Integrative analyses of long and short-read RNA sequencing reveal the spliced isoform regulatory network of seedling growth dynamics in upland cotton.

The polyploid genome of cotton has significantly increased the transcript complexity. Recent advances in full-length transcript sequencing are now widely used to characterize the complete landscape of transcriptional events. Such studies in cotton can help us to explore the genetic mechanisms of the cotton seedling growth. Through long-read single-molecule RNA sequencing, this study compared the transcriptomes of three yield contrasting genotypes of upland cotton. Our analysis identified different numbers of spliced isoforms from 31,166, 28,716, and 28,713 genes in SJ48, Z98, and DT8 cotton genotypes, respectively, most of which were novel compared to previous cotton reference transcriptomes, and showed significant differences in the number of exon structures and coding sequence length due to intron retention. Quantification of isoform expression revealed significant differences in expression in the root and leaf of each genotype. An array of key isoform target genes showed protein kinase or phosphorylation functions, and their protein interaction network contained most of the circadian oscillator proteins. Spliced isoforms from the GIGANTEA (GI) protien were differentially regulated in each genotype and might be expected to regulate translational activities, including the sequence and function of target proteins. In addition, these spliced isoforms generate diurnal expression profiles in cotton leaves, which may alter the transcriptional regulatory network of seedling growth. Silencing of the novel spliced GI isoform Gh_A02G0645_N17 significantly affected biomass traits, contributed to variable growth, and increased transcription of the early flowering pathway gene ELF in cotton. Our high-throughput hybrid sequencing results will be useful to dissect functional differences among spliced isoforms in the polyploid cotton genome.

Efficacy on symptoms and mortality day vs. night administration of EGFR-TKIs for advanced non-small cell lung cancer.

PURPOSE: This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer. METHODS: We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023. RESULTS: Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6 weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43 months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87). CONCLUSIONS: The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes.

Identification of circadian clock-related immunological prognostic index and molecular subtypes in prostate cancer.

BACKGROUND: Evidence suggests that the circadian clock (CIC) is among the important factors for tumorigenesis. We aimed to provide new insights into CIC-mediated molecular subtypes and gene prognostic indexes for prostate cancer (PCa) patients undergoing radical prostatectomy (RP) or radical radiotherapy (RT). METHODS: PCa data from TCGA was analyzed to identify differentially expressed genes (DEGs) with significant fold changes and p-values. A prognostic index called CIC-related gene prognostic index (CICGPI) was developed through clustering methods and survival analysis and validated on multiple data sets. The diagnostic accuracy of CICGPI for resistance to chemotherapy and radiotherapy was confirmed. Additionally, the interaction between tumor immune environment and CICGPI score was explored, along with their correlation with prognosis. RESULTS: TOP2A, APOE, and ALDH2 were used to classify the PCa patients into two subtypes. Cluster 2 had a higher risk of biochemical recurrence (BCR) than cluster 1 for PCa patients undergoing RP or RT. A CIC-related gene prognostic index (CICGPI) was constructed using the above three genes for PCa patents in the TCGA database. The CICGPI score showed good prognostic value in the TCGA database and was externally confirmed by PCa patients in GSE116918, MSKCC2010 and GSE46602. In addition, the CICGPI score had a certain and high diagnostic accuracy for tumor chemoresistance (AUC: 0.781) and radioresistance (AUC: 0.988). For gene set variation analysis, we observed that both beta alanine metabolism and limonene and pinene degradation were upregulated in cluster 1 for PCa patients undergoing RP or RT. For PCa patients undergoing RP, cell cycle, homologous recombination, mismatch repair, and DNA replication were upregulated in cluster 2. A strongly positive relationship between cancer-related fibroblasts and CICGPI score was observed in PCa patients undergoing RP or RT. Moreover, a high density of CAFs was highly closely associated with poorer BCR-free survival of PCa patients. CONCLUSIONS: In this study, we established CIC-related immunological prognostic index and molecular subtypes, which might be useful for the clinical practice.

The food-borne carcinogenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) disrupts circadian rhythms and ameliorated by pterostilbene (PSB) in Caenorhabditis elegans.

