Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy.

There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo.

Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma.

ABSTRACT: B-cell maturation antigen (BCMA)-targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 × BCMA bispecific antibody, 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy-naïve patients. Prior therapy-mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and 1 of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from 1 patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA-directed treatments, underscoring the importance of verifying the presence of a target antigen.

Symmetry in Frontal But Not Motor and Somatosensory Cortical Projections.

The neocortex and striatum are topographically organized for sensory and motor functions. While sensory and motor areas are lateralized for touch and motor control, respectively, frontal areas are involved in decision-making, where lateralization of function may be less important. This study contrasted the topographic precision of cell-type-specific ipsilateral and contralateral cortical projections while varying the injection site location in transgenic mice of both sexes. While sensory cortical areas had strongly topographic outputs to the ipsilateral cortex and striatum, they were weaker and not as topographically precise to contralateral targets. The motor cortex had somewhat stronger projections but still relatively weak contralateral topography. In contrast, frontal cortical areas had high degrees of topographic similarity for both ipsilateral and contralateral projections to the cortex and striatum. Corticothalamic organization is mainly ipsilateral, with weaker, more medial contralateral projections. Corticostriatal computations might integrate input outside closed basal ganglia loops using contralateral projections, enabling the two hemispheres to act as a unit to converge on one result in motor planning and decision-making.

Identifying biochemical changes in the kidney using proton nuclear magnetic resonance in an adenine diet chronic kidney disease mouse model.

This study aimed to investigate the metabolic changes in the kidneys in a murine adenine-diet model of chronic kidney disease (CKD). Kidney fibrosis is the common pathological manifestation across CKD aetiologies. Sustained inflammation and fibrosis cause changes in preferred energy metabolic pathways in the cells of the kidney. Kidney cortical tissue from mice receiving a control or adenine-supplemented diet for 8 weeks (late inflammation and fibrosis) and 12 weeks (8 weeks of treatment followed by 4 weeks recovery) were analysed by 2D-correlated nuclear magnetic resonance spectroscopy and compared with histopathology and biomarkers of kidney damage. Tissue metabolite and lipid levels were assessed using the MestreNova software. Expression of genes related to inflammation, fibrosis, and metabolism were measured using quantitative polymerase chain reaction. Animals showed indicators of severely impaired kidney function at 8 and 12 weeks. Significantly increased fibrosis was present at 8 weeks but not in the recovery group suggesting some reversal of fibrosis and amelioration of inflammation. At 8 weeks, metabolites associated with glycolysis were increased, while lipid signatures were decreased. Genes involved in fatty acid oxidation were decreased at 8 weeks but not 12 weeks while genes associated with glycolysis were significantly increased at 8 weeks but not at 12 weeks. In this murine model of CKD, kidney fibrosis was associated with the accumulation of triglyceride and free lactate. There was an up-regulation of glycolytic enzymes and down-regulation of lipolytic enzymes. These metabolic changes reflect the energy demands associated with progressive kidney disease where there is a switch from fatty acid oxidation to that of glycolysis.

Atypical placental site nodules: Clinicopathologic features, management and patient outcomes in an institutional series.

OBJECTIVE: To report the New England Trophoblastic Disease Center (NETDC) experience with atypical placental site nodules (APSN). METHODS: The NETDC registry was reviewed from 2005 to 2022 and clinical data abstracted. Expert pathologists in GTD reviewed available slides with concurrent immunohistochemical analysis. Targeted deep sequencing was performed for four cases. RESULTS: Among 35 cases of APSN identified, 29 had clinical and demographic data available. Abnormal uterine bleeding (59.3%) was the most common presenting symptom. Most women (79.3%) had an antecedent live birth. Two cases were incidentally diagnosed after hysterectomy for other indications, and one case lost to follow-up. Among the remaining 26 cases, 11 (42.3%) opted for hysterectomy and 15 for re-sampling (57.7%), among whom 3 later underwent hysterectomy for persistent APSN. Subsequent obstetrical outcomes included 3 spontaneous abortions, 1 therapeutic abortion, 1 ectopic pregnancy, 2 cesarean sections, 1 cesarean hysterectomy, and 1 spontaneous vaginal delivery. Subsequent pathology was available for 26 cases: 4 epithelioid trophoblastic tumors (15.4%), 9 APSN (34.6%), 3 PSN (11.5%), and 10 without abnormalities (38.4%). Histopathologic characteristics of APSN included moderate to severe cytologic atypia, median Ki-67 proliferation index of 8%, and typical immunohistochemical profiles (diffuse or multifocal positivity for p63 and GATA-3 and absent or focal CD146). No histopathologic feature predicted ETT. Among 4 sequenced cases, no recurrent genomic features were identified. CONCLUSIONS: APSN is a rare form of gestational trophoblastic proliferation with uncertain malignant potential. While normal obstetric outcomes are possible, the persistence rate is high, and definitive management remains hysterectomy.

