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During and after childhood cancer treatment, impairments in physical fitness are observed, such as reduced muscle strength, fatigue, and changes in body functions. These aspects may result in limitations and restrictions in performance of daily activities. To analyze the relationship between upper and lower limb muscle strength, functional mobility, and performance in activities daily living in children, adolescents, and young adults with cancer, compared to their healthy peers. The cross-sectional observational study involves 45 participants, 15 in the cancer group and 30 in the control group. Personal, environmental, and health data were collected. Participants from both groups were evaluated for upper and lower limb muscle strength, functional mobility (timed up and go test-TUG and five times sit-to-Stand test-5xSTS), and performance in activities of daily living (Pediatric Evaluation Of Disability Inventory-Computer Adaptive Test-PEDI-CAT). The participants were 30 females and 15 males (13.67 ± 5.78 years: cancer group; 13.07 ± 5.11 years: control group). Acute lymphoblastic leukemia (n = 7), chronic myeloid leukemia (n = 2) and Hodgkin's lymphoma (n=2) were the main diagnoses in the cancer group. No significant differences were found in upper and lower limb muscle strength between groups (p > 0.05). However, significant differences were observed in functional mobility (TUG and 5xSTS) and performance (PEDI-CAT-mobility) in activities of daily living, with the cancer group showing worse performance compared to the control group (p ≤ 0.001). Conclusion: Children and adolescents with cancer showed lower functional mobility and performance in activities of daily living compared to the control group. These difficulties were not associated with muscle weakness or level of physical activity. Therefore, it is recommended that physiotherapeutic treatment and follow-up include activities focused on mobility and functional independence., Competing Interests: Declarations During the preparation of this work, AI tools were used to improve the readability and language of the manuscript, and subsequently, the authors revised and edited the content produced by the AI tools as necessary taking full responsibility for the ultimate content of the present manuscript. Ethical approval and consent to participate The study was approved by the Research Ethics Committee of Universidade Federal de Juiz de Fora under opinion no. 28699920.2.0000.5147, in accordance with the Declaration of Helsinki. All participants that agreed to participate signed the informed consent term. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Coronary microvascular dysfunction (CMD) has been implicated as a potential mechanism in the pathophysiology of different clinical presentations, including ischemia and no obstructive coronary artery disease (INOCA), myocardial infarction and nonobstructive coronary arteries (MINOCA), stress cardiomyopathy, heart failure, and myocarditis. There are limited data about the role of CMD in cancer therapy-related cardiovascular toxicities., Case Presentations: Four women with a diagnosis of active cancer receiving treatment who developed subsequent MINOCA or INOCA presented for cardiac catheterization. Upon coronary angiography showing no obstructive coronary arteries, coronary function testing was performed to evaluate for CMD., Methods: Coronary physiology was assessed measuring non-hyperemic (resting full-cycle ratio [RFR]) and hyperemic (fractional flow reserve [FFR]) indices using a physiologic pressure wire. The wire also measured coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and RFR using thermodilution technology. CMD was confirmed if the CFR was <2.5 and the IMR was >25., Results: Among 4 patients with diagnosis of active cancer presenting with chest pain, there was no evidence of obstructive coronary artery disease, leading to separate diagnoses of INOCA, MINOCA, stress cardiomyopathy, and myocarditis. We found CMD in 2 patients (1 with INOCA and 1 with immune checkpoint inhibitor-related myocarditis)., Conclusions: CMD may play a role in cardiovascular toxicities. Further coronary physiology studies are needed to understand the mechanisms of cancer therapy-related cardiovascular toxicity and CMD, as well as optimal preventive and treatment options., Competing Interests: Declaration of competing interest Brian C. Case – Speaker: Asahi Intecc USA, Zoll Medical. Hayder D. Hashim – Advisory Board, Speaker: Abbott Vascular, Boston Scientific, Philips IGT. Ron Waksman – Advisory Board: Abbott Vascular, Boston Scientific, Medtronic, Philips IGT, Pi-Cardia Ltd.; Consultant: Abbott Vascular, Append Medical, Biotronik, Boston Scientific, JC Medical, MedAlliance/Cordis, Medtronic, Philips IGT, Pi-Cardia Ltd., Swiss Interventional/SIS Medical AG, Transmural Systems Inc.; Institutional Grant Support: Biotronik, Medtronic, Philips IGT; Investor: Transmural Systems Inc. All other authors – None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Physical function is associated with cancer-related quality of life and survival. The correlation of patient-reported and objective measures of physical function has not been quantified previously in the cancer rehabilitation medicine setting., Objective: To correlate patient-reported physical function with objective measures of physical function. The secondary aim is to correlate fatigue and social participation levels with objective measures of physical function., Design: Retrospective., Setting: Tertiary university cancer center., Participants: A total of 226 cancer survivors referred to an outpatient cancer rehabilitation medicine clinic., Intervention: Not applicable., Main Outcome Measure: Correlation of Patient-Reported Outcomes Measurement Information System (PROMIS) Cancer Function Brief 3D Profile domains with objective physical function measured by the 30-second sit-to-stand and hand grip strength., Results: Pearson correlation analysis revealed a moderate correlation between patient-reported physical function and the 30-second sit-to-stand test (r = 0.57; p <.001), and a weak correlation of patient-reported physical function and handgrip strength (r = 0.27; p <.001). Multivariable regression modeling controlling for age, gender, and receipt of systemic therapy demonstrated a significant association between patient-reported physical function and the 30-second sit-to-stand test (estimated confidence interval 0.76 [0.60, 0.92], p < .01), in addition to patient-reported function and handgrip strength (estimated 0.22 [0.10, 0.34], p < .01). Multiple myeloma but no other cancer type was inversely associated with lower physical function., Conclusions: Patient-reported physical function correlated moderately with the 30-second sit-to-stand test, whereas hand grip strength demonstrated a weak correlation. The 30-second sit-to-stand test is a suitable substitute for patient-reported physical function. Further work evaluating how measures relate to each other across cancer populations is needed before recommending a standardized set of outcome measures., (© 2024 American Academy of Physical Medicine and Rehabilitation.)

Background: Physical inactivity is a global issue for cancer survivors. Wearable activity trackers are promising to address physical inactivity by providing real-time feedback on physical activity and offering opportunities for self-monitoring and goal setting. Meta-analysis has reported the effects of interventions that incorporate wearable activity trackers on improved physical inactivity and related health outcomes (eg, BMI, anxiety and depression, and self-rated health status). However, wearable activity trackers were often used as an adjunct to physical activity interventions, and the effectiveness of wearable activity trackers alone is unknown., Objective: This study aims to determine the association of wearable activity trackers with physical activity and health outcomes in patients with cancer., Methods: Data from 957 cancer survivors from the Health Information National Trends Survey-Surveillance, Epidemiology, and End Results (HINTS-SEER) were analyzed. The outcome variables examined were time spent in moderate to vigorous physical activity, weekly frequency of strength training, BMI, anxiety and depression levels, and self-assessed health status. The primary independent variable was whether cancer survivors had used wearable activity trackers within the past 12 months. Design-based linear regression for continuous outcome variables and ordinal logistic regression for ordinal outcome variables were conducted to determine the associations after controlling for sociodemographic, cancer-related, and health-related factors. All data analyses accounted for the complex survey design and sample weights., Results: Only 29% of cancer survivors reported wearable activity tracker use. Bivariate analyses showed that younger age (P<.001), higher education (P=.04), higher income (P<.001), and an employed status (P<.001) were significantly associated with wearable activity tracker use. Wearable activity tracker use was significantly associated with higher time spent in moderate to vigorous physical activity (adjusted =37.94, 95% CI 8.38-67.5; P=.01), more frequent strength training per week (adjusted odds ratio [OR] 1.50, 95% CI 1.09-2.06; P=.01), and better self-rated health status (adjusted OR 1.58, 95% CI 1.09-2.29; P=.01), but not with BMI or anxiety and depression., Conclusions: This study suggests that the uptake of wearable activity trackers is low and highlights the digital divide among patients with cancer. This study has confirmed the associations of wearable activity tracker use with physical activity and self-rated health, supporting using wearable activity trackers as a promising tool to facilitate physical activity promotion., (©Weijiao Zhou, Shaomei Shang, Youmin Cho. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 22.10.2024.)

