bluuebunny/crossref_metadata_2025_split huggingface dataset:
PROTACs: Current and Future Potential as a Precision Medicine Strategy to Combat Cancer
Authors: Rutherford Kailee A. , McManus Kirk J. 
Published: January 2024

Abstract
Proteolysis targeting chimeras (PROTAC) are an emerging precision medicine strategy, which targets key proteins for proteolytic degradation to ultimately induce cancer cell killing. These hetero-bifunctional molecules hijack the ubiquitin proteasome system to selectively add polyubiquitin chains onto a specific protein target to induce proteolytic degradation. Importantly, PROTACs have the capacity to target virtually any intracellular and transmembrane protein for degradation, including oncoproteins previously considered undruggable, which strategically positions PROTACs at the crossroads of multiple cancer research areas. In this review, we present normal functions of the ubiquitin regulation proteins and describe the application of PROTACs to improve the efficacy of current broad-spectrum therapeutics. We subsequently present the potential for PROTACs to exploit specific cancer vulnerabilities through synthetic genetic approaches, which may expedite the development, translation, and utility of novel synthetic genetic therapies in cancer. Finally, we describe the challenges associated with PROTACs and the ongoing efforts to overcome these issues to streamline clinical translation. Ultimately, these efforts may lead to their routine clinical use, which is expected to revolutionize cancer treatment strategies, delay familial cancer onset, and ultimately improve the lives and outcomes of those living with cancer.
Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity
Authors: Shah Shreya M. , Demidova Elena V. , Ringenbach Salena , Faezov Bulat , Andrake Mark , Gandhi Arjun , Mur Pilar , Viana-Errasti Julen , Xiu Joanne , Swensen Jeffrey , Valle Laura , Dunbrack Roland L. , Hall Michael J. , Arora Sanjeevani 
Published: January 2024

Abstract

POLE driver mutations in the exonuclease domain (ExoD driver) are prevalent in several cancers, including colorectal cancer and endometrial cancer, leading to dramatically ultra-high tumor mutation burden (TMB). To understand whether POLE mutations that are not classified as drivers (POLE Variant) contribute to mutagenesis, we assessed TMB in 447 POLE-mutated colorectal cancers, endometrial cancers, and ovarian cancers classified as TMB-high ≥10 mutations/Mb (mut/Mb) or TMB-low &lt;10 mut/Mb. TMB was significantly highest in tumors with “POLE ExoD driver plus POLE Variant” (colorectal cancer and endometrial cancer, P &lt; 0.001; ovarian cancer, P &lt; 0.05). TMB increased with additional POLE variants (P &lt; 0.001), but plateaued at 2, suggesting an association between the presence of these variants and TMB. Integrated analysis of AlphaFold2 POLE models and quantitative stability estimates predicted the impact of multiple POLE variants on POLE functionality. The prevalence of immunogenic neoepitopes was notably higher in the “POLE ExoD driver plus POLE Variant” tumors. Overall, this study reveals a novel correlation between POLE variants in POLE ExoD-driven tumors, and ultra-high TMB. Currently, only select pathogenic ExoD mutations with a reliable association with ultra-high TMB inform clinical practice. Thus, these findings are hypothesis-generating, require functional validation, and could potentially inform tumor classification, treatment responses, and clinical outcomes.

Significance:
Somatic POLE ExoD driver mutations cause proofreading deficiency that induces high TMB. This study suggests a novel modifier role for POLE variants in POLE ExoD-driven tumors, associated with ultra-high TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes.
FSH Is Responsible for Androgen Deprivation Therapy–Associated Atherosclerosis in Mice by Exaggerating Endothelial Inflammation and Monocyte Adhesion
Authors: Wang Qiang , Han Jingli , Liang Zhenhui , Geng Xueyu , Du Yiqing , Zhou Jing , Yao Weijuan , Xu Tao 
Published: January 2024

BACKGROUND:
Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. But ADTs with orchiectomy and gonadotropin-releasing hormone (GnRH) agonist are associated with increased risk of cardiovascular diseases, which appears less significant with GnRH antagonist. The difference of follicle-stimulating hormone (FSH) in ADT modalities is hypothesized to be responsible for ADT-associated cardiovascular diseases.

