A conserved chronobiological complex times C. elegans development.

The mammalian PAS-domain protein PERIOD (PER) and its C. elegans orthologue LIN-42 have been proposed to constitute an evolutionary link between two distinct, circadian and developmental, timing systems. However, while the function of PER in animal circadian rhythms is well understood molecularly and mechanistically, this is not true for the function of LIN-42 in timing rhythmic development. Here, using targeted deletions, we find that the LIN-42 PAS domains are dispensable for the protein's function in timing molts. Instead, we observe arrhythmic molts upon deletion of a distinct sequence element, conserved with PER. We show that this element mediates stable binding to KIN-20, the C. elegans CK1δ/ε orthologue. We demonstrate that CK1δ phosphorylates LIN-42 and define two conserved helical motifs, CK1δ-binding domain A (CK1BD-A) and CK1BD-B, that have distinct roles in controlling CK1δ-binding and kinase activity in vitro . KIN-20 and the LIN-42 CK1BD are required for proper molting timing in vivo . These interactions mirror the central role of a stable circadian PER-CK1 complex in setting a robust ∼24-hour period. Hence, our results establish LIN-42/PER - KIN-20/CK1δ/ε as a functionally conserved signaling module of two distinct chronobiological systems.

Racial differences in body composition and survival among older adults with gastrointestinal malignancies.

INTRODUCTION: Muscle and adipose tissue measures can be quantified from routinely obtained computed tomography (CT) images and are predictors of chemotherapy-related toxicities and survival among patients with gastrointestinal (GI) malignancies. Most studies to date have consisted of predominantly White patients, and the role of body composition among minoritized racial groups is unknown. We examined racial differences in body composition and survival among patients with GI malignancies. MATERIALS AND METHODS: This was a prospective cohort study of patients with GI malignancies. Single slices of axial CT images from L3 segments were analyzed using Slice-O-Matic software. The skeletal muscle area (cm2) was divided by height to obtain the skeletal muscle index (SMI, cm2/m2). Skeletal muscle radiodensity (SMD) in Hounsfield units (HU) was used for muscle composition. We compared body composition parameters between non-Hispanic (NH)-White and NH-Black participants. Cox models were used to examine the impact of body composition on survival. We proposed new race-specific cutoffs for body composition using optimal stratification. RESULTS: Five hundred forty patients were included, of which 24% were NH-Black. In Cox models stratified by race, each 5 cm2/m2 decrease in SMI was associated with increase in risk of all-cause mortality in NH-Black patients (hazard ratio [HR] 1.25; 95% confidence interval [CI] 1.04-1.49 p = 0.02). With the existing cut points, neither sarcopenia nor myosteatosis was associated with worse survival. Using a new cutoff for sarcopenia in NH-Black patients, NH-Black patients with sarcopenia (HR 2.31 95%CI 1.10-4.88 p = 0.03) and myosteatosis (HR 2.63 95% CI 1.25-5.53 p = 0.01) had worse survival. DISCUSSION: NH-Black older patients with GI cancers and sarcopenia or myosteatosis have worse overall survival.

Kinematic Investigation of Healthy, Arthritic, and Postsurgery Thumbs: Is the Metacarpophalangeal Joint the Gateway to Carpometacarpal Arthritis?

The thumb carpometacarpal (CMC) joint is one of the most likely joints to develop osteoarthritis (OA). If conservative treatments fail to alleviate symptoms, surgery may be pursued. Kinematic outcomes of CMC surgery techniques have been described, but current tools have limitations in capturing motion abilities. The goals of this study were (1) develop a new and robust set of kinematic outcome measures, and apply them to (2) a cohort of younger and older control individuals without CMC OA to determine age and sex-related changes, and (3) a cohort of participants with CMC OA before, 3 months, and 6 months after undergoing thumb ligament reconstruction with tendon interposition surgery to detect the impacts of surgery. 52 (26 males, 26 females) control and 18 (3 males, 15 females) surgical participants were tested. Kinematics were investigated using motion capture by mapping the three-dimensional motion space of the whole thumb, and two-dimensional motion boundaries of the metacarpal (MC) and proximal phalange (PP). Visual analog pain score was recorded. Older control participants had shifted regions of motion compared to younger participants (p ≤ 0.027), suggesting asymptomatic CMC wear. Control females had 31% more metacarpophalangeal (MCP) motion than control males (p = 0.013), which could alter loading paths through the CMC joint and increase OA risk. Pain at 6 months postsurgery was 72% less than presurgery (p < 0.001), but motion abilities were 20-28% less than presurgery (p ≤ 0.074) and 24-40% less than control participants (p ≤ 0.066). These techniques have the possibility of identifying presymptomatic motion changes, including those at the metacarpophalangeal joint in CMC OA progression.

