorders and to delineate the clinical presentation METHODS: We report extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported., Results: Our analysis led to splitting the cohort into two entities., Discussion: One group had variants in the cholesterol binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A>G p.(Tyr434Cys). These variants probably lead to upregulation of TRKB activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variants that presumably disturb the 3D structure of the protein leading to loss of function. These individuals had a remarkably milder phenotype of developmental delay, obesity and hyperphagia., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Moderate traumatic brain injury (TBI) is a diagnosis that describes diverse patients with heterogeneity of primary injuries. Defined by a Glasgow Coma Scale between 9 and 12, this category includes patients who may neurologically worsen and require increasing intensive care resources and/or emergency neurosurgery. Despite the unique characteristics of these patients, there have not been specific guidelines published before this effort to support decision-making in these patients. A Delphi consensus group from the Latin American Brain Injury Consortium was established to generate recommendations related to the definition and categorization of moderate TBI. Before an in-person meeting, a systematic review of the literature was performed identifying evidence relevant to planned topics. Blinded voting assessed support for each recommendation. A priori the threshold for consensus was set at 80% agreement. Nine PICOT questions were generated by the panel, including definition, categorization, grouping, and diagnosis of moderate TBI. Here, we report the results of our work including relevant consensus statements and discussion for each question. Moderate TBI is an entity for which there is little published evidence available supporting definition, diagnosis, and management. Recommendations based on experts' opinion were informed by available evidence and aim to refine the definition and categorization of moderate TBI. Further studies evaluating the impact of these recommendations will be required., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Over the past four decades, prion diseases have received considerable research attention owing to their potential to be transmitted within and across species as well as their consequences for human and animal health. The unprecedented nature of prions has led to the discovery of a paradigm of templated protein misfolding that underlies a diverse range of both disease-related and normal biological processes. Indeed, the "prion-like" misfolding and propagation of protein aggregates is now recognized as a common underlying disease mechanism in human neurodegenerative disorders such as Alzheimer's and Parkinson's disease, and the prion principle has led to the development of novel diagnostic and therapeutic strategies for these illnesses. Despite these advances, research into the fundamental biology of prion diseases has declined, likely due to their rarity and the absence of an acute human health crisis. Given the past translational influence, continued research on the etiology, pathogenesis, and transmission of prion disease should remain a priority. In this review, we highlight several important "unsolved mysteries" in the prion disease research field and how solving them may be crucial for the development of effective therapeutics, preventing future outbreaks of prion disease, and understanding the pathobiology of more common human neurodegenerative disorders., Competing Interests: The authors declare there are no competing interests.

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo., (© 2024. The Author(s).)

Purpose: Following disclosure of pathogenic or likely pathogenic variants in hereditary cancer genes, patients face cancer risk management decisions. Through this mixed-methods study, we investigated cancer risk management decisions among females with pathogenic or likely pathogenic variants in PALB2, CHEK2, and ATM to understand why some patients follow National Comprehensive Cancer Network guidelines, whereas others do not., Methods: Survey and interview data were cross-analyzed using a 3-stage approach. Identified factors were used to conduct coincidence analysis and differentiate between combinations of factors that result in following or not following guidelines., Results: Of the 13 participants who underwent guideline inconsistent prophylactic surgery, 12 fit 1 of 3 unique patterns: (1) cancer-related anxiety in the absence of trust in care, (2) provider recommending surgery inconsistent with National Comprehensive Cancer Network guidelines, or (3) surgery occurring before genetic testing. Two unique patterns were found among 18 of 20 participants who followed guidelines: (1) anxiety along with trust in care or (2) lack of anxiety and no prophylactic surgery before testing., Conclusion: Health care provider recommendations and trust in care may influence whether individuals receive care that is congruent with risk levels conferred by specific genes. Interventions are needed to improve provider knowledge, patient trust in non-surgical care, and patient anxiety., Competing Interests: Conflict of Interest Tuya Pal is on the scientific advisory board of Natera., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2 mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 -mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations. SIGNIFICANCE: This study shows that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of KEAP1/NFE2L2 -mutant tumors. This article is highlighted in the In This Issue feature, p. 1775 ., (©2020 American Association for Cancer Research.)

Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs., Competing Interests: Declaration of Interests J.J.C. reports paid consultancy from Lexent Bio Inc. A.A.C. reports speaker honoraria and travel support from Roche Sequencing Solutions (RSS), Varian, and Foundation Medicine; a research grant from RSS; and has served as a paid consultant for Oscar Health. T.M. is a co-founder of Imvaq. J.W.N. reports research support from Genentech (GNE)/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Takeda Pharmaceuticals, Nektar Therapeutics, Adaptimmune, and GSK, and has served in a consulting or advisory role for AstraZeneca (AZ), GNE/Roche, Exelixis Inc., Jounce Therapeutics, Takeda Pharmaceuticals, and Eli Lilly. H.A.W. has received honoraria from Novartis and AZ and has participated on the advisory boards of Xcovery, Janssen, and Mirati. S.K.P. reports grant support from EpicentRx, Forty Seven, Bayer, and Boehringer Ingelheim and serves in a consulting or advisory role for AZ, AbbVie, G1 Therapeutics, and Pfizer. M. Das reports grant support from AbbVie, United Therapeutics, Varian, and Celgene and serves in a consulting role for AZ and Bristol-Myers Squibb (BMS). A.M.N. has patent filings related to expression deconvolution and cancer biomarkers and has served as a consultant for Roche, Merck, and CiberMed. M.D.H. reports paid consultancy from BMS, Merck, GNE, AZ/MedImmune, Nektar, Syndax, Janssen, Mirati Therapeutics, Shattuck Labs, and Blueprint Medicines; travel/honoraria from BMS and AZ; research funding from BMS; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics. A.A.A. reports ownership interest in CiberMed and FortySeven, patent filings related to cancer biomarkers, and paid consultancy from GNE, Roche, Chugai, Gilead, and Celgene. M. Diehn reports research funding from Varian, ownership interest in CiberMed, patent filings related to cancer biomarkers, paid consultancy from Roche, AZ, and BioNTech, and travel/honoraria from Reflexion. M.Diehn, A.A.A., B.Y.N., and M.S.E. are co-inventors on a provisional patent application filed by Stanford University relating to this manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non-small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression., Experimental Design: In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (progression-free survival ≥ 12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing. Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing ( n = 18) or by targeted sequencing ( n = 6)., Results: Thirty-one patients with NSCLC with long-term benefit to PD-(L)1 blockade were identified, and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; in contrast, all 4 patients with detectable ctDNA eventually progressed [Fisher P < 0.0001; positive predictive value = 1, 95% confidence interval (CI), 0.51-1; negative predictive value = 0.93 (95% CI, 0.80-0.99)]., Conclusions: ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 blockade and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression., (©2020 American Association for Cancer Research.)

Radiologic screening of high-risk adults reduces lung-cancer-related mortality 1,2 ; however, a small minority of eligible individuals undergo such screening in the United States 3,4 . The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq) 5 , a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

