A novel copy number variant in the murine Cdh23 gene gives rise to profound deafness and vestibular dysfunction.

Hearing loss is the most common congenital sensory deficit worldwide and exhibits high genetic heterogeneity, making molecular diagnoses elusive for most individuals. Detecting novel mutations that contribute to hearing loss is crucial to providing accurate personalized diagnoses, tailored interventions, and improving prognosis. Copy number variants (CNVs) are structural mutations that are understudied, potential contributors to hearing loss. Here, we present the Abnormal Wobbly Gait (AWG) mouse, the first documented mutant exhibiting waltzer-like locomotor dysfunction, hyperactivity, circling behaviour, and profound deafness caused by a spontaneous CNV deletion in cadherin 23 (Cdh23). We were unable to identify the causative mutation through a conventional whole-genome sequencing (WGS) and variant detection pipeline, but instead found a linked variant in hexokinase 1 (Hk1) that was insufficient to recapitulate the AWG phenotype when introduced into C57BL/6J mice using CRISPR-Cas9. Investigating nearby deafness-associated genes revealed a pronounced downregulation of Cdh23 mRNA and a complete absence of full-length CDH23 protein, which is critical for the development and maintenance of inner ear hair cells, in whole head extracts from AWG neonates. Manual inspection of WGS read depth plots of the Cdh23 locus revealed a putative 10.4 kb genomic deletion of exons 11 and 12 that was validated by PCR and Sanger sequencing. This study underscores the imperative to refine variant detection strategies to permit identification of pathogenic CNVs easily missed by conventional variant calling to enhance diagnostic precision and ultimately improve clinical outcomes for individuals with genetically heterogenous disorders such as hearing loss.

Construction of Fall Prevention Exercise Training Scheme for Elderly Discharged Patients Using Self-Efficacy Theory Framework.

Objective: We conducted this study to help older discharged patients recover better, reduce the risk of falls, and improve quality of life through self-efficacy intervention and the Otago exercise program. The purpose of this study was to address specific challenges in rehabilitation and quality of life in older patients. Methods: 60 elderly patients discharged from January 1 to June 10, 2022, were selected as the study subjects and randomly divided into the experimental group (n = 30) and the controls (n = 30). We studied the impact of a self-efficacy intervention combined with the Otago Exercise Program (OEP) in older discharged patients. We included patients aged 65 and above who understood the study protocol and randomly divided them into two groups: one group received a combined self-efficacy intervention and OEP, and the other group received only OEP treatment. The intervention period is 12 weeks, 3 times a week, 30-45 minutes each time. We focused on the exercise capacity, fall risk, quality of life, and well-being of patients in both groups after the intervention. The aim of the study was to determine whether this combined intervention could improve recovery and quality of life in older discharged patients. Results: Comparison of clinical data between the two groups: there were no differences in gender, age, ethnicity, education, residence, family income, complications, and chronic diseases (P > .05). Self-efficacy increased significantly between the two groups after the intervention, but there was no difference before the intervention (P > .05). The self-efficacy of the experimental group was higher than that of the control group on days 15, 30, 45, and 60 (P < .05). Berg balance scale, TUG, PSMS, IADL, ADL, and total fall risk scores were significantly improved, but there was no difference before intervention (P > .05). All indicators of the experimental group were better than those of the control group on days 15, 30, 45, and 60 (P < .05). EAQ scores were significantly improved, but there was no difference between the two groups before intervention (P > .05). The EAQ of the experimental group was higher than that of the control group on days 15, 30, 45, and 60 (P < .05). Conclusions: This study found that a self-efficacy-based intervention combined with the Otago Exercise Program (OEP) was of value to older discharged patients. This comprehensive intervention approach can improve patients' self-efficacy, balance, walking speed, daily functioning, reduce fall risk, and improve quality of life. For healthcare providers and institutions, this means that this approach could be considered to improve the care of older discharged patients. By enhancing patients' self-efficacy and physical function, it can promote better recovery and independent living, reduce the risk of readmissions, and thus reduce the burden on the healthcare system. This study provides important practical guidance for improving the recovery and quality of life of older discharged patients.