The Effect of a Temporary Stoma on Long-term Functional Outcomes Following Surgery for Rectal Cancer.

BACKGROUND: Patients with rectal cancer may undergo surgical resection with or without a temporary stoma. OBJECTIVE: This study primarily aimed to compare long-term functional outcomes between patients with and without a temporary stoma after surgery for rectal cancer. The secondary aim was to investigate the effect of time to stoma reversal on functional outcomes. DESIGN: This was a multicenter, cross-sectional study. SETTINGS: This study was conducted at 7 Dutch hospitals. PATIENTS: Included were patients who had undergone rectal cancer surgery (2009-2015). Excluded were deceased patients, who were deceased, had a permanent stoma, or had intellectual disability. MAIN OUTCOME MEASURES: Functional outcomes were measured using the Rome IV criteria for constipation and fecal incontinence and the low anterior resection syndrome score. RESULTS: Of 656 patients, 32% received a temporary ileostomy and 20% a temporary colostomy (86% response). Follow-up was at 56 (interquartile range, 38.5-79) months. Patients who had a temporary ileostomy experienced less constipation, more fecal incontinence, and more major low anterior resection syndrome than those without a temporary stoma. Patients who had a temporary colostomy experienced more major low anterior resection syndrome than those without a temporary stoma. A temporary ileostomy or colostomy was not associated with constipation or fecal incontinence after correction for confounding factors (eg, anastomotic height, anastomotic leakage, radiotherapy). Time to stoma reversal was not associated with constipation, fecal incontinence, or major low anterior resection syndrome. LIMITATIONS: Cross-sectional design. CONCLUSIONS: Although patients with a temporary ileostomy or colostomy have worse functional outcomes in the long term, it seems that the reason for creating a temporary stoma, rather than the stoma itself, underlies this phenomenon. Time to reversal of a temporary stoma does not influence functional outcomes. See Video Abstract . EL EFECTO DEL ESTOMA TEMPORAL SOBRE LOS RESULTADOS FUNCIONALES A LARGO PLAZO DESPUS DE LA CIRUGA POR CNCER DE RECTO: ANTECEDENTES:Los pacientes con cáncer de recto pueden someterse a resección quirúrgica con o sin un estoma temporal.OBJETIVO:El objetivo principal de este estudio fue comparar los resultados funcionales a largo plazo entre pacientes con y sin estoma temporal después de cirugía por cáncer de recto. El objetivo secundario fue investigar el efecto del tiempo transcurrido hasta la reversión del estoma sobre los resultados funcionales.DISEÑO:Este fue un estudio transversal multicéntrico.ESCENARIO:Este estudio se llevó a cabo en siete hospitales holandeses.PACIENTES:Se incluyeron pacientes sometidos a cirugía de cáncer de recto (2009-2015). Se excluyeron pacientes fallecidos, pacientes con estoma permanente o discapacidad intelectual.PRINCIPALES MEDIDAS DE RESULTADO:Los resultados funcionales se midieron utilizando los criterios de Roma IV para el estreñimiento y la incontinencia fecal y la puntuación del síndrome de resección anterior baja (LARS).RESULTADOS:De 656 pacientes, el 32% recibió una ileostomía temporal y el 20% una colostomía temporal (respuesta del 86%). El seguimiento fue de 56.0 (RIQ 38.5-79.0) meses. Los pacientes a los que se les realizó una ileostomía temporal experimentaron menos estreñimiento, más incontinencia fecal y más LARS mayor que los pacientes sin un estoma temporal. Los pacientes que tuvieron una colostomía temporal experimentaron más LARS mayor que los pacientes sin un estoma temporal. Una ileostomía o colostomía temporal no se asoció con estreñimiento o incontinencia fecal después de la corrección de factores de confusión (p. ej., altura anastomótica, fuga anastomótica, radioterapia). El tiempo hasta la reversión del estoma no se asoció con estreñimiento, incontinencia fecal o LARS mayor.LIMITACIONES:El presente estudio está limitado por su diseño transversal.CONCLUSIONES:Aunque los pacientes con una ileostomía o colostomía temporal tienen peores resultados funcionales a largo plazo, parece que la razón para crear un estoma temporal, más que el estoma en sí, se asocia a este fenómeno. El tiempo hasta la reversión de un estoma temporal no influye en los resultados funcionales. (Traducción-Dr. Jorge Silva Velazco ).

