Innovations in the Treatment of Spinal Cerebrospinal Fluid Leaks.

Spontaneous spinal cerebrospinal fluid (CSF) leaks are uncommon but can be neurologically debilitating. When initial treatments fail, definitive repair or closure of the leak is indicated. Depending upon the type of leak present, innovative strategies for their treatment have been developed. Among them are open surgical techniques using a transdural approach for the closure of ventral CSF leaks, minimally invasive tubular techniques for the reduction and repair of lateral meningeal diverticula, and endovascular embolization of CSF-venous fistulas. Illustrative cases demonstrating the indications for and implementation of these techniques are provided.

Escherichia coli DNA replication: the old model organism still holds many surprises.

Research on Escherichia coli DNA replication paved the groundwork for many breakthrough discoveries with important implications for our understanding of human molecular biology, due to the high level of conservation of key molecular processes involved. To this day, it attracts a lot of attention, partially by virtue of being an important model organism, but also because the understanding of factors influencing replication fidelity might be important for studies on the emergence of antibiotic resistance. Importantly, the wide access to high-resolution single-molecule and live-cell imaging, whole genome sequencing, and Cryo-EM techniques, which were greatly popularized in the last decade, allows us to revisit certain assumptions about the replisomes and offers very detailed insight into how they work. For many parts of the replisome, step-by-step mechanisms have been reconstituted, and some new players identified. This review summarizes the latest developments in the area, focusing on (a) the structure of the replisome and mechanisms of action of its components, (b) organization of replisome transactions and repair, (c) replisome dynamics, and (d) factors influencing the base and sugar fidelity of DNA synthesis.

The safety and prognostic evaluation of subsequent aortic surgery after thoracic endovascular aortic repair: a retrospective cohort study.

Background: Thoracic endovascular aortic repair (TEVAR) is a widely employed clinical procedure for treating various aortic pathologies. However, some patients require subsequent surgical interventions post-TEVAR, particularly due to life-threatening complications such as aortic dissection. This study aimed to evaluate the safety and prognosis associated with additional aortic surgeries following TEVAR. Methods: A retrospective analysis was conducted on 21 patients who underwent aortic surgery after TEVAR at Guangdong Provincial People's Hospital between September 2016 and August 2020. By compiling and reviewing perioperative data, we assessed surgical-related complications and survival rates. Results: Among the 21 patients, 95.2% were male, with an average age of 53 years. Preoperative comorbidities included hypertension in 15 individuals, abdominal aortic aneurysm in one patient, and coronary heart disease in two patients. The primary complications of TEVAR were stent leakage and retrograde aortic dissection, with the latter being the predominant type in subsequent aortic surgeries. The mean duration of aortic clamping during surgery was 130.0 minutes, with a deep hypothermic circulatory arrest time of 8.5 minutes. Postoperatively, two patients suffered in-hospital mortality, one developed renal dysfunction, four required re-entry into the operating room for further treatment, and the average length of hospital stay was 20 days. Following discharge, 14.3% of patients experienced complications, with central nervous system symptoms being the most prevalent. Kaplan-Meier survival analysis indicated a 5-year survival rate of 85.7%. Conclusions: Aortic surgical intervention following TEVAR is a safe therapeutic approach that can improve patient prognosis. However, meticulous management of the perioperative period is crucial for reducing the risk of complications and improving survival rates. This study provides valuable insights into aortic surgery post-TEVAR, but large-scale research is needed to validate these findings.

Inside the genome: understanding genetic influences on oxidative stress.

Genetics is a key factor that governs the susceptibility to oxidative stress. In the body, oxidative burden is regulated by the balance between the prooxidant genes that orchestrate processes that produce oxidant species, while the antioxidant genes aid those involved in scavenging these species. Together, the two components aid in maintaining the oxidative balance in the body. Genetic variations can influence the expression and activity of the encoded proteins which can then affect their efficiency in regulating redox processes, thereby increasing the risk of oxidative stress. This review studies single nucleotide polymorphisms (SNPs) that bear relevance to oxidative stress by exploring the variations in the prooxidant genes, such as XDH, CYBA, CYP1A1, PTGS2, NOS, and MAO and antioxidant genes including SOD, CAT, GPX, GSS, GLUL, GSR, GSTM1, GSTM5, GSTP1, TXN and HMOX1. Early identification of individuals at the increased risk of oxidative stress is possible from the assessment of sequence of these genes. Integrating genetic insights into oxidative stress management measures can pave the way for personalized medicine that tailors' healthcare approaches to individual genetic profiles. Effective genetic assessment along with routine quantification of biological markers can improve and monitor treatment strategies, enhancing mitigation approaches that maintain cellular health and promote longevity.