Corneal confocal microscopy detects early nerve regeneration after pharmacological and surgical interventions: Systematic review and meta-analysis.

Corneal confocal microscopy (CCM) is an ophthalmic imaging technique that enables the identification of corneal nerve fibre degeneration and regeneration. To undertake a systematic review and meta-analysis of studies utilizing CCM to assess for corneal nerve regeneration after pharmacological and surgical interventions in patients with peripheral neuropathy. Databases (EMBASE [Ovid], PubMed, CENTRAL and Web of Science) were searched to summarize the evidence from randomized and non-randomized studies using CCM to detect corneal nerve regeneration after pharmacological and surgical interventions. Data synthesis was undertaken using RevMan web. Eighteen studies including 958 patients were included. CCM identified an early (1-8 months) and longer term (1-5 years) increase in corneal nerve measures in patients with peripheral neuropathy after pharmacological and surgical interventions. This meta-analysis confirms the utility of CCM to identify nerve regeneration following pharmacological and surgical interventions. It could be utilized to show a benefit in clinical trials of disease modifying therapies for peripheral neuropathy.

Peritoneal dialysis versus haemodialysis for people commencing dialysis.

BACKGROUND: Peritoneal dialysis (PD) and haemodialysis (HD) are two possible modalities for people with kidney failure commencing dialysis. Only a few randomised controlled trials (RCTs) have evaluated PD versus HD. The benefits and harms of the two modalities remain uncertain. This review includes both RCTs and non-randomised studies of interventions (NRSIs). OBJECTIVES: To evaluate the benefits and harms of PD, compared to HD, in people with kidney failure initiating dialysis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies from 2000 to June 2024 using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. MEDLINE and EMBASE were searched for NRSIs from 2000 until 28 March 2023. SELECTION CRITERIA: RCTs and NRSIs evaluating PD compared to HD in people initiating dialysis were eligible. DATA COLLECTION AND ANALYSIS: Two investigators independently assessed if the studies were eligible and then extracted data. Risk of bias was assessed using standard Cochrane methods, and relevant outcomes were extracted for each report. The primary outcome was residual kidney function (RKF). Secondary outcomes included all-cause, cardiovascular and infection-related death, infection, cardiovascular disease, hospitalisation, technique survival, life participation and fatigue. MAIN RESULTS: A total of 153 reports of 84 studies (2 RCTs, 82 NRSIs) were included. Studies varied widely in design (small single-centre studies to international registry analyses) and in the included populations (broad inclusion criteria versus restricted to more specific participants). Additionally, treatment delivery (e.g. automated versus continuous ambulatory PD, HD with catheter versus arteriovenous fistula or graft, in-centre versus home HD) and duration of follow-up varied widely. The two included RCTs were deemed to be at high risk of bias in terms of blinding participants and personnel and blinding outcome assessment for outcomes pertaining to quality of life. However, most other criteria were assessed as low risk of bias for both studies. Although the risk of bias (Newcastle-Ottawa Scale) was generally low for most NRSIs, studies were at risk of selection bias and residual confounding due to the constraints of the observational study design. In children, there may be little or no difference between HD and PD on all-cause death (6 studies, 5752 participants: RR 0.81, 95% CI 0.62 