The mitogen-activated protein kinase (MAPK) pathway is a critical effector of oncogenic RAS signaling, and MAPK pathway inhibition may be an effective combination treatment strategy. We performed genome-scale loss-of-function CRISPR-Cas9 screens in the presence of a MEK1/2 inhibitor (MEKi) in KRAS-mutant pancreatic and lung cancer cell lines and identified genes that cooperate with MEK inhibition. While we observed heterogeneity in genetic modifiers of MEKi sensitivity across cell lines, several recurrent classes of synthetic lethal vulnerabilities emerged at the pathway level. Multiple members of receptor tyrosine kinase (RTK)-RAS-MAPK pathways scored as sensitizers to MEKi. In particular, we demonstrate that knockout, suppression, or degradation of SHOC2, a positive regulator of MAPK signaling, specifically cooperated with MEK inhibition to impair proliferation in RAS-driven cancer cells. The depletion of SHOC2 disrupted survival pathways triggered by feedback RTK signaling in response to MEK inhibition. Thus, these findings nominate SHOC2 as a potential target for combination therapy., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Metabolic syndrome contributing to nonalcoholic fatty liver disease (NAFLD) can lead to hepatic dysfunction, steatohepatitis, cirrhosis, and hepatocellular carcinoma., Aims: In this study, we tested whether diet-induced fatty liver in a mouse model physiologically mimicked human NAFLD, and whether transcriptional alterations in mouse fatty liver signified risk for the development of hepatitis, cirrhosis, and/or hepatocellular carcinoma., Methods: SAMP6 strain mice were fed a low-fat diet or high-fat diet (HFD) for 6 months. Mouse livers were isolated and subjected to histology, immunohistochemistry, and whole transcriptome RNA sequencing. Sequences were aligned to the mouse reference genome, and gene expression signatures were analyzed using bioinformatics tools including Cufflinks, Pathview, Cytoscape, ClueGO, and GOstats., Results: Consistent with NAFLD, livers from HFD-fed mice demonstrated steatosis, high levels of inflammation, an up-regulation of genes encoding proteins associated with the complement pathway and immune responses, and down-regulation of those associated with metabolic processes. These livers also showed an up-regulation of genes associated with fibrosis and malignant transformation but no histological evidence of either pathobiology or DNA damage., Conclusions: HFD-fed mice exhibited NAFLD that had incompletely transitioned from fatty liver to NASH. Importantly, bioinformatics approaches identified pre-fibrotic and premalignant signatures, suggesting that the pathogenesis of both fibrosis and cancer may initiate in fatty livers well before associated histological changes are evident.

Pancreatic cancer (PC), a leading cause of cancer-related deaths in the United States, is typically diagnosed at an advanced stage. To improve survival, there is an unmet need to detect pre-malignant lesions and early invasive disease. Prime populations to study for early detection efforts include cohorts of high risk individuals (HRI): those with increased risk to develop pre-malignant pancreatic cysts and PC because of a familial or hereditary predisposition to the disease and those in the general population of sporadic cases who are incidentally found to harbor a pre-malignant pancreatic cyst. The objective of this study was to describe the characteristics and clinical outcomes of cohorts of HRI identified at Moffitt Cancer Center. We set out to determine the uptake of screening, the prevalence and characteristics of solid and cystic pancreatic lesions detected via screening or as incidental findings, and the age at which lesions were detected. Of a total of 329 HRI, roughly one-third were found to have pancreatic lesions, most of which constituted pre-malignant cysts known as intraductal papillary mucinous neoplasms. Individuals with the highest genetic risk for PC were found to have smaller cysts at a much earlier age than sporadic cases with incidental findings; however, many individuals at high genetic risk did not have abdominal imaging reports on file. We also identified a subset of HRI at moderate genetic risk for PC that were found to have cystic and solid pancreatic lesions as part of a diagnostic work-up rather than a screening protocol. These findings suggest the pancreatic research community should consider expanding criteria for who should be offered screening. We also emphasize the importance of continuity of care between cancer genetics and gastrointestinal oncology clinics so that HRI are made aware of the opportunities related to genetic counseling, genetic testing, and screening., Competing Interests: Conflicts of Interest: We declare no conflicts of interest.

Purpose: Awareness of inherited breast cancer has increased bilateral prophylactic mastectomy (BPM) among unaffected genetic mutation carriers, yet many still choose surveillance. We aimed to identify differences among women electing BPM vs high-risk surveillance., Methods: Participants from an IRB-approved database recruited from 11/2000 to 01/2017 with a deleterious/pathogenic, variant suspected deleterious, or likely pathogenic mutation in ≥ 1 of 11 genes with increased risk for breast cancer (per 2017 NCCN guidelines) were identified. Participants with breast cancer and males were excluded. Sociodemographic and clinical data were collected. The BPM and high-risk surveillance groups were compared using Wilcoxon, Fisher's Exact, and Pearson's Chi-Square analyses., Results: A total of 304 unaffected genetic mutation carriers were identified; 22 men were excluded. 113/282 (40%) underwent BPM. There was no significant difference in age, race, marital status, high school graduates, family history of breast cancer, breast biopsies, chemoprevention use, or understanding implications of genetic mutation carriage. BPM participants were more likely to have a prior pregnancy (p = 0.0005), college education (p = 0.04), income > $50,000/year (p = 0.01), first-degree relative with breast cancer (p = 0.04), higher total number of relatives with breast cancer (p = 0.01), and rate of risk-reducing salpingo-oophorectomy (p = < 0.0001). The high-risk surveillance group was more likely to have a history of ovarian cancer (p = 0.009) and cancer worry (p = < 0.0001)., Conclusions: BPM is a common but not universal choice among unaffected genetic carriers of inherited breast cancer syndromes. Parity, education, income, ovarian cancer history, first-degree relatives with breast cancer, and cancer worry play significant roles in these decisions.