The world of cancer science is moving toward a paradigm shift in making connections with neuroscience. After decades of research on genetic instability and mutations or on the tumor microenvironment, emerging evidence suggests that a malignant tumor is able to hijack and use the brain and its network of peripheral and central neurons as disrupters of homeostasis in the body. Whole-body homeostasis requires brain-body circuits to maintain survival and health via the processes of interoception, immunoception, and nociception. It is now likely that cancer disturbs physiological brain-body communication in making bidirectional brain tumor connections., (© 2024 Magnon; Published by Cold Spring Harbor Laboratory Press.)

Our approaches toward understanding cancer have evolved beyond cell-intrinsic and local microenvironmental changes within the tumor to encompass how the cancer interfaces with the entire host organism. The nervous system is uniquely situated at the interface between the brain and body, constantly receiving and sending signals back and forth to maintain homeostasis and respond to salient stimuli. It is becoming clear that various cancers disrupt this dialog between the brain and body via both neuronal and humoral routes, leading to aberrant brain activity and accelerated disease. In this outlook, I discuss this view of cancer as a homeostatic challenge, emphasize cutting-edge work, and provide outstanding questions that need to be answered to move the field forward., (© 2024 Borniger; Published by Cold Spring Harbor Laboratory Press.)

Recent work has highlighted the central role the brain-body axis plays in not only maintaining organismal homeostasis but also coordinating the body's response to immune and inflammatory insults. Here, we discuss how science is poised to address the many ways that our brain is directly involved with disease. In particular, we feel that combining cutting-edge tools in neuroscience with translationally relevant models of cancer will be critical to understanding how the brain and tumors communicate and modulate each other's behavior., (© 2024 Cross et al.; Published by Cold Spring Harbor Laboratory Press.)

Solid tumors that arise in the body interact with neurons, which influences cancer progression and treatment response. Here, we discuss key questions in the field, including defining the nature of interactions between tumors and neural circuits and defining how neural signals shape the tumor microenvironment. This information will allow us to optimally target neural signaling to improve outcomes for cancer patients., (© 2024 Sloan; Published by Cold Spring Harbor Laboratory Press.)

Lymphatic aging represented by cellular and functional changes, is involved in increased geriatric disorders, but the intersection between aging and lymphatic modulation is less clear. Lymphatic vessels play an essential role in maintaining tissue fluid homeostasis, regulating immune function, and promoting macromolecular transport. Lymphangiogenesis and lymphatic remodeling following cellular senescence and organ deterioration are crosslinked with the progression of some lymphatic-associated diseases, e.g., atherosclerosis, inflammation, lymphoedema, and cancer. Age-related detrimental tissue changes may occur in lymphatic vessels with diverse etiologies, and gradually shift towards chronic low-grade inflammation, so-called inflammaging, and lead to decreased immune response. The investigation of the relationship between advanced age and organ deterioration is becoming an area of rapidly increasing significance in lymphatic biology and medicine. Here we highlight the emerging importance of lymphangiogenesis and lymphatic remodeling in the regulation of aging-related pathological processes, which will help to find new avenues for effective intervention to promote healthy aging., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate the effects of prehabilitation on the perioperative functional capacity of patients awaiting oncological resections., Methods: A systematic review and meta-analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist and within the databases Cochrane Library, EBSCOhost, Google Scholar, MEDLINE PubMed, and Web of Science. The eligibility criteria were set to include peer-reviewed randomised control trials including only adult (≥ 18 years old) patients undergoing any type of prehabilitation (PREHAB) prior to any type of oncological resection. The studies had to feature at least one control group undergoing standard care (SC) and had to assess functional capacity by means of a 6-min walk distance (6MWD) or peak oxygen uptake (VO 2Peak ) at different stages pre- and post- operatively., Results: Twenty-seven randomised controlled trials involving 1994 patients were included. After processing the data, the number of patients was 1889. Studies featured different cancer specialties: lung (11), colorectal (5), urological (4), abdominal (3), esophagogastric (2), liver (1), and gastrointestinal (1). Overall, PREHAB enhanced both 6MWD (g = 0.273, 95% CI 0.174 to 0.371, Z = 5.406, p < 0.001) and VO 2Peak (g = 0.615, 95% CI 0.243 to 0.987, Z = 3.240, p = 0.001) compared with SC. The 6MWD subgroup analysis revealed a small mean effect size favouring both unimodal and multimodal PREHAB interventions., Conclusion: These findings support that prehabilitation, whether implemented as unimodal or multimodal format, elicits small preoperative improvements in functional capacity in patients awaiting oncological resections. PROSPERO registration number CRD42023428676., (© 2024. The Author(s).)

Purpose: To correlate the functional performance and impact of dysphagia on the quality of life of cancer patients in palliative care., Methods: This cross-sectional, quantitative study was conducted at the outpatient clinic and oncology ward of a university hospital. Inclusion criteria required patients to respond positively to the question: "Do you have difficulty or problems swallowing?". Patients were excluded if they had been diagnosed with head and neck cancer, were unable to answer questionnaires due to actively dying status, were in a state of drowsiness, experienced extreme pain and systemic instability, or if data collection instruments were incomplete. Two instruments were used in their Brazilian Portuguese versions: the Palliative Performance Scale (PPS) and the M. D. Anderson Dysphagia Inventory (MDADI). The variables were analyzed using descriptive and inferential statistics, with Pearson's correlation used at a 5% significance level., Results: The sample consisted of 39 participants, with an average age of 65.3 years, of whom 24 (61.5%) were women. The most frequent neoplasm sites were the pancreas and stomach. The results of the PPS indicated that the average patient had reduced ambulation and inability to work, but maintained independence in self-care, with a complete level of swallowing and consciousness. The MDADI showed an average degree of limitation. Outpatients exhibited a moderate correlation between the MDADI result and the level of functionality according to the PPS., Conclusion: Cancer patients at the palliative care outpatient clinic demonstrated a correlation between functional performance and the impact of dysphagia on quality of life.

Children/adolescents with cancer can develop adverse effects impacting gross motor function. There is a lack of gross motor function assessment tools that have been validated for this population. The aim of this multicenter cross-sectional study was to preliminary validate the 88-item Gross Motor Function Measure (GMFM-88) for use in children/adolescents with cancer, exploring internal consistency and floor/ceiling effect. Inclusion criteria regarded children/adolescents diagnosed with cancer on treatment or <1 year off therapy. The internal consistency was assessed using Cronbach's α, and the floor-ceiling effects were calculated through percentage. This study involved 217 participants with heterogeneous neoplasm conditions. Internal consistency was good, with a Cronbach's α of 0.989. Floor-ceiling effect analysis reveals that several items obtained a dichotomous scoring distribution in each of the five sub-scales of the GMFM-88. This can be explained by the heterogeneous clinical characteristics of the target population. The preliminary validation of GMFM-88 in a group of children/adolescents affected by cancer suggests that some items are not able to discriminate between different gross motor function levels, and therefore it does not represent an informative tool to measure gross motor function in children with cancer. Future research is needed to define which ones could be more useful for clinical practice.