to 1.07; I2 = 28%; low certainty) and cardiovascular death (3 studies, 7073 participants: RR 1.23, 95% CI 0.58 to 2.59; I2 = 29%; low certainty), and was unclear for infection-related death (4 studies, 7451 participants: RR 0.98, 95% CI 0.39 to 2.46; I2 = 56%; very low certainty). In adults, compared with HD, PD had an uncertain effect on RKF (mL/min/1.73 m2) at six months (2 studies, 146 participants: MD 0.90, 95% CI 0.23 to 3.60; I2 = 82%; very low certainty), 12 months (3 studies, 606 participants: MD 1.21, 95% CI -0.01 to 2.43; I2 = 81%; very low certainty) and 24 months (3 studies, 334 participants: MD 0.71, 95% CI -0.02 to 1.48; I2 = 72%; very low certainty). PD had uncertain effects on residual urine volume at 12 months (3 studies, 253 participants: MD 344.10 mL/day, 95% CI 168.70 to 519.49; I2 = 69%; very low certainty). PD may reduce the risk of RKF loss (3 studies, 2834 participants: RR 0.55, 95% CI 0.44 to 0.68; I2 = 17%; low certainty). Compared with HD, PD had uncertain effects on all-cause death (42 studies, 700,093 participants: RR 0.87, 95% CI 0.77 to 0.98; I2 = 99%; very low certainty). In an analysis restricted to RCTs, PD may reduce the risk of all-cause death (2 studies, 1120 participants: RR 0.53, 95% CI 0.32 to 0.86; I2 = 0%; moderate certainty). PD had uncertain effects on both cardiovascular (21 studies, 68,492 participants: RR 0.96, 95% CI 0.78 to 1.19; I2 = 92%) and infection-related death (17 studies, 116,333 participants: RR 0.90, 95% CI 0.57 to 1.42; I2 = 98%) (both very low certainty). Compared with HD, PD had uncertain effects on the number of patients experiencing bacteraemia/bloodstream infection (2 studies, 2582 participants: RR 0.34, 95% CI 0.10 to 1.18; I2 = 68%) and the number of patients experiencing infection episodes (3 studies, 277 participants: RR 1.23, 95% CI 0.93 to 1.62; I2 = 20%) (both very low certainty). PD may reduce the number of bacteraemia/bloodstream infection episodes (2 studies, 2637 participants: RR 0.44, 95% CI 0.27 to 0.71; I2 = 24%; low certainty). Compared with HD; It is uncertain whether PD reduces the risk of acute myocardial infarction (4 studies, 110,850 participants: RR 0.90, 95% CI 0.74 to 1.10; I2 = 55%), coronary artery disease (3 studies, 5826 participants: RR 0.95, 95% CI 0.46 to 1.97; I2 = 62%); ischaemic heart disease (2 studies, 58,374 participants: RR 0.86, 95% CI 0.57 to 1.28; I2 = 95%), congestive heart failure (3 studies, 49,511 participants: RR 1.10, 95% CI 0.54 to 2.21; I2 = 89%) and stroke (4 studies, 102,542 participants: RR 0.94, 95% CI 0.90 to 0.99; I2 = 0%) because of low to very low certainty evidence. Compared with HD, PD had uncertain effects on the number of patients experiencing hospitalisation (4 studies, 3282 participants: RR 0.90, 95% CI 0.62 to 1.30; I2 = 97%) and all-cause hospitalisation events (4 studies, 42,582 participants: RR 1.02, 95% CI 0.81 to 1.29; I2 = 91%) (very low certainty). None of the included studies reported specifically on life participation or fatigue. However, two studies evaluated employment. Compared with HD, PD had uncertain effects on employment at one year (2 studies, 593 participants: RR 0.83, 95% CI 0.20 to 3.43; I2 = 97%; very low certainty). AUTHORS' CONCLUSIONS: The comparative effectiveness of PD and HD on the preservation of RKF, all-cause and cause-specific death risk, the incidence of bacteraemia, other vascular complications (e.g. stroke, cardiovascular events) and patient-reported outcomes (e.g. life participation and fatigue) are uncertain, based on data obtained mostly from NRSIs, as only two RCTs were included.

Genome-wide gene expression responses to experimental manipulation of Saccharomyces cerevisiae repressor activator protein 1 (Rap1) expression level.

