Novel markers of MCL1 inhibitor sensitivity in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer sub-type with limited treatment options and poor prognosis. Currently, standard treatments for TNBC include surgery, chemotherapy, and anti-PDL1 therapy. These therapies have limited efficacy in advanced stages. Myeloid-cell leukemia 1 (MCL1) is an anti-apoptotic BCL2 family protein. High expression of MCL1 contributes to chemotherapy resistance and is associated with a worse prognosis in TNBC. MCL1 inhibitors are in clinical trials for TNBC, but response rates to these inhibitors can vary and predictive markers are lacking. Currently, we identified a 4-member (AXL, ETS1, IL6, EFEMP1) gene signature (GS) that predicts MCL1 inhibitor sensitivity in TNBC cells. Factors encoded by these genes regulate signaling pathways to promote MCL1 inhibitor resistance. Small molecule inhibitors of the GS factors can overcome resistance and sensitize otherwise resistant TNBC cells to MCL1 inhibitor treatment. These findings offer insights into potential therapeutic strategies and tumor stratification for MCL1 inhibitor use in TNBC.

Does A Longer Waiting Period After Neoadjuvant Radio-chemotherapy Improve the Oncological Prognosis of Rectal Cancer?: Three Years' Follow-up Results of the Greccar-6 Randomized Multicenter Trial.

OBJECTIVE: The aim of this study was to report the 3-year survival results of the GRECCAR-6 trial. SUMMARY BACKGROUND DATA: Current data on the effect of an extended interval between radiochemotherapy (RCT) and resection for rectal cancer on the rate of complete pathological response (pCR = ypT0N0) is controversial. Furthermore, its effect on oncological outcomes is unknown. METHODS: The GRECCAR-6 trial was a phase III, multicenter, randomized, open-label, parallel-group, controlled trial. Patients with cT3/T4 or TxN+ tumors of the mid or lower rectum who had received RCT (45-50 Gy with 5-fluorouracil or capecitabine) were included and randomized into a 7- or 11-week waiting period. Primary endpoint was the pCR rate. Secondary endpoints were 3-year overall (OS), disease-free survival (DFS), and recurrence rates. RESULTS: A total of 265 patients from 24 participating centers were enrolled. A total of 253 patients underwent a mesorectal excision. Overall pCR rate was 17% (43/253). Mean follow-up from surgical resection was 32 ±â€Š8 months. Twenty-four deaths occurred with an 89% OS at 3 years. DFS was 68.7% at 3 years (75 recurrences). Three-year local and distant recurrences were 7.9% and 23.8%, respectively. The randomization group had no impact on the 3-year OS (P = 0.8868) or DFS (P = 0.9409). Distant (P = 0.7432) and local (P = 0.3944) recurrences were also not influenced by the waiting period. DFS was independently influenced by 3 factors: circumferential radial margin (CRM) ≤1 mm [hazard ratio (HR) = 2.03; 95% confidence interval (CI), 1.17-3.51], ypT3-T4 (HR = 2.69; 95% CI, 1.19-6.08) and positive lymph nodes (HR = 3.62; 95% CI, 1.89-6.91). CONCLUSION: Extending the waiting period by 4 weeks following RCT has no influence on the oncological outcomes of T3/T4 rectal cancers.

Pericardial effusion in patients with chronic kidney disease: A two-center study.