The food-borne 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potential human carcinogen abundant in cooked meat. While circadian rhythms are crucial biological oscillations, the negative impact of PhIP on circadian systems and the potential of mitigation remain underexplored. We investigated the effects of PhIP on circadian rhythms and the mitigating effects of the phytochemical antioxidant pterostilbene (PSB) in Caenorhabditis elegans. We show that exposure to 10 µM PhIP disrupts the 24-h circadian rhythms of C. elegans, an effect mitigated by co-exposure to 100 µM PSB. In addition, PhIP-induced circadian disruption can be linked to defective oxidative stress resistance, which is associated with the DAF-16/FOXO pathway and is modulated by PSB. Molecular docking suggested that PhIP and PSB bind similarly to DAF-16. Moreover, 10 µM PhIP abolished the rhythmic expression of the core clock gene prdx-2, which is restored by 100 µM PSB. Findings from this study provide novel insight of how food-borne contaminant like PhIP may contribute to the disruption of circadian rhythms and suggest potential for PSB to mitigate these effects in higher organisms.

Circadian rhythms and breast cancer: from molecular level to therapeutic advancements.

BACKGROUND AND OBJECTIVES: Circadian rhythms, the endogenous biological clocks that govern physiological processes, have emerged as pivotal regulators in the development and progression of breast cancer. This comprehensive review delves into the intricate interplay between circadian disruption and breast tumorigenesis from multifaceted perspectives, encompassing biological rhythms, circadian gene regulation, tumor microenvironment dynamics, and genetic polymorphisms. METHODS AND RESULTS: Epidemiological evidence underscores the profound impact of external factors, such as night shift work, jet lag, dietary patterns, and exercise routines, on breast cancer risk and progression through the perturbation of circadian homeostasis. The review elucidates the distinct roles of key circadian genes, including CLOCK, BMAL1, PER, and CRY, in breast cancer biology, highlighting their therapeutic potential as molecular targets. Additionally, it investigates how circadian rhythm dysregulation shapes the tumor microenvironment, fostering epithelial-mesenchymal transition, chronic inflammation, and immunosuppression, thereby promoting tumor progression and metastasis. Furthermore, the review sheds light on the association between circadian gene polymorphisms and breast cancer susceptibility, paving the way for personalized risk assessment and tailored treatment strategies. CONCLUSIONS: Importantly, it explores innovative therapeutic modalities that harness circadian rhythms, including chronotherapy, melatonin administration, and traditional Chinese medicine interventions. Overall, this comprehensive review emphasizes the critical role of circadian rhythms in the pathogenesis of breast cancer and highlights the promising prospects for the development of circadian rhythm-based interventions to enhance treatment efficacy and improve patient outcomes.

Association between chronic kidney disease stages and changes in ambulatory blood pressure monitoring parameters / Associação entre estágios da doença renal crônica e alterações dos parâmetros da monitorização ambulatorial da pressão arterial

Abstract Introduction: Blood pressure (BP) assessment affects the management of arterial hypertension (AH) in chronic kidney disease (CKD). CKD patients have specific patterns of BP behavior during ambulatory blood pressure monitoring (ABPM). Objectives: The aim of the current study was to evaluate the associations between progressive stages of CKD and changes in ABPM. Methodology: This is a cross-sectional study with 851 patients treated in outpatient clinics of a university hospital who underwent ABPM examination from January 2004 to February 2012 in order to assess the presence and control of AH. The outcomes considered were the ABPM parameters. The variable of interest was CKD staging. Confounding factors included age, sex, body mass index, smoking, cause of CKD, and use of antihypertensive drugs. Results: Systolic BP (SBP) was associated with CKD stages 3b and 5, irrespective of confounding variables. Pulse pressure was only associated with stage 5. The SBP coefficient of variation was progressively associated with stages 3a, 4 and 5, while the diastolic blood pressure (DBP) coefficient of variation showed no association. SBP reduction was associated with stages 2, 4 and 5, and the decline in DBP with stages 4 and 5. Other ABPM parameters showed no association with CKD stages after adjustments. Conclusion: Advanced stages of CKD were associated with lower nocturnal dipping and greater variability in blood pressure.