METHODS:

We administered orchiectomy, GnRH agonist, or GnRH antagonist in male
ApoE

−/−

mice fed with Western diet and manipulated FSH levels by testosterone and FSH supplementation or FSH antibody to investigate the role of FSH elevation on atherosclerosis. By combining lipidomics, in vitro study, and intraluminal FSHR (FSH receptor) inhibition, we delineated the effects of FSH on endothelium and monocytes and the underlying mechanisms.

RESULTS:
Orchiectomy and GnRH agonist, but not GnRH antagonist, induced long- or short-term FSH elevation and significantly accelerated atherogenesis. In orchiectomized and testosterone-supplemented mice, FSH exposure increased atherosclerosis. In GnRH agonist–treated mice, blocking of short FSH surge by anti-FSHβ antibody greatly alleviated endothelial inflammation and delayed atherogenesis. In GnRH antagonist–treated mice, FSH supplementation aggravated atherogenesis. Mechanistically, FSH, synergizing with TNF-α (tumor necrosis factor alpha), exacerbated endothelial inflammation by elevating VCAM-1 (vascular cell adhesion protein 1) expression through the cAMP/PKA (protein kinase A)/CREB (cAMP response element-binding protein)/c-Jun and PI3K (phosphatidylinositol 3 kinase)/AKT (protein kinase B)/GSK-3β (glycogen synthase kinase 3 beta)/GATA-6 (GATA-binding protein 6) pathways. In monocytes, FSH upregulated CD29 (cluster of differentiation 29) expression via the PI3K/AKT/GSK-3β/SP1 (specificity protein 1) pathway and promoted monocyte-endothelial adhesion both in vitro and in vivo. Importantly, FSHR knockdown by shRNA in endothelium of carotid arteries markedly reduced GnRH agonist–induced endothelial inflammation and atherosclerosis in mice.

CONCLUSIONS:
FSH is responsible for ADT-associated atherosclerosis by exaggerating endothelial inflammation and promoting monocyte-endothelial adhesion.
Remote Midlatitude Control of Rainfall Onset at the Southern African Tropical Edge
Authors: Knight Charles , Washington Richard 
Published: January 2024

Abstract
Rainfall over the southern African tropical boundary is highly variable, particularly around the onset of the summer rains. However, understanding of the causes of variability in onset timing is poor. A lack of observational data in the region is compounded by the complexity of climate dynamics and variability at the interface of the tropics and the midlatitudes. The key to onset over the region is the Congo air boundary (CAB), a distinguishing circulation feature present in September and declining in frequency until November. The CAB is crucial to early season rainfall; precipitation is broadly inhibited when the CAB is present, while its breakdown allows large-scale rainfall and onset over central southern Africa. This work identifies a remote midlatitude influence on the timing of CAB breakdown using the high-resolution reanalysis dataset ERA5. Propagating and (upstream) breaking low-wavenumber Rossby waves in the Southern Hemisphere westerly jet are shown to be related to >70% of breakdown events. Breakdown is forced by 1) the replacement of subsidence over eastern southern Africa with synoptically forced ascent and 2) wind field modification that leads to positive 850-hPa continental convergence anomalies and enhanced moisture advection from the Congo basin and Indian Ocean. Upper-level anticyclonic vorticity tendency induced by enhanced convection slows Rossby wave propagation aloft, contributing to wave breaking and the persistence of conditions favorable to convection. The identification of this midlatitude influence on CAB breakdown reveals new potential sources of predictability for onset and demonstrates the significant equatorward extent of midlatitude influences to the tropical edge.