BACKGROUND AND AIMS: Pericardial effusion (PE) is a prevalent form of pericardial involvement in chronic kidney disease (CKD). This study aims to investigate the clinical and laboratory features associated with PE severity in patients with CKD. METHODS: In this cross-sectional study, we examined the medical records of patients admitted to tertiary hospitals with International Classification of Diseases 10th Revision (ICD-10) codes associated with CKD and PE. We included 112 CKD patients in stage 4 and 5 non-dialysis (ND) with PE for assessing the clinical and laboratory features of severity. RESULTS: Patients were divided into two categories based on the severity of PE. Seventy-two patients had mild and 40 had moderate and severe PE. Univariate analysis of demographic and laboratory features on the date of admission demonstrated that chest pain, dyspnea, serum albumin, and neutrophil-to-lymphocyte ratio (NLR) are associated with the severity of PE. The univariate analysis on the date of echocardiography showed significantly higher white blood cell count (WBC), neutrophil count (percentage and absolute count), and NLR, along with significantly lower lymphocyte percentage and serum albumin among patients with moderate and severe PE. In the multivariable analysis of laboratory features, on admission hypoalbuminemia (p-value = 0.014, OR = 4.03, CI: 1.32-12.25) and NLR greater than 5.5 (p-value = 0.015, OR = 4.22, CI: 1.32-13.50) were significantly associated with moderate and severe PE. In a parallel matter, at the time of echocardiography hypoalbuminemia (p-value = 0.004, OR = 5.38, CI: 1.74-16.65) and neutrophilia (p-value = 0.005, OR = 7.94, CI: 1.89-33.44) were significantly associated with moderate and severe PE. CONCLUSION: Despite advancements in the diagnosis and treatment of CKD, PE is still a concerning issue in these patients. This study revealed that hypoalbuminemia, neutrophilia, and NLR greater than 5.5 could be predictive factors of moderate and severe PE in CKD patients with PE. Further prospective study with larger sample size is needed to confirm these results.

The global prevalence of Trichuris trichiura infection in humans (2010-2023): A systematic review and meta-analysis.

This systematic review and meta-analysis study aimed to evaluate global Trichuris infection prevalence, assessing progress towards the WHO's 2030 target. We searched international databases from 2010-2023, categorizing data by regions and socio-economic variables using a random-effects model. Analyzing 757 articles covering 7154,842 individuals from 78 countries, the study found a pooled global prevalence of (6.64-7.57%), with the highest rates in the Caribbean (21.72%; 8.90-38.18%) and South-East Asia (20.95; 15.71-26.71%) regions. Southern Africa (9.58; 2.11-21.46%), Latin America (9.58; 2.11-21.46%), and Middle Africa Middle Africa (8.94; 6.31-11.98%) also exhibited high prevalence. Eastern Europe had the lowest prevalence at 0.16% (0.09-0.24). Approximately 513 (480-547) million people worldwide were estimated to harbor Trichuris. Moreover ∼1.5% of people tested worldwide (2010-2023) had a moderate to heavy intensity of infection. The study emphasizes the persistent global health threat of Trichuris infection, urging tailored strategies for effective control and prevention on a global scale.

CSE1L is a negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC and can be targeted using an HDAC1/2 inhibitor.

P53 represses transcription by activating p21 expression and promoting formation of RB1-E2F1 and RBL1/RBL2-DREAM transcription repressor complexes. The DREAM complex is composed of DP1, RB-family proteins RBL1 or RBL2 (p107/p130), E2F4/5, and MuvB. We recently reported RBL2-DREAM contributes to improved therapy responses in p53 wild-type NSCLC cells and improved outcomes in NSCLC patients whose tumors express wild-type p53. In the current study we identified CSE1L as a novel inhibitor of the RBL2-DREAM pathway and target to activate RBL2-DREAM in NSCLC cells. CSE1L is an oncoprotein that maintains repression of genes that can be reactivated by HDAC inhibitors. Mocetinostat is a HDAC inhibitor in clinical trials with selectivity against HDACs 1 and 2. Knockdown of CSE1L in NSCLC cells or treatment with mocetinostat increased p21, activated RB1 and RBL2, repressed DREAM target genes, and induced toxicity in a manner that required wild-type p53. Lastly, we found high levels of CSE1L and specific DREAM-target genes are candidate markers to identify p53 wild-type NSCLCs most responsive to mocetinostat. Thus, we identified CSE1L as a critical negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC that can be indirectly targeted with HDAC1/2 inhibitors (mocetinostat) in current clinical trials. High expression of CSE1L and DREAM target genes could serve as a biomarker to identify p53 wild-type NSCLCs most responsive to this HDAC1/2 inhibitor.