Precise regulation of transcription in gene expression is critical for all aspects of normal organism form, fitness, and function and even minor alterations in the level, location, and timing of gene expression can result in phenotypic variation within and between species including evolutionary innovations and human disease states. Eukaryotic transcription is regulated by a complex interplay of multiple factors working both at a physical and molecular levels influencing this process. In Saccharomyces cerevisiae, the TF with the greatest number of putative regulatory targets is the essential gene Repressor Activator Protein 1 (RAP1). While much is known about the roles of Rap1 in gene regulation and numerous cellular processes, the response of Rap1 target genes to systematic titration of RAP1 expression level remains unknown. To fill this knowledge gap, we used a strain with a tetracycline-titratable promoter replacing wild-type regulatory sequences of RAP1 to systematically reduce the expression level of RAP1 and followed this with RNA sequencing (RNA-seq) to measure genome-wide gene expression responses. Previous research indicated that Rap1 plays a significant regulatory role in particular groups of genes including telomere-proximal genes, homothallic mating (HM) loci, glycolytic genes, DNA repair genes, and ribosomal protein genes; therefore, we focused our analyses on these groups and downstream targets to determine how they respond to reductions in RAP1 expression level. Overall, despite being known as both an activator and as a repressor of its target genes, we found that Rap1 acts as an activator for more target genes than as a repressor. Additionally, we found that Rap1 functions as an activator of ribosomal protein genes and a repressor for HM loci genes consistent with predictions from the literature. Unexpectedly, we found that Rap1 functions as a repressor of glycolytic enzyme genes contrary to prior reports of it having the opposite effect. We also compared the expression of RAP1 to five different genes related to DNA repair pathway and found that decreasing RAP1 downregulated four of those five genes. Finally, we found no effect of RAP1 depletion on telomere-proximal genes despite its functioning to silence telomeric repeat-containing RNAs. Together our results enrich our understanding of this important transcriptional regulator.

Changes in Shoulder Rotation Based on Elevation in Children With Brachial Plexus Birth Injury.

PURPOSE: Lack of shoulder external rotation is common in children with brachial plexus birth injuries. Development of glenohumeral (GH) dysplasia is associated with progressive loss of passive external rotation. Some authors recommend measuring external rotation with the arm adducted, whereas others recommend measurement with the arm in 90° of abduction. The purpose of this study was to compare active and passive external rotation and internal rotation measured in adduction versus abduction. METHODS: Fifteen children with brachial plexus birth injuries held their affected arms in maximal external and internal rotation with the arm adducted and the arm at approximately 90° of abduction. Active and passive rotations were measured with three-dimensional motion capture. Scapulothoracic (ST) internal/external rotation and GH internal/external rotation joint angles were calculated and compared using multivariable, one-way repeated measures analyses of variance. RESULTS: There were no significant differences for active or passive ST rotation in external rotation in adduction versus abduction. Glenohumeral external rotation was significantly increased with the arm in abduction compared with adduction both actively and passively. There were no differences in ST rotation in active versus passive conditions, but all GH rotations were significantly greater passively. CONCLUSIONS: Shoulder internal/external rotation in abduction and adduction is not interchangeable. Comprehensive assessment of shoulder external and internal rotation should include both adduction and abduction. CLINICAL RELEVANCE: For children with brachial plexus birth injuries, both active and passive GH external rotations were greater in abduction. Therefore, early GH joint dysplasia may be missed if GH external rotation is measured in abduction. Additionally, consistency in arm position is important for comparison over time. The entire ST rotation capacity was used to perform maximal internal and external rotation, but the entire passive GH range of motion was not actively used. This highlights an area for potential surgical intervention to improve motion.

Evaluation of Upper Extremity Reachable Workspace in Children With Brachial Plexus Birth Injury.

PURPOSE: Brachial plexus birth injury (BPBI) results in upper extremity (UE) movement limitations. Current assessments of UE function used to inform clinical decision-making only evaluate a limited set of static postures and/or movements and have been criticized for being insensitive to certain meaningful differences in function. Reachable workspace provides a numeric and visual assessment of global UE movement ability by quantifying the regions in space that patients can reach with their hands, and it can be collected using real-time feedback to elicit a best-effort acquisition of function. This study evaluated the ability of a real-time feedback reachable workspace tool to assess UE movement in BPBI. METHODS: Twenty-two children with BPBI participated. Reachable workspace data were collected with three-dimensional motion capture using real-time visual feedback to measure UE reaching ability in all regions surrounding the body. All outer, far-from-body points reached by the hand were recorded and analyzed by region. A two-way, within-subjects analysis of variance was used to assess interlimb differences in percentage workspace reached and median reach distance for each of the six regions. RESULTS: The affected limb had significantly less percentage workspace reached than the unaffected limb for all six regions (mean interlimb differences by region, 5.7%-38.6%). The affected limb had significantly less median reach distance than the unaffected limb for all six regions (mean interlimb differences by region, 3.1%-36.8%). CONCLUSIONS: The workspace approach was capable of detecting UE movement impairments of the BPBI-affected limb. The reported deficits in workspace on the affected limb correspond to common movement impairments in BPBI, such as limitations in shoulder elevation, external rotation, extension, and elbow extension. CLINICAL RELEVANCE: The real-time feedback reachable workspace tool is sufficiently robust for assessing UE movement impairments in children with BPBI.