Objective: This study examined whether high frequency heart-rate variability (HF-HRV) and HF-HRV reactivity to worry moderate response to cognitive behavioural therapy for insomnia (CBT-I) within both a standard and stepped-care framework among cancer patients with comorbid insomnia. Biomarkers such as HF-HRV may predict response to CBT-I, a finding which could potentially inform patient allocation to different treatment intensities within a stepped-care framework., Methods: 177 participants (86.3 % female; M age  = 55.3, SD = 10.4) were randomized to receive either stepped-care or standard CBT-I. 145 participants had their HRV assessed at pre-treatment during a rest and worry period. Insomnia symptoms were assessed using the Insomnia Severity Index (ISI) and daily sleep diary across five timepoints from pre-treatment to a 12-month post-treatment follow-up., Results: Resting HF-HRV was significantly associated with pre-treatment sleep efficiency and sleep onset latency but not ISI score. However, resting HF-HRV did not predict overall changes in insomnia across treatment and follow-up. Similarly, resting HF-HRV did not differentially predict changes in sleep diary parameters across standard or stepped-care groups. HRV reactivity was not related to any of the assessed outcome measures in both cross-sectional and longitudinal analyses., Conclusion: Although resting HF-HRV was related to initial daily sleep parameters, HF-HRV measures did not significantly predict longitudinal responses to CBT-I. These findings suggest that HF-HRV does not predict treatment responsiveness to CBT-I interventions of different intensity in cancer patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Josee Savard reports financial support was provided by Astellas. Thien Thanh Dang-Vu reports financial support was provided by Eisai,Idorsia,Jazz Pharmaceuticals, andPaladin Labs. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Progressive functional decline is a key element of cancer-associated cachexia. Major barriers to translating preclinical therapies into the clinic include lack of cancer models that accurately mimic functional decline, which develops over time, and use of nonspecific measures, like grip strength, as surrogates for physical function. In this study, we aimed to extend the survival and longevity of a cancer model, to investigate cachexia-related function at the basic science level. Survival extension studies were performed by testing multiple cell lines, dilutions, and vehicle-types in orthotopic implantation of K-ras LSL.G12D/+ ; Trp53 R172H/+ ; Pdx-1-Cre (KPC)-derived cells. One hundred twenty-eight animals in this new model were assessed for cachexia syndrome phenotype using a battery of anatomical, biochemical, and behavioral techniques. We extended the survival of the KPC orthotopic model to 8-9 wk postimplantation using a relatively low 100-cell dose of DT10022 KPC cells ( P < 0.001). In this low-dose orthotopic (LO) model, progressive muscle wasting was detected in parallel to systemic inflammation; skeletal muscle atrophy at the fiber level was detected as early as 3 wk postimplantation compared with controls ( P < 0.001). Gait speed in LO animals declined as early as 2 wk postimplantation, whereas grip strength change was a late event. Principal component and regression analyses revealed distinct cachectic and noncachectic animal populations, which we leveraged to show that the gait speed decline was specific to cachexia ( P < 0.01), whereas grip strength decline was not ( P = 0.19). Gait speed represents an accurate surrogate for cachexia-related physical function as opposed to grip strength. NEW & NOTEWORTHY Previous studies of cancer-induced cachexia have been confounded by the relatively rapid death of animal subjects. Using a lower dose of cancer cells in combination with a battery of behavioral, structural, histological, and biochemical techniques, we show that gait speed is actually the best indicator of functional decline due to cachexia. Future studies are required to define the underlying physiological basis of these findings.

Allostatic load (AL) has been shown to impact cancer outcomes. At present, no gold standard exists surrounding AL computation. As such, a systematic review of the literature was performed to identify studies that retrospectively calculated AL in patients with cancer. The following variables were collected for each study: AL calculation method, including the biomarkers used and their cutoff values, number of biosystems represented, definition of high AL, and the use of proxy biomarkers. Thirteen articles were included for full-text review. The number of biomarkers used in the calculation of AL varied considerably, ranging from 6 to 16. Considerable variability was also observed in terms of utilized biomarkers and biosystem representation. This lack of standardization complicates retrospective AL calculation among patients with cancer. Nonetheless, determining AL in patients with cancer presents an important step in the optimization of patient care and outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The Six Minute Walk Test (6MWT) is a widely used measure of functional capacity in (p)rehabilitation of cancer patients, but it is time-consuming and requires specific space conditions. In this study we explore the association between the 6MWT with other measurements of physical functioning and their predictive value in classifying patients according to their estimated functional capacity., Design: This prospective study included cancer patients referred to a prehabilitation programme prior to major surgery. For each patient, data on different measurements of physical functioning including the Duke Activity Status Index (DASI), the handgrip strength, the 30" Sit-to-Stand Test and self-reported physical activity levels were collected. Bivariate associations were performed to determine the association between the 6MWT and other variables. Multivariate analyses were performed to identify potential predictive factors of 6MWT in this population. A subsequent algorithm was developed to classify patients based on their functional capacity (good performance - 6MWT>400 m or poor performance 6MWT<400 m) RESULTS: Between mid-2018 to mid 2022, 692 patients were assessed of whom the 6MWT was performed in 524 (75.7 %) (mean age 72.5 ± 11.8 years; 57.1 % men). Moderate-to-strong correlations were found between 6MWT and 30" Sit-To-Stand Test (r = 0.54, p < 0.001), DASI (r = 0.68; p < 0.001) and handgrip strength (r = 0.5; p < 0.001). Multivariate analyses confirmed that a combination of six variables were able to classify 80 % of patients in good (>400 m) or poor (<400 m) performance in the 6MWT., Conclusion: The 6MWT was moderately associated with several variables of physical functioning, a combination of which can be used to predict performance in the 6MWT., Competing Interests: Declaration of competing interest The authors of this manuscript have no interests to declare related to this investigation., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Tumour lysis syndrome (TLS) represents a critical oncological emergency characterized by extensive tumour cell breakdown, leading to the swift release of intracellular contents into the systemic circulation, outpacing homeostatic mechanisms. This process results in hyperuricaemia (a by-product of intracellular DNA release), hyperkalaemia, hyperphosphataemia, hypocalcaemia and the accumulation of xanthine. These electrolyte and metabolic imbalances pose a significant risk of acute kidney injury, cardiac arrhythmias, seizures, multiorgan failure and, rarely, death. While TLS can occur spontaneously, it usually arises shortly after the initiation of effective treatment, particularly in patients with a large cancer cell mass (defined as ≥500 g or ≥300 g/m 2 of body surface area in children). To prevent TLS, close monitoring and hydration to improve renal perfusion and urine output and to minimize uric acid or calcium phosphate precipitation in renal tubules are essential. Intervention is based on the risk of a patient of having TLS and can include rasburicase and allopurinol. Xanthine, typically enzymatically converted to uric acid, can accumulate when xanthine oxidases, such as allopurinol, are administered during TLS management. Whether measurement of xanthine is clinically useful to optimize the use of allopurinol or rasburicase remains to be determined., (© 2024. Springer Nature Limited.)

Tumor is a complex and aggressive type of disease that poses significant health challenges. Understanding the cellular mechanisms underlying its progression is crucial for developing effective treatments. In this study, we develop a novel mathematical framework to investigate the role of cellular plasticity and heterogeneity in tumor progression. By leveraging temporal single-cell data, we propose a reaction-convection-diffusion model that effectively captures the spatiotemporal dynamics of tumor cells and macrophages within the tumor microenvironment. Through theoretical analysis, we obtain the estimate of the pulse wave speed and analyze the stability of the homogeneous steady state solutions. Notably, we employe the AddModuleScore function to quantify cellular plasticity. One of the highlights of our approach is the introduction of pulse wave speed as a quantitative measure to precisely gauge the rate of cell phenotype transitions, as well as the novel implementation of the high-plasticity cell state/low-plasticity cell state ratio as an indicator of tumor malignancy. Furthermore, the bifurcation analysis reveals the complex dynamics of tumor cell populations. Our extensive analysis demonstrates that an increased rate of phenotype transition is associated with heightened malignancy, attributable to the tumor's ability to explore a wider phenotypic space. The study also investigates how the proliferation rate and the death rate of tumor cells, phenotypic convection velocity, and the midpoint of the phenotype transition stage affect the speed of tumor cell phenotype transitions and the progression to adenocarcinoma. These insights and quantitative measures can help guide the development of targeted therapeutic strategies to regulate cellular plasticity and control tumor progression effectively., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sarcopenic dysphagia is the term for swallowing difficulty associated with loss of mass, strength, and physical performance, which leads to increased pharyngeal residues. Unlike sarcopenia, presarcopenia is characterized by low muscle mass without decreased muscle strength or physical performance and can develop into dysphagia due to low skeletal muscle mass. This retrospective study investigated the impact of presarcopenic dysphagia (PSD) on 1-year mortality in patients with cancer and dysphagia who underwent a videofluoroscopic swallowing study (VFSS). An operational definition of PSD based on presarcopenia and pharyngeal residues was adopted. The psoas muscle mass index (cm 2 /height [m 2 ]), calculated by the psoas muscle area at the third lumber vertebra via abdominal computed tomography (CT) and related to height, was used to assess presarcopenia with cutoff values of 4.62 for men and 2.66 for women. Pharyngeal residues were assessed using a VFSS to evaluate dysphagia. Patients' medical charts were analyzed to investigate 1-year mortality after a VFSS. Out of 111 consecutive patients with cancer, 53 (47.7%) were defined as having PSD. In a forward-stepwise Cox proportional regression analysis, PSD (HR 2.599; 95% CI 1.158-5.834; p = 0.021) was significantly associated with 1-year mortality after a VFSS, even after adjusting for the factors of operation, Functional Oral Intake Scale (FOIS) scores at discharge, and modified Barthel Index (BI) scores at discharge. PSD, defined as CT-based presarcopenia and pharyngeal residues observed during a VFSS, is associated with increased 1-year mortality in patients with cancer and dysphagia., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Accurate assessment of GFR is crucial to guiding drug eligibility, dosing of systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. Up to 32% of patients with cancer have baseline CKD, and both malignancy and treatment may cause kidney injury and subsequent CKD. To date, there has been lack of guidance to standardize approaches to GFR estimation in the cancer population. In this two-part statement from the American Society of Onco-Nephrology, we present key messages for estimation of GFR in patients with cancer, including the choice of GFR estimating equation, use of race and body surface area adjustment, and anticancer drug dose-adjustment in the setting of CKD. These key messages are based on a systematic review of studies assessing GFR estimating equations using serum creatinine and cystatin C in patients with cancer, against a measured GFR comparator. The preponderance of current data involving validated GFR estimating equations involves the CKD Epidemiology Collaboration (CKD-EPI) equations, with 2508 patients in whom CKD-EPI using serum creatinine and cystatin C was assessed (eight studies) and 15,349 in whom CKD-EPI with serum creatinine was assessed (22 studies). The former may have improved performance metrics and be less susceptible to shortfalls of eGFR using serum creatinine alone. Since included studies were moderate quality or lower, the American Society of Onco-Nephrology Position Committee rated the certainty of evidence as low. Additional studies are needed to assess the accuracy of other validated eGFR equations in patients with cancer. Given the importance of accurate and timely eGFR assessment, we advocate for the use of validated GFR estimating equations incorporating both serum creatinine and cystatin C in patients with cancer. Measurement of GFR via exogenous filtration markers should be considered in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials., (Copyright © 2024 by the American Society of Nephrology.)