Significance Statement
This study aims to improve our understanding of the causes of variability in the start date of the summer rainy season in central southern Africa. The research reveals that certain upper-level waves in the Southern Hemisphere westerly jet are associated with patterns of weather that force a large-scale transition from dry pre-onset conditions to widespread rainfall in a time scale of 2–5 days, and that these waves account for a large proportion of such transitions. This finding is of interest to subseasonal weather forecasters and may help to improve the long-range forecasting of onset date.
Postoperative Gastrointestinal Dysfunction After Neuromuscular Blockade Reversal With Sugammadex Versus Cholinesterase Inhibitors in Patients Undergoing Gastrointestinal Surgery: A Systematic Review and Meta-Analysis
Authors: Sharma Sahil , McKechnie Tyler , Talwar Gaurav , Patel Janhavi , Heimann Luke , Doumouras Aristithes , Hong Dennis , Eskicioglu Cagla 
Published: January 2024

Background Postoperative gastrointestinal dysfunction (POGD) commonly occurs following gastrointestinal (GI) surgery and is associated with specific anesthetic agents. Cholinesterase inhibitors employed for reversing neuromuscular blockade have been implicated in development of POGD. Sugammadex, a novel reversal agent, is linked with reduced POGD. However, there is a lack of comprehensive comparative review between these agents regarding their impact on POGD following GI surgery. This study aims to systematically review the effects of sugammadex on POGD compared to cholinesterase inhibitors following GI surgery. Methods MEDLINE, EMBASE, and CENTRAL were searched as of July 2022 to identify articles comparing sugammadex with cholinesterase inhibitors in patients undergoing gastrointestinal surgery, specifically in relation to POGD. Secondary endpoints included length of hospital stay, readmission rates, pulmonary complications, and postoperative morbidity. Results From 198 citations, 2 randomized controlled trials (RCTs) and 3 retrospective cohorts with 717 patients receiving sugammadex and 812 patients receiving cholinesterase inhibitors were included. Significantly lower rates of prolonged postoperative ileus (OR .44, 95% CI .25-.77, P < .05, I2 = 56%, low certainty evidence) was observed with sugammadex. No significant difference in any other outcome was observed. Narrative review of readmission data demonstrated no significant difference. Conclusion The use of sugammadex following gastrointestinal surgery is associated with significantly lower rates of prolonged postoperative ileus compared to cholinesterase inhibitors. However, these do not translate into a significant reduction in length of stay, morbidity, or postoperative nausea and vomiting. Results are limited by the numer of studies included and missing data, more robust RCTs are needed before recommendations can be made.
Role of Governance Quality in Remittances-poverty Relationship: New Insights from Transition Economies
Authors: Shah Imtiyaz Ahmad , Wani Ghowhar Ahmad 
Published: January 2024

This study examines the moderating role of institutional quality on a remittance-poverty relationship using a panel of 16 transition economies for 2002–2020. The study used pooled mean group/autoregressive distributed lag estimation with unit root and cointegration tests. The poverty is proxied by household consumption expenditure. After establishing cointegration, remittances and institutional quality index were found to positively affect poverty alleviation in the long run. The interactive term showed that remittances and institutional quality complemented the remittance-poverty relationship. In addition, a unidirectional causal relationship existed from remittance to poverty alleviation and institutional quality to poverty. Further, bidirectional causality existed between remittances and institutional quality, which confirms their complementary nature in the remittance-poverty relationship. Lastly, policy prescriptions are provided in the conclusion of the article. JEL Codes: F22, F24, J61
Associated Factors of Suicidal Behavior Among Persons with Physical Disability: A Systematic Review
Authors: Kumar Suneel , Lata Swaran , Verma Saroj , Anupriya  
Published: January 2024

Background: Suicide is common among persons with physical disabilities as they face several physical, social, psychological, and economic problems. They are at risk for suicidal thoughts, behaviors, and death by suicide. We aimed to systematically review empirically published articles and identify the associated factors of suicidal ideation and suicide attempts in persons with physical disabilities. Methods: A systematic search was carried out on the literature published from January 1, 2000 to January 19, 2023 in PubMed, Cochrane, Web of Science, Google Scholar, Shodh Ganga, and so on. All the synonyms of keywords or MeSH terms for suicidal ideation, suicide attempt, and physical disability were used. Two hundred thirty-six articles were found, and after following inclusion and exclusion criteria, 12 remained. Result: The associated factors of suicidal behavior were disability status (11/12 studies), burdensomeness (8/12 studies), felt stigma (4/12 studies), depressive symptoms (6/12 studies), loneliness (2/12 studies), lack of social and emotional connectedness (2/12 studies), long-term physical or mental disability (2/12 studies), congenital disability (1/12 studies), and aggression (1/12 studies). Conclusion: Timely, evidence-based, low-cost interventions can provide great assistance and address the specific needs of this vulnerable population as they have higher risk for suicidal behavior.
Adverse Childhood Experiences, Coping and Resilience in Persons with Alcohol Use Disorder and Their Non-drinking Siblings in High-density Families: A Case-control Study
Authors: Sreenivasulu M.  , Prathyusha Vasuki , Ezhumalai Sinu , Narayanan Gitanjali , Murthy Pratima 
Published: January 2024