Resumo Introdução: A avaliação da pressão arterial (PA) tem impacto no manejo da hipertensão arterial (HA) na doença renal crônica (DRC). O portador de DRC apresenta padrão específico de comportamento da PA ao longo da monitorização ambulatorial da pressão arterial (MAPA). Objetivos: O objetivo do corrente estudo é avaliar as associações entre os estágios progressivos da DRC e alterações da MAPA. Metodologia: Trata-se de um estudo transversal com 851 pacientes atendidos nos ambulatórios de um hospital universitário que foram submetidos ao exame de MAPA no período de janeiro de 2004 a fevereiro de 2012 para avaliar a presença e o controle da HA. Os desfechos considerados foram os parâmetros de MAPA. A variável de interesse foi o estadiamento da DRC. Foram considerados como fatores de confusão idade, sexo, índice de massa corporal, tabagismo, causa da DRC e uso de anti-hipertensivos. Resultados: A PA sistólica (PAS) se associou aos estágios 3b e 5 da DRC, independentemente das variáveis de confusão. Pressão de pulso se associou apenas ao estágio 5. O coeficiente de variação da PAS se associou progressivamente aos estágios 3a, 4 e 5, enquanto o coeficiente de variação da pressão arterial diastólica (PAD) não demonstrou associação. O descenso da PAS obteve associação com estágios 2, 4 e 5, e o descenso da PAD, com os 4 e 5. Demais parâmetros da MAPA não obtiveram associação com os estágios da DRC após os ajustes. Conclusão: Estágios mais avançados da DRC associaram-se a menor descenso noturno e a maior variabilidade da pressão arterial.

Targeting the liver clock improves fibrosis by restoring TGF-ß signaling.

BACKGROUND & AIMS: Liver fibrosis is the major driver for hepatocellular carcinoma and liver disease related death. Approved anti-fibrotic therapies are absent and compounds in development have limited efficacy. Increased TGF-ß signaling drives collagen deposition by hepatic stellate cells (HSC)/myofibroblasts. Here, we aimed to dissect the role of the circadian clock (CC) in controlling TGF-ß signaling and liver fibrosis. METHODS: Using CC-mutant mice, enriched HSCs and myofibroblasts obtained from healthy and fibrotic mice in different CC-phases and loss-of-function studies in human hepatocytes and myofibroblasts, we investigated the relationship between CC and TGF-ß signaling. We explored hepatocyte-myofibroblast communication through bioinformatic analyses of single-nuclei transcriptomes and validation in cell-based models. Using mouse models for MASH fibrosis and spheroids from patients with liver disease, we performed proof-of-concept studies to validate pharmacological targetability and clinical translatability. RESULTS: We discovered that the CC-oscillator temporally gates TGF-ß signaling and this regulation is broken in fibrosis. We demonstrate that HSCs and myofibroblasts contain a functional CC with rhythmic expression of numerous genes, including fibrogenic genes. Perturbation studies in hepatocytes and myofibroblasts revealed a reciprocal relationship between TGF-ß-activation and CC perturbation, which was confirmed in patient-derived ex vivo and in vivo models. Pharmacological modulation of CC-TGF-ß signaling inhibited fibrosis in mouse models in vivo as well as patient-derived liver spheroids. CONCLUSION: The CC regulates TGF-ß signaling, and the breakdown of this control is associated with liver fibrosis in patients. Pharmacological proof-of-concept studies across different models uncover the CC as a therapeutic candidate target for liver fibrosis - a rising global unmet medical need. IMPACT AND IMPLICATIONS: Liver fibrosis due to metabolic diseases is a global health challenge. Many liver functions are rhythmic throughout the day being controlled by the circadian clock (CC). Here we demonstrate that the regulation of the CC is perturbed upon chronic liver injury and this perturbation contributes to fibrotic disease. By showing that a compound targeting the CC improves liver fibrosis in patient-derived models, this study provides a novel therapeutic candidate strategy to treat fibrosis in patients. Additional studies will be needed for clinical translation. Since the findings uncovers a previously undiscovered profibrotic mechanism and therapeutic target, the study is of interest for scientists investigating liver disease, clinical hepatologists and drug developers.

