Pathological-Features-Modified TNM Staging System Improves Prognostic Accuracy for Rectal Cancer.

BACKGROUND: Variations in survival outcomes are observed in the eighth edition of the American Joint Committee on Cancer TNM staging system. OBJECTIVE: Machine learning ensemble methods were used to develop and evaluate the effectiveness of a pathological-features-modified TNM staging system in predicting survival for patients with rectal cancer by use of commonly reported pathological features, such as histological grade, tumor deposits, and perineural invasion, to improve the prognostic accuracy. DESIGN: This was a retrospective population-based study. SETTINGS: Data were assessed from the database of the Surveillance, Epidemiology, and End Results Program. PATIENTS: The study cohort comprised 14,468 patients with rectal cancer diagnosed between 2010 and 2015. The development cohort included those who underwent surgery as the primary treatment, whereas patients who received neoadjuvant therapy were assigned to the validation cohort. MAIN OUTCOME MEASURES: The primary outcome measures included cumulative rectal cancer survival, adjusted HRs, and both calibration and discrimination statistics to evaluate model performance and internal validation. RESULTS: Multivariable Cox regression analysis identified all 3 pathological features as prognostic factors, after which patients were categorized into 4 pathological groups based on the number of pathological features (ie, 0, 1, 2, and 3). Distinct survival differences were observed among the groups, especially with patients with stage III rectal cancer. The proposed pathological-features-modified TNM staging outperformed the TNM staging in both the development and validation cohorts. LIMITATIONS: Retrospective in design and lack of external validation. CONCLUSIONS: The proposed pathological-features-modified TNM staging could complement the current TNM staging by improving the accuracy of survival estimation of patients with rectal cancer. See Video Abstract . EL SISTEMA DE ESTADIFICACIN TNM CON CARACTERSTICAS PATOLGICAS MODIFICADO MEJORA LA PRECISIN DEL PRONSTICO DEL CNCER DE RECTO: ANTECEDENTES:Se observan variaciones en los resultados de supervivencia en el sistema de estadificación TNM del Comité Conjunto Americano del Cáncer 8º ediciónOBJETIVO:Se utilizaron métodos conjuntos de aprendizaje automático para desarrollar y evaluar la eficacia de un sistema de estadificación con características patológicas modificadas de tumores, ganglios y metástasis para predecir la supervivencia de pacientes con cáncer de recto, utilizando algunas características patológicas comúnmente informadas, como el grado histológico, depósitos tumorales e invasión perineural, para mejorar la precisión del pronóstico.DISEÑO:Este fue un estudio retrospectivo de base poblacional.ENTERNO CLINICO:Se recuperaron y evaluaron datos de la base de datos de Vigilancia, Epidemiología y Resultados Finales.PACIENTES:La cohorte del estudio estuvo compuesta por 14,468 pacientes con cáncer de recto diagnosticados entre 2010 y 2015. La cohorte de desarrollo incluyó a aquellos que se sometieron a cirugía como tratamiento primario, mientras que los pacientes que recibieron terapia neoadyuvante fueron asignados a la cohorte de validación.PRINCIPALES MEDIDAS DE RESULTADO:Las medidas de resultado primarias incluyeron supervivencia acumulada del cáncer de recto, índices de riesgo ajustados y estadísticas de calibración y discriminación para evaluar el rendimiento del modelo y la validación interna.RESULTADOS:El análisis de regresión multivariable de Cox identificó las tres características patológicas como factores pronósticos, después de lo cual los pacientes se clasificaron en cuatro grupos patológicos según el número de características patológicas (es decir, 0, 1, 2 y 3). Se observaron distintas diferencias en la supervivencia entre los grupos, especialmente en los pacientes en estadio III. La estadificación propuesta con características patológicas modificadas de tumores-ganglios-metástasis superó a la estadificación TNM tanto en las cohortes de desarrollo como en las de validación.LIMITACIONES:Diseño retrospectivo y falta de validación externa.CONCLUSIONES:La estadificación propuesta con características patológicas modificadas de tumores-ganglios-metástasis podría complementar la estadificación TNM actual al mejorar la precisión de la estimación de supervivencia de los pacientes con cáncer de recto. (Traducción- Dr. Francisco M. Abarca-Rendon ).