The importance of intraoperative echocardiography in the early detection of mitral regurgitation as a postsurgical sequel of aortic valve replacement: a case report.

BACKGROUND: Mitral leaflet perforation (MLP) can rarely be a consequence of aortic valve replacement (AVR), resulting in mitral regurgitation (MR). Determining the cause and severity of MLP following AVR is crucial in preventing hemodynamic consequences, such as pulmonary hypertension and biventricular remodeling. However, the diagnosis of this rare complication requires detailed echocardiographic evaluations. CASE PRESENTATION: In this paper, we report a 37-year-old Persian male with progressive dyspnea on exertion diagnosed with severe MR caused by anterior MLP following AVR and discuss the importance of intraoperative transesophageal echocardiography (TEE) in the proper and on-time diagnosis of this rare complication. CONCLUSION: During AVR procedure, an evaluation with TEE could be beneficial for identifying and treating such condition. Echocardiography is beneficial in providing real-time guidance during surgery, early detection of potential complications, treatment of such complications if present, and prevention of adverse outcomes.

The association between maternal infection and intellectual disability in children: A systematic review and meta-analysis.

BACKGROUND: There is arguing evidence regarding the association between maternal infections during pregnancy and the risk of intellectual disability (ID) in children. This systematic review and meta-analysis are essential to determine and address inconsistent findings between maternal infections during pregnancy and the risk of ID in children. METHODS: The MOOSE and PRISMA guidelines were followed to perform and report on this study. The Medline/PubMed, Web of Science, Embase, and Scopus databases were searched from inception up to March 15, 2023, to identify potentially eligible studies. Inclusion and exclusion criteria were applied, as well as the Newcastle-Ottawa Scale was used to assess the methodological quality of studies included. The included studies were divided into two types based on the participants: (1) ID-based studies, which involved children with ID as cases and healthy children as controls and evaluated maternal infection in these participants; (2) infection-based studies, which assessed the prevalence or incidence of ID in the follow-up of children with or without exposure to maternal infection. We used Random-effects models (REM) to estimate the overall pooled odds ratio (OR) and 95% confidence intervals (CIs). The between-studies heterogeneity was assessed with the χ2-based Q-test and I2 statistic. Subgroup and sensitivity analyses were applied to explore the source of heterogeneity and results consistency. RESULTS: A total of eight studies including 1,375,662 participants (60,479 cases and 1,315,183 controls) met the eligibility criteria. The REM found that maternal infection significantly increased the risk of ID in children (OR, 1.33; 95% CI, 1.21-1.46; I2 = 64.6). Subgroup analysis showed a significant association for both infection-based (OR, 1.27; 95%CI, 1.15-1.40; I2 = 51.2) and ID-based (OR, 1.44; 95%CI, 1.19-1.74; I2 = 77.1) studies. Furthermore, subgroup analysis based on diagnostic criteria revealed a significant association when maternal infection or ID were diagnosed using ICD codes (OR, 1.33; 95% CI, 1.20-1.48; I2 = 75.8). CONCLUSION: Our study suggests that maternal infection during pregnancy could be associated with an increased risk of ID in children. This finding is consistent across different types of studies and diagnostic criteria. However, due to the heterogeneity and limitations of the included studies, we recommend further longitudinal studies to confirm the causal relationship and the underlying mechanisms.

Trichomonas vaginalis infection and risk of cervical neoplasia: A systematic review and meta-analysis.