Heat shock protein 47 (HSP47) is a chaperone protein responsible for regulating collagen maturation and transport, directly impacting collagen synthesis levels. Aberrant HSP47 expression or malfunction has been associated with collagen-related disorders, most notably fibrosis. Recent reports have uncovered new functions of HSP47 in various cellular processes. Hsp47 dysregulation in these alternative roles has been linked to various diseases, such as cancer, autoimmune and neurodegenerative disorders, thereby highlighting its potential as both a diagnostic biomarker and a therapeutic target. In this review, we discuss the pathophysiological roles of HSP47 in human diseases, its potential as a diagnostic tool, clinical screening techniques and its role as a target for therapeutic interventions., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background & Aims: Although it is widely recognized that muscle quality significantly influences adverse outcomes in patients with cancer, the precise definition of muscle quality remains elusive. The muscle quality index (MQI), also known as muscle-specific strength, is a relatively recent functional concept of muscle quality. It is obtained through the ratio of muscle strength to muscle mass, but its predictive value in patients with cancer remains unknown. In this study, we explored the prognostic significance of MQI in patients with cancer. Furthermore, we introduce and assess the prognostic potential of a novel muscle quality metric: the strength-to-muscle-radiodensity index (SMRi)., Methods: A secondary analysis was conducted on a prospective cohort study. CT scans were opportunistically used to assess body composition parameters, including skeletal muscle mass (SM in cm 2 ) and muscle radiodensity (SMD in HU) at the third lumbar vertebra (L3). Handgrip strength (HGS) was measured. MQI CT was calculated using the ratio of HGS to SM (cm 2 ). SMRi was calculated as the ratio of HGS to SMD (HU). For analysis purposes, low MQI CT and SMRi were defined using two approaches: statistical cutoffs associated with survival, and median-based distribution data., Results: A total of 250 patients were included (52.8% females, 52% adults, 20-90 years). Gastrointestinal tumors and stage III-IV were the most frequent diagnosis and stages. SMRi and MQI CT were strongly positively correlated (ρ = 0.71 P < 0.001). Individual components of MQI CT and SMRi were also positively correlated. Patients with both low MQI CT and SMRi had shorter survival (log-rank P = 0.023 and P = 0.003, respectively). When applying median distribution cutoffs, SMRi emerged as the most accurate predictor of mortality (HR adjusted 3.18, 95% CI 1.50 to 6.75, C-index: 0.71), when compared to MQI CT (HR adjusted 1.49, 95% CI 0.77 to 2.87, C-index: 0.68)., Conclusion: This study introduces the concept and potential prognostic significance of the SMRi. The physiological and clinical implications of this new index warrant further investigation across a spectrum of diseases, including cancer., Competing Interests: Conflict of interest APTF reports receiving grant for research from Prodiet Medical Nutrition. CMP has received honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestlé Health Science, Pfizer, and AMRA Medical. MCG has received honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, and Nestlé Health Science Brazil., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: Our study aims to determine whether myostatin (MSTN) is associated with muscle mass and strength in individuals with cancer or obesity, as well as with cancer cachexia (CC) or sarcopenic obesity (SO)., Methods: The ACTICA study included individuals with CC (n = 70) or without CC (NC, n = 73). The MYDIASECRET study included individuals with obesity evaluated before (T0) and 3 months (T3) after bariatric surgery (n = 62). Body composition was assessed using bioelectrical impedance analysis (BIA). Skeletal muscle mass (SMM) and appendicular SMM (ASMM) were calculated from Janssen's and Sergi's equations, respectively, and expressed as indexes (SMMI and ASMMI). Handgrip strength (HGS) was assessed using a Jamar hand-held dynamometer. MSTN plasma levels were measured using ELISA. Spearman's coefficient was used to correlate MSTN with muscle mass and strength. Receiver operating characteristic (ROC) curve analysis was performed to identify an optimal MSTN cutoff level for the prediction of CC or SO., Results: In the ACTICA study, muscle mass and strength were lower in CC individuals than in NC individuals (SMMI: 8.0 kg/m 2 vs 9.0 kg/m 2 , p = 0.004; ASMMI: 6.2 kg/m 2 vs 7.2 kg/m 2 , p < 0.001; HGS: 28 kg vs 38 kg, p < 0.001). MSTN was also lower in CC individuals than in NC individuals (1434 pg/mL vs 2149 pg/mL, p < 0.001). Muscle mass and strength were positively correlated with MSTN (SMMI: R = 0.500, p < 0.001; ASMMI: R = 0.479, p < 0.001; HGS: R = 0.495, p < 0.001). ROC curve analysis showed a MSTN cutoff level of 1548 pg/mL (AUC 0.684, sensitivity 57%, specificity 75%, p < 0.001) for the prediction of CC. In the MYDIASECRET study, muscle mass and strength were reduced at T3 (SMMI: -8%, p < 0.001; ASMMI: -12%, p < 0.001; HGS: -6%, p = 0.005). MSTN was also reduced at T3 (1773 pg/mL vs 2582 pg/mL, p < 0.001). Muscle mass and strength were positively correlated with MSTN at T0 and T3 (SMMI-T0: R = 0.388, p = 0.002; SMMI-T3: R = 0.435, p < 0.001; HGS-T0: R = 0.337, p = 0.007; HGS-T3: R = 0.313, p = 0.013). ROC curve analysis showed a MSTN cutoff level of 4225 pg/mL (AUC 0.835, sensitivity 98%, specificity 100%, p = 0.014) for the prediction of SO at T3., Conclusions: MSTN is positively correlated with muscle mass and strength in individuals with cancer or obesity, suggesting its potential use as a biomarker of muscle mass and strength. The ROC curve analysis suggests the potential use of MSTN as a screening tool for CC and SO., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: [ 51 Cr]CrEDTA is used to measure the Glomerular Filtration Rate (GFR) in different clinical conditions. However, there is no consensus on the ideal number of blood samples to be taken and at what time points to measure its clearance. This study aimed to compare Slope Intercept (SI) and Single-Sample (SS) methods for measuring GFR in patients with solid tumors, stratified by age, GFR, and Body Mass Index (BMI)., Methods: 1,174 patients with cancer were enrolled in this prospective study. GFR was calculated by the SI method using blood samples drawn 2-, 4-, and 6-hours after [ 51 Cr]CrEDTA injection (246-GFR). GFR was also measured using the SI method with samples at 2 and 4 hours (24-GFR) and at 4 and 6 hours (46-GFR), and SS methods according to Groth (4Gr-GFR) and Fleming (4Fl-GFR). Statistical analysis was performed to assess the accuracy, precision, and bias of the methods., Results: Mean 246-GFR was 79.2 ± 21.9 mL/min/1.73 m 2 . ANOVA indicated a significant difference between 4Gr-GFR and the reference 246-GFR. Bias was lower than 5 mL/min/1.73 m 2 for all methods, except for SS methods in subgroups BMI > 40 kg/m 2 ; GFR > 105 or < 45. Precision was adequate and accuracy of 30 % was above 98% for all methods, except for SS methods in subgroup GFR < 45., Conclusion: 46-GFR and 246-GFR have high agreement and may be used to evaluate kidney function in patients with solid tumors. Single-sample methods can be adopted in specific situations, for non-obese patients with expected normal GFR., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier España, S.L.U.)