Polygenic risk scores for mood disorders and actigraphy estimates of sleep and circadian rhythms: A preliminary study in bipolar disorders.

In bipolar disorders, abnormalities of sleep patterns and of circadian rhythms of activity are observed during mood episodes, but also persist during euthymia. Shared vulnerabilities between mood disorders and abnormalities of sleep patterns and circadian rhythms of activity have been suggested. This exploratory study investigated the association between polygenic risk scores for bipolar disorder and major depressive disorder, actigraphy estimates of sleep patterns, and circadian rhythms of activity in a sample of 62 euthymic individuals with bipolar disorder. The polygenic risk score - bipolar disorder and polygenic risk score - major depressive disorder were calculated for three stringent thresholds of significance. Data reduction was applied to aggregate actigraphy measures into dimensions using principal component analysis. A higher polygenic risk score - major depressive disorder was associated with more fragmented sleep, while a higher polygenic risk score - bipolar disorder was associated with a later peak of circadian rhythms of activity. These results remained significant after adjustment for age, sex, bipolar disorder subtype, body mass index, current depressive symptoms, current tobacco use, and medications prescribed at inclusion, but not after correction for multiple testing. In conclusion, the genetic vulnerabilities to major depression and to bipolar disorder might be associated with different abnormalities of sleep patterns and circadian rhythms of activity. The results should be replicated in larger and independent samples.

Circadian rhythms and breast cancer: unraveling the biological clock's role in tumor microenvironment and ageing.

Breast cancer (BC) is one of the most common and fatal malignancies among women worldwide. Circadian rhythms have emerged in recent studies as being involved in the pathogenesis of breast cancer. In this paper, we reviewed the molecular mechanisms by which the dysregulation of the circadian genes impacts the development of BC, focusing on the critical clock genes, brain and muscle ARNT-like protein 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK). We discussed how the circadian rhythm disruption (CRD) changes the tumor microenvironment (TME), immune responses, inflammation, and angiogenesis. The CRD compromises immune surveillance and features and activities of immune effectors, including CD8+ T cells and tumor-associated macrophages, that are important in an effective anti-tumor response. Meanwhile, in this review, we discuss bidirectional interactions: age and circadian rhythms, aging further increases the risk of breast cancer through reduced vasoactive intestinal polypeptide (VIP), affecting suprachiasmatic nucleus (SCN) synchronization, reduced ability to repair damaged DNA, and weakened immunity. These complex interplays open new avenues toward targeted therapies by the combination of clock drugs with chronotherapy to potentiate the immune response while reducing tumor progression for better breast cancer outcomes. This review tries to cover the broad area of emerging knowledge on the tumor-immune nexus affected by the circadian rhythm in breast cancer.

Arsenic-induced disruption of circadian rhythms and glutamine anaplerosis in human urothelial carcinoma.

Inorganic arsenic (iAs)-induced urothelial carcinoma (UC) develops into a poor-prognosis malignancy. Arsenic-induced oxidative stress contributes to circadian rhythm disruption altered metabolism. Glutamine anaplerosis is a common metabolic feature of rapidly proliferating malignant cells, in which glutaminase (GLS) is a key enzyme in this process. Therefore, this study intends to determine if arsenic-induced oxidative stress can alter circadian rhythms and promote glutamine anaplerosis. Exonic expression of core circadian molecules (CLOCK, ARNTL, and NR1D1) and GLS in varying grades of UC were assessed using 423 bladder cancer samples from the TCGA Urothelial Bladder Cancer (BLCA) dataset. The levels of circadian proteins and metabolic markers in 44 UC patients from non-black foot disease (BFD) and BFD areas were detected by immunohistochemistry. In vitro and in vivo experiments elucidated the regulatory mechanisms of arsenic-mediated circadian disturbance and metabolic alteration. Public database analysis showed that ARNTL, NR1D1, and GLS exhibited greater expression in more high-grade UC. Strong immunoreactivity for BMAL1, GLS, and low levels of NR1D1 were found in malignant urothelial lesions, especially in arsenic-exposed UC. Arsenic-induced overexpression of BMAL1 and GLS involves activation of NADH: quinone oxidoreductase 1 (NQO1), continuously altering the NADH oscillations to promote glutamate metabolism in SV-HUC-1, T24 and BFTC-905 cells. These phenomenon were also demonstrated in the urothelium of arsenic-exposed animals. The present findings highlight the potential clinical significance of BMAL1 and GLS in UC in the BFD region. Furthermore, these results suggest that arsenic interferes with circadian rhythm and glutamine anaplerosis by NADH oscillatory imbalance in urothelial cells and urothelial cancer cells, predisposing them to malignant development.