An artificial intelligence difficulty scoring system for stone removal during ERCP: a prospective validation.

BACKGROUND: A computer-assisted (CAD) system was developed to assess, score, and classify the technical difficulty of common bile duct (CBD) stone removal during endoscopic retrograde cholangiopancreatography (ERCP). The efficacy of the CAD system was subsequently assessed through a multicenter, prospective, observational study. METHOD: All patients who met the inclusion criteria were included. Based on cholangiogram images, the CAD system analyzed the level of difficulty of stone removal and classified it into "difficult" and "easy" groups. Subsequently, differences in clinical endpoints, including attempts at stone extraction, stone extraction time, total operation time, and stone clearance rates were compared between the two groups. RESULTS: 173 patients with CBD stones from three hospitals were included in the study. The group classified as difficult by CAD had more extraction attempts (7.20 vs. 4.20, P < 0.001), more frequent machine lithotripsy (30.4 % vs. 7.1 %, P < 0.001), longer stone extraction time (16.59 vs. 7.69 minutes, P < 0.001), lower single-session stone clearance rate (73.9 % vs. 94.5 %, P < 0.001), and lower total stone clearance rate (89.1 % vs. 97.6 %, P = 0.019) compared with the group classified as easy by CAD. CONCLUSION: The CAD system effectively assessed and classified the degree of technical difficulty in endoscopic stone extraction during ERCP. In addition, it automatically provided a quantitative evaluation of CBD and stones, which in turn could help endoscopists to apply suitable procedures and interventional methods to minimize the possible risks associated with endoscopic stone removal.

Which treatment strategy is optimal for acute left-sided malignant colonic obstruction? A Bayesian meta-analysis.

PURPOSE: This study aimed to determine the best treatment for acute left-sided malignant colonic obstruction (ALMCO) among emergency surgery (ES), self-expanding metallic stent (SEMS), transanal drainage tube (TD), and decompressive stoma (DS). METHOD: Articles that compared two or more treatments of ALMCO were searched from PubMed, Cochrane Library, and Embase. Network meta-analyses were performed to calculate the outcomes of primary anastomosis, stoma creation, morbidity, mortality, and 5-year survival. RESULTS: Fifty-one articles met inclusion criteria. TD was the optimal treatment in performing primary anastomosis [probability of ranking first (Pro-1) 0.96], while ES was the worst [probability of ranking fourth (Pro-4) 0.99]. More permanent stoma was formed in ES and TD groups than in SEMS and DS groups [OR (95%CI): TD vs SEMS: 4.12 (1.89, 9.45); TD vs DS: 3.39 (1.46, 8.75); ES vs DS: 2.55 (1.73, 4.17); SEMS vs ES: 0.33 (0.24, 0.42)]. More morbidity occurred in ES group than in SEMS group [OR (95%CI): ES vs SEMS: 1.44 (1.14, 1.82)]. Besides, SEMS was ranked first in avoiding infection (Pro-4 0.95). For in-hospital mortality, ES was ranked first (Pro-1 0.93). TD was ranked first in recurrence (Pro-1 0.97) and metastasis (Pro-1 0.98). There was no discrepancy in 5-year overall and disease-free survival among all strategies. CONCLUSION: SEMS as a bridge to surgery reduces stoma formation, and morbidity especially the infection rate with relatively great oncological outcomes. Therefore, SEMS should be recommended first for ALMCO in the medical center with experience and conditions.

NF-κB downstream miR-1262 disturbs colon cancer cell malignant behaviors by targeting FGFR1.

Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions in vitro using cancer cells and in vivo using a subcutaneous xenograft model. miRNA downstream targets are analyzed, and predicted binding and regulation are verified. miR-1262, an antitumor miRNA, is downregulated in colon cancer tissue samples and cell lines. miR-1262 overexpression suppresses colon cancer malignant behaviors in vitro and tumor development and metastasis in a subcutaneous xenograft model and a lung metastasis mouse model in vivo. miR-1262 directly targets fibroblast growth factor receptor 1 (FGFR1) and inhibits FGFR1 expression. FGFR1 overexpression shows oncogenic functions through the regulation of cancer cell proliferation, invasion, and migration; when cotransfected, lv-FGFR1 partially attenuates the antitumor effects of agomir-1262. NF-κB binds to the miR-1262 promoter region and inhibits transcription activity. The NF-κB inhibitor CAPE exerts antitumor effects; miR-1262 inhibition partially reverses CAPE effects on colon cancer cells. Conclusively, miR-1262 serves as an antitumor miRNA in colon cancer by targeting FGFR1. The NF-κB/miR-1262/FGFR1 axis modulates colon cancer cell phenotypes, including proliferation, invasion, and migration.

Subclinical hypothyroidism in pregnancy rats impaired offspring's spatial learning and memory and the cerebellar development.

Subclinical hypothyroidism (SCH) is a very common preclinical condition during pregnancy. The adverse effect of maternal clinical hypothyroidism (CH) on the nervous system development of offspring is beyond doubt, but it is still controversial in SCH. The aim of this study was to investigate whether spatial learning and memory ability of offspring is inhibited in SCH rat model and its possible mechanism. 45 Wistar female rats were randomly divided into SCH, CH and control (CON) groups, which were induced by semi-thyroid electrocauterization, total thyroidectomy and sham operation, respectively. Rat pups were sacrificed at embryonic day 14 (E14), E18, postnatal day 1 (P1), P3, and P10, and pups' cerebellar tissues were collected. The proliferation, differentiation and migration of cerebellar cells were observed, and RNA level of the thyroid hormone receptor α (TRα) and TRß in the cerebellum was detected by real-time PCR, respectively. Morris Water Maze (MWM) test was performed to detect the spatial learning and memory ability of pups at P40. Our data indicated that maternal SCH will significantly extend the offspring's escape latency time, and pups perform worse in the spatial probe test compared with the CON group. Except for E14, the proliferation of pups' cerebellar granule cells (GCs), and the migration of pups' Purkinje cells (PCs) in the SCH group was significantly inhibited compared with that in the CON group at other time points (P < 0.05 or P < 0.01), and the differentiation of cerebellar astrocytes (As) in SCH group was higher than that in CON group at P3 and P10. Except for E14, the expression of TRα mRNA in SCH group was significantly lower than that in CON group (P < 0.05 or P < 0.01). And the difference of the differentiation of As and the spatial learning and memory between SCH and CH groups was not statistically significant. Our findings suggested that SCH during pregnancy nuisances the offspring's spatial learning and memory. It may be related to the decrease of the expression of TRα in cerebellum, which may further inhibit the proliferation of GCs and the migration of PCs, and increase the differentiation of As.

Long-term oncological outcomes of low anterior resection for rectal cancer with and without preservation of the left colic artery: a retrospective cohort study.