We discuss the mathematical modelling of two of the main mechanisms that pushed forward the emergence of multicellularity: phenotype divergence in cell differentiation and between-cell cooperation. In line with the atavistic theory of cancer, this disease being specific of multicellular animals, we set special emphasis on how both mechanisms appear to be reversed, however not totally impaired, rather hijacked, in tumour cell populations. Two settings are considered: the completely innovating, tinkering, situation of the emergence of multicellularity in the evolution of species, which we assume to be constrained by external pressure on the cell populations, and the completely planned-in the body plan-situation of the physiological construction of a developing multicellular animal from the zygote, or of bet hedging in tumours, assumed to be of clonal formation, although the body plan is largely-but not completely-lost in its constituting cells. We show how cancer impacts these two settings and we sketch mathematical models for them. We present here our contribution to the question at stake with a background from biology, from mathematics and from philosophy of science., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.)

Objective . The distribution of hypoxia within tissues plays a critical role in tumor diagnosis and prognosis. Recognizing the significance of tumor oxygenation and hypoxia gradients, we introduce mathematical frameworks grounded in mechanistic modeling approaches for their quantitative assessment within a tumor microenvironment. By utilizing known blood vasculature, we aim to predict hypoxia levels across different tumor types. Approach . Our approach offers a computational method to measure and predict hypoxia using known blood vasculature. By formulating a reaction-diffusion model for oxygen distribution, we derive the corresponding hypoxia profile. Main results . The framework successfully replicates observed inter- and intra-tumor heterogeneity in experimentally obtained hypoxia profiles across various tumor types (breast, ovarian, pancreatic). Additionally, we propose a data-driven method to deduce partial differential equation models with spatially dependent parameters, which allows us to comprehend the variability of hypoxia profiles within tissues. The versatility of our framework lies in capturing diverse and dynamic behaviors of tumor oxygenation, as well as categorizing states of vascularization based on the dynamics of oxygen molecules, as identified by the model parameters. Significance . The proposed data-informed mechanistic method quantitatively assesses hypoxia in the tumor microenvironment by integrating diverse histopathological data and making predictions across different types of data. The framework provides valuable insights from both modeling and biological perspectives, advancing our comprehension of spatio-temporal dynamics of tumor oxygenation., (Creative Commons Attribution license.)

Background: Creatinine-based estimated glomerular filtration rate (eGFR CRE ) may overestimate kidney function in patients with sarcopenia. While cystatin C-based eGFR (eGFR CYS ) is less affected by muscle mass, it may underestimate kidney function in patients with obesity. We sought to evaluate the relationship between body composition defined by computed tomography (CT) scans and discordance between creatinine, eGFR CRE and eGFR CYS in adult patients with cancer., Methods: This study is a cross-sectional study of consecutive adults with cancer with an abdominal CT scan performed within 90 days of simultaneous eGFR CRE and eGFR CYS measurements between May 2010 and January 2022. Muscle and adipose tissue cross-sectional areas were measured at the level of the third lumbar vertebral body using a validated deep-learning pipeline. CT-defined sarcopenia was defined using independent sex-specific cut-offs for skeletal muscle index (<39 cm 2 /m 2 for women and <55 cm 2 /m 2 for men). High adiposity was defined as the highest sex-specific quartile of the total (visceral plus subcutaneous) adiposity index in the cohort. The primary outcome was eGFR discordance, defined by eGFR CYS  > 30% lower than eGFR CRE ; the secondary outcome was eGFR CYS  > 50% lower than eGFR CRE . The odds of eGFR discordance were estimated using multivariable logistic regression modelling. Unadjusted spline regression was used to evaluate the relationship between skeletal muscle index and the difference between eGFR CYS and eGFR CRE ., Results: Of the 545 included patients (mean age 63 ± 14 years, 300 [55%] females, 440 [80.7%] non-Hispanic white), 320 (58.7%) met the criteria for CT-defined sarcopenia, and 136 (25%) had high adiposity. A total of 259 patients (48%) had >30% eGFR discordance, and 122 (22.4%) had >50% eGFR discordance. After adjustment for potential confounders, CT-defined sarcopenia and high adiposity were both associated with >30% eGFR discordance (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.12-3.24; aOR 2.01, 95% CI 1.15-3.52, respectively) and >50% eGFR discordance (aOR 2.34, 95% CI 1.21-4.51; aOR 2.23, 95% CI 1.19-4.17, respectively). A spline model demonstrated that as skeletal muscle index decreases, the predicted difference between eGFR CRE and eGFR CYS widens considerably., Conclusions: CT-defined sarcopenia and high adiposity are both independently associated with large eGFR discordance. Incorporating valuable information from body composition analysis derived from CT scans performed as a part of routine cancer care can impact the interpretation of GFR estimates., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Variability in biological parameters may be associated with adverse outcomes. The aim of the study was to determine whether variability in body mass index (BMI) and blood pressure is associated with all-cause, cardiovascular mortality and cancer mortality or with renal disease progression in subjects with type 2 diabetes., Methods: The diabetes database was accessed, and all the information on patient visits (consultations) carried out in the study period (1 January 2008-31 December 2019) was extracted and linked to the laboratory database and the mortality register., Results: The total number of patients included in the study population was 26,261, of whom 54.4% were male. Median (interquartile range, IQR) age was 60.2 (51.8-68.3) years. The coefficient of variability of BMI was independently associated with increased all-cause and cardiovascular, but not cancer, mortality. Glycated haemoglobin (HbA 1c ) was associated with increased all-cause, cardiovascular, and cancer mortality as well as with renal progression. Variability in systolic blood pressure, diastolic blood pressure, and pulse pressure was associated with increased all-cause and cardiovascular mortality in bivariate, but not in multivariate, analyses., Conclusions: Variability in BMI was associated with increased all-cause and cardiovascular, but not cancer, mortality in a large real-world contemporary population. Our results also confirm the association of HbA 1c with increased all-cause, cardiovascular, and cancer mortality as well as with renal progression., (© 2024. The Author(s).)

The elevated risk of cardiovascular disease (CVD) in cancer patients and survivors is likely the result of normal age-related pathologies coupled with the direct and indirect effects of cancer therapy that extend across multiple systems. The purpose of this study was to investigate the impact of cardiac rehabilitation (CR) on CVD patients with a history of cancer.In this study, patients who had participated in the outpatient CR program were enrolled and were divided into 2 groups (cancer survivor group and no-cancer group) based on their history of cancer. The cardiopulmonary exercise test (CPET) was performed at the beginning (baseline) and at the end of the CR program (follow-up). The results of CPET at baseline and those at follow-up were analyzed retrospectively.A total of 105 patients were analyzed in this study. The cancer survivor group had 25 patients, and the non-cancer group 80. At baseline, peak oxygen uptake (peak VO 2 ) (14.7 [11.9 to 17.6] mL/kg/minute versus 11.3 [9.7 to 14.7] mL/kg/minute; P = 0.003) was significantly lower in cancer survivors. The percent changes in peak VO 2 between baseline and follow-up were not significantly different between the 2 groups (7.9 % [-11.5 to 24.5] versus 9.4 % [-7.5 to 27.3] P = 0.520).The percent changes in peak VO 2 of CR participants were not significantly different despite their cancer history.

Monitoring vital signs is a key part of standard medical care for cancer patients. However, the traditional methods have instability especially when big fluctuations of signals happen, while the deep-learning-based methods lack pertinence to the sensors. A dual-path micro-bend optical fiber sensor and a targeted model based on the Divided-Frequency-CNN (DFC) are developed in this paper to measure the heart rate (HR) and respiratory rate (RR). For each path, features of frequency division based on the mechanism of signal periodicity cooperate with the operation of stable phase extraction to reduce the interference of body movements for monitoring. Then, the DFC model is designed to learn the inner information from the features robustly. Lastly, a weighted strategy is used to estimate the HR and RR via dual paths to increase the anti-interference for errors from one source. The experiments were carried out on the actual clinical data of cancer patients by a hospital. The results show that the proposed method has good performance in error (3.51 (4.51 %) and 2.53 (3.28 %) beats per minute (bpm) for cancer patients with pain and without pain respectively), relevance, and consistency with the values from hospital equipment. Besides, the proposed method significantly improved the ability in the report time interval (30 to 9 min), and mean / confidential interval (3.60/[-22.61,29.81] to -0.64 / [-9.21,7.92] for patients with pain and 1.87 / [-5.49,9.23] to -0.16 / [-6.21,5.89] for patients without pain) compared with our previous work.