Minimum 10-year follow-up outcomes of arthroscopic Bankart's repair with metallic anchors: Reliable results with low redislocation rates.

BACKGROUND: With stiff competition from alternative albeit more expensive counterparts, it has become important to establish the applicability of metallic anchors for shoulder instability in the modern era. This can be accomplished, in part, by analysing long-term outcomes. AIM: To analyse minimum 10-year outcomes from 30 patients following arthroscopic anterior stabilisation using metallic anchors. METHODS: Prospectively collected data from arthroscopic Bankart repairs performed using metal anchors during 2007P-2010 were retrospectively analysed in this single-surgeon study. Comprehensive data collection included historical and clinical findings, dislocation details, operative specifics, and follow-up radiological and clinical findings including shoulder scores. The primary outcomes were patient-reported scores (Constant, American Shoulder and Elbow Surgeons [ASES], and Rowe scores) and pain and instability on a visual analogue scale (VAS). RESULTS: A 3% recurrence rate of dislocation was noted at the final follow-up. Total constant scores at 10 years postoperatively measured between 76 and 100 (mean 89) were significantly better than preoperative scores (mean 62.7). Congruous improvements were also noted in the Rowe and ASES scores and VAS at the 10-year review. CONCLUSION: Reliable long-term outcomes with metallic anchors in surgery for shoulder instability can be expected. Our results provide additional evidence of their continued, cost-effective presence in the modern scenario.

Roles of cerebrospinal fluid-contacting neurons as potential neural stem cells in the repair and regeneration of spinal cord injuries.

Cerebrospinal fluid-contacting neurons (CSF-cNs) represent a distinct group of interneurons characterized by their prominent apical globular protrusions penetrating the spinal cord's central canal and their basal axons extending towards adjacent cells. Identified nearly a century back, the specific roles and attributes of CSF-cNs have just started to emerge due to the historical lack of definitive markers. Recent findings have confirmed that CSF-cNs expressing PKD2L1 possess attributes of neural stem cells, suggesting a critical function in the regeneration processes following spinal cord injuries. This review aims to elucidate the molecular markers of CSF-cNs as potential neural stem cells during spinal cord development and assess their roles post-spinal cord injury, with an emphasis on their potential therapeutic implications for spinal cord repair.

FAM20A: a potential diagnostic biomarker for lung squamous cell carcinoma.

Background: Lung squamous cell carcinoma (LUSC) ranks among the carcinomas with the highest incidence and dismal survival rates, suffering from a lack of effective therapeutic strategies. Consequently, biomarkers facilitating early diagnosis of LUSC could significantly enhance patient survival. This study aims to identify novel biomarkers for LUSC. Methods: Utilizing the TCGA, GTEx, and CGGA databases, we focused on the gene encoding Family with Sequence Similarity 20, Member A (FAM20A) across various cancers. We then corroborated these bioinformatic predictions with clinical samples. A range of analytical tools, including Kaplan-Meier, MethSurv database, Wilcoxon rank-sum, Kruskal-Wallis tests, Gene Set Enrichment Analysis, and TIMER database, were employed to assess the diagnostic and prognostic value of FAM20A in LUSC. These tools also helped evaluate immune cell infiltration, immune checkpoint genes, DNA repair-related genes, DNA methylation, and tumor-related pathways. Results: FAM20A expression was found to be significantly reduced in LUSC, correlating with lower survival rates. It exhibited a negative correlation with key proteins in DNA repair signaling pathways, potentially contributing to LUSC's radiotherapy resistance. Additionally, FAM20A showed a positive correlation with immune checkpoints like CTLA-4, indicating potential heightened sensitivity to immunotherapies targeting these checkpoints. Conclusion: FAM20A emerges as a promising diagnostic and prognostic biomarker for LUSC, offering potential clinical applications.