The impact of salt stress on the physiology and the transcriptome of the model streptophyte green alga Chara braunii.

Chara braunii is a model for early land plant evolution and terrestrialization. Salt stress has a profound effect on water and ion transport activities, thereby interacting with many other processes, including inorganic carbon acquisition for photosynthesis. In this study, we analyzed the impact of salt stress (5 practical salt units, PSU) on the physiology and gene expression in C. braunii. Photosynthesis was only slightly affected 6 h after salt addition and returned to control levels after 48 h. Several organic compounds such as proline, glutamate, sucrose, and 2-aminobutyrate accumulated in salt-treated thalli and might contribute to osmotic potential acclimation, whereas the amount of K+ decreased. We quantified transcript levels for 17,387 genes, of which 95 were up-regulated and 44 down-regulated after salt addition. Genes encoding proteins of the functional groups ion/solute transport and cell wall synthesis/modulation were enriched among the up-regulated genes 24-48 h after salt stress, indicating their role in osmotic acclimation. However, a homolog to land plant ERD4 osmosensors was transiently upregulated after 6 h, and phylogenetic analyses suggested that these sensors evolved in Charophyceae. Down-regulated genes were mainly related to photosynthesis and carbon metabolism/fixation, consistent with the observed lowered growth after extended cultivation. The changed expression of genes encoding proteins for inorganic carbon acquisition might be related to the impact of salt on ionic relations and inorganic carbon uptake. The results indicate that C. braunii can tolerate enhanced salt concentrations in a defined acclimation process, including distinct gene expression changes to achieve new metabolic homeostasis.

Management of Older Adults With Colorectal Cancer: The Role of Geriatric Assessment.

Older adults share a growing burden of cancer morbidity and mortality. This is present across the spectrum of oncologic diagnoses and is particularly true with colorectal cancer (CRC), where older adults continue to share the burden of diagnoses. However, optimal cancer treatment decision making in older adults remains a significant challenge, as the majority of previous clinical trials shaping the current treatment landscape have focused on younger patients, often with more robust performance status and fewer medical comorbid conditions. The heterogeneous aging process of older adults with CRC necessitates a personalized treatment approach, as approximately three-quarters of older adults with CRC also have a concominant geriatric syndrome and more than half of older adults with CRC are pre-frail or frail. Treatment decisions shoud be multifaceted, including consultation with the patient and their familes regarding their wishes, with consideration of the patient's quality of life, functional status, medical comorbid conditions, social support, and treatment toxicity risk. Geriatric assessment is a systematic and validated approach to assess an older adults's potential strengths and vulnerabilities, which can in turn be used to assist with comprehensive cancer care planning and support. In this review, we will summarize current treatment approaches for older adults with CRC, with a particular focus on the incorporation of the geriatric assessment.

SARC-F as a screening tool to detect computed tomography-based sarcopenia and myosteatosis among older adults with cancer.

BACKGROUND: The European Working Group on Sarcopenia in Older People (EWGSOP) recommends SARC-F as a tool for identifying sarcopenia among older adults. However, the role of SARC-F among older adults with cancer remains unexplored. We aimed to evaluate the diagnostic utility of SARC-F to identify those with sarcopenia, or low muscle mass (using skeletal muscle index [SMI]), and myosteatosis (using skeletal muscle density [SMD]) from computed tomography (CT) imaging and the association of SARC-F with all-cause mortality. METHODS: Older adults (≥60 years) presenting for initial consultation at UAB medical oncology clinic who underwent geriatric assessment were enrolled in a prospective cohort study. We identified study participants who completed SARC-F screening and had available CT imaging within 60 days of study enrollment. Using single-slice CT images at the L3 vertebral level, we computed SMI and SMD using published methods. Sarcopenia and myosteatosis were defined using published cutpoints. We calculated the sensitivity and specificity of SARC-F for detecting low muscle mass and low muscle density using published thresholds. Finally, we computed the impact of SARC-F and CT measures on overall survival using Kaplan-Meier curves and Cox regression models, after adjusting for age, sex, cancer type, and cancer stage. RESULTS: We identified 212 older adults with a median age of 68.8 years; with 60.8% males, 76.6% whites, and pancreatic cancer (21.2%) being the most common malignancy. In the overall cohort, 30.7% had abnormal SARC-F using published cutpoints. SARC-F ≥ 4 had a sensitivity of 35% and a specificity of 76% to identify low muscle mass. SARC-F ≥ 4 had a sensitivity of 38% and a specificity of 74% to identify low muscle density. Those with SARC-F ≥ 4 and low SMI/SMD had worse survival compared to those with low SMI/SMD alone. Incorporating SARC-F improved survival prognostication beyond SMI and SMD (HR = 3.1; p < 0.001; Harrel's C from 0.73 to 0.76). CONCLUSIONS: SARC-F as a screening tool has limited diagnostic utility for identifying older adults with low muscle mass and/or density. However, SARC-F retains prognostic value independent of CT-based muscle measures in predicting mortality among older adults with cancer.