BACKGROUND: There is uncertainty in the literature about preserving the left colic artery (LCA) during low anterior resection for rectal cancer. We analyzed the effect of preserving the LCA on long-term oncological outcomes. METHODS: We retrospectively collected clinicopathological and follow-up details of patients who underwent low anterior resection for rectal cancer in the General Surgery Department of Guangdong Provincial People's Hospital, from January 2014 to December 2015. Cases were divided into low ligation (LL), LCA preserved, or high ligation (HL), LCA not preserved, of the inferior mesenteric artery. The 5-year overall survival (OS) and disease-free survival (DFS) rates were compared between the two groups. RESULTS: Altogether, there were 221 and 295 cases in the LL group and HL groups, respectively. Operating time in the LL group was significantly longer than in the HL group (224.7 vs. 211.7 min, p = 0.039). Postoperative 30-day mortality, early complications including anastomotic leakage showed no significant differences between the LL and HL groups (postoperative 30-day mortality, 0.9% LL, 1.4% HL, p = 0.884; early complications, 41.2% LL, 38.3% HL, p = 0.509; anastomotic leakage 8.6% LL, 13.2% HL, p = 0.100). The median follow-up periods were 51.4 (7-61) months in the LL group and 51.2 (8-61) months in the HL group. During follow-up, the percentages of patients who died, had local recurrence, or had metastases were 39.8, 7.7, and 38.5%, respectively, in the LL group and 39, 8.5, and 40%, respectively, in the HL group; these differences were not significant (all p > 0.05). The 5-year OS and DFS were 69.6 and 59.6% in the LL group, respectively, and 69.1 and 56.2% in the HL group, respectively; these differences were not significant (all p > 0.05). After stratification by tumor-node-metastasis stage, the difference between the 5-year OS and DFS for stages I, II, and III cancer were not significant (all p > 0.05). CONCLUSIONS: The long-term oncological outcomes of LL group are comparable with HL group. LL cannot be supported due to the absence of lower complication rates and the longer operating times.

Intelligent difficulty scoring and assistance system for endoscopic extraction of common bile duct stones based on deep learning: multicenter study.

BACKGROUND: The study aimed to construct an intelligent difficulty scoring and assistance system (DSAS) for endoscopic retrograde cholangiopancreatography (ERCP) treatment of common bile duct (CBD) stones. METHODS: 1954 cholangiograms were collected from three hospitals for training and testing the DSAS. The D-LinkNet34 and U-Net were adopted to segment the CBD, stones, and duodenoscope. Based on the segmentation results, the stone size, distal CBD diameter, distal CBD arm, and distal CBD angulation were estimated. The performance of segmentation and estimation was assessed by mean intersection over union (mIoU) and average relative error. A technical difficulty scoring scale, which was used for assessing the technical difficulty of CBD stone removal, was developed and validated. We also analyzed the relationship between scores evaluated by the DSAS and clinical indicators including stone clearance rate and need for endoscopic papillary large-balloon dilation (EPLBD) and lithotripsy. RESULTS: The mIoU values of the stone, CBD, and duodenoscope segmentation were 68.35 %, 86.42 %, and 95.85 %, respectively. The estimation performance of the DSAS was superior to nonexpert endoscopists. In addition, the technical difficulty scoring performance of the DSAS was more consistent with expert endoscopists than two nonexpert endoscopists. A DSAS assessment score ≥ 2 was correlated with lower stone clearance rates and more frequent EPLBD. CONCLUSIONS: An intelligent DSAS based on deep learning was developed. The DSAS could assist endoscopists by automatically scoring the technical difficulty of CBD stone extraction, and guiding the choice of therapeutic approach and appropriate accessories during ERCP.

Optimal examined lymph node count in node-negative colon cancer should be determined.

Background: We aimed to investigate the association between optimal examined lymph node (ELNs) and overall survival to determine the optimal cutoff point. Methods: Cox models and locally weighted scatterplot smoothing were used to fit hazard ratios and explore an optimal cutoff point based on the Chow test. Results: Overall survival increased significantly with the corresponding increase in the number of ELNs after adjusting for covariates. In Chow's test, the optimal cutoff point for node-negative colon cancer was 15, which was validated in both cohorts after controlling for confounders (Surveillance, Epidemiology, and End Results database: hazard ratio: 0.701, p < 0.001; single-center: HR: 0.563; p = 0.031). Conclusions: We conservatively suggest that the optimal number of ELNs for prognostic stratification is 15 in node-negative colon cancer.

Lay abstract Over the past 20 years, the number of examined lymph nodes (ELNs) has been an important indicator to accurately assess lymph node metastasis, and therefore, many studies have focused on exploring an optimal cutoff point to prevent missed detection of positive lymph nodes. However, in recent years, ELNs has been considered to play other key roles. In the current study, ELNs were deemed an important prognostic factor, and the minimum number of ELNs was recommended to be 15 in node-negative colon cancer via rigorous statistical methods and a large sample of data.

Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality.

Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10-9), CHD by 35% (p = 8.9×10-6), HF by 55% (p = 9.7×10-5), stroke by 25% (p = 4.0×10-2), and ND by 100% (p = 1.3×10-3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10-21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.

Laparoscopic hepatectomy for colorectal liver metastases located in all segments of the liver.

PURPOSE: Laparoscopic hepatectomy is not a well-established treatment modality for colorectal liver metastases. Moreover, most reports have been limited to tumors in the anterolateral segments (segments 2, 3, 4b, 5, and 6). In this study we evaluated the short- and long-term outcomes after laparoscopic hepatectomy for colorectal liver metastases located in all segments, including tumors located in the posterosuperior segments (segments 1, 4a, 7, and 8). METHODS: This retrospective study included 102 patients who underwent laparoscopic hepatectomy for colorectal liver metastases with radical intent between January 2009 and January 2016. The patients were divided into two groups (anterolateral and posterosuperior group) according to tumor location. The clinical and follow-up data of the two groups were reviewed. RESULTS: There was no 30-day postoperative mortality. Most of the postoperative 30-day complications were classified as minor complications (Clavien-Dindo classification). There was no difference in clinicopathologic characteristics between the two groups. Although posterosuperior group patients had significantly longer operative time (p=0.008) and postoperative hospital stay duration (p=0.041), as well as a greater blood loss (p=0.012), there was no significant difference in the rate and severity of postoperative complications (p=0.314 and 1.000 respectively). During a median follow-up of 41 months, the 5-year overall survival (OS) (p=0.449), and disease-free survival (DFS) (p=0.370) showed no significant difference between the two groups. CONCLUSIONS: Laparoscopic hepatectomy for colorectal liver metastases located in all segments of the liver can be safely performed in selected patients, with acceptable postoperative morbidity and oncologic results.

Laparoscopic hepatectomy for colorectal liver metastases located in all segments of the liver.

PURPOSE: Laparoscopic hepatectomy is not a well-established treatment modality for colorectal liver metastases. Moreover, most reports have been limited to tumors in the anterolateral segments (segments 2, 3, 4b, 5, and 6). We evaluated the short- and long-term outcomes after laparoscopic hepatectomy for colorectal liver metastases located in all segments, including tumors located in the posterosuperior segments (segments 1, 4a, 7, and 8). METHODS: TThis retrospective study included 102 patients who underwent laparoscopic hepatectomy for colorectal liver metastases with radical intent between January 2009 and January 2016. The patients were divided into two groups (anterolateral and posterosuperior group) according to tumor location. The clinical and follow-up data of the two groups were retrospectively reviewed. RESULTS: There was no 30-day postoperative mortality. Most of the postoperative 30-day complications were classified as minor complications (Clavien-Dindo classification). There was no difference in clinicopathologic characteristics between the two groups. Although posterosuperior group patients had significantly longer operative time (p=0.008) and postoperative hospital stay duration (p=0.041), as well as a greater blood loss (p=0.012), there was no significant difference in rate and severity of postoperative complications (p=0.314 and 1.000 respectively). During a median follow-up period of 41 months, the 5-year overall survival (OS) (p=0.449), and disease-free survival (DFS) (p=0.370) was no significant difference between the two groups. CONCLUSIONS: Laparoscopic hepatectomy for colorectal liver metastases located in all segments of the liver can be safely performed in selected patients, with acceptable postoperative morbidity and oncologic results.

Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study.