The purpose of this study is to investigate the association between handgrip strength (HGS) and health-related quality of life (HRQoL), demonstrating HGS as an effective indicator for evaluating HRQoL of patients with cancer. Analyzing 1657 Korean adult cancer patients (644 males, 1013 females) aged ≥ 20 years from the Korea National Health and Nutrition Examination Survey (2014-2019), HGS was standardized based on body mass index and categorized by sex. HRQoL was assessed using the Euro Quality of Life-5-Dimension 3-Level version (EQ-5D-3L) Index. Lower relative HGS was associated with decreased HRQoL in female patients, while no significant association was found in male patients. The lowest quartile of relative HGS exhibited a 2.5-fold decrease in HRQoL compared to the highest quartile (OR 2.50, 95% CI 1.59-3.95, p < 0.001). Both male and female patients with cancer were affected by age, subjective health perception, and stress recognition regarding HRQoL. This study suggests that HGS may be associated with the HRQoL of female patients with cancer, emphasizing that the HGS measurement can be effectively utilized as a pivotal tool for evaluating HRQoL in female patients with cancer., (© 2024. The Author(s).)

Mechanical force exerted on cancer cells by their microenvironment have been reported to drive cells toward invasive phenotypes by altering cells' motility, proliferation, and apoptosis. These mechanical forces include compressive, tensile, hydrostatic, and shear forces. The importance of forces is then hypothesized to be an alteration of cancer cells' and their microenvironment's biophysical properties as the indicator of a tumor's malignancy state. Our objective is to investigate and quantify the correlation between a tumor's malignancy state and forces experienced by the cancer cells and components of the microenvironment. In this study, we have developed a multicomponent, three-dimensional model of tumor tissue consisting of a cancer cell surrounded by fibroblasts and extracellular matrix (ECM). Our results on three different organs including breast, kidney, and pancreas show that: A) the stresses within tumor tissue are impacted by the organ specific ECM's biophysical properties, B) more invasive cancer cells experience higher stresses, C) in pancreas which has a softer ECM (Young modulus of 1.0 kPa) and stiffer cancer cells (Young modulus of 2.4 kPa and 1.7 kPa) than breast and kidney, cancer cells experienced significantly higher stresses, D) cancer cells in contact with ECM experienced higher stresses compared to cells surrounded by fibroblasts but the area of tumor stroma experiencing high stresses has a maximum length of 40 μm when the cancer cell is surrounded by fibroblasts and 12 μm for when the cancer cell is in vicinity of ECM. This study serves as an important first step in understanding of how the stresses experienced by cancer cells, fibroblasts, and ECM are associated with malignancy states of cancer cells in different organs. The quantification of forces exerted on cancer cells by different organ-specific ECM and at different stages of malignancy will help, first to develop theranostic strategies, second to predict accurately which tumors will become highly malignant, and third to establish accurate criteria controlling the progression of cancer cells malignancy. Furthermore, our in silico model of tumor tissue can yield critical, useful information for guiding ex vivo or in vitro experiments, narrowing down variables to be investigated, understanding what factors could be impacting cancer treatments or even biomarkers to be looking for., Competing Interests: The authors declares that they have no financial, professional, or personal conflict of interest., (© 2024 The Authors.)

Background: Disrupted circadian rhythm commonly reported in cancer survivors is closely associated with cancer related fatigue, sleep disturbances and compromised quality of life. As more cancer survivors request non-pharmacological treatment strategies for the management of their chronic sleep-related symptoms, there is a need for meta-analyses of various interventions such as exercise on sleep and circadian rhythm disturbances., Methods: A search for RCT's was conducted in April 2020 and updated in July 2023 using relevant keywords for cancer, sleep, circadian rhythm and exercise interventions on PubMed, Scopus, Web of Science, PEDro and CINAHL., Results: Thirty-six studies were included for qualitative analysis and 26, for meta-analysis. Thirty-five studies analyzed sleep outcomes, while five analyzed circadian rhythm. RCT's studying the effect of aerobic exercise, resistance exercise, combined aerobic and resistance exercise, physical activity, yoga, or tai chi were included. Meta-analysis results showed significant exercise-related improvements on sleep quality assessed by Pittsburgh Sleep Quality index (PSQI) (SMD = -0.50 [-0.87, -0.13], p  = 0.008), wake after sleep onset (WASO) (SMD = -0.29 [-0.53, -0.05], p  = 0.02) and circadian rhythm, assessed by salivary cortisol levels (MD = -0.09 (95% CI [-0.13 to -0.06]) mg/dL, p  < 0.001). Results of the meta-analysis indicated that exercise had no significant effect on sleep efficiency, sleep onset latency, total sleep time and circadian rhythm assessed by accelerometry values., Conclusion: While some sleep and circadian rhythm outcomes (PSQI, WASO and salivary cortisol) exhibited significant improvements, it is still somewhat unclear what exercise prescriptions would optimize different sleep and circadian rhythm outcomes across a variety of groups of cancer survivors., Implication: As exercise does not exacerbate cancer-related circadian rhythm and sleep disturbances, and may actually produce some significant benefits, this meta-analysis provides further evidence for cancer survivors to perform regular exercise., Competing Interests: Justin Keogh is an Academic Editor for PeerJ., (©2024 Gururaj et al.)