Effect of time of day on outcomes in elective surgery: a systematic review.

BACKGROUND: The timing of elective surgery could affect clinical outcome because of diurnal rhythms of patient physiology as well as surgical team performance. Waiting times for elective surgery are increasing in many countries, leading to increasing interest in undertaking elective surgery in the evening or at night. We aimed to systematically review the literature on the effect of the timing of elective (but not urgent or emergency) surgery on mortality, morbidity and other clinical outcomes. METHODS: We searched databases for relevant studies combining the terms 'circadian rhythm' and 'anaesthesia/surgery'. Additional relevant articles were found by hand-searching the references. All studies were screened for bias. Included studies examined daytime vs. evening/night-time surgery, morning vs. afternoon surgery, multiple timeslots or used time as a continuous variable. RESULTS: Nineteen retrospective cohort studies, one prospective cohort study and one randomised controlled trial were included (n = 798,914). Evening/night-time elective surgery was associated with a higher risk of mortality when compared with daytime procedures in three studies (n = 611,230), with odds ratios (95%CI) for mortality ranging from 1.35 (1.16-1.56) to 3.98 (1.54-10.30), while no differences were found in three other studies (n = 142,355). No differences were found for morning vs. afternoon surgery (four studies, n = 3277). However, most studies had a low quality of evidence due to their retrospective nature and because not all studies corrected for patient characteristics. Moreover, the studies were heterogeneous in terms of the reported time slots and clinical outcomes. CONCLUSIONS: We found that evening/night-time elective surgery is associated with a higher risk of mortality compared with daytime surgery. However, the quality of evidence was graded as low, and thus, future prospective research should publish individual patient data and standardise outcome measures to allow firm conclusions and facilitate interventions.

Association between PER and CRY gene polymorphisms and the response to caffeine citrate treatment in infants with apnea of prematurity.

Background: Circadian rhythms impact metabolism and the therapeutic effects of drugs. The purpose of this study was to determine the association between PER and CRY polymorphisms and caffeine citrate treatment response in infants with apnea of prematurity. Methods: A total of 221 preterm infants of gestational age <34 weeks were included in this study (160 in the response group and 61 in the non-response group). The propensity score matching method was used to perform a 1:1 matching for all premature infants, and the general characteristics and clinical outcomes of the two groups were compared. The association between polymorphisms of the circadian transcription repressors PER and CRY and caffeine citrate treatment response in infants with apnea of prematurity was analyzed with co-dominant, dominant, recessive, and over-dominant models, as well as analysis of alleles. Generalized multifactor dimensionality reduction (GMDR) analysis was used to analyze the interaction between the PER and CRY genes. Results: After propensity score matching, 45 preterm infants were included in each of the response and non-response groups, and there were no statistically significant differences in general characteristics between the two groups (P > 0.05). Infants in the non-response groups had a higher incidence of moderate and severe bronchopulmonary dysplasia (BPD) (P = 0.043), retinopathy of prematurity (ROP) (P = 0.035), and invasive ventilation (P = 0.027), and their duration of oxygen use (P = 0.041) was longer. When corrected for false discovery rate, the PER3 rs228669 recessive model (P FDR = 0.045) and the over-dominant model (P FDR = 0.045) were both associated with caffeine citrate treatment response. Preterm infants with the rs228669 CC genotype had a significantly lower rate of caffeine citrate non-response in the recessive model (OR = 0.28, 95% CI = 0.12-0.66), which was significantly higher in preterm infants with the CT genotype in the over-dominant model (OR = 4.18, 95% CI = 1.64-10.66). GMDR analysis revealed an interaction between the PER and CRY genes (P < 0.05). Conclusions: Circadian rhythms may play a role in the response of premature infants to caffeine citrate, and polymorphisms of the PER and CRY genes may influence the effectiveness of caffeine citrate treatment for apnea of prematurity.