Insight into the nodal cells transcriptome of the streptophyte green alga Chara braunii S276.

Charophyceae are the most complex streptophyte algae, possessing tissue-like structures, rhizoids and a cellulose-pectin-based cell wall akin to embryophytes. Together with the Zygnematophyceae and the Coleochaetophycae, the Charophyceae form a grade in which the Zygnematophyceae share a last common ancestor with land plants. The availability of genomic data, its short life cycle, and the ease of non-sterile cultivation in the laboratory have made the species Chara braunii an emerging model system for streptophyte terrestrialization and early land plant evolution. In this study, tissue containing nodal cells was prepared under the stereomicroscope, and an RNA-seq dataset was generated and compared to transcriptome data from whole plantlets. In both samples, transcript coverage was high for genes encoding ribosomal proteins and a homolog of the putative PAX3- and PAX7-binding protein 1. Gene ontology was used to classify the putative functions of the differently expressed genes. In the nodal cell sample, main upregulated molecular functions were related to protein, nucleic acid, ATP- and DNA binding. Looking at specific genes, several signaling-related genes and genes encoding sugar-metabolizing enzymes were found to be expressed at a higher level in the nodal cell sample, while photosynthesis-and chloroplast-related genes were expressed at a comparatively lower level. We detected the transcription of 21 different genes encoding DUF4360-containing cysteine-rich proteins. The data contribute to the growing understanding of Charophyceae developmental biology by providing a first insight into the transcriptome composition of Chara nodal cells.

Anxiety is Associated With Geriatric Assessment Impairments and Reduced Quality of Life Among Older Adults With Colorectal Cancer: Results From the CARE Registry.

BACKGROUND: Colorectal cancer (CRC) preferentially affects older adults. Modifiable factors, such as anxiety, can be measured as part of cancer-specific geriatric assessments (GA) completed prior to the start of treatment. We hypothesized that anxiety is prevalent among older adults with CRC and is associated with increased depression, increased frailty, and impaired health-related quality of life (HRQOL). PATIENTS AND METHODS: Patients ≥60 years old with newly diagnosed CRC completed a cancer-specific GA called the Cancer and Aging Resilience Evaluation (CARE). Between September 2017 and February 2023, we analyzed patients with CRC who had not yet received any systemic treatment. Anxiety was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety 4-item short form and reported as t-scores. We used modified Poisson models with robust variance estimation to assess for differences in the prevalence of depression, frailty, and impaired HRQOL. RESULTS: We analyzed 277 older adults with CRC. The median age of the study sample was 68 years. 57% were male, 72% were non-Hispanic White, and most had advanced CRC (35% stage III and 39% stage IV). Moderate/severe anxiety was present in 17% of older adults with newly diagnosed CRC. In adjusted models, as compared to patients without moderate/severe anxiety, patients with moderate/severe anxiety had significantly increased risk of depression (prevalence ratio [PR] 7.60, CI 4.90-11.78), frailty (PR 4.93, CI 3.01-8.07), impaired physical HRQOL (PR 3.57, CI 2.03-6.28), and impaired mental HRQOL (PR 3.82, CI 2.12-6.89). CONCLUSION: Among older adults with CRC, anxiety is associated with increased depression and frailty as well as reduced HRQOL.

Convergence of multiple RNA-silencing pathways on GW182/TNRC6.

The RNA-binding protein TRIM71/LIN-41 is a phylogenetically conserved developmental regulator that functions in mammalian stem cell reprogramming, brain development, and cancer. TRIM71 recognizes target mRNAs through hairpin motifs and silences them through molecular mechanisms that await identification. Here, we uncover that TRIM71 represses its targets through RNA-supported interaction with TNRC6/GW182, a core component of the miRNA-induced silencing complex (miRISC). We demonstrate that AGO2, TRIM71, and UPF1 each recruit TNRC6 to specific sets of transcripts to silence them. As cellular TNRC6 levels are limiting, competition occurs among the silencing pathways, such that the loss of AGO proteins or of AGO binding to TNRC6 enhances the activities of the other pathways. We conclude that a miRNA-like silencing activity is shared among different mRNA silencing pathways and that the use of TNRC6 as a central hub provides a means to integrate their activities.