Impact of Shenmai Injection Combined with Chemotherapy on T-cell Subsets and Cytokine Profiles in Patients with Advanced Non-Small Cell Lung Cancer.

Background: Non-small cell lung cancer (NSCLC) represents a significant portion of lung cancer cases, with a poor prognosis and limited treatment options for advanced stages. Enhancing the effectiveness of chemotherapy through adjunctive therapies is a critical area of research. Objective: To evaluate the effect of Shenmai injection combined with chemotherapy on T-cell subsets and cytokine expression in patients with advanced NSCLC. Methods: A comparative prospective study was conducted, and a total of 96 patients with advanced NSCLC were selected. Patients were divided into two groups based on different chemotherapy regimens: an observation group (48 patients) receiving Shenmai injection combined with chemotherapy and a control group (48 patients) receiving chemotherapy alone. The study measures and compares the levels of T-cell subsets (CD3+, CD4+, CD4+/CD8+) and cytokines (IL-2, IL-4, IL-5, IL-6, TNF-α, IFN-γ, VEGF, bFGF, CA125, and CEA) before and after treatment in both groups. Statistical analysis was performed on the collected data. Results: Significant changes were observed in the levels of T-cell subsets and cytokines before and after chemotherapy in both groups (P < .05). Compared with the control group, the observation group exhibited significant improvement in T-cell subsets CD3+, CD4+, and CD4+/CD8+ (P < .05). Furthermore, the levels of cytokines IL-2, IL-4, IL-5, IL-6, TNF-α, IFN-γ, VEGF, bFGF, CA125, and CEA were significantly lower in the observation group compared to the control group (all P < .05). Conclusions: Shenmai injection combined with chemotherapy enhances the cellular immune function in patients with advanced NSCLC. This combination therapy not only reverses tumor progression but also improves the overall therapeutic effect, suggesting a promising adjunctive treatment strategy for advanced NSCLC.

A Heterozygous Variant of FGF13 Caused X-Linked Developmental and Epileptic Encephalopathy 90 in a Chinese Family.

Developmental and epileptic encephalopathy (DEE) refers to a group of severe epilepsy encephalopathy and development disorders, and its typical clinical features include seizures, drug resistance, and developmental delay or regression. To date, limited studies have reported DEEs driven by FGF13. Here, we reported a girl with developmental and epileptic encephalopathy 90 caused by variant of FGF13. Her electroencephalogram (EEG) showed discontinuous hypsarrhythmia, and a heterozygous nonsynonymous variant in FGF13 [NM_004114.4: c.5C>G, p.(Ala2Gly)] was identified from the proband. The variant was not reported in public databases such as gnomAD and Exome Aggregation Consortium (ExAC), and was predicted to be damaging to proteins and classified as likely pathogenic according to the ACMG guidelines. The seizure was finally controlled by a combination of ACTH + zonisamide (10 mg/kg.d) + levetiracetam (52 mg/kg.d) + clonazepam (0.7 mg/kg.d).

Similar Efficacy Observed for First-Line Immunotherapy in Racial/Ethnic Minority Patients With Metastatic NSCLC.