Impact of tendon transfer on scapulothoracic and glenohumeral motion in children with brachial plexus birth injuries.

BACKGROUND: Tendon transfers are often utilized to improve shoulder external rotation and abduction in children with brachial plexus birth injuries and are designed to improve glenohumeral (GH) joint motion. However, changes in scapulothoracic (ST) and glenohumeral (GH) joint function after tendon transfer are not well defined. The purpose of this study was to quantify changes in GH, ST, and humerothoracic (HT) joint function before and after tendon transfer, and we hypothesized that tendon transfers would reorient the arc of motion into more external rotation and abduction, but not increase GH motion. METHODS: Motion analysis was performed in 15 children (ages 3-16) before and after transfer of teres major and/or latissimus dorsi. Scapulothoracic, GH, and HT joint angles were measured in a neutral, resting position and each of the modified Mallet positions. Joint angular displacements from the neutral position and the total arc of internal-external rotation for each joint were also calculated. Relevant joint angles, joint angular displacements, and internal-external rotation arcs were compared using multivariate analyses of variance with repeated measures and univariate post-hoc analyses. RESULTS: Glenohumeral and HT external rotation were significantly increased in all positions postoperatively. The arc of GH internal-external rotation was unchanged, but oriented in more external rotation after surgery. Only 6 patients gained active external rotation. Glenohumeral and HT internal rotation were significantly decreased after surgery, but ST internal rotation was significantly increased. Two patients had loss of midline function. In the abduction position, GH elevation joint angles were unchanged, but ST and HT elevation increased. DISCUSSION: Only four patients gained active GH external rotation and maintained their internal rotation. Each of those patients underwent isolated tendon transfer without concomitant joint release. Seven patients maintained their preoperative internal rotation, which was attributed to increased ST internal rotation. The other half of patients lost internal rotation and gained external rotation through reorientation of the arc of rotation. Nine patients gained HT elevation, with three attributed to increased ST upward rotation, five attributed to a combination of increased ST upward rotation and increased GH elevation, and one attributed to increased GH abduction contracture. These findings challenge the dogma that teres major/latissimus dorsi tendon transfers augment GH motion and highlight the importance of ST function for outcome determination.

Shoulder Motion Overestimated by Mallet Scores.

BACKGROUND: Brachial plexus birth injuries (BPBI) occur in up 0.4 to 4.6 per 1000 live births. Weakness about the shoulder and development of glenohumeral joint contractures are common sequalae of BPBI. Shoulder function in children with BPBI is frequently assessed using the modified Mallet classification to evaluate upper extremity motion deficits. The purpose of this study was to assess the accuracy of the abduction, external rotation, and hand-to-mouth Mallet classification scores in children with BPBI using motion capture. METHODS: A retrospective study of 107 children with BPBI who underwent motion capture assessment and Mallet scores on the same date were reviewed. Motion capture measurements were used to calculate humerothoracic elevation and external rotation joint angles in the abduction/hand-to-mouth and external rotation positions, respectively. The humerothoracic joint angles were converted to the corresponding Mallet scores. Discrepancies between the Mallet scores determined by clinicians and those determined by motion capture were assessed. RESULTS: For abduction, 24.3% of Mallet scores were misclassified during clinical examination. Of the misclassified scores, 22 were overestimated by 1 point and 4 were underestimated by 1 point compared with motion capture. For external rotation, 72.9% of Mallet scores were misclassified during clinical examination. Only 5 patients had an HT elevation that was less than 40 degrees, with 4 of them (80%) having a Mallet hand-to-mouth score of 4. There were no differences in proportion of patients with HT elevation less than 40 degrees who had a Mallet score of 4 or a Mallet score less than 4. CONCLUSIONS: There was better agreement in global abduction Mallet scores compared with external rotation and hand-to-mouth Mallet scores. This difference was likely due to the complex compensatory strategies that patients employ while performing external rotation and hand-to-mouth positions. The inaccuracy of the clinically determined Mallet scores is alarming given that they are frequently utilized to assist with surgical indications and are commonly used as outcome measures. LEVEL OF EVIDENCE: Level IV Case series.