The apolipoprotein E (apoE) is a classic example of a gene exhibiting pleiotropism. We examine potential pleiotropic associations of the apoE2 allele in three biodemographic cohorts of long-living individuals, offspring, and spouses from the Long Life Family Study, and intermediate mechanisms, which can link this allele with age-related phenotypes. We focused on age-related macular degeneration, bronchitis, asthma, pneumonia, stroke, creatinine, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, diseases of heart (HD), cancer, and survival. Our analysis detected favorable associations of the ε2 allele with lower LDL-C levels, lower risks of HD, and better survival. The ε2 allele was associated with LDL-C in each gender and biodemographic cohort, including long-living individuals, offspring, and spouses, resulting in highly significant association in the entire sample (ß = -7.1, p = 6.6 × 10-44). This allele was significantly associated with HD in long-living individuals and offspring (relative risk [RR] = 0.60, p = 3.1 × 10-6) but this association was not mediated by LDL-C. The protective effect on survival was specific for long-living women but it was not explained by LDL-C and HD in the adjusted model (RR = 0.70, p = 2.1 × 10-2). These results show that ε2 allele may favorably influence LDL-C, HD, and survival through three mechanisms. Two of them (HD- and survival-related) are pronounced in the long-living parents and their offspring; the survival-related mechanism is also sensitive to gender. The LDL-C-related mechanism appears to be independent of these factors. Insights into mechanisms linking ε2 allele with age-related phenotypes given biodemographic structure of the population studied may benefit translation of genetic discoveries to health care and personalized medicine.

Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants.

Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.

How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity.

Increasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field.

A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans.

When both genotype and environment are held constant, 'chance' variation in the lifespan of individuals in a population is still quite large. Using isogenic populations of the nematode Caenorhabditis elegans, we show that, on the first day of adult life, chance variation in the level of induction of a green fluorescent protein (GFP) reporter coupled to a promoter from the gene hsp-16.2 predicts as much as a fourfold variation in subsequent survival. The same reporter is also a predictor of ability to withstand a subsequent lethal thermal stress. The level of induction of GFP is not heritable, and GFP expression levels in other reporter constructs are not associated with differences in longevity. HSP-16.2 itself is probably not responsible for the observed differences in survival but instead probably reflects a hidden, heterogeneous, but now quantifiable, physiological state that dictates the ability of an organism to deal with the rigors of living.

Overweight as a Causal Factor Contributing to Better Survival at the Oldest Old Ages: A Mendelian Randomization Study.

Overweight, defined by a body mass index (BMI) between 25 and 30, has been associated with enhanced survival among older adults in some studies. However, whether being overweight is causally linked to longevity remains unclear. To investigate this, we conducted a Mendelian randomization (MR) study of lifespan 85+ years, using overweight as an exposure variable and data from the Health and Retirement Study and the Long Life Family Study. An essential aspect of MR involves selecting appropriate single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs). This is challenging due to the limited number of SNP candidates within biologically relevant genes that can satisfy all necessary assumptions and criteria. To address this challenge, we employed a novel strategy of creating additional IVs by pairing SNPs between candidate genes. This strategy allowed us to expand the pool of IV candidates with new 'composite' SNPs derived from eight candidate obesity genes. Our study found that being overweight between ages 75 and 85, compared to having a normal weight (BMI 18.5-24.9), significantly contributes to improved survival beyond age 85. Results of this MR study thus support a causal relationship between overweight and longevity in older adults.

Patterns of Aging Changes in Bodyweight May Predict Alzheimer's Disease.

Relationships between patterns of aging-changes in bodyweight and AD are not fully understood. We compared mean age-trajectories of weight between those who did and did not develop late-onset-AD, and evaluated impact of age at maximum weight (AgeMax), and slope of decline in weight, on AD risk. Women with late-onset-AD had lower weight three or more decades before AD onset, and ∼10 years younger AgeMax, compared to AD-free women. APOE4 carriers had younger AgeMax and steeper slope. Older AgeMax and flatter slope predicted lower AD risk. Premature decline in weight could be a sign of accelerated physical aging contributing to AD.

How are APOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis.