BACKGROUND: Limited data exist on the impact of immunotherapy use in ethnic minority patients with non-small cell lung cancer (NSCLC), because they have been underrepresented in immunotherapy trials. This study aims to evaluate race/ethnicity and other demographic, socioeconomic, and clinical factors of patients with metastatic NSCLC treated with first-line immunotherapy. METHODS: A retrospective cohort study of 5,920 patients diagnosed with lung cancer treated at Montefiore Einstein Cancer Center from January 1, 2013, to June 1, 2022, was used to identify patients with metastatic NSCLC without EGFR, ALK, or ROS1 alterations who underwent first-line immunotherapy (n=248). The primary endpoint was overall survival (OS), with secondary endpoints of progression-free survival (PFS) and time to discontinuation (TTD) from the start of immunotherapy. RESULTS: Among the 248 patients, median follow-up time was 12.0 months, median age at start of treatment was 66 years, and 39.1% were non-Hispanic Black, 30.2% were Hispanic, and 30.7% were non-Hispanic White. OS (P=.39), PFS (P=.29), and TTD (P=.98) were similar among racial/ethnic groups. Patients with an ECOG performance status (PS) of <2 at the start of immunotherapy had longer OS compared with those with ECOG PS of ≥2 (P<.0001). PD-L1 expression (<50% vs ≥50%; P=.03) and body mass index (BMI) (P=.01) were also found to be associated with PFS, and ECOG PS (P<.0001) and BMI (P=.02) were associated with TTD. In a multivariate analysis of OS and PFS, ECOG PS was the only variable found to be significant. CONCLUSIONS: Our study observed similar benefits of immunotherapy in patients with metastatic NSCLC in different racial and ethnic groups. Furthermore, ECOG PS was associated with OS, and PD-L1 expression and BMI were associated with PFS and TTD. These findings help identify potential factors associated with outcomes and care while patients are undergoing immunotherapy.

Association between serum uric acid and female infertility: a cross-sectional study of National Health and Nutrition Examination Survey (NHANES) 2013-2018.

BACKGROUND: Female infertility is a major problem for women of reproductive-age worldwide. Oxidative stress and inflammation are involved in processes related to female infertility. Serum uric acid levels, an indicator of oxidative stress and inflammation, have rarely been reported to be associated with female infertility. This study aimed to investigate the relationship between serum uric acid levels and female infertility. METHODS: This cross-sectional study included women aged 18-44 years from the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2018. All data were extracted from NHANES questionnaires and laboratory measurements. Weighted univariable and multivariable logistic regression analyses were utilized to explore the relationship between serum uric acid and female infertility. Stratified analyses were performed based on body mass index (BMI, < 25 kg/m2 and ≥ 25 kg/m2) and age (≤ 30 years and > 30 years). The odds ratio (OR) with 95% confidence interval (CI) was used to report associations. RESULTS: A total of 2,884 women were included, of which 352 (13.30%) had infertility. Women with high serum uric acid concentrations were related to higher odds of infertility (OR = 1.20, 95%CI: 1.03-1.39) after adjusting for confounders. Compared with serum uric acid concentrations ≤ 3.72 mg/dL, women with uric acid concentrations of 4.43-5.13 mg/dL (OR = 1.65, 95%CI: 1.02-2.67) and > 5.13 mg/dL (OR = 1.86, 95%CI: 1.10-3.13) were related to higher odds of infertility. Stratified analyses showed that high serum uric acid concentrations were associated with higher odds of infertility in women with a BMI < 25 kg/m2 (OR = 1.41, 95%CI: 1.04-1.93), but not in women with a BMI ≥ 25 kg/m2 (P = 0.056). In addition, high serum uric acid concentrations were associated with higher odds of infertility in women aged > 30 years (OR = 1.23, 95%CI: 1.04-1.45), but not in women aged ≤ 30 years (P = 0.556). CONCLUSION: Women with high serum uric acid concentrations were associated with higher odds of infertility, and this association may vary by BMI and age.

Lung Cancer in Never Smokers: Delving into Epidemiology, Genomic and Immune Landscape, Prognosis, Treatment, and Screening.