Visual outcomes of the surgical rehabilitative process following open globe injury repair.

Background: The path of rehabilitation of an eye after open globe injury (OGI) may require multiple additional secondary surgeries after the initial repair. Although much has been studied regarding the outcomes of secondary surgeries after open globe repair, it can be challenging to understand the possible implications of the surgical rehabilitative process. This retrospective study considers the benefits of the required additional secondary surgeries for a consecutive series of OGI patients. Methods: OGI patients who had at least one additional surgery after the initial open globe repair (OGR) were studied retrospectively. Additional inclusion criteria included: follow up of at least 12 months since the initial injury and at least 3 months since their most recent surgery, and no additional planned interventions. Preoperative visual acuity was compared to final visual acuity. Additionally, the odds of achieving ambulatory vision (≥20/800) and reading vision (≥20/40) were calculated after each indicated consecutive surgery. Results: A cohort of 74 eyes from 73 patients met our inclusion criteria. These patients underwent a mean of two additional surgeries. The mean logMAR VA improved from 2.3 (HM) at presentation to 1.4 (20/150), or a 9-line Snellen equivalent improvement. Upon reaching their final visit status, 50% of patients had achieved ambulatory vision and 30% of patients had achieved reading vision. The odds of achieving ambulatory vision after completion of all the rehabilitative surgical process compared to the vision prior to the secondary rehabilitative surgery were higher (OR: 19.1, 95% CI: 7.9 - 30.4, p = 0.0008) as were the odds of achieving reading vision (OR: 4.6, 95% CI: 0.2 - 9.0, p = 0.04). With subsequent second, third, and fourth additional surgeries, the odds of achieving either ambulatory or reading vision at the final visit compared to their preoperative visual acuities were not significant (p > 0.05) but the visual acuity continued to trend toward visual improvement. Conclusion: Approximately 50% of individuals who required additional surgery at UMN achieved ambulatory vision and 30% achieved reading vision. The odds of visual improvement through the surgical rehabilitative process were very high, with the greatest gains generally achieved after the first surgery.

The Use of Pressure Recording Analytical Method in Patients Undergoing Endovascular Repair for Abdominal Aortic Aneurysm: The Impact on Clinical Decisions for the Appropriate Postoperative Setting and Cost-effective Analysis.

OBJECTIVE: To analyze the use of the Pressure Recording Analytical Method (PRAM), an hemodynamic monitoring system, in evaluating intraoperative and postoperative hemodynamic instability in patients undergoing endovascular repair for abdominal aortic aneurysm, and to evaluate if the decision to refer patients to a ordinary ward or to a Cardiac Step-Down Unit (CSDU) after the intervention on the basis of intraoperative hemodynamic monitoring could be more cost-effective. MATERIALS AND METHODS: After preoperative clinical evaluation, 44 patients were divided in this non-randomised study into two groups according to their postoperative destination: Group 1-ward (N=22) and Group 2-CSDU (N=22). All patients underwent monitoring with PRAM during the intervention and in the 24 postoperative hours, measuring several indices of myocardial contractility and other hemodynamic variables. RESULTS: According to the variability of two parameters, Stroke Volume Variation and Pulse Pressure Variation, patients were classified as stable or unstable. Unstable patients showed a significant alteration in several hemodynamic indices, in comparison to stable ones. According to the intraoperative monitoring, eight high risk patients could have been sent to an ordinary ward due to their stability, with a reduction in the improper use of CSDU and, consequently, in costs. CONCLUSIONS: Hemodynamic monitoring with PRAM can be useful in these patients, both for intraoperative management and for the choice of the more appropriate postoperative setting, possibly reducing the improper use of CSDU for hemodynamically stable patients who are judged to be at high risk preoperatively, and re-evaluating low surgical risk patients with an unstable intraoperative pattern, with a possible reduction in costs.

