Phenotype divergence and cooperation in isogenic multicellularity and in cancer.

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.

Circulating myostatin as a biomarker of muscle mass and strength in individuals with cancer or obesity.

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/m2vs 9.0 kg/m2, p = 0.004; ASMMI: 6.2 kg/m2vs 7.2 kg/m2, 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.

Retrospective operationalization of allostatic load in patients with cancer: A systematic review.

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.

Comparison of plasma clearance of [51Cr]CrEDTA based on three, two and single samples to measure the glomerular filtration rate in patients with solid tumors: a prospective cross-sectional analysis.

OBJECTIVES: [51Cr]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 [51Cr]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 m2. ANOVA indicated a significant difference between 4Gr-GFR and the reference 246-GFR. Bias was lower than 5 mL/min/1.73 m2 for all methods, except for SS methods in subgroups BMI > 40 kg/m2; 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.

Greater Adherence to Life's Essential 8 for Cardiovascular Health Is Associated With Lower Arterial Stiffness in Survivors of Cancer.

BACKGROUND: Survivors of cancer have elevated risk of cardiovascular disease, likely stemming from the negative impact of anticancer therapies on vascular function. Arterial stiffness is a strong indicator of vascular function and independent predictor of cardiovascular disease. The American Heart Association recommends Life's Essential 8 for optimal cardiovascular health. It is currently unknown, however, whether greater adherence to Life's Essential 8 is associated with low arterial stiffness in survivors of cancer. METHODS AND RESULTS: This cross-sectional study included 172 older adult (≥65 years) survivors of cancer (74±6 years; 58% female). Life's Essential 8 100-point cardiovascular health score, with higher scores indicative of better cardiovascular health, was calculated based on 8 components: diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. Participants were classified as having low (<60), moderate (60-79), or high (≥80) cardiovascular health. Pulse wave velocity (PWV) was used to assess arterial stiffness; with high arterial stiffness defined as a pulse wave velocity ≥10 m/s. The mean cardiovascular health score was 72±11 and 40 survivors (23%) had high arterial stiffness. Compared with low cardiovascular health, the odds ratio of high arterial stiffness was 0.12 (95% CI, 0.03-0.50) and 0.02 (95% CI, 0.003-0.18) for moderate and high cardiovascular health, respectively. Every 10-point increase in the cardiovascular health score was associated with a 0.43 m/s reduction in pulse wave velocity (P<0.001). CONCLUSIONS: Greater adherence to the American Heart Association's Life's Essential 8 was associated with lower prevalence of high arterial stiffness in older adult survivors of cancer. Prospective studies with larger samples are needed.

Impact of Cancer History on Temporal Changes in the Cardiopulmonary Exercise Test of Patients with Cardiovascular Disease.

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 VO2) (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 VO2 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 VO2 of CR participants were not significantly different despite their cancer history.

Strength-to-muscle radiodensity: A potential new index for muscle quality.

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 cm2) and muscle radiodensity (SMD in HU) at the third lumbar vertebra (L3). Handgrip strength (HGS) was measured. MQICT was calculated using the ratio of HGS to SM (cm2). SMRi was calculated as the ratio of HGS to SMD (HU). For analysis purposes, low MQICT 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 MQICT were strongly positively correlated (ρ = 0.71 P < 0.001). Individual components of MQICT and SMRi were also positively correlated. Patients with both low MQICT 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 MQICT (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.

Deciphering oxygen distribution and hypoxia profiles in the tumor microenvironment: a data-driven mechanistic modeling approach.

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.

Modeling Physical Forces Experienced by Cancer and Stromal Cells Within Different Organ-Specific Tumor Tissue.

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.

The role of the nutrition in malnourished cancer patients: Revisiting an old dilemma.

BACKGROUND & AIMS: GLIM definition of malnutrition is recognised all over the world and, when is referring to cancer, it specifies that weight or muscle loss are associated with an inflammatory status. However, the real-world practice shows that GLIM definition cannot encompass all the wide and heterogenous clinical presentations of cancer patients with malnutrition, which involves many other drivers beyond inflammation. Moreover, placing an excessive emphasis on the inflammation can overshadow, in the clinical practice, the role of the nutritional support in malnourished cancer patients. The aim of this paper is not to criticize the rationale of the GLIM definition of cancer cachexia, but to show the complexity and heterogeneity of malnutrition of cancer patients and reasons why nutritional support should deserve such a better consideration among the oncologists. METHODS: Literature pertinent to pathophysiology of malnutrition of cancer patients is scrutinised and reasons for the frequent underuse of nutritional support are critically analysed. RESULTS: The appraisal of the literature shows that there are various pathophysiological patterns of malnutrition among cancer patients and inflammatory markers are not universally present in weight-losing cancer patients. Inflammation alone does not account for weight loss in all cancer patients and factors other than inflammation can drive hypophagia and weight loss, and hypophagia appears to be a primary catalyst for weight loss. Furthermore, malnutrition may be the consequence of the presence of several Nutrition Impact Symptoms or of the oncologic therapy. The nutritional support may fail to show benefits in malnourished cancer patients because the golden standard to validate a therapy relies on RCT, but it is ethically impossible to have an unfed control group of malnourished patients. Furthermore, nutritional interventions often fell short of the optimal standards, adherence to treatment plans was often poor, nutritional support was mainly reserved for very advanced patients and the primary endpoints of the studies on nutritional support were sometimes unrealistic. CONCLUSION: There is a gap between the suggestion of the guidelines which advocate the use of nutritional support to improve the compliance of patients facing intensive oncologic treatments or to prevent an early demise when patients enter a chronic phase of slow nutritional deterioration, and the poor use of nutrition in the real-world practice. This requires a higher level of awareness of the oncologists concerning the reasons for the lacking evidence of efficacy of the nutritional support and an understanding of its potential contribute to improve the outcome of the patients. Finally, this paper calls for a change of the oncologist's approach to the cancer patient, from only focusing on the cure of the tumour to taking care of the patient as a whole.

Sarcopenia, adiposity and large discordance between cystatin C and creatinine-based estimated glomerular filtration rate in patients with cancer.

BACKGROUND: Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with sarcopenia. While cystatin C-based eGFR (eGFRCYS) 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, eGFRCRE and eGFRCYS 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 eGFRCRE and eGFRCYS 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 cm2/m2 for women and <55 cm2/m2 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 eGFRCYS > 30% lower than eGFRCRE; the secondary outcome was eGFRCYS > 50% lower than eGFRCRE. 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 eGFRCYS and eGFRCRE. 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 eGFRCRE and eGFRCYS 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.

Sex differences of the association between handgrip strength and health-related quality of life among patients with cancer.

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.

Association of body mass index and blood pressure variability with 10-year mortality and renal disease progression in type 2 diabetes.

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 (HbA1c) 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 HbA1c with increased all-cause, cardiovascular, and cancer mortality as well as with renal progression.

Importancia biológica de los telómeros / Biological importance of telomeres

Se exponen los hallazgos históricos y la importancia biológica de los telómeros en la vida celular y en los aspectos genéticos del ADN humano. (AU)

The discovery and the biological importance of the telomeres are exposed. (AU)

Vital Sign Monitoring for Cancer Patients Based on Dual-Path Sensor and Divided-Frequency-CNN Model.

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.

Molecular Insight into the Apoptotic Mechanism of Cancer Cells: An Explicative Review.

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.

Impact of Presarcopenic Dysphagia on 1-Year Mortality After Videofluoroscopic Swallowing Study in Patients with Cancer.

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 (cm2/height [m2]), 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.

Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition.

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 104-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.