Lung cancer in never smokers (LCINS) represents a growing and distinct entity within the broader landscape of lung malignancies. This review provides a comprehensive overview of LCINS, encompassing its epidemiologic trends, risk factors, distinct genomic alterations, clinical outcomes and the ongoing initiative aimed at formulating screening guidelines tailored to this unique population. As LCINS continues to gain prominence, understanding its intricate genomic landscape has become pivotal for tailoring effective therapeutic strategies. Moreover, LCINS does not meet the criteria for lung cancer screening as per the current guidelines. Hence, there is an urgent need to explore its heterogeneity in order to devise optimal screening guidelines conducive to early-stage detection. This review underscores the vital importance of detailed research to elucidate the multifaceted nature of LCINS, with the potential to shape future clinical management and screening recommendations for this unique and growing patient cohort.

The influences of social support and emotion regulation strategies on posttraumatic growth of burn survivors: A cross-sectional study in Linyi, China.

This cross-sectional study aimed to test the influences of social support and emotion regulation strategies (cognitive reappraisal and expression suppression) on burn survivors' posttraumatic growth. A convenience sampling method was adopted to recruit 130 burn survivors from the department of burns and plastic surgery of a public hospital in Linyi, China. Data were collected using self-reported questionnaires on social support, emotion regulation strategies, and posttraumatic growth. Structural equation modeling was performed to explore the associations among social support, emotion regulation strategies, and posttraumatic growth in burn survivors. The results showed that social support positively affected cognitive reappraisal and negatively affected expression suppression. Furthermore, it positively affected posttraumatic growth. Moreover, social support indirectly influenced posttraumatic growth through cognitive reappraisal, which implies that cognitive reappraisal played a partial mediating effect in the relationship between social support and posttraumatic growth. These findings provide new insights into the predictors of posttraumatic growth. Cognitive reappraisal and social support should be taken into account to improve burn survivors' posttraumatic growth.

Constitutional delay of growth and puberty in female mice is induced by circadian rhythm disruption in utero.

Constitutional delay of growth and puberty (CDGP) refers to the late onset of puberty. CDGP is associated with poor psychosocial outcomes and elevated risk of cardiovascular and osteoporotic diseases, especially in women. The environmental factors that contribute to CDGP are poorly understood. Here, we investigated the effects of chronic circadian disturbance (CCD) during the fetal stage on the pubertal development of female mice. Compared to non-stressed female (NS-F) mice that were not exposed to CCD in utero, adolescent CCD female (CCD-F) mice exhibited phenotypes that were consistent with CDGP, including lower body weight, reduced levels of circulating gonadal hormones, decreased expression of gonadal hormones and steroid synthesis-related enzymes in the ovary and hypothalamus, irregular estrus cycles, and tardive vaginal introitus initial opening (VO) days (equivalent to the menarche). Phenotypic differences in the above-noted parameters were not observed in CCD-F mice once they had reached adulthood. The expression of genes involved in fatty acid metabolism was perturbed in the ovary and hypothalamus of CCD-F mice. In addition, the ovaries of these animals exhibited altered diurnal expression profiles of circadian clock genes. Together, our findings not only suggest that CCD during fetal development may result in delayed puberty in female mice, they also offer insights on potential mechanisms that underlie CDGP.

Death of a Protein: The Role of E3 Ubiquitin Ligases in Circadian Rhythms of Mice and Flies.

Circadian clocks evolved to enable organisms to anticipate and prepare for periodic environmental changes driven by the day-night cycle. This internal timekeeping mechanism is built on autoregulatory transcription-translation feedback loops that control the rhythmic expression of core clock genes and their protein products. The levels of clock proteins rise and ebb throughout a 24-h period through their rhythmic synthesis and destruction. In the ubiquitin-proteasome system, the process of polyubiquitination, or the covalent attachment of a ubiquitin chain, marks a protein for degradation by the 26S proteasome. The process is regulated by E3 ubiquitin ligases, which recognize specific substrates for ubiquitination. In this review, we summarize the roles that known E3 ubiquitin ligases play in the circadian clocks of two popular model organisms: mice and fruit flies. We also discuss emerging evidence that implicates the N-degron pathway, an alternative proteolytic system, in the regulation of circadian rhythms. We conclude the review with our perspectives on the potential for the proteolytic and non-proteolytic functions of E3 ubiquitin ligases within the circadian clock system.