MYB-bHLH-TTG1 in a Multi-tiered Pathway Regulates Arabidopsis Seed Coat Mucilage Biosynthesis Genes Including PECTIN METHYLESTERASE INHIBITOR14 Required for Homogalacturonan Demethylesterification.

MYB-bHLH-TTG1 (MBW) transcription factor (TF) complexes regulate Arabidopsis seed coat biosynthesis pathways via a multi-tiered regulatory mechanism. The MYB genes include MYB5, MYB23 and TRANSPARENT TESTA2 (TT2), which regulate GLABRA2 (GL2), HOMEODOMAIN GLABROUS2 (HDG2) and TRANSPARENT TESTA GLABRA2 (TTG2). Here, we examine the role of PECTIN METHYLESTERASE INHIBITOR14 (PMEI14) in seed coat mucilage pectin methylesterification and provide evidence in support of multi-tiered regulation of seed coat mucilage biosynthesis genes including PMEI14. The PMEI14 promoter was active in the seed coat and developing embryo. A pmei14 mutant exhibited stronger attachment of the outer layer of seed coat mucilage, increased mucilage homogalacturonan demethylesterification and reduced seed coat radial cell wall thickness, results consistent with decreased PMEI activity giving rise to increased PME activity. Reduced mucilage release from the seeds of myb5, myb23, tt2 and gl2, hdg2, ttg2 triple mutants indicated that HDG2 and MYB23 play minor roles in seed coat mucilage deposition. Chromatin immunoprecipitation analysis found that MYB5, TT8 and seven mucilage pathway structural genes are directly regulated by MYB5. Expression levels of GL2, HDG2, TTG2 and nine mucilage biosynthesis genes including PMEI14 in the combinatorial mutant seeds indicated that these genes are positively regulated by at least two of those six TFs and that TTG1 and TTG2 are major regulators of PMEI14 expression. Our results show that MYB-bHLH-TTG1 complexes regulate mucilage biosynthesis genes, including PMEI14, both directly and indirectly via a three-tiered mechanism involving GL2, HDG2 and TTG2.

The sublingual microcirculation and frailty index in chronic kidney disease patients.

OBJECTIVE: To examine the relationship between sublingual microcirculatory measures and frailty index in those attending a kidney transplant assessment clinic. METHODS: Patients recruited had their sublingual microcirculation taken using sidestream dark field videomicroscopy (MicroScan, Micro Vision Medical, Amsterdam, the Netherlands) and their frailty index score using a validated short form via interview. RESULTS: A total of 44 patients were recruited with two being excluded due to microcirculatory image quality scores exceeding 10. The frailty index score indicated significant correlations with total vessel density (p < .0001, r = -.56), microvascular flow index (p = .004, r = -.43), portion of perfused vessels (p = .0004, r = -.52), heterogeneity index (p = .015, r = .32), and perfused vessel density (p < .0001, r = -.66). No correlation was shown between the frailty index and age (p = .08, r = .27). CONCLUSIONS: There is a relationship between the frailty index and microcirculatory health in those attending a kidney transplant assessment clinic, that is not confounded by age. These findings suggest that the impaired microcirculation may be an underlying cause of frailty.

EMACO for treatment of gestational trophoblastic neoplasia: A multinational multicenter study.

OBJECTIVE: To investigate the efficacy and toxicity of etoposide, methotrexate, actinomycin D alternating with cyclophosphamide, and vincristine (EMACO) for treatment of gestational trophoblastic neoplasia, and for factors independently associated with EMACO resistance and disease-specific death in an international cohort. METHODS: Medical records of GTN patients who received EMACO during 1986-2019 from gestational trophoblastic disease centers from four countries including the USA, Thailand, Hungary, and Brazil, were retrospectively reviewed. Among 335 GTN patients, 266 patients who received EMACO as primary chemotherapy were included in the primary treatment group, and 69 patients who received EMACO after relapse/resistance to single-agent chemotherapy were included in the prior treatment group. RESULTS: Three-quarters (76.1%) of all patients achieved remission, and the survival rate was 89%. The prior treatment group had better outcomes than the primary treatment group relative to remission rate (87.0% vs. 73.3%, p = 0.014) and number of EMACO cycles to achieve remission (3 vs. 6 cycles, p < 0.001). Sustained remission increased to 87.2% in EMACO-resistant patients treated with later-line chemotherapy. Number of metastatic organs ≥2 (adjusted odds ratio [aOR]: 2.33, p = 0.049) was the only independent predictor of EMACO resistance among overall patients. Interval from index pregnancy ≥7 months (aOR: 4.34, p = 0.001), and pretreatment hCG >100,000 IU/L (aOR: 2.85, p = 0.028) were independent predictors of EMACO resistance in the high-risk subgroup. The only factor independently associated with disease-specific death was EMACO resistance (aOR: 176.04, p < 0.001). CONCLUSIONS: EMACO is an effective treatment for GTN. Number of metastatic organs and EMACO resistance were the independent predictors of EMACO resistance and disease-specific death, respectively.