OBJECTIVES: The evidence in the literature regarding the relationship between Trichomonas vaginalis (TV) infection and cervical neoplasia is conflicting. The main aim of this study was to evaluate the magnitude of the risk of cervical neoplasia associated with TV infection. METHODS: A meta-analysis of observational studies, which provided raw data on the association of TV infection with cervical neoplasia, was performed. For this aim, we searched scientific databases (PubMed/Medline, Scopus, the Web of Sciences, and Embase) from inception to March 15, 2023. A random-effects model was applied by Stata 17.0 to calculate the pooled and adjusted odds ratios (ORs) with 95% confidence intervals (CI), including subgroup, sensitivity, and cumulative analyses to explore sources of heterogeneity. RESULTS: Of the 2584 records initially identified, 35 eligible studies contributed data for 67,856 women with cervical neoplasia, and 933,697 healthy controls from 14 countries were included. The pooled (2.15; 1.61-2.87; I2 = 87.7%) and adjusted (2.17; 1.82-2.60; I2 = 31.27%) ORs indicated a significant positive association between TV infection and the development of cervical neoplasia. There was no significant change in pooled and adjusted ORs by applying sensitivity and cumulative analyses, indicating the robustness of our findings. The pooled OR was significant in most sub-group analyses. There was no publication bias in the included studies. CONCLUSION: Our findings indicated that women with a TV infection are at significantly greater risk of cervical neoplasia. Future research, particularly longitudinal and experimental studies, should be done to better understand the various aspects of this association.

Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6).

Purpose A pathologic complete response (pCR; ypT0N0) of a rectal tumor after neoadjuvant radiochemotherapy (RCT) is associated with an excellent prognosis. Several retrospective studies have investigated the effect of increasing the delay after RCT. The aim of this study was to evaluate the effect of increasing the interval between the end of RCT and surgery on the pCR rate. Methods GRECCAR6 was a phase III, multicenter, randomized, open-label, parallel-group controlled trial. Patients with cT3/T4 or Tx N+ tumors of the mid or lower rectum who had received RCT (45 to 50 Gy with fluorouracil or capecitabine) were included. Patients were randomly included in the 7-week or the 11-week (11w) group. Primary end point was the pCR rate defined as a ypT0N0 specimen (NCT01648894). Results A total of 265 patients from 24 centers were enrolled between October 2012 and February 2015. The majority of the tumors were cT3 (82%). After RCT, surgery was not performed in nine patients (3.4%) because of the occurrence of distant metastasis (n = 5) or other reasons. Two patients underwent local resection of the tumor scar. A total of 47 (18.6%) specimens were classified as ypT0 (four had invaded lymph nodes [8.5%]). The primary end point (ypT0N0) was not different (7 weeks: 20 of 133, 15.0% v 11w: 23 of 132, 17.4%; P = .5983). Morbidity was significantly increased in the 11w group (44.5% v 32%; P = .0404) as a result of increased medical complications (32.8% v 19.2%; P = .0137). The 11w group had a worse quality of mesorectal resection (complete mesorectum [I] 78.7% v 90%; P = .0156). Conclusion Waiting 11 weeks after RCT did not increase the rate of pCR after surgical resection. A longer waiting period may be associated with higher morbidity and more difficult surgical resection.

Plasticity in the macromolecular-scale causal networks of cell migration.

Heterogeneous and dynamic single cell migration behaviours arise from a complex multi-scale signalling network comprising both molecular components and macromolecular modules, among which cell-matrix adhesions and F-actin directly mediate migration. To date, the global wiring architecture characterizing this network remains poorly defined. It is also unclear whether such a wiring pattern may be stable and generalizable to different conditions, or plastic and context dependent. Here, synchronous imaging-based quantification of migration system organization, represented by 87 morphological and dynamic macromolecular module features, and migration system behaviour, i.e., migration speed, facilitated Granger causality analysis. We thereby leveraged natural cellular heterogeneity to begin mapping the directionally specific causal wiring between organizational and behavioural features of the cell migration system. This represents an important advance on commonly used correlative analyses that do not resolve causal directionality. We identified organizational features such as adhesion stability and adhesion F-actin content that, as anticipated, causally influenced cell migration speed. Strikingly, we also found that cell speed can exert causal influence over organizational features, including cell shape and adhesion complex location, thus revealing causality in directions contradictory to previous expectations. Importantly, by comparing unperturbed and signalling-modulated cells, we provide proof-of-principle that causal interaction patterns are in fact plastic and context dependent, rather than stable and generalizable.