Do Patients Regret Having Received Systemic Treatment for Advanced Non-Small Cell Lung Cancer: A Prospective Evaluation.

BACKGROUND: Thousands of patients annually receive treatment for advanced non-small cell lung cancer (NSCLC), but little is known about their views on the decision to receive that treatment, or regret. This trial prospectively evaluated the incidence of regret and whether baseline characteristics, patient decision-making parameters, or clinical progress early in the treatment course predicts regret. MATERIALS AND METHODS: Patients receiving systemic treatment for advanced NSCLC completed every 3-week patient reported outcome (PRO) assessment using the electronic Lung Cancer Symptom Scale (eLCSS-QL), including the 3-Item Global Index (3-IGI; assessing overall distress, activities, and quality of life [QL]). A prespecified secondary aim was to determine the frequency of regret evaluated at 3 months after starting treatment. Patients were randomized to usual care or enhanced care (which included use of the DecisionKEYS decision aid). RESULTS: Of 164 patients entered, 160 received treatment and 142 were evaluable for regret. In total, 11.5% of patients and 9% of their supporters expressed regret. Baseline characteristics did not predict regret; regret was rarely expressed by those who had a less than 20% decline or improvement in the 3-IGI PRO score after two treatment cycles. In contrast, when asked if they would make the same decision again, only 1% not having a 20% 3-IGI decline expressed regret, versus 14% with a 3-IGI decline (p = .01). CONCLUSION: The majority of patients having regret were identified early using the PRO 3-IGI of the eLCSS-QL measure. Identifying patients at risk for regret allows for interventions, including frank discussions of progress and goals early in the treatment course, which could address regret in patients and their supporters. IMPLICATIONS FOR PRACTICE: This report documents prospectively, for the first time, the incidence of treatment-related regret in patients with advanced lung cancer and outlines that risk of regret is associated with patient-determined worsening health status early in the course of treatment. Identifying patients at risk for regret early in treatment (before the third cycle of treatment) appears to be crucial. Counseling at that time should include a discussion of consideration of treatment change and the reason for this change.

Update 2021: Management of Small Cell Lung Cancer.

BACKGROUND: Accounting for 14% of lung cancer, small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with rapid proliferation, early spread, and poor survival. AIM AND METHODS: We provide an overview of recent advances regarding SCLC pathogenesis, subtypes, and treatment development through literature review of key trials. RESULTS: There are no validated biomarkers or approved targeted treatments for this overly heterogeneous disease, but recent analyses have identified some promising targets and four major subtypes which may carry unique therapeutic vulnerabilities in SCLC. Treatment wise, only a third of patients present with limited stage SCLC, which can be managed with a combined modality approach with curative intent (usually chemo-radiotherapy, but in some eligible patients, surgery followed by systemic treatment). For advanced or extensive stage SCLC, combined chemotherapy (platinum-etoposide) and immunotherapy (atezolizumab or durvalumab during and after chemotherapy) has become the new standard front-line treatment, with modest improvement in overall survival. In the second-line setting, for disease relapse ≤ 6 months, topotecan, lurbinectedin, and clinical trials are reasonable treatment options; for disease relapse > 6 months, original regimen, topotecan or lurbinectedin can be considered. Moreover, Trilaciclib, a CD4/CD6 inhibitor, was recently FDA-approved to decrease the incidence of chemotherapy-related myelosuppression in SCLC patients. CONCLUSIONS: While modest improvements in survival have been made especially in the metastatic setting with chemo-immunotherapy, further research in understanding the biology of SCLC is warranted to develop biomarker-driven therapeutic strategies and combinational approaches for this aggressive disease.

SOX2 Regulates Neuronal Differentiation of the Suprachiasmatic Nucleus.