Mouse nuclear RNAi-defective 2 promotes splicing of weak 5' splice sites.

Removal of introns during pre-mRNA splicing, which is central to gene expression, initiates by base pairing of U1 snRNA with a 5' splice site (5'SS). In mammals, many introns contain weak 5'SSs that are not efficiently recognized by the canonical U1 snRNP, suggesting alternative mechanisms exist. Here, we develop a cross-linking immunoprecipitation coupled to a high-throughput sequencing method, BCLIP-seq, to identify NRDE2 (nuclear RNAi-defective 2), and CCDC174 (coiled-coil domain-containing 174) as novel RNA-binding proteins in mouse ES cells that associate with U1 snRNA and 5'SSs. Both proteins bind directly to U1 snRNA independently of canonical U1 snRNP-specific proteins, and they are required for the selection and effective processing of weak 5'SSs. Our results reveal that mammalian cells use noncanonical splicing factors bound directly to U1 snRNA to effectively select suboptimal 5'SS sequences in hundreds of genes, promoting proper splice site choice, and accurate pre-mRNA splicing.

Spontaneous Closure of a Coronary Artery Bypass Graft Pseudoaneurysm Embedded in a Mediastinal Hematoma.

Coronary artery bypass graft (CABG) pseudoaneurysms are a rare but often unrecognized clinical entity. They are prone to rupture and hemodynamic compromise and should therefore be on the differential in the appropriate patient. We present a case of a gentleman with a recent CABG surgery who presented with acute onset dyspnea and a large pleural effusion. Imaging revealed a saphenous vein graft pseudoaneurysm embedded in a mediastinal hematoma. Four weeks later, prior to planned stenting, the pseudoaneurysm had spontaneously closed. This case highlights an unusual acute presentation of a CABG pseudoaneurysm and a multidisciplinary approach to its management.

Static and Dynamic Accuracy and Occlusion Robustness of SteamVR Tracking 2.0 in Multi-Base Station Setups.

The tracking of objects and person position, orientation, and movement is relevant for various medical use cases, e.g., practical training of medical staff or patient rehabilitation. However, these demand high tracking accuracy and occlusion robustness. Expensive professional tracking systems fulfill these demands, however, cost-efficient and potentially adequate alternatives can be found in the gaming industry, e.g., SteamVR Tracking. This work presents an evaluation of SteamVR Tracking in its latest version 2.0 in two experimental setups, involving two and four base stations. Tracking accuracy, both static and dynamic, and occlusion robustness are investigated using a VIVE Tracker (3.0). A dynamic analysis further compares three different velocities. An error evaluation is performed using a Universal Robots UR10 robotic arm as ground-truth system under nonlaboratory conditions. Results are presented using the Root Mean Square Error. For static experiments, tracking errors in the submillimeter and subdegree range are achieved by both setups. Dynamic experiments achieved errors in the submillimeter range as well, yet tracking accuracy suffers from increasing velocity. Four base stations enable generally higher accuracy and robustness, especially in the dynamic experiments. Both setups enable adequate accuracy for diverse medical use cases. However, use cases demanding very high accuracy should primarily rely on SteamVR Tracking 2.0 with four base stations.

Differential phosphorylation of Clr4SUV39H by Cdk1 accompanies a histone H3 methylation switch that is essential for gametogenesis.

Methylation of histone H3 at lysine 9 (H3K9) is a hallmark of heterochromatin that plays crucial roles in gene silencing, genome stability, and chromosome segregation. In Schizosaccharomyces pombe, Clr4 mediates both di- and tri-methylation of H3K9. Although H3K9 methylation has been intensely studied in mitotic cells, its role during sexual differentiation remains unclear. Here, we map H3K9 methylation genome-wide during meiosis and show that constitutive heterochromatin temporarily loses H3K9me2 and becomes H3K9me3 when cells commit to meiosis. Cells lacking the ability to tri-methylate H3K9 exhibit meiotic chromosome segregation defects. Finally, the H3K9 methylation switch is accompanied by differential phosphorylation of Clr4 by the cyclin-dependent kinase Cdk1. Our results suggest that a conserved master regulator of the cell cycle controls the specificity of an H3K9 methyltransferase to prevent ectopic H3K9 methylation and to ensure faithful gametogenesis.