Advancements in high-throughput technology offer researchers an extensive range of multi-omics data that provide deep insights into the complex landscape of cancer biology. However, traditional statistical models and databases are inadequate to interpret these high-dimensional data within a multi-omics framework. To address this limitation, we introduce DriverDBv4, an updated iteration of the DriverDB cancer driver gene database (http://driverdb.bioinfomics.org/). This updated version offers several significant enhancements: (i) an increase in the number of cohorts from 33 to 70, encompassing approximately 24 000 samples; (ii) inclusion of proteomics data, augmenting the existing types of omics data and thus expanding the analytical scope; (iii) implementation of multiple multi-omics algorithms for identification of cancer drivers; (iv) new visualization features designed to succinctly summarize high-context data and redesigned existing sections to accommodate the increased volume of datasets and (v) two new functions in Customized Analysis, specifically designed for multi-omics driver identification and subgroup expression analysis. DriverDBv4 facilitates comprehensive interpretation of multi-omics data across diverse cancer types, thereby enriching the understanding of cancer heterogeneity and aiding in the development of personalized clinical approaches. The database is designed to foster a more nuanced understanding of the multi-faceted nature of cancer., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Calreticulin (CRT) was originally identified as a key calcium-binding protein of the endoplasmic reticulum. Subsequently, CRT was shown to possess multiple intracellular functions, including roles in calcium homeostasis and protein folding. Recently, several extracellular functions have been identified for CRT, including roles in cancer cell invasion and phagocytosis of apoptotic and cancer cells by macrophages. In the current report, we uncover a novel function for extracellular CRT and report that CRT functions as a plasminogen-binding receptor that regulates the conversion of plasminogen to plasmin. We show that human recombinant or bovine tissue-derived CRT dramatically stimulated the conversion of plasminogen to plasmin by tissue plasminogen activator or urokinase-type plasminogen activator. Surface plasmon resonance analysis revealed that CRT-bound plasminogen (K D  = 1.8 μM) with moderate affinity. Plasminogen binding and activation by CRT were inhibited by ε-aminocaproic acid, suggesting that an internal lysine residue of CRT interacts with plasminogen. We subsequently show that clinically relevant CRT variants (lacking four or eight lysines in carboxyl-terminal region) exhibited decreased plasminogen activation. Furthermore, CRT-deficient fibroblasts generated 90% less plasmin and CRT-depleted MDA MB 231 cells also demonstrated a significant reduction in plasmin generation. Moreover, treatment of fibroblasts with mitoxantrone dramatically stimulated plasmin generation by WT but not CRT-deficient fibroblasts. Our results suggest that CRT is an important cellular plasminogen regulatory protein. Given that CRT can empower cells with plasmin proteolytic activity, this discovery may provide new mechanistic insight into the established role of CRT in cancer., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Homozygous 5'-methylthioadenosine phosphorylase (MTAP) deletions occur in approximately 15% of human cancers. Co-deletion of MTAP and methionine adenosyltransferase 2 alpha (MAT2a) induces a synthetic lethal phenotype involving protein arginine methyltransferase 5 (PRMT5) inhibition. MAT2a inhibitors are now in clinical trials for genotypic MTAP -/- cancers, however the MTAP -/- genotype represents fewer than 2% of human colorectal cancers (CRCs), limiting the utility of MAT2a inhibitors in these and other MTAP +/+ cancers. Methylthio-DADMe-immucillin-A (MTDIA) is a picomolar transition state analog inhibitor of MTAP that renders cells enzymatically MTAP-deficient to induce the MTAP -/- phenotype. Here, we demonstrate that MTDIA and MAT2a inhibitor AG-270 combination therapy mimics synthetic lethality in MTAP +/+ CRC cell lines with similar effects in mouse xenografts and without adverse histology on normal tissues. Combination treatment is synergistic with a 10 4 -fold increase in drug potency for inhibition of CRC cell growth in culture. Combined MTDIA and AG-270 decreases S-adenosyl-L-methionine and increases 5'-methylthioadenosine in cells. The increased intracellular methylthioadenosine:S-adenosyl-L-methionine ratio inhibits PRMT5 activity, leading to cellular arrest and apoptotic cell death by causing MDM4 alternative splicing and p53 activation. Combination MTDIA and AG-270 treatment differs from direct inhibition of PRMT5 by GSK3326595 by avoiding toxicity caused by cell death in the normal gut epithelium induced by the PRMT5 inhibitor. The combination of MTAP and MAT2a inhibitors expands this synthetic lethal approach to include MTAP +/+ cancers, especially the remaining 98% of CRCs without the MTAP -/- genotype., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Mitosis of somatic cells produces a daughter cell. Apoptosis, a naturally programmed cellular death mechanism, kills abnormal cells produced by mitosis. Cancer can develop when this equilibrium is disrupted, either by an upsurge in cell propagation or a reduction in tissue demise. Cancer therapy aims to cause cancer cells to die while inflicting little harm to healthy cells. This review of apoptotic mechanism processes improves our understanding of how certain malignancies begin and develop. The current cancer treatments can operate either by inducing apoptosis or causing direct cell damage. An insight into the resistance to apoptosis may explicate why malignancy treatments fail in some situations. New therapies grounded on our understanding of apoptotic processes are being developed to induce apoptosis of cancer cells while limiting the simultaneous death of normal cells. Various biological activities require redox equilibrium to function properly. Antineoplastic medications that cause oxidative stress by raising ROS and blocking antioxidant mechanisms have recently attracted much interest. The rapid accumulation of ROS impairs redox balance and damages cancer cells severely. Here, we discuss ROS-instigating malignancy therapy and the antineoplastic mechanism used by prooxidative drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ferroptosis is a form of programmed cell death and plays an important role in many diseases. Dihydroorotate dehydrogenase (DHODH) and glutathione peroxidase 4 (GPX4) play major roles in cell resistance to ferroptosis. Therefore, inactivation of these proteins provides an excellent opportunity for efficient ferroptosis-based synergistic cancer therapy. In this study, a multifunctional nanoagent (BPN pro ) containing a GPX4 targeting boron dipyrromethene (Bodipy) probe (BP) and a DHODH targeting proteolysis targeting chimera (PROTAC) is reported. BPN pro is prepared using a nanoprecipitation method in the presence of a thermoresponsive liposome, where BP is encapsulated inside and the cathepsin B (CatB)-cleavable PROTAC peptide (DPCP) is modified on the outer surface. In the presence of near-infrared (NIR) photoirradiation, BPN pro is melted and BP is released in tumor cells. Subsequently, BP inhibits the activity of GPX4 by covalently bonding with the selenocysteine at the enzyme active site. In addition, DPCP achieves sustained degradation of DHODH upon activation by CatB overexpressed in the tumor. The synergistic deactivation of GPX4 and DHODH induces extensive ferroptosis and subsequent cell death. In vivo and in vitro studies clearly show that the proposed ferroptosis therapy provides excellent antitumor effect., (© 2023 Wiley-VCH GmbH.)

SUMOylation is a post-translational modification frequently found on nuclear proteins, including transcription factors (TFs) and coactivators. By controlling the activity of several TFs, SUMOylation may have far-reaching effects. MYB is an example of a developmental TF subjected to SUMO-mediated regulation, through both SUMO conjugation and SUMO binding. How SUMO affects MYB target genes is unknown. Here, we explored the global effect of reduced SUMOylation of MYB on its downstream gene programs. RNA-Seq in K562 cells after MYB knockdown and rescue with mutants having an altered SUMO status revealed a number of differentially regulated genes and distinct gene ontology term enrichments. Clearly, the SUMO status of MYB both quantitatively and qualitatively affects its regulome. The transcriptome data further revealed that MYB upregulates the SUMO protease SENP1, a key enzyme that removes SUMO conjugation from SUMOylated proteins. Given this role of SENP1 in the MYB regulome, we expanded the analysis, mapped interaction partners of SENP1, and identified UXT as a novel player affecting the SUMO system by acting as a repressor of SENP1. MYB inhibits the expression of UXT suggesting that MYB is able not only to control a specific gene program directly but also indirectly by affecting the SUMO landscape through SENP1 and UXT. These findings suggest an autoactivation loop whereby MYB, through enhancing SENP1 and reducing UXT, is itself being activated by a reduced level of repressive SUMOylation. We propose that overexpressed MYB, seen in multiple cancers, may drive this autoactivation loop and contribute to oncogenic activation of MYB., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: African American (AA) women navigate the world with multiple intersecting marginalized identities. Accordingly, AA women have higher cumulative stress burden or allostatic load (AL) compared to other women. Studies suggest that AA women with a college degree or higher have lower AL than AA women with less than a high school diploma. We examined the joint effect of educational attainment and AL status with long-term risk of cancer mortality, and whether education moderated the association between AL and cancer mortality., Methods: We performed a retrospective analysis among 4,677 AA women within the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2010 with follow-up data through December 31, 2019. We fit weighted Cox proportional hazards models to estimate adjusted hazard ratios (aHRs) of cancer death between educational attainment/AL (adjusted for age, income, and smoking status)., Results: AA women with less than a high school diploma living with high AL had nearly a 3-fold increased risk (unadjusted HR: 2.98; 95%C CI: 1.24-7.15) of cancer death compared to AA college graduates living with low AL. However, after adjusting for age, this effect attenuated (age-adjusted HR: 1.11; 95% CI: 0.45-2.74). AA women with high AL had 2.3-fold increased risk of cancer death (fully adjusted HR: 2.26; 95% CI: 1.10-4.57) when compared to AA with low AL, specifically among women with high school diploma or equivalent and without history of cancer., Conclusions: Our findings suggest that high allostatic load is associated with a higher risk of cancer mortality among AA women with lower educational attainment, while no such association was observed among AA women with higher educational attainment. Thus, educational attainment plays a modifying role in the relationship between allostatic load and the risk of cancer death for AA women. Higher education can bring several benefits, including improved access to medical care and enhanced medical literacy, which in turn may help mitigate the adverse impact of AL and the heightened risk of cancer mortality among AA women., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The nervous system regulates tissue stem and precursor populations throughout life. Parallel to roles in development, the nervous system is emerging as a critical regulator of cancer, from oncogenesis to malignant growth and metastatic spread. Various preclinical models in a range of malignancies have demonstrated that nervous system activity can control cancer initiation and powerfully influence cancer progression and metastasis. Just as the nervous system can regulate cancer progression, cancer also remodels and hijacks nervous system structure and function. Interactions between the nervous system and cancer occur both in the local tumour microenvironment and systemically. Neurons and glial cells communicate directly with malignant cells in the tumour microenvironment through paracrine factors and, in some cases, through neuron-to-cancer cell synapses. Additionally, indirect interactions occur at a distance through circulating signals and through influences on immune cell trafficking and function. Such cross-talk among the nervous system, immune system and cancer-both systemically and in the local tumour microenvironment-regulates pro-tumour inflammation and anti-cancer immunity. Elucidating the neuroscience of cancer, which calls for interdisciplinary collaboration among the fields of neuroscience, developmental biology, immunology and cancer biology, may advance effective therapies for many of the most difficult to treat malignancies., (© 2023. Springer Nature Limited.)