Shedding Light on Iron Nutrition: Exploring Intersections of transcription factor cascades in light and iron deficiency signaling.

In the dynamic environment of plants, the interplay between light-dependent growth and iron nutrition is a recurring challenge. Plants respond to low iron levels by adjusting growth and physiology through enhanced iron acquisition from the rhizosphere and internal iron pool reallocation. Iron deficiency response assays and gene co-expression networks aid in documenting physiological reactions and unraveling gene regulatory cascades, offering insight into the interplay between hormonal and external signaling pathways. However, research directly exploring the significance of light in iron nutrition remains limited. This review provides an overview on iron deficiency regulation and its cross-connection with distinct light signals, focusing on transcription factor cascades and long-distance signaling. The circadian clock and retrograde signaling influence iron uptake and allocation. The light-activated shoot-to-root mobile transcription factor ELONGATED HYPOCOTYL5 (HY5) affects iron homeostasis responses in roots. Blue light triggers the formation of biomolecular condensates containing iron deficiency-induced protein complexes. The potential of exploiting the connection between light and iron signaling remains underutilized. With climate change and soil alkalinity on the rise, there is a need to develop crops with improved nutrient use efficiency and modified light dependencies. More research is needed to understand and leverage the interplay between light signaling and iron nutrition.

Efficacy of timing­dependent infusion of nivolumab in patients with advanced gastric cancer.

Although an association exists between the timing of immune checkpoint inhibitor (ICI) administration and therapeutic efficacy in several types of cancer, to the best of our knowledge, no reports exist regarding this relationship in gastric cancer (GC). The present study aimed to evaluate the optimal timing of ICI (nivolumab) administration in patients with advanced GC. A total of 58 consecutive patients with advanced GC who received nivolumab monotherapy after ≥2 chemotherapy regimens were retrospectively evaluated. These patients were divided into two groups according to the median time of nivolumab administration: i) Early-timing and (ii) late-timing groups, and the efficacy was assessed in both groups. The early-timing group had significantly longer overall survival (OS) than the late-timing group [median OS 8.2 months; 95% confidence interval (CI), 4.2-12.9 vs. median OS 5.4 months; 95% CI, 3.6-6.1]. Moreover, patients in the early-timing group had significantly longer progression-free survival (PFS) than those in the late-timing group (median PFS 2.6 months; 95% CI, 1.3-3.9 months vs. median PFS 1.6 months; 95% CI, 0.9-2.1 months). Furthermore, univariate analysis showed that early timing, immune-related adverse events and nonsteroidal anti-inflammatory drug administration were associated with longer OS and PFS. Cutoff Finder analysis revealed that the optimal timing of nivolumab administration for achieving better outcomes was before 12:06 p.m. Nivolumab administration in the morning, especially before 12:06 p.m., had a better clinical impact on patients with advanced GC.

Exploring the association between melatonin and nicotine dependence (Review).