Background: Adverse childhood experiences (ACEs) increase the odds of alcohol use disorder (AUD). Aim: To study the ACEs, coping, and resilience in persons with AUD and their non-drinking siblings from high-density families. Methods: The study used a case-control study design. Using purposive sampling, 135 participants were selected; the sample consists of persons with AUD ( n = 45), non-drinking siblings ( n = 45), and healthy controls ( n = 45), selected from out-patient and in-patient services from a government-run de-addiction centre in Bengaluru. Individuals were administered an ACEs questionnaire, Brief-COPE, and Connor-Davison Resilience scale. Descriptive statistics, Friedman’s test, and Bonferroni’s post-hoc test, Binary Logistic Regression were used for analysis. Results: ACEs, coping, and resilience significantly differ across the three groups. Persons with AUD and their non-drinking siblings are comparable in terms of ACEs and having dysfunctional family members. Non-drinking siblings and healthy controls have similar coping and resilience. None of the healthy controls had dysfunctional family members. Conclusion: ACEs are more prevalent and more frequent in persons with AUD. Individuals with AUD showed higher avoidant coping and lower resilience than their non-drinking siblings and healthy controls. Early identification of ACEs and interventions to build resilience and coping strategies could prevent individuals from developing AUD in high-density families.
Third generation of laser (>1900) for endovenous thermoablation (EVLA) of varicose veins: A systematic review and meta-analysis
Authors: Palombi Luca , Morelli Monica , Bruzzese Dario , Quarto Gennaro 
Published: January 2024

Objectives Third generation lasers with longer wavelengths (>1900 nm) have been introduced, in recent years, for the treatment of varicose veins. The possible advantage of the new generation lasers is that they allow complete damage to the vein wall using a lower Power in Watts (W: J/sec) and a lower linear energy density (LEED: J/cm). The aim of this work is to evaluate the results present in the literature regarding efficacy and safeness of the new generation lasers for the treatment of varicose veins. Methods Published articles were searched on PubMed database and on Cochrane Library, entering the keywords “1940 nm or 1920 nm laser AND varicose veins laser thermoablation (EVLA).” The primary endpoint of the study was to value rate of occlusion and adverse events at the short term follow-up. The search yielded a total of 14 studies. In the end, only six studies were judge eligibility. Results The studies were heterogenous in their documentation, EVLA, duplex ultrasound protocol and result reporting. A total of 540 limbs of 377 patients were treated with endovenous laser ablation (EVLA) with laser 1920–1940 nm. The treated veins had a mean diameter of 0.74 ± 0.17 cm and a mean length of 27.87 ± 20.63 cm. The pooled estimates of immediate occlusion rate was of 99.8% (95% CI: 97.9% to 100.0) with high heterogeneity (I2 = 60%; 95% PI: 89.7% to 100%), while at short-term follow-up was of 98.2% (95% CI: 94.0% to 100.0%) with higher heterogeneity (I2:79%; 95% PI: 77.1% to 100.0%). EHIT occurred in 7 cases (pooled estimate: 0.7%). The other adverse events rate reported were 1% of hyperpigmentation, 2.8% of neurological complications, 0.6% thrombophlebitis and 1.9% of bruising/hematoma. The pooled mean estimates of LEED was equal to 38.2 J/cm (95% CI: 26.3 to 50.1 J/cm) although with a very large heterogeneity (I2 = 100%). Conclusions The overall success rate of EVLA was high. The analysis of these studies suggests that using lower parameters (Power and linear administered energy) may have no effect on the treatment success rate. Short-term results demonstrate comparable occlusion rates respect the second-generation lasers. Instead, data suggest a low complication rates. Short-term results demonstrate comparable complications rates respect the second-generation lasers (1300-1470 nm). Randomized studies with longer follow-up are required to evaluate the EVLA 1900 nm procedure further.
Disappointment’s Magic: Negative Emotions, Transitional Justice and Resistance
Authors: Mrovlje Maša 
Published: January 2024