Tissue fibrosis is mediated by the actions of multiple pro-fibrotic proteins that can induce myofibroblast phenoconversion through diverse signaling pathways coupled predominantly to Smads or MEK/Erk proteins. The TGFβ/TGFβR and CXCL12/CXCR4 axes induce myofibroblast phenoconversion independently through Smads and MEK/Erk proteins, respectively. To investigate these mechanisms at the genetic level, we have now elucidated the TGFβ/TGFβR and CXCL12/CXCR4 transcriptomes in human fibroblasts. These transcriptomes are largely convergent, and up-regulate transcripts encoding proteins known to promote myofibroblast phenoconversion. These studies also revealed a molecular signature unique to CXCL12/CXCR4 axis activation for COPII vesicle formation, ubiquitination, and Golgi/ER localization/targeting. In particular, both CUL3 and KLHL12, key members of the Cullin-RING (CRL) ubiquitin ligase family of proteins involved in procollagen transport from the ER to the Golgi, were highly up-regulated in CXCL12-, but repressed in TGFβ-, treated cells. Up-regulation of CUL3 and KLHL12 was correlated with higher procollagen secretion by CXCL12-treated cells, and this affect was ablated upon treatment with inhibitors specific for CXCR4 or CUL3 and repressed by TGFβ/TGFβR axis activation. The results of these studies show that activation of the CXCL12/CXCR4 axis uniquely facilitates procollagen I secretion through a COPII-vesicle mediated mechanism to promote production of the ECM characteristic of fibrosis.

Benign prostate hyperplasia (BPH), an enlargement of the prostate common in aging in men, is associated with urinary voiding dysfunction manifest as Lower Urinary Tract Symptoms (LUTS). Although inflammation and abnormal smooth muscle contractions are known to play key roles in the development of LUTS, tissue fibrosis may also be an important and previously unrecognized contributing factor. Tissue fibrosis arises from the unregulated differentiation of fibroblasts or other precursor cell types into myofibroblasts, which is usually accomplished by activation of the TGFβ/TGFβR axis. Previously we reported that the CXC-type chemokines, CXCL5, CXCL8 and CXCL12, which are up-regulated in the aging in the prostate, can drive this differentiation process as well in the absence of TGFβ. Based on this data we sought to elucidate the molecular mechanisms employed by CXCL12, and its receptor CXCR4, during prostate myofibroblast phenoconversion. The results of these studies suggest that CXCL12/CXCR4-mediated signaling events in prostate myofibroblast phenoconversion may proceed through non-canonical pathways that do not depend on TGFβ/TGFβR axis activation or Smad signaling. Here we report that CXCL12/CXCR4 axis activation promotes signaling through the EGFR and downstream MEK/ERK and PI3K/Akt pathways during myofibroblast phenoconversion, but not through TGFβ/TGFβR and downstream Smad signaling, in prostate fibroblasts undergoing myofibroblast phenoconversion. We document that EGFR transactivation is required for CXCL12-mediated signaling and expression of genes associate with myofibroblast phenoconversion (α-SMA, COL1a1). Our study successfully identified TGFβ/TGFβR-independent molecular mechanisms that promote CXCL12/CXCR4-induced myofibroblast phenoconversion. This information may be crucial for the development of novel therapies and potential biomarkers for prostatic fibrosis.

This is a case report of a median mandibular cyst in a 30 years-old male, treated at the Maxillofacial Service of the "Hospital de Especialidades del Centro Médico La Raza", I.M.S.S. It includes clinical, radiological and histological features plus a review of bibliography, in order to analyze the established parameters and arrive at a diagnosis.