Immunoprecipitation of HDAC6 and Interacting Proteins.

The lysine deacetylase HDAC6 has unique structural and functional properties: It contains tandem catalytic domains that can deacetylate a variety of proteins and a zinc finger domain that binds ubiquitin. HDAC6 has been implicated in a variety of biological processes, normal or pathological, such as cellular motility, stress response, cancer, neurodegeneration, or viral infection. Due to this, HDAC6 is considered an attractive therapeutic target, and there is a major interest to identify small molecule inhibitors. To gain a mechanistic understanding of how HDAC6 impacts these different biological processes, there is a continued need to discover additional substrates as well as interacting proteins in different paradigms. One approach to achieve this is to perform HDAC6 immunoprecipitations to identify partner proteins. We describe here our optimized protocols to immunoprecipitate HDAC6 with the goal to identify or validate interacting proteins.

Anastomotic Height Is a Valuable Indicator of Long-term Bowel Function Following Surgery for Rectal Cancer.

BACKGROUND: The exact relation between anastomotic height after rectal cancer surgery and postoperative bowel function problems has not been investigated in the long term, resulting in ineffective treatment. OBJECTIVE: The goal of this study was to determine the effect of anastomotic height on long-term bowel function and generic quality of life. DESIGN: This was a multicenter, cross-sectional study. SETTINGS: Seven hospitals in the north of the Netherlands participated. PATIENTS: All patients who underwent rectal cancer surgery between 2009 and 2015 in participating hospitals received the validated Defecation and Fecal Continence and Short-Form 36 questionnaires. Deceased patients, patients with a permanent stoma or an anastomosis >15 cm from the anal verge, patients with intellectual disability, and patients living abroad were excluded. MAIN OUTCOME MEASURES: Primary outcomes were constipation (Rome IV), fecal incontinence (Rome IV), and major low anterior resection syndrome. Secondary outcomes were the generic quality of life scores. RESULTS: The study population ( n = 630) had a median follow-up of 58.0 months. In multivariable analysis, constipation (OR = 1.08; 95% CI, 1.02-1.15; p = 0.011), fecal incontinence (OR = 0.91; 95% CI, 0.84-0.97; p = 0.006), and major low anterior resection syndrome (OR = 0.93; 95% CI, 0.87-0.99; p = 0.027), were significantly associated with anastomotic height. The curves illustrating the probability of constipation and fecal incontinence crossed at an anastomotic height of 7 cm, with 95% CIs overlapping between 4.5 and 9.5 cm. There was no relation between quality-of-life scores and anastomotic height. LIMITATIONS: The study is limited by its cross-sectional design. CONCLUSIONS: This study might serve as a guide for the clinician to effectively screen and treat fecal incontinence and constipation during patient follow-up after rectal cancer surgery. More attention should be paid to fecal incontinence in patients with an anastomosis below 4.5 cm and toward constipation in patients with an anastomosis above 9.5 cm. See Video Abstract at http://links.lww.com/DCR/B858 . LA ALTURA ANASTOMTICA ES UN INDICADOR VALIOSO DE LA FUNCIN INTESTINAL A LARGO PLAZO DESPUS DE LA CIRUGA PARA EL CNCER DE RECTO: ANTECEDENTES:La relación exacta entre la altura anastomótica después de la cirugía de cáncer de recto y los problemas posoperatorios de la función intestinal no se ha investigado a largo plazo, lo que causa un tratamiento ineficaz.OBJETIVO:Determinar el efecto de la altura anastomótica sobre la función intestinal a largo plazo y la calidad de vida genérica.DISEÑO:Estudio multicéntrico transversal.DISEÑO DEL ESTUDIO:Participaron siete hospitales holandeses en el norte de los Países Bajos.PACIENTES:Todos los pacientes que se sometieron a cirugía de cáncer de recto entre 2009 y 2015 en los hospitales participantes recibieron los cuestionarios validados de Defecación y Continencia Fecal y Short-Form 36. Se excluyeron pacientes fallecidos, pacientes con estoma permanente o anastomosis > 15 cm del borde anal, discapacidad intelectual o residentes en el extranjero.PRINCIPALES MEDIDAS DE RESULTADO:Los resultados primarios fueron estreñimiento (Roma IV), incontinencia fecal (Roma IV) y síndrome de resección anterior baja mayor. Los resultados secundarios fueron las puntuaciones genéricas de calidad de vida.RESULTADOS:La población de estudio (N = 630) tuvo una mediana de seguimiento de 58.0 meses. En el análisis multivariable el estreñimiento (OR = 1,08, IC del 95%, 1,02-1,15, p = 0,011), incontinencia fecal (OR = 0,91, IC del 95%, 0,84-0,97, p = 0,006) y síndrome de resección anterior baja mayor (OR = 0,93, IC del 95%, 0,87-0,99, p = 0,027) se asociaron significativamente con la altura anastomótica. Las curvas que ilustran la probabilidad de estreñimiento e incontinencia fecal se cruzaron a una altura anastomótica de 7 cm, con IC del 95% superpuestos entre 4,5 y 9,5 cm. No hubo relación entre las puntuaciones de calidad de vida y la altura anastomótica.LIMITACIONES:El estudio está limitado por su diseño transversal.CONCLUSIONES:Este estudio podría servir como una guía para que el médico evalúe y trate eficazmente la incontinencia fecal y el estreñimiento durante el seguimiento de los pacientes después de la cirugía de cáncer de recto. Se debe prestar más atención a la incontinencia fecal en pacientes con anastomosis por debajo de 4,5 cm y al estreñimiento en pacientes con anastomosis por encima de 9,5 cm. Consulte Video Resumen en http://links.lww.com/DCR/B858 . (Traducción-Dr. Yazmin Berrones-Medina ).