20 Years of Triple-Valve Surgery in the United Kingdom: Demographic and Outcome Trends.

OBJECTIVES: To describe evolving demographic trends and early outcomes in patients undergoing triple-valve surgery in the UK, between 2000-2019. METHODS: We planned a retrospective analysis of national registry data including patients undergoing triple valve surgery for all aetiologies of disease. We excluded patients in a critical preoperative state and those with missing admission dates. The study cohort was split into 5 consecutive 4-year cohorts (groups A, B, C, D and E). The primary outcome was in-hospital mortality, and secondary outcomes included prolonged admission, re-exploration for bleeding, postoperative stroke and postoperative dialysis. Binary logistic regression models were used to establish independent predictors of mortality, stroke, postoperative dialysis and re-exploration for bleeding in this high-risk cohort. RESULTS: We identified 1,750 patients undergoing triple-valve surgery in the UK between 2000-2019. Triple valve surgery represents 3.1% of all patients in the dataset. Overall mean age of patients was 68.5 years ±12, having increased from 63 years ±12 in group A to 69 years ±12 in group E (p < 0.001). Overall in-hospital mortality rate was 9%, dropping from 21% in group A to 7% in group E (p < 0.001). Overall rates of re-exploration for bleeding (11%, p = 0.308) and postoperative dialysis (11%, p = 0.066) remained high across the observed time period. Triple valve replacement, redo sternotomy and poor preoperative left ventricular ejection fraction emerged as strong independent predictors of mortality. CONCLUSIONS: Triple valve surgery remains rare in the UK. Early postoperative outcomes for triple valve surgery have improved over time. Redo sternotomy is a significant predictor of mortality. Attempts should be made to repair the mitral and/or tricuspid valves where technically possible.

Single-stranded DNA binding protein hitches a ride with the Escherichia coli YoaA-χ helicase.

The Escherichia coli XPD/Rad3-like helicase, YoaA, and DNA polymerase III subunit, χ, are involved in E. coli DNA damage tolerance and repair. YoaA and χ promote tolerance to the DNA chain-terminator, 3 -azidothymidine (AZT), and together form the functional helicase complex, YoaA-χ. How YoaA-χ contributes to DNA damage tolerance is not well understood. E. coli single-stranded DNA binding protein (SSB) accumulates at stalled replication forks, and the SSB-χ interaction is required to promote AZT tolerance via an unknown mechanism. YoaA-χ and SSB interactions were investigated in vitro to better understand this DNA damage tolerance mechanism, and we discovered YoaA-χ and SSB have a functional interaction. SSB confers a substrate-specific effect on the helicase activity of YoaA-χ, barely affecting YoaA-χ on an overhang DNA substrate but inhibiting YoaA-χ on forked DNA. A paralog helicase, DinG, unwinds SSB-bound DNA in a similar manner to YoaA-χ on the substrates tested. Through use of ensemble experiments, we believe SSB binds behind YoaA-χ relative to the DNA ds/ss junction and show via single-molecule assays that SSB translocates along ssDNA with YoaA-χ. This is, to our knowledge, the first demonstration of a mechanoenzyme pulling SSB along ssDNA.

Analysis of clinical characteristics of mismatch repair status in colorectal cancer: a multicenter retrospective study.

BACKGROUND: Microsatellite instability (MSI) caused by DNA mismatch repair (MMR) deficiency is of great significance in the occurrence, diagnosis and treatment of colorectal cancer (CRC). AIM: This study aimed to analyze the relationship between mismatch repair status and clinical characteristics of CRC. METHODS: The histopathological results and clinical characteristics of 2029 patients who suffered from CRC and underwent surgery at two centers from 2018 to 2020 were determined. After screening the importance of clinical characteristics through machine learning algorithms, the patients were divided into deficient mismatch repair (dMMR) and proficient mismatch repair (pMMR) groups based on the immunohistochemistry results and the clinical feature data between the two groups were observed by statistical methods. RESULTS: The dMMR and pMMR groups had significant differences in histologic type, TNM stage, maximum tumor diameter, lymph node metastasis, differentiation grade, gross appearance, and vascular invasion. There were significant differences between the MLH1 groups in age, histologic type, TNM stage, lymph node metastasis, tumor location, and depth of invasion. The MSH2 groups were significantly different in age. The MSH6 groups had significant differences in age, histologic type, and TNM stage. There were significant differences between the PMS2 groups in lymph node metastasis and tumor location. CRC was dominated by MLH1 and PMS2 combined expression loss (41.77%). There was a positive correlation between MLH1 and MSH2 and between MSH6 and PMS2 as well. CONCLUSIONS: The proportion of mucinous adenocarcinoma, protruding type, and poor differentiation is relatively high in dMMR CRCs, but lymph node metastasis is rare. It is worth noting that the expression of MMR protein has different prognostic significance in different stages of CRC disease.

Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Effect of fly ash and curing temperature on the properties of magnesium phosphate repair mortar.

This article is aimed at discussing the combined effect of mineral admixture and servicing temperature, especially in cold environment, on the properties of magnesium phosphate repair mortar (MPM). The influence mechanism of fly ash content on the microstructure and performance of MPM were firstly investigated, and then the evolution rules in properties of fly ash modified MPM cured at - 20 °C, 0 °C, 20 °C and 40 °C were further revealed. The results show that the incorporation of fly ash has no significant effect on the setting time and fluidity of MPM. When MPM is modified with 10 wt% and 15 wt% fly ash, its mechanical properties, adhesive strength, water resistance, and volume stability are effectively improved. Fly ash reduces the crystallinity and continuity of struvite enriched in hardened MPM, and its particles are embedded among struvite and unreacted MgO. The compressive strength of MPM-10 cured for various ages increases with the elevating of curing temperature, while the flexural strength, interfacial bonding strength, strength retention and linear shrinkage exhibits the opposite laws. When cured at 0 °C and - 20 °C, MPM-10 still has good early strength, water resistance and interfacial bonding properties, which indicates that MPM-10 provides with an ability of emergency repair of cracked components served in cold environments.

Comparison of the clinical efficacy and prognosis of the two techniques for treating partial articular-sided supraspinatus tendon tears under arthroscopy.

BACKGROUND: At present, shoulder arthroscopy is usually used for treatment of rotator cuff injuries. There is still debate over the precise technique of using shoulder arthroscopy to treat partial articular-sided supraspinatus tendon injuries. OBJECTIVE: To compare the clinical efficacy of the arthroscopic transtendon repair method and the arthroscopic full-thickness repair method in the treatment of patients with Ellman III partial articular-sided supraspinatus tendon tears and to analyze the influencing factors of postoperative efficacy. STUDY DESIGN: Cohort study; level of evidence,4. METHODS: A total of 84 partial-thickness rotator cuff tear (PTRCT) patients with Ellman III injuries who underwent surgical treatment in our hospital between January 2017 and January 2020 were selected and divided into the arthroscopic trans-tenon repair group (32 cases) and the arthroscopic full-thickness repair group (52 cases). Shoulder joint pain and functional status were assessed by the Constant score, ASES score and VAS score; shoulder mobility was assessed by measuring shoulder ROM. The clinical outcomes of the two groups of patients were compared, and the factors affecting the postoperative efficacy of the patients were investigated. RESULTS: All patients were followed up for at least 2 years. The Constant score, ASES score, and VAS score of the two groups of patients were all improved compared with those before surgery, and the differences were statistically significant (P < 0.05). There were no significant differences in the Constant score, ASES score, or VAS score between the two groups (P > 0.05). The results of binary logistic regression analysis showed that the preoperative ASES score and whether biceps tenotomy was performed were independent risk factors for satisfactory postoperative efficacy (P < 0.05). CONCLUSION: For patients with Ellman III partial articular-sided supraspinatus tendon tears, the arthroscopic transtendon repair method and the arthroscopic full-thickness repair method can both significantly improve the shoulder pain and function of the patient, but there is no significant difference between the efficacy of the two surgical methods. The preoperative ASES score and whether biceps tenotomy was performed were independent risk factors for satisfactory postoperative efficacy in PTRCT patients with Ellman III injury.

Establishment of an ovarian cancer exhausted CD8+T cells-related genes model by integrated analysis of scRNA-seq and bulk RNA-seq.