The impact of the distance traveled between residence and gestational trophoblastic neoplasia reference center and clinical outcomes in Brazilian women.

OBJECTIVE: To relate the distance traveled from the patient's residence to the gestational trophoblastic neoplasia (GTN) reference center (RC) and the occurrence of unfavorable clinical outcomes, as well as to estimate the possible association between this distance and the risk of metastatic disease at presentation, the need for multiagent chemotherapy to achieve remission and loss to follow-up before remission. STUDY DESIGN: Retrospective historical cohort study of patients with GTN followed at 8 Brazilian GTN-RC, from January 1st, 2000 - December 31st, 2017. RESULTS: Evaluating 1055 cases of GTN, and using a receiver operating characteristic curve, we found a distance of 56 km (km) from the residence to the GTN-RC (sensitivity = 0.57, specificity = 0.61) best predicted the occurrence of at least one of the following outcomes: occurrence of metastatic disease, need for multiagent chemotherapy to achieve remission, or loss to follow-up during chemotherapy. Multivariate logistic regression adjusted by age, ethnicity, marital status and the reference center location showed that when the distance between residence and GTN-RC was ≥56 km, there was an increase in the occurrence of metastatic disease (relative risk - RR:3.27; 95%CI:2.20-4.85), need for multiagent chemotherapy (RR:1.36; 95%CI:1.05-1.76), loss to follow-up during chemotherapy (RR:4.52; 95CI:1.93-10.63), occurrence of chemoresistance (RR:4.61; 95%CI:3.07-6.93), relapse (RR:10.27; 95%CI:3.08-34.28) and death due to GTN (RR:3.62; 95%CI:1.51-8.67). CONCLUSIONS: The distance between the patient's residence and the GTN-RC is a risk factor for unfavorable outcomes, including death from this disease. It is crucial to guarantee these patients get prompt access to the GTN-RC and receive follow-up support.

Presentation, medical complications and development of gestational trophoblastic neoplasia of hydatidiform mole after intracytoplasmic sperm injection as compared to hydatidiform mole after spontaneous conception - a retrospective cohort study and literature review.

OBJECTIVE: To describe the natural history of hydatidiform mole (HM) after intracytoplasmic sperm injection (ICSI), emphasizing the clinical and oncological outcomes, as compared to patients who had HM after spontaneous conception (SC). STUDY DESIGN: Retrospective historical cohort study of patients with HM followed at the Rio de Janeiro Federal University, from January 1st 2000-December 31st 2020. RESULTS: Comparing singleton HM after SC to those following ICSI there were differences in terms of maternal age (24 vs 34 years, p < 0.01), gestational age at diagnosis (10 vs 7 weeks, p < 0.01), preevacuation human chorionic gonadotropin levels (200,000 vs 99,000 IU/L, p < 0.01), occurrence of genital bleeding (60.5 vs 26.9%, p < 0.01) and hyperemesis (23 vs 3.9%, p = 0.02) at presentation, and time to remission (12 vs 5 weeks, p < 0.01), respectively. There were no differences observed in the cases of twin mole, regardless of the form of fertilization that gave rise to HM, except molar histology with greater occurrence of partial hydatidiform mole (10.7 vs 40.0%, p = 0.01) following ICSI. Univariate logistic regression for occurrence of postmolar GTN after ICSI identified no predictor variable for this outcome. However, after adjusting for maternal age and complete hydatidiform mole histology, multivariable logistic regression showed the risk of GTN with HM after ICSI had an adjusted odds ratio of 0.22 (95%CI:0.05-0.93, p = 0.04), suggesting a possible protective effect when compared to HM after SC. CONCLUSIONS: Singleton HM after ICSI are diagnosed earlier in gestation, present with fewer medical complications, and may be less likely to develop GTN when compared with HM after SC.