In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, orchestrating behavioral and physiological rhythms in alignment to the environmental light/dark cycle. The neurons that comprise the SCN are anatomically and functionally heterogeneous, but despite their physiological importance, little is known about the pathways that guide their specification and differentiation. Here, we report that the stem/progenitor cell transcription factor, Sex determining region Y-box 2 (Sox2), is required in the embryonic SCN to control the expression of SCN-enriched neuropeptides and transcription factors. Ablation of Sox2 in the developing SCN leads to downregulation of circadian neuropeptides as early as embryonic day (E) 15.5, followed by a decrease in the expression of two transcription factors involved in SCN development, Lhx1 and Six6, in neonates. Thymidine analog-retention assays revealed that Sox2 deficiency contributed to reduced survival of SCN neurons during the postnatal period of cell clearance, but did not affect progenitor cell proliferation or SCN specification. Our results identify SOX2 as an essential transcription factor for the proper differentiation and survival of neurons within the developing SCN.

Contribution of DNA methylation in chronic stress-induced cardiac remodeling and arrhythmias in mice.

It is recognized that stress can induce cardiac dysfunction, but the underlying mechanisms are not well understood. The present study aimed to test the hypothesis that chronic negative stress leads to alterations in DNA methylation of certain cardiac genes, which in turn contribute to pathologic remodeling of the heart. We found that mice that were exposed to chronic restraint stress (CRS) for 4 wk exhibited cardiac remodeling toward heart failure, as characterized by ventricular chamber dilatation, wall thinning, and decreased contractility. CRS also induced cardiac arrhythmias, including intermittent sinus tachycardia and bradycardia, frequent premature ventricular contraction, and sporadic atrioventricular conduction block. Circulating levels of stress hormones were elevated, and the cardiac expression of tyrosine hydroxylase, a marker of sympathetic innervation, was increased in CRS mice. Using reduced representation bisulfite sequencing, we found that although CRS did not lead to global changes in DNA methylation in the murine heart, it nevertheless altered methylation at specific genes that are associated with the dilated cardiomyopathy (DCM) (e.g., desmin) and adrenergic signaling of cardiomyocytes (ASPC) (e.g., adrenergic receptor-α1) pathways. We conclude that CRS induces cardiac remodeling and arrhythmias, potentially through altered methylation of myocardial genes associated with the DCM and ASPC pathways.-Zhang, P., Li, T., Liu, Y.-Q., Zhang, H., Xue, S.-M., Li, G., Cheng, H.-Y.M., Cao, J.-M. Contribution of DNA methylation in chronic stress-induced cardiac remodeling and arrhythmias in mice.

Leptomeningeal Metastases in Non-small Cell Lung Cancer: Optimal Systemic Management in NSCLC With and Without Driver Mutations.

OPINION STATEMENT: As a devastating complication of non-small cell lung cancer (NSCLC), the incidence of leptomeningeal metastasis (LM) is rising, largely due to overall longer survival of NSCLC, especially in patients with targetable molecular driver mutations. There is no clear consensus on the optimal management of LM. This review will cover recent advances in diagnosis, monitoring, and treatment of LM in NSCLC. In LM without oncogene drivers, systemic chemotherapy, intrathecal therapy, and radiation have modestly improved the clinical outcomes. Emerging data have also suggested encouraging activity of immunotherapy. At the same time, in LM with sensitizing EGFR mutations, osimertinib should be considered regardless of T790M status. Pulse erlotinib, afatinib, and newer agents with improved CNS penetration have also shown benefits. Moreover, accumulating evidences support potential benefits of molecularly targeted therapy in ALK-rearranged and other oncogene-driven NSCLC with LM. Future studies are warranted to better define the underlying mechanism, to optimize the clinical management, and to improve patient outcomes.

Update 2020: Management of Non-Small Cell Lung Cancer.