Due to the addictive qualities of tobacco products and the compulsive craving and dependence associated with their use, nicotine dependence continues to be a serious public health concern on a global scale. Despite awareness of the associated health risks, nicotine addiction contributes to numerous acute and chronic medical conditions, including cardiovascular disease, respiratory disorders and cancer. The nocturnal secretion of pineal melatonin, known as the 'hormone of darkness', influences circadian rhythms and is implicated in addiction­related behaviors. Melatonin receptors are found throughout the brain, influencing dopaminergic neurotransmission and potentially attenuating nicotine­seeking behavior. Additionally, the antioxidant properties of melatonin may mitigate oxidative stress from chronic nicotine exposure, reducing cellular damage and lowering the risk of nicotine­related health issues. In addition to its effects on circadian rhythmicity, melatonin acting via specific neural receptors influences sleep and mood, and provides neuroprotection. Disruptions in melatonin signaling may contribute to sleep disturbances and mood disorders, highlighting the potential therapeutic role of melatonin in addiction and psychiatric conditions. Melatonin may influence neurotransmitter systems involved in addiction, such as the dopaminergic, glutamatergic, serotonergic and endogenous opioid systems. Preclinical studies suggest the potential of melatonin in modulating reward processing, attenuating drug­induced hyperactivity and reducing opioid withdrawal symptoms. Chronotherapeutic approaches targeting circadian rhythms and melatonin signaling show promise in smoking cessation interventions. Melatonin supplementation during periods of heightened nicotine cravings may alleviate withdrawal symptoms and reduce the reinforcing effects of nicotine. Further research is required however, to examine the molecular mechanisms underlying the melatonin­nicotine association and the optimization of therapeutic interventions. Challenges include variability in individual responses to melatonin, optimal dosing regimens and identifying biomarkers of treatment response. Understanding these complexities could lead to personalized treatment strategies and improve smoking cessation outcomes.

Identification of a circadian-based prognostic signature predicting cancer-associated fibroblasts infiltration and immunotherapy response in bladder cancer.

Circadian rhythm disruption impacts the efficiency of both chemotherapy and immunotherapy, yet identifying the key factors involved remains challenging. Circadian rhythm disruption can trigger aberrant fibroblasts activation, suggesting potential roles of cancer-associated fibroblasts (CAFs) in addressing this issue. In this paper, TCGA-BLCA patients were classified into two subgroups based on the expression of core circadian rhythm genes (CCRGs). The CCRG-based subgroups showed distinct fibroblast-related signals, from which a risk model composed of five fibroblast-related genes was finally established with excellent survival prognostic value in both TCGA and GEO datasets. The risk model was positively associated with the infiltration of CAFs and can efficiently predict the immunotherapy response in BLCA. Besides, high-risk score was associated with reduced sensitivity to a majority of traditional chemotherapeutic drugs such as oxaliplatin and gemcitabine. Further, the correlation between CCRGs and the risk genes was analyzed. Among the five risk genes, FAM20C displayed the most extensive correlation with the CCRGs and exhibited the strongest connection with CAFs infiltration. Moreover, FAM20C independently served as a predictor for the response to immunotherapy in BLCA. In conclusion, this study has identified a circadian-based signature for evaluating CAFs infiltration and predicting the efficacy of chemotherapy and immunotherapy. The central gene FAM20C has emerged as a promising candidate which merits further investigations.

Exploring the associations between chronotype, meal frequency, and physical activity: A population-based study in adults.

Chronotype is an established concept designed to capture the internal clock's phase in real-life conditions. It is vital in many aspects of daily life and can interfere considerably with numerous factors in a given population. Recognizing nonmodifiable and modifiable factors is crucial for identifying covariates of interest when studying the link between chronotype and health status. To date, chronotype and its related factors have not been extensively investigated. The present study aimed to explore the association of chronotypes with meal frequency, physical activity, and demographic factors among the Saudi population. This cross-sectional web-based questionnaire involved 1369 adults (aged 18 years and above) from the general public in Saudi Arabia and was conducted between March and May 2019. Chronotype was assessed using the reduced version of the original Horne and Ostberg morningness-eveningness questionnaire (MEQ). Meal frequencies and demographics data (age, gender, marital status, place of residence, educational level, employment status, income) were obtained. Physical activity level was also obtained using the international physical activity questionnaire. The MEQ scores group individuals into three categories: morning-type, neither-type, and evening-type. The neither-type individuals represented 41.6% (95% confidence interval [CI], 37.5% - 45.6%) of the study population, followed by the morning-type (34.1%; 95% [CI], 29.8% - 38.4%), then the evening-type (24.3%, 95% [CI], 19.6% - 28.9%). Chronotype was significantly associated with age, marital status, employment status and monthly income (All p < 0.05). Significant associations between chronotype with meal frequencies (number of meals per day, breakfast frequency, lunch frequency, and dinner frequency) and physical activity were also observed (All p < 0.05). This study highlights that meal frequencies and physical activity levels are associated with chronotype distribution. Furthermore, demographics, including age, marital status, employment status, and income, were associated with chronotype distribution.