Influence of COVID-19 pandemic on molar pregnancy and postmolar gestational trophoblastic neoplasia: An observational study.

OBJECTIVE: To assess whether the incidence and aggressiveness of molar pregnancy (MP) and postmolar gestational trophoblastic neoplasia (GTN) changed during the COVID-19 pandemic. DESIGN: Observational study with two separate designs: retrospective multicentre cohort of patients with MP/postmolar GTN and a cross-sectional analysis, with application of a questionnaire. SETTING: Six Brazilian Reference Centres on gestational trophoblastic disease. POPULATION: 2662 patients with MP/postmolar GTN treated from March-December/2015-2020 were retrospectively evaluated and 528 of these patients answered a questionnaire. METHODS: Longitudinal retrospective multicentre study of patients diagnosed with MP/ postmolar GTN at presentation and a cross-sectional analysis, with application of a questionnaire, exclusive to patients treated during the period of study, to assess living and health conditions during the COVID-19 pandemic compared with previous years. MAIN OUTCOME MEASURES: The incidence of MP/postmolar GTN. RESULTS: Compared with the last 5 pre-pandemic years, MP/postmolar GTN incidence remained stable during 2020 (COVID-19 pandemic). Multivariable logistic regression, adjusted for the patient age, showed that during 2020, presentation with MP was more likely to be >10 weeks of gestation (adjusted odds ratio [aOR] 2.50, 95% confidence interval [CI] 1.90-3.29, P < 0.001), have a pre-evacuation hCG level ≥100 000 iu/l (aOR 1.77, 95% CI 1.38-2.28, P < 0.001) and time to the initiation of chemotherapy ≥7 months (aOR 1.86, 95% CI 1.01-3.43, P = 0.047) when compared with 2015-2019. CONCLUSIONS: Although the incidence of MP/postmolar GTN remained stable during the COVID-19 pandemic in Brazil, the pandemic was associated with greater gestational age at MP diagnosis and more protracted delays in initiation of chemotherapy for postmolar GTN.

Relationship between cortical and medullary thickness and glomerular filtration rate among living kidney donors.

The relationship between the kidney cortex and medulla is not well understood in healthy populations. This study characterised the relationship between cortical/medullary thickness and measured glomerular filtration rate (GFR) in 390 living kidney donors. A positive relationship was observed between medullary, but not cortical, thickness and GFR. We propose that this reflects a correlation between juxtamedullary nephron number and GFR.

A prospective, observational study of frailty, quality of life and dialysis in older people with advanced chronic kidney disease.

BACKGROUND: Frailty is prevalent in older people with chronic kidney disease (CKD) and robust evidence supporting the benefit of dialysis in this setting is lacking. We aimed to measure frailty and quality of life (QOL) longitudinally in older people with advanced CKD and assess the impact of dialysis initiation on frailty, QOL and mortality. METHODS: Outpatients aged ≥65 with an eGFR ≤ 20ml/minute/1.73m2 were enrolled in a prospective observational study and followed up four years later. Frailty status was measured using a Frailty Index (FI), and QOL was evaluated using the EuroQol 5D-5L instrument. Mortality and dialysis status were determined through inspection of electronic records. RESULTS: Ninety-eight participants were enrolled. Between enrolment and follow-up, 36% of participants commenced dialysis and 59% died. Frailty prevalence increased from 47% at baseline to 86% at follow-up (change in median FI = 0.22, p < 0.001). Initiating dialysis was not significantly associated with change in FI. QOL declined from baseline to follow-up (mean EQ-5D-5L visual analogue score of 70 vs 63, p = 0.034), though commencing dialysis was associated with less decline in QOL. Each 0.1 increment in baseline FI was associated with 59% increased mortality hazard (HR = 1.59, 95%CI = 1.20 to 2.12, p = 0.001), and commencing dialysis was associated with 59% reduction in mortality hazard (HR = 0.41, 95%CI = 0.20 to 0.87, p = 0.020) irrespective of baseline FI. CONCLUSIONS: Frailty increased substantially over four years, and higher baseline frailty was associated with greater mortality. Commencing dialysis did not affect the trajectory of FI but positively influenced the trajectory of QOL from baseline to follow-up. Within the limitations of small sample size, our data suggests that frail participants received similar survival benefit from dialysis as non-frail participants.