Long-term Bowel Dysfunction and Decline in Quality of Life Following Surgery for Colon Cancer: Call for Personalized Screening and Treatment.

BACKGROUND: Differences in long-term outcomes regarding types of colon resections are inconclusive, precluding patient counseling, effective screening, and personalized treatment. OBJECTIVE: This study aimed to compare long-term bowel function and quality of life in patients who underwent right or left hemicolectomy or sigmoid colon resection. DESIGN: This was a multicenter cross-sectional study. SETTINGS: Seven Dutch hospitals participated in this study. PATIENTS: This study included patients who underwent right or left hemicolectomy or sigmoid colon resection without construction of a permanent stoma between 2009 and 2015. Patients who were deceased, mentally impaired, or living abroad were excluded. Eligible patients were sent the validated Defecation and Fecal Continence and Short-Form 36 questionnaires. MAIN OUTCOME MEASURES: Constipation, fecal incontinence (both Rome IV criteria), separate bowel symptoms, and generic quality of life were the main outcomes assessed. RESULTS: This study included 673 patients who underwent right hemicolectomy, 167 who underwent left hemicolectomy, and 284 who underwent sigmoid colon resection. The median follow-up was 56 months. Sigmoid colon resection increased the likelihood of constipation compared to right and left hemicolectomy (OR, 2.92; 95% CI, 1.80-4.75; p < 0.001 and OR, 1.93; 95% CI, 1.12-3.35; p = 0.019). Liquid incontinence and fecal urgency increased after right hemicolectomy compared to sigmoid colon resection (OR, 2.15; 95% CI, 1.47-3.16; p < 0.001 and OR, 2.01; 95% CI, 1.47-2.74; p < 0.001). Scores on quality-of-life domains were found to be significantly lower after right hemicolectomy. LIMITATIONS: Because of the cross-sectional design, longitudinal data are still lacking. CONCLUSIONS: Different long-term bowel function problems occur after right or left hemicolectomy or sigmoid colon resection. The latter seems to be associated with more constipation than right or left hemicolectomy. Liquid incontinence and fecal urgency seem to be associated with right hemicolectomy, which may explain the decline in physical and mental generic quality of life of these patients. See Video Abstract at http://links.lww.com/DCR/C13 . DISFUNCIN INTESTINAL A LARGO PLAZO Y DISMINUCIN DE LA CALIDAD DE VIDA DESPUS DE LA CIRUGA DE CNCER DE COLON SOLICITUD DE DETECCIN Y TRATAMIENTO PERSONALIZADOS: ANTECEDENTES:Las diferencias en los resultados a largo plazo con respecto a los tipos de resecciones de colon no son concluyentes, lo que impide el asesoramiento preoperatorio del paciente y la detección eficaz y el tratamiento personalizado de la disfunción intestinal postoperatoria durante el seguimiento.OBJETIVO:Comparar la función intestinal a largo plazo y la calidad de vida en pacientes sometidos a hemicolectomía derecha o izquierda, o resección de colon sigmoide.DISEÑO:Estudio transversal multicéntrico.AJUSTES:Participaron siete hospitales holandeses.PACIENTES:Se incluyeron pacientes sometidos a hemicolectomía derecha o izquierda, o resección de colon sigmoide sin construcción de estoma permanente entre 2009 y 2015. Se excluyeron pacientes fallecidos, con discapacidad mental o residentes en el extranjero. A los pacientes elegibles se les enviaron los cuestionarios validados de Defecación y Continencia Fecal y Short-Form 36.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron el estreñimiento, la incontinencia fecal (ambos criterios de Roma IV), los síntomas intestinales separados y la calidad de vida genérica.RESULTADOS:Se incluyeron 673 pacientes con hemicolectomía derecha, 167 con hemicolectomía izquierda y 284 con resección de colon sigmoide. La mediana de seguimiento fue de 56 meses (RIC 41-80). La resección del colon sigmoide aumentó la probabilidad de estreñimiento en comparación con la hemicolectomía derecha e izquierda (OR, 2,92, IC 95%, 1,80-4,75, p < 0,001 y OR 1,93, IC 95%, 1,12-3,35, p = 0,019). La incontinencia de líquidos y la urgencia fecal aumentaron después de la hemicolectomía derecha en comparación con la resección del colon sigmoide (OR, 2,15, IC 95%, 1,47-3,16, p < 0,001 y OR 2,01, IC 95%, 1,47-2,74, p < 0,001). Las puntuaciones en los dominios de calidad de vida fueron significativamente más bajas después de la hemicolectomía derecha.LIMITACIONES:Debido al diseño transversal, aún faltan datos longitudinales.CONCLUSIONES:Se producen diferentes problemas de función intestinal a largo plazo después de la hemicolectomía derecha o izquierda, o la resección del colon sigmoide. Este último parece estar asociado con más estreñimiento que la hemicolectomía derecha o izquierda. La incontinencia de líquidos y la urgencia fecal parecen estar asociadas a la hemicolectomía derecha, lo que puede explicar el deterioro de la calidad de vida física y mental en general de estos pacientes. Consulte Video Resumen en http://links.lww.com/DCR/C13 . (Traducción-Dr. Yolanda Colorado ).