Background: Discrimination can adversely affect health and accelerate aging, but little is known about these relationships in cancer survivors. This study examines associations of discrimination and aging among self-identified African American survivors., Methods: A population-based sample of 2232 survivors 20-79 years old at diagnosis were enrolled within 5 years of breast (n = 787), colorectal (n = 227), lung (n = 223), or prostate (n = 995) cancer between 2017 and 2022. Surveys were completed post-active therapy. A deficit accumulation index measured aging-related disease and function (score range, 0-1, where <0.20 is robust, 0.20 to <0.35 is pre-frail, and 0.35+ is frail; 0.06 is a large clinically meaningful difference). The discrimination scale assessed ever experiencing major discrimination and seven types of events (score, 0-7). Linear regression tested the association of discrimination and deficit accumulation, controlling for age, time from diagnosis, cancer type, stage and therapy, and sociodemographic variables., Results: Survivors were an average of 62 years old (SD, 9.6), 63.2% reported ever experiencing major discrimination, with an average of 2.4 (SD, 1.7) types of discrimination events. Only 24.4% had deficit accumulation scores considered robust (mean score, 0.30 [SD, 0.13]). Among those who reported ever experiencing major discrimination, survivors with four to seven types of discrimination events (vs. 0-1) had a large, clinically meaningful increase in adjusted deficits (0.062, p < .001) and this pattern was consistent across cancer types., Conclusion: African American cancer survivors have high deficit accumulated index scores, and experiences of major discrimination were positively associated with these deficits. Future studies are needed to understand the intersectionality between aging, discrimination, and cancer survivorship among diverse populations., (© 2023 American Cancer Society.)

Plant homeodomain (PHD) fingers are structurally conserved zinc fingers that selectively bind unmodified or methylated at lysine 4 histone H3 tails. This binding stabilizes transcription factors and chromatin-modifying proteins at specific genomic sites, which is required for vital cellular processes, including gene expression and DNA repair. Several PHD fingers have recently been shown to recognize other regions of H3 or histone H4. In this review, we detail molecular mechanisms and structural features of the noncanonical histone recognition, discuss biological implications of the atypical interactions, highlight therapeutic potential of PHD fingers, and compare inhibition strategies., Competing Interests: Conflict of interest The author declares that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Although cancer is a genetic disease, physical changes such as stiffening of the extracellular matrix also commonly occur in cancer. Cancer cells sense and respond to extracellular matrix stiffening through the process of mechanotransduction. Cancer cell mechanotransduction can enhance cancer-promoting cell behaviors such as survival signaling, proliferation, and migration. Glycans, carbohydrate-based polymers, have recently emerged as important mediators and/or modulators of cancer cell mechanotransduction. Stiffer tumors are characterized by increased glycan content on cancer cells and their associated extracellular matrix. Here we review the role of cancer-associated glycans in coupled mechanical and biochemical alterations during cancer progression. We discuss the recent evidence on how increased expression of different glycans, in the form of glycoproteins and proteoglycans, contributes to both mechanical changes in tumors and corresponding cancer cell responses. We conclude with a summary of emerging tools that can be used to modify glycans for future studies in cancer mechanobiology., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The expression of human papillomavirus (HPV) oncoproteins perturbed multiple cellular events of the host cells, leading to the formation of cancer phenotypes. Our current and previous studies indicated that Aurora kinase A (AurA), a mitotic regulator that is often aberrantly expressed in human cancers, is preferentially bound to E6-encoded by cancer-causing HPV. AurA is believed to be important for the proliferation and survival of HPV-positive cells. Nonetheless, the interaction between AurA and E6, and the mechanism of how this association is involved in carcinogenesis, have not been elucidated clearly. Hence, we performed a series of biochemical assays to characterize the AurA-E6 association and complex formation. We found the C-terminus of E6, upstream of the PDZ binding motif of E6, is important to forming the AurA-E6 complex in the nucleus. We also showed that the expression level of E6 corresponded positively with AurA expression. Meanwhile, the functional consequences of the AurA-E6 association to AurA kinase function and host cellular events were also delineated. Intriguingly, we revealed that AurA-E6 association regulated the expression of cyclin E and phosphor-Histone H3, which are involved in G1/S and mitotic phases of the cell cycle, respectively. Depletion of AurA also reduced the invasive ability of HPV-positive cells. AurA inhibition may not be sufficient to reduce the oncogenic potential exerted by E6. Altogether, our study unleashed the mechanism of how HPVE6 deploy AurA to promote cancer phenotypes, particularly through dysregulation of cell cycle checkpoints and suggests that the AurA-E6 complex possesses a therapeutic value. IMPORTANCE We unveiled the mechanism of how HPV employs Aurora kinase A (AurA) of host cells to exert its oncogenic capability synergistically. We systematically characterized the mode of interaction between E6-encoded by cancer-causing HPV and AurA. Then, we delineated the consequences of AurA-E6 complex formation on AurA kinase function and changes to cellular events at molecular levels. Using a cell-based approach, we unleashed that disruption of AurA-E6 association can halt cancer phenotype exhibited by HPV-positive cancer cells. Our findings are vital for the designing of state-of-the-art therapies for HPV-associated cancers.

There is an urgent need to identify reliable genetic biomarkers for accurate diagnosis, prognosis, and treatment of different tumor types. Described as a prognostic marker for many tumors is the neuronal protein carnitine palmitoyltransferase 1 C (CPT1C). Several studies report that CPT1C is involved in cancer cell adaptation to nutrient depletion and hypoxia. However, the molecular role played by CPT1C in cancer cells is controversial. Most published studies assume that, like canonical CPT1 isoforms, CPT1C is a mediator of fatty acid transport to mitochondria for beta-oxidation, despite the fact that CPT1C has inefficient catalytic activity and is located in the endoplasmic reticulum. In this review, we collate existing evidence on CPT1C in neurons, showing that CPT1C is a sensor of nutrients that interacts with and regulates other proteins involved in lipid metabolism and transport, lysosome motility, and the secretory pathway. We argue, therefore, that CPT1C expression in cancer cells is not a direct regulator of fat burn, but rather is a regulator of lipid metabolic reprograming and cell adaptation to environmental stressors. We also review the clinical relevance of CPT1C as a prognostic indicator and its contribution to tumor growth, cancer invasiveness, and cell senescence. This new and integrated vision of CPT1C function can help better understand the metabolic plasticity of cancer cells and improve the design of therapeutic strategies., (© 2023. The Author(s).)

Epidermal growth factor receptor (EGFR) signaling is frequently dysregulated in various cancers. The ubiquitin ligase Casitas B-lineage lymphoma proto-oncogene (Cbl) regulates degradation of activated EGFR through ubiquitination and acts as an adaptor to recruit proteins required for trafficking. Here, we used stable isotope labeling with amino acids in cell culture mass spectrometry to compare Cbl complexes with or without epidermal growth factor (EGF) stimulation. We identified over a hundred novel Cbl interactors, and a secondary siRNA screen found that knockdown of Flotillin-2 (FLOT2) led to increased phosphorylation and degradation of EGFR upon EGF stimulation in HeLa cells. In PC9 and H441 cells, FLOT2 knockdown increased EGF-stimulated EGFR phosphorylation, ubiquitination, and downstream signaling, reversible by EGFR inhibitor erlotinib. CRISPR knockout (KO) of FLOT2 in HeLa cells confirmed EGFR downregulation, increased signaling, and increased dimerization and endosomal trafficking. Furthermore, we determined that FLOT2 interacted with both Cbl and EGFR. EGFR downregulation upon FLOT2 loss was Cbl dependent, as coknockdown of Cbl and Cbl-b restored EGFR levels. In addition, FLOT2 overexpression decreased EGFR signaling and growth. Overexpression of wildtype (WT) FLOT2, but not the soluble G2A FLOT2 mutant, inhibited EGFR phosphorylation upon EGF stimulation in HEK293T cells. FLOT2 loss induced EGFR-dependent proliferation and anchorage-independent growth. Lastly, FLOT2 KO increased tumor formation and tumor volume in nude mice and NSG mice, respectively. Together, these data demonstrated that FLOT2 negatively regulated EGFR activation and dimerization, as well as its subsequent ubiquitination, endosomal trafficking, and degradation, leading to reduced proliferation in vitro and in vivo., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)