Immune checkpoint inhibitor infusion times and clinical outcomes in patients with melanoma.

BACKGROUND: Circadian rhythms impact immune function; a previous study demonstrated that immunotherapy treatment times taking place later in the day correlated with poorer outcomes in patients with melanoma. However, this finding has not been replicated, and other infusion timing schemas are unexplored. The objective of this retrospective, cohort study was to determine if the time of immunotherapy infusion affects outcomes. MATERIALS AND METHODS: Five hundred and sixteen participants age ≥18 years diagnosed with cutaneous, acral, mucosal, or unknown primary melanoma treated with >1 infusion of nivolumab, pembrolizumab, or combination ipilimumab/PD-1 inhibitors were included. Response rate, toxicity rate, overall survival (OS), and progression-free survival (PFS) were determined based on infusion timing. RESULTS: Patients with ≥1 late infusion (after 4 pm) among their first 4 infusions had slightly poorer objective response rate compared with only pre-4 pm infusions (39.7% vs 44.5%), but no significant associations with late infusions and PFS and OS (P = .23, .93, respectively). Multivariable analyses showed no statistically significant association with outcomes for patients with any post-4 pm infusion among the first 4; median infusion time was also not associated with outcomes. However, considering all infusion times, we found inferior PFS (median 10.6 vs 38.9 months, P < .0001), and numerically inferior OS (median 54.6 vs 81.2 months, P = .19) in patients with ≥20% late infusions. Multivariable models had similarly inferior response and PFS for patients with ≥20% late infusions, and later median infusion times were associated with inferior response, PFS, and OS. CONCLUSIONS: Late immunotherapy infusion times were associated with inferior outcomes when considering all infusions, but not when considering initial (first 4) infusions.

The timing of the mouse hind paw incision does not influence postsurgical pain.

Chronobiological approaches have emerged as tools to study pain and inflammation. Although time-of-day effects on the expression of pain after injury have been studied, it remains unaddressed whether the timing of the injury itself can alter subsequent pain behaviors. The aim of this study was to assess postsurgical pain behaviors in a mouse hind paw incision assay in a circadian-dependent manner. Incisions were made at one of four equally spaced time points over a 24-hour period, with evoked and spontaneous pain behaviors measured using the von Frey mechanical sensitivity test, Hargreaves' radiant heat paw-withdrawal test, and the Mouse Grimace Scale. Algesiometric testing was performed in C57BL/6 mice prior to and at multiple time points after incision injury, at the same time of day, until pain resolution. No statistically significant differences were observed between groups. This study adds to the literature on circadian rhythms and their influence on pain in the pursuit of more biologically informed pre- and postoperative care.

The "Hungry Judge" effect on prostate MRI reporting: Chronobiological trends from 35'004 radiologist interpretations.

AIM: To investigate the associations between the hour of the day and Prostate Imaging-Reporting and Data System (PI-RADS) scores assigned by radiologists in prostate MRI reports. MATERIALS AND METHODS: Retrospective single-center collection of prostate MRI reports over an 8-year period. Mean PI-RADS scores assigned between 0800 and 1800 h were examined with a regression model. RESULTS: A total of 35'004 prostate MRI interpretations by 26 radiologists were included. A significant association between the hour of day and mean PI-RADS score was identified (ß2 = 0.005, p < 0.001), with malignant scores more frequently assigned later in the day. CONCLUSION: These findings suggest chronobiological factors may contribute to variability in radiological assessments. Though the magnitude of the effect is small, this may potentially add variability and impact diagnostic accuracy.