This article explores how an existential account of emotions can enrich debates about negative emotions in transitional justice and peacebuilding scholarship. A growing literature has examined the challenge that the ex-resisters’ negative emotions, including disappointment, pose to the creation of sustainable peace in post-conflict societies. It has however not sufficiently accounted for disappointment’s potentially productive political value. The paper fills this gap by examining how the ex-resisters’ disappointment affects their capacity for political action against the remainders of past violence and oppression, with a specific focus on the South African context. I draw on Jean-Paul Sartre’s existential account of the emotions’ ‘magic’ as a way of coping with the complexities of political action arising from our situated condition. I put Sartre’s account in conversation with Nadine Gordimer’s novel No Time Like the Present and experiences of disappointment among South African ex-resisters to show how disappointment can lead ex-resisters to different ways of confronting the complexity of political engagement in the wake of the incomplete transition. This dialogue reveals disappointment as a powerful source of resistance against the persistence of injustice, while also disclosing significant constraints upon political engagement in conditions of systemic violence. Le magique de la déception : Émotions négatives, justice transitionnelle et résistance
Incidence of and Risk Factors for Medial Meniscal Lesions at the Time of ACL Reconstruction: An Analysis of 4697 Knees From the SANTI Study Group Database
Authors: Giurazza Giancarlo , Saithna Adnan , An Jae-Sung , Lahsika Mohammed , Campos Joao Pedro , Vieira Thais Dutra , Guier Christian A. , Sonnery-Cottet Bertrand 
Published: January 2024

Background: Medial meniscal (MM) lesions (MMLs) are a common finding at the time of anterior cruciate ligament reconstruction (ACLR). It is recognized that evaluation of the posteromedial compartment reduces the rate of missed MML diagnoses. Purpose: To determine the incidence of MMLs in patients undergoing ACLR, when using a standardized arthroscopic approach that included posteromedial compartment evaluation, as well as to determine how the incidence of MMLs changed with increasing time intervals between injury and surgery, and to investigate what risk factors were associated with their presence. Study Design: Case series; Level of evidence, 4. Methods: A retrospective analysis of prospectively collected data was performed. All patients who underwent primary ACLR between January 2013 and March 2023 were considered for study eligibility. The epidemiology was defined by categorizing and reporting the incidence and categorizing the spectrum of MM tear types. Risk factors associated with MMLs were analyzed using a logistic regression model. Results: MMLs were identified in 1851 (39.4%) of 4697 consecutive patients undergoing ACLR. The overall incidence of MMLs was 33.1% for the period of 0 to 3 months, 38.7% for the period of 3 to 12 months, and 59.6% for the period of >12 months. The overall incidence of MMLs increased with longer durations of time between injury and surgery, along with significant increases in complex, bucket-handle, ramp, and/or flap lesions. The largest increase in incidence of MMLs was observed for complex MM tear patterns. Risk factors associated with MMLs included time between injury and surgery >3 months (odds ratio [OR], 1.320; 95% CI, 1.155-1.509; P < .0001) and >12 months (OR, 3.052; 95% CI, 2.553-3.649; P < .0001), male sex (OR, 1.501; 95% CI, 1.304-1.729; P < .0001), body mass index (BMI) ≥25 (OR, 1.193; 95% CI, 1.046-1.362; P = .0088), and lateral meniscal lesion (OR, 1.737; 95% CI, 1.519-1.986; P < .0001). Conclusion: Overall, MMLs were identified in 39.4% of 4697 patients undergoing ACLR when posteromedial compartment evaluation was performed in addition to standard anterior viewing. The incidence of MMLs and the complexity of tear types increased significantly with increasing time intervals between the index injury and ACLR. Secondary risk factors associated with an increased incidence of medial meniscal tears include male sex, increased BMI, and lateral meniscal lesions.