The ε4 allele of the APOE gene (APOE4) is known for its negative association with human longevity; however, the mechanism is unclear. APOE4 is also linked to changes in body weight, and the latter changes were associated with survival in some studies. Here, we explore the role of aging changes in weight in the connection between APOE4 and longevity using the causal mediation analysis (CMA) approach to uncover the mechanisms of genetic associations. Using the Health and Retirement Study (HRS) data, we tested a hypothesis of whether the association of APOE4 with reduced survival to age 85+ is mediated by key characteristics of age trajectories of weight, such as the age at reaching peak values and the slope of the decline in weight afterward. Mediation effects were evaluated by the total effect (TE), natural indirect effect, and percentage mediated. The controlled direct effect and natural direct effect are also reported. The CMA results suggest that APOE4 carriers have 19%-22% (TE p = 0.020-0.039) lower chances of surviving to age 85 and beyond, in part, because they reach peak values of weight at younger ages, and their weight declines faster afterward compared to non-carriers. This finding is in line with the idea that the detrimental effect of APOE4 on longevity is, in part, related to the accelerated physical aging of ε4 carriers.

Predicting surgical benefit of primary tumor resection in patients with stage IV colorectal cancer.

BACKGROUND: There exists continuous controversy regarding the benefit of primary tumor resection (PTR) for stage IV colorectal cancer (CRC) patients. Little is known about how to predict the patients' benefit from PTR. This study aimed to develop a tool for surgical benefit prediction. METHODS: Stage IV CRC patients diagnosed between 2010 and 2015 from the Surveillance, Epidemiology and End Results database were included. Patients receiving PTR who survived longer than the median cancer-specific survival (CSS) time of those who did not undergo PTR were considered to benefit from surgery. Logistic regression analysis identified prognostic factors influencing surgical benefit, based on which a nomogram was constructed. The data of patients who underwent PTR from our institution was used for external validation. A user-friendly webserver was then built for convenient clinical use. RESULTS: The median CSS of the PTR group was 23 months, significantly longer than that of the non-PTR group (7 months, P < 0.001). In the PTR group, 23.3% of patients did not benefit from surgery. Logistic regression analysis identified age, marital status, tumor location, CEA level, chemotherapy, metastasectomy, tumor size, tumor deposits, number of examined lymph nodes, N stage, histological grade and number of distant metastases as independently associated with surgical benefit. The established prognostic nomogram demonstrated satisfactory performance in both the internal and external validation. CONCLUSION: PTR was associated with prolonged CSS in stage IV CRC. The proposed nomogram could be used as an evidenced-based platform for risk-to-benefit assessment to select appropriate patients for undergoing PTR.

Comparative single-cell analysis reveals heterogeneous immune landscapes in adenocarcinoma of the esophagogastric junction and gastric adenocarcinoma.

Adenocarcinoma of the esophagogastric junction (AEG) is a type of tumor that arises at the anatomical junction of the esophagus and stomach. Although AEG is commonly classified as a subtype of gastric adenocarcinoma (GAC), the tumor microenvironment (TME) of AEG remains poorly understood. To address this issue, we conducted single-cell RNA sequencing (scRNA-seq) on tumor and adjacent normal tissues from four AEG patients and performed integrated analysis with publicly available GAC single-cell datasets. Our study for the first time comprehensively deciphered the TME landscape of AEG, where heterogeneous AEG malignant cells were identified with diverse biological functions and intrinsic malignant nature. We also depicted transcriptional signatures and T cell receptor (TCR) repertoires for T cell subclusters, revealing enhanced exhaustion and reduced clone expansion along the developmental trajectory of tumor-infiltrating T cells within AEG. Notably, we observed prominent enrichment of tumorigenic cancer-associated fibroblasts (CAFs) in the AEG TME compared to GAC. These CAFs played a critical regulatory role in the intercellular communication network with other cell types in the AEG TME. Furthermore, we identified that the accumulation of CAFs in AEG might be induced by malignant cells through FGF-FGFR axes. Our findings provide a comprehensive depiction of the AEG TME, which underlies potential therapeutic targets for AEG patient treatment.