Ovarian cancer (OC) was the fifth leading cause of cancer death and the deadliest gynecological cancer in women. This was largely attributed to its late diagnosis, high therapeutic resistance, and a dearth of effective treatments. Clinical and preclinical studies have revealed that tumor-infiltrating CD8+T cells often lost their effector function, the dysfunctional state of CD8+T cells was known as exhaustion. Our objective was to identify genes associated with exhausted CD8+T cells (CD8TEXGs) and their prognostic significance in OC. We downloaded the RNA-seq and clinical data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. CD8TEXGs were initially identified from single-cell RNA-seq (scRNA-seq) datasets, then univariate Cox regression, the least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression were utilized to calculate risk score and to develop the CD8TEXGs risk signature. Kaplan-Meier analysis, univariate Cox regression, multivariate Cox regression, time-dependent receiver operating characteristics (ROC), nomogram, and calibration were conducted to verify and evaluate the risk signature. Gene set enrichment analyses (GSEA) in the risk groups were used to figure out the closely correlated pathways with the risk group. The role of risk score has been further explored in the homologous recombination repair deficiency (HRD), BRAC1/2 gene mutations and tumor mutation burden (TMB). A risk signature with 4 CD8TEXGs in OC was finally built in the TCGA database and further validated in large GEO cohorts. The signature also demonstrated broad applicability across various types of cancer in the pan-cancer analysis. The high-risk score was significantly associated with a worse prognosis and the risk score was proven to be an independent prognostic biomarker. The 1-, 3-, and 5-years ROC values, nomogram, calibration, and comparison with the previously published models confirmed the excellent prediction power of this model. The low-risk group patients tended to exhibit a higher HRD score, BRCA1/2 gene mutation ratio and TMB. The low-risk group patients were more sensitive to Poly-ADP-ribose polymerase inhibitors (PARPi). Our findings of the prognostic value of CD8TEXGs in prognosis and drug response provided valuable insights into the molecular mechanisms and clinical management of OC.

Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors.

BACKGROUND: Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. METHODS: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. RESULTS: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. CONCLUSIONS: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.

The dynamic progression of temporomandibular joint osteoarthritis-like lesions elicited by mandibular shift in a rat model.

BACKGROUND: Temporomandibular joint osteoarthritis (TMJ-OA) presents significant challenges due to its complex etiology, often insidious onset, high incidence, and progressive structural deterioration. While research has explored genetic and molecular factors, treatment outcomes remain suboptimal, emphasizing the need for a deeper understanding of disease progression. OBJECTIVE: This study employs a specific mandibular shift rat model to explore the dynamic progression of TMJ-OA-like lesions and evaluate the potential for self-repair at different stages, aiming to inform early diagnosis and preventative strategies. METHODS: Seventy-two female Sprague-Dawley rats were randomized into three groups: a control group (n=24; average weight: 157.23±1.63 g) receiving sham surgery. an experimental group (n=24; average weight: 157.78±1.88 g) subjected to mandibular shift induction, and a removal group (n=24; average weight: 158.11±2.20 g) experiencing mandibular shift for one, two, or four weeks followed by a one-month recovery period (designated as 1w Removal, 2w Removal and 4w Removal, respectively). Histomorphological and molecular analyses were conducted at designated time points. RESULTS: Rats in the 1-week removal group exhibited substantial recovery in condylar morphology, cartilage thickness, extracellular matrix composition, and expression of OA-related genes. Conversely, the 4-week removal group mirrored the experimental group, indicating limited self-repair capacity at later stages. The 2-week removal group presented with variable outcomes, with some animals showing signs of recovery and others resembling the experimental group, indicating a potential transitional phase in the disease process. CONCLUSION: Recovery from early-stage TMJ-OA involves eliminating provoking factors such as occlusal interference or reducing joint loading. However, advanced stages exhibit diminished self-repair capabilities, necessitating additional therapeutic interventions. These findings emphasize the importance of early diagnosis and intervention in TMJ-OA management.

Asparaginase-like protein 1 as a prognostic tissue biomarker in clinicopathologically and molecularly characterized endometrial cancer.