The past decade has seen a revolution of new advances in the management of non-small cell lung cancer (NSCLC) with remarkable progresses in screening, diagnosis, and treatment. The advances in systemic treatment have been driven primarily by the development of molecularly targeted therapeutics, immune checkpoint inhibitors, and anti-angiogenic agents, all of which have transformed this field with significantly improved patient outcomes. This review will address updates in lung cancer screening, liquid biopsy, and immunotherapy in the front-line setting. We discuss recent advances and highlight the plethora of new approvals of molecular-targeted therapy for subgroups of NSCLC patients with sensitizing EGFR, ALK, ROS1, RET, BRAF V600E, MET, and NTRK alterations.

RFamide-related peptide-3 (RFRP-3) suppresses sexual maturation in a eusocial mammal.

Neuroendocrine mechanisms underlying social inhibition of puberty are not well understood. Here, we use a model exhibiting the most profound case of pubertal suppression among mammals to explore a role for RFamide-related peptide-3 [RFRP-3; mammalian ortholog to gonadotropin-inhibitory hormone (GnIH)] in neuroendocrine control of reproductive development. Naked mole rats (NMRs) live in sizable colonies where breeding is monopolized by two to four dominant animals, and no other members exhibit signs of puberty throughout their lives unless they are removed from the colony. Because of its inhibitory action on the reproductive axis in other vertebrates, we investigated the role of RFRP-3 in social reproductive suppression in NMRs. We report that RFRP-3 immunofluorescence expression patterns and RFRP-3/GnRH cross-talk are largely conserved in the NMR brain, with the exception of the unique presence of RFRP-3 cell bodies in the arcuate nucleus (Arc). Immunofluorescence comparisons revealed that central expression of RFRP-3 is altered by reproductive status, with RFRP-3 immunoreactivity enhanced in the paraventricular nucleus, dorsomedial nucleus, and Arc of reproductively quiescent NMRs. We further observed that exogenous RFRP-3 suppresses gonadal steroidogenesis and mating behavior in NMRs given the opportunity to undergo puberty. Together, our findings establish a role for RFRP-3 in preserving reproductive immaturity, and challenge the view that stimulatory peptides are the ultimate gatekeepers of puberty.

Emerging drugs for EGFR-mutated non-small cell lung cancer.

INTRODUCTION: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with metastatic non-small-cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, these agents are associated with inevitable treatment resistance. Newer generations of TKIs are under development that may prevent or overcome resistance and enhance intracranial activity. Areas covered: In this review, we will discuss newer generations of EGFR TKIs for EGFR-mutated NSCLC. We will also address resistance mutations and escape pathways associated with these agents such as secondary mutations, downstream signaling, bypass pathways, phenotypic transformation, anti-apoptotic signaling, immune evasion, and angiogenesis. Furthermore, this article encompasses emerging data from combination trials with next-generation TKIs that are being pursued to delay or prevent the occurrence of resistance. Expert opinion: The promise and challenge of precision oncology is encapsulated in the treatment of EGFR-mutated NSCLC with TKIs. Third generation TKIs have shown superior efficacy in the front-line setting and have become standard of care. A better understanding of mechanisms of treatment failure and disease relapse will be required to develop novel therapeutic strategies to further improve patient outcomes in the future.

A Symphony of Signals: Intercellular and Intracellular Signaling Mechanisms Underlying Circadian Timekeeping in Mice and Flies.

The central pacemakers of circadian timekeeping systems are highly robust yet adaptable, providing the temporal coordination of rhythms in behavior and physiological processes in accordance with the demands imposed by environmental cycles. These features of the central pacemaker are achieved by a multi-oscillator network in which individual cellular oscillators are tightly coupled to the environmental day-night cycle, and to one another via intercellular coupling. In this review, we will summarize the roles of various neurotransmitters and neuropeptides in the regulation of circadian entrainment and synchrony within the mammalian and Drosophila central pacemakers. We will also describe the diverse functions of protein kinases in the relay of input signals to the core oscillator or the direct regulation of the molecular clock machinery.