SETDB1-like MET-2 promotes transcriptional silencing and development independently of its H3K9me-associated catalytic activity.

Transcriptionally silenced heterochromatin bearing methylation of histone H3 on lysine 9 (H3K9me) is critical for maintaining organismal viability and tissue integrity. Here we show that in addition to ensuring H3K9me, MET-2, the Caenorhabditis elegans homolog of the SETDB1 histone methyltransferase, has a noncatalytic function that contributes to gene repression. Subnuclear foci of MET-2 coincide with H3K9me deposition, yet these foci also form when MET-2 is catalytically deficient and H3K9me is compromised. Whereas met-2 deletion triggers a loss of silencing and increased histone acetylation, foci of catalytically deficient MET-2 maintain silencing of a subset of genes, blocking acetylation on H3K9 and H3K27. In normal development, this noncatalytic MET-2 activity helps to maintain fertility. Under heat stress MET-2 foci disperse, coinciding with increased acetylation and transcriptional derepression. Our study suggests that the noncatalytic, focus-forming function of this SETDB1-like protein and its intrinsically disordered cofactor LIN-61 is physiologically relevant.

BANP opens chromatin and activates CpG-island-regulated genes.

The majority of gene transcripts generated by RNA polymerase II in mammalian genomes initiate at CpG island (CGI) promoters1,2, yet our understanding of their regulation remains limited. This is in part due to the incomplete information that we have on transcription factors, their DNA-binding motifs and which genomic binding sites are functional in any given cell type3-5. In addition, there are orphan motifs without known binders, such as the CGCG element, which is associated with highly expressed genes across human tissues and enriched near the transcription start site of a subset of CGI promoters6-8. Here we combine single-molecule footprinting with interaction proteomics to identify BTG3-associated nuclear protein (BANP) as the transcription factor that binds this element in the mouse and human genome. We show that BANP is a strong CGI activator that controls essential metabolic genes in pluripotent stem and terminally differentiated neuronal cells. BANP binding is repelled by DNA methylation of its motif in vitro and in vivo, which epigenetically restricts most binding to CGIs and accounts for differential binding at aberrantly methylated CGI promoters in cancer cells. Upon binding to an unmethylated motif, BANP opens chromatin and phases nucleosomes. These findings establish BANP as a critical activator of a set of essential genes and suggest a model in which the activity of CGI promoters relies on methylation-sensitive transcription factors that are capable of chromatin opening.