OBJECTIVE: Prognostic stratification of endometrial cancer involves the assessment of stage, uterine risk factors, and molecular classification. This process can be further refined through annotation of prognostic biomarkers, notably L1 cell adhesion molecule (L1CAM) and hormonal receptors. Loss of asparaginase-like protein 1 (ASRGL1) has been shown to correlate with poor outcome in endometrial cancer. Our objective was to assess prognostication of endometrial cancer by ASRGL1 in conjunction with other available methodologies. STUDY DESIGN: This was a retrospective study of patients who underwent primary treatment at a single tertiary center. Tumors were molecularly classified by the Proactive Molecular Risk Classifier for Endometrial Cancer. Expression of ASRGL1, L1CAM, estrogen receptor, and progesterone receptor was determined by immunohistochemistry. ASRGL1 expression intensity was scored into four classes. RESULTS: In a cohort of 775 patients, monitored for a median time of 81 months, ASRGL1 expression intensity was related to improved disease-specific survival in a dose-dependent manner (P < 0.001). Low expression levels were associated with stage II-IV disease and presence of uterine factors, i.e. high grade, lymphovascular space invasion, and deep myometrial invasion (P < 0.001 for all). Among the molecular subgroups, low expression was most prevalent in p53 abnormal carcinomas (P < 0.001). Low ASRGL1 was associated with positive L1CAM expression and negative estrogen and progesterone receptor expression (P < 0.001 for all). After adjustment for stage and uterine factors, strong ASRGL1 staining intensity was associated with a lower risk for cancer-related deaths (hazard ratio 0.56, 95 % confidence interval 0.32-0.97; P = 0.038). ASRGL1 was not associated with the outcome when adjusted for stage, molecular subgroups, L1CAM, and hormonal receptors. When analyzed separately within the different molecular subgroups, ASRGL1 showed an association with disease-specific survival specifically in "no specific molecular profile" subtype carcinomas (P < 0.001). However, this association became nonsignificant upon controlling for confounders. CONCLUSIONS: Low ASRGL1 expression intensity correlates with poor survival in endometrial cancer. ASRGL1 contributes to more accurate prognostication when controlled for stage and uterine factors. However, when adjusted for stage and other biomarkers, including molecular subgroups, ASRGL1 does not improve prognostic stratification.

Development and Validation of a User Friendly Morphology Grading System (PATENT) Predicting Aortic Remodelling After Thoracic Endovascular Aortic Repair in High Risk Uncomplicated Type B Aortic Dissection.

OBJECTIVE: This study aimed to create a morphology grading system, solely based on 2D images from computed tomography angiography, to predict negative aortic remodelling (NAR) for patients with high risk uncomplicated type B aortic dissection (TBAD) after thoracic endovascular aortic repair (TEVAR). METHODS: This single centre retrospective cohort study extracted and analysed consecutive patients diagnosed with high risk uncomplicated TBAD. Negative aortic remodelling was defined as an increase in the diameter of a false lumen or total aorta, or decrease in the diameter of a true lumen. The multivariate Cox regression model identified risk factors and a prediction model was created for two year freedom from NAR. A three category grading system, in which patients were classified into low, medium, and high risk groups, was further developed and internally validated. RESULTS: Of 351 patients included, 99 (28%) of them developed NAR. The median age was 52 years (interquartile range 45, 62 years) and 56 of them (16%) were female. The rate of two year freedom from NAR was 71% (95% CI 65 - 77%). After the multivariate Cox regression analysis, Patent false lumen, Aberrant right subclavian artery, Taper ratio, abdominal circumferential Extent, coeliac artery or reNal artery involved, and four channelled dissection (Three false lumens) remained independent predictors and were included in the PATENT grading system. The risk score was significantly associated with NAR (HR 1.21; 95% CI 1.14 - 1.29; p < .001). The medium and high risk groups demonstrated a higher rate of NAR (medium risk, HR 2.82; 95% CI 1.57 - 5.01; p = .001; high risk, HR 4.39; 95% CI 2.58 - 7.48; p < .001). The grading system was characterised by robust discrimination with Harrell's C index of 0.68 (95% CI 0.63 - 0.75). CONCLUSION: The PATENT grading system was characterised with good discrimination and calibration, which may serve as a clinician friendly tool to aid in risk stratification for TBAD patients after TEVAR.